Diet and Nutrition in Neurological Disorders 9780323898348, 0323898343

Table of contents :
Front Cover
Diet and Nutrition in Neurological Disorders
Copyright
Dedication
Contents
Contributors
Preface
Chapter 1: Neurological disorders in the context of the global burden of disease
Introduction
Ranking of DALYs due to neurological disorders
Comparing neurological disorders to cardiovascular disease and cancers
References
Part I: Alzheimer's disease and dementias
Chapter 2: Lifestyle modifications and nutrition in Alzheimer's disease
Introduction
Understanding AD through its sign and symptoms
Science behind the scenario
Age
Family history
Oxidative stress
Apoptosis
Molecular genetics
Chemistry, anatomy, and pathophysiology of the AD brain
Epidemiology of AD
Diagnostic approach
Therapeutic strategies for AD
Therapies targeting amyloid-β
Therapies targeting tau proteins
Therapies targeting neuroinflammation and oxidative stress
Cell-based therapies
Lifestyle: Way to healthy living
Physical fitness
Say no to smoking and excessive drinking
Keep distance from depression
A bit more care to strengthen them
Calorie restriction
Nutritional interventions
Vitamins and minerals
Flavonoids
Turmeric
Conclusion
Applications to other neurological conditions
Other components of interest
Mini-dictionary
Key facts
Summary points
References
Chapter 3: The Gut microbiota and Alzheimer's disease
What is Alzheimer's disease?
Aging and the diversity of the Gut microbiota
Gut microbiota alterations as a risk factor of Alzheimer's disease
Transgenic mouse models of Alzheimer's disease and the bacteria-Gut-brain axis
Modulation of the Gut microbiota to prevent Alzheimer's disease
Applications to other neurological conditions
Other components of interest
Key facts
Mini-dictionary of terms
Summary points
References
Chapter 4: The Mediterranean diet: Unsaturated fatty acids and prevention of Alzheimer's disease
Introduction
Neuroscientific aspects
Neuroinflammation and Alzheimer's disease
Nutritional aspects
The Mediterranean diet and Alzheimer's disease risk
Polyunsaturated fatty acids and Alzheimer's disease
Specialized proresolving mediators and Alzheimer's disease
Supplementation with PUFAs and Alzheimer's disease risk
Conclusion
Applications to other neurological conditions
Other components of interest
Key facts of the Mediterranean diet
Key facts of PUFAs and Alzheimer's disease risk
Mini-dictionary of terms
Summary points
References
Chapter 5: Malnutrition and early-stage Alzheimer's disease
Introduction
Neuroscientific aspects
Brain lobe damage hypothesis
Neurofibrillary tangle (NT) hypothesis
Amyloid plaque (AP) hypothesis
Identification of vulnerable neurons
Symptom progression
Nutritional aspects
Oral health
Vitamin D deficiency
Micronutrient deficiencies
Applications to other neurological conditions
Other components of interests
Mini-dictionary of terms
Summary points
References
Part II: Amyotrophic lateral sclerosis
Chapter 6: Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease
Introduction
Amyotrophic lateral sclerosis/motor neuron disease
Classification and clinical condition
Amyotrophic lateral sclerosis
Progressive bulbar palsy
Progressive muscle atrophy
Primary lateral sclerosis
ALS patient functionality scale
Risk factors for dehydration
Dysphagia
Difficulty in the mobility of lower and upper limbs
Cognitive alteration
Strategies for improving hydration
Importance of teamwork
Applications to other neurological conditions
Other components of interest
Key facts
Mini-dictionary of terms
Summary points
References
Further reading
Chapter 7: Diet, disease severity, and energy expenditure in amyotrophic lateral sclerosis (ALS)
Introduction
The challenge of energy balance in ALS
Addressing malnutrition in ALS
The impact of macronutrients in ALS
Protein
Fiber
High-calorie oral and enteral diets
High-calorie supplements
Other components of interest
Micronutrients
Antioxidants
Polyunsaturated fatty acids
Applications to other neurological conditions
Alzheimer's disease
Parkinson's disease
Huntington's disease
Conclusion
Mini-dictionary of terms
Key facts
Summary points
References
Chapter 8: Nutrition, percutaneous endoscopic gastrostomy and ALS
Introduction
Malnutrition
Artificial nutrition in ALS
Artificial nutrition in other neurological pathologies
Other components of interest
Key facts
Mini-dictionary
Summary points
References
Chapter 9: Fatty acid profiling in amyotrophic lateral sclerosis
Introduction
Pathology in ALS
Endogenous lipids
Fatty acid properties and nomenclature
Fatty acid metabolism
Synthesis of fatty acids
Oxidation of fatty acid
Metabolic aspects of ALS
Fatty acid status in ALS patients
Fatty acid intake and ALS
Dietary intervention and ALS
Dietary intervention in ALS models
Dietary interventions in ALS patients
Fatty acids as auxiliary treatment/treatment in other neurological conditions
Other components of interest
Key facts about fatty acids
Mini-dictionary
Summary points
References
Part III: Brain injury
Chapter 10: High-fat diets in traumatic brain injury: A ketogenic diet resolves what the Western diet messes up neuroinfl ...
Introduction
Traumatic brain injury: A debilitating neurological disease
Primary injury
Secondary injury
Altered cerebral metabolism associated with TBI (Fig. 1)
Glucose metabolism: A transition from hyper- to hypoglycolysis
The mitochondrial permeability transition pore and intrinsic apoptosis
Neuroinflammation and extrinsic apoptosis
Features of high-fat, Western, and ketogenic diets and associated systemic metabolic states
Interplay between fat and sugar: A determinant of metabolic state
Fatty acids and mitochondrial uncoupling
Effects of high-fat, Western, and ketogenic diets on the brain, irrespective of TBI
Effects on brain energy homeostasis
Linking energy homeostasis to cognition and synaptic plasticity (Fig. 3)
Effects of Western diet pre- and post-TBI and associated molecular mechanisms (Fig. 4A)
WD exacerbates neuroinflammation and neuronal cell death
WD aggravates neuroplastic, neuropathological, and neurobehavioral impairment
WD induces genetic and epigenetic changes
WD impairs neurovascular coupling and the BBB
Effects of ketogenic diet pre- and post-TBI: Preventative, direct (acute), and long-term (chronic) therapeutic benefits (Fi ...
KD and favorable brain energetics
Effect of KD on mitochondrial efficiency and intrinsic apoptosis
Effect of KD on neuroinflammation and autophagy
KD and pro-survival genetic and epigenetic changes
KD as an anti-epileptogenic treatment in TBI
Applications to other neurological conditions
Other components of interest
Conclusion
Mini-dictionary of terms
Key facts of high-fat diets in traumatic brain injury
Summary points
References
Chapter 11: Brain injury, anthropometry, and nutrition
Introduction
Traumatic brain injury
Significance of nutrition in TBI
Complex metabolic cascade
Altered feeding pattern
Impaired GI function
Increased nutritional demand
Stress-induced hyperglycemia
Serum sodium abnormalities
Nutrition management in TBI
Nutritional screening
Ongoing nutritional assessment
Anthropometric measurements
Clinical manifestations
Nutritional support
Time to initiate feeding
Amount of feed and nutrients
Nutritional supplements
Route of feeding
Method of feeding
Parenteral feeding
Glycemic control
Hyponatremia prevention and management
Initiation of oral diet
Weaning from altered feeding to normal diet
Possible complications during nutritional support
Conclusion
Applications to other neurological conditions
Mini-dictionary of terms
Key facts relating to nutrition in TBI
Key facts relating to anthropometry and TBI
Summary points
References
Chapter 12: Calorie and protein intake in traumatic brain injury patients
Introduction
Dietary intake among TBI patients
Current dietary managements
Feeding initiation
Feeding target
Duration to achieve feeding target
Calorie and protein requirements in TBI
Determination of calorie and protein requirement
The current calorie and protein recommendations in TBI
The new insight of nutritional recommendation
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of calorie
Key facts of protein
Key facts of TBI
Summary points
References
Chapter 13: Lipids, docosahexaenoic acid (DHA), and traumatic brain injury
Introduction
Traumatic brain injury
Brain damage in TBI
Neuroinflammation in TBI
The effect of fat diets on TBI
High-fat diet
Short-chain fatty acid
Medium-chain fatty acid
Polyunsaturated fatty acid
Omega-6: Arachidonic acid
Omega-3: Docosahexaenoic acid
DHA as a therapeutic option for TBI
Mechanism(s) of action of DHA
Gut-brain axis
Glymphatic pathway
Applications to other neurological conditions
Neurodegenerative diseases
Neuropsychiatric disorders
Conclusion
Mini-dictionary of terms
Key facts of TBI
Summary points
References
Chapter 14: Brain trauma, ketogenic diets, and ketogenesis via enteral nutrition
Introduction
Review of cerebral energetics
Glucose metabolism
Glycogen stores
Anaerobic glycolysis
Acute brain injury and dysfunctional cerebral metabolism
Ketones-Metabolisms ``ugly duckling´´
Metabolism of ketones
Ketones and the brain
Inducing hyperketonemia
Dietary modulation and medium-chain triglycerides
Ketone esters
Intravenous beta-hydroxybutyrate
Ketones and acute brain injury
ABI in animals
ABI in humans
Other components of interest
Applications to other neurological conditions
Conclusion
Mini-dictionary of terms
Key facts of ketone bodies
Summary points
References
Part IV: Cerebral palsy
Chapter 15: Nutrition and cerebral palsy
Introduction
Cerebral palsy: Definition, epidemiology, etiology, and classification
Malnutrition in cerebral palsy
Assessment of nutritional status in cerebral palsy
Anthropometric measurements
Weight for height and body mass index
Triceps skinfold thickness measurement
Mid-arm circumference
Specialized growth charts
Knee height and tibia length
Body composition
Energy expenditure
Energy intakes
Nutritional intervention in cerebral palsy
Oral nutrition
Enteral tube feeding
Gastrostomy tube feeding
Diet composition
Follow-up and monitoring
Applications to other neurological conditions
Other components of interest
Key facts
Mini-dictionary of terms
Summary points
References
Chapter 16: Metabolic syndrome in the adult with cerebral palsy: Implications for diet and lifestyle enhancement
Introduction
Cardiovascular disease and metabolic syndrome in patients with CP
Mobility challenges and physical exercise
Nutritional status
Obesity
Oropharyngeal dysphagia and difficulties in meeting nutrition guidelines
Bone health and nutritional considerations
Nutritional programs for adults with CP
Additional wellness interventions
Clinical recommendations
Summary and future research
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of metabolic syndrome in adult cerebral palsy: Implications for diet
Key facts of cerebral palsy
Key facts of metabolic syndrome
Key facts of nutritional interventions for CP
Summary points
References
Further reading
Chapter 17: Gut microbiota characteristics in children with cerebral palsy
Introduction
GM and nutritional absorption in CP children
GM and neurologic regulations in CP children
GM and gastrointestinal complications in CP children
Applications to other neurological conditions
GM and neurologic complications in CP children
Other components of interest
Personalized diet, GM, and CP treatment
Mini-dictionary of terms
Key facts
Summary points
References
Chapter 18: Swallowing problems: Major components of nutritional deficits in adults with cerebral palsy
Introduction
Swallowing problems in individuals with cerebral palsy: A lifelong problem
Characteristics of dysphagia symptoms and their impact on quality of life in adults with cerebral palsy
Nutritional problems and sarcopenia in adults with cerebral palsy
Assessment of dysphagia in adults with cerebral palsy
Use of the eating and drinking ability classification system in people with cerebral palsy
Nutritional supplements according to the eating and drinking ability classification system in adults with cerebral palsy
Application in other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts on dysphagia in adults with cerebral palsy
Summary points
References
Further reading
Part V: Dietary neurotoxins
Chapter 19: Dietary neurotoxins: An overview
Introduction
Regulatory accommodation
Factors driving the acceptance of certain foods
Incorporation of toxins during growth, processing, or storage
Contaminants from environment
Methylmercury in seafood
Selenium in grain
Naturally formed substances
Furocoumarins
Lectins in legumes
Oxalic acid
Safrole
Myristicin
Tomatine in tomatoes
Prussic acid in peach pits, apple, and cherry
Substances formed because of product abuse
Glycoalkaloids in potatoes (chaconine and solanine)
Furocoumarin in parsnips
Substances produced because of processing
Polycyclic aromatic hydrocarbons
Acrylamide
Furan
Summary
Mini-dictionary
Key facts
References
Chapter 20: Alcohol consumption induces oxidative damage, neuronal injury, and synaptic impairment: Consequences for the ...
Introduction
Alcohol toxicity
Alcohol affects brain function
Hangover
Binge drinking
Chronic ethanol consumption
Ethanol withdrawal
Fetal alcohol syndrome
Alcohol consumption contributes to the pathogenesis of different neurological diseases
Conclusions
Summary points
Other components of interest
Key facts
Mini-dictionary of terms
References
Further reading
Chapter 21: Dietary effects of lead as a neurotoxicant
Introduction
Gastrointestinal structure-function relationships
Gastrointestinal pathways and Ca2+ absorption
Pb2+ uptake in the duodenum
Pb2+/Ca2+ competition alters Ca2+ channel uptake
Vitamin-D metabolism increases intestinal Pb2+ absorption
Pb2+ neurotoxicity through the paracellular pathway
Assessing the effects of Pb2+ on the GI gradient through histological Alcian blue staining
Sex-dependent effects between control male and female rat's gastrointestinal villi and crypt gradients
Pb2+ exposure effects on the male rat's gastrointestinal villi and crypt gradients
Pb2+ exposure effects on the female rat's gastrointestinal villi and crypt gradients
Revisiting early models of gastrointestinal Pb2+ uptake in a modern low-level exposure paradigm
Pb2+ exposure-induced sex-based differences in gastrointestinal absorption
The role of developmental time-periods of Pb2+ exposure on potential gut-brain interactions
Conclusion
Mini-dictionary of terms
Summary points
References
Chapter 22: Environmental toxicants (OPs and heavy metals) in the diet: What are their repercussions on behavioral/neurol ...
Introduction
Organophosphate compounds (OPs) and potentially toxic elements (heavy metals) as environmental-pollutant agents in the diet
From the origin to the diet: The input
Organophosphate compounds used as pesticides for food pest control
Potentially toxic elements in the food and drinking water
The impact of environmental toxic elements on the behavior system: The output
Behavioral disabilities and OP exposure via diet
Behavioral disabilities and heavy metal exposure via diet
Neurodegenerative pathologies and chronic environmental toxicant exposure: The role of oxidative stress and antioxidants
Conclusions
Applications to other neurological conditions
Other components of interest
Key facts of OPs and heavy metals
Mini-dictionary of terms
Summary points
References
Part VI: Epilepsy
Chapter 23: Hypercholesterolemic diet and status epilepticus
Introduction
Neurological aspect
What is epilepsy?
Possible causes of epilepsy
Nutritional aspects
Dietary cholesterol and its metabolism by the peripheral system
Cholesterol metabolism in the central nervous system
Role of cholesterol in the brain
Merging neurological and nutritional aspects
Measuring the brain activity of rats fed a hypercholesterolemic diet and submitted to the status epilepticus
Evaluating the effects of a hypercholesterolemic diet on status epilepticus
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of epilepsy
Summary points
References
Chapter 24: Low glycemic index therapy: What it is and how it compares to other epilepsy diets
History
Evolution
Ketogenic diet
Modified Atkins diet
Low glycemic index therapy
LGIT: Concept and composition
Mechanism of action
Efficacy
Initiation of LGIT
Adverse events
Follow-up
Diet discontinuation
Which diet to use?
Applications to other neurological disorders
Epilepsy syndromes and status epilepticus
Alzheimer's disease
Parkinson's disease
Amyotrophic lateral sclerosis
Aging
Traumatic brain injury
Stroke
Autism spectrum disorder
Cancer
Others
Other components of interest
Conclusion
Mini-dictionary of terms
Key facts of LGIT
Summary points
References
Chapter 25: Ketogenic diet in pediatric epilepsies
Introduction
Historical background
Antiepileptogenic mechanisms of ketogenic diet
Variants of ketogenic diet
The classic ketogenic diet
Medium-chain triglyceride (MCT) diet and modified MCT diet
Modified Atkins diet (MAD)
Low glycemic index treatment (LGIT)
Evaluation of candidates for ketogenic diet
Monitoring children on ketogenic diet
Adverse effects and tolerability
Ketogenic diet in pediatric drug-resistant epilepsies
Ketogenic diet as gold standard therapy: GLUT-1 deficiency syndrome and pyruvate dehydrogenase deficiency
Ketogenic diet in the intensive care units
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts
Summary points
References
Part VII: Headaches and migraines
Chapter 26: The value of fruit and vegetable consumption in pediatric migraine
Introduction
Review of the available studies and discussion
Review of the available studies
Discussion
Results of our study
Conclusion
Neuroscientific aspects
Nutritional aspects
Applications to other neurological conditions
Other components of interest
Review of the available studies
Results of our study
Mini-dictionary of terms
Key facts of fruits, vegetables, and pediatric migraine headache
Summary points
References
Chapter 27: Dietary trigger factors of migraine
Introduction
Mechanism of dietary influence on migraine episodes
Onset of migraine from the time of consumption of food
Foods and drinks as trigger factors of migraine
Alcohol
Coffee/caffeine
Cheese
Chocolate
Citrus fruits
Fatty food
Food containing monosodium glutamate
Eggs and meat
Fish
Meat
Bread
Missing meals and fasting
Meal schedule in migraine patients
Diet interventions
Elimination diets
Ketogenic diets
Modified Atkins diets
Epigenetic diet
Migraine diary
Functional disability due to migraine
Management of migraine triggered by dietary factors
Conclusion
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of dietary trigger factors of migraine
Summary points
References
Part VIII: Multiple sclerosis
Chapter 28: Dietary management of multiple sclerosis
Introduction
Neuroscientific aspects
Nutritional aspects: Dietary management of multiple sclerosis (MS)
Specific nutrients in MS management
Saturated fats
Polyunsaturated fats
Monounsaturated fats (MUFAs)
High-fiber foods
Dairy products
Salt (sodium chloride)
Cholesterol
Overall diet quality
Special diets for MS management
Paleo diet
McDougall diet
Swank diet
Mediterranean diet
Gluten-free diet
Overcoming MS (OMS) diet
Best bet diet (BBD)
Fasting and multiple sclerosis
Conflicting findings
General dietary guidelines for MS management
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Summary points
References
Chapter 29: Dietary fish intake and multiple sclerosis: A new narrative
Introduction
Fish intake and the risk of MS
Dietary fish intake or fish oil supplementation and comorbidities in MS patients
Mechanisms behind the association between fish intake and MS
Conclusion
Applications with other neurological conditions
Other components of interest
Key facts
Mini-dictionary of terms
Summary points
References
Chapter 30: Linking diet and gut microbiota in multiple sclerosis
Introduction
Diet and dysbiosis risk in MS patients
High-salt concentration diet
High-fat concentration diet
Nutritional interventions as modifiers of gut dysbiosis in MS patients
SCFAs
High-fiber concentration diet (prebiotic)
Probiotics
Calorie restriction
Conclusion
Applications to other neurological conditions
Other components of interest
Key facts
Mini-dictionary of terms
Summary points
References
Chapter 31: Restoration of myelination in the central nervous system via specific dietary bioactive lipids: An opportunit ...
Introduction
Myelin synthesis, demyelination, and remyelination
Myelin lipid composition
Biosynthesis and supply of myelin lipids
Modulation of exogenous lipid in demyelination and remyelination
High-fat diets and MS outcomes
Plasmalogens in MS therapy
Plasmalogens in myelin: Synthesis and function
Plasmalogens in neurodegenerative contexts
Modulating plasmalogen deficit in MS using alkylglycerols
Sphingolipids in MS therapy
Sphingolipids in myelin: Synthesis and function
Sphingosine-1-phosphate in myelination
S1P modulation in MS: Pharmaceutical avenues
Conclusion
Applications to other neurological conditions
Mini-dictionary of terms
Key facts of myelin lipids
Summary points
References
Part IX: Neuroinflammation
Chapter 32: Effect of diet and nutrition on neuroinflammation: An overview
Introduction
Brain and inflammation
Neuroinflammation and CNS disorders
Diet and neuroinflammation
Calorie restriction and neuroinflammation
Ketogenic diet and neuroinflammation
Mediterranean diet and neuroinflammation
Vitamins and neuroinflammation
Other component of interest
Conclusion
Summary points
Mini-dictionary of terms
References
Chapter 33: High-fat diet-induced cellular neuroinflammation: Alteration of brain functions and associated aliments
Introduction
Inflammation and neuroinflammation
High-fat diet-induced neuroinflammation
Different pathways leading to neuroinflammation
Microglia
NF-κB
Pro-inflammatory cytokines
Mitochondrial dysfunction and ROS
Applications to other neurological conditions
Dementia
Multiple sclerosis
Traumatic brain injury
Parkinson's disease
Anxiety
Depression
Other components of interest
Mini-dictionary of terms
Key facts of neuroinflammation
Summary points
References
Chapter 34: Neuro-behavioral implications of a high-fructose diet
Introduction
Fructose metabolism
Metabolic syndrome and fructose
Development and fructose consumption
Neural and behavioral consequences of fructose diet
Potential mechanisms
Potential mechanisms: Glucocorticoids
Potential mechanisms: Neuroinflammation
Potential mechanisms: Mitochondrial function
Conclusions
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of neuroprotection
Key facts of sex differences
Summary points
References
Part X: Parkinson's disease
Chapter 35: Role of mediterranean diet in Parkinson's disease
Introduction to Parkinson's disease
Mediterranean diet and PD
Olive oil and PD
Possible neuroprotective mechanisms of olive oil
Polyunsaturated fatty acids and PD
Possible neuroprotective mechanisms of polyunsaturated fatty acids
Vitamins and PD
Vitamin E
Possible neuroprotective mechanisms of vitamin E
Vitamin D
Possible neuroprotective mechanisms of vitamin D
Vitamin C
Possible neuroprotective mechanisms of vitamin C
Vitamin B
Possible neuroprotective mechanisms of vitamin B
Other components of interest
Mediterranean diet in other neurological disorders
Final conclusion
Dictionary of terms
Key facts of the role of the Mediterranean diet in Parkinson's disease
Summary
References
Chapter 36: Role of dietary antioxidants and redox status in Parkinson's disease
Introduction
Oxidative stress and Parkinson's disease
Source of ROS is involved in the pathogenesis of PD
Antioxidant and PD
Vitamins antioxidant and PD
Vitamin A and PD
Vitamin C and PD
Vitamin E and PD
Vitamin D and PD
Dietary zinc intake and PD
Omega-3 and PD
Glutathione
Whey and PD
N-Acetylcysteine and PD
Antioxidant-targeted mitochondria (Q10 and MitoQ)
MitoQ and PD
Melatonin and PD
Creatine and PD
Inosine and PD
Polyphenols and PD
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key fact of Parkinson's disease and oxidative stress
Summary points
References
Chapter 37: Beverages, caffeine, and Parkinson's disease
Introduction
Parkinson's disease
Caffeine
Beverage-containing caffeine
Pharmacokinetics (the body's effect on caffeine)
Pharmacodynamics (the effects of caffeine on the body)
Caffeine and Parkinson's disease
Epidemiological studies
Clinical studies
Clinical experimental studies
Neuroprotection?
Critical appraisal
Other components of interest
Future prospects
Applications to other neurological conditions
Key facts of caffeine and Parkinson's disease
Mini-dictionary of terms
Summary points
References
Chapter 38: The association of diet and its components with changes in gut microbiota and improvement in Parkinson's disease
Introduction
The association of nutrients and diet with Parkinson's disease
Caffeine
Tea
Dairy production
Mediterranean Diet
Vitamin
Fats
Carbohydrate
The association between gut microbiota and Parkinson's disease
The association of nutrition with gut microbial
The association of nutrition with gut microbial in Parkinson's disease
Conclusion
Neuroscientific aspects
Nutritional aspects
Mini-dictionary of terms
Key facts
Summary points
References
Part XI: Peripheral neuropathy
Chapter 39: Alcohol-related autonomic dysfunction and peripheral neuropathy
Introduction
Epidemiology
Natural history of large fiber neuropathy
Natural history of autonomic neuropathy
Cardiovascular reflex test abnormalities
Sympathetic skin response abnormality
Erectile dysfunction
Gastrointestinal features
Risk factors
Age
Sex
Ethnicity
Genetics
Alcohol intake
Alcohol type consumed
Smoking
The role of malnutrition
Hepatic dysfunction
The role of oxidative stress
Neuropathology
Management
Alcoholic-related autonomic dysfunction
Alcoholic-related peripheral neuropathy
Conclusion
Applications to other areas of neurological conditions
Other components of interest
Mini-dictionary of terms
Summary points/key facts
References
Web pages
Further reading
Chapter 40: Dietary saturated and unsaturated fatty acids and peripheral neuropathy
Introduction
Differential effects of fatty acid saturation on clinical systemic metabolic status
Differential effects of fatty acid saturation on clinical PN phenotype
Differential effects of fatty acid saturation on PN phenotype in preclinical models
Differential effects of fatty acid saturation on lipid metabolism and mitochondrial (dys)function
Applications to other neurological conditions
Other components of interest
Key facts of metabolically acquired peripheral neuropathy
Mini-dictionary of terms
Summary points
References
Chapter 41: Caloric restriction as a nutrition strategy in counteracting peripheral neuropathies
Introduction
An overview of peripheral neuropathies: Causes, risk factors, and incidence
Wallerian and Wallerian-like degeneration in axonal and demyelinating neuropathies
Schwann cells: The multitasking specialized glial cells
Schwann cells orchestrate the first phase of Wallerian degeneration determining the fate of the axons
Autophagy and neuropathy
Autophagy: A survival cell mechanism and its nutrient regulation
Schwann cells autophagy or myelinophagy in peripheral nerve degeneration
Dietary interventions inducing autophagy
Caloric restriction-induced autophagy: Effects on NPs
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts
Summary points
References
Part XII: Prenatal effects and neurodevelopment
Chapter 42: The interplay between stress and nutrition during pregnancy: Influence on fetal brain development
Introduction
Human and animal studies
Effect of stress on the developmental outcomes on offspring
Behavior of the offspring
Cognitive development of the offspring
Biological mechanism by which stress altered offspring development
Importance of nutrition on fetal brain development
Developmental programming
Other components of interest
Mini-dictionary of terms
Key facts
Summary points
References
Further reading
Chapter 43: Maternal and neonatal polyunsaturated fatty acid intake and risk of neurodevelopmental impairment in prematur ...
Introduction
LCPUFA and neurodevelopment
LCPUFA influence inflammatory signaling
LCPUFA accretion into fetal tissues
In utero LCPUFA accretion
LCPUFA accretion into adipose
What is the evidence linking maternal and neonatal PUFA intake with neurodevelopmental outcomes?
Randomized controlled trials
Reviews and systematic reviews
LCPUFA supplementation: How much and when?
Dynamic rates and ratios of placental LCPUFA transfer
Organ-specific effects of LCPUFA
Challenges for appropriate LCPUFA supplementation
The wider contexts of LCPUFA supplementation
Dietary LA affects infant AA and DHA availability
Maternal LCPUFA status
The socioeconomic context of LCPUFA availability
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of LCPUFA and infant development
Summary points
References
Chapter 44: Early nutrition, growth, and neurodevelopment in the preterm infant
Introduction
How preterm birth affects the brain
Postnatal influences
Postnatal nutrition and brain development
Nutrition is a key modifiable factor for improving neurodevelopment
Neonatal growth and neurodevelopment
Effects of neonatal nutrition on neurodevelopment
Breastmilk
Macronutrients
Recommended protein intakes
Evidence from randomized controlled trials on protein and neurodevelopment
Evidence from observational studies on protein and neurodevelopment
Sex differences in neurodevelopmental response to nutrition
Long-term neurodevelopmental outcomes
Reasons for lack of clarity in research findings
Barriers to achieving prescribed nutritional intakes
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of preterm neurodevelopment
Summary points
References
Chapter 45: Breast milk and cognitive performance in children
Introduction
Human milk composition
Macronutrients
Protein
Carbohydrates
Fats/lipids
Micronutrients
Choline
Vitamins and minerals
Bioactive factors
Factors influencing milk composition
Maternal nutrition
Maternal age, parity, and BMI
Smoking
Mode of delivery
Adverse pregnancy outcomes
Brain development
Breastfeeding and cognitive outcomes in children
Milk components and cognitive development in children
Milk proteins
Milk amino acids
Milk carbohydrate
Milk cholesterol
Milk fatty acids
Milk choline
Conclusion
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts
Summary points
References
Chapter 46: Effects of ketogenic diets and ketone supplementation on the nervous system during development: Applications ...
Introduction
The role of glucose in shaping and maintaining the brain
The effects of ketogenic diet in animal models of autism spectrum disorder
Genetic animal models
Black and tan Brachyury (BTBR) animal model
Engrailed genes (En) model
Epileptic seizure-prone EL (epilepsy 1 gene)
Neurodevelopmental animal models
Valproic acid (VPA) animal model
MIA model
The effects of ketogenic diet in animal models of schizophrenia
Genetic
Pharmacological model of schizophrenia
Clinical studies of ketogenic diet in schizophrenia
Summary points
References
Part XIII: Stroke
Chapter 47: Fluids, energy intake, and stroke
Introduction
Neuroscientific aspects
Nutritional aspects
Risk factors for the disease and its prognosis
Nutrition and hydration during the hospitalization
Nutrition and hydration during rehabilitation and at home
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of fluids, energy intake, and stroke
Key facts of nutrition and hydration assessment and monitoring
Summary points
References
Chapter 48: Body weight after stroke
Introduction
The obesity paradox in stroke
Body weight loss after stroke
Stroke-related sarcopenia
Skeletal muscle changes in sarcopenia
Prevalence of sarcopenia
Diagnosis of sarcopenia
Cachexia after stroke
Nutritional status and cachexia in stroke
Treatment of cachexia in stroke
Applications to other neurological conditions
Other components of interest
Mini-dictionary of terms
Key facts of cachexia after stroke
Summary points
References
Chapter 49: Linking dietary pattern and stroke: An Indian perspective
Introduction
Dietary patterns in India
Staple food
Oils
Non-alcoholic beverages
Alcoholic beverages
Eating habits
Dietary restrictions
Rural versus Urban dietary habits
Dietary pattern studies
Dietary pattern and relationship with health outcome
Dietary patterns and stroke
Dietary pattern and stroke studies from India
Diet and cardiovascular risk and stroke risk
Diet as a modifiable risk factor for stroke
Comparison of traditional local diet with the specialized diet
Resource documents
Other components of interest
Applications to other areas of neurological conditions
Key facts
Mini-dictionary of terms
Conclusion
Summary points
References
Chapter 50: Dietary lipids: The effect of docosahexaenoic acid on stroke-related neuronal damage
Introduction
Stroke overview
Overview of docosahexaenoic acid
Health benefits of DHA as shown in previous studies
Purpose
Neuroscientific aspects
Nutritional aspects
The importance of stroke onset and prevention
Stroke prevention effect by ingestion of fish and DHA: Epidemiological research
Prevention of stroke caused by fish intake
DHA intake and stroke prevention
Biosynthesis of DHA and supply of docosahexaenoic acid to neuronal cells
Biosynthesis of DHA in the body
Synthesis of DHA in astrocytes and supply to neuronal cells
Neuroprotective mechanism of docosahexaenoic acid through astrocytes in the brain
Transportation of diet-derived DHA via BBB and accumulation in astrocytes
Supply of DHA to nerve cells and neuroprotective action by astrocytes
Inhibition of DHA against oxidative stress produced in association with ischemic stroke
Effect of DHA-derived neuroprotectin on stroke
Conclusion
Applications to other neurological conditions
Other components of interest
Key facts
About stroke
Mini-dictionary of terms
Summary points
References
Chapter 51: Diet quality and stroke
Introduction
Patho-etiology of stroke
Mechanisms by which diet quality may modify stroke risk
Food components and risk of ischemic stroke
Fruits and vegetables
Fish
Red and processed meats
Fat
Carbohydrate intake
Diet quality and primary prevention of stroke
Mediterranean diet
DASH diet
Other healthy diet patterns
The Southern diet pattern
Vegetarian and plant-based diets
Diet quality and secondary prevention of stroke
Future directions
Applications to other neurologic conditions
Diet and dementia
Other components of interest
Folic acid
Multivitamins
Mini-dictionary of terms
Key facts of stroke and diet quality
Summary points
References
Chapter 52: Recommended resources for diet and nutrition in neurological disorders
Introduction
Resources
Other resources
Summary points
References
Index
Back Cover

Citation preview

DIET AND NUTRITION IN NEUROLOGICAL DISORDERS

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DIET AND NUTRITION IN NEUROLOGICAL DISORDERS

Edited by

COLIN R. MARTIN Professor of Clinical Psychobiology and Applied Psychoneuroimmunology & Clinical Director: Institute for Health and Wellbeing, University of Suffolk, Ipswich, United Kingdom

VINOOD B. PATEL Reader in Clinical Biochemistry, University of Westminster, London, United Kingdom

VICTOR R. PREEDY Emeritus Professor of Nutritional Biochemistry, King’s College London, London, United Kingdom Professor of Clinical Biochemistry and Pathology (Hon), King’s College Hospital, London, United Kingdom

Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, United Kingdom 525 B Street, Suite 1650, San Diego, CA 92101, United States 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, United States The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, United Kingdom Copyright © 2023 Elsevier Inc. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. ISBN 978-0-323-89834-8 For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals

Publisher: Nikki P. Levy Acquisitions Editor: Natalie Farra Editorial Project Manager: Timothy J. Bennett Production Project Manager: Sreejith Viswanathan Cover Designer: Miles Hitchen Typeset by STRAIVE, India

Dedication

This book is dedicated to my wonderful daughter, Dr. Caragh Brien, a caring, compassionate, and evidence-based junior doctor, of whom I am so incredibly proud. Colin R. Martin

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Contents

Contributors Preface

1. Neurological disorders in the context of the global burden of disease

xxix xli

1

Rajkumar Rajendram, Vinood B. Patel, and Victor R. Preedy Introduction Ranking of DALYs due to neurological disorders Comparing neurological disorders to cardiovascular disease and cancers References

1 8 8 10

PART I Alzheimer's disease and dementias 2. Lifestyle modifications and nutrition in Alzheimer's disease

13

Gurjit Kaur Bhatti, Jayapriya Mishra, Abhishek Sehrawat, Eva Sharma, Rubal Kanozia, Umashanker Navik, P. Hemachandra Reddy, and Jasvinder Singh Bhatti Introduction Understanding AD through its sign and symptoms Science behind the scenario Chemistry, anatomy, and pathophysiology of the AD brain Epidemiology of AD Diagnostic approach Therapeutic strategies for AD Lifestyle: Way to healthy living Nutritional interventions Conclusion Applications to other neurological conditions Other components of interest Mini-dictionary Key facts Summary points References

14 14 16 20 23 23 24 26 28 30 30 31 32 33 33 34

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3. The Gut microbiota and Alzheimer's disease

41

Mónica Morales, Daniel Cuervo-Zanatta, Julieta Hernandez-Acosta, Marina Chacón, Vicente Sánchez-Valle, and Claudia Perez-Cruz What is Alzheimer's disease? Aging and the diversity of the Gut microbiota Gut microbiota alterations as a risk factor of Alzheimer's disease Transgenic mouse models of Alzheimer's disease and the bacteria-Gut-brain axis Modulation of the Gut microbiota to prevent Alzheimer's disease Applications to other neurological conditions Other components of interest Key facts Mini-dictionary of terms Summary points References

4. The Mediterranean diet: Unsaturated fatty acids and prevention of Alzheimer's disease

42 43 44 56 60 62 63 63 63 64 64

69

Jose A. Estrada and Irazú Contreras Introduction Neuroscientific aspects Nutritional aspects Conclusion Applications to other neurological conditions Other components of interest Key facts of the Mediterranean diet Key facts of PUFAs and Alzheimer's disease risk Mini-dictionary of terms Summary points References

5. Malnutrition and early-stage Alzheimer's disease

69 70 73 78 78 79 80 81 81 82 82

87

Sameer Chaudhary, Sapana Chaudhary, Sakshi Rawat, Jayashri Prasanan, and Ghulam Md Ashraf Introduction Neuroscientific aspects Nutritional aspects Applications to other neurological conditions Other components of interests Mini-dictionary of terms

88 89 91 94 94 98

Contents

Summary points References

98 98

PART II Amyotrophic lateral sclerosis 6. Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

105

Adriana Leico Oda and Cristina C.S. Salvioni Introduction Amyotrophic lateral sclerosis/motor neuron disease Classification and clinical condition ALS patient functionality scale Risk factors for dehydration Dysphagia Difficulty in the mobility of lower and upper limbs Cognitive alteration Strategies for improving hydration Importance of teamwork Applications to other neurological conditions Other components of interest Key facts Mini-dictionary of terms Summary points References Further reading

7. Diet, disease severity, and energy expenditure in amyotrophic lateral sclerosis (ALS)

105 106 106 109 110 110 111 112 112 114 115 116 118 118 119 120 122

123

Zoe Castles, Lauren Buckett, Leanne Jiang, Frederik J. Steyn, and Shyuan T. Ngo Introduction The challenge of energy balance in ALS Addressing malnutrition in ALS The impact of macronutrients in ALS Protein Fiber High-calorie oral and enteral diets High-calorie supplements Other components of interest Applications to other neurological conditions

123 124 125 128 128 128 129 130 131 132

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Conclusion Mini-dictionary of terms Key facts Summary points Author contributions Author disclosures Funding support References

8. Nutrition, percutaneous endoscopic gastrostomy and ALS

134 135 135 136 136 136 136 136

141

Michele Barone and Isabella Laura Simone Introduction Malnutrition Artificial nutrition in ALS Artificial nutrition in other neurological pathologies Other components of interest Key facts Mini-dictionary Summary points References

9. Fatty acid profiling in amyotrophic lateral sclerosis

141 143 144 148 149 150 150 150 151

155

Minic Rajna, Stevic Zorica, and Arsic Aleksandra Introduction Pathology in ALS Endogenous lipids Fatty acid properties and nomenclature Fatty acid metabolism Metabolic aspects of ALS Fatty acid status in ALS patients Fatty acid intake and ALS Dietary intervention and ALS Fatty acids as auxiliary treatment/treatment in other neurological conditions Other components of interest Key facts about fatty acids Mini-dictionary Summary points Acknowledgments References

155 156 156 157 158 161 162 163 164 167 167 168 168 169 169 169

Contents

PART III Brain injury 10. High-fat diets in traumatic brain injury: A ketogenic diet resolves what the Western diet messes up neuroinflammation and beyond

175

Nour-Mounira Z. Bakkar, Stanley Ibeh, Ibrahim AlZaim, Ahmed F. El-Yazbi, and Firas Kobeissy Introduction Traumatic brain injury: A debilitating neurological disease Altered cerebral metabolism associated with TBI Features of high-fat, Western, and ketogenic diets and associated systemic metabolic states Effects of high-fat, Western, and ketogenic diets on the brain, irrespective of TBI Effects of Western diet pre- and post-TBI and associated molecular mechanisms Effects of ketogenic diet pre- and post-TBI: Preventative, direct (acute), and long-term (chronic) therapeutic benefits Applications to other neurological conditions Other components of interest Conclusion Mini-dictionary of terms Key facts of high-fat diets in traumatic brain injury Summary points References

11. Brain injury, anthropometry, and nutrition

176 176 178 180 183 185 188 192 192 193 193 193 193 194

199

Manju Dhandapani and Sivashanmugam Dhandapani Introduction Traumatic brain injury Significance of nutrition in TBI Nutrition management in TBI Possible complications during nutritional support Conclusion Applications to other neurological conditions Mini-dictionary of terms Key facts relating to nutrition in TBI Key facts relating to anthropometry and TBI Summary points References

199 199 200 204 215 215 215 216 216 217 217 217

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12. Calorie and protein intake in traumatic brain injury patients

223

Mohd Ibrahim Abdullah and Aryati Ahmad Introduction Dietary intake among TBI patients Current dietary managements The new insight of nutritional recommendation Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of calorie Key facts of protein Key facts of TBI Summary points References

13. Lipids, docosahexaenoic acid (DHA), and traumatic brain injury

223 223 225 229 231 232 232 233 234 234 234 235

239

Batoul Darwish, Carla El-Mallah, Firas Kobeissy, Wassim Abou-Kheir, and Farah Chamaa Introduction Traumatic brain injury The effect of fat diets on TBI DHA as a therapeutic option for TBI Applications to other neurological conditions Conclusion Mini-dictionary of terms Key facts of TBI Summary points References

14. Brain trauma, ketogenic diets, and ketogenesis via enteral nutrition

239 240 243 247 248 250 250 250 251 251

257

Hayden White and Aaron Heffernan Introduction Review of cerebral energetics Acute brain injury and dysfunctional cerebral metabolism Ketones—Metabolisms “ugly duckling” Ketones and the brain Inducing hyperketonemia Other components of interest Applications to other neurological conditions Conclusion

257 258 261 263 265 267 272 273 273

Contents

Mini-dictionary of terms Key facts of ketone bodies Summary points References

274 274 275 275

PART IV Cerebral palsy 15. Nutrition and cerebral palsy

283

Esma Keles¸ Alp Introduction Cerebral palsy: Definition, epidemiology, etiology, and classification Malnutrition in cerebral palsy Assessment of nutritional status in cerebral palsy Nutritional intervention in cerebral palsy Follow-up and monitoring Applications to other neurological conditions Other components of interest Key facts Mini-dictionary of terms Summary points References

16. Metabolic syndrome in the adult with cerebral palsy: Implications for diet and lifestyle enhancement

283 284 286 287 291 294 295 295 296 296 296 297

301

Patricia C. Heyn, Elizabeth Terhune, Alex Tagawa, and James J. Carollo Introduction Cardiovascular disease and metabolic syndrome in patients with CP Nutritional status Summary and future research Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of metabolic syndrome in adult cerebral palsy: Implications for diet Summary points References Further reading

17. Gut microbiota characteristics in children with cerebral palsy

301 302 306 311 313 313 314 314 315 316 319

321

Yinhu Li and Shuai Cheng Li Introduction GM and nutritional absorption in CP children

321 322

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GM and neurologic regulations in CP children GM and gastrointestinal complications in CP children Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts Summary points References

18. Swallowing problems: Major components of nutritional deficits in adults with cerebral palsy

324 326 327 328 330 331 331 332

335

You Gyoung Yi Introduction Swallowing problems in individuals with cerebral palsy: A lifelong problem Characteristics of dysphagia symptoms and their impact on quality of life in adults with cerebral palsy Nutritional problems and sarcopenia in adults with cerebral palsy Assessment of dysphagia in adults with cerebral palsy Use of the eating and drinking ability classification system in people with cerebral palsy Nutritional supplements according to the eating and drinking ability classification system in adults with cerebral palsy Application in other neurological conditions Other components of interest Mini-dictionary of terms Key facts on dysphagia in adults with cerebral palsy Summary points References Further reading

335 336 337 338 340 340 341 342 343 343 343 344 344 348

PART V Dietary neurotoxins 19. Dietary neurotoxins: An overview

351

Ojaskumar D. Agrawal and Yogesh A. Kulkarni Introduction Regulatory accommodation Factors driving the acceptance of certain foods Incorporation of toxins during growth, processing, or storage Summary Mini-dictionary Key facts References

351 352 352 353 360 360 361 361

Contents

20. Alcohol consumption induces oxidative damage, neuronal injury, and synaptic impairment: Consequences for the brain health

365

Margrethe A. Olesen and Rodrigo A. Quintanilla Introduction Alcohol toxicity Alcohol affects brain function Alcohol consumption contributes to the pathogenesis of different neurological diseases Conclusions Summary points Other components of interest Key facts Mini-dictionary of terms References Further reading

21. Dietary effects of lead as a neurotoxicant

366 367 369 376 377 377 377 378 378 378 385

387

Ericka Cabañas, George B. Cruz, Michelle A. Vasquez, Jewel N. Joseph, Evan G. Clarke, Asma Iqbal, Bright U. Emenike, Wei Zhu, Patrick Cadet, Narmin Mekawy, Abdeslem El Idrissi, Morri E. Markowitz, and Lorenz S. Neuwirth Introduction Gastrointestinal structure-function relationships Gastrointestinal pathways and Ca2+ absorption Pb2+ uptake in the duodenum Pb2+/Ca2+ competition alters Ca2+ channel uptake Vitamin-D metabolism increases intestinal Pb2+ absorption Pb2+ neurotoxicity through the paracellular pathway Assessing the effects of Pb2+ on the GI gradient through histological Alcian blue staining Sex-dependent effects between control male and female rat's gastrointestinal villi and crypt gradients Pb2+ exposure effects on the male rat's gastrointestinal villi and crypt gradients Pb2+ exposure effects on the female rat's gastrointestinal villi and crypt gradients Revisiting early models of gastrointestinal Pb2+ uptake in a modern low-level exposure paradigm Pb2+ exposure-induced sex-based differences in gastrointestinal absorption The role of developmental time-periods of Pb2+ exposure on potential gut-brain interactions Conclusion Mini-dictionary of terms Summary points References

388 389 390 390 391 392 392 393 397 397 397 401 404 405 406 407 407 407

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22. Environmental toxicants (OPs and heavy metals) in the diet: What are their repercussions on behavioral/neurological systems?

411

Caridad López-Granero, Michael Aschner, and Fernando Sánchez-Santed Introduction From the origin to the diet: The input The impact of environmental toxic elements on the behavior system: The output Conclusions Applications to other neurological conditions Other components of interest Key facts of OPs and heavy metals Mini-dictionary of terms Summary points References

411 412 415 420 420 421 422 422 422 423

PART VI Epilepsy 23. Hypercholesterolemic diet and status epilepticus

431

Romildo de Albuquerque Nogueira, Edbhergue Ventura Lola Costa, Jeine Emanuele Santos da Silva, and Daniella Tavares Pessoa Introduction Neurological aspect Nutritional aspects Merging neurological and nutritional aspects Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of epilepsy Summary points References

24. Low glycemic index therapy: What it is and how it compares to other epilepsy diets

432 432 434 438 441 443 444 445 445 446

449

Vishal Sondhi and Sheffali Gulati History Evolution LGIT: Concept and composition Mechanism of action Efficacy Initiation of LGIT

449 450 454 454 456 457

Contents

Adverse events Follow-up Diet discontinuation Which diet to use? Applications to other neurological disorders Other components of interest Conclusion Mini-dictionary of terms Key facts of LGIT Summary points References

25. Ketogenic diet in pediatric epilepsies

460 460 461 461 462 465 465 465 466 466 466

471

Mario Mastrangelo, Dario Esposito, Sabrina De Leo, and Federica Gigliotti Introduction Historical background Antiepileptogenic mechanisms of ketogenic diet Variants of ketogenic diet Evaluation of candidates for ketogenic diet Monitoring children on ketogenic diet Adverse effects and tolerability Ketogenic diet in pediatric drug-resistant epilepsies Ketogenic diet as gold standard therapy: GLUT-1 deficiency syndrome and pyruvate dehydrogenase deficiency Ketogenic diet in the intensive care units Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts Summary points References

471 472 473 474 477 479 480 481 482 484 484 485 485 486 486 487

PART VII Headaches and migraines 26. The value of fruit and vegetable consumption in pediatric migraine

493

Soodeh Razeghi Jahromi, Shadi Ariyanfar, Pegah Rafiee, and Mansoureh Togha Introduction Review of the available studies and discussion Conclusion Neuroscientific aspects

493 495 497 499

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Nutritional aspects Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of fruits, vegetables, and pediatric migraine headache Summary points References

27. Dietary trigger factors of migraine

499 499 500 501 502 502 502

507

Mei-Ling Sharon Tai Introduction Foods and drinks as trigger factors of migraine Conclusion Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of dietary trigger factors of migraine Summary points References

507 509 517 517 518 520 520 520 520

PART VIII Multiple sclerosis 28. Dietary management of multiple sclerosis

527

Rabie Khattab and Yasmin Algindan Introduction Neuroscientific aspects Nutritional aspects: Dietary management of multiple sclerosis (MS) Specific nutrients in MS management Special diets for MS management General dietary guidelines for MS management Applications to other neurological conditions Other components of interest Mini-dictionary of terms Summary points References

29. Dietary fish intake and multiple sclerosis: A new narrative

527 529 530 530 534 538 538 539 539 540 540

545

Sama Bitarafan, Mohammad Hossein Harirchian, Payam Farahbakhsh, and Danesh Soltani Introduction Fish intake and the risk of MS

545 546

Contents

Dietary fish intake or fish oil supplementation and comorbidities in MS patients Mechanisms behind the association between fish intake and MS Conclusion Applications with other neurological conditions Other components of interest Key facts Mini-dictionary of terms Summary points References

30. Linking diet and gut microbiota in multiple sclerosis

548 549 550 551 551 551 552 552 552

557

Sama Bitarafan, Mohammad Hossein Harirchian, Payam Farahbakhsh, and Danesh Soltani Introduction Diet and dysbiosis risk in MS patients Nutritional interventions as modifiers of gut dysbiosis in MS patients Conclusion Applications to other neurological conditions Other components of interest Key facts Mini-dictionary of terms Summary points References

31. Restoration of myelination in the central nervous system via specific dietary bioactive lipids: An opportunity to halt disease progression in multiple sclerosis

557 559 560 565 565 566 566 567 567 567

571

Liam Graneri, John C.L. Mamo, Ryusuke Takechi, and Virginie Lam Introduction Myelin synthesis, demyelination, and remyelination Modulation of exogenous lipid in demyelination and remyelination Conclusion Applications to other neurological conditions Mini-dictionary of terms Key facts of myelin lipids Summary points References

571 572 577 587 588 588 588 589 589

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PART IX Neuroinflammation 32. Effect of diet and nutrition on neuroinflammation: An overview

597

Manisha J. Oza, Anil B. Gaikwad, and Yogesh A. Kulkarni Introduction Brain and inflammation Neuroinflammation and CNS disorders Diet and neuroinflammation Calorie restriction and neuroinflammation Ketogenic diet and neuroinflammation Mediterranean diet and neuroinflammation Vitamins and neuroinflammation Other component of interest Conclusion Summary points Mini-dictionary of terms References

33. High-fat diet-induced cellular neuroinflammation: Alteration of brain functions and associated aliments

598 599 599 600 601 603 604 604 606 607 607 608 608

613

Mohit D. Umare, Komal K. Bajaj, Nitu L. Wankhede, Brijesh G. Taksande, Aman B. Upaganlawar, Milind J. Umekar, and Mayur B. Kale Introduction Inflammation and neuroinflammation High-fat diet-induced neuroinflammation Different pathways leading to neuroinflammation Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of neuroinflammation Summary points References

34. Neuro-behavioral implications of a high-fructose diet

614 615 616 617 620 623 624 624 624 625

631

Alix H. Kloster, Emilie L. Bjerring, and Gretchen N. Neigh Introduction Fructose metabolism Metabolic syndrome and fructose Development and fructose consumption

631 632 633 633

Contents

Neural and behavioral consequences of fructose diet Potential mechanisms Conclusions Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of neuroprotection Key facts of sex differences Summary points References

634 636 639 639 640 640 641 641 641 642

PART X Parkinson's disease 35. Role of mediterranean diet in Parkinson's disease

649

Mohannad A. Almikhlafi, Badrah Alghamdi, and Ghulam Md Ashraf Introduction to Parkinson's disease Mediterranean diet and PD Other components of interest Mediterranean diet in other neurological disorders Final conclusion Dictionary of terms Key facts of the role of the Mediterranean diet in Parkinson's disease Summary References

36. Role of dietary antioxidants and redox status in Parkinson's disease

649 651 659 660 660 660 660 661 661

667

Reza Amani and Sanaz Mehrabani Introduction Oxidative stress and Parkinson's disease Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key fact of Parkinson's disease and oxidative stress Summary points References

37. Beverages, caffeine, and Parkinson's disease

667 668 687 687 688 688 689 689

699

Karl Bjørnar Alstadhaug, Charalampos Tzoulis, and Axel Meyer Simonsen Introduction Parkinson's disease

699 700

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Caffeine Caffeine and Parkinson's disease Other components of interest Future prospects Applications to other neurological conditions Key facts of caffeine and Parkinson's disease Mini-dictionary of terms Summary points References

38. The association of diet and its components with changes in gut microbiota and improvement in Parkinson's disease

700 706 709 709 710 710 710 711 711

717

Abdolreza Norouzy, Maryam Mohamadinarab, and Hamed Mirzaei Ghazi Kalayeh Introduction The association of nutrients and diet with Parkinson's disease The association between gut microbiota and Parkinson's disease The association of nutrition with gut microbial The association of nutrition with gut microbial in Parkinson's disease Conclusion Mini-dictionary of terms Key facts Summary points References

717 719 720 722 723 724 725 725 725 726

PART XI Peripheral neuropathy 39. Alcohol-related autonomic dysfunction and peripheral neuropathy

731

Andreas Liampas, Thomas Henry Julian, and Panagiotis Zis Introduction Epidemiology Natural history of large fiber neuropathy Natural history of autonomic neuropathy Risk factors Neuropathology Management Conclusion Applications to other areas of neurological conditions Other components of interest Mini-dictionary of terms Summary points/key facts

731 732 732 733 734 737 737 739 739 740 740 741

Contents

References Web pages Further reading

40. Dietary saturated and unsaturated fatty acids and peripheral neuropathy

741 743 743

745

Masha G. Savelieff, Bhumsoo Kim, Amy E. Rumora, and Eva L. Feldman Introduction Applications to other neurological conditions Other components of interest Key facts of metabolically acquired peripheral neuropathy Mini-dictionary of terms Summary points Acknowledgments References

41. Caloric restriction as a nutrition strategy in counteracting peripheral neuropathies

745 759 760 760 760 761 762 762

767

Sara Marinelli Introduction Autophagy and neuropathy Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts Summary points References

767 772 780 780 781 782 783 783

PART XII Prenatal effects and neurodevelopment 42. The interplay between stress and nutrition during pregnancy: Influence on fetal brain development

791

Nitu L. Wankhede, Mohit D. Umare, Komal K. Bajaj, Mayur B. Kale, Vaibhav S. Marde, Brijesh G. Taksande, Milind J. Umekar, and Aman B. Upaganlawar Introduction Human and animal studies Effect of stress on the developmental outcomes on offspring Biological mechanism by which stress altered offspring development Importance of nutrition on fetal brain development Other components of interest Mini-dictionary of terms

791 792 793 796 798 799 800

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Key facts Summary points References Further reading

43. Maternal and neonatal polyunsaturated fatty acid intake and risk of neurodevelopmental impairment in premature infants

800 800 800 803

805

Rory J. Heath, Susanna Klevebro, and Thomas R. Wood Introduction What is the evidence linking maternal and neonatal PUFA intake with neurodevelopmental outcomes? LCPUFA supplementation: How much and when? The wider contexts of LCPUFA supplementation Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of LCPUFA and infant development Summary points References

44. Early nutrition, growth, and neurodevelopment in the preterm infant

806 809 819 821 823 823 824 824 825 825

831

Barbara Cormack and Frank Bloomfield Introduction How preterm birth affects the brain Postnatal influences Postnatal nutrition and brain development Nutrition is a key modifiable factor for improving neurodevelopment Neonatal growth and neurodevelopment Effects of neonatal nutrition on neurodevelopment Evidence from randomized controlled trials on protein and neurodevelopment Evidence from observational studies on protein and neurodevelopment Sex differences in neurodevelopmental response to nutrition Long-term neurodevelopmental outcomes Reasons for lack of clarity in research findings Barriers to achieving prescribed nutritional intakes Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of preterm neurodevelopment Summary points References

831 833 833 835 836 836 838 839 840 841 841 842 842 843 844 844 844 845 845

Contents

45. Breast milk and cognitive performance in children

851

Kamini Dangat and Sadhana Joshi Introduction Human milk composition Factors influencing milk composition Brain development Breastfeeding and cognitive outcomes in children Milk components and cognitive development in children Conclusion Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts Summary points References

46. Effects of ketogenic diets and ketone supplementation on the nervous system during development: Applications to autism spectrum disorders and schizophrenia

851 852 855 857 857 858 861 861 861 862 862 862 863

869

Calogero Longhitano, Ann-Katrin Kraeuter, Shaileigh Gordon, and Zoltan Sarnyai Introduction The effects of ketogenic diet in animal models of autism spectrum disorder Clinical studies of ketogenic diet in schizophrenia Summary points References

869 870 881 885 885

PART XIII Stroke 47. Fluids, energy intake, and stroke

893

Alex Buoite Stella, Marina Gaio, and Paolo Manganotti Introduction Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of fluids, energy intake, and stroke Summary points References

893 897 899 900 901 901 901

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48. Body weight after stroke

907

Nadja Jauert and Wolfram Doehner Introduction The obesity paradox in stroke Body weight loss after stroke Stroke-related sarcopenia Cachexia after stroke Treatment of cachexia in stroke Applications to other neurological conditions Other components of interest Mini-dictionary of terms Key facts of cachexia after stroke Summary points References

49. Linking dietary pattern and stroke: An Indian perspective

907 908 909 910 913 914 915 916 916 916 917 917

921

Sandhya Manorenj and Reshma Sultana Shaik Introduction Dietary patterns in India Dietary pattern studies Dietary pattern and relationship with health outcome Dietary patterns and stroke Dietary pattern and stroke studies from India Diet and cardiovascular risk and stroke risk Diet as a modifiable risk factor for stroke Comparison of traditional local diet with the specialized diet Resource documents Other components of interest Applications to other areas of neurological conditions Key facts Mini-dictionary of terms Conclusion Summary points References

50. Dietary lipids: The effect of docosahexaenoic acid on stroke-related neuronal damage

921 922 924 925 925 926 927 928 928 931 931 932 933 933 934 934 934

937

Kazuo Yamagata Introduction The importance of stroke onset and prevention Stroke prevention effect by ingestion of fish and DHA: Epidemiological research

937 940 941

Contents

Biosynthesis of DHA and supply of docosahexaenoic acid to neuronal cells Neuroprotective mechanism of docosahexaenoic acid through astrocytes in the brain Inhibition of DHA against oxidative stress produced in association with ischemic stroke Effect of DHA-derived neuroprotectin on stroke Conclusion Applications to other neurological conditions Other components of interest Key facts Mini-dictionary of terms Summary points References

51. Diet quality and stroke

942 944 946 946 948 948 949 949 949 950 950

955

Mitchell Wilson and Jennifer L. Dearborn-Tomazos Introduction Patho-etiology of stroke Mechanisms by which diet quality may modify stroke risk Food components and risk of ischemic stroke Diet quality and primary prevention of stroke Diet quality and secondary prevention of stroke Future directions Applications to other neurologic conditions Other components of interest Mini-dictionary of terms Key facts of stroke and diet quality Summary points References

52. Recommended resources for diet and nutrition in neurological disorders

955 955 957 957 961 963 964 964 965 966 966 967 967

971

Rajkumar Rajendram, Vinood B. Patel, and Victor R. Preedy Introduction Resources Other resources Summary points Acknowledgments References Index

971 972 978 978 978 979 981

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Contributors Mohd Ibrahim Abdullah School of Nutrition and Dietetics, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu, Malaysia Wassim Abou-Kheir Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Ojaskumar D. Agrawal Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra; Vivekanand Education Society’s College of Pharmacy, Chembur (E), University of Mumbai, Mumbai, India Aryati Ahmad School of Nutrition and Dietetics, Faculty of Health Sciences, Universiti Sultan Zainal Abidin, Kuala Terengganu, Malaysia Arsic Aleksandra Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia Badrah Alghamdi Department of Physiology, King Abdulaziz University, Rabigh; Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia Yasmin Algindan Clinical Nutrition Department, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia Mohannad A. Almikhlafi Department of Pharmacology and Toxicology, Taibah University, Madinah, Saudi Arabia Esma Keles¸ Alp Department of Pediatrics, Dr. Ali Kemal Belviranlı Women’s Maternity and Children’s Hospital; Guest Faculty Member, Department of Pediatrics, KTO Karatay University, Konya, Turkey Karl Bjørnar Alstadhaug Department of Neurology, Nordland Hospital, Bodø; Institute of Clinical Medicine, UiT The Arctic University of Norway, Tromsø, Norway Ibrahim AlZaim Department of Pharmacology and Toxicology; Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Reza Amani Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran

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Contributors

Shadi Ariyanfar Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran Michael Aschner Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States Ghulam Md Ashraf Pre-Clinical Research Unit, King Fahd Medical Research Center; Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia Komal K. Bajaj Shrimati Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India Nour-Mounira Z. Bakkar Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Michele Barone Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Policlinic University Hospital, Bari, Italy Gurjit Kaur Bhatti Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab, India Jasvinder Singh Bhatti Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India Sama Bitarafan Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran; Neurology Department, FHMS Clinic, University of British Columbia, Vancouver, BC, Canada Emilie L. Bjerring Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States Frank Bloomfield Liggins Institute, The University of Auckland, Auckland, New Zealand Lauren Buckett Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia Alex Buoite Stella Department of Medicine, Surgery and Health Sciences, Clinical Unit of Neurology, Trieste University Hospital, University of Trieste, Trieste, Italy

Contributors

Ericka Caban˜as Department of Biology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Patrick Cadet Department of Biology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States James J. Carollo Department of Physical Medicine and Rehabilitation; Department of Orthopedics, School of Medicine, University of Colorado, Anschutz Medical Campus; Center for Gait and Movement Analysis, Musculoskeletal Research Center, Children’s Hospital Colorado, Aurora, CO, United States Zoe Castles School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia Marina Chaco´n Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico Farah Chamaa Cellular Imaging and Energetics Lab, Biological and Environmental Sciences and Engineering Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia Sameer Chaudhary RASA Life Science Informatics, Pune, India Sapana Chaudhary RASA Life Science Informatics, Pune, India Evan G. Clarke Department of Biology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Irazu´ Contreras Neurochemistry Laboratory, Faculty of Medicine, Autonomous University of the State of Mexico, Toluca, Estado de M
exico, M
exico Barbara Cormack Liggins Institute, The University of Auckland, Auckland, New Zealand Edbhergue Ventura Lola Costa Laboratory of Theoretical, Experimental and Computational Biophysics, Department of Animal Morphology and Physiology, Rural Federal University of Pernambuco, Recife, Pernambuco, Brazil George B. Cruz Department of Biology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Daniel Cuervo-Zanatta Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico

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Contributors

Kamini Dangat Mother and Child Health Department, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune, India Batoul Darwish Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Sabrina De Leo Unit of Internal Medicine and Clinical Nutrition, Department of Internal Medicine, EndocrineMetabolic Sciences and Infectious Diseases, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Roma, Italy Jennifer L. Dearborn-Tomazos Division of Stroke, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States Manju Dhandapani Department of Neurosurgery, PGIMER, Chandigarh, India Sivashanmugam Dhandapani Department of Neurosurgery, PGIMER, Chandigarh, India Wolfram Doehner Berlin-Brandenburg Center for Regenerative Therapies (BCRT); Department of Neurology, Centre for Stroke Research Berlin (CSB); Department of Cardiology, Charit
eUniversit€atsmedizin Berlin; German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany Abdeslem El Idrissi Department of Biology, Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY, United States Carla El-Mallah Department of Nutrition and Food Sciences, Faculty of Agricultural and Food Sciences, American University of Beirut, Beirut, Lebanon Ahmed F. El-Yazbi Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Deparment of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria; Faculty of Pharmacy, Al Alamein International University, El-Alamein, Egypt Bright U. Emenike Department of Chemistry & Physics, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Dario Esposito Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza Universita` di Roma, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Roma, Italy Jos
e A. Estrada Neurochemistry Laboratory, Faculty of Medicine, Autonomous University of the State of Mexico, Toluca, Estado de M
exico, M
exico

Contributors

Payam Farahbakhsh Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran Eva L. Feldman NeuroNetwork for Emerging Therapies, University of Michigan; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States Anil B. Gaikwad Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani, Rajasthan, India Marina Gaio Clinical Unit of Neurology, Trieste University Hospital, Trieste, Italy Federica Gigliotti Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza Universita` di Roma, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Roma, Italy Shaileigh Gordon Mental Health Service Group, Townsville University Hospital, Douglas, QLD, Australia Liam Graneri Curtin Medical School; Curtin Health Innovation Research Institute, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia Sheffali Gulati Center of Excellence & Advanced Research on Childhood Neurodevelopmental Disorders, Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India Mohammad Hossein Harirchian Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran Rory J. Heath Intensive Care Unit, Southmead Hospital, North Bristol NHS Foundation Trust, Bristol, United Kingdom Aaron Heffernan Department of Intensive Care Medicine, Logan Hospital, Metro South, Queensland Health, , Meadowbrook, QLD, Australia Julieta Hernandez-Acosta Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico Patricia C. Heyn Center for Optimal Aging, Marymount University, Arlington, VA; Department of Physical Medicine and Rehabilitation, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States Stanley Ibeh Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon

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Contributors

Asma Iqbal Department of Counseling and Clinical Psychology, Teachers College, Columbia University, New York, NY, United States Soodeh Razeghi Jahromi Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran Nadja Jauert Berlin-Brandenburg Center for Regenerative Therapies (BCRT); Department of Neurology, Centre for Stroke Research Berlin (CSB); Department of Cardiology, Charit
eUniversit€atsmedizin Berlin; German Centre for Cardiovascular Research (DZHK), partner site Berlin, Berlin, Germany Leanne Jiang Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD; School of Biological Sciences, The University of Western Australia, Perth, WA, Australia Jewel N. Joseph Department of Biology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Sadhana Joshi Mother and Child Health Department, Interactive Research School for Health Affairs (IRSHA), Bharati Vidyapeeth (Deemed to be) University, Pune, India Thomas Henry Julian Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, United Kingdom Hamed Mirzaei Ghazi Kalayeh Department of Microbiology and Immunobiology, Kashan University of Medical Sciences, Kashan, Iran Mayur B. Kale Department of Pharmacology, Shrimati Kishoritai Bhoyar College of Pharmacy, Nagpur, Maharashtra, India Rubal Kanozia Department of Mass Communication and Media Studies, Central University of Punjab, Bathinda, Punjab, India Rabie Khattab Clinical Nutrition Department, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia Bhumsoo Kim NeuroNetwork for Emerging Therapies, University of Michigan; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States Susanna Klevebro Department of Clinical Science and Education, Stockholm South General Hospital, Karolinska Institute, Stockholm, Sweden

Contributors

Alix H. Kloster Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States Firas Kobeissy Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Program of Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, Psychiatry, Neuroscience and Chemistry, University of Florida, Gainesville, FL, United States Ann-Katrin Kraeuter Brain Performance and Nutrition Research Centre (BPN); NUTRAN, Faculty of Health and Life Sciences, Northumbria University; Faculty of Health and Life Sciences, Psychology, Newcastle upon Tyne, United Kingdom Yogesh A. Kulkarni Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Virginie Lam Curtin Health Innovation Research Institute; School of Population Health, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia Shuai Cheng Li Department of Computer Science, City University of Hong Kong, Hong Kong, China Yinhu Li Department of Computer Science, City University of Hong Kong, Hong Kong, China Andreas Liampas Department of Neurology, Nicosia New General Hospital, 215, Palaios Dromos Lefkosias Lemesou Str. Strovolos, Nicosia, Cyprus Calogero Longhitano Department of Psychiatry, James Cook University Clinical School, Townsville University Hospital; Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine (AITHM),Discipline of Biomedicine, College Public Health, Medical and Veterinary Sciences, James Cook University, Douglas, QLD, Australia Caridad Lo´pez-Granero Department of Psychology and Sociology, Faculty of Social and Human Sciences, University of Zaragoza, Teruel, Spain John C.L. Mamo Curtin Health Innovation Research Institute; School of Population Health, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia Paolo Manganotti Department of Medicine, Surgery and Health Sciences, Clinical Unit of Neurology, Trieste University Hospital, University of Trieste, Trieste, Italy Sandhya Manorenj Department of Neurology, Princess Esra Hospital, Deccan College of Medical Sciences, Hyderabad, Telangana, India

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Contributors

Vaibhav S. Marde Department of Pharmaceutical Chemistry, Indian Institute of Technology, Hyderabad, India Sara Marinelli Department of Biomedical Science, Institute of Biochemistry and Cell Biology, Consiglio Nazionale delle Ricerche, Monterotondo, RM, Italy Morri E. Markowitz Children’s Hospital at Montefiore, The University Hospital for Albert Einstein College of Medicine, Bronx; SUNY Neuroscience Research Institute, Old Westbury, NY, United States Mario Mastrangelo Unit of Child Neurology and Psychiatry, Department of Human Neuroscience, Sapienza Universita` di Roma, Azienda Ospedaliero-Universitaria Policlinico Umberto I, Roma, Italy Sanaz Mehrabani Department of Clinical Nutrition, School of Nutrition and Food Science, Isfahan University of Medical Sciences, Isfahan, Iran Narmin Mekawy Department of Biology, Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY, United States Jayapriya Mishra Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India Maryam Mohamadinarab Department of Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran Mo´nica Morales Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico Umashanker Navik Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India Gretchen N. Neigh Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States Lorenz S. Neuwirth Department of Psychology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Shyuan T. Ngo Australian Institute for Bioengineering and Nanotechnology; Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia Romildo de Albuquerque Nogueira Laboratory of Theoretical, Experimental and Computational Biophysics, Department of Animal Morphology and Physiology, Rural Federal University of Pernambuco, Recife, Pernambuco, Brazil

Contributors

Abdolreza Norouzy Department of Nutrition, Mashhad University of Medical Sciences, Mashhad, Iran Adriana Leico Oda Department of Clinical Neurology—Neuromuscular Diseases, Federal University of Sa˜o Paulo; Clinical, Education and Research in Health, Neuroqualis, Sa˜o Paulo, SP, Brazil Margrethe A. Olesen Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biom
edicas, Facultad de Ciencias de la Salud, Universidad Auto´noma de Chile, Santiago, Chile Manisha J. Oza SVKM’s Dr. Bhanuben Nanavati College of Pharmacy, Mumbai, Maharashtra, India Vinood B. Patel School of Life Sciences, University of Westminster, London, United Kingdom Claudia Perez-Cruz Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico Daniella Tavares Pessoa Laboratory of Theoretical, Experimental and Computational Biophysics, Department of Animal Morphology and Physiology, Rural Federal University of Pernambuco, Recife, Pernambuco, Brazil Jayashri Prasanan RASA Life Science Informatics, Pune, India Victor R. Preedy School of Life Course and Population Sciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom Rodrigo A. Quintanilla Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biom
edicas, Facultad de Ciencias de la Salud, Universidad Auto´noma de Chile, Santiago, Chile Pegah Rafiee Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran Rajkumar Rajendram College of Medicine, King Saud bin Abdulaziz University for Health Sciences; Department of Medicine, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia Minic Rajna Department of Scientific Research, Institute of Virology, Vaccines and Sera, Torlak; Group for Immunology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia Sakshi Rawat RASA Life Science Informatics, Pune, India

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xxxviii Contributors

P. Hemachandra Reddy Department of Internal Medicine; Department of Pharmacology and Neuroscience; Department of Public Health, Graduate School of Biomedical Sciences; Department of Neurology; Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, United States Amy E. Rumora NeuroNetwork for Emerging Therapies, University of Michigan; Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States Cristina C.S. Salvioni Department of Clinical Neurology—Neuromuscular Diseases, Federal University of Sa˜o Paulo; Clinical, Education and Research in Health, Neuroqualis, Sa˜o Paulo, SP, Brazil Fernando Sa´nchez-Santed Department of Psychology, Centro de Investigacio´n en Salud/ Universidad de Almerı´a (CEINSA/UAL), Almerı´a, Spain Vicente Sa´nchez-Valle Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico Zoltan Sarnyai Laboratory of Psychiatric Neuroscience, Australian Institute of Tropical Health and Medicine (AITHM),Discipline of Biomedicine, College Public Health, Medical and Veterinary Sciences, James Cook University, Douglas, QLD, Australia Masha G. Savelieff NeuroNetwork for Emerging Therapies, University of Michigan, Ann Arbor, MI, United States Abhishek Sehrawat Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India Reshma Sultana Shaik Department of Neurology, Princess Esra Hospital, Deccan College of Medical Sciences, Hyderabad, Telangana, India Eva Sharma Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India Jeine Emanuele Santos da Silva Laboratory of Theoretical, Experimental and Computational Biophysics, Department of Animal Morphology and Physiology, Rural Federal University of Pernambuco, Recife, Pernambuco, Brazil Isabella Laura Simone Section of Neurology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University “Aldo Moro” of Bari, Policlinic University Hospital, Bari, Italy Axel Meyer Simonsen Department of Neurology, Nordland Hospital, Bodø, Norway

Contributors

Danesh Soltani Iranian Center of Neurological Research, Neuroscience Institute, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran Vishal Sondhi Department of Pediatrics, Armed Forces Medical College, Pune, India Frederik J. Steyn School of Biomedical Sciences; Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia Alex Tagawa Center for Gait and Movement Analysis, Musculoskeletal Research Center, Children’s Hospital Colorado, Aurora, CO, United States Mei-Ling Sharon Tai Division of Neurology, Department of Medicine, University of Malaya, Kuala Lumpur, Malaysia Ryusuke Takechi Curtin Health Innovation Research Institute; School of Population Health, Faculty of Health Sciences, Curtin University, Bentley, WA, Australia Brijesh G. Taksande Department of Pharmacology, Shrimati Kishoritai Bhoyar College of Pharmacy, Nagpur, Maharashtra, India Elizabeth Terhune Department of Orthopedics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States Mansoureh Togha Department of Nutrition, Headache Department, Iranian Center of Neurological Research, Neuroscience Institute Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran Charalampos Tzoulis Neuro-SysMed Center; Department of Neurology, Haukeland University Hospital, Bergen, Norway Mohit D. Umare Shrimati Kishoritai Bhoyar College of Pharmacy, Kamptee, Nagpur, Maharashtra, India Milind J. Umekar Department of Pharmaceutics, Shrimati Kishoritai Bhoyar College of Pharmacy, Nagpur, Maharashtra, India Aman B. Upaganlawar Department of Pharmacology, SNJB’s Shriman Sureshdada Jain College of Pharmacy, Neminagar, Chandwad, Nashik, Maharashtra, India Michelle A. Vasquez Department of Chemistry & Physics, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Nitu L. Wankhede Department of Pharmacology, Shrimati Kishoritai Bhoyar College of Pharmacy, Nagpur, Maharashtra, India

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Contributors

Hayden White Department of Critical Care Medicine, Logan Hospital, MetroSouth, Queensland Health, Griffith University, Meadowbrook, QLD, Australia Mitchell Wilson Division of Stroke, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA, United States Thomas R. Wood Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, United States Kazuo Yamagata Department of Food Bioscience & Biotechnology, College of Bioresource Science, Nihon University (NUBS), Fujisawa, Kanagawa, Japan You Gyoung Yi Department of Rehabilitation Medicine, Seoul National University Hospital; Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea Wei Zhu Department of Psychology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Panagiotis Zis Assistant Professor of Neurology and Clinical Neurophysiology, Department of Neurology, Medical School, University of Cyprus, 215, Palaios Dromos Lefkosias Lemesou Str. Strovolos, Nicosia, Cyprus Stevic Zorica Faculty of Medicine, Neurology Clinic, University Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia

Preface

Neurological disorders have an enormous impact on the individual, family unit, community, and society at large. For example, the World Health Organization reports that on a global basis, 6 million people die from stroke each year, 50 million people have epilepsy, and a similar number have dementia, of which the most common is Alzheimer’s disease. Half of the world’s adult population had a headache at least once in the last year. Many of these neurological conditions have a central feature: poor or good diet and nutrition may either worsen or lessen symptoms. Some neurological conditions arise directly as a consequence of poor nutrition, or the ingestion of toxic dietary components such as alcohol. Much of the research on diet and nutrition is focused around single neurological diseases. However, consideration must be taken of the fact that the information relating to one neurological condition may well be relevant to other conditions. For example, the Mediterranean diet has been investigated in amyotrophic lateral sclerosis, but not in relation to headache and migraine. On the other hand, the Dietary Approaches to Stop Hypertension diet has been studied in relation to headache but not amyotrophic lateral sclerosis. It is therefore possible that information relating to one neurological disease may very well have relevance to understanding or treating other neurological diseases. Furthermore, studies showing the beneficial effects of plant or natural extracts provide the foundation for further rigorous studies in clinical trials. Crossing this trans-speciality divide is somewhat difficult as many textbooks are focused on single neurological conditions. There is also a trans-intellectual divide that makes some texts extremely difficult for the novice or student to comprehend and understand. The editors have sought to overcome these limitations and advance the understanding of neurosciences and nutrition with a series of three books collectively called “Nutrition and Neurological Disorders”. The three books are as follows: Book 1: Diet and Nutrition in Neurological Disorders Book 2: Vitamins and Minerals in Neurological Disorders Book 3: Treatments, Nutraceuticals, Supplements, and Herbal Medicine in Neurological Disorders Each chapter has the following sections that we consider unique: • Abstract (published online) • Applications to other neurological conditions • Other components of interest

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• Key facts • Mini-dictionary of terms • Summary points The section Applications to other neurological conditions is particularly important as it highlights the translational aspect of nutritional research. The section Other components of Interest emphasizes the fact that diet and nutrition are complex areas and that there may be other components that can confer health benefits or even be detrimental. The section Key facts gives important information about individual components in each chapter. The section Mini-dictionary of terms is suited for both nonexperts and those working in other fields or areas. The section Summary points encapsulates the entire chapter in brief sets of simple sentences. Diet and Nutrition in Neurological Disorders is divided into 13 parts as follows: • Part I: Alzheimer’s disease and dementias • Part II: Amyotrophic lateral sclerosis • Part III: Brain injury • Part IV: Cerebral palsy • Part V: Dietary neurotoxins • Part VI: Epilepsy • Part VII: Headaches and migraines • Part VIII: Multiple sclerosis • Part IX: Neuroinflammation • Part X: Parkinson’s disease • Part XI: Peripheral neuropathy • Part XII: Prenatal effects and neurodevelopment • Part XIII: Stroke This book is designed for research and teaching purposes. It is suitable for nutritionists, dietitians, neurologists, physicians, health scientists, healthcare workers, pharmacologists, and researchers. The audience also includes federal and state program directors. This book is valuable as a personal reference book and is also suitable for academic libraries that covers the domains of nutrition, neurology, or health sciences. Contributions are from leading national and international experts, including those from world-renowned institutions. The book is suitable for undergraduates, postgraduates, lecturers, and academic professors. Colin R. Martin Vinood B. Patel Victor R. Preedy

CHAPTER 1

Neurological disorders in the context of the global burden of disease Rajkumar Rajendrama,b, Vinood B. Patelc, and Victor R. Preedyd a

College of Medicine, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia Department of Medicine, King Abdulaziz Medical City, King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia c School of Life Sciences, University of Westminster, London, United Kingdom d School of Life Course and Population Sciences, Faculty of Life Science and Medicine, King’s College London, London, United Kingdom b

Abbreviations COVID-19 DALYs GBD TB

Coronavirus Disease 2019 disability-adjusted life years Global Burden of Disease tuberculosis

Introduction Neurological disorders are the leading cause of disability and the second leading cause of death worldwide (Global Burden of Disease 2015 Neurological Disorders Collaborator Group, 2017; Global Burden of Disease 2016 Neurology Collaborators, 2019). Thus, neurological disorders cause significant morbidity and mortality. The Global Burden of Disease study attempts to quantify these conditions. The methodology of each iteration of the GBD study is improved, with more data and better modeling (Rajendram, Patel, & Preedy, 2022a, 2022b). The GBD data demonstrated that in many countries, the incidence, mortality, and prevalence of many neurological disorders declined from 1990 to 2015 (Global Burden of Disease 2015 Neurological Disorders Collaborator Group, 2017; Global Burden of Disease 2016 Neurology Collaborators, 2019). Yet, the absolute numbers dying, or remaining disabled from neurological disorders increased worldwide (Global Burden of Disease 2015 Neurological Disorders Collaborator Group, 2017; Global Burden of Disease 2016 Neurology Collaborators, 2019). Understanding the harm attributable to neurological disorders is fundamental to acknowledging the scale of the problem. The regular assessment of the changes in morbidity and mortality associated with neurological disorders with time enables an evidence-based approach to public health, setting priorities, and allocating resources. It may also generate hypotheses on the relevance of demographic and socioeconomic factors to the burden of disease attributable to neurological disorders. The burden of disease in terms of disability-adjusted life years (DALYs) worldwide and in select countries is therefore presented in Figs. 1–7. This provides a quantitative Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00053-2

Copyright © 2023 Elsevier Inc. All rights reserved.

1

Fig. 1 Burden of disease: World data of DALYs. Total disease burden in 2019. DALYs, disability-adjusted life years. One DALY equals one lost year of healthy life. The blue arrow at the 11th position (97.72 million DALYs per year) identifies the position of neurological disorders. Blue bars: noncommunicable diseases. Red bars: communicable, maternal, neonatal, and nutritional diseases. Green bars: injuries. (From Our World in Data under the Creative Commons BY license. The text for the legend was adapted from the source of figures. Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https://ourworldindata.org/burden-of-disease.)

Fig. 2 Burden of disease as a percent of total disease burden: World data. Share of disease burden as a percent of total in 2019. DALYs, disabilityadjusted life years. The blue arrow at the 11th position (3.32% of all global DALYs) identifies the position of neurological disorders. For other details, see legend to Fig. 1. (From Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https://ourworldindata.org/burden-of-disease.)

Fig. 3 Burden of disease as a percent of total disease burden: United States data. Share of disease burden as a percent of total in 2019. DALYs, disability-adjusted life years. The blue arrow at the eighth position (5.27% of all DALYs for the United States) identifies the position of neurological disorder. For other details, see legend to Fig. 1. (From Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https://ourworldindata.org/burden-of-disease.)

Fig. 4 Burden of disease as a percent of total disease burden: United Kingdom data. Share of disease burden as a percent of total in 2019. DALYs, disability-adjusted life years. The blue arrow at the fifth position (6.76% of all DALYs for the United Kingdom) identifies the position of neurological disorders. For other details, see legend to Fig. 1. (From Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https://ourworldindata.org/burden-of-disease.)

Fig. 5 Burden of disease as a percent of total disease burden: Japan data. Share of disease burden as a percent of total in 2019. DALYs, disabilityadjusted life years. The blue arrow at the fourth position (8.69 of all DALYs for Japan) identifies the position of neurological disorders. For other details, see legend to Fig. 1. (From Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https:// ourworldindata.org/burden-of-disease.)

The percentage of DALYs for each country

Neurological disorders in context of global burden of disease

25

20

15

10

5

0

Neurological Disorders

Cardiovascular Disease

Cancers

The percentage of DALYs for each country

Fig. 6 Ranking of burden of disease as a percent of total disease burden for different countries: top 10 due to neurological disorders. Share of disease burden due to neurological disorders as a percent of total in 2019. DALYs, disability-adjusted life years. For comparison, we have included DALYs for cardiovascular disease and cancers. For other details, see legend to Fig. 1. (Data from Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https:// ourworldindata.org/burden-of-disease. Figure compiled by authors.)

7 6

5 4 3 2 1 0

Neurological Disorders

Cardiovascular Disease

Cancers

Fig. 7 Ranking of burden of disease as a percent of total disease burden for different countries: bottom 10 due to neurological disorders. Share of disease burden due to neurological disorders as a percent of total in 2019. DALYs, disability-adjusted life years. S. Sudan (South Sudan) and Cen. Afr. Rep. (Central African Republic). For comparison, we have included DALYs for cardiovascular disease and cancers. For other details, see legend to Fig. 1. (Data from Roser, M., Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from: https://ourworldindata.org/burden-of-disease. Figure compiled by authors.)

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Diet and nutrition in neurological disorders

measure of the total burden of disease, numerically derived from both the number of years living with a disability and years of life lost because of premature death. The position of neurological disorders in relation to other conditions is also compared. This approach has been previously described (Rajendram et al., 2022a, 2022b; Rajendram, Patel, & Preedy, 2022c).

Ranking of DALYs due to neurological disorders In terms of the most recent global data available at the time of writing, the DALYs due to neurological disorders approaches 100 million per year (Fig. 1). In terms of total DALYs, neurological disorders rank 11th, behind cardiovascular diseases, cancers, neonatal disorders, other noncommunicable diseases, respiratory infection and tuberculosis (TB), musculoskeletal disorders, mental disorders, diabetes and kidney disease, unintentional injuries, and respiratory diseases. In terms of the proportion of DALYs, neurological disorders account for 3.32% of all DALYs (Fig. 2). However, the position of disorders in terms of DALYs varies between different countries and geographical regions. The DALYs due to neurological disorders ranks eighth in United States (Fig. 3), and fifth in the United Kingdom (Fig. 4). However, in Japan, neurological disorders ranks fourth in terms of total DALYs (Fig. 5). In fact, Japan has the highest proportion of DALYs due to neurological disorders (Fig. 6). The leading countries (top 10) with the highest proportion of DALYs due to neurological disorders are Japan, Italy, Iceland, France, Norway, Spain, Switzerland, Belgium, Israel, and Sweden (Fig. 6): this ranges from 7.3% to 8.7% of all DALYs for a particular country. The lowest (bottom 10) proportion of DALYs due to neurological disorders occurs in Somalia (1.1%; Fig. 7), followed by the Central African Republic, Lesotho, South Sudan, Niger, Chad, Mozambique, Mali, Burundi, and Burkina Faso (range 1.2%–1.6% of DALYs; Fig. 7). More detailed analysis of neurological disorders can be found elsewhere, in relation to the Human Development Index (HDI; Borumandnia, Majd, Doosti, & Olazadeh, 2022), aging (Martin, Preedy, & Rajendram, 2021), and disease burdens (Dhamija & Saluja, 2021). However, it is important to point out that the disease burdens are not a reflection of targeted research nor funding (Rajendram, Lewison, & Preedy, 2006). Also, measures of disease burdens do not reflect the impact on either the patient nor family unit and carers (caregivers). Quality of life measures are a way of addressing this (Rajendram et al., 2022a).

Comparing neurological disorders to cardiovascular disease and cancers As mentioned above, it is worth comparing specific diseases with other conditions that have a major public health or medical impact, an approach we used previously (Rajendram et al., 2022a, 2022b, 2022c). In this instance, we examine neurological disorders with respect to

Neurological disorders in context of global burden of disease

cardiovascular disease and cancers. In the United States and United Kingdom, the DALYs caused by cardiovascular disease or cancers is about 3 times that due to neurological disorders (Figs. 2 and 3). In the top 10 countries, the contribution of cardiovascular diseases to total DALYs ranges from 10.6% (Israel) to 18.6% (Sweden). The contribution of cancers to total DALYs ranges from 16.7% (Israel) to 20.4% (Japan) in the top 10 countries. In other words, the contribution of DALYS to either cardiovascular disease or cancers is twice that of neurological disorders. In contrast, in the bottom 10, which are lower-income countries, the contribution of DALYS to either cardiovascular disease or cancers is approximately three and two times greater than that of neurological disorders, respectively. The position of neurological disorders in these lower-income countries is due to the high contribution of other conditions of poverty ( Jaffer & Hotez, 2016). In Somalia, for example, the highest contributor to total DALYs is respiratory diseases and TB (19.5% of total DALYs), neonatal disorders (13.7%), enteric infections (9.4%), and nutritional deficiencies (5.4%) account for almost half of all DALYS for that country (Roser & Ritchie, 2021). Civil conflict and other socioeconomic factors are important contributors to the high TB incidence (500 per 100,000) with delays in diagnosis and the presence of multiresistant TB are confounding factors (Sheikh, Salad, & Gele, 2021). Malnutrition also contributes to infection rates. Stunting and wasting in children (under 5-year-olds) in Somalia is one in 6 and one in 10, respectively (Donkor et al., 2022). Further analysis of the interlinking between neurological disorders in Africa with infection and immunology can be found elsewhere (Ngarka, Siewe Fodjo, Aly, Masocha, & Njamnshi, 2022). From the point of view of a physician, or healthcare professional, specializing in neurological disorders, it could be argued that the disease itself represents a microcosm that requires focused attention on the patient, family unit, and caregivers. From another perspective, the global context and public health impact of the condition is important. However, as argued before, and in this brief narrative review, the burden of a particular disease or its impact on the individual does not necessary reflect the scientific interest (i.e., the amount of research conducted or published Rajendram et al., 2006). Nor do the disease burdens themselves represent worldwide commercial aspects. For example, the largest market share of drug sales worldwide (actual and projected) pertain to cancers (16.0% and 21.7% of sales for 2019 and 2026, respectively), followed by antidiabetic medications (5.6% and 4.7% of sales for 2019 and 2026, respectively) (EvaluatePharma, 2020). Currently, in terms of market share, therapies for multiple sclerosis rank 10th and antihypertensives rank 11th in this commercial hierarchy, while antipsychotics rank 13th, which collectedly account for just over 6% of current market share (EvaluatePharma, 2020). However, with the onset of severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) pandemic, Coronavirus disease 2019 (COVID-19) and the unforeseen consequences of long COVID, such ranking is likely to change.

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References Borumandnia, N., Majd, H. A., Doosti, H., & Olazadeh, K. (2022). The trend analysis of neurological disorders as major causes of death and disability according to human development, 1990-2019. Environmental Science and Pollution Research International, 29(10), 14348–14354. Dhamija, R. K., & Saluja, A. (2021). Challenges in estimating the burden of neurological disorders across Indian states. The Lancet Global Health, 9(11), e1503. Donkor, W. E. S., Mbai, J., Sesay, F., Ali, S. I., Woodruff, B. A., Hussein, S. M., et al. (2022). Risk factors of stunting and wasting in Somali pre-school age children: Results from the 2019 Somalia micronutrient survey. BMC Public Health, 22(1), 264. EvaluatePharma. (2020). World preview 2020, outlook to 2026. EvaluatePharma. https://www.evaluate.com/ thought-leadership/pharma/evaluatepharma-world-preview-2020-outlook-2026. (Accessed 4 May 2022). Global Burden of Disease 2015 Neurological Disorders Collaborator Group. (2017). Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurology, 16, 877–897. Global Burden of Disease 2016 Neurology Collaborators. (2019). Global, regional, and national burden of neurological disorders, 1990–2016: A systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurology, 18(5), 459–480. Jaffer, A., & Hotez, P. J. (2016). Somalia: A nation at the crossroads of extreme poverty, conflict, and neglected tropical diseases. PLoS Neglected Tropical Diseases, 10(9), e0004670. Martin, C. R., Preedy, V. R., & Rajendram, R. (Eds.). (2021). Factors affecting neurological aging. In Genetics, neurology, behavior and diet. United States: Academic Press, Elsevier. Ngarka, L., Siewe Fodjo, J. N., Aly, E., Masocha, W., & Njamnshi, A. K. (2022). The interplay between neuroinfections, the immune system and neurological disorders: A focus on Africa. Frontiers in Immunology, 12, 803475. Rajendram, R., Lewison, G., & Preedy, V. R. (2006). Worldwide alcohol-related research and the disease burden. Alcohol and Alcoholism, 41, 99–106. Rajendram, R., Patel, V. B., & Preedy, V. R. (2022a). The context and comparison of mental health disorders with other communicable and non-communicable diseases: Interlinking cognitive behavioral therapy. In C. R. Martin, V. R. Preedy, & V. B. Patel (Eds.), Handbook of cognitive behavioural therapy by disorders. Cambridge, MA: Elsevier. Rajendram, R., Patel, V. B., & Preedy, V. R. (2022b). Substance misuse and addictions in context. In V. B. Patel, & V. R. Preedy (Eds.), Handbook of substance misuse and addictions: From biology to public health. New York: Springer. Rajendram, R., Patel, V. B., & Preedy, V. R. (2022c). Life span related mental health disorders and cognitive behavioral therapy. In C. R. Martin, V. B. Patel, & V. R. Preedy (Eds.), Handbook of lifespan cognitive behavioural therapy. Cambridge, MA: Elsevier. Roser, M., & Ritchie, H. (2021). Burden of disease. Published online at Our World in Data. Retrieved from https://ourworldindata.org/burden-of-disease. Sheikh, N. S., Salad, A. M., & Gele, A. A. (2021). Delay of TB patients in diagnosis in a conflict setting of Mogadishu, Somalia—A cross-sectional study. medRxiv.

PART I

Alzheimer’s disease and dementias

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CHAPTER 2

Lifestyle modifications and nutrition in Alzheimer’s disease Gurjit Kaur Bhattia, Jayapriya Mishrab, Abhishek Sehrawatb, Eva Sharmab, Rubal Kanoziac, Umashanker Navikd, P. Hemachandra Reddye,f,g,h,i, and Jasvinder Singh Bhattib a

Department of Medical Lab Technology, University Institute of Applied Health Sciences, Chandigarh University, Mohali, Punjab, India b Department of Human Genetics and Molecular Medicine, School of Health Sciences, Central University of Punjab, Bathinda, Punjab, India c Department of Mass Communication and Media Studies, Central University of Punjab, Bathinda, Punjab, India d Department of Pharmacology, Central University of Punjab, Bathinda, Punjab, India e Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States f Department of Pharmacology and Neuroscience, Texas Tech University Health Sciences Center, Lubbock, TX, United States g Department of Public Health, Graduate School of Biomedical Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, United States h Department of Neurology, Texas Tech University Health Sciences Center, Lubbock, TX, United States i Department of Speech, Language, and Hearing Sciences, Texas Tech University Health Sciences Center, Lubbock, TX, United States

Abbreviations AD APP APOE ATP BDNF CAT CR CSF CVD ESCs fMRI iPSCs MAPT MSCs NFT PSEN1 ROS SPECT WHO

Alzheimer’s disease amyloid beta precursor protein apolipoprotein E adenosine triphosphate brain derived neurotrophic factor computer-assisted tomography calorie restriction cerebrospinal fluid cardiovascular disease embryonic stem cells functional magnetic resonance imaging induced pluripotent stem cells microtubule associated protein tau mesenchymal stem cells neurofibrillary tangles presenilin 1 reactive oxygen species single photon emission computed tomography World Health Organization

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00049-0

Copyright © 2023 Elsevier Inc. All rights reserved.

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Introduction In human beings, the brain is known to be one of the most delicate organs of the body that has great command of control and coordination of the system. Traumatic events are heading the brain toward damage both structurally and functionally with increased risk of neurodegeneration, commonly called traumatic brain injury. Decades of research have indicated the development of Alzheimer’s disease (AD), Parkinson’s disease, and other neurodegenerative disorders after the age of 60 years. Among all these neurodegenerative disorders, the foremost dementia like ADs with more than 20 million cases worldwide is affecting daily life very seriously leading to death (Hardy, 2006). AD is a progressive neurodegenerative disease that is involving in memory deficit and deterioration of cognitive and motor functions over time. Impairment in quality of life and failure in balancing of activities of daily routine for living are consequences of the declining of cognitive functions. AD is the utmost common form of dementia with two major risk factors, aging and depression (Goedert & Spillantini, 2006). Patients are most often seen with symptoms like delusion, hallucination, and memory loss in this fatal neurological disorder. Apart from this, many changes have also been noted, like metabolic and physiologic changes like trouble sleeping at night, loss of appetite, the decline of cognitive functions, and difficulties in doing familiar tasks. Pathophysiology shows structural variation in protein folding and neurons and neural circuit in the brain of Alzheimer’s patients. Abnormal chemical changes resulting in the formation of neurofibrillary tangles (NFTs) due to the failure of attachment of microtubules with tau protein lead to the twisting of misfolded tau protein threads that interfere with cellular machinery (Fig. 1) (Brion, 1998). Another prime suspect is the accumulation of amyloid-beta protein that is associated with the formation of plaques between the nerve cells (Citron, 2010). Complicacy increases with time, and the sufferer is found with complete loss of coordination and cognition heading toward problems with doing day-to-day things. Changing behavior can be observed very closely in relation to social life and lifestyle like the patient found with difficulties in remembering new information and seems to be demotivated. They often prefer to avoid social interactions because they have confusion in identifying persons and even family members (Hardy, 2006). It will not be an exaggeration to say that AD disease is disastrous to the patient and as well as to their caregivers and family members. As this life-threatening disease has no cure, it is better to prevent it by maintaining healthy living, including a healthy lifestyle and nutrition.

Understanding AD through its sign and symptoms According to WHO, dementia can be explained as a chronic disorder that includes symptoms like declining memory, cognitive functions, and orientation. Different forms of dementia are seen in people of varying age-groups, and the variation depends only on the changes in the brain. It must be said that these changes are

Lifestyle modifications and nutrition in Alzheimer's disease

Fig. 1 Comparison between healthy and Alzheimer’s affected brain. (A) The healthy brain wherein the normal tau proteins help in the formation and stabilization of microtubules that help in the transport of nutrients from one nerve cell to another; (B) The accumulation of tau and amyloid-beta fibers leading to the formation of neurofibrillary tangles and amyloid-beta plaques. The deposition of tangles or plaque directly affects the neurons, subsequently resulting in the disruption of neuronal function and loss of synaptic communication.

usually chronic and progressive and it gets worse over time. AD is the most common form of dementia, which is known as the major neurodegenerative disorder among old-age people since the last century. While it is not true to say that Alzheimer’s disease is a common part of aging, there is strong evidence from several case studies supporting that aging is one of the major risk factors for it. A little ignorance of the patient can push their life toward danger over time. Hence, it is more important to understand the symptoms very well, so that the caregiver should handle everything carefully. At the onset of AD, people are becoming lost and confused in familiar places and have trouble driving. They are having difficulties with communication as they cannot coordinate properly and are confused with languages also. They lose interest in interacting with people and work they are fond of. Their less active and demotivated behavior to do work seems that the tiredness comes due to old age. As early-stage symptoms are not sufficient to recognize the people suffering from AD, it is often seen that

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dementia can be detected in the middle stage. In this stage, people become more forgetful and will not be able to make decision. They have more confusion regarding comprehension and languages, which increases difficulties with communication. Alteration in sleep patterns, loss of cognition, and thinking are usually seen in this stage. Delusion, hallucination, and unconstrained-like mental abnormalities are frequently seen in a person’s behavior. So, they need more help and care to perform their day-to-day work. So many challenging situations appear in the last stage not only for the sufferer but also for their family members. The caregiver should be taken care of their movement, personal care, feeding, and every minute thing a person usually does in daily life. Obviously, the disturbances of memory and declining physical health are very distressing and are the reasons for bounding them to depend on somebody for their daily living. They become more aggressive, and many other deteriorated changes are observed in their physical and mental health, so that it has a great impact on withdrawal of social life as the sufferer feels demotivated due to change in social behavior and impairment in psychological and emotional control. Change in personalities and behavior affects a person’s functioning and also makes uncomfortable with familiar place and society. Although it is incurable, but to handle the patient carefully and to make easy their life, one should understand the disease properly, which is very necessary to the patient as well as their caregivers.

Science behind the scenario Incidence of neurodegenerative disease appears in the people with increasing age after their 60s, which is different from normal aging process. In the case of older individuals, loss of body’s function is accompanied by their physical activities and body metabolism, but forgetfulness and cognitive decline are seen in the later phase due to the seizing of growth and senescence of the nervous system (Duncan, 2011). Researchers have been trying to correlate all the hidden mechanisms and causes for which such fatal neurodegenerative diseases are rising their heads in society, particularly among older individuals. The insights are strongly influenced that there are two major causes of AD, environmental and genetic factors.

Age Aging is an inevitable process, which is accompanied by cognitive decline, leading to appear as a major risk factor to many neurodegenerative diseases (Yankner, Lu, & Loerch, 2008). Although symptoms of AD are totally different from the processes of normal aging, the appearance of this disease is seen in the people after attaining their 60s. Age-related issues can be increasing rapidly and affect different areas of the brain in this case, so that the patients are suffering from memory and cognitive dysfunction and physical activities are gradually slowing down that disrupts daily life. With increasing age, the

Lifestyle modifications and nutrition in Alzheimer's disease

brain cells and tissues shrink in their size and starts degrading which may lead to the development of AD (Dubois et al., 2010).

Family history Family history is another major factor involved in the increased risk of developing Alzheimer’s disease. Genes and disease history are playing important role in developing the disease. Although aging-associated deterioration in neural function is a common process, AD development has become the most common form of dementia among the elderly population. From the pathophysiological point of view, this is identified as the presence of senile plaques, NFTs, and hyperphosphorylated tau proteins. But from clinical consideration, it can be categorized into two types: early-onset AD (where the suffering people are shown with symptoms from 40 to 55 years old) and late-onset AD (where the people are showing symptoms after their 60s) (Braak & Braak, 1991). Similar to the genetic basis of other diseases, AD is associated with the involvement of several genes that form the protein, like amyloid beta and tau, the main culprits in its pathology (Bettens, Sleegers, & Van Broeckhoven, 2013). Once we look at the inheritance pattern of AD, it shows that the disease could penetrate in an age-dependent manner with autosomal dominant transmission characteristics. But it has been recorded that the criterion is true for only early-onset AD, which appears at the age of 40s. And for lateonset AD, which normally dominated the old-age people in their 60s, external factors like environmental interference and genetic interactions are the underlying mechanisms behind this disorder (Fitch, Becker, & Heller, 1988).

Oxidative stress Every cell in the living system that undergoes cellular stress has a cellular stress response mechanism to avoid damage and survive without altering its structure and function. Among various cellular stresses, oxidative stress has the most hazardous effect on organisms because it acts like the hidden enemy having slow poison in the cell. Balancing this stress with antioxidants is a very interesting mechanism to neutralize the harmful effects of stress. By studying the pathogenesis of AD, oxidative stress could lead us in a direction with full of evidence supporting that it should be one of the major causative agents in appearance of damages in aging brain. Harman (1956) formulated the free radical theory of aging, which suggests that the progressive cellular changes in aging are related to the accumulation of oxidative damages of biomolecules (Harman, 1956). Literatures are suggesting that the neural cells are more prone to the deteriorative effects of free radicals because the brain regions are having high oxygen consumption rate, are abundantly found in lipid content, and have relatable lower activity of antioxidant machineries than the other organs (Floyd & Hensley, 2002). Morphological and functional modifications are observed in neural cells and circuits in normal aging brains, which greatly affect

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neurotransmission, synaptic transmission, DNA fragmentation, structural abnormalities of dendrites, and metabolism, which can alter memory and cognitive function. Being an important risk factor for aging, there is also increasing vulnerability to oxidative damage in brain cells and communications of AD patients in old age (Hensley & Floyd, 2002). Oxidizing conditions with accumulations of free radicals are favorable in the formation of senile plaques through cross-linking and aggregation of amyloid proteins found in AD (Dyrks, Dyrks, Masters, & Beyreuther, 1993). Although Aβ peptide has antioxidant properties that fight against neuronal damage, it also shows prooxidant properties under certain conditions that may damage brain cells. The prooxidant property can be produced by this peptide when it is subjected to any kind of modifications like aggregation and cross-linking. In that case, it acts as the source of free radicals instead of antioxidants, leading cause of the increase in oxidative damages in neuronal cells. This mechanism in the aging brain is highly responsible for miscommunication of neurons and synaptic failure, decrement in useful metabolism, and homeostasis in the AD brain (Smith, Rottkamp, Nunomura, Raina, & Perry, 2000).

Apoptosis The programmed cell death or apoptosis is a crucial cellular mechanism that regulates the cell cycle by eliminating damaged or unwanted cells that fail to undergo the repair mechanism. Several researches regarding apoptosis suggest that functional impairment in mitochondria leads to the alternation of apoptosis signaling pathway by changing the mitochondrial membrane potential (Xiong, Mu, Wang, & Jiang, 2014). Loss of neural cells and anatomical changes in the brain are also contributed by elevated apoptosis in aging brain cells. Alternation in gene expression clearly defines the deterioration in the function of different tissues in different parts of the body during the aging process. Modulation of apoptotic genes regulates apoptosis in such a way that senescence and age-related diseases are triggered. The protected mechanism works like a critical function in many tissue systems where the loss of cellular function is due to cell death (Muradian & Schachtschabel, 2001). Apoptotic cell death of neurons is due to some cellular changes that induce this cell death; for example, the neurons exposed to β-amyloid plaques show programmed cell death (Smale, Nichols, Brady, Finch, & Horton, 1995). But some research shows controversial statements regarding neuronal cell death mediated by apoptosis in the aging brain and neuronal cell death in the AD brain. It is due to the absence of terminal phases of apoptosis in AD patients (Bancher, Lassmann, Breitschopf, & Jellinger, 1997). On the other hand, many literatures support the fact that apoptotic mechanism could lead to neuronal cell death in AD patients. Evidences of cleaving Aβ precursor protein by caspases are strongly supported in the literature (Raina et al., 2001).

Lifestyle modifications and nutrition in Alzheimer's disease

Molecular genetics Although the pathophysiology of AD is still under controversy, many advance researches reveal so many facts behind the mechanism of this neurodegenerative disorder. Genetic analysis of AD pathology provides information regarding various causatives associated with genes and gene products. The amyloid-beta precursor protein (APP) is a membrane protein that plays an important role in the growth and repair of nerve cells. The breakdown of this peptide and consequent accumulation in the brain cells may interfere with neural growth and communications, resulting in the degeneration of neural functions. Senile plaques are polymorphous beta-amyloid protein deposits derived from amyloid precursor protein (APP) residues and are found to be involved in the neurodegeneration of brain in AD patients. While people with trisomy in the same chromosome develop Down’s syndrome, it is very likely to get AD in the individuals who already have Down’s syndrome with advancing age. As they have that extra chromosome that encodes, APP is increasing the chance of getting mutation also. The most common sign of Down’s syndrome is intellectual disability, whereas in the case of AD, progressive deterioration of synaptic transmission, loss of neurons, and atrophy in brain cells are observed. So, it is very clear that in both cases, the individuals must experience mental retardation (Cohen, Head, & Lee, 2019; Gomez, Morales, Maracaja-Coutinho, Parra, & Nassif, 2020; Hartley et al., 2015). Like Aβ precursor molecules, NFTs are also responsible for disease formation. The presence of significant number of neurofibrillary tangles is directly proportional to neural dysfunction, which ultimately leads to Alzheimer’s dementia. The accumulation of abnormal twisted filaments (paired helical filaments), which results from hyperphosphorylation of tau protein, forms these NFTs in brain parts like dendrites, axons, and neuronal perikarya. Tau protein plays a key role in axoplasmic transmission and maintenance of neuronal shape by assembling the microtubules. Microtubule-associated protein tau (MAPT) gene encoding tau protein is involved in neuronal loss and injuries found in many neurodegenerative diseases including AD. Any abnormalities to this protein greatly affect neurons’ normal functioning by disintegrating microtubules and collapsing the neuronal communication system. Unlike amyloid-beta precursor protein, there is no evidence found that mutation in tau protein has been associated with formation in AD. But along with APP, mutation in presenilin 1 is the most common pathological condition in AD and carriers of these mutated individuals are very likely to develop the disease. In early-onset AD pathology, the most familial mutation is reported as presenilin 1 (PS1) found in chromosome number 14, which causes the elevation of amyloid-beta and is responsible for severe cerebellar pathology (Russo et al., 2000). Hence, on the basis of abundance in the brain cells of individuals with Aβ and tau protein, it can be said that these are the hallmarks of AD (Brion, 1998; Williams, 2006). Another significant genetic risk factor for AD pathogenesis is apolipoprotein E, specifically ApoEε4 that is located on chromosome 19. It enhances the Aβ

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deposition in brain cells, which ultimately produces senile plaques and causes disease pathogenesis (Poirier et al., 1993).

Chemistry, anatomy, and pathophysiology of the AD brain Neuroimaging is the most advanced and sophisticated technique emerging in the field of neuroscience and is a boon to identify and understand many neurodegenerative disorders. Many techniques are known to serve mankind in cases like computer-assisted tomography (CAT), functional magnetic resonance imaging (fMRI), positron emission tomography (PET scan), and single-photon emission computed tomography (SPECT) and are useful to study comparative anatomy and other physiological conditions of brain cells and neural connections. It made it easy to understand the changes adapted by the brain in normal aging and also suffering from any kind of neurodegenerative disorders. The different patterns of neuronal activities behind the function of the brain can be observed in different stages like from childhood to adulthood and from normal to diseased conditions. Changing brain structure like atrophy in cortical parts, reduced weight, and abundant presence of senile plaques and NFTs of tau protein in the hippocampal area are clearly observed, which discriminate the AD brain from the normal aging brain (Rossini, Rossi, Babiloni, & Polich, 2007). Looking into the anatomy of a normal aged brain and an AD brain, we found that the shrinkage of hippocampal areas is involved, atrophy of the cerebral cortex is observed in cognitive and memory function, while the fluid-filled space ventricles and sulci are enlarging (Fig. 2). All these changes appear in old age, but they can be highly affected in the case of AD leading to the deterioration of neuronal activities. Considering microscopic changes, a significant amount of evidence is reported, like structure of brain cells, depositions of amyloid plaques and neurofibrillary tangles, neuroinflammation, and synaptic and neuronal loss also seen in diseased brain. These abnormalities may lead to the loss of neuronal communications and a degraded or leaky blood-brain barrier that disrupts the internal environment in the brain (Newcombe et al., 2018) (Fig. 3). The APP undergoes proteolysis and produces the amyloid-beta (Aβ) protein. A rise in the levels of Aβ protein is observed in the brain when there is an overexpression of APP gene. This leads to the disruption of the calcium homeostasis, oxidative stress, and accumulation of Aβ (Querfurth & LaFerla, 2010). Another mechanism that might be responsible for the pathogenesis of AD is the disruption of neuronal autophagy, which is involved in causing an increase in the amount of endosomes and disturbing the endosomal lysosomal pathway, which in normal cells regulates APP processing and cellular maintenance (Boland et al., 2008). The high amount of Aβ causes the proteins to form oligomers from the monomers, which are normally produced. The accumulation leads to fibril formation, which further forms the senile plaques. This rise in amount of oligomers

Lifestyle modifications and nutrition in Alzheimer's disease

Fig. 2 Major anatomical changes in the brain during different stages of Alzheimer’s disease. The accumulation of neurofibrillary tangles or amyloid plaques increases during the progression of AD (from mild to severe stage), eventually destroying neurons and many other areas of the brain, specifically the hippocampus and brain ventricles. With increasing severity of AD, abnormal enlargement of brain ventricles as well as shrinkage of the hippocampus takes place, resulting in memory loss, impaired reasoning, and thinking ability and various changes in behavior and personality or cognitive declination.

is responsible for neural toxicity and degeneration (Martorana et al., 2015). The concentration of the Aβ protein is maintained in the normal brain by a balanced generation and clearance of the protein, whereas in patients suffering from AD, abnormalities are observed in the Aβ clearance, which lead to its accumulation in the brain (Wang, Dickson, & Malter, 2006). The abnormal amounts of Aβ in the brain are also due to a decrease in the expression of the LRP-1 receptor, which is the lipoprotein receptor-related protein 1. In normal brain, this receptor mediates the passage of Aβ to the blood from the brain by interacting with p-glycoproteins (Sanabria-Castro, Alvarado-Echeverrı´a, & Monge-Bonilla, 2017). Aβ protein undergoes proteolytic degradation with the help of insulin-degrading enzyme (IDE) and neprilysin (NEP), the concentration of both of which is reduced in the aging brain and causes the accumulation of Aβ in the brain (Miners, Baig, Tayler, Kehoe, & Love, 2009). Certain kinases like GSK3-β get activated by the Aβ proteins. The GSK3-β catalyzes the hyperphosphorylation of tau proteins, which form the NFTs (Blurton-Jones &

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Fig. 3 Pathophysiological changes in neurons and neural communications in Alzheimer’s disease. Aggregation of beta-amyloid plaques and neurofibrillary tangles leads to severe damage to neurons including demyelination of nerve fibers, loss of communication, as well as impairment of the blood-brain barrier (BBB), followed by disruption of tight junctions. These alterations ultimately result in the loss of various signals, especially between feet of astrocytes and pericytes in BBB, eventually deteriorating the nervous tissue and cognitive deficits.

LaFerla, 2006). The hyperphosphorylated tau proteins aggregate with the cytoskeletal protein, which results in the malfunctioning of the axonal transport (Rafii & Aisen, 2009). Oxidative stress is another major characteristic of the brain of an affected AD patient. By the activation of the NMDA receptors, Aβ protein accumulations induce the formation of reactive oxygen species, which disturb the level of antioxidants in the brain and cause free radical damage (Makhaeva et al., 2015). Oxidative stress is also the cause of metabolic abnormalities, reduced energy production, and membrane potential loss in the neuronal mitochondria, which are observed in the AD brain (Zhu et al., 2006). Calcium homeostasis is also disrupted in AD. The neurons cannot properly regulate the influx and efflux of calcium ions, which results in excitotoxicity, calcium channel deregulation, and mitochondrial abnormalities. These compromises are due to Aβ

Lifestyle modifications and nutrition in Alzheimer's disease

protein accumulation, age-related oxidative stress, and mutations in the presenilin gene (Green, Smith, & Laferla, 2007). Other than APP, genes associated with AD are presenilin 1 (PSEN1) and presenilin 2 (PSEN2) mutations, which are responsible for 80% and 5% of the total cases respectively (Calero et al., 2015). Genetic factors like apolipoprotein E (APOE) (Wang et al., 2018) and Sortilin-related receptor (SORL1) (Young et al., 2015) along with host factors like diabetes, obesity, and hypertension are also related to late-onset AD (Soldner & Jaenisch, 2015).

Epidemiology of AD The appearance of this particular neurodegenerative disease was more than 100 years ago, and the scenario of the world suffering from AD is increasing with time. According to the current research from Alzheimer’s Association Report, 2021, it is reported that the number of patients is growing very fast in the American population. Some highlighted points are as follows: • About 6.2 million Americans are living with AD at the age of 65 and older than that. • One in nine people is suffering from AD at the age of 65 and more. • Life expectancy can be a maximum of 10 years after the appearance of the disease if proper care would be given to the patients. • Approximately two-thirds of the Americans patients are females detected with AD. One can easily understand the growth of neurodegenerative disorders in the population of old-age groups. The prevalence of AD has been reported as more in females than that in male individuals (Alzheimer’s Association Report, 2020). Research suggests that this difference comes due to variation in genetic constituents, which increases susceptibility to the disease pathology. Genetic risk factor ApoE-ε4 genotype, which has the capacity to cause disease by associating with Aβ-binding motifs, may have some influencing activity with the female sex hormones after a particular age (Riedel, Thompson, & Brinton, 2016).

Diagnostic approach To fight against any disease, detection should be must to understand it and recognize the person suffered from. This is a progressive neurodegenerative disorder, which appears in older individuals. Hence, diagnostic tool should be used to differentiate the signs and symptoms of early-onset AD from normal aging, so that from the very beginning, patient would be getting proper treatment and care. There is no such particular diagnostic tool present, which can exactly detect the disease accurately. But the advancement achieved by science with the help of neuroimaging and neurophysiological techniques makes this

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possible to diagnose the fatal neurodegenerative diseases earlier. Biomarkers of this disease like amyloid plaques, neurofibrillary tangles, and CSF are used to add diagnostic accuracy. In the case of AD, hippocampal region is greatly damaged, which is responsible for learning and memory; in particular, episodic memory is lost during the course of disease progression. This can be visible from the neuroimaging results of CT scan, SPECT, fMRI, and PET scan. Neuropathology also reveals the condition of damage caused from the disease by observing the degree of Aβ deposition in different regions of the brain. Another important approach could be the assays detecting mitochondrial abnormalities due to oxidative stress and damage from free radicals ( Jakob-Roetne & Jacobsen, 2009). Along with standard tests like blood and urine tests to detect dementia and neurophysiological tests like brain scan to detect any damage or abnormalities, it is also essential to do psychological tests to confirm AD pathology.

Therapeutic strategies for AD In this advanced era, medical science developed several strategies to keep mankind disease-free or cure them from painful experiences. But there is no such particular and permanent treatment available against AD; rather, some medications and therapies are present and the most important thing is to handle the patients with extreme love and care. Antiamyloid deposition agents are beneficial in the prevention of Aβ deposition and lowering the formation of amyloid plaques. Proteolytic cleavage of APP results in Aβ42 by β-secretase, so to lower this cleavage effect, targeting drug should act against the enzyme β-secretase. Multiple compounds are available to act as tau aggregation inhibitors or interfere with tau phosphorylation, which are important drug delivery mechanisms that could protect neurons by preventing the formation of NFTs (Yiannopoulou & Papageorgiou, 2013). The caregiver should have patience and help them memorize the things, maintain their daily lives, and not feel alone or embrace due to anxieties and forgetfulness. Apart from this, exercise and meditations can be helpful to fight against loss of memory and cognitive functions (Citron, 2010; Jakob-Roetne & Jacobsen, 2009).

Therapies targeting amyloid-β The accumulation of amyloid-β (Aβ) protein in the brain is one of the major hallmarks of AD, and for years, this has been the key target for the therapies. Some therapies aim at reducing the generation of Aβ proteins, whereas others aim to increase its clearance. Β-site APP-cleaving enzyme 1 or the BACE1 inhibitors have been developed, which can reduce the amount of Aβ produced in the brain (May et al., 2015). γ-secretase inhibitors are also being developed, which aim to reduce the amount of Aβ in the brain (Dovey et al., 2001). Active and passive vaccine-based immunotherapies are also being used as

Lifestyle modifications and nutrition in Alzheimer's disease

therapeutic approaches in AD. A big challenge that this approach faces is the autoimmune responses that are generated. These vaccines aim to help accelerate the clearance of the Aβ aggregates in the brain (Bachurin, Bovina, & Ustyugov, 2017). Gantenerumab, crenezumab, and aducanumab are antibodies that target both aggregated and soluble Aβ proteins and are currently under trial (Cao, Hou, Ping, & Cai, 2018).

Therapies targeting tau proteins Tau proteins form NFTs in the brain and contribute to the pathophysiology of AD. Some therapies utilize tau stabilizers and inhibitors of tau aggregation, but the key challenge with using them is unwanted toxic side effects (Hung & Fu, 2017). Another type of therapy majorly targets the posttranslational modifications in tau proteins that are toxic in nature. They achieve this through the inhibition of the tau protein hyperphosphorylation kinases like GSK-3β and CDK5, by promoting the activity of PP2A, which is the dephosphorylation enzyme protein phosphate 2A, and also by manipulating the acetylation of tau proteins and their cis transformation ( Jia, Deng, & Qing, 2014; Pei, Bj€ orkdahl, Zhang, Zhou, & Winblad, 2008). One more type of therapy is called antitau immunotherapy, which with the help of high-affinity antibodies aims to reduce the uptake as well as the propagation of the abnormal tau proteins in the brain (Yanamandra et al., 2013). Passive immunization, which is targeted toward tau proteins, can help reduce the transcellular spread of tau proteins as well as increase its clearance in the AD brain.

Therapies targeting neuroinflammation and oxidative stress Neuroinflammation and microglial involvement amplify the neuronal damage in AD. Reducing the release and expression of cytokines, preventing the binding between cytokines and their receptors, and inhibiting the tau phosphorylation kinases can help reduce neuroinflammation (Green & Nolan, 2012; Von Bernhardi, Cornejo, Parada, & Eugenı´n, 2015). The usage of mitochondrial enhancers, inhibition of cyclooxygenase 2, etc., can restore the neuronal function and reduce oxidative stress in the brain (Hu, Ferreira, & Van Eldik, 1997).

Cell-based therapies The drugs that are currently available only provide relief from the symptoms temporarily. The attention has therefore shifted to stem cell-based therapies for curing AD. Stem cell transplantation has been proven to help in improving cognitive behavior in patients suffering from AD (Maler et al., 2006). Transplantation of MSCs helps reduce Aβ levels, improve neural microenvironment, and activate the endogenous microglia (Lee, Jin, & Bae, 2009). They also raise the levels of acetylcholine and release certain important growth factors in the brain (Park et al., 2013). NSCs help decrease cognitive decline, control tau

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protein and Aβ levels in the brain, and also promote neurogenesis (Lilja et al., 2015). The ESCs have the capability to form the neural precursor cells and can be used for cell replacement therapies. They can form cholinergic neurons and can even improve memory deficits (Bissonnette et al., 2011). The iPSCs also can be used to screen drugs for the disease and study the actions of novel compounds, which can be used to treat the disease.

Lifestyle: Way to healthy living Physical fitness Along with the modernization of society, lifestyle and daily habits are changed also to cope with it. This change is clearly visible within one decade among the people from developed as well as developing countries. Modern lifestyle basically focused on doing more and more works to keep continuing the race, the race of earning money, and better position in the growing society. Parallel with growth, their stress is also getting increased and affecting their physical and mental health state. Stress can lead to mental instability and affect daily routine works like loss of appetite, disrupting sleep patterns, and hypertension that directly influence neurodegeneration. So, we can say that these are the indications prior to disease and it is time to think about it and care about it. Including age and family history, one more risk factor can be taken into consideration, that is, cardiovascular disease (CVD). Because people with CVD are more likely to develop AD, interestingly, ApoEε4 involved in AD formation is also a significant risk factor for CVD. As the disease appears in old age, it affects mental health, and consequently, physical health also degrades with disease progression. So to keep a person healthy and more active, physical exercises and meditations are the natural and efficient methods to strengthen it. Physical exercises can enhance the blood flow to the brain and keep a person fit against early deterioration of physical activities, while meditation is a very good practice to improve memory and cognitive function (Bhatti, Reddy, Reddy, & Bhatti, 2020). Skeletal muscle function could be improved and, due to energy expenditure in such process, reduce the chance of deposition of bad cholesterol inside the body. Experimentally proven facts are there in favor of exercise that is really helpful in maintaining cognitive functions more efficiently (Kivipelto, Mangialasche, & Ngandu, 2018).

Say no to smoking and excessive drinking Keeping into mind the deteriorative effects of these diseases, it is very necessary to avoid any kind of addictions that are injurious to health like smoking and alcoholism. There is a strong evidence that excessive consumption of alcohol also declines neuronal activities and potential effect on damaging brain cells and communications. Alcoholic brain damage is not restricted to a small area; rather, it can affect the hippocampus, cerebellum, and brain stem and could block neural connections. Like that, smoking can cause high risk of

Lifestyle modifications and nutrition in Alzheimer's disease

cardiovascular diseases and also reduce cognitive performance (Carmelli, Swan, Reed, Schellenberg, & Christian, 1999). So, keeping away from these products could protect the person from its harmful effects and also decline the deteriorative effects of diseased condition.

Keep distance from depression Any disturbances to psychological state have a great impact on physical and mental health of a person. Social interactions and activities are reduced in this condition, and in severe cases, increasing agitation or aggressiveness will give rise to many health disorders like hypertension, cardiovascular diseases, and other depressive disorders. Ultimately, developing risk for AD is having a strong influence for disease causing in that person. These disturbances are creating certain a barrier between the person and his social relationships, which leads to the impairment in quality of life. Although it is not directly associated with the formation of the disease, it is definitely associated with anxiety- and stress-related pathophysiological conditions, which are directly connected with AD. Hence, it is recommendable to identify the reason behind the depression and consult with counselor or close friends or family, so that the problem can be eradicated easily without hampering any physical or mental health (Lyketsos & Olin, 2002).

A bit more care to strengthen them To live a healthy lifestyle, one cannot ignore social interactions and activities, because it is most important for his mental health. Family members, friends, and relatives are playing a key role in the person by making him happy, relaxing, encouraging, and supporting him to fight against the disease. Hence, people should understand the disease pathology properly, so that they could pay attention to the patient’s health and could easily deal with his changing behaviors. AD patients are most often encountered with anxiety and aggressive behaviors, are worried due to memory loss, are incapable of recognizing the persons and things very used to, and are unable to complete easy task in daily life and even their personal routine work also. In this miserable situation, the patient needs his family member or caregiver and also depends on them (Churchill et al., 2002; Hardy, 2006). Dietary intervention is an unavoidable thing in any respect to disease condition. The type of food we intake and the required nutrients and vitamins we get from that food are very necessary to select accordingly. Like that, in AD, nutrition taken by the person is carefully determined in such a way that they should be rich in antioxidants and essential vitamins. Because oxidative damages are very common in this neurodegenerative disorder and aging effect is the greatest known risk factor, the neutral effect of antioxidants is most helpful to protect DNA and neurons against the damage.

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Calorie restriction Calorie restriction (CR) is known as one of the potential improving metabolic rates by reducing the production of reactive oxygen species (Bhatti et al., 2020). CR has a significant role in neuroprotection, as it can neutralize oxidative stress and involve in some neurotrophic signaling mechanisms (Mattson, 2000). Along with this, CR has been reported with many other neuroprotective mechanisms like increasing the level of brain-derived neurotrophic factor, which enhances cognition and memory and lesion caused by amyloid plaques and NFTs (Duan et al., 2003). Considering the promising role of CR, it may be used as an important dietary intervention in the neuroprotection against chronic neurodegenerative disorders.

Nutritional interventions Vitamins and minerals Vitamins and minerals that add nutritional value are more essential and effective in building immunities. As neuronal damage could be best treated through antioxidant pathway, necessary vitamins could be included as vitamin E, vitamin C, and β-carotene and minerals like zinc, copper, and selenium are reported as preventing some of the damage caused by free radicals (Morris, 2009). These supplements not only fight against the free radicals but also have beneficial effect to prevent diseases like CVD, hypertension, and stress-related disorders (Bhatti et al., 2020).

Flavonoids Dietary polyphenols like flavonoids are plant-derived substances that act as neuroprotective in two ways. There is a wide range of availability of this particular compound such as in plant parts like leaves, flower, and fruits, and synthetic substance like wine also contains significant amount of flavonoids. They can be used directly as antioxidants or involved in antioxidant pathway by modulating the required enzymes, so that total antioxidant capacity will be increased in the blood plasma. Many forms of flavonoids could easily pass through the blood-brain barrier and protect the neurons from oxidative damages (Gutierrez-Merino et al., 2011). A number of studies are suggesting that the antioxidant properties of flavonoids are efficiently preventing the neuronal death that appears in AD condition (Airoldi, La Ferla, D’Orazio, Ciaramelli, & Palmioli, 2018; Ramassamy, 2006). According to abundant evidences available in favor of neuroprotective role of flavonoids, it should be taken in the diet to act against AD (Engelhart et al., 2002).

Turmeric In indigenous medicinal system, lots of plant materials are used to treat a wide range of diseases and they have proven as the best therapeutic values with no side effects. Among those medicinal plants, turmeric is one of the popular plants, which is used as a common spice in the kitchen and also has many medicinal properties. Curcumin is a natural compound found in turmeric and is believed to have antiinflammatory properties. Also, it is a

Lifestyle modifications and nutrition in Alzheimer's disease

well-known antioxidant, which can scavenge the nitric oxide free radicals and protect the brain cells against the harmful effects of lipid peroxidation (Martı´n-Arago´n, Benedı´, & Villar, 1997; Rao, 1997). In India, it is used in the diet on the daily basis, blessed with antiinflammatory, antiviral, antimicrobial, anticancer, and many more medicinal values, which may cause a low prevalence of AD in the Indian population. It has been seen that intake of food and appetite are reduced in adulthood, whereas excess intake gives rise to obesity and many other vascular diseases that also have negative effect on the life span of the individual. Consumption of food with less amount of saturated fat and trans-fat is reducing the risk of developing these diseases and therefore reduces the chance of oxidative stress, neuroinflammation, and amyloid deposition. As the appetite and digestive functions are declining with increasing age, dairy products and meats should be avoided in order for easy digestion, and to add natural antioxidants into the diet, vegetables and fruits should be prioritized (Barnard et al., 2014). While these diseases are directly correlated with cognitive decline and neurodegeneration, a bit of imbalance in diet will give rise to age-associated ailments, weaken the immunity, and make the body prone to infection with disease-causing agents (Pugazhenthi, Qin, & Reddy, 2017) (Fig. 4).

Fig. 4 Therapeutic strategies for Alzheimer’s disease. The pathophysiology and treatment of AD are not completely understood yet. However, recent studies have highlighted the importance of lifestyle modifications in addition to therapeutics during the course of the treatment of AD. Progressive treatment involves targeting of amyloid-beta plaques and neurofibrillary tangles. Lifestyle interventions including a healthy diet and physical activities have shown positive impact on the mental health of AD patients.

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Conclusion With the advancement of medical science and awareness among the people, life expectancy is also going to increase and the population of the old-age group survive a bit more. But people these days suffer from stress and anxiety disorder, which is very common, and AD is also seen in maximum population, which belongs to developed countries. This rapid prevalence of the disease and its fatality are totally unavoidable and garnered special attention in current research field. Because major population are suffering from this disorder and the number is increasing day by day, there is no permanent cure discovered till today. Understanding the disease pathology makes it somewhat easier to deal with it, and most importantly, a better understanding may lead you in the right direction in implementing all the necessary information. The gap between the underlying mechanism of disease pathology and its treatment is a matter of concern today. Hence, it is necessary to focus on lifestyle and nutritional interventions that may prevent the disease progression and further increase the patient’s survival. Physical exercise and fitness of the person could delay age-associated ailments, increase physical performance, and keep healthy also. Aerobic exercise and meditation have the capacity to struggle against neurodegenerative disorders. Also, one of the most promising approaches is nutritional intervention, to provide the required amount of energy and supplements for the perfection of metabolic activities, so that immunity of the body develops in proper way and reduces the risk of disease pathology. Cognitive declining process could be prevented by the intake of recommended diet, which is rich in antioxidants and immunity boosters. In-depth research is required to discover the targeting molecule, which can interfere with the molecular mechanism behind the disease pathology and prevent the disease progression. The combining strategy of indigenous medicine with extracting the particular bioactive compound, which has potential therapeutic value to fight against Alzheimer’s disease, may appear as a hope to fulfill the desire of overcoming this progressive neurodegenerative disease.

Applications to other neurological conditions The rise in number of cases and lack of effective therapies against various neurodegenerative disorders have been constrained to explore various nonpharmacological interventions for these life-threatening diseases. In this study, we found that the dietary and lifestyle intervention, including regular exercise, destressing (via meditation), intake of diet rich in vitamins and minerals, flavonoids as well as other natural products with antioxidative and antiinflammatory properties, have a positive impact on the pathophysiology of AD. Similar effects of these nonpharmacological interventions have been observed in other neurological conditions as well, such as dementia (Polidori, Nelles, & Pientka, 2010), depression ( Jacka et al., 2017; Kvam, Kleppe, Nordhus, & Hovland, 2016), Parkinson’s disease (Chromiec, Urbas, Jacko, & Kaczor, 2021; Gao et al., 2007; Gao,

Lifestyle modifications and nutrition in Alzheimer's disease

Cassidy, Schwarzschild, Rimm, & Ascherio, 2012), multiple sclerosis (Oken et al., 2004; Polidori et al., 2010; Weinstock-Guttman et al., 2005), and stroke (Ding, Ding, Li, Bessert, & Rafols, 2006). One of the important strategies that might have a potential to counteract neurological and cognitive disorders is exercise or physical activity. Regular exercise not only maintains the physical fitness, but also helps to overcome depression and anxiety as well as improves the quality of life. It has been demonstrated that aerobic exercise helps in improving the motor symptoms of Parkinson’s disease (Shu et al., 2014) as well as it protects against the oxidative damage and inflammation or brain injury in stroke (Austin, Ploughman, Glynn, & Corbett, 2014; Li, Geng, Huber, Stone, & Ding, 2020). Moreover, regular exercise enhances physical fitness and cognitive function, and it may also delay the onset of dementia (Heyn, Abreu, & Ottenbacher, 2004; Larson et al., 2006). Studies also support the fact that the intake of vitamins negatively correlates with the pathophysiology of Parkinson’s disease, multiple sclerosis, and epilepsy due to their antioxidative and immunomodulatory effects (Belcastro & Striano, 2012; Correale, Ysrraelit, & Gaitan, 2009; de Lau, Koudstaal, Witteman, Hofman, & Breteler, 2006; Moretti, Fraga, & Rodrigues, 2017; Schirinzi et al., 2019). Moreover, flavonoids including polyphenols and quercetin appear to be promising therapeutic agents in multiple sclerosis due to their remarkable antiinflammatory and immune-modulating effects (Sternberg et al., 2008). Similarly, quercetin improves cognitive deficit in Parkinson’s disease (El-Horany, El-Latif, ElBatsh, & Emam, 2016; Sriraksa et al., 2012). The polyphenol from green tea, that is, epigallocatechin gallate (EGCG), as well as curcumin (a polyphenol derived from turmeric), inhibits the aggregation of alpha-synuclein in Parkinson’s disease (Wang, Boddapati, Emadi, & Sierks, 2010; Xu et al., 2016). It has also been observed that polyphenols also alleviate cerebrovascular damages in the brain stroke model (Arcambal et al., 2020). In addition, various experimental studies in diseased models strongly support the therapeutic potential of curcumin due to its free radical scavenging and antiinflammatory activity. Seyedzadeh et al. demonstrated that curcumin exhibits neuroprotective effects against astrocyte-mediated inflammation in the pathogenesis of multiple sclerosis (Seyedzadeh et al., 2014). It is also highlighted that the intake of curcumin might reduce depression and anxiety or act as an antidepressant (Lopresti & Drummond, 2017). Altogether, it can be concluded that these dietary and lifestyle interventions might have a possible therapeutic impact against pathology of neurological disorders. However, further experimental studies in the near future are required to support their value in affected individuals.

Other components of interest A series of recent studies have indicated that the prevalence of AD has emerged as a crucial disorder with a higher risk of social burden. Despite progression in pathological

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hallmarks of AD Aβ-plaques and NFTs, frequent failures in drug development against this disease are the major issues. The utmost socioeconomic challenge is to search for a concrete outcome in finding the treatment of AD and reducing the incidence of this neurodegenerative disease. The current pharmacological approaches targeting the causal agents of AD pathology have many side effects including nausea, insomnia, confusion, drowsiness, blurred vision, and lower efficacy. Hence, the present research focuses on disease-modifying therapies for AD. The integrative effect of psychotropic medications and psychotherapy has also been observed in neurodegenerative diseases like dementia and other disorders. Nutritional interventions and lifestyle modifications are part of this disease-modifying therapeutic strategy, which will delay the onset of symptoms in oldage people (Cummings, Ritter, & Zhong, 2018). Dementia people also experience depression as a result of their loss of episodic memory. Trouble in their lifestyle causes them to be both aggressive and depressed. Exercise interventions including aerobic exercises, strength training, physical education classes, stretching exercises, yoga, qi gong, and tai chi are known to decrease depressive symptoms (Pascoe et al., 2020). One of the most vigorous nonpharmacological approaches well-investigated in the treatment of dementia is known as a cognitive intervention. Many experimental studies suggest the efficacy of this treatment against AD. Positive findings are there in research, which show improvement in retention of memory, language, and orientation in AD patients and reduced risk of the disease in old-age people (Zucchella et al., 2018). Sufficient data are not available in support of aromatherapy for AD or any dementia disorders, but kinds of the literature suggest that senile plaques are reduced with this therapy. Aromatherapy has a positive impact on enhancing cerebrovascular plasticity and neurogenesis ( Jimbo, Kimura, Taniguchi, Inoue, & Urakami, 2009). Several studies on reminiscence therapy in dementia care depict that it has a significant role in improving the quality of life. Improvement in cognitive functions through this therapy is still debatable, but at a long-term follow-up, the benefits are visible to a greater extent. During this therapy, previous events are constantly reminded by the psychiatrist and also handled by the caregiver. One of the psychotherapies enhances memory and eases the feeling of loneliness in AD patients (Woods, O’Philbin, Farrell, Spector, & Orrell, 2018).

Mini-dictionary Amyloid precursor protein. It is a transmembrane protein found in many tissues and organs, including the brain, and normally functions as a cell surface receptor. The cleavage of APP via β-secretase produces the Aβ peptide. Antioxidants. Compounds having the ability to remove free radicals/scavenging activity.

Lifestyle modifications and nutrition in Alzheimer's disease

Axoplasmic transmission. A process of movement of different cellular cargos to and fro neuron’s cell body. Aβ peptide. These are the neurotoxic peptides resulting from the cleavage of the amyloid precursor protein. Blood-brain barrier. The semipermeable membrane of endothelial cells, which acts as a border and regulates the movement of ions and various molecules between the brain and blood. Cholinergic neurons. Mostly located in subcortical regions and release a neurotransmitter acetylcholine (ACh). Excitotoxicity. The process of nerve cell damage and apoptosis mediated by excitatory amino acids such as L-glutamate and the subsequent influx of Ca2+. It is also known as “glutamate excitotoxicity.” Neurofibrillary tangles. Hyperphosphorylation of tau protein, resulting in the formation of protein aggregates or tangles.

Key facts • • • • •

The prevalence of AD is higher in females compared to males. AD is characterized by the formation of Aβ-plaques and NFTs that are responsible for the loss of synaptic communication. Under normal pathophysiological conditions, balance between generation and clearance of protein maintains the concentration of Aβ, while it is disturbed in AD. Inability of microtubules to bind with misfolded tau proteins leads to the formation of NFTs and subsequent cellular dysfunction in AD. BBB injury precedes the cognitive impairment and appearance of other neurodegenerative changes in AD.

Summary points • •

•

• •

Genetic, age-related, and various environmental risk factors are responsible for detrimental alterations in metabolic pathways resulting in AD pathogenesis. Various anatomical changes involving shrinkage of hippocampus and enlargement of sulci as well as pathophysiological changes such as disruption of BBB, demyelination, and loss of neuronal communication are the characteristics of AD pathology. For the prevention of AD, one must follow a multi-dimensional approach including pharmacological and nonpharmacological interventions such as lifestyle and dietary modifications. Early intervention of AD, at a stage where the brain has capacity of self-healing, might be a possible therapeutic strategy against AD. Amyloid biomarkers can also be used for the diagnosis and prognosis of AD.

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CHAPTER 3

The Gut microbiota and Alzheimer’s disease Mónica Morales, Daniel Cuervo-Zanatta*, Julieta Hernandez-Acosta, Marina Chacón, Vicente Sánchez-Valle, and Claudia Perez-Cruz

Department of Pharmacology, Center of Research and Advance Studies (Cinvestav) Av Instituto Polit
ecnico Nacional, M
exico City, Mexico

Abbreviations Aβ Abx AD ADAS-cog AHAD APP APP/PS1 APP/PS1–21 B. fragilis B. dorei C. clostridioforme CD11b CDR CSF COX-2 CXCL2 DAO DL-5-MTP DNA E. rectale FMT GF GLUT GM IL IPyA LEfSe LPS MCI mM

amyloid-beta antibiotic Alzheimer’s disease Alzheimer’s disease assessment scale-cognitive American Heart Association Diet amyloid precursor protein APPswe/PS1dE9 transgenic mice APPswe/PS1L166P transgenic mice Bacteroides fragilis Bacteroides dorei Clostridium clostridioforme cluster of differentiation molecule 11b clinical dementia rating cerebrospinal fluid cyclooxygenase 2 chemokine (C-X-C motif ) ligand 2 diamine oxidase 5-methoxy-DL-tryptophan deoxyribonucleic acid Eubacterium rectale fecal microbiota transfer germ-free glucose transporter gut microbiota interleukin indole-3-pyruvic acid linear discriminant analysis of effect size lipopolysaccharide mild cognitive impairment millimolar

* Current affiliation: School of Engineering, Ana´huac University, Rancho San Emigdio, Co´rdobaVeracruz, Mexico. Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00050-7

Copyright © 2023 Elsevier Inc. All rights reserved.

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Diet and nutrition in neurological disorders

MMKD MMSE MoCA MOS NF-κβ NLRP3 NLGF p65 P-gp PICRUSt pTau PS1 PS2 sCD14 SCFAs SPF Tg Th1 TNF t-RFLP WAIS WT yo YKL-40 3xTgAD 5xFAD mice 5-HTP

modified mediterranean-ketogenic diet mini-mental state examination montreal cognitive assessment mannan oligosaccharides nuclear factor κβ NOD-like receptor protein 3 Swedish, Iberian, Arctic mutations transcription factor p65 (RELA) P-glycoprotein phylogenetic investigation of communities by reconstruction of unobserved states Tau hyperphosphorylated Presenilin 1 Presenilin 2 Serum CD14 short-chain fatty acids specific-pathogen-free transgenic T-helper cells tumor necrosis factor terminal restriction fragment length polymorphism Wechsler Adult Intelligence Scale wild-type years old Chitinase 3-like 1 129-Psen1tm1Mpm Tg (APPswe, tauP301L)1Lfa/J transgenic mice K670N, M671L, I716V; PS1 M146L, L286V transgenic mice 5-hydroxytryptophan

What is Alzheimer’s disease? Alzheimer’s disease (AD) is a syndrome that principally affects older people, causing a chronic deterioration in memory, thinking, and behavior. Aging is the main risk factor to develop AD as the percentage of cases increases to 3% in people 65–74 years old (yo), to 17% in 75–84 age range, and 32% in people older than 85 yo (Hebert, Weuve, Scherr, & Evans, 2013). Two histological hallmarks define AD pathology: amyloid-beta (Aβ) peptide, aggregated into Aβ plaques, and tau hyperphosphorylation (pTau) that forms neurofibrillary tangles (Blennow, de Leon, & Zetterberg, 2006; Braak & Del Tredici, 2012; Hardy & Selkoe, 2002). Synaptic loss and neuroinflammation are also observed since early stages of the disease (Heneka et al., 2015). AD is a multifactorial condition with only 2%–4% of the cases of the familiar type, associated with protein mutations in the amyloid precursor protein (APP) and in the catalytic subunit of presenilin 1 and presenilin 2 (PS1 and PS2, respectively); the remaining 98% of the cases are of the sporadic type (Alzheimer Association, 2019). Sporadic AD is

Dysbiosis and neurodegenerative diseases

associated with several lifestyle factors, such as obesity, type 2 diabetes, metabolic syndrome, lack of early education, among others (Livingston et al., 2017). Currently, drugs approved for treating AD are only symptomatic, and most of pharmaceutical pipeline agents target the pathological hallmarks of the disease (i.e., Aβ plaques and pTau) (Cummings, Ritter, & Zhong, 2018). Unfortunately, most phase II and phase III clinical trials have been canceled due to poor drug efficacy or adverse events (Aisen et al., 2020). Notwithstanding, new research has shed light into novel therapeutic targets, residing in the periphery. Decades ago, several reports documented the presence of gastrointestinal disorders (Chalzonitis & Rao, 2018), chronic low-grade inflammation (Brestoff & Artis, 2013), and recurrent and chronic infections as life-treating disorders associated with the onset of dementia (F€ ul€ op, Itzhaki, Balin, Miklossy, & Barron, 2018; Itzhaki et al., 2017; Sochocka, Zwoli
nska, & Leszek, 2017). The community of intestinal microorganisms is known as gut microbiota (GM), and its diversity and composition are essential in maintaining host health. Alteration in the composition of the GM is known as gut dysbiosis, associated with the development of several metabolic diseases (Cani, Bibiloni, Knauf, Neyrinck, & Delzenne, 2008; Cha´vez-Carbajal et al., 2020) and, most recently, with the development of AD.

Aging and the diversity of the Gut microbiota Aging is the main risk factor for AD. Aging is the biological process during which the body changes according to the accumulated years. During the first years of life, the intestinal community of a healthy infant is less complex than adults, and it is characterized by an increased abundance of Firmicutes and Actinobacteria (Hollister et al., 2015). Children show higher abundance of Bifidobacteria and Clostridia than adults, but this is not associated with infection. During the adolescent period, the GM changes slowly, decreasing the number of aerobic and facultative anaerobes, while increasing the anaerobic species (Hopkins, Sharp, & Macfarlane, 2002). In adulthood, Firmicutes is the predominant phylum (Claesson et al., 2011), and the taxa C. leptum and C. coccoides are increased compared to the lactating stage, whereas Bifidobacteria are decreased. Notably, Escherichia coli is highly abundant since the first years of life, and then, it decreases in adulthood and stabilizes in old age (Mariat et al., 2009). Aging alters the composition of GM, reaching a stabilization around 75–80 yo (Biagi et al., 2010), where the reduction in chewing capacity, the lower salivary function, and the loss of dentition limit the nutrient intake and therefore the microbial growth (Soenen, Rayner, Horowitz, & Jones, 2015). Elderly subjects (> 65 yo) showed a higher proportion of Bacteroides spp. than younger subjects. When comparing microbiota taxa between young adults, elders, and centenarians (>100 yo), the latest show a significantly less diverse microbiota than other groups. In centenarians, GM is characterized by higher amounts of Proteobacteria and Bacilli and decreased amounts of Clostridium cluster XIVa, which associates with increased amounts of pro-inflammatory cytokines in

43

44

Diet and nutrition in neurological disorders

plasma (interleukin (IL)-6 and IL-8) (Biagi et al., 2010), a condition also known as inflammaging (Franceschi & Campisi, 2014). Conversely, extreme longeval subjects (>105 yo) present overgrowth of several health-associated taxa, such as butyrate-producing bacteria, compared to elderly or adults, a condition that might be associated with a successful aging (Biagi et al., 2016). AD’s clinical onset is after 65 yo, when the GM turns more proinflammatory. Therefore, it is important to revise and critically analyze current literature of GM alterations in AD, in order to determine potential coincidences or discrepancies, to further validate GM dysbiosis as a clinical feature in AD patients.

Gut microbiota alterations as a risk factor of Alzheimer’s disease A decade ago, AD was considered a disease exclusively affecting the brain. However, challenging investigations have exposed the role of peripheric alterations in the onset of neurodegenerative diseases (Castillo et al., 2019). Low-grade inflammation has been widely reported in prodromal stages of AD (Brestoff & Artis, 2013). Notably, dysbiosis results in systemic inflammation (Larsen, 2017; Leite et al., 2017). GM alterations depend on the geographical location, diets, and habits from the specific population. In addition, differential results can rely on methodological variables. Therefore, here, we describe recent data on GM dysbiosis in AD and mild cognitive impairment (MCI) patients, with special emphasis on the possible factors that may affect the GM data (Tables 1 and 2). The first two reports about a dysbiotic microbiome in dementia or AD subjects came from Italy and United States, respectively. Pioneering work was made by Cattaneo et al. (2017) when they analyzed the abundance of selected bacterial taxa (Escherichia/Shigella, Pseudomonas aeruginosa, Eubacterium rectale, E. hallii, Faecalibacterium prausnitzii, and Bacteroides fragilis) in fecal samples of cognitively impaired subjects Aβ-positive (Amy +) or Aβnegative (Amy-) by positron emission tomography (PET) (average age of groups: 69 yo). Amy + subjects exhibited higher abundance of Escherichia/Shigella, which was positively correlated with plasma levels of IL-1β, chemokine (C-X-C motif ) ligand 2 (CXCL2), and NOD-like receptor protein 3 (NLRP3), all of which increase between 20% and 40% compared to controls, and compared to Amy- subjects. In addition, Amy + group exhibited less abundance of B. fragilis and E. rectale and showed greater tumor necrosis factor (TNF)α, but lesser IL-10 plasma levels (Cattaneo et al., 2017). Soon later, an American study analyzed the fecal GM composition by amplification of the variable region V4 amplicon of the bacterial 16S rRNA gene by high-throughput Illumina MiSeq platform, from AD patients and healthy controls fecal samples (average age of groups: 70 yo) (Vogt et al., 2017). AD subjects had lower GM diversity with a decreased abundance of Firmicutes and increased Bacteroidetes, compared to controls. In addition, AD patients showed lower Bifidobacterium abundance. CSF AD biomarkers (pTau and pTau/Aβ-42 in cerebrospinal fluid, CSF) correlated with a higher abundance of

Table 1 Gut microbiota alterations in Alzheimer’s patients.

Cattaneo et al. (2017)

Actinobacteria (P) Bifidobacteriaceae (f ) Adlercreutzia ( g) Bifidobacterium ( g) Adlercreutzia equolifaciens (s) Bacteroidetes (P) Bacteroidia (c) Bacteroidaceae (f ) Porphyromonadaceae (f ) Rikenellaceae (f ) Alistipes ( g) Bacteroides ( g) Barnesiella ( g) Odoribacter ( g) Parabacteroides ( g) Paraprevotella ( g) Bacteroides fragilis (s) Bacteroides vulgatus (s) (P) Firmicutes Bacilli (c) Negativicutes (c) Clostridiales (o) Lactobacillales (o) Clostridiaceae (f )

Vogt Zhuang et al. et al. (2017) (2018)

# # # #

"

"

#

"

# #

"

" " "

#

#

¼ " # #

Saji, Murotani, et al. (2019) (MCI)

" MCI # # AD

" "

#

" "

#

" #

* +

" # # #

# " #

Saji, Niida, Liu Li et al. et al. et al. (2019) (2019) (2019)

Nagpal, Neth, Wang, Craft, and Ling Wu Haran Yadav Stadlbauer et al. et al. et al. (2019) et al. (2020) (2021) (2021) CONSENSUS (2019) (MCI)

#

# # #

#

"

" " " "

"MCI

"

"

*

#

+

#

+

#

Continued

Table 1 Gut microbiota alterations in Alzheimer’s patients—cont’d

Cattaneo et al. (2017)

Gemellaceae (f ) Enterococcaceae (f ) Erysipelotrichaceae (f ) Lachnospiraceae (f ) Lactobacillaceae (f ) Mogibacteriaceae (f ) Peptostreptococcaceae (f ) Ruminococcaceae (f ) Turicibacteraceae (f ) Veillonellaceae (f ) Blautia ( g) Butyricicoccus ( g) Butyrivibrio ( g) Cc115 ( g) Clostridium ( g) Coprococcus ( g) Dialister ( g) Dorea ( g) Eisenbergiella ( g) Eubacterium ( g) Faecalibacterium ( g) Gemella ( g) Gemmiger ( g) Lachnoclostridium ( g) Lactobacillus (g)

Vogt Zhuang et al. et al. (2017) (2018)

"

# # # # "

Saji, Niida, Li Liu et al. et al. et al. (2019) (2019) (2019)

Saji, Murotani, et al. (2019) (MCI)

Nagpal, Neth, Wang, Craft, and Wu Ling Haran Yadav Stadlbauer et al. et al. et al. (2019) et al. (2020) (2021) (2021) CONSENSUS (2019) (MCI)

" # "

#

"

#

#

"

"

" MCI #

# # #

#

#

#

" # #

" #

"

#

+

#

+

#

#

# #

" " #

# # #

" # "

# # "

+ +

Romboutsia ( g) Roseburia ( g) Ruminococcus ( g) SMB53 ( g) Subdoligranulum ( g) Streptococcus ( g) Turicibacter ( g) Clostridium clostridioforme (s) Eubacterium eligens (s) Eubacterium hallii (s) Eubacterium rectale (s) # Faecalibacterium prausnitzii (s) Streptococcus salivarius (s) Proteobacteria (P) Gammaproteobacteria (c) Enterobacteriales (o) Enterobacteriaceae (f ) Sutterella ( g) Escherichia coli (s) " Klebsiella pneumoniae (s) Pseudomonas aeruginosa (s) " Verrucomicrobia (P) Coriobacteriaceae (f ) Corynebacteriaceae (f ) Verrucomicrobiaceae (f ) Akkermansia ( g) Eggerthella lenta ( g)

#

# "

#

#

#

# #

" "

# # # #

# "

" " " "

# "

"

" "

#

# " "

+

"

" " " " "

Gut microbiota differences between Alzheimer’s patients and control subjects. Increased (") or decreased (#) abundance of specific taxa in Alzheimer’s (AD) or mild cognitive impairment (MCI) patients compared to age-matched healthy controls according to the Reference. The last column showed a consensus when at least three studies report the same result (* increase; +, decrease).

Table 2 Gut microbiota alterations in transgenic mice of Alzheimer’s disease. Bonfili et al. (2017)

Acidobacteria (P) Koribacter (g) Actinobacteria (P) Actinomycetales (o) Bifidobacteriales (o) Actinomycetaceae (f ) Bifidobacteriaceae (f ) Coriobacteriaceae (f ) Actinomyces (g) Adlercreutzia (g) Enterorhabdus (g) Bifidobacterium (g) Bifidobacterium bifidum (s) Bacteroidetes (P) Bacteroidia (c) Bacteroidales (o) Bacteroidaceae (f ) Paraprevotellaceae (f ) Prevotellaceae (f ) Rikenellaceae (f ) S24-7 (f ) Alloprevotella (g) Bacteroides (g) Odoribacter (g) Parabacteroides (g) Paraprevotella (g)

Brandscheid et al. (2017)

Harach et al. (2017)

Shen Zhang et al. et al. (2017) (2017)

€uerl Ba et al. (2018)

Syeda et al. (2018)

Sun Chen et al. et al. (2019) (2020)

# # # # # # # #

" "

# #

# "

"

#

" "

# # #

"

" # # "

"

"

" " " "

" " "

"

CuervoZanatta et al. (2021)

Shukla et al. (2021)

CONSENSUS

"

" " "

# " # " #

# # "

+ *

Prevotella (g) Rikenella (g) Rikenellaceae RC9 (g) Bacteroides fragilis (s) Bacteroides uniformis (s) Parabacteroides distasonis (s) Prevotella copri (s) Cyanobacteria (P) 4C0d-2 (c) YS2 (o) Deferribacteres (P) Mucispirillum (g) Mucispirillum schaedleri (s) Firmicutes (P) Bacilli (c) Clostridia (c) Erysipelotrichia (c) Mollicutes (c) Anaeroplasmatales (o) Bacillales (o) Clostridiales (o) Erysipelotrichales (o) Lactobacillales (o) Mycoplasmatales (o) RF39 (o) Turicibacterales (o) Acidaminococcaceae (f ) Aerococcaceae (f ) Anaeroplasmataceae (f ) Carnobacteriaceae (f ) Christensenellaceae (f ) Clostridiaceae (f )

"

#

# "

# # #

#

# #

# #

#

"

#

# #

" # "

#

+

#

#

# # "

"

# " #

#

#

#

#

# # # " #

#

" # " # #

# " Continued

Table 2 Gut microbiota alterations in transgenic mice of Alzheimer’s disease—cont’d Bonfili et al. (2017)

Enterococcaceae (f ) Erysipelotrichaceae (f ) Lachnospiraceae (f ) Lactobacillaceae (f ) Mogibacteriaceae (f ) Mycoplasmataceae (f ) Peptostreptococcaceae (f ) Ruminococcaceae (f ) Staphylococcaceae (f ) Streptococcaceae (f ) Turicibacteraceae (f ) Aerococcus (g) Allobaculum (g) Anaeroplasma (g) Anaerostipes (g) Anaerotruncus (g) Blautia (g) Butyricicoccus (g) Butyrivibrio (g) Clostridium (g) Coprobacillus (g) Coprococcus (g) Dorea (g) Enterococcus (g) Erysipelatoclostridium (g) Eubacterium (g)

"

Brandscheid et al. (2017)

Harach et al. (2017)

Zhang Shen et al. et al. (2017) (2017)

# #

€uerl Ba et al. (2018)

#

" # " " " # #

# "

Chen Sun et al. et al. (2019) (2020)

CuervoZanatta et al. (2021)

# # #

"

# "

" #

#

# #

"

#

"

#

# #

"

# #

" "

Syeda et al. (2018)

# " # # "

# #

#

" " # " "

Shukla et al. (2021)

CONSENSUS

+ +

*

*

Fusibacter (g) Gemella (g) Granulicatella (g) Jeotgalicoccus (g) Lachnobacterium (g) Lachnoclostridium (g) Lactobacillus (g) Lactococcus (g) Marvinbryantia (g) Mycoplasma (g) Oscillospira (g) Phascolarctobacterium (g) Roseburia (g) Ruminiclostridium (g) Ruminococcus (g) SMB53 (g) Staphylococcus (g) Streptococcus (g) Turicibacter (g) Tyzzerella (g) Bacillus AF12 (s) Butyricicoccus pullicaecorum (s) Clostridium leptum (s) Clostridium saccharogumia (s) Coprococcus catus (s) Dorea formicigenerans (s) Eubacterium biforme (s) Faecalibacterium prausnitzii (s) Lactobacillus reuteri (s) Lactobacillus ruminis (s) Roseburia faecis (s) Ruminococcus bromii (s)

"

# # #

#

# #

"

" #

#

# # # "

#

#

"

" #

#

#

#

" "

#

#

" "

" #

#

# "

+

"

*

# # " " # # " " # Continued

Table 2 Gut microbiota alterations in transgenic mice of Alzheimer’s disease—cont’d Bonfili et al. (2017)

Ruminococcus callidus (s) Ruminococcus flavefaciens (s) Streptococcus anginosus (s) Fusobacteria (P) Fusobacteria (c) Fusobacteriales (o) Fusobacteriaceae (f ) Psychrilyobacter (g) Nitrospira (g) Proteobacteria (P) Alphaproteobacteria (c) Betaproteobacteria (c) Deltaproteobacteria (c) Burkholderiales (o) Desulfovibrionales (o) RF32 (o) Vibrionales (o) Alcaligenaceae (f ) Desulfovibrionaceae (f ) Enterobacteriaceae (f ) Helicobacteraceae (f ) Sphingomonadaceae (f ) Vibrionaceae (f ) Bilophila (g) Desulfovibrio (g) Escherichia (g)

Brandscheid et al. (2017)

Harach et al. (2017)

Zhang Shen et al. et al. (2017) (2017)

€uerl Ba et al. (2018)

Syeda et al. (2018)

# # "

"

"

"

"

" " "

# #

"

#

"

Chen Sun et al. et al. (2019) (2020)

# # # # #

" " "

#

# # # # " #

"

# #

CuervoZanatta et al. (2021)

"

Shukla et al. (2021)

CONSENSUS

*

Flexispira (g) Helicobacter (g) Ignatzschineria (g) Klebsiella (g) Shigella (g) Sphingomonas (g) Sutterella (g) Variovorax (g) Vibrio (g) Actinobacillus parahaemolyticus (s) Desulfovibrio C21c20 (s) Escherichia coli (s) Haemophilus parainfluenzae (s) Helicobacter apodemus (s) Tenericutes (P) TM7 (P) TM7-3 (c) CW040 (o) F16 (f ) Verrucomicrobia (P) Verrucomicrobiaceae (f ) Akkermansia (g) Akkermansia muciniphila (s)

"

"

" "

#

# "

" " "

" "

"

"

#

"

"

# # # # #

"

#

# # #

#

# #

+

" " "

Gut microbiota differences in transgenic mouse models of Alzheimer’s disease. Increased (") or decreased (#) abundance of specific taxa in Tg mouse models compared to age-matched WT controls according to the reference. Data were taken from studies when Tg mice showed a mild-to-moderate brain pathology (APP/PS1, 3xTgAD, 5xFAD, or P301L mice, aged 2–6 months, 4–12 months, 2–6 months, or 3–6 months, respectively). The ast column showed a consensus when at least three studies report the same trend (*, increase; +, decrease).

54

Diet and nutrition in neurological disorders

Bacteroides and Blautia, but a negative correlation with SMB53 and Dialister was found in AD subjects. A positive relationship of KL-40, a marker of astroglial and/or microglial activation, with increased abundance of Bacteroides and decreased abundance of Turicibacter and SMB53 was also found. Of note, 40% of participants included in the AD group had clinical dementia rating (CDR) scores of 0.5, classified as MCI by other authors (Liu et al., 2019; Saji, Murotani, et al., 2019). Contrary to this study, a Chinese cohort of AD patients with moderate-to-severe dementia according to cognitive test scores (average age of groups: 69 yo) reported rather a significant decrease in Bacteroidetes and significant increase in Actinobacteria and Ruminococcaceae abundance, but a decreased Lachnospiraceae compared to age-matched controls. It is worth highlighting that this study was based on terminal restriction fragment length polymorphism (t-RFLP) analysis, instead of massive sequence of the 16S rRNA gene (Zhuang et al., 2018). In a larger cohort of Chinese AD patients, Ling et al. (2021) aimed to discriminate the principal bacteria taxa associated with dementia cases (average age of groups: 74 yo). Those authors corroborated that AD patients present a lower GM diversity compared to agematched controls. A decreased Firmicutes abundance (but no change in Bacteroidetes) was determined in AD samples, and linear discriminant analysis of effect size (LEfSe) revealed several differential taxa associated with AD, as Faecalibacterium, Roseburia, C. sensu stricto, Gemmiger, Dialister, Romboutsia, Coprococcus, and Butyricicoccus were reduced compared to the control group. Correlation analysis further determined that cognitive scores and cytokine levels effectively discriminate AD from the control group, as Bifidobacterium abundance correlated with lower cognitive scores, but Faecalibacterium with higher scores (Ling et al., 2021). Increased abundance of Bifidobacterium has also been reported in other Chinese cohorts (Li et al., 2019; Saji, Niida, et al., 2019), but it was decreased in an American study (Vogt et al., 2017). A small pilot study, ran in Europe, evaluated whether dietary factors can be potentially related to GM composition and cognition in AD and cognitively healthy subjects (average age of groups: 81 yo) (Stadlbauer et al., 2020). Notably, more females were included in both groups and four subjects in the AD group were diagnosed with mixed dementia. Malnutrition was present in 74% of dementia patients, who also showed higher diamine oxidase (DAO) and soluble form of cluster of differentiation 14 (sCD14) levels, suggesting an increased gut permeability and endotoxin load. There were no changes in GM diversity, but at species level, Clostridium clostridioforme, Anaerostipes hadrus, and B. dorei were associated with dementia. In addition, L. NK4A136 and E. rectale were less abundant in dementia patients, similar to previous reports by Cattaneo et al. (2017). In an attempt to identify well-being associated factors, such as malnutrition, medications, and GM as predictors of AD, a longitudinal study (for 5 months) was run in a large cohort of American patients with AD dementia, no-AD dementia, and control subjects (average age of groups: 84 yo). Shotgun metagenomics and mixed modeling for GM analysis were used. AD patients’ microbiome showed an increased proportion of

Dysbiosis and neurodegenerative diseases

Bacteroides, Alistipes, Odoribacter, and Barnesiella and decreased proportions of Lachnoclostridium than nondemented elders. Frailty and malnutrition scores were determined as good predictors of dementia. In vitro intestinal epithelial cell functional assays of P-glycoprotein (P-gp) showed a dysregulation when T84 intestinal epithelial cells were incubated with supernatant from AD stool samples, compared to supernatant from cognitive healthy controls (Haran et al., 2019). Thus, the authors argue that malnutrition and GM composition may disrupt gut barrier permeability, leading to increased inflammatory status in aged AD patients. Unlike other studies (i.e., Liu et al., 2019; Vogt et al., 2017; Zhuang et al., 2018), patients with comorbidities such as immune compromise or chronic kidney disease were included. MCI is the prodromal stage of AD, with slight cognitive dysfunctions 8 to 10 years before the onset of dementia (Mistridis, Krumm, Monsch, Berres, & Taylor, 2015). Among MCI complainers, 10%–15% will develop dementia, annually (Ganguli et al., 2010). Thus, it could be expected that alterations in GM could begin years before the clinical onset of dementia. Li et al. (2019) attempted to differentiate fecal and blood microbiota between control, MCI, and AD subjects (average age of groups: 64 yo). They found that diversity indexes were similar between groups. However, in blood samples, a lower Chao1, observed species, and Shannon indexes were seen in AD subjects compared to controls. Furthermore, lower Bacteroides but higher Escherichia and Lactobacillus abundances were seen in fecal samples of AD and MCI compared to controls. A greater abundance of Akkermansia positively correlated with medial temporal atrophy in MCI and AD patients, while a relative abundance of Fusicatenibacter, Blautia, and Dorea associated with lower mini-mental state examination (MMSE) scores. Contrarily, Faecalibacterium, Butyricicoccus, and Hungatella abundances were related to higher MMSE. Finally, Megamonas enrichment was positively correlated with a longer duration of the disease (Li et al., 2019). Further evidence indicates that GM alterations associate with disease severity. In a Chinese cohort, Liu et al. (2019) showed that AD patients had a gradual enrichment of Proteobacteria compared to MCI and control subjects (19.48%, 5.86%, 4.66% relative abundances, respectively) (average age of groups: 73 yo). Discrimination models based on the predominant microbiota showed that Enterobacteriaceae abundance accurately distinguishes AD patients from MCI and controls (Liu et al., 2019). In another study, Saji et al. (Saji, Murotani, et al., 2019; Saji, Niida, et al., 2019) assessed GM alterations in MCI subjects without dementia and controls by the use of t-RFLP analysis. There was a higher prevalence of Bacteroides in the MCI group than in controls (average age of groups: 73 yo), and GM dysbiosis correlated with lower global cognitive function and impaired memory dysfunction (Saji, Murotani, et al., 2019). However, in a larger study with dementia patients, the same research group report a lower Bacteroides abundance in the dementia group compared to the non-dementia group (average age of groups: 76 yo) (Saji, Niida, et al., 2019). These two studies used t-RFLP, and the groups were segregated by bacteria enterotypes, with a lower discrimination at specific taxa.

55

56

Diet and nutrition in neurological disorders

A step further to understand the impact of gut dysbiosis on mental function was achieved by Wu et al. (2021). In a Chinese cohort, they analyzed GM metabolites in AD and MCI patients (average age of groups: 72 yo). They observed a metabolic dysregulation in pathways such as tryptophan, short-chain fatty acids (SCFAs), and bile acids, with an increase in indole-3-pyruvic acid (IPYA) and a decrease in formic, acetic, propionic, butyric, methylbutyric, and isovaleric acids already in MCI patients. Decreased levels of short-chain fatty acids (SCFAs) and 5-hydroxytryptophan (5-HTP) were associated with greater cognitive and functional impairment. In contrast, IPYA showed a progressive increase from controls to MCI and AD, which was associated with lower Montreal Cognitive Assessment (MoCA) scores. Based on predictive models, these authors suggest the use of IPYA, formic acid, acetic acid, propanoic acid, methylbutyric acid, and isovaleric acid as potential biomarkers to discriminate MCI and AD stages from a healthy status (Wu et al., 2021). A cutting-edge Chinese study evaluated T-helper (Th1) cell expression in blood samples of subjects with MCI due to AD and age-matched controls (Wang et al., 2019). Serum phenylalanine and isoleucine concentrations, as well as peripheral Th1 cell frequency in the blood were significantly higher in MCI than in age-matched controls. Sodium oligomannate (GV-971), a compound whose mechanism of action is through the modulation of the GM composition, was able to reduce the phenylalanine/isoleucine blood accumulation and to reverse the cognitive impairment in AD patients (Xiao et al., 2021). This body of data suggests that a dysbiotic microbiome may cause a higher gut permeability and a pro-inflammatory status, both events associated with a chronic low-grade systemic and central inflammation. Despite the methodological differences among human studies, we can conclude that gut dysbiosis is a feature of MCI and AD patients, with a gradual progression along disease severity.

Transgenic mouse models of Alzheimer’s disease and the bacteria-Gutbrain axis Animals have been used for decades to understand the functioning of the brain. Transgenic (Tg) mice expressing disease-related genes of human neurodegenerative conditions have been widely used in the pharmaceutical industry for preclinical screening and target validation studies. Tg mice overexpressing human genes associated with familiar AD develop memory impairment, Aβ plaques, hyperphosphorylation of tau, and neuroinflammation (Esquerda-Canals, Montoliu-Gaya, G€ uell-Bosch, & Villegas, 2017). Since the first description of GM alterations in dementia and AD patients (Cattaneo et al., 2017; Vogt et al., 2017), tens of studies have persistently described GM alterations in Tg-AD mice. Moreover, Tg mice enable the prevention or reduction of AD pathology through GM modulation. Specific-pathogen-free (SPF), germ-free (GF), or antibiotic (Abx)-treated mice have revealed important information to understand the interaction

Dysbiosis and neurodegenerative diseases

between bacteria residing in the gut and the functioning of the brain, or the bacteria-gutbrain axis. APPswe/PS1dE9 Tg (APP/PS1) mice develop age-related cognitive impairment and brain amyloidosis and a decreased microbiota diversity with aging. However, increased Prevotellaceae, Helicobacteraceae, Desulfovibrionaceae, and Odoribacter, and reduced Ruminococcus abundances are seen in APP/PS1 mice compared to wild-type (WT) controls along aging (Shen, Liu, & Ji, 2017). In a more aggressive mouse line, the 5xFAD mice (APP: K670N, M671L, I716V; PS1 M146L, L286V), a prevalence of Bacteroidetes over Firmicutes was reported in 5- and 15-month-old mice compared to controls (Shukla et al., 2021). A higher bacterial diversity in APP/PS1 mice, composed by a predominance of Bacteroides, was seen during the ontogeny, but at 6 months of age, a higher abundance of Proteobacteria was observed compared to control mice. A small number of animals per age-group (n ¼ 3) and the use of C57BL/6 mice as control group must be taken into account (B€auerl, Collado, Diaz Cuevas, Vin˜a, & P
erez Martı´nez, 2018). A higher fecal microbiota richness in 5–6-month-old SPF-APP/PS1 mice, but a reduced Shannon index in 8–12-month-old mice were reported compared to SPFWT littermates. Also, the Firmicutes/Bacteroidetes ratio varied along aging, Actinobacteria and Deferribacteres were reduced in both groups, but Verrucomicrobia was increased in SPF-APP/PS1 compared to SPF-WT mice with aging. Similar to human reports (i.e., Vogt et al., 2017), Proteobacteria abundance was doubled in SPF-APP/ PS1 mice at 5–6 months of age, but at a later time point (8–12 months old), Ruminococcus and Butyricicoccus were significantly reduced compared to their WT littermates. It is known that dietary fiber is fermented by some bacteria in the gut releasing SCFAs into circulation. Acetate, propionate, and butyrate are the most abundant SCFAs with important effects on host health, with butyrate being a potent anti-inflammatory agent (Vinolo, Rodrigues, Nachbar, & Curi, 2011). Zhang et al. (2017) analyzed the levels of SCFAs in fecal and brain samples of SPF-APP/PS1 mice along the ontogeny. Lower butyrate concentrations were observed in SPF-APP/PS1 mice compared to the control group (Zhang et al., 2017). In 3xTgAD mice, a gradual reduction in butyrate and an increase in propionate were seen in 3-, 6-, and 11-month-old mice compared to WT controls (Syeda et al., 2018). Propionate potentiates inflammation and reactive astrogliosis in the brain (MacFabe et al., 2007). In this regard, abnormally elevated expression of NOD-like receptor protein 3 (NLRP3) in the intestine of 5xFAD mice correlated with enhanced IL-1b levels in the gut. Moreover, increased astrogliosis and microglial activation are associated with an enhanced NLRP3 inflammasome and IL-1β brain’s production in 5xFAD mice compared to controls (Shukla et al., 2021). Therefore, propionate has been suggested as an important neurotoxic bacterial product (Syeda et al., 2018). Aggregation of Aβ may develop in organs that are constantly exposed to microorganisms, such as the intestine. In 5xFAD mice, a strong Aβ aggregation is detected in duodenum, jejune, and cecum, in parallel to GM dysbiosis already from the 9th week of age.

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Aβ aggregation associates with an increased Firmicutes/Bacteroides ratio compared to the WT group (Brandscheid et al., 2017). A seminal work by Harach et al. (2017) demonstrated a direct communication between gut bacteria and Aβ aggregation. They first proved GM dysbiosis in 8 months of APP/PS1–21 mice (KM670/671NL Swedish/ L166P) with a higher alpha diversity and reduced Firmicutes/Bacteroides ratio than age-matched WT controls. GF-APP/PS1 mice showed a reduced brain amyloidosis compared to native APP/PS1 mice. Fecal microbiota transfer (FMT) from 12-month-old APP/PS1 mice induced a stronger amyloidosis similar to conventional raised APP/PS1 mice. Brain Aβ aggregation was associated with higher abundance of Parabacteroides, Akkermansia, Pseudomonas, Odoribacter, Anaerofustis, Mogibacteriaceae spp., and Xanthomonadaceae in fecal samples (Harach et al., 2017). Other studies employed broad-spectrum Abx treatment to reduce bacterial diversity (Ianiro, Tilg, & Gasbarrini, 2016) and explored its impact on brain amyloidosis. Reduced brain Aβ deposition and increased soluble Aβ peptide levels were seen in Abx-APP/PS1 mice compared to the non-Abx-treated group (Minter et al., 2016). Moreover, early post-natal (P14-P21) Abx treatment induced permanent microbiota alterations with reductions in brain Aβ deposition in aged APP/PS1 mice (Minter et al., 2017). If GM depletion and FMT ameliorate AD pathology in Tg-AD mice, it may also have an impact in cognitive functions. Sun et al. (2019) evaluated the cognitive effect of FMT from WT mice to APP/PS1 mice. Daily intragastric FMT from WT mice to APP/PS1 mice (both groups, 6 months old) for four weeks effectively attenuated spatial learning impairments and improved recognition memory. In addition, soluble Aβ peptides (1–40 and 1–42) were reduced in brain samples of FMT-treated APP/PS1 mice. GM analysis showed that the abundance of Proteobacteria, Verrucomicrobia, Akkermansia, and Desulfovibrio was decreased, while Bacteroidetes were increased in the FMT-treated mice, restoring GM to WT values. GM restoration increased butyrate concentration in fecal samples and reduced pTau231 in brain samples of APP/PS1 mice. Kim et al. (2019) demonstrated that long-term FMT of WT to ADLPAPT mice (daily for 4 months) reduced Aβ and tau pathology, neuroinflammation, and intestinal macrophage activity to WT levels. Gut permeability and short-term memory were both rescued in FMT-ADLPAPT mice. However, the beneficial effects of FMT were correlated with Aβ, but not with taurelated pathology. Moreover, in contrast to previous reports, Abx treatment did not reduce Aβ aggregation or tau pathology in ADLPAPT mice (Kim et al., 2019). Dodiya et al. (2019) treated APP/PS1–21 mice (APPswe/PS1L166P, which develop Aβ aggregates exclusively in the brain) with Abx treatment and observed a reduction in Aβ pathology, as previous reports with APP/PS1 mice (Minter et al., 2016, 2017). Notably, Abx treatment reduced Aβ aggregation in the brain tissue of male, but not in female APP/ PS1–21 mice. In addition, an increased M0 microglial state was seen in Abx-treated male mice. These authors further showed that FMT from APP/PS1–21 mice to Abx-treated APP/PS1–21 mice (daily for 3 weeks) restored GM composition, and increased Aβ

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pathology and microglial activation (Dodiya et al., 2019). To further understand the causal link between the gut microbiome and brain amyloidosis, Sisodia’s group determined the impact of individual Abx treatment on Aβ pathology. They determined that individual antibiotic treatment had no effect on Aβ pathology in APP/PS1–21 mice, but rather the Abx combination that renders a synergetic effect. This was not attributable to a direct effect of Abx on the brain, as only metronidazole was slightly detected in brain tissue (Dodiya et al., 2020). In GF-5xFAD mice, microglia displayed an immature phenotype leading to impaired innate immune responses (Erny et al., 2015). However, 4-month-old GF-5xFAD mice showed an enhanced microglial phagocytosis associated with a reduced Aβ aggregation in the hippocampus, and lower GM diversity, a condition not detected when animals grow older (10 months of age) (Mez€ o et al., 2020). This contrasting data revealed some limitations related to GM interventions (i.e., Abx, GF, and SPF) and the use of different Tg-AD mouse lines. In addition, as outlined in previous sections, GM differs during the ontogenetic process, becoming more pro-inflammatory as we age. As previously described, Tg-AD mice showed an altered GM composition since young ages (Shen et al., 2017; B€auerl et al., 2018), even before detectable Aβ deposition and plaquelocalized microglial activation (Chen et al., 2020). Thus, age-dependent GM alterations may affect the course of AD pathology. In human studies, GM alterations are already detected in prodromal stages of the disease, MCI. Thus, we must pay attention when revising animals’ data, as age and Tg mouse lines may strongly impact GM results. Another important factor to take into consideration is sex-dependent differences in GM and AD pathology. Female sex represents a risk factor to develop AD, as two-thirds of the cases worldwide are women (Alzheimer Association, 2019). Previous studies describing GM alterations in AD patients failed to discriminate between sexes. However, we recently reported that GM alterations are dissociated from the cognitive impairment in 6-month-old male and female APP/PS1 mice (Cuervo-Zanatta, Garcia-Mena, & Perez-Cruz, 2021). Similar to the human condition, sex-dependent differences in cognitive skills were observed, as female WT mice showed better cognitive scores than male WT and female/male Tg-AD mice. This cognitive advantage was lost in female Tg-AD mice. Few sex-related differences were observed in GM composition between WT mice. However, male Tg-AD mice presented a more severe dysbiosis than their Tg-female counterpart. Enriched butyrate content in fecal samples was associated with enhanced cognitive skills in female WT mice, and lower Ruminococcaceae abundance correlated with impaired memory performance in female Tg-AD mice (Cuervo-Zanatta et al., 2021; Shukla et al., 2021). Therefore, we can conclude that the use of Tg-AD mice is a useful strategy to understand the bacteria-gut-brain axis in AD pathology. Tg-AD mice develop GM since early stages of the disease, similar to the changes observed in MCI patients. The direct communication between bacteria in the gut and brain amyloidosis can be modulated by the use of Abx or FMT. However, attention must be paid when making a

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conclusion or translating animal data to the human condition, as important differences are observed depending on the Tg mouse line, the age of assessment, and the experimental design.

Modulation of the Gut microbiota to prevent Alzheimer’s disease As described in previous sections, GM modulation has a strong impact on Aβ pathology. Therefore, several studies have focused on the modulation of the GM as logical intervention against AD. Probiotics have been widely used to prevent Aβ pathology and to restore cognitive functions in Tg mice. Bonfili et al. used a probiotic formulation (SLAB51: Streptococcus thermophilus, Bifidobacteria longum, B. breve, B. infantis, Lactobacillus acidophilus, L. plantarum, L. paracasei, L. delbrueckii subsp. bulgaricus, L. brevis)] in 3xTgAD mice (B6; 129-Psen1tm1Mpm Tg (APPswe, tauP301L)1Lfa/J). An improvement in object recognition memory was seen only 10 weeks after treatment, but at later time points. A decrease in Aβ plaque size and lower soluble oligomers were detected after 10 and 16 weeks of treatment. Plasma pro-inflammatory cytokines were also reduced, and an increased abundance of Bifidobacterium spp. and a reduction in Campylobacterales were associated with increased energy metabolism, DNA repair, recombination proteins, glycolysis, and gluconeogenesis by PICRUSt analysis. However, despite 3xTgAD mice developing pTau, no data on this marker were shown (Bonfili et al., 2017). The same research group tested another probiotic formulation: VSL#3 (S. thermophilus, Bifidobacterium lactis, B. lactis, L. acidophilus, L. helveticus, L. paracasei, L. plantarum, and L. brevis) in 3xTgAD mice. VSL#3 treatment ameliorated pTau pathology and restored the levels of glucose transporters (GLUT3, GLUT1) and insulin-like growth factor receptor-b in aged (14 months old), but not in young (4 months old) Tg mice (Bonfili et al., 2020). The same probiotic formulation (VSL#3) has shown a decrease in intestinal inflammation, gut permeability, and serum bile acids in 8-month-old AppNL-G-F mice (Swedish “NL,” Iberian “F,” and Arctic “G” mutations), without significant effects on soluble and insoluble Aβ1–40 and Aβ1–42 levels in the brain, neuroinflammation, or memory (Kaur et al., 2020). A single bacteria formulation was evaluated by Sun et al. (2020), who treated 6-month-old APP/PS1 mice with C. butyricum for 4 weeks. As expected, butyrate levels were increased in fecal samples, which were associated with cognitive improvement, lower amyloidosis and neuroinflammation, and a reduced production of proinflammatory cytokines (TNF-α and IL-1β) in the brain (Sun et al., 2020). Interestingly, butyrate treatment alone reduced CD11b, cyclooxygenase (COX)-2, and phosphorylated κβ nuclear factor from p65 transcription factor (p-NF-κβ p65) in brain samples (Sun et al., 2020). A recent study showed that a probiotic formulation (L. acidophilus and L. rhamnosus) did not show significant cognitive effects in 5xFAD mice, but a transient increase in Lactobacillaceae abundance (dos Guilherme, Nguyen, Reinhardt, & Endres, 2021). These mild effects with probiotics formulations evidence their

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controversial benefits in AD. However, a combination of probiotics with exercise for 20 weeks improved spatial memory and decreased Aβ plaques in 8.5-month-old APP/ PS1 mice, stopping the progression of Aβ pathology (Abraham et al., 2019). On the other hand, prebiotics intake has been proposed as strong modulator of GM diversity. Eightweek treatment with Morinda Officinalis (a fructooligosaccharide) improved cognitive performance and reduced pTau and Aβ aggregation in adult rats injected with 10 μg of Aβ 1–42 in the CA1 hippocampal region (Chen et al., 2017). A combination of bioactive food with prebiotic actions (dried nopal, soy protein, chia seed oil, and turmeric) given for 7 months to female 3xTg-AD mice showed improvement in working memory, reduced neuroinflammation, and diminished synaptic alterations. A reduced gut dysbiosis accompanied by enhanced levels of butyrate but reduced propionate levels was related to less neuroinflammation in prebiotics-fed mice compared to control-fed animals (Syeda et al., 2018). Similarly, a 6-month treatment with high and low doses of jatrorrhizine (active component of the traditional Chinese herb Coptis chinensis) has proven beneficial effects in 9-month-old APP/PS1 mice, as it decreased Aβ plaques and improved learning and memory, while restoring gut dysbiosis in APP/PS1mice (Wang et al., 2019). Mannan oligosaccharides (MOS) given during eight-week- to 6-month-old 5xFAD mice improved cognitive function and reduced brain Aβ aggregation. In addition, MOS rescue the gut barrier permeability, increase the relative abundance of Lactobacillus but reduce that of Helicobacter, accompanied by an increased production of butyrate. These authors also tested whether direct SCFA treatment (65.5 mM acetate, 40 mM propionate, 25 mM butyrate) improved cognitive impairment and inflammatory markers in Tg mice. Eight-week SCFA treatment in 5xFAD mice resulted in memory improvements, increased anti-inflammatory cytokines (IL10), and decreased pro-inflammatory cytokines (IL6) in the systemic circulation (Liu et al., 2021). A recent and relevant translational study demonstrates the effectiveness of a prebiotic formulation, GV-971 (a mixture of acidic linear oligosaccharides derived from brown algae), with specific impact on GM composition. Nine-month-old APP/PS1 mice treated with GV-971 for 3 months showed a decreased brain immune cell infiltration and neuroinflammation, a reduced Aβ burden, pTau, and cognitive deficits, all of those effects mediated by the modulation of the GM. GV-971 also decreased plasma concentrations of phenylalanine and isoleucine in Tg mice. Phenylalanine and isoleucine promoted Th1 cell differentiation in an in vitro assay. In MCI and AD patients, plasma concentrations of phenylalanine and isoleucine, and Th1 cell frequency were higher than in age-matched healthy controls. This author suggests that a dysbiotic condition promotes the infiltration of various peripheral immune cells into the brain, causing a strong neuroinflammation and cognitive impairment (Wang, Sun, et al., 2019). A phase II randomized trial evaluated the efficacy of GV-971 for 24 weeks in a Chinese cohort of AD patients (average age of groups ¼ 68 yo) using two doses of GV-971 (900 mg, n ¼ 83; 600 mg, n ¼ 76; and placebo, n ¼ 83). GV-971 treatment tends to improve AD

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assessment scale-cognitive subscale-12 (ADAS-cog12) scores and ameliorate the decline of cerebral metabolic rate compared to placebo group, but non-significantly (Wang et al., 2020). A phase III clinical trial with GV-971 (450 mg, n ¼ 334) or placebo (n ¼ 344) has recently been completed in China, with mild-to-moderate AD patients treated for 36 weeks (average age of groups ¼ 67 yo). There was a significant improvement in the ADAS-12 scores in the treated group, even after 4 weeks of treatment (Xiao et al., 2021). The mechanism of action of this novel compound is still undefined, but preclinical data strongly suggest that GM modulation and the release of bacterial products may be responsible for the cognitive improvement in AD patients. Nagpal et al. (2019) evaluated the impact of the modified Mediterranean-ketogenic diet (MMKD) or American Heart Association Diet (AHAD) on GM composition and AD biomarkers in a short pilot study. MCI and cognitively normal subjects (average age of groups: 67 yo) were given a 6-week intervention with those diets. No differences in alpha or beta diversity between groups were observed, but an increase in Proteobacteria, Enterobacteriaceae, and Mogibacteriaceae was observed in MCI subjects. Moreover, Enterobacteriaceae was positively associated with tau-p181 and tau-p181/Aß42 ratio, while Mogibacteriaceae was positively correlated with Aβ 1–42/1–40 ratio. SCFAs in fecal samples showed propionate and butyrate to be correlated negatively with Aβ 1–42 in subjects with MCI, while MMKD ingestion slightly reduced fecal lactate and acetate while increasing propionate and butyrate. In summary, all the presented data suggest that GM modulation impacts the release of different bacterial metabolites and bioproducts that could be responsible for a significant decrease in cerebral Aβ deposition, neuroinflammation, and cognitive improvement. Preclinical studies using Tg-AD mouse models confirm and replicate human data, as GM dysbiosis associates with brain Aβ pathology since early stages of AD. FMT and Abx treatment are effective strategies to reduce Aβ aggregation, but safety concerns and long-term treatment may result in important health issues. However, intake of prebiotics and adherence to diets rich in vegetables, fruits, and cereals may offer beneficial effects on brain function through the modulation of the GM.

Applications to other neurological conditions The composition of the GM and its related bioproducts has shown important roles in the etiology of several neurological conditions such as autism, depression, Parkinson’s disease, among others. Multidomain intervention projects (i.e., FINGERS and POINTER) have recently shown promising results in reducing the incidence or delaying the onset of AD when starting before clinical symptoms (Ngandu et al., 2015; Rosenberg, Mangialasche, Ngandu, Solomon, & Kivipelto, 2020; Rosenberg et al., 2018). Modulation of the GM by the diet may be a real preventive strategy for neurological disorders. Multidomain interventions consisting in nutritional counseling, regular exercise,

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cognitive stimulation, and social interactions must be taken as a holistic approach to reduce the prevalence of complex neurodegenerative diseases that are projected to affect a large percentage of persons in the upcoming years.

Other components of interest In this chapter, we related the state of the art in the field of Alzheimer’s disease and gut microbiota. Human studies indicate that gut dysbiosis initiates years before the clinical diagnosis of Alzheimer’s disease. A lack of commensal bacteria is related to chronic low-grade inflammation. Dietary interventions have promising results as diet can restore gut’s communities to healthy values. Exercise and wellness are also related to healthy microbiota. Hence, modifications in our lifestyle may render significant protection against age-associated chronic neurodegenerative diseases, such as Alzheimer’s disease.

Key facts – Age is the main risk factor for Alzheimer’s disease. During aging, the ecology of our gut is characterized by an abundant amount of bacteria that induce an activation of the host immune system. – After 65 years of age, the systemic inflammatory status becomes more pronounced, a condition that can last for decades. The gut-brain axis has been implicated in several neurodegenerative diseases and is a leading cause of some histopathological hallmarks of Alzheimer’s disease. – Germ-free conditions or fecal transplant from healthy donors restores gut dysbiosis in transgenic mice with Alzheimer’s disease and hence amyloid pathology. – The gut microbiota can be modified by the use of medications, such as antibiotics, but also by the diet. Ingestion of diets rich in vegetables, fruits, and cereals can restore the gut microbiota to healthy reference values, reducing systemic and central inflammation, and improving memory performance in humans and in transgenic animal mice with Alzheimer’s disease.

Mini-dictionary of terms Gut microbiota: Ecosystem containing trillions of microorganisms continuously shaped by factors, such as dietary habits, seasonality, lifestyle, stress, antibiotics use, or diseases. Dysbiosis: Persistent imbalance of intestinal microbial community. Alzheimer’s disease: Chronic neurodegenerative disease characterized by memory loss and an aberrant protein processing and polymerization pathway that results in large aggregates in the brain.

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Bacteria-gut-brain axis: Network of connections that allows a bidirectional communication between gut bacteria and the brain. Neurodegenerative disease: Hereditary or sporadic conditions that result in the progressive loss of the structure and function of neurons as well as neuronal death.

Summary points • • • • •

Alzheimer’s patients had a different gut microbiota than healthy controls. Transgenic mouse models of Alzheimer’s disease develop severe gut dysbiosis as the disease progresses. Bacterial bioproducts affect brain functioning. Modulation of the gut microbiota by the diet or by the use of prebiotics mitigates the onset of AD in animal models. Multifactorial interventions with a special focus on nutrition, exercise, and social interaction may reduce the incidence of several neurodegenerative diseases.

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Dysbiosis and neurodegenerative diseases

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CHAPTER 4

The Mediterranean diet: Unsaturated fatty acids and prevention of Alzheimer’s disease  A. Estrada and Irazú Contreras Jose

Neurochemistry Laboratory, Faculty of Medicine, Autonomous University of the State of Mexico, Toluca, Estado de Mexico, Mexico

Abbreviations ARA DHA EPA MCI PUFAs SCFAs SPMs

arachidonic acid docosahexaenoic acid eicosapentaenoic acid mild-cognitive impairment polyunsaturated fatty acids short-chain fatty acids specialized proresolving mediators

Introduction As the leading cause of dementia worldwide, Alzheimer’s disease is a serious public health issue that as yet has no effective prevention or treatment options. As a chronicdegenerative disease, some of the most relevant characteristics of Alzheimer’s include extensive oxidative and inflammatory damage to the brain, beginning years before the onset of clinical symptoms. Therefore, nutritional interventions attempting to decrease oxidative stress and inflammation systemically have demonstrated their usefulness for reducing the risk of developing age-related cognitive impairment and Alzheimer’s disease in a multitude of settings. In particular, adherence to a Mediterranean-style diet is now considered a significant tool to prevent the incidence of chronic oxidative and inflammatory damage to the brain and is correlated to decreased risk for development of Alzheimer’s disease. Although this type of diet contains multiple bioactive compounds that have demonstrated their potential beneficial effect for human health, including high concentrations of antioxidant vitamins, polyphenols, and dietary fiber, polyunsaturated fatty acids (PUFAs),

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00041-6

Copyright © 2023 Elsevier Inc. All rights reserved.

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particularly those of the omega-3 and -6 varieties, are thought to provide significant benefits for maintaining brain health and cognitive function during aging. The current chapter summarizes relevant information on the nutritional aspects underlying the beneficial effects of the main PUFAs contained in the Mediterranean diet on oxidative stress, inflammation, and the risk of developing cognitive impairment and Alzheimer’s disease.

Neuroscientific aspects Alzheimer’s disease is considered the leading cause of dementia in people over 60 years of age. It is characterized by progressive cognitive deterioration, initially involving processes related to memory and language and eventually causing inability to perform even the most common motor functions, such as walking, eating, and drinking, leading to patients needing constant care until death (Braak, Thal, Ghebremedhin, & Del Tredici, 2011). Although the disease is thought to begin decades before the onset of symptoms, available clinical biomarkers still lack adequate sensitivity and specificity to achieve common use on a population-wide scale, making early treatment and preventative measures hard to apply. Molecular hallmarks of Alzheimer’s disease, including accumulation of misfolded beta-amyloid and tau proteins in the brain, impaired glucose metabolism and progressive brain atrophy due to the fact that neuronal damage can be found 10 to 20 + years before clinical symptoms appear (Barthelemy et al., 2020; Gordon et al., 2018; Quiroz et al., 2020). Development of age-related cognitive impairment and Alzheimer’s disease has been associated with multiple risk factors (Table 1). In particular, cardiovascular disease, Table 1 Risk factors for the development of Alzheimer’s disease. Known risk factors for development of mild cognitive impairment and Alzheimer’s disease Risk factor

Biological effects

Effects on cerebral aging

- Cardiovascular disease - Hypertension - Dyslipidemia - Diabetes mellitus - Sedentarism - Hearing loss - Social isolation - Unhealthy dietary patterns

- Increased oxidative stress - Chronic lowgrade inflammation - Insulin resistance - Metabolic dysregulation

- Enhanced formation of beta-amyloid plaques - Neuroinflammation - Neuronal apoptosis - Increased risk for developing mild cognitive impairment and Alzheimer’s disease

This table describes the main known risk factors for development of Alzheimer’s disease, with an emphasis on unhealthy dietary patterns. These factors usually promote the generation and maintenance of chronic low-grade inflammatory reactions and increased oxidative stress, leading to metabolic dysregulation and tissue damage. The loss of systemic homeostasis leads to enhanced extracellular accumulation of beta-amyloid proteins and neuroinflammation, promoting neuronal dysfunction and apoptosis.

Unsaturated fatty acids and prevention of Alzheimer’s disease

Table 2 Lifestyle interventions and Alzheimer’s disease Proposed lifestyle interventions for reducing the risk of developing mild cognitive impairment and Alzheimer’s disease Intervention

Biological effects

Effects on cerebral aging

- Increased physical activity - Increased education - Decreased alcohol consumption - Decreased smoking - Healthier social interactions - Prevention of hearing loss - Healthier nutritional patterns

- Reduced oxidative stress - Reduced inflammation - Improved Insulin sensitivity - Improved systemic metabolism

- Improved production of neurotrophic factors - Enhanced clearance of beta-amyloid plaques - Decreased neuroinflammation - Enhanced neuronal survival - Decreased risk for developing mild cognitive impairment and Alzheimer’s disease

This table shows the main suggested lifestyle interventions for reducing the risk of developing age-related cognitive impairment and Alzheimer’s disease in all populations, with an emphasis on the establishment of healthier nutritional patterns. These interventions promote systemic homeostasis by improving overall metabolism, reducing oxidative stress, and decreasing systemic inflammatory activity under sterile conditions. Maintenance of systemic homeostasis leads in turn to improved cerebral health by promoting the production of neurotrophic factors, decreasing the extracellular accumulation of beta-amyloid proteins and its associated neuroinflammatory reactions, enhancing neuronal function and survival, thus reducing the risk for developing age-related cognitive impairment and Alzheimer’s disease.

hypertension, and dyslipidemia are considered relevant lifestyle-related variables involved in metabolic alterations promoting oxidative stress and inflammation, which, if untreated, lead to eventual neurological damage and cognitive decline (Livingston et al., 2020). These risk factors are susceptible to modification by relatively simple changes to common lifestyle aspects like physical activity, education, alcohol consumption, smoking, and nutritional interventions promoting healthier diets. Recent studies suggest that interventions to improve healthier lifestyles may be able to decrease the incidence of dementia up to 40% (Livingston et al., 2020) (Table 2). Although there is conflicting evidence on the usefulness of specific lifestyle modifications, such as increased intake of vitamin C, E, and omega-3 polyunsaturated fatty acids, for the prevention of Alzheimer’s disease, there are sufficiently robust data suggesting that diets rich in fruits, vegetables, whole-grain cereals, and unsaturated fat, such as the Mediterranean diet, are strongly associated with delayed onset or prevention of age-related cognitive impairment and Alzheimer’s disease (Hardman, Kennedy, Macpherson, Scholey, & Pipingas, 2016).

Neuroinflammation and Alzheimer’s disease Inflammatory activation of microglia (microgliosis) and astrocytes (astrocytosis) is a common event associated with the presence of “senile plaques,” pathological features consisting of extracellular beta-amyloid protein aggregates, and neurofibrillary tangles

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containing phosphorylated tau protein, along with synaptic dysfunction and neuronal loss (Sastre, Klockgether, & Heneka, 2006; Serrano-Pozo, Frosch, Masliah, & Hyman, 2011) (Fig. 1). Although in normal conditions this inflammatory response would be associated with maintenance of neuronal homeostasis, the chronic inflammatory response observed in the brain of patients with Alzheimer’s disease is thought to promote a cycle of betaamyloid accumulation, neuronal damage, microglial and astrocytic activation, production of proinflammatory mediators, and further accumulation of beta-amyloid, causing progressive neuronal loss (Whittington, Planel, & Terrando, 2017).

Beta-Amyloid plaques

Hyperphosphorylated Tau Protein

Synaptic dysfunction and neuronal damage

Apoptotic neurons

Microgliosis Pro-inflammatory cytokines

Astrocytosis

Leukocyte infiltration Pro-inflammatory and activation cytokines

Blood-Brain Barrier disruption

Fig. 1 General characteristics of senile plaques in Alzheimer’s disease. Senile plaques are pathological structures comprising accumulation of extracellular beta-amyloid proteins causing neuronal dysfunction and death. Hyperphosphorylation of intraneuronal tau proteins causes microtubule alterations that affect synaptic vesicle transport and neurotransmission. Accumulation of betaamyloid promotes microglia and astrocyte activation and production of proinflammatory cytokines, which in turn promote endothelial activation and leakage of the blood-brain barrier, leading to leukocyte infiltration into the cerebral parenchyma. Infiltrating leukocytes become activated in situ and contribute to the establishment of a chronic neuroinflammatory response, further worsening neuronal damage and death.

Unsaturated fatty acids and prevention of Alzheimer’s disease

Nutritional aspects The Mediterranean diet and Alzheimer’s disease risk Mediterranean diets are often characterized by high intake of unsaturated fatty acids from different sources, mostly found in fish and olive oil, as well as antioxidants obtained from fruit, legumes, vegetables, and cereals, as well as moderate consumption of wine, with its corresponding health benefits, particularly for the cardiovascular system. This is often accompanied by low intake of saturated fats from red meat and dairy products (Simopoulos, 2001) (Table 3). Due to its putative health benefits, the Mediterranean diet has been proposed as a useful nutritional tool to prevent the development of cognitive decline associated with normal aging, as well as decreasing the risk of developing Alzheimer’s disease. Multiple studies have found direct associations between adherence to Mediterranean-style diets and reduced rates of cognitive decline in elderly patients, which are in turn associated Table 3 The Mediterranean diet and Alzheimer’s disease. General dietary characteristics of the Mediterranean diet High-intake components

• • • • •

Olive oil Fruit Legumes Vegetables Cereals

Moderate-intake components

Low-intake components

• • • •

• •

Fish Poultry Wine Cheese

Red meat Dairy products

Main beneficial micronutrients found in the classical components of the Mediterranean diet Micronutrient

Biological effects

Effects on cerebral aging

-

- Antioxidant activity - Antiinflammatory activity - Increased production of adiponectin - Decreased production of C-reactive protein - Improved insulin sensitivity - Improved systemic metabolism

- Enhanced clearance of beta-amyloid plaques - Decreased neuroinflammation - Enhanced neuronal survival - Decreased risk for developing mild cognitive impairment and Alzheimer’s disease

Vitamins C Vitamin E Folate Polyphenols Omega-3 polyunsaturated fatty acids

This table shows the main dietary components that are part of traditional Mediterranean diets, as well as the main beneficial micronutrients in them and their known biological effects, with an emphasis on polyunsaturated fatty acids. The beneficial micronutrients in the Mediterranean diet possess significant antiinflammatory and antioxidant activities, promoting optimal metabolic regulation and maintaining systemic homeostasis. In the brain, these micronutrients have been shown to enhance the clearance of beta-amyloid plaques, decreasing neuroinflammation, promoting neuronal survival and health, and reducing the risk for development of Alzheimer’s disease.

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with decreased risk for Alzheimer’s disease in different populations, including people from North America, Europe, and Australia (Feart et al., 2009; Gardener et al., 2012; Scarmeas, Stern, Tang, Mayeux, & Luchsinger, 2006; Tangney et al., 2011). In general, decreased risk for cognitive decline and Alzheimer’s disease is thought to derive from lower incidence of cardiovascular alterations, such as hypertension, dyslipidemias, and coronary heart disease, as well as improved glucose metabolism and insulin production, in people consuming Mediterranean-style diets (Esposito et al., 2004; Psaltopoulou et al., 2004; Singh et al., 2002). As these conditions are related to pathological changes in physiological parameters including oxidative stress and inflammation, the high concentrations of antioxidant compounds found in the components of the Mediterranean diet, such as polyphenols, folate, and vitamins C and E, may be directly responsible for ameliorating these risk factors for Alzheimer’s disease (Fito et al., 2005; Joshipura et al., 2001). Similarly, consumption of Mediterranean-style diets is associated with increased concentrations of adiponectin, an antiinflammatory and insulin-sensitizing adipokine, as well as decreased production of C-reactive protein, a marker of systemic inflammatory reactions in humans (Blum, Aviram, Ben-Amotz, & Levy, 2006; Yannakoulia, Kontogianni, & Scarmeas, 2015) (Table 3). Furthermore, hypertension, dyslipidemias, and inflammation are intrinsically related with overweight and obesity. Multiple studies have found a significant increase in the risk of developing dementia in patients who were overweight or obese patients in midlife (Emmerzaal, Kiliaan, & Gustafson, 2015). Diet-related obesity usually correlates with excessive intake of energy-rich food, mostly containing high concentrations of saturated fatty acids and simple carbohydrates, which in turn cause long-term metabolic dysregulation if left unchecked. Importantly, saturated fatty acids have been shown to increase proinflammatory responses within the brain and may have a detrimental impact on the development of age-related cognitive decline (Morris, Evans, Bienias, Tangney, & Wilson, 2004). Hence, the Mediterranean diet may be useful to prevent development of diet-related obesity, with its corresponding complications.

Polyunsaturated fatty acids and Alzheimer’s disease As part of cell membranes’ phospholipids, polyunsaturated fatty acids (PUFAs) play essential roles in the regulation of membrane permeability and intercellular communication. Neuronal cells, in particular, contain high concentrations of PUFAs that are necessary for adequate synaptic function and neurotransmission. These compounds have demonstrated a relevant role in cognitive processes involving learning and memory in humans (Vauzour, Martinsen, & Laye, 2015). Omega-3 and -6 PUFAs are considered relevant for neuroinflammatory conditions since they are precursors of multiple bioactive compounds called specialized proresolving mediators (SPMs), which display significant immunomodulatory, antiinflammatory, and

Unsaturated fatty acids and prevention of Alzheimer’s disease

Specialized proresolving mediators (SPMs)

Polyunsaturated fatty acids (PUFAs)

Omega-3 PUFAs (n-3) O HO Docosahexaenoic Acid (DHA; 22:6, n-3)

n-3

Omega Carbon

Maresin 1 Protectin D1 D-series Resolvins

O n-3 Omega Carbon

HO

E-series Resolvins

Eicosapentaenoic Acid (EPA; 20:5, n-3)

Omega-6 PUFA (n-6) O n-6 HO Arachidonic Acid (ARA; 20:4, n-6)

Omega Carbon

Lipoxins

Fig. 2 PUFAs and specialized proresolving mediators. This figure depicts the most well-studied omega-3 and omega-6 PUFAs found in high concentrations in Mediterranean-style diets and the main beneficial specialized proresolving mediators derived from them. PUFA, polyunsaturated fatty acids; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; ARA, arachidonic acid.

neuroprotective functions (Whittington et al., 2017) (Fig. 2). For example, the essential omega-3 PUFA docosahexaenoic acid (DHA) is a precursor of the D-series of resolvins, as well as protectins and maresins, while eicosapentaenoic acid (EPA) is the precursor of the E-series resolvins (Whittington et al., 2017). Similarly, the omega-6 PUFA arachidonic acid (ARA) is a precursor of the first described class of proresolving mediators, the lipoxins (Serhan, Hamberg, & Samuelsson, 1984). These bioactive molecules have shown significant effects in reducing inflammatory damage, oxidative stress, and accumulation of amyloid beta in the brain when used in tandem (Tan et al., 2012), and they can also induce macrophage polarization to a regulatory M2 phenotype with enhanced phagocytic activity for beta-amyloid (Fiala, Kooij, Wagner, Hammock, & Pellegrini, 2017).

Specialized proresolving mediators and Alzheimer’s disease Exploration of the effects of PUFA-derived SPMs on Alzheimer’s disease is based on evidence demonstrating persistent and unresolved inflammatory responses in the brain of

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affected patients, with defective beta-amyloid clearance due to inhibited microglial phagocytosis, chronic microgliosis, and astrogliosis, accompanied by constant production of proinflammatory mediators and leukocyte infiltration in the brain (Elali & Rivest, 2016; Fiala et al., 2017; Heneka et al., 2015; Osborn, Kamphuis, Wadman, & Hol, 2016). Additionally, there is also evidence showing decreased production of SPMs in the brain of patients with Alzheimer’s disease. Despite significantly reduced levels of resolvin D5, neuroprotectin D1, and maresin 1, SPMs produced from the metabolism of omega-3 PUFAs, particularly DHA, are found in the hippocampus, an area of the brain related to memory formation and maintenance that is affected in early stages of the pathology (Lukiw et al., 2005; Zhu et al., 2016). SPMs have a very high potential for reducing Alzheimer’s disease risk by promoting neuronal survival and decreasing inflammation (Fraga, Carvalho, Caramelli, De Sousa, & Gomes, 2017). These molecules enhance beta-amyloid clearance by promoting the phagocytic activity of microglia and macrophages, as well as reducing inflammation by promoting macrophage and microglial differentiation into a regulatory M2 phenotype and inhibiting leukocyte activation in general and their ability to produce proinflammatory cytokines (Fiala et al., 2017; Zhu et al., 2016). Furthermore, PUFA-derived SPMs also enhance neuronal survival and reduce beta-amyloid-induced neuronal apoptosis in vitro (Zhao et al., 2011; Zhu et al., 2016). The main mechanisms that have been suggested for the potential neuroprotective effects of these compounds are shown in Fig. 3.

Supplementation with PUFAs and Alzheimer’s disease risk Clinical studies on supplementation of omega-3 PUFAs have shown significant positive effects in vivo. A Japanese study found decreased incidence of Alzheimer’s disease after 3-year supplementation with omega-3 PUFAs and other nutritional compounds (Bun et al., 2015). Similarly, a 3-month regime of supplementation with a mixture of DHA and ARA improved clinical scores for memory and cognition in patients with MCI (Kotani et al., 2006). More importantly, large-scale clinical trials have provided a wealth of data on the antiinflammatory and neuroprotective effects of PUFA supplementation in patients with mild and moderate Alzheimer’s disease. The OmegAD study found that a 6-month supplementation regime with both DHA and EPA not only increased PUFA concentrations in plasma and cerebrospinal fluid of the patients, but that these correlated with decreased levels of phosphorylated tau proteins in the brain, reduced concentrations of proinflammatory cytokines in circulation, reduced leukocyte activation and proinflammatory activity, and improved cognitive performance in supplemented subjects (Fraga et al., 2017). These positive data have allowed the formulation of currently available nutritional formulas containing DHA and EPA for use in elderly populations at risk for developing Alzheimer’s disease, which have shown potential for decreasing brain atrophy and cognitive deterioration in patients in the initial stages of Alzheimer’s disease (Fraga et al., 2017).

Unsaturated fatty acids and prevention of Alzheimer’s disease

Suggested mechanisms underlying beneficial effects for the brain

Increased amyloidbeta phagocytosis and polarization of microglia and macrophages to M2 phenotypes

M2 Microglia

Amyloidbeta plaque

Decreased leukocyte activation and production of proinflammatory cytokines

Leukocytes

Pro-inflammatory cytokines

Inhibition of amyloidbeta-induced neuronal apoptosis Neurons and amyloid plaques

Enhanced cognitive performance in elderly subjects and patients in the initial stages of Alzheimer’s disease

Apoptotic neuron

Normal ageing MCI + PUFAs Cognitive Performance

Mild cognitive impairment Alzheimer’s Disease Years of Age

Fig. 3 Neuroprotective mechanisms of specialized proresolving mediators. This figure depicts the principal suggested mechanisms underlying the neuroprotective mechanisms of specialized proresolving mediators derived from omega-3 and omega-6 PUFAs, as well as their effect on the risk of developing MCI and Alzheimer’s disease. PUFAs, polyunsaturated fatty acids; MCI, mild cognitive impairment.

Nevertheless, the positive effects of dietary supplementation with omega-3 PUFAs for the prevention of Alzheimer’s disease are still controversial, as other studies have not been able to replicate the beneficial effects described in the previous paragraph. For example, an study using daily supplementation with DHA alone for 18 months did not show significant improvement in cognitive performance in patients with mild or moderate Alzheimer’s disease (Quinn et al., 2010), and a similar study using mixed DHA/EPA supplementation also found no significant benefits on mood and cognition in patients with mild cognitive impairment or Alzheimer’s disease (Phillips, Childs, Calder, & Rogers, 2015). Therefore, despite having a large amount of data on the

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antiinflammatory, antioxidant, and neuroprotective effects of omega-3 PUFAs in multiple studies, both in vitro and in vivo, the actual role for these compounds in the prevention of Alzheimer’s disease is still unclear. Although these negative results may be the result of differences between the various experimental setups used, including variations in PUFA concentration, time of administration, omega-3/omega-6 ratios, vegetable and animal sources of PUFAs or use of precursor molecules, patient age, genetics, and degree of cognitive impairment, these data also strengthen the idea that the beneficial effects of the Mediterranean diet derive not only from the dietary components in it, but from an overall healthier lifestyle in people in that geographic region (Calder, 2013; Gillette-Guyonnet, Secher, & Vellas, 2013).

Conclusion Available evidence suggests that the Mediterranean diet should be considered as a useful tool to delay or prevent cognitive decline in aging populations due to its multiple health benefits. The high concentrations of polyunsaturated fatty acids commonly found in this dietary pattern provide positive effects as precursors for specialized proresolving mediators with demonstrated antioxidant and antiinflammatory effects that are related to reduced risk of developing age-related cognitive decline and Alzheimer’s disease in multiple experimental settings. Further work is needed to promote the adoption of similar healthy dietary patterns worldwide.

Applications to other neurological conditions This chapter focuses on the potential benefits of diets rich in polyunsaturated fatty acids for the prevention of age-related cognitive decline and Alzheimer’s disease. However, due to their role as precursors of important antiinflammatory and immunomodulatory molecules, their potential beneficial effects in other neuroinflammatory and neurodegenerative conditions have also been explored. Studies in patients with Parkinson’s disease, a neurodegenerative condition characterized by loss of dopaminergic neurons in the substantia nigra of the brain, leading to motor neuron dysfunction and movement problems, among other symptoms, have shown that supplementation with DHA promotes production of neurotrophic factors and reduces the activation of inflammatory signaling pathways in the brain, promoting neuroprotective effects in vivo, reducing dopaminergic neuron loss and the symptomatology of disease in animal models (Hacioglu et al., 2012; Mahmoudi et al., 2009; Tanriover et al., 2010). However, human trials of dietary PUFA supplementation have not yet produced significant benefits in patients with Parkinson’s disease, showing only mild improvements on cognitive parameters and depression (Da Silva et al., 2008).

Unsaturated fatty acids and prevention of Alzheimer’s disease

The positive effect of omega-3 PUFAs in psychiatric conditions is a point of notice, as it has also been reported that higher plasma concentrations of EPA are associated with decreased symptomatology in elderly patients with depression (Feart et al., 2008). Accordingly, with the suspected relevance for omega-3 PUFAs in psychiatric disorders, decreased concentrations of DHA and EPA have been found in patients having schizophrenia and depression and are also related to increased risk for cardiovascular disease, which in turn is a risk factor for developing dementia (Parletta et al., 2016).Therefore, high dietary intake of omega-3 PUFAs may be a useful tool for the prevention and treatment of psychiatric disease. In addition, studies in patients with multiple sclerosis, an autoimmune neuroinflammatory disease characterized by neuronal loss and destruction of the myelin sheaths that provide insulation for neuronal axons and regulate neurotransmission, leading to irreversible neurodegeneration in multiple areas of the brain, have demonstrated beneficial effects after dietary supplementation with omega-3 PUFAs, reducing symptomatology and slowing the evolution of disease, possibly due to the antiinflammatory and immunomodulatory properties of these compounds (Kouchaki et al., 2018; WeinstockGuttman et al., 2005). In accordance with this idea, studies in animal models of multiple sclerosis have demonstrated reduced autoimmune activity and improved remyelination in the brain, delaying disease onset and decreasing clinical scores in animals supplemented with omega-3 PUFAs (Adkins, Soulika, Mackey, & Kelley, 2019; Siegert, Paul, Rothe, & Weylandt, 2017).

Other components of interest This chapter describes the relevance of PUFAs contained in the Mediterranean diet for decreasing risk of developing Alzheimer’s disease. It is important to note that additional molecules present in Mediterranean-style diets have also shown significant antiinflammatory, antioxidant, and neuroprotective effects in multiple experimental models. For example, supplementation regimes with vitamins C, D, E, and B complex vitamins promote reduction of oxidative damage and formation of extracellular beta-amyloid fibrils in the brain (Lloret, Esteve, Monllor, & Cervera-Ferri, 2019; Monacelli, Acquarone, Giannotti, Borghi, & Nencioni, 2017), reduce brain atrophy and cognitive decline in elderly patients with mild cognitive impairment (De Jager, Oulhaj, Jacoby, Refsum, & Smith, 2012), reduce production of amyloid beta and proinflammatory cytokines (Chen et al., 2016), enhance beta-amyloid phagocytosis, and improve specific memory functions (Ito et al., 2011; Pettersen, 2017) in humans. Importantly, in some cases, the beneficial effects of some of these vitamins were only observed when patients had relatively high concentrations of PUFAs in their organisms ( Jerneren et al., 2015), suggesting a synergistic neuroprotective effect for these molecules.

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Similarly, other nutritional components present in the Mediterranean diet such as resveratrol, a polyphenol found in berries, grapes, and wine, also present significant antioxidant, antiinflammatory, and neuroprotective properties, showing potential benefits for reducing inflammation and accumulation of beta-amyloid plaques in Alzheimer’s patients (Martin, 2017). Finally, recent studies have begun focusing on the role of the intestinal microbiota on the incidence and evolution of various neurodegenerative conditions, including Alzheimer’s disease. The intestinal microbiome is a relevant source of bioactive compounds, including neurotransmitters, immunomodulatory short-chain fatty acids, particularly butyrate, and even toxins (Doifode et al., 2021), some of which have been associated with the modulation of inflammation and beta-amyloid accumulation in the brain. The predominant presence of pathogenic or proinflammatory microbes in the intestine, a process called “dysbiosis,” has been related to detrimental effects in the brain, whereas the presence of beneficial bacteria producing higher quantities of immunomodulatory molecules reduces neuroinflammation and may reduce cognitive impairment in some neuroinflammatory conditions (Ceccarelli et al., 2017). It is also important to note that the individual makeup of a person’s intestinal microbiome is directly related to his/her nutrition. Particularly, dietary patterns with high intake of dietary fiber and other compounds found in fruits and vegetables, along with decreased consumption of red meat and saturated fat, such as the Mediterranean diet, are related to increased presence of neuroprotective bacterial species in the intestine, with corresponding benefits for decreasing the risk of developing Alzheimer’s disease (Pistollato et al., 2016).

Key facts of the Mediterranean diet •

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The Mediterranean diet is a common term that usually describes singular dietary patterns observed in Southern European countries around the Mediterranean Sea, like Crete, Italy, France, and Spain. The term was first established in the 70s by American physiologist Ancel Benjamin Keys (b.1904–d.2004), while studying the effects of saturated fat and cholesterol on cardiovascular health. It is characterized by high intake of olive oil, fruit, vegetables, and cereals, as well as moderate consumption of fish, poultry, cheese, and wine, while avoiding consumption of large quantities of red meat, dairy products, and saturated fatty acids in general. Frequent intake of Mediterranean-style diets has been associated with decreased risk for development of cardiovascular disease, insulin resistance, and cancer, as well as improving longevity and healthy aging. Mediterranean-style diets contain high concentrations of polyunsaturated fatty acids (PUFAs), particularly those of the omega-3 and -6 kinds, along with high quantities of dietary fiber, antioxidants, vitamins, and polyphenols.

Unsaturated fatty acids and prevention of Alzheimer’s disease

Key facts of PUFAs and Alzheimer’s disease risk •

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Polyunsaturated fatty acids (PUFAs) are lipid molecules containing multiple carboncarbon double bonds. These molecules include arachidonic acid (ARA, omega-6), docosahexaenoic acid (DHA, omega-3), and eicosapentaenoic acid (EPA, omega-3). PUFAs are the precursor of relevant antiinflammatory lipid derivatives known as specialized proresolving mediators (SPMs), including E and D series resolvins, protectins, maresins, and lipoxins. PUFA-derived SPMs improve beta-amyloid clearance in the brain by stimulating phagocytosis, promoting the polarization of microglia and macrophages to an M2 phenotype, and inhibiting neuronal apoptosis and the production of proinflammatory cytokines by leukocytes. Concentration of PUFAs and SPMs are decreased in the brain and cerebrospinal fluid of patients with Alzheimer’s disease. Researchers have found significant beneficial effects on cognition and memory in patients with mild cognitive impairment after dietary supplementation with PUFAs, as well as reduced risk of developing Alzheimer’s disease.

Mini-dictionary of terms •

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Mediterranean diet: Dietary pattern common to Southern European countries, characterized by frequent intake of olive oil, fruits, vegetables, fish, nuts, and wine, with low consumption of red meat and dairy products. It is considered beneficial for human health. Mediterranean-style diets: Diets that contain similar elements found in the classical Mediterranean diet, but that are consumed in other geographical regions, such as Asia or Northern Europe. Mild cognitive impairment: Small but significant reduction in cognitive performance, determined by a physician that may be related to normal aging processes of the brain and is more common in elderly patients. People developing MCI are at increased risk of developing Alzheimer’s disease later on. Polyunsaturated fatty acids: Subset of fatty acids whose main characteristic is the presence of multiple double carbon–carbon bonds in their molecular structure. This subset contains the essential omega-3 α-linolenic, docosahexaenoic (DHA), and eicosapentaenoic (EPA) acids, as well as the omega-6 linoleic and arachidonic (ARA) acids. Senile plaques: Pathological features of Alzheimer’s disease containing abnormal accumulation of beta-amyloid and phosphorylated tau proteins in the brain, accompanied by local inflammatory reactions and neuronal damage. Specialized proresolving mediators: Lipid molecules produced by metabolic oxidation of polyunsaturated fatty acids. They include multiple immunomodulatory molecules,

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such as lipoxins, E and D series resolvins, and maresins. These molecules have significant antiinflammatory and tissue-regenerative properties. Microgliosis and astrogliosis: Term used to describe the reactive activation of microglia and astrocytes in the brain, usually in response to, and as part of, an inflammatory reaction within the brain. Reactive microglia and astrocytes actively participate in the development and evolution of neuroinflammatory responses.

Summary points •

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The Mediterranean diet is a dietary pattern found in Southern Europe characterized by high concentrations of antioxidant, antiinflammatory, and immunomodulatory nutritional components. Adherence to Mediterranean-style diets has been demonstrated to decrease the risk for development of age-related cognitive impairment and Alzheimer’s disease in different populations. Polyunsaturated fatty acids (PUFAs) are one of the main compounds thought to underlie the beneficial effects of Mediterranean-style diets, due to their antioxidant and immunomodulatory effects. Omega-3 and -6 PUFAs have demonstrated significant antiinflammatory and neuroprotective effects in humans, mainly through their in vivo transformation into specialized proresolving mediators (SPMs), including resolvins, protectins, maresins, and lipoxins. PUFA and SPM concentrations are reduced in the brain of patients with Alzheimer’s disease. PUFA-derived SPMs promote beta-amyloid clearance through phagocytosis, reduce microglia and astrocyte activation, decrease the production of proinflammatory cytokines, and promote neuronal survival. Dietary supplementation with PUFAs increases the production of SPMs in vivo and has demonstrated significant potential to prevent or delay the onset of mild cognitive impairment and Alzheimer’s disease in clinical settings.

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Unsaturated fatty acids and prevention of Alzheimer’s disease

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CHAPTER 5

Malnutrition and early-stage Alzheimer’s disease Sameer Chaudharya, Sapana Chaudharya, Sakshi Rawata, Jayashri Prasanana, and Ghulam Md Ashrafb,c a

RASA Life Science Informatics, Pune, India Pre-Clinical Research Unit, King Fahd Medical Research Center, King Abdulaziz University, Jeddah, Saudi Arabia c Department of Medical Laboratory Technology, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia b

List of abbreviations AAICAD AD ADCS ALA ALS AP/BAP BACE1 BMI BPSD CoQ10 CRISPR CSF DHA EPA FDA FL FTC GEM HCy KBs MAPT MCI MCTs MCTs NMDA NRI NT OL PL PUFA

Alzheimer’s Association International Conference on Alzheimer’s Disease Alzheimer’s disease Alzheimer’s Disease Cooperative Study alpha-lipoic acid amyotrophic lateral sclerosis amyloid plaques; beta-amyloid plaques beta-amyloid cleaving enzyme body mass index behavioral and psychological symptoms of dementia coenzymeQ10 clustered regularly interspaced short palindromic repeats cerebrospinal fluid docosahexaenoic acid eicosapentaenoic acid Food and Drug Administration frontal lobe Federal Trade Commission ginkgo evaluation and memory homocysteine ketone bodies multidomain Alzheimer preventive trial mild cognitive impairment medium-chain triglycerides medium-chain triglycerides N-methyl-D-aspartate nutritional risk index neurofibrillary tangle occipital lobe parietal lobe polyunsaturated fatty acids

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00024-6

Copyright © 2023 Elsevier Inc. All rights reserved.

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ROBR TL UCSF UTI

RAR-related orphan receptor B temporal lobe UC San Francisco urinary tract infection

Introduction Dementia is used to describe an individual’s impaired thinking ability, which hinders their memory recall and decision-making, thereby affecting and interfering with daily routine and activities. Despite dementia being commonly noticed in elderly populations, it does not result from the usual aging process (Sanders, Kaufman, Holmes, & Diamond, 2016). Alzheimer’s disease (AD) is a severe form of dementia characterized by moderate loss of memory at an early stage in senior citizens. Further progression results in eventually losing the ability to maintain a conversation and react to their environment. The death of brain cells in AD affects those neuronal areas controlling language, memory, and thoughts, and symptoms are generally noticeable around 60 years (Fig. 1). AD onset is primarily influenced by age beyond 60 years, while researchers believe that genetics, diet, high blood pressure, environment, high cholesterol, and education are high-risk factors. AD’s spread is predicted to reach 14 million in the United States alone (Kivipelto, Ngandu, Fratiglioni, et al., 2005; Sanders et al., 2016).

Fig. 1 Healthy vs. AD-affected brain. (Dreamstime.com, 02/01/2021.)

Assessing nutritional risk in development of Alzheimer’s disease

Diet and nutrition are significantly associated with severe dementia symptoms (Cortes et al., 2008; Feart, Samieri, Rondeau, et al., 2009). Malnutrition affects elders severely causing poor appetite, resulting in insufficient caloric intake leading to loss of weight and muscle mass (Dorner, 2010), while higher midlife BMI and weight loss in elderly have been reported to increase the risk of developing AD by 75% (Barrett-Connor, Edelstein, Corey-Bloom, et al., 1996; Guerin, Andrieu, Schneider, et al., 2005; Guerin, Soto, Brocker, Robert, et al., 2005; Kivipelto et al., 2005). Loss in cognitive ability coupled with some behavioral and psychological symptoms of dementia (BPSD) defines Alzheimer’s disease, with >80% patients exhibiting neuropsychiatric symptoms (Lyketsos, Lopez, Jones, et al., 2002). Despite decades of extensive AD research, there is no medical treatment yet to halt the progression or cure. The prevention of AD onset in patients at risk or appropriate care of affected individuals poses a great challenge (Kimura, Sugimoto, Kitamori, et al., 2019). The occurrence of dementia could suggest an increased neurodegenerative disease such as Alzheimer’s, Parkinson’s, and others (Kimura et al., 2019).

Neuroscientific aspects Though researchers are yet to identify the underlying cause of brain cell destruction, various possibilities have been hypothesized and explored.

Brain lobe damage hypothesis AD eventually affects the entire brain, but the effects noticed vary individually as influenced by the nature and extent of damage caused to different areas of the brain. AD is primarily marked by significant damage to the temporal lobes, gradually extending to frontal, occipital, and parietal lobes (Fig. 2). Frontal lobes (FLs) play an important role in learning actions and behaviors as well as planning and organizing tasks. Any damage to the FL would require re-learning even the simplest tasks, characterized by repetitive actions or repeated touching or picking of objects, a common symptom associated with AD. In certain cases, an affected individual’s overall behavior might change to inappropriate, reflected in their temperament in private and public (Silveri, 2007). Damage to the occipital lobe (OL) affects the ability to perceive objects, lacking comprehension of visuals, and could result in hallucinations (Cooper & Lee, 1991). In most AD patients, OL remains unaffected, though some extreme cases may exhibit such symptoms probably because of the extensive spread of neurodegeneration to different lobes. The temporal lobe (TL) is extremely crucial to memory; the type and extent of damage differs. For example, episodic memory followed by proper storage of information allows retrieval by remembering or recollecting events. Damage to TL affects the ability

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Brain Cross-Sections

Language

Memory

Normal

Alzheimer’s

Fig. 2 Brain functionalities affected in AD. (Buckeye Psychiatry, LLC, last accessed 02/04/2021.)

to gain a new memory or support retrieval, though certain objects might be recognizable, another hallmark of AD behavior. In cases of early diagnosis, this can be resolved by using cues to improve identification of people, objects, places, things, or events (Cooper & Lee, 1991). Similarly, damage to the nondominant parietal lobe (PL) affects recognition of faces, objects, or surroundings, along with challenges faced in locating objects and performing skilled movements (Cooper & Lee, 1991), another hallmark behavior noticed in AD-afflicted individuals.

Neurofibrillary tangle (NT) hypothesis Neurofibrillary tangles, generated by aggregates of hyperphosphorylated tau protein, have been recognized as an AD-specific marker. Tau protein aggregation impairs the functioning of axons resulting in neurodegeneration, though the role of glial Tau pathology is yet unclear if neurodegeneration is the cause or effect of AD. These are thought to play a key role in neurodegenerative diseases in general (Ito, Arai, Yoshiyama, et al., 2008).

Amyloid plaque (AP) hypothesis The accumulation of sticky and microscopic brain-specific protein fragments called betaamyloid, due to errors in the mechanisms overseeing their production, accumulation, or disposal, disrupts and affects the communication between brain cells, eventually resulting in their death. Earlier study reports implicated large beta-amyloid accumulations in

Assessing nutritional risk in development of Alzheimer’s disease

causing nerve cell toxicity in AD (Selkoe & Hardy, 2016). Therefore, inhibition of BACE1 could be considered imperative in managing AD as it is crucial to cleaving Aβ domain at the N-terminus in APP (Muhammad, Abdul, Muhammad, et al., 2017).

Identification of vulnerable neurons Though researchers have been successful in identifying susceptible neurons in related degenerative disorders like Parkinson’s disease and ALS, knowledge about similar vulnerable neurons in AD has been a mystery. Unlike vulnerable neurons, certain neurons seem unaffected by the surrounding degenerated cells until the final stages. A combined team of molecular biologists and neuropathologists (UCSF Weill Institute for Neurosciences) identified a certain subset of neurons, which disappear during early stages, while another similar group of neurons were susceptible once degeneration reached the brain’s superior frontal gyrus. Using CRISPR-based technology, these groups exhibited RORBexpressing neurons and accumulated NT quicker than the adjacent non-RORBexpressing neurons, though it is yet unclear if presence of RORB enhances the neuron’s susceptibility.

Symptom progression AD is known to develop gradually worsening over time and progresses from minor forgetfulness to eventual impairment of the brain’s functioning as depicted in Fig. 3. The death of crucial brain cells leads to a drastic change in personality, behavior, cognitive abilities, life skills, and skilled movements.

Nutritional aspects Prior investigations conducted on patients with moderate-to-severe AD reports that nutritional deficiencies have been associated with a quick cognitive decline (Soto, Secher, Gillette-Guyonnet, et al., 2012) leading to an increased rate of institutionalization (Payette, Coulombe, Boutier, & Gray-Donald, 2000), and accounting for higher incidences of mortality (Fax
en-Irving, Basun, & Cederholm, 2005). Recent studies explored appetite changes, weight loss, and sarcopenia to begin with MCI and early-stage AD ( Johnson, Wilkins, & Morris, 2006; Kai, Hashimoto, Amano, et al., 2015; Sugimoto, Ono, Murata, et al., 2016; Suma, Watanabe, Hirano, et al., 2018; Ye, Jang, Kim, et al., 2016), though its actual effect in AD onset is yet to be unraveled. However, in elderly suffering from dementia, cognitive, functional, and neuropsychiatric symptoms have been predicted successfully based on their nutritional status (Cortes et al., 2008; Feart et al., 2009; Guerin, Andrieu, et al., 2005; Guerin, Soto, et al., 2005; Malara, Sgro`, Caruso, et al., 2014; Vellas et al., 2012). Nutrient biomarkers such as blood-based nutrients, subsequent metabolites, or metabolic indicators permitted an objective

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Fig. 3 Onset and progress of Alzheimer’s symptoms. (thepurplealmond.com, last accessed 02/02/2021.)

evaluation of the correlation between cognitive decline and dementia risk to diet quality and nutrient interactions (Bowman, Dodge, Guyonnet, et al., 2019). Recent studies on nutrient biomarker patterns have explored the interactive properties between nutrients, thereby providing significant differences in domain-specific cognitive functions (Bowman, Silbert, Howieson, et al., 2012), long-term risk of dementia (Amadieu, Lefe`vre-Arbogast, Delcourt, et al., 2017), and highly favorable neuroimaging parameters (Bowman et al., 2012; Zwilling, Talukdar, Zamroziewicz, & Barbey, 2019). Since no effective pharmacological therapies exist to reduce or prevent AD progression, various nutritional strategies have been considered to treat AD (Martins, Silveira, & Teixeira, 2021) (Fig. 4). (a) Consume adequate micronutrients such as minerals and vitamins, especially those linked to pathways for AD pathophysiology and modulating microbiota. (b) Correction of nutritional deficiencies. (c) Maintain healthy weight. (d) Prevent and/or treat obesity, especially in midlife. (e) Prevent weight loss in later stages of AD. Previous studies reported contradictory results in certain studies on diets high in carbohydrates, whole crops, poultry, and legumes in decreasing the risk for cognitive impairment and development of AD (Roberts, Geda, Cerhan, et al., 2010; Scarmeas, Stern, Tang, et al., 2006). Random trials on the use of dietary supplements conducted under controlled conditions for delaying cognitive deterioration in elders with and without AD or MCI showed disappointing outcomes with some notable exceptions (Aisen, Schneider, Sano, et al., 2008; Durga et al., 2007; Kang, Cook, Manson, et al., 2006, 2008; Petersen, Thomas, Grundman, et al., 2005; Quinn, Clare, & Woods, 2010; Smith, Smith, de Jager, et al., 2010).

Oral health Malnutrition is being caused through ill-fitting dentures, edentulism, and changes in the sense of smell and taste of foods as a result of aging (Sharma, Gupta, Sharma, & Jaswal,

Assessing nutritional risk in development of Alzheimer’s disease

Fig. 4 Influence of multiple nutritional aspects in AD. (Frontiers in Aging Neuroscience, last accessed 20/3/2021.)

2021). As a result, maintaining a healthy diet necessitates the improvement of oral hygiene. A link among both malnutrition and oral health has been found in several studies. In a study of 286 dementia patients providing home-care services, Furuta et al. found that cognitive impairment, denture wear, and tooth number all influenced nutritional status by interfering with oral function, resulting in malnutrition and limitations in everyday activities (Gil-Montoya, de Mello, Barrios, Gonzalez-Moles, & Bravo, 2015). In a study involving 1094 geriatric institutionalized patients, considerable stress was placed on the significance of routine dental examinations in preventing malnutrition (Furuta, Komiya-Nonaka, Akifusa, et al., 2013).

Vitamin D deficiency Inadequate exposure to sunlight, age, and weakened fluid intake influence vitamin D deficiency in occurrence of dementia. A regular dosage of minimum 800 IU vit. D has been recommended as safe for geriatrics, with up to 4000 IU being tolerated (Boucher, 2012). In a recent meta-analysis of previous research on Alzheimer’s disease and five researches on Parkinson’s disease, researchers discovered that these two common problems in aged people make them more susceptible to vitamin D deficiency than normal age-matched populations (Liu, Woo, Wu, & Ho, 2013). From a different point of

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view, vitamin D deficiency has been linked to Alzheimer’s disease. Vitamin D-driven Alzheimer’s disease is mediated by calcium-sensing receptor, amyloid, interleukin-10, matrix metalloproteinases, heme oxygenase-1, reduced NADP, L-type voltage-sensitive calcium channels, nerve growth factor, prostaglandins, cyclooxygenase 2, reactive oxygen species (ROS), and nitric oxide (NO) synthase (Luong, Richard, & Christopher, 2013; Lu’o’ng & Nguy^en, 2011).

Micronutrient deficiencies Essential nutrients have also been linked to the physiopathology of Alzheimer’s disease. Low levels of vitamin B12, A, E, and C, as well as folate, were reported to be linked with Alzheimer’s disease in a major meta-analysis of 80 eligible experiments. Inadequate levels of these compounds, as well as protein and energy deprivation, resulted in a serious case of dementia. As a result, dietary treatments may be able to halt the development of dementia well before permanent cognitive impairment occurs (Chaves-Lopez, Serio, GrandeTovar, et al., 2014).

Applications to other neurological conditions a. Previous literature reports that symptoms similar to AD are also caused by mini stroke, Lyme disease, UTI, and certain medications, leading to possible confusion in diagnosing early-stage AD, thereby affecting quick diagnosis, treatment, and prognosis. Other neurodegenerative diseases include Parkinson’s disease, Huntington’s disease, AIDS dementia, Pick’s disease, B vitamin deficiency-induced neurological disorders, and progressive brain disorders.

Other components of interests Use of acetylcholinesterase inhibitors or NMDA receptor antagonists offering only symptomatic relief has given rise to a need to explore additional approaches to slow AD progression. Based on reports suggesting a decrease in glucose metabolism in brains, it has been hypothesized that neurons be protected using sources that increase neuronal metabolism. To delay the onset, halt or prevent progression, supplementing diet with the following nutrition sources could prove to be effective. (i) Antioxidant supplementation Supplementation with cytosolic antioxidants like Vit E, Vit C, mitochondrial cofactors (CoQ10), organic selenium, Lipoic acid,-carotene, and other bioflavonoids could positively affect patients with mild-to-moderate AD. A clinical trial was conducted by randomly assigning a 4-month treatment comprising of 800 IU/d of vitamin E (α-tocopherol), 500 mg/d of vitamin C, 900mg/d of α-lipoic acid (E/C/ALA), and 400 mg of coenzyme Q 3 times/day or placebo. The primary findings indicated that

Assessing nutritional risk in development of Alzheimer’s disease

antioxidants did not exert any influence on CSF biomarkers linked to amyloid or tau pathology, though lowering of CSF F2-isoprostane levels in the E/C/ALA group was indicative of reduced oxidative stress in the brain, and this study hinted at quicker cognitive decline, a cause of concern requiring monitoring and assessment (Galasko, Peskind, Clark, Quinn, et al., 2012). (ii) Omega-3 fatty acids: PUFA (DHA, EPA) A blood-based NRI investigated the effect of n-3 PUFA, D, and HCy at baseline levels in MAPT participants. MAPT findings demonstrated that n-3 PUFA and DHA promoted neurogenesis, increased synaptic activity, reduced Aβ production and accumulation, and preserved memory and learning (Bowman et al., 2019; Calon, Lim, Yang, Morihara, et al., 2004; Hashimoto, Nawa, Chiba, Aiso, et al., 2006; Kawakita, Hashimoto, & Shido, 2006; Lim, Calon, Morihara, Yang, et al., 2005; Ma et al., 2007; Moriguchi, Greiner, & Salem Jr., 2000). (iii) B vitamins, folate Supplementation with B vitamins, specifically B6, folate, and B12, could assist in slowing the onset and progression of AD as influenced by their correlation with the plasma homocysteine levels that regulate cognitive decline. Supplementing with vit. B has been associated with lowering of total plasma homocysteine, thereby reducing the risks of cognitive decline or dementia (Ghosh, 2021). (iv) Medium-chain triglycerides MCTs get metabolized to ketone bodies that function as an alternate source of energy (for neurons). Clinical trial findings are indicative that MCTs improved cognitive abilities in apolipoprotein E4-negative patients suffering from mild-to-moderate AD, and adverse effects of administering MCTs were noted to be mild like dyspepsia, diarrhea, and flatulence. The role of MCTs in clinical settings needs further investigations and genomic profiling (Sharma, Bemis, & Desilets, 2014). (v) Combination medical foods. Identifying specific nutritional needs in AD, specifically to halt or slow the progression, necessitates a greater understanding of AD and its pathophysiology. There are three medical foods (Table 1): Axona (ketone bodies are used as an alternative source of energy for neurons), Souvenaid (claims to improve synaptic function), and CerefolinNAC (claims to treat oxidative stress linked to loss of memory) (Thaipisuttikul & Galvin, 2012). Tramiprosate, though, originally investigated for its therapeutic benefits to treat AD, has been eventually launched as a medical food. (vi) Traditional medicine/herbs Numerous (prospective) cohort trials have demonstrated insufficient evidence to highlight the effects of Mediterranean diet’s individual components (resveratrol, omega-3 fatty acids, flavonols) promoting cognition improvement in AD and MCI, though significant positive association was noticed with following the Mediterranean diet (Sofi, Macchi, & Casini, 2013). Coconut oil is being commonly used as an alternative to

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Table 1 An overview of medical foods for AD (Thaipisuttikul & Galvin, 2012). Medical food type

Ingredients

Suggested mode of action Clinical trials’ findings

Axona

Caprylic triglyceride

Souvenaid (daily administration for 12 weeks)

Omega-3 fatty acids (EPA, DHA, vitamins B6, B12, C, and E, choline, folic acid, selenium, uridine monophosphate, phospholipids)

CerefolinNAC

L-methyl

Caprylic acid metabolized A substantial increase noted in Moderate sample size to ketone bodies (KBs) serum ketone bodies 2 h Outcomes applicable to KB acts as an energy after administration (Feart mild-to-moderate AD source for neurons but et al., 2009) No generalization glucose utilization Axona group improving applicable to more severe compromised and controls worsening cases Benefits limited to ApoE4negative participants (Feart et al., 2009) Impact on deficiencies in A considerable improvement Moderate sample size the composition and observed in delayed verbal Short duration functioning of neuronal recall Unable to diagnose membranes Clinical outcomes remained probable AD as per Improvement of synapse the same (Scheltens, established criteria formation Kamphuis, Verhey, et al., Insufficient clinical and 2010) ecological relevance of A neuropsychological test neuropsychological battery showed a significant outcomes improvement in memory domain function (Scheltens, Twisk, Blesa, et al., 2012) Effect on metabolic A significant decrease in Small sample size imbalances and hippocampal and cortical No randomization. neurovascular oxidative atrophy rates in participants Improper placebo stress in with both AD and condition hyperhomocysteinemia hyperhomocysteinemia Extrapolation to (Shankle, Hara, individuals with normal Barrentine, & Curole, 2016) homocysteine levels not available

folate, methyl cobalamin, N-acetylcysteine

Limitations of clinical trials

Assessing nutritional risk in development of Alzheimer’s disease

Table 2 Interventions to prevent and treat malnutrition (Mostafa et al., 2020). Approach

Advantages

Disadvantages

Nutritional supplements

Low-cost physiological maintains the satisfaction of tasting In cases of dysphagia, the risk of aspiration is found to lower level. Physiological is a safe way to administer enough caloric intake and an easy route of nutrition for the caregiver, bypassing the need for hand feeding

In long-term administration, drink adherence is poor. It has the potential to cause diarrhea To apply, a procedure is required. It has the potential to cause diarrhea. The rate of aspiration and malnutrition is not as poor as initially assumed. Recurrent hospitalization can be caused by tube blockage and skin problems at the infection site. In feverish patients, tube displacement is normal, due to the use of physical and chemical restraints It is costly to use in patient’s community—dwelling patients. Possible biochemical malfunctions, hypervolemia risk, and nonphysiological, integrity of the oral mucosa and raises the risk of translocation in the bacteria

Tube feeding

Parenteral nutrition

Dietary supplements that work

caprylic acid due to its easy availability. A synthetic version of CoQ10 was found to show no benefits, but exact dosage is unknown as excess amounts could be harmful. Coral calcium has claimed beneficial effects, but FTC and FDA have filed complaints for exaggerated claims and lack of scientific evidence. The GEM study was conducted on 3000 individuals (75 or older) exhibiting MCI or no signs of dementia. The study administered 120 mg of Ginkgo biloba extract twice daily against a placebo group for 6 months and demonstrated no statistical difference regarding the rates of dementia or AD in the test and placebo groups. A clinical trial conducted by ADCS to evaluate the effects of Huperzine A in treating mild-to-moderate AD exhibited no superior benefits. Studies conducted by AAICAD in 2009 to assess the benefits of DHA exhibited mixed outcomes. Though phosphatidylserine’s beneficial effects have been claimed, FDA has recommended that they might not reduce dementia risk in elderly since preliminary research findings supporting this claim are limited (Alternative Treatments j Alzheimer’s Association, last accessed 03/15/2021). (vii) Artificial nutrition Artificial nutrition is generally administered to terminal stage AD patients who are unable to intake food naturally and required to be tube-fed for survival. Though, FDA does not

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approve artificial feeding sane patients who are able to attend their daily needs (Gillick, 2001). Mounting evidence recommends exploring treatments targeting the epigenetic regulators involving different modifications of the epigenetic pathway (DNA methylation, histone posttranslational modifications, microRNAs) are linked with pathogenesis of various neurodegenerative diseases (Gray, 2011; Sezgin & Dincer, 2014; Zhu, Feng, Liu, & Wu, 2015) (Table 2).

Mini-dictionary of terms 1. 2. 3. 5.

MCI: It is commonly defined as a subtle but common memory disorder. Placebo group: A group of subjects kept as control for the study. Test group: A group of subjects administered the drug under study. Artificial nutrition: It involves delivering the patient’s nutritional support such that it does not require chewing and swallowing by the patient. 5. Cohort study: A type of panel study, in which the subjects share a common characteristic or feature (s).

Summary points • • • •

Alzheimer’s disease (AD) is one of the most common types of dementia, with symptoms that are associated and severity affected by risk factors and age. Different hypotheses have been proposed to understand the pathophysiology of the onset and progression. Since AD cannot be cured, it is quite prudent to identify various strategies and devise treatment protocols to delay the onset or prevent or halt the progression. Epigenetic regulators can be crucial in preventing the initiation of Alzheimer’s disease and delaying or halting its development.

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PART II

Amyotrophic lateral sclerosis

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CHAPTER 6

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease Adriana Leico Odaa,b and Cristina C.S. Salvionia,b a

Department of Clinical Neurology—Neuromuscular Diseases, Federal University of Sa˜o Paulo, Sa˜o Paulo, SP, Brazil Clinical, Education and Research in Health, Neuroqualis, Sa˜o Paulo, SP, Brazil

b

List of abbreviations ALS ALSFRS-R kg LMN MND mL UMN

amyotrophic lateral sclerosis amyotrophic lateral sclerosis functional rating scale—revised kilogram lower motor neuron motor neuron disease milliliter upper motor neuron

Introduction Motor neuron diseases are subdivided according to the topography of the involvement, in relation to lower and/or upper motor neurons. In general, it affects the motricity of voluntary, appendicular, and bulbar skeletal muscles, leading the patient to loss of strength, trophism, muscle ability and functionality, as well as changes in reflexes. The progression of signs and symptoms reduces the patient’s autonomy and gradually increases his dependence until the muscles are completely paralyzed. Death happens around 3–5 years after the onset of symptoms, in general, due to the involvement of the respiratory muscles, despite the use of mechanical ventilation. Such a clinical condition can cause the patient with ALS to have a reduction in fluid and food intake, which added to the increase in energy expenditure can bring clinical, nutritional, water, metabolic, and respiratory complications. During the clinical course, the treatment of the interdisciplinary team should be aimed at maintaining functionality and homeostasis, with the stabilization of the condition, as far as possible, minimizing discomfort, avoiding adverse situations, and preventing secondary comorbidities as well as complications to clinical management and not exactly, to the evolution of the disease. Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00029-5

Copyright © 2023 Elsevier Inc. All rights reserved.

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In this scenario, attention focused on hydration care deserves special consideration from all professionals involved in the treatment of patients with ALS given that it is a condition that can be prevented and treated.

Amyotrophic lateral sclerosis/motor neuron disease The term motor neuron disease (MND) applies to progressive clinical syndromes with different clinical variability and etiology, but a final common event is the loss of upper and/or lower motor neurons (Chieia, 2005). The classification of MNDs depends on several criteria, including the predominance of involvement of types of motor neurons, morphological alterations, inheritance pattern, electrophysiological findings, and biochemical and immunological abnormalities. The clinical presentation depends on the affected motor neuron: damage to the upper motor neurons (UMN) brings weakness, spasticity, and hyperreflexia. The death of lower motor neurons (LMN) causes weakness, absent or diminished deep reflexes, and fasciculations. On the other hand, changes in bulbar nerve fibers cause dysphagia, dysarthria, dysphonia, atrophy and tongue fasciculations, and facial weakness (Talbott et al., 2016). Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative disease characterized by the degeneration of both motor neurons: superior (i.e., neurons that project from the cortex to the brainstem and spinal cord) and lower motor neurons (i.e., neurons that project from the brainstem or spinal cord to the muscle), leading to motor and extra-motor symptoms. Its initial presentation may vary among patients; some have an appendicular-onset disease (i.e., the onset of limb muscle weakness), while others may have bulbar-onset disease characterized by dysarthria (speech disorder), dysphonia (voice disorder), dyspnea (respiratory disorder), and dysphagia (altered swallowing) (Hardiman et al., 2017; Talbott et al., 2016). ALS is the most common form of MND and the third most frequent neurodegenerative disease, after Parkinson’s and Alzheimer’s disease (Swinnen et al., 2014; Talbot, 2014). Although the primary symptoms of ALS are associated with motor dysfunction with muscle weakness, spasticity, and dysphagia, up to 50% of patients develop cognitive and/ or behavioral impairment during the course of the disease, with 13% of patients developing frontotemporal dementia (FTD), with concomitant behavioral variant (Elamin et al., 2013; Neumann et al., 2006; Phukan et al., 2012).

Classification and clinical condition The ALS classification may vary according to the criteria used. Traditional definitions of ALS subgroups are based on the extent of involvement of upper and lower motor neurons, although other classification systems include different parameters such as onset (i.e., disease with bulbar or appendicular onset), the level of certainty of diagnosis according to

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

the revised El Escorial criteria, and heritability (sporadic or familial disease) (Al-chalabi et al., 2016; Brooks et al., 2000). Two types of motor neurons are affected in ALS: upper motor neurons (UMN), located in the precentral gyrus, and lower motor neurons (LMN), located in the motor nuclei of the cranial nerves in the brainstem and in the anterior horn of the spinal cord. UMN regulates LMN activity by sending chemical messages via neurotransmitters. Activation of LNM allows contraction of the voluntary muscles of the body. LMN in the brainstem activates bulbar-innervating muscles (face, mouth, tongue, larynx, and pharynx). Those in the spinal cord activate all other voluntary muscles in the body, such as those in the upper and lower limbs, trunk, neck, as well as diaphragm. The clinical diagnosis is based on the initial topographic sites of involvement in the nervous system (UMN, brainstem motor neurons, and spinal motor neurons), characterized by the presence of characteristic signs and symptoms, but in ALS, the simultaneous combined occurrence or at different times of the clinical evolution of signs of dysfunction of the UMN and LMN is necessary (Table 1). Motor neuron disease variants have different clinical progression and prognostic presentations (Chieia et al., 2014), as shown in Fig. 1. Below is the description of the main variants:

Amyotrophic lateral sclerosis Amyotrophic lateral sclerosis (ALS) is characterized by signs of involvement of the UMN and LMN, generating a condition of progressive paresis. It is the most common form of motor neuron disease and the term ALS is often used interchangeably for other forms of MND. The clinical presentation begins with a reference of fatigue for light activities and, not rarely, cramps on exertion. Then, weakness and fasciculations in the limbs or bulbar muscles are associated. In the course of time, regardless of the form of onset, the weakness becomes generalized.

Table 1 Clinical characterization, according to topographic site. Upper motor neuron dysfunction

Lower motor neuron dysfunction

Dysfunction of brainstem motor neurons

Muscle weakness

Muscle weakness

Alive/exalted osteotendinous reflexes (hyperreflexia) Increased muscle tone (spastic hypertonia/ spasticity) Presence of pathological signs (Babinski signs and substitutes, clonus)

Fasciculations

Tongue atrophy and fasciculation Dysphagia

Muscle atrophy

Dysarthria

Hypotonia (reduced muscle tone)

Dysphonia

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a

Spinal onset

e Pseudopolyneuritic ALS

b

Bulbar onset

C

Progressive muscular atrophy

d

Primary lateral sclerosis

f

Hemiplegic ALS

g

Flail arm syndrome

h

Flail leg syndrome

LMN UMN

Fig. 1 Pattern of motor involvement in different ALS phenotypes. Red indicates LMN involvement and blue indicates UMN involvement. Darker shading indicates more severe involvement. (A) In spinalonset ALS, patchy UMN and LMN involvement is observed in all limbs. (B) In bulbar-onset ALS, UMN and LMN involvement is observed in the bulbar muscles. (C) In progressive muscular atrophy, LMNs in arms and legs are involved, often proximally. (D) In primary lateral sclerosis, UMNs of arms and legs are primarily involved, but later in the disease, discrete LMN involvement can be detected. (E) In pseudopolyneuritic ALS, only LMNs restricted to the distal limbs are involved. (F) In hemiplegic ALS, unilateral UMN involvement with sparing of the face, and sometimes discrete LMN involvement, can be observed. (G) In flail arm syndrome, LMN involvement is restricted to the upper limbs, but mild UMN signs can be detected in the legs. (H) In flail leg syndrome, LMN involvement is restricted to the lower limbs and is often asymmetric. Abbreviations: ALS, amyotrophic lateral sclerosis; LMN, lower motor neuron; UMN, upper motor neuron. (Modified from Swinner, B., & Robberrecht, W. (2014). The phenotypic variability of amyotrophic lateral sclerosis. Nature Reviews Neurology, 10(11):661–670.)

Signs of UMN involvement are characteristic and are present in almost all cases, even though sometimes the intensity of atrophy and weakness can mask them. Extrinsic ocular motility and sphincters are preserved. This diagnosis should be suspected when there is clinical and electroneuromyographic involvement of the lower motor neuron, neurogenic electroneuromyographic alterations in clinically normal muscles, signs of UMN involvement, and disease progression.

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

Progressive bulbar palsy Progressive bulbar palsy (PBP) is characterized by predominant impairment of the bulbar innervation muscles, with or without UMN involvement. Dysarthria, dysphonia, and dysphagia are the first clinical symptoms observed, secondary to signs of weakness, atrophy, and fasciculations of the tongue and oropharyngolaryngeal muscles. The involvement of the cervical muscles may also be found. Signs of UMN impairment and emotional lability might be present. Due to the involvement of functions such as swallowing and breathing, the survival of this group of patients is lower than the conditions previously described.

Progressive muscle atrophy Progressive muscle atrophy (PMA) is a specific LMN disease, of cause not yet identified; it is uncommon, accounting for about 5%–20% of MND cases. The clinical manifestation progresses with weakness, atrophy, and fasciculations, usually starting in the upper limbs and progressively involving the lower limbs and the bulbar region. There is no evidence of pyramidal release. Deep reflexes are diminished or abolished. Disease progression can be rapid as in ALS, or slower, with periods of clinical stabilization.

Primary lateral sclerosis Primary lateral sclerosis (PLS) is characterized by an insidious outbreak, with a slow evolution, without signs and symptoms of involvement of any other part of the nervous system, besides the corticobulbar and corticospinal tracts. There is no evidence, at least in the early stages of the disease, of clinical or electroneuromyographic involvement of LMN. Clinically, it manifests as spastic tetraparesis, deep exalted reflexes, bilateral Babinski sign, spastic dysarthria, and emotional lability, characterized by unmotivated crying and laughter, resulting from the pseudobulbar condition (Pringle et al., 1992).

ALS patient functionality scale Studies of progressive diseases, as in the case of ALS, make use of scales as instruments that help recognize the clinical stage of the disease and the patient’s degree of functionality. One of the most frequently mentioned scales in the literature is the Amyotrophic Lateral Sclerosis Functional Rating—Revised (ALSFRS-R), widely used even as a parameter for the definition of clinical behaviors during patient treatment. The ALSFRS-R functional assessment scale was adapted and validated for the Portuguese language (Guedes et al., 2010) and consists of four domains: • Bulbar function (speech, salivation, and swallowing) • Fine motor activities (calligraphy, food-handling skills, handling utensils, and ability to dress and perform hygiene)

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• •

Gross motor activities (turning around in bed, walking, and climbing stairs) Respiratory function (orthopnea, use of mechanical ventilation, and respiratory failure) Each item is scored from 0 to 4 and the total score ranges from 0 to 48, with 0 being incapacity and 48 being normal. Low scores denote a more severe condition of disease. The purpose of functioning scales in neuromuscular diseases is to assess diseaserelevant outcomes while recognizing and controlling patient impairments and incapacities.

Risk factors for dehydration To maintain body hydration, the water source has 70%–80% coming from ingested liquids and 20%–30% from solid foods, such as vegetables and fruits. The calculation of the fluid requirement for the patient with ALS is estimated at 30–35 mL/kg/day (Salvioni et al., 2014). In ALS, there are several risk factors for the development of dehydration, such as (1) reduced fluid intake, which can happen due to motor changes, such as dysphagia, difficulty in the mobility of the upper limbs, difficulty in locomotion, or due to emotional and psychological alterations, such as depression, emotional stress, cognitive changes, reduced decision-making capacity, anorexia, fear of incontinence, fear of not bothering or depending on the caregiver, among others. Or even (2) by the increased demand arising from breathing, motor dysfunction, and hypermetabolism, characteristic of the pathology. Both malnutrition and dehydration may impact the reduction of survival time for these patients in around 12 months (Scagnelli et al., 2018). The main symptoms of dehydration are dizziness, darkened urine and less volume, thirst, dry mouth, headache, fatigue, cramps, tiredness, constipation, thicker secretions as well as rapid weight loss. As they are nonspecific symptoms and of insidious onset, recognition is not always easy. In addition, some of the symptoms of dehydration described here are common to the symptoms of ALS, making diagnosis even harder (Scagnelli et al., 2018). Recognizing the etiological factor that triggers or aggravates the dehydration condition is of fundamental importance for the team to be able to propose assertive therapeutic approaches during the treatment of patients with ALS.

Dysphagia Swallowing is a complex and interlinked neuromotor sequence that ensures the passage of the bolus or saliva from the oral cavity to the stomach, in a safe way. Therefore, coordinated motor adjustments between the orofacial muscles and the laryngopharyngeal

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

region are necessary. In addition, it is essential that coordination between the swallowing and breathing functions exists, so that adequate airway protection can be guaranteed. Dysphagia, which is the difficulty in chewing and swallowing functions, occurs in more than 80% of patients with ALS, during the advanced stages of the disease (Yunusova et al., 2019). Because it is so frequent and due to the seriousness of the nutritional and respiratory risks it can bring to the patient, dysphagia deserves to be diagnosed and treated early. Therefore, dysphagia is the main risk factor for the onset of dehydration, as dysphagia for thin fluids is the earliest sign since muscle weakness does not allow the agility and coordination necessary for the accommodation and ejection the liquid bolus requires. Faced with such difficulty, it is common for the patient to stop drinking liquids, due to fear and discomfort of the occurrence of choking (Alves et al., 2018). After clinical evaluation, the speech therapist will be able to define whether the origin of the presented difficulty occurs due to an alteration in the oral phase and/or pharyngeal phase of swallowing, or even due to incoordination between breathing and swallowing. Other factors can contribute to dysphagia for thin liquids, such as global postural alteration, alteration in cervical adjustment, distractions, co-occurrence of speech/laughing during swallowing, compensatory alteration due to difficulty in taking the utensil to the mouth, difficulty in capturing the content liquid, among others. When the cough strength is weak, the removal of the bolus that eventually enters the airways becomes deficient, increasing the patient’s risk of developing an aspiration bronchopneumonia. One study indicates that while 6.7% of elderly patients are diagnosed with dehydration at the time of hospital admission, this number increases to 44%–75% of dehydration among elderly people with dysphagia (Murray et al., 2015).

Difficulty in the mobility of lower and upper limbs The motor difficulty can impact both the access to the water container and the mobility of the patient to the toilet. The atrophy of the muscles of the hand, especially the thenar muscles, characteristic of ALS, compromises the grip of objects, due to the difficulty in opposing the thumb. This, added to the weakness of the proximal muscles of the upper limbs, prevents handling of objects in activities of daily living, such as serving a glass of water or even taking the glass already filled to put in the mouth and drink. While speech therapy will monitor and create ways to promote safe swallowing, the occupational therapist will create resources to facilitate the gripping and handling of the utensils up to the mouth. As the disease progresses, there is a progressive worsening of the appendicular muscle condition so that the caregiver’s presence becomes necessary to deliver food and liquid to the patient’s oral cavity. Difficulties in relation to locomotion to the toilet, the sequence of actions necessary for using it, and performing hygiene are also observed and must be monitored in order to

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understand when independence becomes compromised, with the need for a caregiver to help in these tasks. A joint approach between occupational therapy and physiotherapy can help the patient in this demand.

Cognitive alteration Behavioral symptoms can coexist with changes in cognitive domains, in the evolution of motor symptoms, in ALS. Cognitive alterations can include alteration of memory, attention, language, executive functioning, and processing speed. Behavioral changes can include apathy, disinhibition, loss of sympathy, as well as egocentric, perseverative, and stereotyped behavior and also changes in eating habits. It is important not to confuse pseudobulbar alterations with disinhibition, inappropriate behavior, or even depression. Changes related to cognition and behavior can bring a series of disadvantages to the patient with ALS, such as nonperception and nonrecognition of their difficulties, as well as nonadherence to the recommendations proposed by the interdisciplinary team, compromising decision-making, including for interventions of life support; thus, it may imply a reduction in the quality of life and also a reduction in survival time. In addition, the caregiver burden becomes even more intense in the presence of cognitive symptoms associated with the motor condition (Caga et al., 2019). The interdisciplinary team needs to be alert to the smallest signs of cognitive and/or behavioral change presented by the patient. And, once diagnosed, it is important that such aspects be incorporated into the therapeutic planning of each professional, with proper readjustment of guidance, stimulation, and strategies to be carried out.

Strategies for improving hydration Dehydration is a clinical condition that has serious consequences for anyone, especially for the patient diagnosed with ALS. The presence of dysphagia can be the primary cause of dehydration and, at the same time, it is the factor that makes management difficult to reestablish water balance. In the presence of dysphagia, the speech therapist can offer the patient some strategies, such as increasing the afference to the thin liquid, such as changing the temperature, flavoring, or gassing. It is known that the afferent is able to modulate the efferent, improving the swallowing motor control response (Reber et al., 2019). Other strategies involve changing the utensil, with the offer of a straw (for those who have good control of the orbicular muscles of the lips and good control of the orofacial muscles and breathing, for controlled suction), a wider cup and other appliances that facilitate the arrival of the utensil to the mouth and others that minimize the movement of cervical extension to capture the liquid bolus because the cervical extension movement can favor the posterior escape of the liquid bolus, even before the swallowing triggers.

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

Teaching the patient some swallowing maneuvers is also an educational resource of great value since it is an orientation that equips the patient with the knowledge that can be applied at all times when he/she swallows the liquid. An example of a maneuver: guide the patient to swallow with the head lowered at approximately 45°, as it is a posture that favors the closing of the airway, facilitating the biomechanics of laryngeal elevation. This maneuver should only be considered for patients who have good cervical control. After swallowing, the speech therapist may also guide the patient to perform some hygiene maneuvers in order to ensure the removal of residues from the laryngopharyngeal region, as it also represents a risk of choking for the patient in the postswallowing moment. There is also the option of thickening the liquids, as a strategy to reduce the risk of bronchoaspiration. The modification of liquids can be done in two different ways: 1. Industrialized thickeners: basically composed of modified corn starch and maltodextrin. Industrialized thickeners only require product dilution to achieve the desired consistency and texture. 2. Homemade thickeners: these add nutritional value to foods and preparations and consist of food products that require manipulation for cooking or liquefying to achieve consistency and texture, for example, thicker juices or with the addition of vegetables such as yam, pumpkin, or sweet potato as well as fruit shakes. It is important to consider that the use of industrialized thickeners can reduce patient acceptability and, in this situation, the fluid recommendation is hardly achieved. Therefore, evaluating the patient’s acceptance and mapping the amount ingested throughout the day are precautions that the team must take, after prescribing the change in the consistency of the thin liquid. This shows us that achieving the ideal consistency for safe swallowing is only part of the process. Another point to be taken into consideration is the worsening of intestinal constipation due to the excessive use of industrialized thickeners. Thus, quite often, the use of natural thickeners is often a simpler, safer, more accepted and cheaper alternative compared to industrialized thickeners. In addition, in the cases of installed dysphagia, the offer of high-liquid foods such as purees, fruits, and vegetables, in addition to shakes and fruit juices, can help with hydration. Reducing the distracting elements of the environment and also the co-occurrence of speech, laughter, and conversation while swallowing liquids are also recommended. For acute cases, the first solution would be to increase the oral supply of thin liquids or foods with a large amount of liquid, avoiding foods that contain sodium. However, in the presence of moderate-to-severe dysphagia, the enteral route via a nasoenteral tube or gastrostomy becomes the most appropriate. Patients with access to the enteral route, when properly oriented, have fewer episodes of dehydration, as the diet itself is able to provide a large part of the necessary amount of fluids. In more extreme cases of dehydration, the patient must be taken to the hospital environment, so that it can be administered parenterally, with monitoring of the general clinical condition.

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Evidence suggests that multimodal interventions are very efficient in the control, prevention, and treatment of dehydration, such as awareness of the team regarding the importance of the theme of hydration (since many professionals are unaware of the real importance and harmful effects that it can cause on the body), assistance with the act of drinking (offering the liquid and assisting in the motor act of taking the utensil to the patient’s mouth, ensuring the necessary control for safe swallowing), and assistance to help the patient move to the bathroom and also use the toilet and do his/her personal hygiene. When patients feel more confident about the support they receive in all these instances, their adherence to the proposed hydration adequacy increases.

Importance of teamwork In the absence of curative treatment, symptomatic interventions and supportive care are still the best way to manage the treatment of the ALS/MND patient. Every effort should be made to increase survival, improve quality of life, and help maintain patient autonomy for as long as possible. The increase in survival of patients with ALS/MND is due to the effectiveness of the care program that aims at the performance of the multidisciplinary team in an integrated manner, keeping the patient actively at the center of all decisions. Thus, the interdisciplinary team has a key role in the therapeutic management of this disease, and the integration among professionals is essential for the treatment to occur in a cohesive way to achieve better results. Interdisciplinary care is the standard approach recommended by European and US guidelines (Andersen et al., 2012; Miller et al., 2009). To maintain functionality independently and safely, managing motor, respiratory, and cognitive symptoms and maintaining and/or recovering good nutritional status, in addition to providing autonomy and quality of life, are part of the rehabilitation team’s goals. As this is a progressive disease, it is of fundamental importance to have periodicity and regularity in therapeutic follow-up so that strategies and behaviors are reassessed, according to the evolution of the disease. Regular and quarterly care integrated between areas was able to increase survival in the group of ALS patients assessed (Sukockien_e et al., 2020). Furthermore, the knowledge and specialization of the team are differentiating factors in the treatment of patients with ALS (Oda et al., 2020). The specialized interdisciplinary approach to managing the disease allows the concentration of the health professional’s experience in an infrequent disease and improves communication among team members, facilitating decision-making from different points of view and faster and appropriate access to the interventions needed for treatment (Paipa et al., 2019). There are studies showing that patients followed by a specialized interdisciplinary team, with experienced professionals in the area, have a better quality of life, in addition to longer survival and lower mortality in the first year, from diagnosis onward, when

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

compared to the group of patients followed by a nonspecialized team. In the statistical analysis, this effect proved to be independent of other factors, such as gastrostomy, noninvasive ventilation, and the use of the drug Riluzole (Aridegbe et al., 2013). Multidisciplinary models of care have been developed as a predictor of survival, reducing the risk of death by 45% in 5 years when compared to patients treated in general neurology clinics (Kiernan et al., 2011). Two population studies have demonstrated a survival benefit for patients attending specialized multidisciplinary clinics. This benefit was regardless of other prognostic factors, including age, disease duration, bulbar-onset disease, and rate of progression (Chio` et al., 2006). Besides, patients attending a multidisciplinary clinic have fewer admissions and shorter hospital stays compared to those attending general clinics (Chio` et al., 2006). The combination of all nonpharmacological therapeutic interventions proposed by the specialized team, added to the drug treatment, allows an integrated view of the clinic, which itself improves the ability to perform the patient’s daily activities, ensuring greater autonomy, functionality, and quality of life in addition to increasing survival.

Applications to other neurological conditions The same care in relation to hydration should be applied to other neuromotor conditions, whether it be progressive or not, and/or also to diseases that lead to cognitive deficits, such as chronic encephalopathy, Parkinson’s disease, stroke, and dementia. Cognitive changes may compromise the patient’s perception regarding the sensation of thirst, as well as the memory of drinking water, and making it a habit to be incorporated into their daily lives. In the field of gerontology, elderly people tend to have a decreased sensation of thirst, due to reduced sensitivity to antidiuretic hormones. This may be one of the factors that contribute to the report of dehydrated elderly people in some studies. Other related risk factors in this population were functional and/or cognitive alterations, dysphagia, speech disorders, and lack of human technical support during meals. Considering that there are neurological diseases that generally affect people over the 6th decade of life, it is also important to be aware of the aspect of the lack of sensation of thirst reported by the elderly patient. Chronic diseases that reduce the functionality, autonomy, and independence of the patient require the presence of a caregiver, who can be formal or a family member as the element that helps the patient in their daily activities, in whole or in part, depending on the health condition and the degree of functional independence. In these cases, it is essential that the team provide guidance and training for these caregivers, in order to emphasize the importance of offering water, within the conditions of swallowing and handling the utensil, which the patient presents, as well as helping him/her with his/her personal hygiene.

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Other factors, psychic and emotional, should also be considered as risk factors for the development of dehydration: anorexia, inappetence, fragility condition, and depression. Patients undergoing treatment with diuretic medications should be monitored, as well as clinical situations in which there is an alteration in renal perfusion (such as chronic kidney disease or cardiac alterations), where it is necessary to reduce the ingested water volume. This situation must be carefully treated in order to guarantee the water balance necessary for the proper functioning of the systems.

Other components of interest The distribution of water in different body compartments in healthy individuals, around 60% of body weight, guarantees homeostasis of various physiological functions, such as temperature regulation, chemical reaction solvent, electrolyte balance, among others. In ALS, with the evolution of the disease, there is an important loss of muscle mass, which also impacts the aspects of hydration, since the skeletal muscle tissue has a large amount of intra- and extracellular water (Bartok et al., 2004; Kehayias et al., 2012). A study that evaluated the hydration parameters using the bioelectrical impedance method found that nonsarcopenic individuals had better hydration rates when compared to sarcopenic individuals (Espo´sito et al., 2015). It is noteworthy that the definition of sarcopenia, in addition to a reduction in muscle mass, encompasses a decrease in muscle strength and poor performance and physical functioning. Hydration levels have been positively associated with muscle strength and functionality, in addition to appearing as determinants of functional independence in the elderly (Yamada et al., 2014), which demonstrates the importance of analyzing body compartments with a view to hydration as well. For the assessment of body compartments in ALS, bioelectrical impedance (BIA) has already been validated compared to dual-energy X-ray absorptiometry (DEXA), a method considered the gold standard for analyzing body composition. It is a simple, quick method, more available for evaluating these patients in clinical practice, in addition to being cheaper when compared to DEXA (Burgos et al., 2018; Desport et al., 2008). Some more developed bioimpedances assess the intra- and extracellular water in a compartmentalized way, qualifying more assertively the hydration of the individual. Detailed reviews demonstrate that there is insufficient evidence of the effectiveness of antioxidants in the treatment of patients with ALS (Orrell et al., 2004). The high tolerance and safety, allied to a relatively low cost, would explain the established use of vitamins and minerals in degenerative diseases. It is essential that the use of nutraceuticals and dietary supplements for patients with ALS be more widely studied, considering their widespread use in this population and the benefits and potential risks of consumption. Furthermore, its prescription must always be based on scientific evidence.

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

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Coenzyme Q10: Ubiquinol or coenzyme Q10 (CoQ10) is an essential cofactor in the mitochondrial respiratory chain and has been used as a food supplement due to the promising results found in transgenic animal models of ALS (Matthews et al., 1998). Its prescription has been performed for patients with ALS, although without scientific support (randomized trials do not confirm the supposed benefits of such supplementation with antioxidant characteristics) (Kaufmann et al., 2009). Curcumin: The main component of polyphenol curcuminoid has been studied for its antioxidative protective properties against neurodegenerative contexts. Its theoretical potential benefit is related to effects against oxidative stress, mitochondrial dysfunction, antiinflammation, and reduced protein aggregation. Its mechanism of action is attributed to different factors, including the reduction of activation of the NF-kB pathway and the activation of the Nrf2 factor (nuclear factor erythroid-2-related factor), reducing mitochondrial dysfunction and the possibility of oxidative damage, and reducing the rate of aggregation and excitotoxicity by SOD1 and TDP-43 (CarreraJulia´ et al., 2020). A double-blind clinical study showed evidence of a reduction in the rate of progression of ALS in the group that used curcumin, as well as in the rate of oxidative damage (Chico et al., 2018). At the moment, there is no current formal indication for the use of such medication in clinical practice. Creatine: It is a compound of amino acids present in the muscle fibers and brain, with fundamental importance in the supply of energy for adenosine triphosphate resynthesis as well as intracellular energy deposition (Groeneveld et al., 2003). Sufficient amounts of creatine are therefore important to prevent energy depletion (Tefera & Borges, 2016). Aiming to increase energy deposits, Klivenyi et al. (1999) found that the oral dose of creatine improved motor performance and survival in G93A transgenic rats, in addition to slowing the oxidative damage caused by the disease. Furthermore, long-term creatine supplementation in SOD1G93A mice was able to reduce NMDA-induced glutamate release in the cerebral cortex (Andreassen et al., 2001). Although preclinical studies were promising, several clinical trials failed to show significant beneficial effects in improving disease progression or patient survival (Rosenfeld et al., 2008; Shefner et al., 2004). L-Serine: It is an amino acid that emerged as a possible adjuvant in the treatment of ALS. This amino acid, after several studies, proved to be useful in hindering the formation of poorly enveloped or nonenveloped proteins. Furthermore, L-serine prevented an increase in the formation of an enzyme that causes the death of motor cells in the brain and spinal cord induced by beta-methylamino-L-alanine (BMAA). The first preclinical study with L-serine in ALS was so promising that it has now been used in human trials to determine its beneficial potential in the natural history of the disease and, of course, in the intricacies of the pathophysiological framework of ALS. The first study, a phase I clinical trial, was conducted to assess the safety of the amino acid (Levine et al., 2017). The results presented were relevant with the dosage of 15 g twice a day.

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Branched-chain amino acids: In ALS/MND, the supplementation of branched-chain amino acids is not recommended in the literature. Excessive and recurrent consumption through nutritional supplementation of these amino acids contributes to the worsening of disease progression, possibly because they are glutamate precursors (Carunchio et al., 2010; The Italian ALS Study Group, 1993; Venerosi et al., 2011).

Key facts • • • • • • • •

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Neurogenic oropharyngeal dysphagia affects more than 80% of patients diagnosed with advanced ALS. Respiratory and nutritional complications can result from neurogenic dysphagia, especially when the patient does not receive adequate treatment. Bulbar muscle weakness can reduce the survival of patients with ALS, due to the continuous risk of bronchoaspiration and inadequate food and water intake. Percutaneous endoscopic gastrostomy is a measure that has been adopted for patients with ALS, as it worsens dysphagia and respiratory failure. The water recommendation for adults is 30–35 mL/kg of weight and for the elderly, 30 mL/kg of weight. Cognitive alterations, in a mild-to-moderate degree, may be present in 35% of patients with ALS and frontal dementia in 15% of patients with the disease. Dehydration has an impact on the survival time of patients with ALS, which can reduce this time by around 12 months. Maintaining fluid and electrolyte balance is the key to preventing and treating dehydration; two important strategies are to perform fluid replacement and avoid foods/ liquids containing sodium. Evidence suggests that multimodal interventions can be effective in preventing dehydration, such as increased awareness of the team, assistance to help the patient ingest fluids, support to help the patient use the bathroom and offer a wide variety of fluids, modifying the afference of the liquid, the utensil, or the swallowing maneuver.

Mini-dictionary of terms •

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Motor neuron disease: The term motor neuron disease (MND) applies to progressive clinical syndromes, characterized by the loss of upper and/or lower motor neurons, although they are conditions with great clinical variability. Amyotrophic lateral sclerosis: A disease that is part of the list of motor neuron diseases. It is characterized by the involvement of upper motor neurons and lower motor neurons. Fasciculation: Involuntary contraction of muscle fibers innervated by a motor unit. Lower motor neuron injury is the etiology of fasciculations.

Strategies for improving hydration in patients with amyotrophic lateral sclerosis/motor neuron disease

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Hyporeflexia/areflexia: A neurological condition in which reflexes are diminished or absent due to lower motor neuron injury. Spasticity: Hypertonia condition, that is, increased muscle tone, secondary to upper motor neuron injury. Dehydration: A clinical condition in which the decrease in total body water volume is greater than the volume of water that the body is able to replace, either due to insufficient intake and/or excessive loss. Neurogenic dysphagia: Difficulty in chewing and swallowing of neurological etiology, which affects the passage of the bolus from the mouth to the stomach. Hypermetabolism: Significant increase in the measurement of energy expenditure at rest in relation to the predicted energy expenditure. Laryngeal penetration: Reference to the ingested material (food, liquid, or saliva) that enters the airways, in a region above the vocal folds, leading the patient to a choking episode. Bronchoaspiration or laryngotracheal aspiration: Occurrence of the passage of ingested material (food, liquid, or saliva) in the airways, in a region below the level of the vocal folds. If it is not expectorated, this content can lead the patient to aspiration pneumonia.

Summary points • •

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This chapter focuses on the characterization of motor neuron disease/amyotrophic lateral sclerosis and its particularities, in relation to its pathophysiology. The hydration of patients with ALS/MND may be compromised by dysphagia, especially for thin fluids, which is one of the first signs of dysphagia observed in the clinical assessment of speech therapy. Other factors can also interfere with the intake of the recommended amount of liquids, such as difficulty in the upper limbs that makes it difficult for objects to reach the mouth; difficulty in walking, which makes it impossible for the patient to access the bathroom; and lack of autonomy for self-care and hygiene. Emotional aspects can also be related to lower fluid intake, as the patient may not want to bother the family member and/or caregiver, with the request for water or asking for help to go to the bathroom. Still, regarding adaptations to lack of mobility, not all patients can comfortably get used to wearing pull-up diapers, even if it is only during some period of the day or night. Decreased hydration may imply difficulties related to the quality of secretion located in the oral pharyngolaryngeal region, which may intensify the patient’s respiratory discomfort.

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In the case of dysphagic patients, the indication to ingest thickened fluids can be a strategy adopted for greater airway safety. However, the acceptability of the use of industrialized thickeners may be low, causing an even greater decrease in fluid intake. Dehydration can reduce not only the quality of life but also the survival time of patients with ALS, around 12 months. Adequate hydration for an ALS patient requires integrated teamwork, which involves not only nutritionists and speech therapists but also physiotherapists, occupational therapists, and psychologists, in addition to family members and caregivers.

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Sukockien_e, E., Iancu Ferfoglia, R., Truffert, A., Heritier Barras, A. C., Genton, L., Viatte, V., … Janssens, J. P. (2020). Multidisciplinary care in amyotrophic lateral sclerosis: A 4-year longitudinal observational study. Swiss Medical Weekly, 150, w20258. https://doi.org/10.4414/smw.2020.20258. Swinnen, B., et al. (2014). The phenotypic variability of amyotrophic lateral sclerosis. Nature Reviews. Neurology, 10(11), 661–670. Talbot, K. (2014). Amyotrophic lateral sclerosis: Cell vulnerability or system vulnerability? Journal of Anatomy, 224(1), 45–51. https://doi.org/10.1111/joa.12107. Talbott, E. O., Malek, A. M., & Lacomis, D. (2016). The epidemiology of amyotrophic lateral sclerosis. Handbook of Clinical Neurology, 138, 225–238. https://doi.org/10.1016/B978-0-12-802973-2.00013-6. Tefera, T. W., & Borges, K. (2016). Metabolic dysfunctions in amyotrophic lateral sclerosis pathogenesis and potential metabolic treatments. Frontiers in Neuroscience, 10, 611. The Italian ALS Study Group. (1993). Branched-chain amino acids and amyotrophic lateral sclerosis: A treatment failure? Neurology, 43(12), 2466–2470. Venerosi, A., et al. (2011). Complex behavioral and synaptic effects of dietary branched chain amino acids in a mouse model of amyotrophic lateral sclerosis. Molecular Nutrition & Food Research, 55(4), 541–552. Yamada, Y., et al. (2014). Application of segmental bioelectrical impedance spectroscopy to the assessment of skeletal muscle cell mass in elderly men. Geriatrics & Gerontology International, 14(Suppl 1), 129–134. Yunusova, Y., Plowman, E. K., Green, J. R., Barnett, C., & Bede, P. (2019). Clinical measures of bulbar dysfunction in ALS. Frontiers in Neurology, 19(10), 106. https://doi.org/10.3389/fneur.2019.00106.

Further reading Cappellar, A., et al. (2008). The pseudopolyneuritic form of amyotrophic lateral sclerosis (Patrikios’ disease). Electromyography and Clinical Neurophysiology, 48(2), 75–81. Chio`, A., et al. (2009). Prognostic factors in ALS: A critical review. Amyotrophic Lateral Sclerosis, 10(5–6), 310–323. Patel, B. P., et al. (2009). Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis. Clinical Nutrition (Edinburgh, Scotland), 28(6), 604–617.

CHAPTER 7

Diet, disease severity, and energy expenditure in amyotrophic lateral sclerosis (ALS) Zoe Castlesa, Lauren Buckettb, Leanne Jiangb,c, Frederik J. Steyna,d, and Shyuan T. Ngob,d a

School of Biomedical Sciences, The University of Queensland, Brisbane, QLD, Australia Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, QLD, Australia c School of Biological Sciences, The University of Western Australia, Perth, WA, Australia d Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia b

List of abbreviations AD ALS ALSFRS-R BMI ESPEN GLIM HD MND PD PUFAs SGA SOD1 TDP-43 TEE

Alzheimer’s disease amyotrophic lateral sclerosis ALS Functional Rating Scale-Revised body mass index European Society for Clinical Nutrition and Metabolism global leadership initiative on malnutrition Huntington’s disease motor neuron disease Parkinson’s disease polyunsaturated fatty acids subjective global assessment superoxide dismustase 1 TAR DNA-binding protein-43 total energy expenditure

Introduction Amyotrophic lateral sclerosis (ALS), the most common variant of motor neuron disease (MND), is characterized by the loss of motor neurons in the brain and spinal cord that control voluntary movement and respiration. The disease is devastating for individuals, families, and their support networks as it results in progressive worsening paralysis, significant disability, and eventual death within 3–5 years following disease onset (Cleveland & Rothstein, 2001; Kiernan et al., 2011). Currently, there is no cure, and the one therapeutic treatment available in Australia, Riluzole, extends life by 6–19 months in some patients (Andrews et al., 2020; Miller, Mitchell, & Moore, 2012). As such, research aimed at understanding the pathogenesis of disease, and identifying effective treatments for the disease is ongoing. Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00007-6

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Ensuring adequate nutrition and dietary intake has become an important aspect of multidisciplinary care and disease management in ALS. Malnutrition, largely characterized by weight loss (Lopez-Gomez et al., 2021), is evident in 10%–55% of patients at the time of diagnosis and is related to both shorter survival and reduced quality of life (Korner et al., 2013; Marin et al., 2016). Early assessment of nutritional status can address malnutrition and prevent associated symptoms of fatigue, reduced muscle strength, depression, anxiety, and self-neglect (Bianchi, Herrera, & Laura, 2021; Janse van Mantgem et al., 2020; Lopez-Gomez et al., 2021; Stavroulakis & McDermott, 2016). Emerging evidence also suggests that dietary management may modify disease severity and survival in neurodegeneration in general (Bianchi et al., 2021). There are several challenges associated with addressing nutritional needs in patients with ALS. Firstly, the cause of malnutrition appears to be multifactorial (Korner et al., 2013) and the most effective means for estimating and addressing energy requirements in ALS is still debated (Marin et al., 2011). Dietitians currently follow European Society for Clinical Nutrition and Metabolism (ESPEN) (2018) guidelines to identify and manage malnutrition to ensure early gastronomy intervention where necessary (Burgos et al., 2018). However, given the lack of disease-specific dietary assessment tools, it is difficult to determine whether weight loss in ALS is due to the degeneration of muscle and/or nutritional factors. Secondly, reliance on supplements and tube feeding can become the only means to meet energy requirements for some patients. While the placement of a feeding tube and the use of dietary supplements can improve quality of life (Korner et al., 2013), there are limited supplement options available, and not all patients accept this intervention (Pols & Limburg, 2016). The direct effect of diet on improving outcomes for people living with ALS is yet to be fully established. There is likely to be no stand-alone dietary intervention that works uniformly in combatting ALS. However, recent studies have investigated how the consumption and manipulation of macronutrient content, an easily modifiable dietary element, can aid in weight maintenance and address physiological aspects of the disease (Bianchi et al., 2021; Kim et al., 2020; Ludolph et al., 2020). Here, we summarize what is known about the challenges of achieving energy balance and addressing nutritional needs in ALS. We also highlight current evidence for the use of nutritional assessment tools in ALS, and the influence of macronutrients (including dietary forms of protein, fiber, fats, carbohydrates), high-calorie diets, and dietary supplementation on disease outcomes. Lastly, we discuss the influence and applications of dietary modification with respect to other neurological diseases.

The challenge of energy balance in ALS Maintaining energy homeostasis is challenge for individuals with ALS (Ioannides et al., 2016; Ngo & Steyn, 2015). Up to 68% of patients with ALS may exhibit an increase in

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resting metabolic rate (referred to as hypermetabolism) (Ahmed, Dupuis, & Kiernan, 2018; Ioannides et al., 2016; Jesus et al., 2019; Pape & Grose, 2020). Hypermetabolism is associated with faster disease progression and earlier death in patients with ALS (Steyn et al., 2018). Interestingly, hypermetabolism is not always associated with weight loss (Steyn et al., 2018), and studies using the SOD1G93A mouse model of ALS would suggest that decreases in weight gain, and weight loss might precede the development of hypermetabolism (Steyn et al., 2020). Regardless, the capacity to sustain adequate nutrition to potentially offset this increase in energy expenditure can be affected by disease-related changes to swallow, taste, mood, and saliva excretion (Genton et al., 2011; Mezoian et al., 2020). The ability to obtain nutrients can also be affected by a decrease in upper body strength that limits independent feeding, and/or constipation resulting from weakness in abdominal muscles as well as reduced physical activity and fluid intake (Burgos et al., 2018; Lopez-Gomez et al., 2021). Moreover, alterations in appetite and eating behavior may arise from changes in cognition (Achi & Rudnicki, 2012; Ahmed et al., 2016; Govaarts et al., 2016), or structural changes in brain regions that govern appetite control (Bede & Hardiman, 2018). While loss of appetite does contribute to weight loss in patients with ALS (Ngo et al., 2019), not all individuals exhibit changes in nutrition, appetite, and/or weight loss. This indicates that the causes for, and possibly the impact of, altered energy balance varies greatly between ALS individuals (McCombe et al., 2020). The interplay between factors that underpin loss of appetite, dysregulated energy balance, malnutrition, and weight loss in ALS is not yet fully understood and requires further research. In the interim, addressing energy intake and malnutrition is a potential way to manage one aspect of the energy imbalance in ALS.

Addressing malnutrition in ALS Preventing and adequately addressing malnutrition in ALS requires the accurate assessment of daily energy requirements and nutritional state. Energy requirements and physical function change over the course of disease. Given the progressive nature of ALS and the prevalence of hypermetabolism, accurately calculating individual daily energy requirements can be difficult. Ideally, total energy expenditure (TEE) would be measured for each individual at regular intervals using the gold-standard method of indirect calorimetry (Burgos et al., 2018). However, this is not generally feasible in clinics given the need for costly equipment. Hence, equations for estimating energy expenditure are the preferred tool. Standard equations tend to either over- or underestimate the energy requirements of patients with ALS (Georges et al., 2014). As such, the validity of predictive equations for energy requirements in ALS remains to be verified. Current ESPEN guidelines for nonventilated ALS patients suggest that intake should be estimated as 30 kcal/kg body weight depending on physical activity, while also being adapted to

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account for alterations in body composition (Burgos et al., 2018). Kasarkis and colleagues (2014) proposed the use of a modified Harris-Benedict equation, integrated into a web-based calculator, which factors in height, weight, age, sex, ALSFRS-R score (ALS Functional Rating Scale-Revised score; a measure of functional capacity), and energy intake from a 24-h food diary recall. Although not without limitations, this formula seems accurate and practical for estimating daily TEE in a clinical or homebased setting. Determining nutritional status can help identify those at risk of malnutrition and thus inform direct nutritional intervention. Currently, there is no ALS-specific nutrition assessment tool, so malnutrition is largely assessed based on anthropometric measures of weight or BMI (Stanich et al., 2015), which does not account for specific changes in eating behavior, or categorize risk for developing malnutrition. Tools such as the Subjective Global Assessment (SGA) and Global Leadership Initiative on Malnutrition (GLIM) criteria appear more comprehensive; these are sensitive to small changes in condition and can predict survival in ALS (Lopez-Gomez et al., 2021). The SGA incorporates weight loss, changes in dietary intake, gastrointestinal symptoms, functional capacity, metabolic demand related to disease, muscle wasting and fat loss through patient recollection, biochemistry, and physical variables. It identifies and categorizes malnutrition into three groups: good nutritional status, moderate malnutrition, and severe malnutrition (da Silva Fink, Daniel de Mello, & Daniel de Mello, 2015). The GLIM criteria define malnutrition more specifically by the sum of two factors: (1) a phenotypic criterion between weight loss, BMI, and a decrease in fat free mass and (2) an etiological criterion between a decrease in food intake below 50% of estimated requirements and the presence of a disease that increases inflammatory stress (Lopez-Gomez et al., 2021). Both tools may provide an alternative to anthropometric measures for assessing, monitoring, and treating malnutrition in ALS. While the risk of weight loss in ALS is well documented, there are contrasting findings around whether weight gain is beneficial over the disease course (Heritier et al., 2015). Weight gain has the potential risks of obesity and metabolic syndromes, which could exacerbate neurodegeneration due to insulin resistance and inflammation (Bianchi et al., 2021). Furthermore, weight gain can limit maintenance of passive and active movement for patients and their caregivers (Heritier et al., 2015). According to the ESPEN guidelines (Burgos et al., 2018), where baseline BMI < 25, weight gain is recommended (Fig. 1A). On the contrary, where BMI > 35, weight loss is advised. These recommendations reinforce the notion that a generalized dietary intervention approach is not likely to be fit for purpose in ALS and that dietary advice should be tailored to the individual, their weight status and clinical presentation.

Diet and energy expenditure in ALS

Fig. 1 Risk of faster disease progression in ALS is associated with BMI (A). Having a low BMI increases risk for faster progression and shorter survival (Dardiotis et al., 2018); however, mortality risk increases again, as BMI increases beyond 35 (i.e., extreme obesity). The cause for this u-shaped association is not currently known; however, increased risk for earlier death in morbidly obese patients is likely associated with increased risk of other comorbidities that are associated with obesity (Kirk et al., 2019). Consequently, current ESPEN guidelines encourage weight gain if BMI < 25, and weight loss is encouraged if BMI > 35 in patients with ALS (Burgos et al., 2018). (B) Given that factors that contribute to weight loss in patients with ALS vary between individuals (i.e., not all patients experience hypermetabolism, loss of appetite, or other factors known to impact dietary intake), individualized approaches to support weight maintenance or gain is recommended. There is a need to establish effective strategies to establish the nutritional needs of patients. When coupled with intensive and personalized care (that includes regular revision of strategy), there is potential to stabilize weight, which ultimately could improve disease outcome.

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The impact of macronutrients in ALS The impact of macronutrients on disease outcome has been assessed in retrospective dietary analysis studies and intervention studies in mouse models and ALS patients. The findings of these studies are significantly variable and are collated in the discussion below. Although not heavily reported on, diet has the potential to positively or negatively impact quality of life (Korner et al., 2013), and as such, the suitability of the interventions reviewed here must consider individual factors beyond disease presentation alone including lifestyle, food preferences/habits, intolerances, and socioeconomic status.

Protein High-protein intake could be beneficial in ALS, as protein stimulates muscle growth, which may compensate for the hypercatabolic state observed in some patients with ALS (Kim et al., 2020). However, despite the theoretical benefit, a limited number of studies have looked at protein intake and its impact on disease outcomes. In a small clinical trial, Silva and colleagues (2010) found that a protein supplement of 70% milk serum protein and 30% modified starch per 1.2 g/kg body weight led to a preservation of lean body mass and skeletal muscle turnover markers, while also stabilizing ALSFRS-R. To our knowledge, no other study has trialed a high-protein diet in ALS, and thus, this observation is yet to be validated. In observational studies, Pupillo and colleagues (2018) reported an increased risk of ALS in individuals consuming pork/processed meat and red meat, suggesting protein from particular sources may be disadvantageous to the disease. However, contrasting this, Kim et al. (2020) reported that ALS patients with longer disease duration, tracheostomy or ventilator intervention, consumed significantly more protein (particularly from meat sources) than those with shorter disease duration. The discrepancy across these studies is difficult to discern; however, it must be noted that the studies by Pupillo et al. and Kim et al. relied on the recall of dietary information through a once off 24-h diet diary, which may not accurately represent longterm diet and has inherent recall bias. No study has indicated the mechanism through which protein exerts benefit in ALS beyond stating the benefit in contributing to overall energy intake. Hence, there is a need for clinical studies to further investigate the role of dietary protein in ALS.

Fiber Fiber is known to lower inflammatory markers in some diseases and influence gut bacteria (Ngo et al., 2017; Xu et al., 2014). The impact of gut bacteria on ALS disease outcomes is contradictory with some studies reporting dysbiosis (Rowin et al., 2017), some reporting no difference (Brenner et al., 2018), and others reporting slight differences (Boddy et al.,

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2021). Whether gut dysbiosis elicits negative effects in ALS is also contradictory (McCombe et al., 2019; Ngo et al., 2020). Nevertheless, the intake of fiber and its potential to influence the gut bacteria, and thereby, disease outcomes have been a primary area of focus in ALS research. A recent study conducted by Blacher and colleagues (2019) collected microbiome data from SOD1 mouse models and from ALS patients. The study is the first of its kind and identified changes in the gut bacteria that correlated with biological activity of nicotinamide, a microbial metabolite, which may influence the expression of mitochondrial genes in the spinal cord (Blacher et al., 2019). Interestingly, changes in gut bacteria were found to correlate with disease severity in mice and ALS patients. A recent longitudinal ALS cohort study examined dietary fiber intake and its impact on disease severity and survival (Yu et al., 2020). Using a 24-h dietary recall and retrospective analysis of fasting blood chemistry and cerebral spinal fluid, researchers found that the intake of fiber-rich foods including nuts, seeds, and vegetables were positively associated with ALSFRS-R and longer survival in patients with ALS. It was subsequently suggested that a minimum of 20 g of fiber per day could be recommended for individuals with ALS. Although an interesting finding, microbiome data were not collected in this study, and hence, a direct impact of the dietary fiber on gut bacteria cannot be concluded from this study. Vegetable fiber may be advantageous over fiber from other sources such as cereals and fruits, as it yields a greater amount of butyrate (Casterline, Oles, & Ku, 1997; McBurney & Thompson, 1990). Butyrate, a by-product of fiber digestion, is proposed to impact disease progression through modulating intestinal homeostasis and exerting an antiinflammatory effect (Yu et al., 2020). Butyrate treatment was found to be beneficial in SOD1 mice, indicating potential for it to be a supplement in the diet of ALS patients (Zhang et al., 2017). Phenylbyturate has since been found to be safe and well tolerated in a phase-2 clinical trial in ALS patients (Cudkowicz et al., 2009). As such, it is now being progressed to larger scale safety and efficacy trials. It is plausible that further evidence from these clinical trials will confirm whether increased fiber intake in the diet or through supplementation alone can elicit benefits in ALS.

High-calorie oral and enteral diets High-calorie diets have been proposed as a potential dietary intervention both alone or in combination with drug therapies (Pape & Grose, 2020). As depletion of fat and muscle stores is frequently observed during disease course, providing additional substrates through a high-calorie diet may benefit patients with ALS by promoting weight gain (Pape & Grose, 2020). Increasing the availability of specific metabolites may also improve energy production (in the form of ATP), which may be particularly beneficial for the function of neurons (Vandoorne, De Bock, & Van Den Bosch, 2018).

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Numerous studies using mouse models of ALS show that high-fat diets mitigate loss of fat mass while improving survival (Coughlan et al., 2016; Zhao et al., 2015). Coughlan et al. (2016) and Zhao et al. (2015) found that a high-fat diet improved survival in SOD1 and TDP-43 ALS mice by increasing fat stores and improving motor function. One theorized mechanism for the observed benefits in mice is that a high-fat diet relieves elements of the hypermetabolic stress (Pape & Grose, 2020). Nevertheless, it has also been noted that a high-fat diet can contribute negatively to the high lipid metabolism observed in ALS, which can have a toxic effect on mitochondria (Ngo et al., 2017). The ketogenic diet, another high-fat and low-carbohydrate diet originally created for the treatment of epilepsy, has shown promise in two studies on SOD1 mice (Ari et al., 2014; Zhao et al., 2006). Zhao and colleagues (2006) found that body weight and number of spinal cord neurons were higher in mice receiving a ketogenic diet when compared to those not receiving a ketogenic diet. By stimulating the production of ketone bodies, it is hypothesized that a ketogenic diet has multifactorial benefits which protect the neuromuscular system. This includes enabling access to a more energy efficient fuel source and providing a larger mitochondrial load, managing oxidative stress through antioxidant effects, and improving the transmission of signals through the neuron (Zhao et al., 2006). To our knowledge, the effects and inherent risks of this diet in humans have not been studied, and thus, its benefits in human ALS cannot be concluded. Clinically, there is concern that the ketogenic diet can result in weight loss, which would compound malnutrition in ALS. Further clinical research is needed (Ngo et al., 2017). The benefits of high-fat versus high-calorie diets of varying constituents remain to be clarified, as comparative clinical studies are contradictory. In a small study conducted by Wills and colleagues (2014), patients on a high-fat high-calorie enteral diet were unable to gain weight while those who were on the high-carbohydrate high-calorie diet were able to do so. Moreover, a number of studies trialing high-fat diets in ALS patients report gastrointestinal discomfort as a common side effect (Pape & Grose, 2020). Further studies are needed to elucidate how fatty acids elicit beneficial or harmful effects, whether there is a specific ratio of carbohydrates and fats that is most beneficial in ALS patients, or whether increasing calories alone should be the focus of interventions.

High-calorie supplements The use of supplements may be of benefit to patients with ALS who exhibit dysphagia or loss of appetite. These enable macronutrients to be administered in an alternate and easily digestible form that can be an adjunct to a regular diet. Retrospective epidemiological studies indicate that patients on a high-calorie food supplement have improved survival (Lopez-Gomez et al., 2021). However, there are conflicting findings in prospective studies.

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Dupuis et al. (2004) found that a high-fat supplement added to a regular chow diet in SOD1 mice improved mean survival time by 20% in comparison to a regular chow diet. Similarly, Dorst and colleagues (2013) found that high-calorie supplementation is effective in promoting weight gain in ALS patients and that a high-fat supplement may be more effective than a high-carbohydrate supplement. However, as alluded to earlier, there appears to be low tolerance to high-fat diets in human studies, which limits the feasibility of this intervention approach and necessitates that further qualitative studies be conducted to determine their suitability in ALS. Ludolph and colleagues (2020) investigated the impact of high-calorie supplementation in addition to normal food intake in patients with ALS. Their study found that supplementation provided no survival benefit, although post hoc analysis revealed a subgroup of fast progressing patients on supplementation who had increased survival. Further studies are needed to confirm this and the effect of high-calorie supplements in ALS patients in general.

Other components of interest Micronutrients Similar to macronutrients, the affect and effect of micronutrients (vitamins) in ALS have been debated for some time. Micronutrients are essential for guiding pathways of neurodevelopment and may confer susceptibility to disease if a deficiency occurs. For example, evidence suggests that vitamin D is neuroprotective in some neurological disorders. Karam and Scelsa (2011) proposed the use of vitamin D as a potential therapeutic for patients with ALS. However, studies to date have shown mixed responses. An in vitro study, mouse-derived motor neurons treated with vitamin D were completely rescued from death (Camu et al., 2014). While it has been suggested that vitamin D deficiencies are associated with poorer prognosis in patients (Blasco et al., 2015), no relationship between vitamin D and disease progression has been identified (Paganoni et al., 2017). It is feasible to propose a relationship between micronutrients and ALS. Studies have reported thiamine deficiencies ( Jesse, Thal, & Ludolph, 2015) and increased vitamin A and E levels in patients with ALS (Wang et al., 2020), while supplementation with vitamin C and E has been linked to improved patient prognoses (Ascherio et al., 2005; Fitzgerald et al., 2013; Michal Freedman et al., 2013). However, as this association was not replicated in an analysis of a large patient database (Prell et al., 2020), it is evident that further analyses of the impact of micronutrients in ALS are required.

Antioxidants Given that increased oxidative stress is proposed to be a potential mechanism that contributes to ALS, the use of antioxidants, both diet-derived and supplemented, have been

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suggested as treatment options for the disease. While a Cochrane systematic review on trials using antioxidants found no significant effect, most of these studies were under powered or had poor study design (Orrell, Lane, & Ross, 2007). Nieves and colleagues (2016) found that high intake of dietary antioxidants and carotenoids was associated with better function at the time of study enrolment. Likewise, Edaravone, the second FDAapproved drug for ALS, is an antioxidant therapeutic known to slow disease progression (Cruz, 2018), further supporting the beneficial effect of antioxidants in ALS.

Polyunsaturated fatty acids Polyunsaturated fatty acids (PUFAs) such as omega-3 and omega-6, are essential for brain function (Scarmeas et al., 2007). PUFAs play an important role in improving outcomes in many diseases (Huang, Zhang, & Chen, 2016). Studies have suggested that the high intake of PUFAs can reduce the risk for ALS (Fitzgerald et al., 2013; Veldink et al., 2007). There is also evidence to suggest that there is a decrease in PUFAs in the plasma of patients with ALS (O’Reilly et al., 2020). However, the effects of PUFAs as a therapeutic to slow ALS disease progression are currently unknown. Evidence from other neurological diseases does suggest a neuroprotective role of PUFAs (Bousquet et al., 2009; Pratley et al., 2000; Trejo et al., 2004), and thus, this may be an important area for investigation in ALS in future.

Applications to other neurological conditions Many neurodegenerative disorders share similar metabolic features and nutritional dysregulation to ALS. Dietary interventions have been shown to improve symptomology and disease course and thus are an important clinical aspect of these diseases.

Alzheimer’s disease Alzheimer’s disease (AD) is the most common form of dementia. People with AD typically present with memory loss, behavioral disturbances, and cognitive impairment (Alzheimer et al., 1995). Unlike ALS, it is not currently known if aberrations in systemic metabolism occur in AD. However, poor nutrition and lifestyle factors appear to be a risk factor for AD (Hu et al., 2013) and dietary interventions have improved symptomology and disease course (Von Arnim, Gola, & Biesalski, 2010). In recent years, interest on the effects of specific diets has grown in the field of AD research. The Mediterranean diet, characterized by high intake of vegetables high in antioxidants, fruits, cereals, and PUFAs, has shown to reduce risk of developing AD (Scarmeas et al., 2007). It is believed that the Mediterranean diet protects against and improves AD due to its high levels of antioxidants (Von Arnim et al., 2010). Oxidative stress, caused by the overproduction of reactive oxygen species, plays a pivotal role in the pathophysiology of AD (Huang

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et al., 2016), and thus, the Mediterranean diet may help reduce reactive oxygen species (Scarmeas et al., 2007). Similarly, the ketogenic diet, a high-fat, low-carbohydrate diet, has been shown to improve cognitive impairment (Henderson et al., 2009) and reduce the hallmark pathology of amyloid plaques in a mouse model of AD (Van der Auwera et al., 2005). It is hypothesized that the ketogenic diet exerts beneficial effects by reducing the levels of reactive oxygen species (Sullivan et al., 2004). However, more research is needed to confirm the exact mechanisms through which Mediterranean and ketogenic diets improve outcomes in AD.

Parkinson’s disease Parkinson’s disease (PD) is a progressive neurodegenerative movement disorder caused by the destruction of dopaminergic neurons. The loss of these neurons leads to tremors, stiffness, slowed movements, and problems with balance (Poewe et al., 2017). Similar to ALS, progressive weight loss due to malnutrition is a major contributor to disease progression (Kashihara, 2006). Additionally, there are several studies implicating alterations in the gut microbiome and intestinal inflammation as a leading cause of PD (Romano et al., 2021). The association between the gut microbiota and PD plays a critical role in building an effective dietary management strategy for individuals living with PD. A battery of scientific evidence has shown that there are some beneficial effects of supplements such as vitamin B, C, D, and E as antioxidants (Hughes et al., 2016), PUFAs as an antioxidant and antiinflammatory (Knekt et al., 2010; Taghizadeh et al., 2017; Zhang et al., 2002), and whey protein as an antioxidant (Tosukhowong et al., 2016). Indeed, vitamin E is associated with slow disease progression in patients with PD (Fahn, 1992). Another study, however, did not replicate the slowing of functional decline (Scheider et al., 1997). Other studies have demonstrated increased risk of PD due to increased intake of vitamins such as A, C, and E (Gaenslen, Gasser, & Berg, 2008). There is still much contention on the effectiveness of supplements and developing an efficacious dietary intervention for patients with PD. It has been proposed that a Mediterranean-like diet may be beneficial for PD patients (Gao et al., 2007; Sofi et al., 2008). It is suggested that interventions should focus on nutritional balance, with the view to prevent and treat any nutritional deficiencies (Barichella, Cereda, & Pezzoli, 2009). Lastly, it is important to consider the effects of PD medication such as L-dopa, which, due to its mechanism of action, may interfere with dietary intake (Kempster & Wahlqvist, 1994).

Huntington’s disease Huntington’s disease (HD) is a progressive neurodegenerative disease that causes cognitive decline, behavioral changes, and motor defects (Stavroulakis & McDermott, 2016).

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Similar to what is seen in ALS, individuals with HD have a higher-than-expected resting energy expenditure (Marin et al., 2011), and rapid weight loss and malnutrition present as a major problem. Indeed, low BMI at diagnosis has been reported in people with HD when compared to healthy people (Burgos et al., 2018). Poor nutritional status may impact many facets of the disease (Pols & Limburg, 2016). The effects of diets and how macro- and micronutrients impact disease have not been extensively studied in HD. However, the European Huntington’s Disease Network Dietitians Group recommend the following dietary guidelines for those diagnosed with HD: 25–35 kcal/kg/day total energy intake, including that derived from protein, carbohydrate-to-fat ratio the same as the normal population, adequate intake of micro- and macronutrients, and supplementation on a per-person basis as required. Nevertheless, the European Huntington’s Disease Network Dietitians Group caution that these values are a guideline and that they need to be tailored based on individual needs. Some studies in mouse models of HD have shown that a low-protein diet ameliorates urea cycle symptoms (Chen et al., 2015), and a ketogenic diet did not impair cognitive function and delayed weight loss (Ruskin et al., 2011). One study in Spanish HD patients found that the Mediterranean diet improved quality of life and was associated with decreased motor impairment (Rivadeneyra et al., 2016). Thus, it is clear that further research needs to be conducted on nutritional interventions in HD, in order to provide adequate care to those experiencing the negative nutritional and quality-of-life outcomes reported.

Conclusion Malnutrition and weight loss are a significant concern in ALS and other neurodegenerative disorders. There are a multitude of physiological, behavioral, and psychological factors that could contribute to these presentations that are yet to be fully understood, and here, we attempted to provide insights into some of these (Fig. 1B). Determining energy needs and risk of malnutrition in ALS requires ongoing assessment of nutritional, biochemical, and anthropometric measures. The use of modified formulas that predict energy expenditure, combined with SGA and GLIM criteria assessment tools, may be useful in complementing this pursuit. There is a lack of large-scale human studies that replicate the benefits seen in response to manipulating macronutrients and other dietary changes in mouse models of ALS. Therefore, there is insufficient evidence to conclude whether macronutrients have a significant impact on disease outcomes in ALS. Again, additional studies are needed to address this gap in knowledge. However, to date, high-calorie supplementation appears to be most beneficial in aiding weight maintenance in ALS, although large sample size, placebo-controlled, double-blinded trials are needed to increase the power of this evidence. Overall, given the negative impact of malnutrition and weight loss on ALS

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prognosis, it is pertinent that we improve our knowledge of the role of nutrition and energy balance in the disease to provide dietary advice that is tailored to the individual. In parallel, the impact of dietary interventions on quality of life and survival should be assessed in larger, randomized controlled trials. While further research is required to uncover the mechanisms driving the improvements seen in neurodegenerative disorders upon nutritional intervention, the heterogeneity of these diseases likely means that interventions will need to be developed on a per-patient basis. Such strategies will have to consider the needs of the individual (their energy requirements but also limitations in accessing energy), before individualized strategies can be defined. Once implemented, it is critical that patients be monitored and that recommendations be adjusted as needed, and revised as disease progresses, and as such, as needs change (Fig. 1B). It is evident that further research and intervention strategies are required to improve dietary management in people who are living with neurodegenerative disease. As such, there is likely benefit for increased and earlier engagement of dietitians in standard clinical care for persons with neurodegenerative disorders, and dietary support is advanced for improved disease outcomes.

Mini-dictionary of terms Anthropometric: the scientific study of measurements and proportions of the human body. Harris-Benedict equation: an equation used to calculate an estimate of an individual’s energy expenditure at rest. Hypermetabolism: a higher-than-expected energy expenditure at rest. Malnutrition: inappropriate amount or balance of nutrients to maintain optimal health. Neurodegeneration: the progressive loss of function of neuronal cells within the central nervous system, leading to cell death. Total energy expenditure: the total calories burnt by the human body in a 24-h period adjusted for level of activity.

Key facts • • • •

ALS is caused by the death of motor neurons in the brain and spinal cord leading to the loss of motor function; the average lifespan is approximately 3–5 years. Many ALS patients burn more calories at rest than is expected. Many ALS patients experience rapid weight loss (independent of higher energy expenditure), which is shown to be a negative prognostic factor. Many ALS patients experience loss of appetite, making it harder for these patients to maintain or to gain weight.

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Summary points •

• • •

•

Up to 68% of individuals diagnosed with ALS have hypermetabolism, where their measured resting energy expenditure is higher than their predicted energy expenditure. Hypermetabolic ALS patients have been shown to have faster disease progression and earlier death. Malnutrition is evident in 10%–55% of patients with ALS at time of diagnosis. Several factors may impact nutritional imbalance in ALS including loss of appetite, dysphagia, salivary dysregulation, constipation due to weakness in abdominal muscles, cognitive changes, and limitations associated with independent feeding due to limb weakness and mood. While dietary interventions have shown some promise in assisting in nutritional management in ALS, the heterogeneous nature of the disease means that dietary interventions will need to be tailored on a per-person basis.

Author contributions ZC, LB, and LJ conducted the literature search. ZC wrote the original draft. LB, LJ, FJS, and STN revised and finalized the manuscript.

Author disclosures The authors have no competing interests to declare.

Funding support STN is supported by a FightMND Mid-career Fellowship and the Australian Institute for Bioengineering and Nanotechnology (AIBN) at the University of Queensland. LJ is supported by the University of Western Australia.

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CHAPTER 8

Nutrition, percutaneous endoscopic gastrostomy and ALS Michele Baronea and Isabella Laura Simoneb a

Section of Gastroenterology, Department of Emergency and Organ Transplantation, University “Aldo Moro” of Bari, Policlinic University Hospital, Bari, Italy b Section of Neurology, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University “Aldo Moro” of Bari, Policlinic University Hospital, Bari, Italy

List of abbreviations EN PEG SOD1 TARDBP FUS TBK1 BMI TEE cREE mREE CNS TDP-43 PEG-J

enteral nutrition percutaneous endoscopic gastrostomy superoxide dismutase 1 TARDNA-binding protein-43 fused in sarcoma TANK-binding kinase body mass index total daily energy expenditure calculated resting energy expenditure measured resting energy expenditure central nervous system transactive response DNA-binding protein-43 percutaneous endoscopic gastrostomy with a jejunal extension

Introduction The first description of the disease dates back to 1869, when Jean-Martin Charcot described lesions of the anterior horn of the spinal cord resulting in a progressive paralysis without contractures; the term “amyotrophic lateral sclerosis” came later in 1874 (Kumar, Aslinia, Yale, & Mazza, 2011). Amyotrophic lateral sclerosis (ALS) is the most frequent motor neuron disease (MND), characterized by a progressive neurodegeneration of motor neurons in the brain and spinal cord, resulting in progressive paralysis and fatal course. Approximately in 10% of cases, it is possible to demonstrate a direct inheritance of the disease (familial ALS) (Nijssen, Comley, & Hedlund, 2017). However, more recent studies suggest that the hereditary character in apparently sporadic cases of ALS ranges from 5% to 28%, depending on the methods utilized for the determination of

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the variants or even the definition of familial ALS (Al-Chalabi, van den Berg, & Veldink, 2017; Garcia-Santibanez, Burford, & Bucelli, 2018). More than 20 genes have been associated with ALS. The five most common genetic causes are hexanucleotide expansions in chromosome 9 open reading frame 72 (C9orf72), mutations in superoxide dismutase 1 (SOD1), TARDNA-binding protein-43 (TARDBP), fused in sarcoma (FUS) and TANK-binding kinase 1 (TBK1). Together, they explain about 15% of all patients (Brown & Al-Chalabi, 2017; Hardiman et al., 2017; van Es et al., 2017). The pathogenesis of ALS includes multiple molecular pathways, such as excitotoxicity, neuroinflammation, mitochondrial dysfunction and oxidative stress, cytoskeletal disturbances and axonal transport defects, altered RNA metabolism, and impaired DNA repair. Furthermore, many of the genes associated with ALS may influence the pathogenetic mechanisms involved in the disease, such as the protein degradation, RNA metabolism, and cytoskeletal and axonal transport (Brown & Al-Chalabi, 2017; Taylor, Brown Jr., & Cleveland, 2016). Three classic presentations of ALS are recognized, and each of them has a different prognostic correlation with survival: (1) the bulbar onset disease, which is the more rapidly progressive form, (2) the limb onset (spinal onset) disease, and (3) the pure lower motor neuron disease (Chancellor et al., 1993; del Aguila, Longstreth Jr, McGuire, Koepsell, & van Belle, 2003; Norris et al., 1993). The most prevalent form of ALS is characterized by a limb onset, while about 20%–33% of the cases show a bulbar onset (del Aguila et al., 2003; Swinnen & Robberecht, 2014). Some patients have isolated motor neurons damages in the spinal region for many years, and therefore, they show a slow progression of the disease compared to classic ALS (Burrell, Vucic, & Kiernan, 2011; Chio et al., 2011; Dimachkie et al., 2013; Katz et al., 1999; Wijesekera et al., 2009). On the contrary, in 3%–5% of the patients, the onset of disease occurs in respiratory muscles and these subjects have the worst prognosis (Swinnen & Robberecht, 2014). As a result of these different clinical presentations, the average survival is 3–5 years from the diagnosis, with a minimum of 2 years in the patients with bulbar onset, and 5–8 years only in about 10% of patients (Forbes, Colville, Cran, & Swingler, 2004; Nijssen et al., 2017; Zoccolella et al., 2008). The most frequent cause of death reported in an ALS European cohort is represented by respiratory failure (77%–81% of the cases) (Gil et al., 2008; Spataro, Lo Re, Piccoli, Piccoli, & La Bella, 2010). A more recent study in an ALS Japan cohort reports that the respirator dependent rate was increased in the last two decades from 69% to 93% and that the main cause of death in patients with tracheostomy invasive ventilation was the respiratory infections (Saito, Kuru, Takahashi, Suzuki, & Ogata, 2021). Although respiratory failure is the leading cause of death, nutritional aspects play an important prognostic role in terms of survival, especially in the view of a prolonged survival time related to an improvement of the supportive and medical therapies.

Nutrition and PEG in ALS patients

Due to the involvement of the several cranial nerves (V, VII, IX, X, and XII) up to 100% of patients with ALS develop oropharyngeal dysphagia (Sasegbon & Hamdy, 2017). This symptom consists of the loss of the ability to swallow food and liquids, and therefore, it is the major cause of malnutrition in these patients. Oropharyngeal dysphagia appears earlier in case of bulbar onset, but represents an inevitable event with the progression of the neurological damage. However, it does not necessarily appear in the end stage of the disease and therefore requires the initiation of artificial nutrition (Barone et al., 2019).

Malnutrition Malnutrition develops from the imbalance between nutrients intake and nutritional requirements of the subject. The latest criteria, namely GLIM criteria, to define malnutrition include three phenotypic criteria (unintentional weight loss, low body mass index (BMI), reduced muscle mass) and two etiologic criteria (reduced food intake/assimilation, and inflammation/disease burden) (Cederholm et al., 2019). A recent study on the diagnosis of malnutrition in ALS using GLIM criteria has pointed out the importance of measuring this parameter considering its prognostic value on survival (Lo´pez-Go´mez et al., 2021). However, in this study, it is not clear how the application of these new criteria improved/modified the diagnosis of malnutrition compared the previous criteria (Cederholm et al., 2015). To our opinion, GLIM criteria, and more specifically the ones relating to the phenotypical characteristics, are not completely suitable in the specific setting of ALS patients since they can overestimate the diagnosis of malnutrition. In fact, they do not take in consideration the fact that in the setting of neurodegenerative disease, the development of a unintentional weight loss, a BMI 50% (Greenwood, 2013). The performance of percutaneous endoscopic gastrostomy consists of the insertion of a tube (Fig. 2) that passing through the abdominal wall reaches the gastric cavity, allowing the nutritional fluids to reach the stomach. The use of food reduced in a smoothie is strongly contraindicated since it requires high volumes of water to be prepared, a procedure that reduces the quantity of food intake without ensuring the formation of a clot in the tube. As an alternative to PEG, radiologically guided percutaneous gastrostomy does not

Fig. 2 Description of a replacement tube for PEG.

Nutrition and PEG in ALS patients

require patient sedation for tube insertion and therefore seems to be safer in cases with moderate-to-severe respiratory impairment (Soriani & Desnuelle, 2017). In those patients with high risk of aspiration pneumonia due to an important phenomenon of gastroesophageal reflux, it has been suggested to perform a percutaneous endoscopic gastrostomy with a jejunal extension (PEG-J), although a recent analysis of the literature indicates that PEG-J does not seem able to completely prevent aspiration (Hitawala & Mousa, 2021). Moreover, the data reported in the study of Kirstein et al. suggest that PEG might be a better tolerable option compared to PEG-J, with a lower complication-free survival rate and similar overall survival compared to PEG-J (Kirstein et al., 2018). Unfortunately, the placement procedure and the use of PEG expose ALS patients to some complications (Table 1). The major complications related to the procedure of placement are rare and consist of bleeding, aspiration pneumonia, intraabdominal organ injury, necrotizing fasciitis, and buried bumper syndrome; the minor complications include peristomal granuloma, infection, leakage, tube dislocation, gastric outlet obstruction, and pneumoperitoneum (Barone et al., 2014; Rahnemai-Azar, Rahnemaiazar, Naghshizadian, Kurtz, & Farkas, 2014). We have previously demonstrated that in course of EN at patients’ home, patients affected by neurological disease have higher complication rates as compared with cancer patients (p ¼ 0.04). This is probably due to several causes: presence of severe disabilities, requiring more intense caregiver assistance, use of numerous medications, which increases the episodes of tube clogging and accidental removal, and the longer period of treatment compared to cancer patients (Barone et al., 2014). Finally, parenteral nutrition has been recently proposed as an alternative to enteral feeding for patients with advanced ALS and poor respiratory function (Abdelnour-Mallet et al., 2011; Verschueren, Monnier, Attarian, Lardillier, & Pouget, 2009). In conclusion, the complexity of the disease, which involves the respiratory tract and the upper gastrointestinal system and has important psychological repercussions, makes Table 1 Complications related to the performance of percutaneous endoscopic procedure.

1. Early complications (related to the procedure) Bleeding Aspiration pneumonia Intraabdominal organ injury Necrotizing fasciitis Pneumoperitoneum 2. Local complications (within 4 weeks from placement) Peristomal granuloma Leakage from the stoma 3. Late complication Tube dislocation Gastric outlet obstruction Buried bumper

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Fig. 3 All professional figures involved in the ALS team.

necessary the intervention of multiple professional figures that together with the neurologist constitute the ALS team responsible for the care of the patient (Fig. 3).

Artificial nutrition in other neurological pathologies Other numerous neurological and neuromuscular diseases can be responsible of the development of oropharyngeal dysphagia. Table 2 summarizes the more common diseases that are associated up to 100% of the cases with dysphagia. These patients may experience a progressive alteration of their ability to take a normal oral diet that usually occurs later in the progression of the disease. Therefore, all the considerations described in the previous paragraph about how to support oral nutrition for as long as possible are useful in this setting of patients. Even the placement of PEG follows the same indications, limitations, and complications. What makes the difference between ALS and other neurological pathologies is represented by the timing of intervention and the severity of the disease. An exception can be represented by acute CNS accidents in which a partial or a total recovery of the swallowing capacity is possible, especially in younger patients. In these subjects, the acute appearance of dysphagia can be treated with the placement of a

Nutrition and PEG in ALS patients

Table 2 Neurological diseases responsible for dysphagia.

Acute injuries Cerebrovascular accident Head trauma Tumors of the central nervous system Immune-mediated disorder Multiple sclerosis Neurodegenerative diseases Alzheimer’s disease Amyotrophic lateral sclerosis Parkinson’s disease Huntington’s disease Friedreich ataxia Infective Tabes dorsalis Bulbar polio

Neuromuscular diseases Polymyositis Dermatomyositis Myasthenia gravis Duchenne’s disease

nasogastric tube for 1–2 months, until the severity of the neurological damage allows to correct dysphagia by a rehabilitation treatment.

Other components of interest This section will deal with the possible different modalities to be used to administer nutritional products to the patient. First of all, it is important to know if the patient is still selfsufficient, as more frequently occurs in subjects with a bulbar onset, and if the nutritional program will be continued at home or in a nursing home, since the latter aspect will condition the type of assistance. In the first case, the patient can receive the nutritional treatment during the day, while he or she is doing other activities, thanks to the use of a portable peristaltic pump housed in a backpack together with the nutrition bag. Nonself-sufficient patients followed at home can be fed by respecting the interval of the three daily meals or using a continuous administration of nutrients during the day time, in both cases through a peristaltic pump. For subjects in a more advanced stage of the disease, ad followed in a nursing home, the enteral nutrition will be performed in the day time, usually through a continuous administration by a peristaltic pump while the bedridden patient is in a semi-sitting position (to counteract as much as possible gastroesophageal reflux). In any case, only liquid products for enteral nutrition should be used. Homeprepared grinded food should be avoided for at least some simple reasons: To make the food more fluid, a large volume of water is used, reducing the real amount of food administered and increasing the gastroesophageal reflux; in addition, this type of preparation requires the manual injection of the “food” by the use of large syringes and increases the probability to damage the PEG tube.

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Key facts 1. Oropharyngeal dysphagia is an inevitable event associated with the progression of the disease. 2. Oropharyngeal dysphagia is the main cause of malnutrition in course of ALS. 3. The evaluation of the real caloric need of the patient is difficult. 4. The reduction of food intake requires at first dietary adjustments to facilitate patients’ meals. 5. With the progression of the disease, the use of artificial nutrition becomes necessary. 6. Nutritional aspects play an important prognostic role in terms of survival in ALS patients.

Mini-dictionary Oral dysphagia: Dysfunction of one or more parts of the swallowing apparatus which is constituted by labial and masticatory muscles, working in association with the numerous muscles controlling the movements of tongue, veli palatine, pharynx, larynx, and upper esophageal sphincter. Resting energy expenditure (REE): Amount of energy expended to maintain vital physiological functions of a person at rest, awake, in a fasted state, and exposed to a room temperature of 22–24°C. It corresponds to the energy necessary to support normal metabolic functions. Total energy expenditure (TEE): The total daily amount of energy resulting from the sum of (1) the resting energy expenditure, (2) the energy expenditure required for feeding (due to the masticatory, digestive, and absorptive activity combined to the thermogenic effect related to food ingestion), and (3) physical activity. Indirect calorimetry: Method to measure the energy required for the metabolism of the whole body based on the determination of gas exchange measurements (CO2 production and O2 consumption at rest). It is the most sensitive, accurate, and noninvasive clinically used method to measure energy expenditure in a person. Buried bumper syndrome: A rare and late complication characterized by intense local pain associated or not with fever due to the displacement of the internal bumper of the PEG tube between the gastric wall and skin. It develops because of an excessive external traction of the tube that produces a sort of erosion of the gastric/abdominal wall.

Summary points 1. In patients with ALS, oropharyngeal dysphagia compromises oral nutrition. 2. The reduction of food intake can induce malnutrition with a direct impact on survival.

Nutrition and PEG in ALS patients

3. The presence of oropharyngeal dysphagia can also negatively impact on survival by causing ab ingestis pneumonia. 4. Enteral nutrition by percutaneous endoscopic gastrostomy is the most common therapeutic approach to counteract malnutrition and prevent respiratory complications. 5. The major complications related to the percutaneous endoscopic gastrostomy are rare, whereas local complications are more common and usually occur within 4 weeks from the completion of the endoscopic procedure.

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McDonald, T. S., McCombe, P. A., Woodruff, T. M., & Lee, J. D. (2020). The potential interplay between energy metabolism and innate complement activation in amyotrophic lateral sclerosis. The FASEB Journal, 34, 7225–7233. Nijssen, J., Comley, L. H., & Hedlund, E. (2017). Motor neuron vulnerability and resistance in amyotrophic lateral sclerosis. Acta Neuropathologica, 133, 863–885. Norris, F., Shepherd, R., Denys, E., Mukai, K. U. E., Elias, L., Holden, D., et al. (1993). Onset, natural history and outcome in idiopathic adult motor neuron disease. Journal of the Neurological Sciences, 118, 48–55. Onesti, E., Schettino, I., Gori, M. C., Frasca, V., Ceccanti, M., Cambieri, C., et al. (2017). Dysphagia in amyotrophic lateral sclerosis: Impact on patient behavior, diet adaptation, and riluzole management. Frontiers in Neurology, 8, 94. Paganoni, S., Deng, J., Jaffa, M., Cudkowicz, M. E., & Wills, A. M. (2011). Body mass index, not dyslipidemia, is an independent predictor of survival in amyotrophic lateral sclerosis. Muscle & Nerve, 44, 20–24. Piccione, E. A., Sletten, D. M., Staff, N. P., & Low, P. A. (2015). Autonomic system and amyotrophic lateral sclerosis. Muscle & Nerve, 51, 676–679. Prasad, A., Bharathi, V., Sivalingam, V., Girdhar, A., & Patel, B. K. (2019). Molecular mechanisms of TDP43 misfolding and pathology in amyotrophic lateral sclerosis. Frontiers in Molecular Neuroscience, 14(12), 25. Rahnemai-Azar, A. A., Rahnemaiazar, A. A., Naghshizadian, R., Kurtz, A., & Farkas, D. T. (2014). Percutaneous endoscopic gastrostomy: Indications, technique, complications and management. World Journal of Gastroenterology, 20, 7739–7751. Saito, T., Kuru, S., Takahashi, T., Suzuki, M., & Ogata, K. (2021). Changing medical care for amyotrophic lateral sclerosis patients and cause of death—Review of muscular dystrophy wards (1999-2013). Rinsho Shinkeigaku (Clinical Neurology), 61, 161–165. Sasegbon, A., & Hamdy, S. (2017). The anatomy and physiology of normal and abnormal swallowing in oropharyngeal dysphagia. Neurogastroenterology and Motility, 29. Soriani, M.-H., & Desnuelle, C. (2017). Care management in amyotrophic lateral sclerosis. Revue Neurologique, 173, 288–299. Spataro, R., Lo Re, M., Piccoli, T., Piccoli, F., & La Bella, V. (2010). Causes and place of death in Italian patients with amyotrophic lateral sclerosis. Acta Neurologica Scandinavica, 122, 217–223. Stutzki, R., Weber, M., Reiter-Theil, S., Simmen, U., Borasio, G. D., & Jox, R. J. (2014). Attitudes towards hastened death in ALS: A prospective study of patients and family caregivers. Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration, 15, 68–76. Swinnen, B., & Robberecht, W. (2014). The phenotypic variability of amyotrophic lateral sclerosis. Nature Reviews Neurology, 10, 661–670. Taylor, J. P., Brown, R. H., Jr., & Cleveland, D. W. (2016). Decoding ALS: From genes to mechanism. Nature, 539, 197–206. van Es, M. A., Hardiman, O., Chio, A., Al-Chalabi, A., Pasterkamp, R. J., Veldink, J. H., et al. (2017). Amyotrophic lateral sclerosis. Lancet, 390, 2084–2098. Verschueren, A., Monnier, A., Attarian, S., Lardillier, D., & Pouget, J. (2009). Enteral and parenteral nutrition in the later stages of ALS: An observational study. Amyotrophic Lateral Sclerosis, 10, 42–46. Wijesekera, L. C., Mathers, S., Talman, P., Galtrey, C., Parkinson, M. H., Ganesalingam, J., et al. (2009). Natural history and clinical features of the flail arm and flail leg ALS variants. Neurology, 72, 1087–1094. Winge, K., Rasmussen, D., & Werdelin, L. M. (2003). Constipation in neurological diseases. Journal of Neurology, Neurosurgery and Psychiatry, 74, 13–19. Zoccolella, S., Beghi, E., Palagano, G., Fraddosio, A., Guerra, V., Samarelli, V., et al. (2008). Predictors of long survival in amyotrophic lateral sclerosis: A population-based study. Journal of the Neurological Sciences, 268, 28–32.

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CHAPTER 9

Fatty acid profiling in amyotrophic lateral sclerosis Minic Rajnaa,b, Stevic Zoricac, and Arsic Aleksandrad a

Department of Scientific Research, Institute of Virology, Vaccines and Sera, Torlak, Belgrade, Serbia Group for Immunology, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia c Faculty of Medicine, Neurology Clinic, University Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia d Centre of Research Excellence in Nutrition and Metabolism, Institute for Medical Research, National Institute of Republic of Serbia, University of Belgrade, Belgrade, Serbia b

Abbreviations ALA ARA DHA FA HDL LCFA LDL MUFA PUFA SCFA SFA VLCFA

α-linolenic acid arachidonic acid docosahexaenoic acid fatty acid high-density lipoprotein long-chain fatty acid low-density lipoprotein monounsaturated fatty acid polyunsaturated fatty acid short-chain fatty acid saturated fatty acid very-long-chain fatty acid

Introduction Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder of the upper and lower motor neurons, which results in weakness and wasting of muscles in the arms, legs, trunk and the bulbar region. Aspiration pneumonia and progressive respiratory insufficiency often lead to death within 3–5 years of symptom onset (Chio` et al., 2009). Beside primary motor neurons, there is also involvement of other brain regions, especially those involving cognition. The onset of ALS usually occurs in the sixth and seventh decade of life when it is the most frequent neurodegenerative disorder. The pathogenic processes in ALS are complex and incompletely understood. Commonly proposed pathogenic mechanisms include RNA metabolism and protein metabolism. An estimated incidence of ALS is 1–2/100,000 people, with the majority of ALS cases being sporadic (sALS, 90% of cases) and the remaining the familial (fALS), which are due to inherited genetic mutations (Gros-Louis, Gaspar, & Rouleau, 2006) expressed in an autosomal dominant fashion. Apart from the mutations in the SOD1 gene (Rosen Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00023-4

Copyright © 2023 Elsevier Inc. All rights reserved.

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et al., 1993), which were first linked to the disease, an increasing number of genes are recognized as associated and causative of ALS. The most common are C9orf72, SOD1, TARDBP and FUS, which is nicely summarized by Zou et al. (2017). The information gathered from fALS has enabled the construction of rodent models of the disease (McGoldrick, Joyce, Fisher, & Greensmith, 2013) which are helping researchers analyze disease pathogenesis and test therapeutic approaches.

Pathology in ALS The primary reason for motor neurons suddenly dying is still elusive, and therapeutic interventions which could make a reversal of the conditions are lacking. Fast fatigable motor units, which are responsible for exerting heavy force over a short period of time and which are composed of large α-motor neurons and glycolytic muscle fibers, with preference for glucose utilization, are the first to degenerate in both ALS patients and mouse models of the disease (Atkin et al., 2005; Pun, Santos, Saxena, Xu, & Caroni, 2006; Schmied, Pouget, & Vedel, 1999; Schmitt, Hussain, Dupuis, Loeffler, & Henriques, 2014). Small motor neurons and oxidative muscle fibers, which preferentially use fatty acids for energy to produce less intense, constant strength, are spared in ALS. In SOD1 mice, a model of ALS, glycolytic muscles switch to oxidative due to the loss of connection with large motor neurons (Carp & Wolpaw, 2010; Sharp, Dick, & Greensmith, 2005). These facts imply that higher vulnerability of large motor neurons could be due to higher energetic needs. Satisfying energetic needs becomes even more problematic during ALS progression as dysphagia occurs in ALS, frequently with respiratory difficulties while eating. Segmental and total colonic transit times can also be markedly delayed in ALS, which may have several causes such as physical inactivity, dehydration or inadequate fiber intake; or it may represent gastrointestinal autonomic involvement (Toepfer et al., 2000).

Endogenous lipids Lipids are present throughout the human body, as structural components of biological membranes and as energy storage lipids. Membranes of cells and organelles are formed of lipid bilayers composed mainly of phospholipids (including glycerol phospholipids and sphingolipids) and glycolipids (including sphingolipids) and contain cholesterol. Storage lipids and lipids present in the circulation are called triglycerides and are triesters of glycerol with long-chain carboxylic acids. Fatty acids (FAs) are saturated or unsaturated monocarboxylic acids, usually with an even number of carbon atoms that occur in the form of glycerides in fats and fatty oils. FAs in the body are organized in two forms: free or unesterified and esterified. While most of the FAs are in circulation, about 95% of total FA are in the form of triglycerides,

Fatty acids in ALS

cholesterol esters and phospholipids, and 5% of total FA are free and bound to albumin and to a lesser extent to globulins and lipoproteins. Based on the tissue of origin or the intracellular location/function, membranes have different phospholipid composition and FA profiles.

Fatty acid properties and nomenclature Chemical properties of FA are defined by the length and the degree of unsaturation of the carbon chain (Table 1). Whereas SCFAs are soluble in water, LCFAs are almost completely insoluble. The level of saturation influences packaging in lipid layers; hence, PUFAs confer the feature of “fluidity” to membranes, while cholesterol and saturated fatty acids have the opposite effect. There are several forms of fatty acid nomenclature, and throughout this text, we will mostly use trivial names, abbreviations of the trivial names or a simplified nomenclature which consists of the number of carbon atoms present, followed by a semicolon and the number of double bonds. If the acid is an unsaturated fatty acid, the position of a double bond is written with the delta symbol followed by a superscript number marking the first carbon atom in of the double bond. The counting, in this case, starts from the carboxyl group carbon atom. In example, if the trivial name is docosahexaenoic acid (DHA), the systemic name is all-cis-docosa-4,7,10,13,16,19-hexaenoic acid and it can be written as 22:6 Δ4,7,10,13,16,19. Additionally, for PUFAs with a large number of double bonds, an even simpler writing would be 22:6n-3, where n is the number of the first double bond carbon atom counting from the methyl group end of the molecule (Table 2). The most commonly occurring FAs have an unbranched carbon chain of 12–24 atoms; in most MUFAs, a double bond is located between C9 and C10. The double bonds in PUFAs are almost never conjugated, but are separated by a methylene group and are almost always in cis configuration. Table 1 FA classification according to chemical properties. Fatty acids

Number of C-atoms

Abbreviation

Short chain Medium chain Long chain Very long chain

22

SCFA MCFA LCFA VLCFA

/ 1 >1

SFA MUFA PUFA

Number of double bonds

Saturated fatty acid Monounsaturated fatty acid Polyunsaturated fatty acid

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Table 2 Trivial names, types and abbreviations of fatty acids mentioned in this text. Trivial names

Type

C-atoms: double bonds

Abbreviation

Palmitic acid Stearic acid Palmitoleic acid Vaccenic acid Oleic acid Linoleic acid γ-Linolenic acid Dihomo-gamma-linolenic acid Arachidonic acid α-Linoleic acid Eicosapentaenoic acid Docosapentaenoic acid Docosahexaenoic acid

SFA SFA MUFA n-7 MUFA n-7 MUFA n-9 PUFA n-6 PUFA n-6 PUFA n-6 PUFA n-6 PUFA n-3 PUFA n-3 PUFA n-3 PUFA n-3

16:0 18:0 16:1n-7 18:1n-7 18:1n-9 18:2n-6 18:3n-6 20:3n-6 20:4n-6 18:3n-3 20:5n-3 22:5n-3 22:6n-3

PA SA PAL VA OA LA GLA DGLA ARA ALA EPA DPA DHA

Fatty acids are important signaling molecules and are at the core of obesity-related diseases (Micallef, Munro, Phang, & Garg, 2009). PUFA can either directly bind to transcription factors, such as liver X-receptor and retinoic X-receptor (Yoshikawa et al., 2002), to stimulate the expression of genes involved in energy homeostasis or can be converted to active molecules. Eicosapentaenoic acid (EPA, 20:5n-3) and arachidonic acid (ARA, 20:4n-6), when oxidized are converted to prostaglandins and leukotrienes, while the oxidation of DHA yields neuroprotectin D1 which is beneficial for cell survival under stress.

Fatty acid metabolism Synthesis of fatty acids Synthesis of FAs takes place in the cytosol of the liver, adipose tissue, lung and brain. The precursor of all FA carbon atoms is acetyl-CoA generated by oxidative decarboxylation of pyruvate, degradation of amino acids and β-oxidation of FA. The formation of malonyl-CoA from acetyl-CoA by the action of acetyl-CoA carboxylase announces the FA synthesis. After the synthesis of malonyl-CoA, a reaction of condensation, reduction, dehydration and reduction again happens in repeating cycles and leads to the extension of the FA chain. The syntheses of SFA, of up to 16 carbons in length, are catalyzed by the enzyme system called the fatty acid synthase (FAS). Synthesis of long-chain PUFA in mammalian tissues is performed in the endoplasmic reticulum. The formation of long-chain FAs starts the same as with FAS, with the reaction of malonyl-CoA and acyl-CoA and the formation of β-ketoacyl-CoA, in the presence of

Fatty acids in ALS

elongases, known as elongases of very-long-chain fatty acids (ELOVLs). There are seven ELOVLs, including elongases 1, 3, 6 and 7 which are involved in the elongation of SFA and MUFA, while elongases 2, 4 and 5 are involved in the elongation of PUFA. Unsaturated FAs are synthesized by introducing a double bond at a specific position on the acyl chain of long-chain FAs, using the enzyme acyl-CoA desaturase. These desaturases are present in the membrane of the endoplasmic reticulum. Desaturases can be divided into two distinct families referred to as stearoyl-CoA desaturases (SCDs) or D9 desaturase and FA desaturases, which include D6 and D5 desaturases (Zhang, Kothapalli, & Brenna, 2016) (Fig. 1). While D9 desaturase participates in MUFA synthesis, the synthesis of PUFA is catalyzed by D6 desaturase and D5 desaturase. The D6 desaturase can introduce a double bond at position D6 of the essential FAs of the n-6 (LA, C18:2n-6) and n-3 family (α-linolenic acid (ALA), C18:3n-3). Opposite to plants, mammals lack D12 and D15 desaturases, which introduce double bonds at carbon atoms beyond C9 in the FA chain and do not have the ability to synthesize LA and ALA de novo. Thus, these FAs are essential for mammals and must be obtained from food. Depending on the tissue and its metabolic demand, FAs in cells can be converted to either triacylglycerols or membrane phospholipids or oxidized in the mitochondria for energy production.

Fig. 1 Schematic diagram of FA synthesis. FAS, fatty acid synthase; ELOVLs, elongases of very-longchain fatty acids; D9, D6 and D5, different fatty acid desaturases. Mitochondria, red; endoplasmic reticulum, green.

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Oxidation of fatty acid The process of FA oxidation is schematically shown in Fig. 2. Before FA oxidation, FAs must be activated to acyl-CoA. The process of FA activation occurs at the outer mitochondrial membrane, whereas the process of FA β-oxidation takes place in the mitochondrial matrix. While short-chain acyl-CoA and medium-chain acyl-CoA are transported into the mitochondrial matrix directly, transfer of long-chain acyl CoA through the inner mitochondrial membrane requires carnitine and three proteins. The β-oxidation pathway, which comprises a repeating sequence of four reactions catalyzed by acyl-CoA dehydrogenase, enoyl-CoA hydratase, hydroxy acyl-CoA dehydrogenase and ketoacyl-CoA thiolase, respectively, cleaves two carbons from the acyl chain each time to produce acetyl-CoA. The complete oxidation of palmitoyl-CoA requires seven repeated cycles. The tricarboxylic acid (TCA) cycle or the Krebs cycle is the final common pathway for the oxidation of acetyl CoA derived from carbohydrates, fats and proteins into CO2 and H2O to generate a form of usable energy (Houten, Violante, Ventura, & Wanders, 2016). The process of β-oxidation is also performed in peroxisomes that have a major role in the degradation of very-long-chain FAs. Besides β-oxidation, enzymes for α-oxidation, which are necessary for the oxidation of branched-chain FAs, are also present in peroxisomes. Peroxisomes lack the Krebs cycle and cannot degrade the acetyl CoA to produce CO2 and water ( Jenkins, West, & Koulman, 2015).

Fig. 2 Schematic diagram of FA catabolism. Krebs cycle—the final common pathway for the oxidation of acetyl CoA derived from carbohydrates, fats and proteins into CO2 and H2O to generate a form of usable energy. Mitochondria, red; peroxisome, pink; microsome, blue.

Fatty acids in ALS

In microsomes, very-long-chain FAs are undergoing ω-oxidization and forming eicosanoids and epoxy and hydroxy FAs. Thus, prostaglandins, thromboxanes and leukotrienes, known as eicosanoids, are formed from ARA and EPA by enzymes cyclooxygenases and lipoxygenase. Eicosanoids, act as paracrine and autocrine hormones, are involved in the regulation of local inflammation, but they also modify blood pressure, aggregation of blood platelets and cardiac function. Additionally, eicosanoids inhibit the mobilization of FAs from adipose tissue and are included in the functions of the central nervous system and the contraction of smooth muscles (Petrovic & Arsic, 2015).

Metabolic aspects of ALS One of the first studies regarding metabolic abnormalities in ALS patients investigated the responses of ALS inpatients to intravenous glucose tolerance test (GTT), the insulin tolerance test (ITT) and the tolbutamide tolerance test (TTT) (Mueller & Quick, 1970). Lower rates of glucose utilization and higher postglucose insulin levels during the intravenous GTT were observed in the ALS group and interpreted as resistance to endogenous insulin in ALS, which was confirmed with ITT. The authors further stated that insulin resistance and decreased glucose utilization cannot be explained purely by muscular dysfunction, other adventitious factors secondary to this motor neuron disease or pancreatic dysfunction. There was no relationship among the metabolic abnormalities and clinical state of the ALS patients. Hypermetabolism or increased resting energy expenditure was noted in two-thirds of ALS patients (Desport et al., 2001). Dyslipidaemia also has high incidence in ALS patients. In fact, according to published studies, BMI is significantly and inversely associated with ALS progression (Dardiotis et al., 2018). Metabolic abnormalities and relation of BMI with disease duration are indicative of metabolic involvement in disease pathogenesis. In ALS patients, in a Serbia-based cohort, hyperlipidaemia, which was found in 52.43% of ALS patients, at the time of diagnosis, was not related to significantly longer survival (Dedic et al., 2012). For the sake of the topic discussed here, we have analyzed again a large number of ALS patients (n ¼ 192) and found that the average cholesterol value was near the upper level of normal cholesterol values, but we should note that for the age group in question (age 59.7  11.2 years), hyperlipidaemia is not uncommon. Other parameters of lipid metabolism such as high-density lipoprotein (HDL), low-density lipoprotein (LDL) and triglycerides were also within the reference range. Nevertheless, in this cohort, over 50% of patients had dyslipidaemia, according to the guidelines of the National Cholesterol Program (NCEP) Adult Treatment Panel III. Dyslipidaemia in ALS patients is documented in numerous studies, but some reports even revealed opposite results. Thus, Yang et al. found that total cholesterol, LDL, triglyceride and protein levels, as well as

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LDL/HDL ratios, were significantly lower in men with ALS compared to controls, while such differences were not found in females (Yang et al., 2013). The authors concluded that metabolic demand might increase in ALS and that it may be affected by gender. ALS is also more common in males, and there is approximately 3:2 male-to-female ratio. Finally, there is evidence for significant lipid metabolism alterations in advanced stages of ALS (Tracey, Steyn, Wolvetang, & Ngo, 2018). From this, it can be concluded that the changes occurring in lipid metabolism in ALS patients are difficult to evaluate and indicate that the lipid content should be analyzed more thoroughly.

Fatty acid status in ALS patients The best biological marker of dietary fatty acid intake is the FA composition in serum/ plasma, erythrocytes and adipose tissue (Arsic et al., 2020). But the FA level of different tissues reflects not only dietary FA quality, but also on the endogenous metabolism of FAs and genetic variations affecting FA metabolism (Arsic, Vucic, Tepsˇic, et al., 2012). Nevertheless, the great number of physiological and pathological conditions can influence the FA status in blood as well (Arsic, Vucic, Prekajski, et al., 2012; Kojadinovic et al., 2017). As previously mentioned, both fat and FA metabolism is altered in ALS patients. However, a limited number of studies investigated the FA status in ALS patients. O’Reilly et al. (2020) examined the association between prediagnostic plasma PUFA levels and the occurrence of ALS. They identified 275 individuals who were previously enrolled in five US prospective cohort studies and who later developed ALS, but they observed no association between prediagnostic plasma levels of total PUFA, n-3 or n-6 PUFA, EPA or DPA with ALS. Interestingly, they noticed that a higher level of ALA was associated with a lower risk of ALS but only in men. On the other hand, they found a positive association between DHA level in men and the level of ARA in women and ALS risk. In addition, one study identified a significant decrease in the level of PUFA in the free FA fractions of plasma in ALS patients (Nagase, Yamamoto, Miyazaki, & Yoshino, 2016). Further, Henriques et al. in a case-control study showed that the proportion of total plasma SFAs, palmitic and behenic acids were decreased, while total MUFA and oleic acid were increased in ALS patients. Their results also show lower level of total PUFA, ARA and DHA in blood pellets; higher total MUFA as well as oleic, palmitoleic and cis 11-eicosenoic acids in ALS patients. Finally, they suggested that the ratio of 16:1/16:0 in blood cells can predict the life expectancy of ALS patients better than other previously proposed metabolic biomarkers, independently of age, site of onset, disease status and BMI. Patients with a higher 16:1/16:0 ratio have lower lipid peroxidability and better survival rates and their disease progresses slower, at least for a period of 6 months (Henriques et al., 2015).

Fatty acids in ALS

Fig. 3 Possible link between metabolic changes and FA changes in ALS. SFA, saturated fatty acid; MUFA, monounsaturated fatty acid; PUFA, polyunsaturated fatty acid. Mitochondria, red; damaged mitochondria, pale red.

Similar to their results, our unpublished data showed significantly higher levels of total and individual SFA and MUFA and lower levels of PUFA in ALS patients. The proposed changes leading to FA changes in ALS are shown in Fig. 3.

Fatty acid intake and ALS The most common method for investigating fatty acid intake is by using semiquantitative food-frequency questionnaires (FFQ) to estimate food preferences and evaluate eating habits. However, only a few human studies have investigated the relationship between dietary factors and the risk of ALS. Nelson, Matkin, Longstreth, and McGuire (2000) found a positive association of ALS with fat intake especially due to high intake of saturated fats, polyunsaturated fats and linoleic acid and suggested that the high levels of PUFA in the brain contribute to enhanced lipid peroxidation leading to additional consequences in ALS patients. Huisman et al. (2015) investigated the association between the risk of sporadic ALS and premorbid dietary intake of fat and found total fat, saturated fat, trans-fatty acids and cholesterol to be positively associated with an increased risk of ALS. Contrarily, in a case-controlled study in Japan, which comprised 153 ALS patients, low risk of ALS was associated with decreased intake of carbohydrates and increased intake of saturated fat, monounsaturated fat and total PUFA, while there was no association with

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n-3PUFA (Okamoto et al., 2007). Similarly, the diet with high levels of PUFA and vitamin E was associated with a decreased risk of developing ALS (Veldink et al., 2007). On the other hand, a pooled prospective study comprising 1,002,082 participants and a total of 995 ALS cases showed an inverse association between n-3 PUFA intake and the risk for ALS (Fitzgerald et al., 2014). The authors noticed that both α-linolenic acid and marine n-3 PUFA contributed to a lower risk of ALS, while the intake of n-6 PUFA was not associated with ALS risk. Also, they suggested that the consumption of foods high in n-3 PUFAs could be beneficial in preventing or delaying the onset of ALS. The contradictory conclusions between studies, whereby one favors an n-3 PUFA and the others SFA and MUFA, make it hard to conclude which type of diet should be used in ALS. However, the disproportion between studies may be contributed by other factors such as individual interpretation of the patient’s perception of food intake, and/or the type of FFQ used. Therefore, to better assess FA intake in ALS patients, protocols and measurements need to be standardized between study centres. Also, investigating biological markers that reflect dietary and FA intake could help the understanding of the relationship between nutrition and ALS.

Dietary intervention and ALS Dietary intervention in ALS models There is a need to better understand the relationship between diet and the changes in composition and metabolism of FA in ALS, which would hopefully open up the possibility of dietary intervention for improving the condition. The established ALS mouse models display the hallmarks of the disease and are invaluable for understanding pathological mechanisms and for therapeutic development. Although some studies show a direct association between n-3 intake and disease slowing, pretreatment with high doses of EPA accelerated disease progression in a mouse model of ALS (Yip et al., 2013). Namely, Yip et al. have shown that daily dietary EPA exposure for 8 weeks initiated at the disease onset did not significantly alter disease presentation or progression. In contrast, EPA treatment initiated at the presymptomatic stage induced a significantly shorter lifespan. They suggested that dietary EPA supplementation in ALS has the potential to worsen the condition and accelerate disease progression. Further, Boumil, Vohnoutka, Liu, Lee, and Shea (2017) compared two diets designed as Mediterranean (n-3 PUFA:n-6 PUFA ¼ 1:1) and Western diet (n-3 PUFA:n-6 PUFA ¼ 1:10) and showed that Mediterranean diet hastened motor neuron pathology and death, while Western diet significantly delayed motor neuron pathology. Oliva´n et al. (2014) demonstrated that feeding SOD1G93A mice with diet enriched with 20% extra virgin olive oil increased survival rate, improved motor coordination, autophagy and muscle damage, compared to diet enriched with 20% palm oil. We also notice that the changes in FA levels of different organs in experimental animals depend on

Fatty acids in ALS

probiotic supplementation; both on regular (Ivanovic et al., 2015) and on high-fat diet (Ivanovic et al., 2016), highlighting the influence of microbiota composition on FA levels. One of the pathological hallmarks of ALS disease is the accumulation of the TAR DNA-binding protein-43 (TDP-43) in cytoplasmic aggregates, in both glial and neuronal cells (Neumann et al., 2006). Overexpression of TDP-43 in Drosophila leads to the accumulation of LCFA and a significant reduction in carnitine and β-hydroxybutyrate in the motor neuron. In line with this, Manzo et al. have shown that a diet supplemented with a mixture of MCFA from coconut oil mitigates locomotor defects caused by TDP-43 overexpression in motor neurons in the Drosophila model of ALS (Manzo et al., 2018). Namely, the MCFA may be able to enter the mitochondria, bypass carnitine shuttle dysfunction, improving locomotor function and providing neuroprotection.

Dietary interventions in ALS patients Consistent with the results of animal studies about dietary intervention in ALS, Wills et al., in a phase II, prospective, double-blind, placebo-controlled, randomized, multicenter clinical trial testing hypercaloric enteral nutrition with or without excess EPA and γ-linolenic acid, found it safe and tolerable but suggested that nutritional interventions should be studied in larger randomized controlled trials at earlier stages of the disease (Wills et al., 2014). A randomized, double-blind, placebo-controlled trial has shown that the administration of acetyl-L-carnitine, which supports the transport of fatty acids into mitochondria, for 48 weeks, slowed down the worsening of motor symptoms in ALS patients (Beghi et al., 2013). In addition, Dorst, Cypionka, and Ludolph (2013) suggested that highfat and high-carbohydrate diet may stabilize weight loss in ALS patients after 12-week intervention period. According to our knowledge, there were two recent registered randomized, parallelgroup, clinical trials which aimed at retarding disease progression by using high-caloric food supplements. The first trial study (NCT02306590) compared a treatment consisting of a high caloric fatty diet (an additional intake of 45 g fat per day) with placebo to evaluate the impact on survival (Dorst et al., 2022). The second trial determined the effects of a high-protein and high-energy supplement on the functional status of newly diagnosed ALS patients (NCT02152449). Although results of this study have not been published yet, the ongoing research on lipid biomarkers and their implication in ALS will certainly pave the way for developing new therapeutic strategies for ALS patients. If we conclude the obvious, from the fact that increased BMI is linked with longer survival, hypermetabolism in ALS should be addressed and high-calorie diets currently seem to be the correct choice. Dietary interventions in ALS patients are summarized in Table 3.

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Table 3 Clinical trials of supplementation in ALS patients.

Nutrients

A high-carbohydrate hypercaloric (HC/HC) diet or a high-fat hypercaloric (HF/HC) diet with EPA and γ-linolenic acid Acetyl-L-carnitine (ALC)

A high fat (35% fat, 50% carbohydrate and 15% protein) and high carbohydrate (0% fat, 89% carbohydrate and 11% protein) High-caloric fatty diet for drinking

A fat- and protein-enriched diet

Intervention dose and duration of study

Type of study and number of patients

Jevity 1.5 (29% calories from fat) or Oxepa (55% calories from fat + EPA + GLA)

Prospective, double-blind, placebo-controlled, randomized, multicenter clinical trial 24 patients A randomized, double-blind, placebo-controlled trial 82 patients A prospective interventional study

4 months 3 g/day ALC or placebo + riluzole 100 mg/day 48 weeks Three times daily (3  200 mL) supplements 12 weeks

405 kcal/90 mL/day (45 g fat per day)

18 months Oral nutritional supplementation (ONS) 1, 2 or 3 ONS/day per os 6 months

Primary outcome

Authors or registered clinical trials number

Safety and tolerability hypercaloric diets with or without excess eicosapentaenoic acid and γ-linolenic acid, in people with advanced ALS receiving enteral nutrition Adverse events and serious adverse events of ALC on organ systems

Wills et al. (2014)

Survival of ALS patients

Dorst et al. (2013)

Survival of ALS patients

NCT02306590, Dorst et al. (2022)

Change in the ALSFRS-R slope between T0 and T0 + 6 months in newly diagnosed ALS patients

NCT02152449

Beghi et al. (2013)

26 patients

A prospective, multicenter, randomized, stratified, parallel-group, double-blind trial 200 patients A randomized, parallel-group, clinical trial

229 patients

Fatty acids in ALS

Fatty acids as auxiliary treatment/treatment in other neurological conditions Lipid content of the brain is exceptionally high, comprising about 50% in dry weight, whereas PUFA accounts for 30% of brain FA, 30% of which is DHA. Since it was determined that n-3 FAs are necessary for optimal brain development, the addition of n-3 FAs to baby formulas has become universal. When it comes to the supplementary usage of FA in neurological disorders, caprylidene, labeled as medical food in the United States, is sometimes used for the clinical management of hypometabolism in mild-to-moderate Alzheimer’s disease. It is a triglyceride composed of MCFA. MCFA metabolism is not dependent on transport proteins for entering mitochondria and the processing of MCFA competes with LCFA to generate ketone bodies (acetoacetate and 3-hydroxybutirate) which are returned to the circulation, to be used by other organs for energy. In fact, the ketogenic diet, which is based on high-fat/low nonfat content, induces a higher level of ketone bodies in the circulation, which has certain health benefits. The opinions are divided on the successfulness of this approach. The extraordinary story of Lorenzo’s oil is also worth a mention here, as the oil developed for the treatment of adrenoleukodystrophy may benefit some presymptomatic patients. The dietary intervention, in this case, is composed of early intake of oleic and erucic acids in addition to VLCFA restriction. The most successful FA-derived medicament, so far, is probably valproate; a branch chained carboxylic acid, which is used as an anticonvulsant to treat epilepsy and more recently bipolar disorders.

Other components of interest SCFA content, which is mainly not discussed here, is intimately related to nutrition, and microbiota and perturbations of microbiota were found in patients with ALS (Zeng et al., 2020), but it is still early to say whether these alterations precede the disease manifestation or are the consequence of the disease. SCFAs have been found to regulate the balance between FA synthesis, FA oxidation and lipolysis (den Besten et al., 2013). This occurs in such a way that SCFAs activate FA oxidation, while de novo synthesis and lipolysis are inhibited, resulting in the reduction of free FA levels in plasma (Ge et al., 2008) and a decrease in body weight (Kondo et al., 2009; Yamashita et al., 2007). In the last few decades, SCFAs have been shown to exert multiple beneficial effects on mammalian energy metabolism and it became apparent that SCFAs might play a key role in the prevention and treatment of some pathological states (den Besten et al., 2013).

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Key facts about fatty acids • • • • • • •

FAs are universal structural and functional elements of living organisms. The content of fatty acids of different tissues is dependent on intake, catabolism and anabolism. Chemical properties of fatty acids are determined by the length and the saturation level; so is the metabolic faith of these molecules. Neuronal tissue has very high percentage of PUFA, about 15%–30% dry mass; especially of ARA and DHA. The changes of FA levels occur with aging and in different pathological states. Nutritional interventions have shown beneficial effects with some pathologies which include metabolic changes. Nutritional interventions are not expected to have a profound nor immediate effect, especially on severe pathologies once structural alterations have occurred.

Mini-dictionary Amyotrophic lateral sclerosis (ALS)—a progressive neurological disease caused by the degeneration of motor neurons, usually affecting people aged 55–75 years, with a 3:2 male-tofemale ratio. ALS is a multifactorial disease, primarily characterized as a proteinopathy, involving dysregulation of RNA. Fatty acids—monocarboxylic acids, with varying length of the carbon chain; often include double bonds between carbon atoms. Hypermetabolism—in this context, increased energy expenditure while resting. Dyslipidaemia—abnormal blood lipid or lipoprotein concentration. Glycolysis—an anaerobic katabolic pathway occurring in the cytosol in which each mole of glucose produces 2 mol of ATP. Body mass index (BMI)—it is calculated by dividing the weight in kilograms with the square of height in meters; if calculation is performed in other units, an additional factor should be included. β-oxidation—major multistep oxidative katabolic process occurring in mitochondria in which the oxidation and splitting of FA that have been converted to acyl-CoA occurs at a β-carbon, resulting in sequential removal of acetyl-CoA units. Food-frequency questionnaires (FFQ)—questionnaires designed to determine the eating habits of subjects. Double-blind, placebo-controlled, randomized, clinical trial—a clinical trial which contains randomly selected groups of people, some receive the therapeutic/s and some receive no therapeutic (placebo), in which neither the study subjects nor the clinical staff knows who belongs to which group.

Fatty acids in ALS

Summary points • • • • • • •

This chapter focuses on metabolic alterations in ALS patients reflected through the perturbations in the fatty acid status. Hypermetabolism or increased resting energy expenditure was noted in two-thirds of ALS patients. Both fat and FA metabolism are altered in ALS patients. Lower level of total PUFAs were found in the blood pellets in ALS patients. Fatty acid analysis in ALS could be a useful tool for the evaluation of different nutritional interventions in ALS. The diagnostic value of FA analysis is generally understated, and ALS is a model disease in which this could be meaningful. The final decision whether a lipid-rich diet should be recommended to ALS patients can only be based on a double-blind placebo-controlled interventional trials.

Acknowledgments Funding was provided by Ministry of Education, Science and Technological Development, of the Republic of Serbia, Grant Nos. 451-03-68/2020-14/200015, 175043, 41005 and 175083. We apologize if we have nondeliberately omitted to cite research important to the topic.

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PART III

Brain injury

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CHAPTER 10

High-fat diets in traumatic brain injury: A ketogenic diet resolves what the Western diet messes up neuroinflammation and beyond Nour-Mounira Z. Bakkara, Stanley Ibehb, Ibrahim AlZaima,b, Ahmed F. El-Yazbia,c,d, and Firas Kobeissyb,e a

Department of Pharmacology and Toxicology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon c Deparment of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt d Faculty of Pharmacy, Al Alamein International University, El-Alamein, Egypt e Program of Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, Psychiatry, Neuroscience and Chemistry, University of Florida, Gainesville, FL, United States b

Abbreviations ATP Bax BBB BDNF CaMKII CCI CREB ETC Fgf2 GSH HFD HFHS IGF-1 KB KD MCFA mPTP NAD/NADH NF-κB PGC-1 PND ROS SIRT1 TBI

adenosine triphosphate Bcl-2-associated protein X blood-brain barrier brain-derived neurotrophic factor calmodulin protein kinase II controlled cortical impact cyclic adenosine monophosphate response element binding protein electron transport chain fibroblast growth factor 2 glutathione peroxidase high-fat diet high fat high sucrose insulin growth factor 1 ketone bodies ketogenic diet medium-chain fatty acid mitochondrial permeability transition pore nicotinamide adenine dinucleotide nuclear factor-kappa B proliferator-activated receptor gamma coactivator-1 postneonatal day reactive oxygen species silent information regulator 1 traumatic brain injury

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00022-2

Copyright © 2023 Elsevier Inc. All rights reserved.

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TNFR TNF-α UCP WD

tumor necrosis factor receptor tumor necrosis factor-alpha uncoupling protein Western diet

Introduction Transition to a Western diet (WD) has been associated with increased prevalence of the metabolic syndrome. The latter is defined by the presence of at least three of the following conditions: high blood pressure, high blood glucose, dyslipidemia, hypertriglyceridemia (low high-density lipoproteins and high low-density lipoproteins), and abdominal (visceral) obesity. The metabolic syndrome is known to increase the risk of occurrence and worsen the prognosis of several pathological complications, among which are neurological disorders like Alzheimer’s disease, Parkinson’s disease, epilepsy, and traumatic brain injury (TBI). Interestingly, as dietary habits were shown to be responsible for deteriorating health conditions, management by alternative dietary interventions gained attention as a safe and effective therapy for metabolically induced neurological derangements. In fact, understanding how diets interfere with and modify the metabolic state of a system of organs to bring about adverse outcomes or desired therapeutic benefits requires in-depth knowledge of the peculiar, organ-specific metabolic profile of the intended target. Indeed, switching from one energy source to another leads to structural and functional changes characteristic of the activated metabolic processes. Such changes are best delineated by the distinctive and particularly opposite effects of high-fat diets (HFDs), namely the WD versus ketogenic diet (KD). The purpose of this book chapter is to discuss the impact of HFDs on complications of TBI in light of the brain metabolic, oxidative, and inflammatory state as well as the status of autophagy and apoptosis. The chapter provides evidence about the deleterious versus desirable consequences of WD and KD, respectively, on experimental models of TBI, shedding light on the possible molecular mechanisms underlying such effects.

Traumatic brain injury: A debilitating neurological disease TBI is a major public health burden in many countries as it is one of the leading causes of death and disability in people of all ages (Al-Hajj et al., 2021). It is described as an impact to the head that causes brain penetration or movement, disrupting normal brain function. The severity and clinical complications following TBI can vary by age, gender, form, and location of the injury, so no two TBIs are alike (Prins et al., 2013; Rutland-Brown et al., 2006; Taylor et al., 2017). Preexisting medical conditions can exacerbate the effects of a brain injury. Moreover, TBI is a risk factor for neurodegenerative diseases including

HFD in TBI: Neuroinflammation and beyond

Alzheimer’s disease, stroke, and chronic traumatic encephalopathy (Sundman, Hall, & Chen, 2014; Xiong, Mahmood, & Chopp, 2018).

Primary injury Based on the clinical manifestation of the injury, TBI could be classified as mild, moderate, or severe, using the Glasgow Coma Scale (Maas et al., 2017). The initial impact on the brain, which is referred to as the primary injury, involves the direct damage that is elicited at the point of injury. These include tissue damage, hemorrhage, subdural and epidural hematoma, and contusion. The aftermath of the primary brain injury can lead to either focal or diffuse injury (Ng & Lee, 2019). Focal injury is a result of collision force that is exerted on the skull, which causes compression of brain tissue at the impact site (Andriessen, Jacobs, & Vos, 2010). However, injuries that are due to rapid acceleration or deceleration of the head give rise to diffuse brain injury. This type of injury often leads to axonal damage, ischemia, and edema (Gennarelli et al., 1982). TBI, be it a single or multiple event, could affect different regions of the brain, leading to functional impairment (McAllister, 2011). The frontal cortex and subfrontal white matter, the deeper midline structures such as the basal ganglia and diencephalon, the rostral brain stem, and the temporal lobes, including the hippocampi, are all especially vulnerable to neurotrauma. TBI affects certain neurotransmitter systems, particularly the catecholaminergic and cholinergic systems, both of which are essential for behavioral homeostasis (Arciniegas, 2003; McAllister, 2011; McAllister et al., 2004).

Secondary injury Although the primary injury produces noticeable neurobehavioral and functional impairment, it can progress to alter several cellular and molecular events in the brain eventually resulting in a secondary brain injury (Kochanek et al., 2000). Indeed, one of the main determinants of TBI functional outcome is the severity of the secondary injury that follows the initial impact. Of note, mild TBI produces no physical damage but leads to several pathological and neurobehavioral alterations (Xu et al., 2021). The effect of the secondary injury is not always evident immediately after TBI, as it could take weeks or even months for these sequelae to manifest. As a result, not only does it worsen the initial pathologies observed in the injured brain, but it also exerts alterations which could increase hospital stay and deteriorate the functional outcome of TBI victims (Lazaridis, Rusin, & Robertson, 2019). The pathologies of the secondary injury include neuroinflammation, necrotic or apoptotic cell death, distorted energy metabolism, oxidative stress, altered cerebral vasculature, ischemia, and excitotoxicity (Akamatsu & Hanafy, 2020; Kochanek et al., 2000; Kumar & Loane, 2012; Lazaridis et al., 2019). The fact that the secondary injury progresses slowly and can produce a lasting impact makes it an important target for TBI therapy development (Ng & Lee, 2019).

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Altered cerebral metabolism associated with TBI (Fig. 1) Glucose metabolism: A transition from hyper- to hypoglycolysis The culprit of oxidative stress in the immediate post-TBI period is related to ionic changes secondary to brain movement. An increase in extracellular potassium and glutamate (Katayama et al., 1990) along with an elevation in intracellular levels of calcium (Fineman et al., 1993) require a transient state of increased glycolysis (Bergsneider et al., 1997), subsequently leading to enhanced reactive oxygen species (ROS) production (Hall, Andrus, & Yonkers, 1993). Particularly, increased energy demand required for the reestablishment of ion concentrations necessary for Na+/K+ ATPase functioning (Patet et al., 2016) drives hyperglycolysis and the associated oxidative stress. The latter produces DNA strand breaks, resulting in the activation of poly-ADP ribose polymerase

Fig. 1 Pathological consequences of traumatic brain injury (TBI) on brain metabolism. Disruption of ionic gradients following brain movement is associated with altered cerebral metabolism culminating in increased oxidative stress, neuroinflammation, and apoptosis. Transient hyperglycolysis is followed by prolonged suppression of glucose metabolism, a shift to anaerobic glycolysis and lactate accumulation, and a drop in energy levels. Increased activity of mitochondrial permeability transition pore (mPTP) contributes to altered amino acid metabolism post-TBI. ATP: adenosine triphosphate, BAX: Bcl-2-associated protein X, ETC: electron transport chain, GAPDH: glyceraldehyde-3-phosphate dehydrogenase, IL: interleukin, NAD+: nicotinamide adenine dinucleotide, NF-κB: nuclear factor-kappa B, PARP: poly-ADP ribose polymerase, PPP: pentose phosphate pathway, ROS: reactive oxygen species, TNF-α: tumor necrosis factor-α, TNFR: TNF receptor.

HFD in TBI: Neuroinflammation and beyond

(PARP) in an attempt to repair DNA damage. Consequently, nicotinamide adenine dinucleotide (NAD+) levels drop inhibiting the activity of the glycolytic enzyme, glyceraldehyde-3-phosphate dehydrogenase (Sheline, Behrens, & Choi, 2000). Indeed, one of the consequences of TBI on long-term cerebral metabolism is prolonged depression of glycolysis, the magnitude and duration of which are dependent on injury severity, age, and cerebral maturation (Hovda et al., 1994; Prins & Hovda, 2001; Prins & Hovda, 2009; Prins & Matsumoto, 2014; Thomas et al., 2000). Interestingly, shifting glucose degradation to the pentose phosphate pathway is shown to be responsible for the reduction in glycolysis and ATP production (Bartnik et al., 2005); thus, the need for an alternative energy substrate becomes indispensable. In fact, the abrupt change in metabolism from hyper- to hypoglycolysis impairs the activity of pyruvate dehydrogenase along with that of mitochondrial transport chain complexes, including complexes I, III, and VI, marking the transition to anaerobic glycolysis followed by lactate accumulation (Patet et al., 2016). In addition to altered glucose metabolism, TBI provokes altered neuronal amino acid metabolism. This is demonstrated by decreased levels of N-acetyl aspartate following injury, an event precipitated by increased mitochondrial permeability (Vagnozzi et al., 2007). Indeed, elevated efflux of this amino acid makes it prone to degradation by oligodendrocytes and suppresses its synthesis.

The mitochondrial permeability transition pore and intrinsic apoptosis Increased mitochondrial permeability secondary to the formation of a mitochondrial permeability transition pore (mPTP) in the inner membrane is another mechanism associated with decreased ATP bioavailability following TBI. The hypoxia resulting from injury-induced infarction is implicated in the formation of the mPTP (Galluzzi, Kepp, & Kroemer, 2012; Tsujimoto & Shimizu, 2007). Consequently, the release of the electron transport chain (ETC) component, cytochrome c, from the mitochondrial inner membrane to the cytosol through the mPTP instigates the activation of apoptosis along the intrinsic pathway (Wang, 2001). Augmented intracellular calcium levels have also been found to promote cytochrome c release (Shore, Papa, & Oakes, 2011). Particularly, heightened signaling through metabotropic glutamate receptors along the Gq11 pathway mediates inositol triphosphate-induced release of calcium ions from the endoplasmic reticulum. Components of the Bcl-2 family regulate the opening of the mPTP, in such a way that Bcl-2-associated protein X (Bax) promotes its formation, while Bcl-2 hinders it (Wong & Puthalakath, 2008).

Neuroinflammation and extrinsic apoptosis Alternatively, neuronal apoptosis along the extrinsic pathway is implicated as well in cell loss following TBI. Indeed, in an attempt to repair damaged neurons and clear out cell

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debris resulting from intrinsic apoptosis and necrosis, microglia, the primary immune cells in the brain, are activated (Donat et al., 2017). Chronic activation of microglia is associated with transition from a ramified to the classical phenotype, which is associated with pro-inflammatory cytokines release (Ansari, 2015). Of particular importance to the extrinsic apoptotic cascade is tumor necrosis factor-alpha (TNF-α), the binding of which to its cognate receptor TNF receptor 1 (TNFR1) ignites a series of pro-inflammatory and pro-apoptotic downstream processes ultimately resulting in the activation of nuclear factor-kappa B (NF-κB) and the executioner caspase-3, respectively (Wilson, Dixit, & Ashkenazi, 2009; You et al., 2017). TNFR2, on the other hand, is known to exert protective, pro-survival effects (Dong et al., 2016; Probert, 2015). In addition to pro-inflammatory signaling via TNF-α, it has been shown that TBI increases cerebral expression of interleukin-1 beta (IL-1β) and interleukin-10 (IL-10) (Kamm et al., 2006). Astrocytes also participate in reactive gliosis, secreting inflammatory cytokines like TNF-α. Disruption of basic astrocytic functions post-TBI compromises neurovascular coupling and blood-brain barrier (BBB) integrity (Shlosberg et al., 2010). The latter exacerbates neuroinflammation by allowing the infiltration of systemic inflammatory mediators. For instance, fibrinogen is one of the plasma proteins recruited into the brain which acts through transforming growth factor-beta (TGF-β) to initiate astrocytic scar formation (Schachtrup et al., 2010). Despite increased research on finding an acceptable therapy over the past few years, many factors have been a major bottleneck to developing an effective post-TBI treatment. These include injury heterogeneity, individual variations among brain injury patients, and the inability of most substances to cross the BBB. To this end, the FDA has yet to authorize a treatment for TBI (Diaz-Arrastia et al., 2014). As a result, nutritional control of TBI has become increasingly important.

Features of high-fat, Western, and ketogenic diets and associated systemic metabolic states Interplay between fat and sugar: A determinant of metabolic state Although a high percentage of energy is derived from fat in both WD and KD, these diets mainly differ in the ratio of fat-to-carbohydrate provided and the type of fats consumed. Generally, a WD is a high-fat, high-carbohydrate diet, while a KD is a high-fat, lowcarbohydrate nutritional regimen. Particularly, a KD provides around 80% of calories from fat, 5% from carbohydrates, and 15% from proteins as opposed to a traditional diet which is composed of 30%, 55%, and 15% of calories from fat, carbohydrates, and proteins, respectively (Włodarek, 2019). In contrast to an American diet which has a diet ratio of around 0.3:1 corresponding to grams of fat to carbohydrates + proteins, the diet ratio of a KD is typically 4:1 (Kossoff & Dorward, 2008).

HFD in TBI: Neuroinflammation and beyond

Difference in dietary composition promotes peculiar systemic and organ-specific changes associated with a particular metabolic state. This is supported by the concept of interdependence between dietary components (Tapsell et al., 2016). While a HFD is believed to cause detrimental cardiovascular, cerebrovascular, and neurological consequences, it is only in combination with high carbohydrates, comprising a WD, that it results in such pathologies. Alternatively, a high-fat, low-carbohydrate diet promotes a state of ketosis where the body uniquely uses fat in the form of ketone bodies as an energy source. Such an energetic state was shown to be metabolically favorable in preserving homeostatic functions and reversing the deleterious effects of disorders associated with altered metabolic control. Particularly, a WD is associated with a pro-oxidative and a low-grade proinflammatory milieu related to glucose intolerance, ensuing mitochondrial dysfunction, and a hypoxic environment. Elevated fat storage under the effect of hyperinsulinemia is thought to induce a pro-inflammatory state related to hypoxia. Moreover, alterations in gut microbiota population in response to a WD contribute to the progression of systemic inflammation through compromising the intestinal barrier allowing endotoxin access to the blood. Progressively, exaggerated systemic pro-inflammatory markers disrupt the integrity of the BBB initiating neuroinflammation (Fig. 2A). Interestingly, a KD has been described to exhibit insulin-like functions related to mitochondrial energy transduction and reduced insulin resistance (Sato et al., 1995).

Fatty acids and mitochondrial uncoupling The aforementioned processes can be attributed not only to glucose dysmetabolism and associated fat accumulation but also to the specific fat type comprising the diet. A WD is typically composed of saturated fats which are the culprit of systemic diseases related to the presence of all-single bonds in their corresponding carbon chains, while a KD is made up of unsaturated fats. More specifically, a KD is desirably rich in medium-chain triglycerides comprised of medium-chain fatty acids (MCFAs) which have better accessibility to the brain across the BBB compared to longer chains. Subsequently, transport of MCFAs to the mitochondria does not require the carnitine shuttle which makes them more efficient substrates for β-oxidation. Fatty acids are known inducers of mitochondrial uncoupling proteins (UCPs), which uncouple the mitochondrial proton motive force from oxidative phosphorylation. However, as WD and KD are essentially distinct HFDs in terms of carbohydrate content as well as fat percentage and quality, their impact on mitochondrial dynamics is indeed variable. Differential, tissue-specific changes in UCP expression and activity in response to WD and KD partly explain the consequences. For example, consumption of a WD is linked to elevated UCP1 expression in beige adipose depots. This is particularly associated with detrimental, hypoxia-driven inflammatory pathways linked to exaggerated

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Fig. 2 (A and B) Differential systemic and cerebral effects of high-fat diets. (A) Consuming a Western diet promotes localized, low-grade inflammation related to adipocyte hypertrophy and free fatty acid (FFA)-induced mitochondrial dysfunction. Dysbiosis of the gut microbiota (GM) induces systemic inflammation responsible for compromising the integrity of the blood-brain barrier (BBB), subsequently leading to neuroinflammation. (B) A ketogenic diet is associated with increased peripheral energy expenditure via nonshivering thermogenesis of brown adipose tissues (AT). Ketosis enhances brain bioenergetics via efficient energy production mechanisms, combating cerebral oxidative stress and inflammation. AT: adipose tissue, BBB: blood-brain barrier, ATP: adenosine triphosphate, FFA: free fatty acids, GM: gut microbiota, HIF-α: hypoxia inducible factor, NADH: nicotinamide adenine dinucleotide, NF-κB: nuclear factor-kappa B, PGC-1β: peroxisome proliferatoractivated receptor-γ coactivator-1 beta, TNF-α: tumor necrosis factor-alpha, UCP: uncoupling protein.

HFD in TBI: Neuroinflammation and beyond

signaling downstream of hypoxia-inducible factor-alpha (HIF-α) and NF-κB (Fig. 2A). On the other hand, the favorable outcomes promoted by KD are thought to be the result of energy dissipation via nonshivering thermogenesis carried out by UCP1 of brown adipose tissues, possibly leading to weight loss (Ma et al., 2021) (Fig. 2B). Interestingly, despite the fact that UCP1 is known to have high oxygen consumption, KD leads to the formation of ketone bodies that are known to provide more energy per oxygen unit than glucose, particularly for β-hydroxybutyrate (Włodarek, 2019).

Effects of high-fat, Western, and ketogenic diets on the brain, irrespective of TBI Effects on brain energy homeostasis In addition to the opposing effects of WD and KD on peripheral metabolism and systemic markers, it is their ability to variably alter brain bioenergetics that creates the paradox (Mainardi & Maffei, 2019). A study by Selfridge et al. (2015) investigated the effect of long-term feeding of either a WD or a KD on peripheral and central markers of energy homeostasis, brain bioenergetics, and mitochondrial mass proteins (Selfridge et al., 2015). Results showed that although WD and KD differentially altered peripheral insulin resistance, central insulin sensitivity was similar and presumably unaffected or otherwise compensated for. On the other hand, a KD exclusively increased brain peroxisome proliferatoractivated receptor-γ coactivator-1 beta (PGC-1β) gene expression, which is associated with enhanced aerobic energy production, and hence energy efficiency (Selfridge et al., 2015). In addition, one of the mechanisms through which KD exerts a neuroprotective effect is by increasing mitochondrial energy efficiency via enhancing NADH oxidation and decreasing mitochondrial permeability (Masino & Rho, 2012). The latter ultimately results in increased ATP production. Alternatively, the uncoupling of oxygen consumption from energy production achieved by a KD was shown to culminate in decreased ROS production in the hippocampus of juvenile mice (Sullivan et al., 2004). Indeed, a KD was observed to increase the expression of UCP2, UCP4, and UCP5 in the dentate gyrus, an event which is accompanied with enhanced defense mechanisms against elevated ROS production like increased glutathione peroxidase (GSH) activity in the hippocampus (Ziegler et al., 2003). Nevertheless, the reduced ATP production is compensated for by two mechanisms. First, the decreased oxidative stress in hippocampal tissues triggers an increased activity of cytochrome c oxidase subunit II of complex IV of the ETC ultimately elevating ATP levels (Diano et al., 2003; Vaynman et al., 2006). Additionally, UCP2 upregulation augments mitochondrial proliferation increasing ATP production per cell rather than per mitochondrion (Garcı´aMartı´nez et al., 2001; Horvath et al., 1999) (Fig. 2B).

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Interestingly, some of the central effects seen with KDs are independent of the presence or absence of a ketotic state. This can be potentially explained by the direct effects derived from MCFAs, a major constituent of KDs (Thevenet et al., 2016). MCFAs were implicated in desirable astrocytic metabolism. Particularly, in a single cell-based model, MCFA inhibited astrocytic mitochondrial respiration, an event which is otherwise associated with ROS production, alternatively enhancing astrocytic ketogenesis and lactate synthesis and activating shuttle systems securing fuel in the form of lactate and KBs to neighboring neurons.

Linking energy homeostasis to cognition and synaptic plasticity (Fig. 3) Interestingly, in adult male rats, enhanced UCP2 activity was shown to interface the relationship between metabolic status of energy consumption and brain neuroplasticity (Vaynman et al., 2006). Particularly, exercise-induced benefits on learning and memory were demonstrated to be carried out by UCP2-mediated enhancement of brain-derived neurotrophic factor (BDNF) signaling cascade, downstream of tropomyosin receptor kinase B (TrkB), involving calmodulin protein kinase II (CaMKII), cyclic adenosine monophosphate response element binding protein (CREB), and synapsin I (Vaynman et al., 2006). Of note, UCP2’s localization near pre- and postsynaptic membranes (close to NMDA receptor) endows it with a calcium buffering capacity, which is especially important in regulating excitotoxicity and apoptosis. Additionally, through its ability to modulate calcium influx, UCP2 is capable of stimulating vesicular release of synapsin I and its activation by CAMK-II. The latter is upstream of CREB which in turn affects BNDF expression. Akt, or protein kinase B, intersects the pathway leading to CREB activation, whereby its phosphorylation is dependent on CAMK-II. Alternatively, Akt is downstream of insulin growth factor-I receptor (IGF-IR) (Leinninger et al., 2004). Hence, alteration of brain insulin sensitivity, like that seen with WD, can affect CREB, a survival transcription factor (Go´mez-Pinilla, 2008). Glycogen synthase kinase-3β (GSK-3β), a pro-apoptotic protein, is phosphorylated by Akt leading to its inhibition (Leinninger et al., 2004). Through increased oxidative stress, WD was shown to decrease the expression of BDNF, CREB, and synapsin I (Wu, Ying, & Gomez-Pinilla, 2004). On the other hand, the capacity of a KD to increase the efficiency of ATP production could mediate its permissive effect on IGF-I and BNDF expression. Along the same lines, other energy-regulating proteins such as ubiquitous mitochondrial creatine kinase and AMP-activated protein kinase can alter synaptic plasticity via BDNF (Go´mez-Pinilla, 2008). Silent information regulator 1 (SIRT1) is another molecule implicated in the link between energy homeostasis and synaptic plasticity through its ability to reduce oxidative stress. Indeed, CREB is an activator of SIRT1. Being a histone deacetylase, SIRT1 is capable of carrying out

HFD in TBI: Neuroinflammation and beyond

Fig. 3 Linking Energy Homeostasis to Synaptic Plasticity. Uncoupling protein 2 (UCP2) is situated next to NMDA-R on presynaptic and postsynaptic terminal where it acts as a calcium buffer to enhance synaptic plasticity via brain-derived neurotrophic factor (BDNF) signaling through tropomyosin receptor kinase B (TrkB) and synapsin I secretion. It promotes calmodulin protein kinase II (CaMKII) phosphorylation and cyclic adenosine monophosphate response element binding protein (CREB) expression. NMDA-R: N-methyl-D-aspartate receptor, VDCC: voltage-dependent calcium channel.

epigenetic modifications associated with cognition by modifying chromatin condensation (Go´mez-Pinilla, 2008).

Effects of Western diet pre- and post-TBI and associated molecular mechanisms (Fig. 4A) Consumption of a WD has been shown to potentially slow down brain regeneration after a TBI (Shaito et al., 2020). Even though several studies found worsening of the neurological and behavioral profile with WD feeding (Shaito et al., 2020), there is still a huge gap in the literature about the underlying cellular and molecular events. In experimental TBI models, WD has been linked to altered neurological profile, aggravated

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neuroinflammation, impaired synaptic plasticity, apoptotic cell death, oxidative stress, and compromised neurovascular coupling (Shaito et al., 2020).

WD exacerbates neuroinflammation and neuronal cell death Even though TBI causes activation of microglia, which could be reparative or deleterious, consumption of a WD has been reported to be associated with exaggerated microglial reactivity, an event that is linked to aggravated secondary injury and reduced functional outcome after TBI (Shaito et al., 2020). A study that looked at the impact of obesity, induced by 4 months of HFD feeding, on TBI found that HFD worsened secondary brain injury. Thirty days after closed head controlled skull impact, obese mice exhibited neuroinflammation, characterized by increased microglial activation in the hypothalamus, cortex, and corpus callosum, compared to their standard diet-fed counterparts (Sherman et al., 2016). In addition, obese mice displayed increased anxiety-like behavior. Interestingly, HFD-induced aggravation of TBI consequences was only observed in male versus female mice (Sherman et al., 2016). Kuo et al. also reported neuroinflammation, marked by reactive gliosis and increased expression of TNF-α in a TBI-induced rat fed a HFD (Kuo et al., 2020). Significantly, the rats also showed increased neuronal apoptosis (Kuo et al., 2020). In fact, although there was no standard-diet-fed reference group in this study, the authors found a significant correlation between serum triglyceride levels on day 3 post-TBI and neuroinflammation as well as apoptosis, implicating increased delivery of triglycerides across the BBB. Recently, Chong et al. employed the same TBI model and HFD to compare the effects observed in high-fat-fed rats 3 days after TBI to those in control, normal chow-fed rats (Chong et al., 2020). Surprisingly, although HFD-fed TBI rats showed decreased motor function compared to their normal diet-fed counterparts, no significant difference was observed in the neuroinflammatory and apoptotic markers between these groups (Chong et al., 2020). Exaggerated neuroinflammation might thus take the upper hand later in the prospect of the postinjury events. Alternatively, differences in the sensitivities of species (mice vs. rats) to TBI and/or dietary challenge and their propensity to metabolic changes might account for the discrepant results in different studies.

WD aggravates neuroplastic, neuropathological, and neurobehavioral impairment WD feeding has been reported to impair synaptic plasticity in several animal models of TBI. In a mild form of fluid percussion injury, rats were fed a WD diet for 4 weeks before being exposed to head injury. One week after TBI, rats on the WD diet demonstrated worsened learning and memory abilities compared to those fed a standard diet. On the molecular level, these rats had lower hippocampal levels of BDNF and its downstream signaling molecules CREB and synapsin I (Wu et al., 2003). A different study reported

HFD in TBI: Neuroinflammation and beyond

the involvement of BDNF signaling in anxiety-like behavior post-TBI. Particularly, WD-induced reductions in the expression of BDNF, its receptor TrkB, CaMKII, Akt, and CREB were associated with reduced expression of the anxiolytic substrate neuropeptide Y1 and its receptor, associating WD with increased risk of posttraumatic stress disorder (Tyagi et al., 2013). Interestingly, these changes were seen in the light of aggravated neuroinflammation, as indicated by increased levels of IL-1β expression in the frontal cortex of WD-fed rats. Another study revealed that WD hindered functional recovery after acute TBI (Hoane, Swan, & Heck, 2011). Eight weeks of WD feeding prior to TBI in male rats brought about a greater loss of cortical tissue 2 days after. This was accompanied with altered recovery patterns of sensorimotor and cognitive activities, as well as working memory (Hoane et al., 2011). Similarly, a study that looked at the impact of diet, age, and prior injury exposure on the outcomes of mild concussive TBI showed that WD exacerbated behavior deficits (Mychasiuk et al., 2015a). Particularly, long-term WD-fed rats that experienced mild concussive TBI had persisting symptoms 60 days after the injury, indicating delayed recovery. Additionally, TBI in WD-fed rats produced cumulative, yet differential, deterioration patterns in motor functioning, depressive behavior, and short-term memory in rats experiencing a single mild TBI or those receiving repeated TBI events (Mychasiuk et al., 2015a).

WD induces genetic and epigenetic changes The effects of WD on TBI complications extend to alterations in the epigenetic machinery bringing about long-term changes in gene expression. Since increased oxidative stress and neuroinflammation exist at the crossroad between WD consumption, TBI, telomere shortening, and neurodegenerative diseases, researchers invested in studying the impact of dietary intake on the long-term risk of neurological pathology mediated by telomere shortening. Results revealed that rats kept on HFD had shorter telomeres in peripheral cells after TBI compared to their counterparts on regular diet (Mychasiuk et al., 2015a). A similar observation was made in a study, by Mychasiuk et al., which reported a significant correlation between peripheral and brain telomere length (Mychasiuk et al., 2015b). Telomere shortening has been linked to a number of neurological conditions, including Alzheimer’s and Parkinson’s disease (Levstek et al., 2020), which exhibit similar pathologies to TBI. In a rat model of mild TBI, the gene expression of IGF1, Tau, and fibroblast growth factor 2 (fgf2) were differentially increased in the prefrontal cortex and hippocampus of the HFD-fed rodents, possibly indicating the initiation of neurodegenerative, Alzheimer-like processes (Mychasiuk et al., 2015b). Indeed, IGF1 has been reported to be implicated in neuroplasticity, nerve growth, and neurotransmitter synthesis; however, at high levels, it is linked to neurodegeneration (Rabinovsky, 2004). In this context, fgf2 has been associated with Tau reactivity, secondary to its disruptive effect

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of oligodendrocytes (Butt & Dinsdale, 2005). Additionally, leptin, which plays an essential role in long-term potentiation, depression, and spatial learning, was significantly reduced in the hippocampus of mice fed a HFD. Similar to what has been previously reported, the expression level of BDNF was further reduced in the hippocampus and prefrontal cortex of rats with TBI and on a HFD (Mychasiuk et al., 2015b). Surprisingly, in a compensatory mechanism for HFD-induced stress, CREB expression was increased with respect to standard diet. However, this increase was lower in rats with concomitant TBI when compared to their sham counterparts, reflecting the cumulative effect of TBI and HFD. It was also observed that HFD led to notable epigenetic alterations which include reduced expression of DNA methyltransferase 1 (DNMT1) and SIRT1 in the hippocampus and cortex, and that of telomerase reverse transcriptase (TERT) and PGC-1α in the cortex only (Mychasiuk et al., 2015b). DNMT1 is involved in epigenetic processes that function to increase synaptic plasticity and genome stability. It acts together with SIRT1, which in turn leads to an increased expression of TERT and PGC-1α. These changes were concerted with motor and behavioral deficits.

WD impairs neurovascular coupling and the BBB The neurovascular unit (NVU) is a multicellular compartment that represents the structural and functional relationship between the brain and blood vessels. Neurons, perivascular astrocytes, microglia, pericytes, endothelial cells, and the basement membrane are the cellular components that make up the NVU (Bell et al., 2020). The NVU is in charge of maintaining cerebral homeostasis and the highly selective blood-brain barrier (BBB), as well as controlling cerebral blood flow (CBF). The intensity of CBF to a particular brain region is regulated by the functional operation in that area of the brain (Tan et al., 2014). One of the prominent effects of TBI is the uncoupling of the NVU, which results in an impaired cerebral blood flow, with a subsequent effect on cerebral metabolism ( Jang et al., 2017). Evidence has shown that HFD consumption exacerbates the neurovascular alteration in a mouse model of ischemic brain injury (Li et al., 2013). Eight weeks of HFD feeding in ischemic rats impaired functional hyperemia and cerebral blood flow possibly due to endothelial dysfunction. So far, no studies have investigated the combined effect of HFD and TBI on cerebrovascular and endothelial function. Further research is required to fully understand the impact of WD on NVU.

Effects of ketogenic diet pre- and post-TBI: Preventative, direct (acute), and long-term (chronic) therapeutic benefits (Fig. 4B) KD and favorable brain energetics Although a KD was first prescribed for the treatment of intractable epilepsy, knowledge about its neuroprotective effects motivates its use in other neurological disorders

HFD in TBI: Neuroinflammation and beyond

Fig. 4 (A and B) Impact of high-fat diets on traumatic brain injury. (A) Western diet (WD) consumption exacerbates neuronal inflammation, oxidative stress, and apoptosis and delays recovery post-TBI. Aggravation of behavioral deficits is mediated by disruption of brain-derived neurotrophic factor (BDNF) signaling. WD promotes genetic and epigenetic alterations associated with deterioration of synaptic plasticity and neurodegeneration. (B) Ketogenic diet (KD) improves brain bioenergetics post-TBI by providing an efficient substrate for fuel production. A ketotic state ameliorates mitochondrial function by enhancing anti-oxidative defense mechanisms and promoting the expression of homeostatic genes. KD promotes neuroprotection associated with recovery of functional outcomes post-TBI. ATP: adenosine triphosphate, Cr: creatine, DNMT1: DNA methyltransferase 1, fgf2: fibroblast growth factor 2, ΔG: change in Gibb’s free energy, IGF-1: insulin growth factor 1, KB: ketone bodies, MCT: monocarboxylate transporter, mPTP: mitochondrial permeability transition pore, NAD(P)H: nicotinamide adenine dinucleotide phosphate, NPYR: neuropeptide Y1 receptor, PCr: phosphocreatine, SIRT1: silent information regulator 1 (sirtuin 1), SOD: superoxide dismutase, TERT: telomerase reverse transcriptase.

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associated with altered metabolism like TBI, which can precipitate seizures in its most intense forms. This is especially supported by the fact that dysmetabolism secondary to WD consumption aggravates neuronal injury resulting from TBI (Shaito et al., 2020). Indeed, KD provides benefits which range from the direct post-TBI period to the long-term aftermath of the concussion. When used in the immediate period postTBI, KD provides an alternative energy substrate to compensate for the depressed glucose metabolic rate. It was demonstrated that following TBI, the brain increases its reliance on KB oxidation as an adaptive mechanism for obstructed glucose processing and limited energy availability. This is achieved by increased cerebral uptake of KBs, particularly β-hydroxybutyrate, and is accompanied with elevated cortical ATP concentration (Prins et al., 2004). Significantly, the impact of a postinjury KD feeding was shown to be determined by age-dependent metabolism; in the sense that better neuroprotection is derived from such a diet in adolescence (Prins, Fujima, & Hovda, 2005). This was related to an earlier increase in the plasma concentration of the KB, βHB, its sustenance for a longer duration (Prins & Giza, 2006), and its enhanced uptake by cerebrovascular transporters, namely monocarboxylate transporters 1 and 2, compared to younger and older age counterparts. Indeed, neuroprotection as well as motor and cognitive improvement were associated with an amelioration of brain energetics demonstrated by desirable levels of ATP, creatine, and phosphocreatine and a deviation from anaerobic, lactic acid metabolism (Deng-Bryant et al., 2011). The latter could be partially explained by the observed capacity of the KD to rescue TBI-induced depression of cellular rate of glucose metabolism.

Effect of KD on mitochondrial efficiency and intrinsic apoptosis Direct administration of KD to juvenile rats demonstrated intrinsic anti-apoptotic and edema suppression capacity in the postweight drop injury brain, limiting cell loss. Indeed, Bax blockade was shown to be carried out by inhibition of mitochondrial cytochrome c release into the cytosol, the culprit of apoptosis (Hu et al., 2009). This was associated with lower levels of caspase-3. Such ameliorative effects are possibly derived from elevated anti-oxidative defense mechanisms, like superoxide dismutase and NAD(P)H dehydrogenase quinone 1 (Greco et al., 2016). Indeed, in light of reduced oxidative stress, enhanced mitochondrial efficiency as reflected by improved postinjury activity of complexes II-III was observed (Greco et al., 2016). Another mechanism by which a KD can increase ATP availability and improve cognitive function post-TBI is through limiting mPTP formation, which was shown to be associated with better cognition postinjury (Readnower et al., 2011). Additionally, KD was shown to recover the mRNA expression levels of optic atrophy 1, a protein indispensable for maintaining the integrity of mitochondrial inner membrane and cristae, and

HFD in TBI: Neuroinflammation and beyond

promote positive behavioral outcomes (Salberg et al., 2019). However, more research into the mediating role of mPTP in the effect of KB on cognitive function is warranted.

Effect of KD on neuroinflammation and autophagy While it inhibits neuronal cell death by apoptosis, a KD was also shown to promote cellular repair mechanisms like autophagy. By rescuing the function of tight junction proteins, KD feeding was shown to be associated with lower microglial activation as indicated by lower expression of ionized calcium-binding adaptor protein (Iba1) in the prefrontal cortex as well as the hippocampus of mildly injured rats (Salberg et al., 2019). Along with a decrease in neuroinflammation, a KD activates microglial autophagy, a pro-survival process indispensable for clearing cell debris and plaque aggregates associated with TBI (Zhang et al., 2018).

KD and pro-survival genetic and epigenetic changes Contrary to WD consumption, KD feeding was shown to be protective against telomere length shortening following TBI (Salberg et al., 2019). Alongside changes in epigenetics, results reveal a possible desirable effect of KD on fgf2 expression, whereby pathological increase in fgf2 expression following TBI was evident in the standard diet- but not in the KD-fed group (Salberg et al., 2019). Importantly, both these effects were seen with KD feeding preceding TBI, reflecting the protective—i.e., preventive—rather than therapeutic role of such an intervention.

KD as an anti-epileptogenic treatment in TBI One of the few studies evaluating the preventive effects of KD-induced cascades distinguished between its anti-epileptogenic versus anti-convulsant properties in TBI models (Schwartzkroin et al., 2010). The study demonstrates the capacity of a ketotic state to reduce seizure sensitivity when administered at the time of brain excitation with flurothyl postinjury. However, no proof of the ability of a preinjury treatment with KD to halt early processes involved in epileptogenesis was established. Moreover, the study suggests that a persistent ketotic state is necessary for maintenance of antiseizure processes. Interrupted post-TBI KD failed to attenuate brain excitability at a later challenge, proposing the KD as a long-term postinjury recovery therapy. Nevertheless, considering the age differences in response to postinjury treatment with KD, it isprudent to study the anti-epileptogenic potential endowed by a pretreatment with KD in younger and perhaps adolescent rats, especially that the neurometabolic effects of a KD post-TBI seems less sustained in the old. Interestingly, while an anti-epileptogenic effect was absent in immature rats, administration of KD prior to TBI provided protection against shrinkage of ipsilateral hippocampal volume compared to posttreatment with KD (Schwartzkroin et al., 2010). Indeed, anti-epileptic effects

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provided by a KD may be attributed to attenuated cell damage and elevation of seizure threshold. Aside from TBI-induced epilepsy, KD feeding, particularly a modified omega-3 diet, prior to repetitive mild TBI promoted cognitive improvement in adult rats as revealed by a novel object recognition test (Wang et al., 2013).

Applications to other neurological conditions The derangements associated with a WD and the benefits derived from a KD do not only apply to TBI but also extend to other neurological diseases characterized by metabolic impairment. One of these conditions is Alzheimer’s disease whereby studies have shown that the development of the hallmarks of the disease, its progression, and prognosis can be worsened or delayed with the different high-fat diets presented. Indeed, while a WD was shown to be associated with adverse outcomes, a KD was demonstrated to carry putative disease-modifying effects or produce symptomatic relief (Włodarek, 2019).

Other components of interest Alternative to a KD, a ketotic state can be triggered by circumventing β-oxidation of fat and providing its end products, i.e., ketone esters. Interestingly, intermittent or therapeutic fasting has also been identified as a potential nutritional intervention for the amelioration of post-TBI complications (Davis et al., 2008). Indeed, fasting promotes a metabolic state similar to that induced by a KD. That is, fasting stimulates the production and use of KBs as an alternate fuel (Matsuyama et al., 2009). Fasting is also associated with bioenergetic changes manifested as tissue-specific rendering of UCP expression and activity (Dwaib et al., 2021). Importantly, both fasting and a KD trigger similar changes in the gut microbiota which affect systemic and neuronal functions. In fact, the profile of the bacterial species resident in the gut was demonstrated to mediate the effects of both HFDs previously discussed on cerebral integrity and neuronal activity. Similarly, calorie restriction was shown to aid in recovery from post-TBI complications (Mychasiuk et al., 2015b). Additionally, nutritional interventions with single, specific micro- or macronutrients, such as omega-3 or omega-6 supplementations, can bring about desirable metabolic consequences which mitigate or at least improve systemic and neuronal TBI-induced derangements (Agrawal et al., 2014; Keating, Browne, & Cullen, 2021; Tyagi et al., 2013), through or independent of changes in gut microbiota. Particularly, metabolic preconditioning, also known as metabolic programming, has shown to be efficient not only in deterring some of the consequences of TBI, but also in providing neuronal resilience against the effects of a WD on TBI secondary injury (Tyagi et al., 2013).

HFD in TBI: Neuroinflammation and beyond

Conclusion Different factors limit the generalizability of the results reported by the different studies on the effects of HFDs on TBI manifestations including the TBI form and severity, diet composition and duration, subject sex, age, and predispositions, as well as the time of intervention. Notwithstanding the plethora of variabilities in models of study, results point out to the deleterious consequences of a WD on TBI insults and the capacity of a KD to mitigate resulting neurometabolic and functional deficits.

Mini-dictionary of terms • •

•

Metabolic efficiency: Amount of energy produced per oxygen consumed Synaptic plasticity: The capacity of neuronal circuits to adapt their connectivity and activity to metabolic conditions to manage behavioral responses (Maffei & Mainardi, 2019) Thermogenic density: The amount of UCP-induced oxygen consumption per gram tissue

Key facts of high-fat diets in traumatic brain injury Key facts of TBI: TBI is an impact to the head that causes brain penetration or movement, disrupting normal brain function. Key facts of high-fat diets: High-fat diets can be classified based on their carbohydrate content as either Western or ketogenic. A Western diet is a high-carbohydrate diet, while a ketogenic diet is a low- carbohydrate one. Key facts of ketogenic diet: A ketogenic diet was first prescribed for the management of intractable epilepsy. Key facts on neuroinflammation: Neuroinflammation is characterized by the presence of pro-inflammatory cytokines produced in response to an insult affecting the nervous system.

Summary points • • •

Western diet (WD) aggravates secondary TBI worsening anxiety, as well as motor and cognitive functions. Exaggerated oxidative stress and neuroinflammation due to aggravated mitochondrial dysfunction are linked to WD-induced deterioration of TBI outcomes. Ketogenic diet (KD) resolves motor and cognitive deficits and suppresses TBIinduced excitotoxicity and epilepsy.

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• •

Variable long-term epigenetic changes are shown to play a role in WD and KD modulation of TBI secondary injury severity. Brain-derived neurotrophic factor (BDNF) mediates the effect of diet-induced changes in brain energetics on neuroplasticity.

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Matsuyama, S., et al. (2009). Food deprivation induces monocarboxylate transporter 2 expression in the brainstem of female rat. Journal of Reproduction and Development, 0903030143. McAllister, T. W. (2011). Neurobiological consequences of traumatic brain injury. Dialogues in Clinical Neuroscience, 13(3), 287–300. McAllister, T. W., et al. (2004). Working memory deficits after traumatic brain injury: catecholaminergic mechanisms and prospects for treatment—A review. Brain Injury, 18(4), 331–350. Mychasiuk, R., et al. (2015a). Diet, age, and prior injury status differentially alter behavioral outcomes following concussion in rats. Neurobiology of Disease, 73, 1–11. Mychasiuk, R., et al. (2015b). Dietary intake alters behavioral recovery and gene expression profiles in the brain of juvenile rats that have experienced a concussion. Frontiers in Behavioral Neuroscience, 9. Ng, S. Y., & Lee, A. Y. W. (2019). Traumatic brain injuries: Pathophysiology and potential therapeutic targets. Frontiers in Cellular Neuroscience, 13(528). Patet, C., et al. (2016). Cerebral lactate metabolism after traumatic brain injury. Current Neurology and Neuroscience Reports, 16(4), 31. Prins, M., & Giza, C. (2006). Induction of monocarboxylate transporter 2 expression and ketone transport following traumatic brain injury in juvenile and adult rats. Developmental Neuroscience, 28(4–5), 447–456. Prins, M., et al. (2004). Increased cerebral uptake and oxidation of exogenous βHB improves ATP following traumatic brain injury in adult rats. Journal of Neurochemistry, 90(3), 666–672. Prins, M., Fujima, L., & Hovda, D. (2005). Age-dependent reduction of cortical contusion volume by ketones after traumatic brain injury. Journal of Neuroscience Research, 82(3), 413–420. Prins, M., et al. (2013). The pathophysiology of traumatic brain injury at a glance. Disease Models & Mechanisms, 6(6), 1307–1315. Prins, M. L., & Hovda, D. A. (2001). Mapping cerebral glucose metabolism during spatial learning: Interactions of development and traumatic brain injury. Journal of Neurotrauma, 18(1), 31–46. Prins, M. L., & Hovda, D. A. (2009). The effects of age and ketogenic diet on local cerebral metabolic rates of glucose after controlled cortical impact injury in rats. Journal of Neurotrauma, 26(7), 1083–1093. Prins, M. L., & Matsumoto, J. H. (2014). The collective therapeutic potential of cerebral ketone metabolism in traumatic brain injury. Journal of Lipid Research, 55(12), 2450–2457. Probert, L. (2015). TNF and its receptors in the CNS: The essential, the desirable and the deleterious effects. Neuroscience, 302, 2–22. Rabinovsky, E. D. (2004). The multifunctional role of IGF-1 in peripheral nerve regeneration. Neurological Research, 26(2), 204–210. Readnower, R. D., et al. (2011). Post-injury administration of the mitochondrial permeability transition pore inhibitor, NIM811, is neuroprotective and improves cognition after traumatic brain injury in rats. Journal of Neurotrauma, 28(9), 1845–1853. Rutland-Brown, W., et al. (2006). Incidence of traumatic brain injury in the United States, 2003. The Journal of Head Trauma Rehabilitation, 21(6), 544–548. Salberg, S., et al. (2019). The behavioural and pathophysiological effects of the ketogenic diet on mild traumatic brain injury in adolescent rats. Behavioural Brain Research, 376, 112225. Sato, K., et al. (1995). Insulin, ketone bodies, and mitochondrial energy transduction. The FASEB Journal, 9(8), 651–658. Schachtrup, C., et al. (2010). Fibrinogen triggers astrocyte scar formation by promoting the availability of active TGF-β after vascular damage. Journal of Neuroscience, 30(17), 5843–5854. Schwartzkroin, P. A., et al. (2010). Does ketogenic diet alter seizure sensitivity and cell loss following fluid percussion injury? Epilepsy Research, 92(1), 74–84. Selfridge, J. E., et al. (2015). Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure. Journal of Bioenergetics and Biomembranes, 47(1–2), 1–11. Shaito, A., et al. (2020). Western diet aggravates neuronal insult in post-traumatic brain injury: Proposed pathways for interplay. eBioMedicine, 57, 102829. Sheline, C. T., Behrens, M. M., & Choi, D. W. (2000). Zinc-induced cortical neuronal death: Contribution of energy failure attributable to loss of NAD + and inhibition of glycolysis. Journal of Neuroscience, 20(9), 3139–3146. Sherman, M., et al. (2016). Adult obese mice suffer from chronic secondary brain injury after mild TBI. Journal of Neuroinflammation, 13(1), 171.

HFD in TBI: Neuroinflammation and beyond

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CHAPTER 11

Brain injury, anthropometry, and nutrition Manju Dhandapani and Sivashanmugam Dhandapani Department of Neurosurgery, PGIMER, Chandigarh, India

List of abbreviations BEE BMI CHI CSW DHA EN GALT GCS GI MAC MAMC PN RME SIADH TBI TPN TSF

basal energy expenditure body mass index creatinine height index cerebral salt wasting syndrome docosahexaenoic acid enteral nutrition gut-associated lymphoid tissue Glasgow Coma Scale gastrointestinal mid-arm circumference mid-arm muscle circumference parenteral nutrition resting metabolic expenditure syndrome of inappropriate antidiuretic hormone secretion traumatic brain injury total parenteral nutrition triceps skinfold thickness

Introduction Traumatic brain injury (TBI) requires a comprehensive nutritional assessment and management to prevent complications and enhance the recovery of patients. Though the nutritional aspect of management in TBI was once neglected, the evidence generated on various aspects of nutrition in TBI over the past three decades threw light on developing appropriate guidelines for nutritional status assessment and nutritional management of patients with TBI.

Traumatic brain injury Traumatic brain injury is any traumatic insult to the brain: extraparenchymal, intraparenchymal, or intraventricular. It is the most common cause of death and disability in Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00032-5

Copyright © 2023 Elsevier Inc. All rights reserved.

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young people. It contributes immensely to socioeconomic losses globally, especially the low- to middle-income countries (Devi et al., 2020; Karthigeyan, Gupta, et al., 2021). Head injuries can be classified based on multiple factors such as neurological status or neuroimaging findings. Based on the initial postresuscitation Glasgow Coma Scale (GCS), head injury is categorized into mild (GCS 13–15), moderate (GCS 9–12), and severe (GCS 3–8) (Dhandapani, Sarda, et al., 2015; Karthigeyan, Dhandapani, et al., 2021; Mukherjee et al., 2015). Severe head injury initiates a complex cascade of metabolic sequelae, some of which are seen uniformly in all trauma and burn patients, but a few are unique to a head injury. Treatment approaches toward patients with brain injury, both conservative and surgical, are highly complex, and adequate nutritional support is essential for management to provide an optimal milieu for neurological and systemic recovery.

Significance of nutrition in TBI Multiple factors contribute to challenging nutritional management in patients with TBI. They include the complex metabolic cascade in TBI, altered feeding pattern, impaired gastrointestinal (GI) function and absorption, increased nutritional demand, stressinduced hyperglycemia, and hyponatremia (Kurtz & Rocha, 2020; Lucke-Wold et al., 2018; Scrimgeour & Condlin, 2014).

Complex metabolic cascade The stress response of TBI increases cortisol, glucagon, epinephrine, and norepinephrine, initiating a biochemical cascade (Daradkeh et al., 2014). The altered cerebral perfusion due to TBI aggravates the hypermetabolic response and high energy expenditure, increasing the nutritional demands (Bindu et al., 2017; Clifton et al., 1984; Dhandapani, Sharma, Sharma, & Das, 2014; Dhandapani, Bajaj, et al., 2018; LuckeWold et al., 2018; Scrimgeour & Condlin, 2014). Hypermetabolic and hypercatabolic response in TBI mobilizes amino acids from skeletal muscles for gluconeogenesis and increases nitrogen excretion with skeletal muscle wasting and weight loss. This process may result in depletion of nutritional reserves, resulting in impaired immunity, unfavorable outcome, and high mortality (Clifton et al., 1984; Dhandapani et al., 2015; Scrimgeour & Condlin, 2014). In the 1980s, numerous studies on metabolic demands of head-injured patients demonstrated the changes like increased energy expenditure and increased nitrogen excretion following a head injury (Clifton et al., 1984; Young et al., 1985). The more severe the head injury, the greater is the release of catecholamines (epinephrine and norepinephrine) and cortisol, thus more is the hypermetabolic response (Robertson et al., 1988; Rosner, Newsome, & Becker, 1984). Few studies have also reported hypoalbuminemia in patients with severe TBI (Young et al., 1988). Due to the release of cytokines due to acute inflammation, there may be a

Brain injury, anthropometry, and nutrition

reduction in acute-phase reactants (APRs) such as albumin and transferrin (TFR) and elevation of APRs such as C-reactive protein (CRP), α1-acid glycoprotein (AAG), α-1 antitrypsin (AAT), haptoglobin (Hp), and ceruloplasmin (C3). Hypoalbuminemia at admission in head injury patients is mediated via altered endothelial permeability properties due to endothelial dysfunction caused by acute postinjury elevation of cytokines such as interleukin-1(IL-1) and interleukin-6 (IL-6) (Young et al., 1988). Hypoalbuminemia in critically ill neuro patients is associated with poor outcomes (Dhandapani, Manju, Vivekanandhan, Sharma, & Mahapatra, 2009; Kapoor et al., 2018). Under the fasting condition, the central nervous system depends on systemic stores for all of the substrates necessary to sustain its metabolic activity. The brain’s glucose consumption accounts for approximately 25% of the total resting systemic glucose consumption occurring at a rate of 110–145 g/24 h. Hyperglycolysis is the mechanism by which the brain compensates for the enhanced cerebral metabolism (Brooks & Martin, 2014). With a short period of fasting for 24–48 h, glucose remains the primary energy substrate for the brain. A continuous supply of glucose is obtained initially from the body’s glycogen stores, and as they become depleted, from the breakdown of muscle protein and triglycerides from adipose tissue. More extended periods of fasting also lead to the breakdown of visceral proteins (Robertson et al., 1988) (Fig. 1). In brain injuries, fasting along with hypermetabolism increases the rate of gluconeogenesis. Amino acids are mobilized from skeletal muscles during the early stage and other visceral organs in the later stage during increased protein catabolism which in turn leads to severe wasting of the lean body mass, impairment of vital organ function, and diminution in reparative and immune process (Chapple et al., 2017; Wilson, Dente, & Tyburski, 2001). The reduction in lean body mass is reflected as decreased anthropometric measures

Fig. 1 Biochemical response to TBI.

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Fig. 2 Anthropometry and TBI.

[mid-arm circumference (MAC) and mid-arm muscle circumference (MAMC)] and a decrease in urine creatinine (Fig. 2). Excessive catabolism and biochemical changes in patients with a critical illness are associated with poor outcomes.

Altered feeding pattern Only less than 30% of TBI patients can independently manage their feeding. Swallowing requires multiple neuronal inputs, but the damage to the neuronal circuit due to a brain injury impairs the process of swallowing (Daradkeh et al., 2014). Oral feeding is altered due to various reasons such as impaired cognition, impaired communication, deranged consciousness, presence of artificial airway, dysphagia, associated GI trauma, or associated facial or dental fractures. Tube feeding or parenteral nutrition is usually initiated in patients with a severe TBI and most moderate TBI to achieve nutritional adequacy. Diagnostic and therapeutic procedures also interfere with feeding and result in delayed or interrupted feeding in TBI patients. Feeding delay may also be due to stress gastritis, lower esophageal dysfunction, and delayed gastric emptying (Ott et al., 1991; Piek et al., 1992), leading to reduced caloric replacement complicating the hypermetabolism following a head injury. It is reported that patients with mild-to-severe TBI do not meet their recommended daily allowance for any nutrient, and the daily caloric deficit was associated with poor outcomes (Institute of Medicine Committee on Nutrition Trauma, and the Brain, 2011). Altered feeding patterns also cause patients associated complications related to tube feeding or parenteral nutrition (Daradkeh et al., 2014).

Impaired GI function Intolerance to enteral feeding is reported in almost 50% of TBI patients and can affect the early attainment of complete enteral nutrition. It may result in a delay of up to 2 weeks in

Brain injury, anthropometry, and nutrition

attaining total enteral nutrition and therapeutic compliance and rehabilitation. There are various causes of gastric intolerance in patients with TBI. Increased intracranial pressure due to TBI may reduce the lower esophageal sphincter pressure and may cause reflux. Increased ICP has been proven to reduce gastric motility and gastric emptying due to suppressed parasympathetic system (Norton et al., 1988; Tan, Zhu, & Yin, 2011). Increased corticotropin-releasing hormone resulting from traumatic stress-induced hypothalamic-pituitary-adrenal axis may stimulate the sympathetic nervous system and significantly inhibit gastric emptying and intestinal motility (Stengel & Tache, 2009). The sympathetic nervous system activity may also stimulate vasoconstriction and ischemic changes in the gastric mucosa resulting in stress ulcers with microbleeding or gastritis due to bacterial colonization. Colonization of pathogenic organisms and antibiotic use may compromise the presence of protective GI flora such as lactobacilli, Bifidobacteria, or Clostridia and lead to gastric dysmotility (Yu, Yin, & Zhu, 2011). Changes in the gastric mucosa affect the GI absorption of nutrients as well. Increased cortisol level post-TBI leads to stress ulcers (Li et al., 2010; Tan et al., 2011). The high level of cholecystokinin may stimulate the inhibitory enteral nervous system neurons resulting in gastric lethargy and poor gastric function (Nguyen et al., 2007). Other causes of impaired gastric motility include medications such as sedatives, muscle relaxants, or opioids and electrolyte disturbances such as hypokalemia and hypomagnesemia (Khansari, Sohrabi, & Zamani, 2013). Cytokines such as interleukin-1B ad interleukin-6 and tumor necrosis factors may exaggerate the gastric inflammation or edema and may coexist with stress ulcers and further complicate the GI integrity resulting in gastric dysfunction and poor absorption (Li et al., 2010; Ziebell & Morganti-Kossmann, 2010). Reduced gastric absorption of all nutrients (protein, carbohydrate, and fat) is reported in the literature even up to 2–3 weeks (Chapman et al., 2009; Singh, Harkema, Mayberry, & Chaudry, 1994). Malabsorption of fats is also reported in TBI patients, with reduced perfusion due to vasoconstriction, edema, and mucosal atrophy resulting in poor gastric absorption. Both overhydration and dehydration due to various factors may result in poor absorption (Tan et al., 2011). Other causes of enteral nutritional intolerance include hypoalbuminemia, resulting in diarrhea and poor absorption (Ford, Jennings, & Andrassy, 1987; Guenter et al., 1991). The enteral intolerance may further result in aspiration pneumonia and increased hospital stay (Tan et al., 2011). Enteral intolerance may also lead to a caloric deficit in patients with TBI.

Increased nutritional demand Increased nutritional demand due to excessive protein catabolism is well reported in critically ill patients. Severe metabolic alterations, high energy expenditure, high caloric

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demand, and caloric deficit due to daily inadequate nutritional support greatly enhance the consumption of lean body mass, mainly skeletal muscle mass resulting in weight loss and malnutrition-related complications. Excessive catabolism and biochemical changes in patients with a critical illness are associated with poor outcomes (Dhandapani, Kapoor, et al., 2015; Dhandapani, Manju, Sharma, & Mahapatra, 2007). Patients who are already malnourished with a body mass index (BMI) 10% during the past 6 months, and a reduction in MAMC are significantly associated with unfavorable outcomes and high mortality (Dhandapani et al., 2019).

Brain injury, anthropometry, and nutrition

Table 1 Nutritional indicators in TBI. Assessment category

Indicators

Anthropometric measurements

Weight Body mass index Mid-arm circumference Triceps skinfold thickness Mid-arm muscle circumference Serum protein Serum albumin Urine creatinine Creatinine height index Hemoglobin Trace elements Extremity edema Cheilosis Gum bleed Dry and scaly skin Koilonychia Skeletal prominence Pressure ulcer

Biochemical indicators

Clinical manifestations

Weight and BMI: Weight is difficult to measure in TBI patients, but there are devices such as chair scales, under-bed scales, or hoist scales to check the weight of bedridden patients. Weight also may be estimated from the nomograms based on the height of the patient. Mid-arm circumference (MAC): MAC measures both muscle mass and subcutaneous fat. A nonstretchable inch tape is used to measure MAC in centimeters. MAC is measured on the right arm at the midpoint between the top of the acromion process and the olecranon process of the ulna with the forearm flexed at 90° (Fig. 4A) and the mean reading of three measurements is recorded (CDC, 2007). Triceps skin fold thickness (TSF): TSF calipers measure the triceps subcutaneous fat in millimeters. A pinch of skin and subcutaneous fat 1 cm above the midpoint on the posterior aspect of the right arm between the acromion and olecranon process is pulled by keeping the arm freely hanging by the side, and the calipers applied (Fig. 4B) (CDC, 2007). The mean reading of three measurements is recorded. Mid-arm muscle circumference (MAMC): MAMC is calculated from MAC and TSF measurements and provides an index of muscle mass (somatic protein store). Although the measurement is not sensitive to small changes in muscle mass, it does provide a quick estimation of muscle mass, is minimally affected by edema, and may be a better predictor of nutritional stress (Fig. 2). MAMC is calculated using the formula: MAMC (cm) ¼ MAC (cm)  [3.14  TSF (cm)] (Dhandapani et al., 2019).

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Fig. 4 (A) Measurement of mid-arm circumference. (B) Measurement of triceps skin fold thickness.

Biochemical indicators: Numerous studies have reported the changes in biochemical measures like resting metabolic expenditure (RME) (Clifton et al., 1984; Phillips, Ott, Young, & Walsh, 1987), nitrogen excretion (Clifton et al., 1984; Clifton, Robertson, & Contant, 1985; Phillips et al., 1987), blood glucose (Bosarge et al., 2015), and serum albumin (Dhandapani et al., 2009) in patients with TBI. Routine biochemical/blood parameters that can indicate the nutritional status include serum protein, serum albumin, urine creatinine, hemoglobin, magnesium, and phosphorous. Hypoalbuminemia is one of the independent predictors of unfavorable outcome and mortality in patients with a TBI. Serum protein: Because the primary objective of nutritional therapy is to preserve or restore body protein, assessment of this component is essential. Laboratory tests are used to determine the total protein, the products of the protein anabolism (albumin) (Manning & Shenkin, 1995), and protein catabolism (urea and creatinine). The usual range of serum total protein varies from 6 to 8 g/dL. Depletion in protein indicates a decreased source of amino acids. Serum albumin: Albumin, a product of protein anabolism, is the most abundant form of protein in the blood. The usual range of serum albumin levels is 3.6–5 g/dL. The serum albumin level has been described as a valid nutritional indicator because it reflects the availability of amino acids to the liver for hepatic protein synthesis. Depletion of protein stores and malnutrition are reflected in low serum albumin concentration (Fig. 1). In TBI, serum albumin tends to fall for the first 2 weeks (Dhandapani et al., 2009) progressively. Fall of more than 15% is found to be associated with mortality and unfavorable outcome (Dhandapani, Manju, Vivekanandhan, Agarwal, & Mahapatra, 2010).

Brain injury, anthropometry, and nutrition

Depletion in albumin adversely affects the patients’ neurological outcome, respiratory function, and the rehabilitation process due to the loss of muscle mass (Dhandapani et al., 2009). Degree of depletion (Gottschlich & Shronts, 1991) Mild: 2.8–3.5 g/dL Moderate: 2.1–2.7 g/dL Severe: 55) (Lakshminarayanan et al., 2021). However, the efficacy of this diet to induce ketosis is questionable given that average BHB concentrations are only 0.8 mM, although data are limited (Pfeifer & Thiele, 2005). Initiating and maintaining the ketogenic diet in hospitalized and critically ill patients is complex (Katz et al., 2021). The onset of ketosis (BHB >2 mM) with the ketogenic diet is prolonged (
1–2 days) relative to the acute onset of many presentations involving critically ill patients where hours are of vital importance (Worden, Abend, & Bergqvist, 2020). Patients should be closely monitored for potential adverse events. Hypoglycemia may occur in approximately 20% of patients, although data are currently limited (Francis, Fillenworth, Gorelick, Karanec, & Tanner, 2019). Glucose should therefore be closely monitored. Furthermore, metabolic acidosis occurs commonly (
80%) in patients commencing the ketogenic diet (Francis et al., 2019). Other complications such as nephrolithiasis tend to only occur with long-term diets.

Ketone esters As discussed, owing to the slow onset, using dietary modifications to induce ketosis was only appropriate for chronic neurological disorders such as epilepsy or Alzheimer’s disease. Recently, the development of oral ketone esters, such as 3-hydroxybutyl-3-hydroxybutyrate, has led to the potential to increase ketones rapidly via the enteral route. Following ingestion, ketone esters are hydrolyzed by carboxylesterases and nonspecific esterases throughout the gastrointestinal tract to produce BHB and R-1,3,-butanediol that is converted to BHB and AcAc (Desrochers et al., 1995; Tate, Mehlman, & Tobin, 1971). A noncompartmental pharmacokinetic study in healthy volunteers of ketone esters by demonstrated peaks of 3.30 mM at 2.5 h postingestion in those receiving 714 mg/kg of 3-hydroxybutyl-3-hydroxybutyrate (Fig. 5) (Clarke et al., 2012). The BHB concentration returned to baseline (
0.01 mM) within 10 h and remained >1 mM for approximately 5 h postdose (Clarke et al., 2012). Therefore, doses administered three or four times daily may be required to sustain hyperketonemia. One case report demonstrated

Ketone metabolism in brain injury

10.000

Concentration (mM)

D-b-Hydroxybutyrate 1.000

0.100

0.010

714 mg/kg 357 mg/kg 140 mg/kg

0.001 0

5

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25

Time (hours) 10.000

Concentration (mM)

Acetoacetate 714 mg/kg 357 mg/kg 140 mg/kg

1.000

0.100

0.010 0

5

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25

Time (hours) Fig. 5 Changes in circulating D-β-hydroxybutyrate and acetoacetate concentrations for 24 h following ingestion of a single dose of the ketone monoester. (Reprinted by permission from Elsevier Publishers Ltd.: Regulatory Toxicology and Pharmacology. Clarke et al. 63:401–408, Copyright 2012.)

similar findings with doses >35 g achieving peak BHB concentrations of 5–7 mM, returning to baseline within approximately 6 h postingestion (Newport, VanItallie, Kashiwaya, King, & Veech, 2015). These studies show that oral ketone ester supplementation can induce hyperketonemia within a clinically meaningful time course (hours).

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Despite this, few clinical studies exist (Cox & Clarke, 2014). In one study, athletes ingesting 573 mg/kg of ketone ester achieved D-BHB concentrations of approximately 3.5 mM improving endurance performance by 2% with altered skeletal muscle glycolysis (Cox & Clarke, 2014). One case report on a patient with severe Alzheimer’s disease noted significantly improved cognitive function following the administration of a ketone monoester, 28.7 g thrice daily for 20 months (Newport et al., 2015). This was well tolerated with no severe adverse reactions. A small, controlled study of 11 patients with heart failure and reduced ejection fraction (HFrEF) showing that the BHB fractional extraction correlated with BHB concentration (Monzo et al., 2021). Adverse events in short-term studies appear mild and primarily related to gastrointestinal discomfort with abdominal distension, nausea, diarrhea, constipation, vomiting, and flatulence (Clarke et al., 2012). Similar findings were reported for one study conducted over 28 days (Soto-Mota, Vansant, Evans, & Clarke, 2019).

Intravenous beta-hydroxybutyrate An alternative method of inducing hyperketonemia is through intravenous infusions of BHB. It is clear that the administration of intravenous formulations will rapidly increase the BHB concentration relative to the infusion rate, an important consideration given the rapid onset of many pathological states such as traumatic brain injury and stroke. Intravenous BHB is commonly formulated as the racemic sodium salt at concentrations of approximately 7.5% in recently studies with additional excipients to balance the pH and ensure isotonicity as appropriate (Nielsen et al., 2019; Thomsen et al., 2018). As the dextroenantiomer of BHB is the physiological active form, some studies have included this enantiomer only in the formulation (Mikkelsen, Seifert, Secher, Grøndal, & van Hall, 2015). Most studies use a weight-based dose starting from 0.18 g/kg/h, correlating with a total dose ranging from 30 to 101 g of BHB. Importantly, these doses achieve BHB concentrations >1 mM within 15 min. One study demonstrated plasma BHB concentrations >3 mM within 3 h of initiating an infusion of a 7.5% Na-3-OHB solution (Nielsen et al., 2019). This was similar to a separate study showing an increase in plasma BHB from 0.20  0.10 to 2.12  0.30 mM and cerebral tissue BHB from 0.16  0.07 to 0.24  0.04 mM following a 75-min infusion of dextro-BHB (Pan et al., 2001). This has also been demonstrated in animal models where a 6-h infusion of hypertonic solution containing 120 mM BHB increased plasma BHB from 0.26  0.05 to 0.70  0.27 mM with a proportional increase in cerebral tissue BHB (White et al., 2013). Overall, BHB infusions were well tolerated in study participants. Alkalemia has been reported in study participants, although this appears mild (few patients with a pH >7.5) (Desir, Bratusch-Marrain, & DeFronzo, 1986) (Mikkelsen et al., 2015). This contrasts with the acidemia observed in patients following the ketogenic diet. Similar to the

Ketone metabolism in brain injury

ketogenic diet, hypoglycemia may be encountered with a reduction in the glucose concentration by up to 25% (Sherwin, Hendler, & Felig, 1976). Therefore, glucose and pH monitoring are considered necessary in patients receiving intravenous BHB. Despite the potential advantages of intravenous administration, there is currently no commercially available product. This may be due to several reasons. Firstly, the cost of producing a commercially available product is prohibitively high at present. Secondly, the optimal formulation and dose is currently unknown. Lastly, there is a lack of evidence for exogenous BHB administration in pathological states limiting the potential use of a product to research or compassionate access in specific situations. Ketones and acute brain injury In the fed state, cerebral ketone concentrations are dependent on both plasma concentrations and time as ketone transporters upregulate to increase ketone flux. However, following ABI, the brains ability to metabolize ketones is altered. Evidence suggests that a number of adaptive changes take place including an increase in MCT1/2 expression and an increase in BHD enzyme, thus replacing glucose with ketones as preferred energy source (Gasior, Rogawski, & Hartman, 2006; Greco, Glenn, Hovda, & Prins, 2016; Hasselbalch et al., 1996).

ABI in animals Research on ketone supplementation for ABI is limited to animal and small cohort studies. Animal research has largely been limited to rats and examines a number of differing mechanisms of injury including glutamate-induced injury, cerebral hypoxia, cerebral ischemia, and TBI. In these studies, ketones were administered orally through a ketogenic diet or via a variety of intravenous formulations (which tended to consist of BHB as a salt). In general, irrespective of whether ketosis was induced before or after injury, studies demonstrated decreased neuronal damage, decrease lesion volume, improved cellular ATP levels, decrease cerebral lactate, decreased cerebral edema, and apoptosis and decreased mortality (Prins, 2008a; White & Venkatesh, 2011). More specifically, Suzuki et al. administered an IV BHB solution at 30–50 mg/kg/h after carotid artery and middle cerebral artery occlusion in a rat model of cerebral ischemia. They noted a decrease in cerebral edema and sodium content and increased ATP (Suzuki et al., 2001; Suzuki et al., 2002). They also found a 50% reduction in cerebral infarct volume. Subsequently, Prins et al. examined the impact of both oral and intravenous ketone supplementation in a TBI rat model (Prins et al., 2004). They noted an increase in uptake of BHB and improvement in cerebral ATP after injury. They also noted a reduction in the cortical contusion volume. There was some concern that BHB may impact on BBB integrity, but more research is needed to examine this issue.

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ABI in humans Research evaluating ketone supplementation in humans with ABI is lacking. Observational studies suggest ketone concentrations tend to be in the normal range following ABI. Most studies induce ketosis via enteral supplementation which requires as much as 150 g per day in order to generate blood ketone concentrations above 4 mM (the suggested target concentration to achieve a therapeutic response in refractory epilepsy) (White, Venkatesh, & Kruger, 2017; White, Venkatesh, & Venkatesh, 2017). Inducing ketones via the enteral route can be difficult in adults although this has become easier with the advent of ketone esters. To date, only a limited number of studies have examined human subjects. The first by Ritter et al. examined the impact of a ketogenic diet on biochemical markers in 20 severely head injured patients (Ritter, Robertson, Goodman, Contant, & Grossman, 1996). They noted improved glycemic control with lower lactate and higher ketones (although BHB remained significantly 2 mmol/L. Tricarboxylic acid cycle. Ketone bodies are metabolized to form acetyl-CoA, which is the starting point of the tricarboxylic acid cycle that ultimately produces ATP, or cellular energy.

Key facts of ketone bodies Ketone bodies are a descriptive term comprising beta-hydroxybutyrate, acetoacetate, and acetone. These compounds are produced by fatty acid metabolism and converted to acetylCoA, which enters the tricarboxylic acid cycle to produce ATP, or cellular energy as an alternative to glycolysis. They may be exogenously (beta-hydroxybutyrate or acetoacetate) administered via intravenous administration with a rapid onset of ketosis (beta-hydroxybutyrate >2 mmol/L) or induced gradually (
days) with a ketogenic diet that consists of increasing the caloric intake derived from lipid to induce fatty acid metabolism. In acute brain injury, ketone body metabolism may provide an alternative energy source to glucose and alter the ratio of NAD+/NADH, thereby reducing the transcription of proapoptotic factors such as PARP-1. These underlying mechanisms are thought to mediate the reduced neuronal damage and associated lesion volume in animal models of cerebrovascular accidents following beta-hydroxybutyrate administration.

Ketone metabolism in brain injury

Summary points • •

•

•

•

The central nervous system generally utilizes glucose as the primary form of energy for ATP synthesis. Acute brain injuries (including traumatic brain injury and cerebrovascular accidents) are common and associated with significant morbidity and mortality, which is, in part, due to the reduced capacity to metabolize glucose leading to altered ion gradients and apoptosis. Ketogenesis occurs following fatty acid metabolism during periods of starvation or reduced carbohydrate/protein intake leading to acetyl-CoA production and entry into the tricarboxylic acid cycle for ATP synthesis. This bypasses the need for glycolysis and associated pyruvate production. Ketogenesis may be induced slowly over days using the ketogenic diet whereby caloric intake from protein and carbohydrates is reduced, while the calories obtained from lipids are increased. Alternatively, ketogenesis may be rapidly induced (minutes) by intravenous administration of ketone bodies or enteral administration of ketone esters that are metabolized in the liver to ketone bodies. Ketone body administration in animal models of traumatic brain injury and cerebrovascular accidents reduce the lesion size by up to 50%, likely due to increased ATP production and reduced cerebral edema.

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PART IV

Cerebral palsy

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CHAPTER 15

Nutrition and cerebral palsy Esma Keles¸ Alpa,b,∗ a

Department of Pediatrics, Dr. Ali Kemal Belviranlı Women’s Maternity and Children’s Hospital, Konya, Turkey Guest Faculty Member, Department of Pediatrics, KTO Karatay University, Konya, Turkey

b

Abbreviations BIA BMI CDC CP DEXA GMFCS MAC REE TEE TSFT WHO

bioelectrical impedance analysis body mass index Centers for Disease Control and Prevention cerebral palsy dual-energy X-ray absorptiometry gross motor function classification system mid-arm circumference resting energy expenditure total energy expenditure triceps skinfold thickness World Health Organization

Introduction Cerebral palsy (CP) is one of the most frequent causes of motor disability in children. Over the years, the definition of cerebral palsy has been repeatedly changed and according to the current definition, developed by an international team of experts, cerebral palsy is a group of permanent, but not unchanging, disorders of movement and/or posture and of motor function, which are due to a nonprogressive interference, lesion, or abnormality of the developing/immature brain (Cans et al., 2007). The primary etiology of a cerebral palsy syndrome should always be identified if possible. Making a precise diagnosis of a metabolic or genetic disorder has important implications for the possibility of treatment, accurate prognosis, and genetic counseling (Pearson, Pons, Ghaoui, & Sue, 2019). Cerebral palsy commonly coexists with epilepsy, in particular drug-resistant epilepsy, but also with mental retardation, visual and hearing impairment, as well as feeding and behavioral disorders. The degree of motor problem varies from mild to very severe making the child totally dependent on caregivers. Cerebral palsy is divided into forms depending on the type of motor disorders that dominate the clinical presentation. ∗

In Absentia Contact Person: Hayrullah Alp, Department of Pediatric Cardiology, Dr. Ali Kemal Belviranlı Women’s, Maternity and Children’s Hospital, Konya, Turkey. Telephone: +90 5066487653, Fax:+90 3322376025, Email: [email protected].

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00027-1

Copyright © 2023 Elsevier Inc. All rights reserved.

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Feeding disorders play a key role in the onset of undernutrition, documented in 29%–46% of CP children with a prevalence that increases among children with older age, lower intelligence quotients, and more severe neurological impairment (Marchand et al., 2006). A relevant part of the abnormal growth and body composition in children with CP is directly related to poor nutritional status, independent of potential confounders such as age, gender, ambulatory status, disease severity, and socioeconomic status (Aydın and Turkish Cerebral Palsy Study Group, 2018; Caramico-Favero, Guedes, & Morais, 2018; Johnson et al., 2017). Considering the detrimental effect of undernutrition on physical and cognitive development, monitoring of nutritional status in children with neurological impairment is mandatory.

Cerebral palsy: Definition, epidemiology, etiology, and classification Cerebral palsy (CP) is a group of permanent, but not unchanging, disorders of movement and/or posture and of motor function, which are due to a nonprogressive interference, lesion, or abnormality of the developing/immature brain (Cans et al., 2007). The diagnosis of cerebral palsy is mainly based on motor function and posture disorders that occur in early childhood and persist until the end of life; they are nonprogressive, but change with age. Motor function disorders, which are the core symptoms of cerebral palsy, are frequently accompanied by other dysfunctions, such as sensational, perceptual, cognitive, communicational, and behavioral disorders, epilepsy, and secondary musculoskeletal disorders (Cans et al., 2007; Rosenbaum et al., 2007). The prevalence of CP is approximately 1.5–3.5 cases per 1000 live births and a peak up to 65 per 1000 live births particularly in prematures weighing 20th centile on disease-specific growth charts; (b) a weight gain velocity of 4–7 g/day in children older than 1 year; (c) a protein and micronutrient intake similar to the requirements of age-matched peers, with a calcium and vitamin D intake that meets the age-appropriate requirements; and (d) a triceps skinfold thickness between 10th and 25th centile for age (Walker, Bell, Caristo, Boyd, & Davies, 2011).

Oral nutrition Oral nutrition can be maintained in children without oral-motor impairment and with a low risk of aspiration. The most widely used interventions are positioning therapy, to ensure a correct position and support of the head during the meals including the use of appropriate chairs and utensils, the increase in the caloric density of meals, and the adjustment of the textures of foods/liquids by modifying consistency and viscosity to suit the child’s needs. The adjustment of the textures of foods/fluids is a common experience in the treatment of children with CP. Recent studies showed that children with cerebral palsy often exhibit inadequate food intake, severe anthropometric deficits, and a high frequency of gastrointestinal symptoms associated with certain diet characteristics (Benfer et al., 2017; Caramico-Favero et al., 2018). There are many varieties of commercial enteral feeds available including polymeric, semielemental, and elemental formulations, tailored for different age groups based on the changing nutritional requirements throughout the life span. Most enteral feeds are designed to provide complete nutrition, that is, to serve as the sole source of nutrition by meeting all essential nutrient requirements (ESPGHAN Committee on Nutrition, 2010). The initial feed of choice is usually a standard energy density (1.0 kcal/mL (4.2 kJ/mL)) polymeric feed suitable for the age of the child. For those children with an increased energy requirement or poor tolerance to large volumes of feed, a high energy density formula may be useful (for example, 1.5 kcal/mL (6.3 kJ/mL)). For children with lower energy needs, such as those that gain weight too rapidly, a lower energy density formula can be used (0.75 kcal/mL (3.15 kJ/mL)) (ESPGHAN Committee on Nutrition, 2010). Feeds with dietary fiber have potential beneficial effects for the prevention of both diarrhea and constipation (Samson-Fang & Bell, 2013). Whey-based formulas may be beneficial in children with poor tolerance because of delayed gastric emptying.

Nutrition and cerebral palsy

Enteral tube feeding Enteral tube feeding is indicated in children with CP with a functional gastrointestinal tract who are unable to meet their nutritional requirements orally, despite oral nutritional support; those with severe undernutrition; and those with significant feeding and swallowing dysfunction (ESPGHAN Committee on Nutrition, 2010; Sullivan et al., 2006). Enteral tube-feeding regimens must be tailored to the individual child’s needs and will be influenced by the route of access, tolerance of feeds, contribution of oral intake, and family routine and lifestyle. Continuous feeding regimens are often recommended in children with poor feed tolerance (Sullivan et al., 2006). Postpyloric feeds must be delivered continuously to prevent diarrhea and dumping syndrome (Sullivan et al., 2006). A period of time off feeds during the day can be managed for many children requiring continuous infusions allowing for daily activities such as bathing and transport. Bolus feeding can provide greater opportunity for oral intake and may be more suitable to the lifestyles of many families.

Gastrostomy tube feeding Expertise in the management of enteral feeding via gastrostomy tubes and the availability of appropriate devices and nutritional formulas have contributed to the improved ability to provide nutritional rehabilitation to children with CP. However, families experience considerable decisional uncertainty regarding gastrostomy tube placement, because they and their children often value oral feeding despite the significant challenges that may accompany it. Despite the challenges with weight gain seen in children with CP who are orally fed, gastrostomy tube feeding can lead to an unexpectedly rapid weight gain (Sullivan et al., 2006). Frequent monitoring of the children’s weight, weight gain velocity, and TSFT after gastrostomy tube placement ensures that the child’s overall growth and nutritional status are improved while avoiding the negative consequences of overnutrition (Sullivan et al., 2006). Starting with a low caloric intake, which can be increased depending on weight gain velocity and carefully monitored anthropometric measurements, has the advantage that the tube feeding may be better tolerated from the onset and that weight gain will not be excessive. Dietary changes should be made by 5%–10% increments of the total caloric intake, always ensuring the protein, vitamin D, and micronutrient intake is adequate (Le Roy et al., 2021). Once the appropriate nutritional goals have been achieved, monitoring of the children’s nutritional status with complete anthropometric measurements should occur every 6 to 12 months.

Diet composition There are no evidence-based guidelines for nutritional requirements in CP children. According to a few observations, already mentioned, the caloric requirements of children

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with CP can be estimated between 60% and 70% of their normally developing counterparts (Trivic & Hojsak, 2019). In case of severe malnutrition, an intake of 2 g/kg/day of protein and an additional 15%–20% increase of caloric intake should be sufficient to ensure “catch up growth” (Penagini et al., 2015). Constipation is one of the most common comorbidities in children with CP, with an estimated prevalence ranging from 26% to 74% (Sullivan et al., 2006; Trivic & Hojsak, 2019). Dietary intakes of water and fibers of patients with CP are usually below the recommended amounts, mainly due to an objective difficulty in orally managing whole, fiber-rich vegetable foods. Indeed, children with CP frequently have symptoms related to constipation and gastrointestinal dysmotility, such as gastroesophageal reflux, delayed gastric emptying, and vomiting. Since the rate of gastric emptying can be influenced by meal’s volume, caloric content, fat content, and viscosity, a change in the composition of the formula may have an impact on gastrointestinal symptoms. However, children consuming the 50% whole whey protein formula experienced less symptoms than those consuming the formula with 100% whey partially hydrolyzed proteins (Caramico-Favero et al., 2018). As for fats, the interplay between medium-chain fatty acids, comparable to simple sugars as for effects, saturated fats, good for energy storage, and unsaturated fats, with multiple potential effects from inflammation to membranes and brain structure, should be carefully evaluated. Concerning micronutrients, the standard recommendations for the intake of vitamins, minerals, and trace elements should be followed as well. The only exception is vitamin D, because of the increased risk of deficiency due to antiepileptic drugs and insufficient sunlight exposure. Based on expert opinion, the suggested dose for vitamin D supplementation in this population is around 800–1000 UI of vitamin D (Le Roy et al., 2021; Penagini et al., 2015).

Follow-up and monitoring The effectiveness of any nutrition intervention must be determined through regular nutrition monitoring. Monitoring may involve measures of actual nutrient delivery and comparison with measured or estimated needs (ESPGHAN Committee on Nutrition, 2010). A more sensitive indicator that the child is receiving enough dietary energy is adequacy of weight gain. Generally speaking, follow-up and monitoring of nutrition interventions will involve ensuring the child’s nutrition is adequate or improving management of difficulties with feed tolerance, ensuring the safety of feeds and nutrient intake, balancing enteral tube feeding with oral intake, and working toward weaning off tube feeding where appropriate. The frequency of nutritional monitoring depends upon the severity of the child’s clinical condition, age, nutritional status, and existing nutrient deficiencies (ESPGHAN Committee on Nutrition, 2010). Once a child is established on nutrition support and weight gain is occurring at desired rates, follow-up in 6–12 months has been suggested (Penagini et al., 2015).

Nutrition and cerebral palsy

Applications to other neurological conditions Many children with CP are at risk of poor nutritional status, particularly those with severe gross motor impairment and oropharyngeal dysfunction (Kuperminc & Stevenson, 2008). The early involvement of a multidisciplinary team should aim to prevent malnutrition and provide adequate nutritional support. Determining the need for nutrition intervention in children with CP requires the use of multiple methodologies. Nutritional problems of children with CP are plateaus in weight gain or growth resulting in a deviation from an established “pattern”; evidence of low body-fat stores in combination with low weight in respect to height or length; prolonged or stressful oral feeding or signs of pulmonary aspiration, or dehydration; and evidence of micronutrient deficiencies. Thorough nutritional assessment, including body composition, should be a prerequisite for the nutritional intervention. As in typically developed children, nutritional support should start with dietary advice and the modification of oral feeding, if safe and acceptable. However, for prolonged feeding, in the presence of unsafe swallowing and inadequate oral intake, enteral nutrition should be promptly initiated and early gastrostomy placement should be evaluated and discussed with parents/caregivers (Sullivan et al., 2006). Gastrointestinal problems in children with CP are frequent and should be actively detected and adequately treated as they can further worsen the feeding process and nutritional status. Since undernutrition may have a detrimental impact on physical and cognitive development, the introduction of an adequate nutritional support should always be considered in children with other neurological impairments.

Other components of interest In light of the important role micronutrients have in human physiological functioning and the potential for suboptimal feeding practices in persons with CP, careful monitoring of whole-body micronutrient status is imperative in order to optimize functioning in these individuals (Schoendorfer, Boyd, & Davies, 2010). Many nutrients play an indispensable role in brain development and cognitive function. Clinical signs of micronutrient insufficiencies and excess occur secondarily to underlying end-stage changes in metabolic function. The well-documented problems with growth and development, immunity, and bone health in children with CP make it advisable to perform routine functional biochemical tests, such as mean cell volume as an indicator of anemia, and body composition calculations to determine the status of protein and other associated nutrients, along with screening for such micronutrients (vitamin A, B1, B2, B6, B12, folic acid, vitamin C, D, E, magnesium, calcium, zinc, selenium, iodine, and iron). Children who are severely impaired, with limited sun exposure, or who are chronically ill, as well as those who are on high levels of medications, are considered to be at greater risk of deficiencies for micronutrients. The appropriate monitoring of micronutrient status in these children may have a substantial and measurable impact on their nutritional adequacy, hospital costs, and future outcomes.

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Key facts • • • • •

Most of the children with CP have poor nutritional status. Anthropometric measurements are useful for the determination of severity of malnutrition in children with CP. Different anthropometric measurements can be used to determine the nutritional status of children with CP according to GMFCS scales. Appropriate nutritional techniques such as oral nutrition, enteral tube feeding, and gastrostomy tube feeding should be selected for children with CP. Close and frequent follow-ups are important in the nutritional status of children with CP.

Mini-dictionary of terms •

•

• • •

Cerebral palsy. A group of permanent, but not unchanging, disorders of movement and/or posture and of motor function, which are due to a nonprogressive interference, lesion, or abnormality of the developing/immature brain. Gross motor function classification system (GMFCS). It is developed by Palisano et al. (2006) which is based on the evaluation of a child’s independence when performing basic motor functions, such as walking or moving with the aid of ancillary equipment: crutches, walking frames, and wheelchairs. Knee height. The knee height is the distance from the heel to the anterior surface of the thigh over the femoral condyles. Tibia length. The tibial length is measured from the superomedial edge of the tibia to the inferior edge of the medial malleolus. Body mass index (BMI). Body mass index is a person’s weight in kilograms divided by the square of height in meters.

Summary points •

• •

The majority of children with CP have malnutrition, feeding difficulties, and gastrointestinal problems such as oropharyngeal dysfunction, gastroesophageal disease, and constipation. Assessing anthropometric parameters is a crucial procedure in children with CP. However, assessment of height in these children is more challenging. Different anthropometric measurements such as weight and height, TSFT, mid-arm circumference, knee height, tibia length, specialized growth charts, and certain techniques for calculating body composition can be used in children with CP to determine the nutritional status.

Nutrition and cerebral palsy

• •

Oral nutrition, enteral tube feeding, and gastrostomy tube feeding can be used in children with CP to achieve normal growth and nutrition. Once a child with CP is established on nutrition support and weight gain is occurring at desired rates, follow-up in 6–12 months has been suggested.

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CHAPTER 16

Metabolic syndrome in the adult with cerebral palsy: Implications for diet and lifestyle enhancement Patricia C. Heyna,b,*, Elizabeth Terhunec, Alex Tagawad, and James J. Carollob,c,d a

Center for Optimal Aging, Marymount University, Arlington, VA, United States Department of Physical Medicine and Rehabilitation, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States c Department of Orthopedics, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO, United States d Center for Gait and Movement Analysis, Musculoskeletal Research Center, Children’s Hospital Colorado, Aurora, CO, United States b

Abbreviations ATP BMI CP CPAT CVD DEXA GMFCS IDF MS NCEP WHO

adult treatment panel body mass index cerebral palsy cerebral palsy adult transition longitudinal study cardiovascular disease dual-energy X-ray absorptiometry Gross Motor Function Classification System International Diabetes Federation metabolic syndrome National Cholesterol Education Program World Health Organization

Introduction Cerebral palsy (CP) describes a group of chronic, nonprogressive conditions affecting body movement and muscle coordination (Odding, Roebroeck, & Stam, 2006). CP occurs in 3 to 4 out of every 1000 live births and is caused by damage or injury to one or more areas of the brain during fetal development or infancy (Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, 2019). CP is further divided into three subtypes: spastic, ataxic, and dyskinetic (Surveillance of Cerebral Palsy in Europe, 2000); however, for the purposes of this chapter, we will not distinguish between them unless specifically * In absentia communication: Whitney Maine, Program Coordinator, Physical Therapy Department, School of Health Sciences, Marymount University, Arlington, VA, United States Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00015-5

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noted. While CP is typically considered a childhood disorder, almost all children with CP survive well into adulthood, making CP a lifelong condition that presents cumulative challenges (Haak, Lenski, Hidecker, Li, & Paneth, 2009; Horsman, Suto, Dudgeon, & Harris, 2010). Motor disorders from CP often include disturbances of sensation, perception, communication, and cognition, as well as secondary musculoskeletal issues and epilepsy (Bax et al., 2005). Additionally, individuals with CP can suffer from malnutrition and other nutritional intake problems (Henderson et al., 2002; Sullivan et al., 2000), which, combined with weaknesses in movement, can further exacerbate physical disability (Fig. 1). One of the challenges that young adults with CP experience is the development of secondary health conditions (Carter & Tse, 2009; Horsman et al., 2010; Odding et al., 2006). Recent studies have shown that many adults with CP experience increased adipose tissue deposition, insulin resistance, and sarcopenia (Peterson, Gordon, & Hurvitz, 2013), in addition to being at a greater risk for developing metabolic syndrome and cardiovascular disease (CVD), compared to the general population (Heyn, Tagawa, Pan, Thomas, & Carollo, 2019; McPhee, Claridge, Noorduyn, & Gorter, 2018; Peterson et al., 2013; Peterson, Ryan, Hurvitz, & Mahmoudi, 2015). To prevent or alleviate these secondary health conditions, clinicians and other health advisors must work together to develop specialized treatment and care plans, specifically in regard to nutrition and wellness. In the general population, changes in diet and lifestyle have been reported to improve insulin resistance and metabolic syndrome (Hoyas & Leon-Sanz, 2019). However, due to the nature of CP, it is unclear whether these same dietary changes can be used to help prevent the onset of insulin resistance, metabolic syndrome, and CVD.

Cardiovascular disease and metabolic syndrome in patients with CP Although CP is known as a nonprogressive disorder, secondary effects such as obesity, a long-term sedentary lifestyle, and mental health conditions compound the risks of cardiometabolic diseases, frailty, and early mortality into adulthood. Recent research has demonstrated that adults with CP are at an increased risk for cardiovascular disease (CVD) compared to the general population. In one study using Medical Expenditure Surveys, adults with CP reported significantly increased rates of CVD, myocardial infarction, angina, and other cardiovascular conditions as compared to the general population (15.1% vs 9.1%) (Peterson et al., 2013). A systematic review of CVD in adults with CP concluded that much of this risk is due to lifestyle factors that accompany CP, including obesity and inactivity (McPhee et al., 2018). Metabolic syndrome (MS) refers to a constellation of metabolic markers often associated with CVD, type II diabetes, and some cancers (Huang, 2009; Moore, Chaudhary, & Akinyemiju, 2017), including obesity, hyperglycemia, hypercholesterolemia/hypertriglyceridemia, and hypertension (Ramos-Jimenez, Hernandez-Torres, Wall-Medrano, &

Health Decline in CP due to Decreased Walking Performance Health Conditions that ↓Supply for Walking

Walking Efficiency (Gait Performance)

Decreased Health & Wellbeing

• Inflammation -> Joint Pain -> ↓ROM • Lower Fitness Level ↓endurance Sarcopenia -> ↓muscle strength

Physical & Biological

Osteopenia -> ↓force supply

Disease State

Joint Disease • Osteoarthritis • Chronic Joint Pain • Total joint replacement

Spasticity ↑ Muscle Tone

↓ Motor Control Weakness

↓Supply

Compensatory Gait Pattern

Resources Available to Walk Supply Demand

Resources Required to Walk

If Supply < Demand

Decreased Independent Ambulation •GMFCS Level •Activity Level •Temporal/Spatial •Kinematics and Kinetics • Overall Gait Performance • Cardio endurance (O2/CO2, walking in minutes)

Health Conditions that ↑Demand of Walking • Abnormal Gait Biomechanics • Excess Weight, Obesity

Sedentary Lifestyle ---------------Disability

Metabolic Dysfunction • Insulin resistance • Glucose impairment • Diabetes Cardiovascular • Hypertension • Heart Disease • Reduced lung capacity

Psychological •Altered mood •Depression •Cognitive impairment

Quality of Life •Decreased Independence •Decreased Participation

© Carollo & Heyn, 2013

Fig. 1 Mechanisms contributing to health decline in individuals with CP due to impaired mobility. Musculoskeletal impairments associated with CP that are manageable with parental support as children often become insurmountable obstacles as adults. When everyday movements become arduous and painful, adults with CP inevitably become less active, putting them at risk of developing a sedentary lifestyle. This increases the risk of prematurely developing secondary health conditions common in older adults, including joint disease, metabolic dysfunction, and cardiopulmonary disease. Cognitive impairment, depression, and a reduced quality of life can also result. (Figure adapted from Oliveira T, James J. Carollo., Robertson D, Zhaoxing P, Heyn, P. (2014). Incidence of epilepsy in adults with cerebral palsy and secondary health outcomes: A review and proposed feasibility study [Review]. Neurological Disorders, 2(6). https://doi.org/10.4172/2329-6895.1000188.)

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Villalobos-Molina, 2014). MS markers tend to occur in tandem and together they increase the risk of CVD, type II diabetes, and other conditions including cancer (Huang, 2009). A diagnosis of MS generally requires the patient to show insulin resistance plus at least two risk factors that are part of the diagnostic criteria, with specific definitions deferring across health organizations (Table 1). Organizations defining MS include the World Health Organization (WHO) (Alberti & Zimmet, 1998), the International Diabetes Foundation (IDF) (Zimmet, Magliano, Matsuzawa, Alberti, & Shaw, 2005), and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) (Grundy et al., 2005) and include the following possible diagnostic criteria: • Obesity, as determined by elevated waist circumference or waist:hip ratio • Hyperglycemia (fasting glucose 100 mg/dL) Table 1 Definitions of MS across health organizations. Definitions of metabolic syndrome (MS)

Diagnostic criteria

Obesity

Hyperglycemia Dyslipidemia

WHO (1998)

NCEP ATP III (2005)

IDF (2005)

Insulin resistance or diabetes required, plus 2 of the markers below BMI >30 or waist:hip ratio >0.9 (M) or 0.85 (F) Insulin resistance (required) Triglycerides 150 mg/dL, or HDL-C 35 in (F)

Waist 94 cm (M) or 80 cm (F) Fasting glucose 100 mg/dL Triglycerides 150 mg/dL or Rx

Hypertension

140/90 mmHg

Microalbuminuria

N/A

Fasting glucose 100 mg/dL or Rx (1) Triglycerides 150 mg/dL or Rx, or (2) HDL cholesterol: 85 mmHg diastolic or Rx Urinary albumin excretion of 20 μg/min or albumin-tocreatinine ratio of 30 mg/g

>130 mmHg systolic or > 85 mmHg diastolic or Rx N/A

World Health Organization (WHO), National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP), and International Diabetes Foundation (IDF) are described. Adapted from Huang, P. L. (2009). A comprehensive definition for metabolic syndrome. Disease Models & Mechanisms, 2(5–6), 231-237. https://doi.org/10.1242/dmm.001180 and Heyn, P. C., Tagawa, A., Pan, Z., Thomas, S., & Carollo, J. J. (2019). Prevalence of metabolic syndrome and cardiovascular disease risk factors in adults with cerebral palsy. Developmental Medicine and Child Neurology, 61(4), 477–483. https://doi.org/10.1111/dmcn.14148.

Nutrition and adult with cerebral palsy

Dyslipidemia (generally, TG 150 mg/dL or low HDL cholesterol) Hypertension Microalbuminuria [criteria specific to the WHO definition (Alberti & Zimmet, 1998). To date, there is no consensus for the best combination of metabolic markers that define MS (Kassi, Pervanidou, Kaltsas, & Chrousos, 2011). Furthermore, these diagnostic criteria were primarily validated in typically developing children and older individuals (Viitasalo et al., 2014) and therefore may not be appropriate for young adults and individuals with CP. Recent research has shown that young adults with CP are at an increased risk of developing MS (Heyn et al., 2019; Moore et al., 2017). This recent study of ambulatory young adults with CP showed the prevalence of MS at 17.1% (95% CI 9.2–28.0), 12.9% (95% CI 6.1–23.0), and 12.9% (95% CI 6.1–23.0) by NCEP ATP III, WHO, and IDF criteria respectively. Thus, the NCEP ATP III guidelines were found to be the most sensitive in this population of CP adults. The prevalence of obesity was 24.30—57.1% in the study cohort, depending on the diagnostic threshold (Heyn et al., 2019). In contrast, the prevalence of MS in the general population was approximately 10%, according to the NHANES registry (Moore et al., 2017). Although there is limited available evidence on this population, the current literature suggests that individuals with CP are at an increased risk for developing MS and developing complications from MS, including CVD. Thus, it may be beneficial for providers to encourage routine visits to ensure that individuals who develop MS and CVD are appropriately monitored (see Clinical Recommendations for further information). • • •

Mobility challenges and physical exercise The Gross Motor Function Classification System (GMFCS) was developed to assess the motor function of children with CP and has been used to determine ambulatory changes after treatment or growth (Palisano, Rosenbaum, Bartlett, & Livingston, 2008; Wood & Rosenbaum, 2000). The GMFCS provides healthcare workers with a tool to assess everyday mobility activities, such as sitting, walking, and the use of mobility devices. The GMFCS classifies the motor abilities of individuals into levels I–V, with higher levels indicating an increased need for mobility assistance (Gross Motor Function Classification System (GMFCS), 2018). Physical exercise and avoiding sedentary behaviors are crucial to promoting good health. Adults and children with CP have several physical difficulties that often present barriers to obtaining the recommended amounts of physical activity. In addition to possessing difficulties with mobility, children with CP display reduced aerobic capacity (VO2 max) (Verschuren & Takken, 2010) and reduced muscle strength as compared to typically developing children (Eek, Tranberg, & Beckung, 2011; Wiley &

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Damiano, 1998). A systematic review showed that children with CP participated in habitual physical exercise 13%–53% less than typical children and that activity levels were 30% under recommended physical activity limits (Carlon, Taylor, Dodd, & Shields, 2013). Furthermore, total sedentary time was twice the recommended amount in children with CP. Additional research into the physical behaviors of adults with CP is needed, although one study showed that adults with CP generally do not obtain recommended guidelines for physical activity (Heyn et al., 2019). Kidney function: Poor kidney health increases the risk of CVD and MS. Adults with CP are at an increased risk for developing chronic kidney disease (CKD), even when adjusting for demographics and diabetes (Whitney, Schmidt, Bell, Morgenstern, & Hirth, 2020). A recent study of 16,700 adults with CP found that 7.3% had kidney disease, which was also associated with increased mortality (Whitney & Oliverio, 2021). This study also noted that estimated glomerular filtration rate (eGFR) using serum creatinine may overestimate kidney function, as adults with CP typically have low muscle mass and low creatinine levels by default. This may cause providers to miss problems with kidney function, as the creatinine levels will tell more about reduced muscle mass than kidney function in this population. In some cases, this test will erroneously indicate that kidney function improves with increasingly severe CP (Whitney, Wolgat, Ellenberg, Hurvitz, & Schmidt, 2021). Cystatin C may be a better biomarker for kidney function in adults with CP, although further research is needed (Vij et al., 2016).

Nutritional status Individuals with CP are at an increased risk of both malnutrition and obesity. According to a study, over 80% of adults with CP appeared to be malnourished (Norte, Alonso, Martinez-Sanz, Gutierrez-Hervas, & Sospedra, 2019). In a survey-based study of adults and adolescents with CP, 71% reported their eating habits as “fair” and none reported them as “excellent” (McPhee, Verschuren, Peterson, Tang, & Gorter, 2020). Nutritional deficiencies may be suspected from abnormal physical examination findings, including abnormalities in skin, hair, nails, or results from a complete blood count (e.g., anemia) ( Jesus & Stevenson, 2020). A combination of challenges with swallowing and communication, primarily in children, increases the risk of malnutrition in this population. Consequences of nutrition then include reduced BMD, muscle mass, concentration, neurodevelopment, and quality of life, which can exacerbate eating difficulties further ( Jesus & Stevenson, 2020).

Obesity The risk of obesity in individuals with CP may be compounded by challenges with mobility and muscle wasting that limit physical activity (Heyn et al., 2019; Peterson

Nutrition and adult with cerebral palsy

et al., 2013). Children with CP have been shown to have higher rates of obesity than the general population, and overweight or obese adolescents with CP have a higher prevalence of dyslipidemia, hypertension, and fatigue (Rimmer, Yamaki, Lowry, Wang, & Vogel, 2010). Additionally, there have been debates on how to classify obesity within the CP population. Body mass index (BMI) measurements do not take into account body composition or increased adiposity (Peterson et al., 2013), and adults with CP with low muscle mass may be identified as normal weight, despite being overfat. As many as 30 million Americans may have a normal BMI with an obese phenotype, which is strongly associated with MS and CVD (Romero-Corral et al., 2010). The risk for normal-weight obesity may be significantly higher for individuals with CP or other disabilities associated with low muscle mass. Therefore, BMI might not be sufficient for determining CVD and MS risk in this population (Peterson et al., 2013). Although providers may suspect malnutrition in underweight individuals, it is important to note that individuals with obesity can still suffer from significant micronutrient deficiencies. In particular, insufficiencies or deficiencies in vitamin D (45 min to eat a meal had a mean BMI in the underweight category (mean BMI 16.87 kg/m2, range 10.7–23.9 kg/m2) (Yi et al., 2019). Routine swallowing evaluations for adults with CP have been recommended, as well as determining the time required to eat a meal (Yi et al., 2019). These difficulties may impair patients from obtaining adequate nutrition and reduce the overall quality of life.

Bone health and nutritional considerations Maximizing bone quality and bone mineral density (BMD) is a crucial concern for both children and adults with CP, with up to 77% of children with CP meeting clinical

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guidelines for low BMD (Henderson et al., 2002; King, Levin, Schmidt, Oestreich, & Heubi, 2003). A systematic review of children and adults with CP found evidence of low BMD across 16 studies, and that low BMD was not limited to nonambulatory persons (Mus-Peters et al., 2019). In a study specific to adults with CP (mean age of 28.3 years), 38% reported a history of fragility fractures (Trinh et al., 2016). However, more high-quality research is needed for healthcare providers to help improve bone health in individuals with CP. Inadequate nutrition often correlates to low serum levels of micronutrients including calcium, vitamin D, and phosphorus ( Jesus & Stevenson, 2020). Furthermore, medications commonly prescribed to individuals with CP may worsen bone health by altering the absorption or metabolism of nutrients. Specific anticonvulsants and proton-pump inhibitors have been linked to reduced bone health, although evidence is mixed (Henderson, Lin, & Greene, 1995; Kecskemethy & Harcke, 2014). In a study of BMD in 139 children and adolescents with spastic CP, low BMD averaged one standard deviation below healthy controls and was correlated with low serum calcium (Henderson et al., 1995). Ambulatory status was found to correlate most strongly with BMD, with nutritional status being the second most important factor (Henderson et al., 1995). In combination with physical therapy and careful monitoring of medications, optimizing nutrition is beneficial for improving overall bone health. Further research efforts are needed to improve treatment strategies to optimize bone health in adults and children with CP.

Nutritional programs for adults with CP Recommendations for growth and nutritional standards of care have been established for children with CP ( Jesus & Stevenson, 2020; Samson-Fang & Bell, 2013; Sullivan et al., 2000) but fewer guidelines have been developed for the adult population. One recent study of diet quality in adults with CP found that the US Department of Agriculture (USDA) nutritional guidelines were largely unmet and recommended routine assessment of nutritional intake and further study (Brown, Marciniak, Garrett, & GaeblerSpira, 2021). Cerebral Palsy Adult Transition Study (CPAT): There is limited evidence examining the links between MS, CVD risk factors, and physical function in individuals with CP or other disabilities. CPAT, conducted through Children’s Hospital Colorado and the University of Colorado Healthcare Systems, is an ongoing study designed to understand the relationships between walking ability, overall health, and risk of developing secondary health conditions in young adults with CP (Heyn et al., 2019; Robertson, Heyn, Pan, & Carollo, 2016). Another objective of this study is to determine the relationships between metabolic markers, CVD risk factors, and the GMFCS classification system in adults with CP. A health and nutritional assessment tool (CPAT Health-Self Promotion and Health

Nutrition and adult with cerebral palsy

Passport Tool Initiative [CHAMP]) was also designed under this study (Robertson et al., 2016; Schwartz, Capo-Lugo, & Heyn, 2019), with the aim to identify health disparities and promote wellness in individuals with CP, including in nutrition. An abbreviated version of the CP-CHAMP dietary guidelines is shown in Fig. 3. Nutritional assessment: A nutritional assessment may be beneficial to routinely screen adults with CP for potential dietary insufficiencies, thus allowing referral to a nutritionist. One screening tool, the Mini Nutritional Assessment (MNA) (Salva Casanovas, 2012; Vellas et al., 1999), was used to efficiently screen for diet quality in adults with CP (Norte et al., 2019). A similar tool has been used for children with CP, in combination with assessments of oral-motor function and other physical parameters (Scarpato et al., 2017).

Additional wellness interventions Physical health is only one component of total health in both individuals with CP and in the general population, as illustrated by the Wellness Wheel (Fig. 2). Additional health considerations must be addressed for optimal wellness in this population. This is addressed in the CHAMP tool for individuals with CP (see the previous section), which includes exercise, mental health, risky behavior, self-care, and nutrition assessments and recommendations.

Clinical recommendations We recommend that healthcare providers closely monitor individuals with CP for the risk of developing secondary conditions, including CVD, MS, and premature frailty. Wellness Wheel

Spiritual

Occupational

Social

Physical

Intellectual

Emotional

Fig. 2 The wellness wheel. Wellness can be defined as a positive health behavior or lifestyle structured around well-being, disease prevention, and improved quality of life. The following diagram integrates equally important lifestyle components to address for optimal well-being. (Adapted from Hettler, B. (2020). The six dimensions of wellness. National Wellness Institute. https://nationalwellness.org/ resources/six-dimensions-of-wellness/.)

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Nutrition Recommendations for Optimal Health: Recommendation (example): If you have a family history of cardiovascular disease (i.e., diabetes, hypertension, high cholesterol, obesity), you should give special attention to your dietary habits. Because of your abnormal body fat, you should try to eat less fry and fast food and have a diet reach in fiber, vegetables, and fruits. Monitor your salt and sugar intake as both can also increase your risk for high cholesterol and diabetes. Individuals with disabilities should give special attention to their fluid intake. Keep your body nourished by drinking water and fresh fruit juices. Avoid (or consume sporadically) sugary soft drinks like sodas and drinks with artificial sweeteners like aspartame, saccharin, and sucralose. These types of drinks have shown to have a harmful effect on health.

Below are additional great tips to improve dietary habits: 1. Avoid sugary and refined foods. Simple carbohydrates, such as sugar and foods made with white flour, can increase triglycerides. 2. Limit the cholesterol in your diet. Aim for no more than 300 milligrams (mg) of cholesterol a day — or less than 200 mg if you have heart disease. Avoid the most concentrated sources of cholesterol, including meats high in saturated fat, fried food, egg yolks and whole milk products. 3. Choose healthier fats. Trade saturated fat found in meats for healthier monounsaturated fat found in plants, such as olive, peanut and canola oils. Substitute fish high in omega-3 fatty acids — such as mackerel and salmon — for red meat. 4. Eliminate trans-fat. Trans-fat can be found in some fried foods and commercial baked products, such as cookies, crackers and snack cakes. But don't rely on packages that label their foods as free of trans-fat. In the United States, if a food contains less than 0.5 grams of trans-fat a serving, it can be labeled trans-fat-free. Even though those amounts seem small, they can add up quickly if you eat a lot of foods containing small amounts of trans-fat. Instead, read the ingredients list. You can tell that a food has trans-fat in it if it contains partially hydrogenated oil. 5. Limit how much alcohol you drink. Alcohol is high in calories and sugar and has a particularly potent effect on triglycerides. Even small amounts alcohol can raise triglyceride levels. 6. Some foods may have a healthy effect on blood cholesterol levels. Some options include: 7. Whole grains, such as oatmeal, oat bran and whole-wheat products. In general, choose foods that are rich in grain and less processed items like wheat bread and pasta instead of white. 8. Nuts, such as walnuts, almonds and brazil nuts 9. Plant sterols such as beta-sitosterol and -sitostanol (typically found in margarine spreads 10. Omega-3 fatty acids, such as fatty fish, fish oil supplements, flaxseeds and flaxseed oil. 11. Eat salads and greens frequently as they help to digest fatty foods and promote digestive functions. 12. Choose color and shape variation when consuming vegetables and fruits. Each vegetable/fruit with color and shape variations will have different essential nutrients. 13. Hydration. It is important to have from 6 to 8 8oz cups of water per day. This is difficult for many people to obtain and is especially inconvenient if using the restroom is difficult. Try to plan your fluid intake around your personal schedule by drinking water when it will be convenient for you, taking into account the time (30 – 45 min) that it will take for the water to pass through your body. Keep your body nourished by drinking water and fresh fruit juices. Avoid (or consume sporadically) sugary soft drinks like sodas and drinks with artificial sweeteners like aspartame, saccharin, and sucralose. These types of drinks have shown to have a harmful effect on health. Exercise regularly. Aim for at least 30 minutes of physical activity on most or all days of the week. Regular exercise can boost "good" cholesterol while lowering "bad" cholesterol and triglycerides. Take a brisk daily walk, swim laps, or join an exercise group. If you don't have time to exercise for 30 minutes, try squeezing it in 10 minutes at a time. Take a short walk, swim, or try some chair exercises as you watch television. Talk to your doctor about a good diet plan that can fit your lifestyle and your dietary needs. Your lifestyle has the single greatest impact on your health!

Fig. 3 (See figure legend on opposite page)

(Continued)

Nutrition and adult with cerebral palsy

The Health/Disease Continuum

Optimal State

(Low risk)

H E A L T H

Pre Disease

Normal State (Risk)

(Signs)

Disease

(Symptoms, illness)

Advanced Disease (Disability, death)

High-Level Wellness

Neutral Health Point Pre-Mature Death

D I S E A S E

Fig. 3 Example nutritional recommendations for CP patients. (Adapted from the Cerebral Palsy Health Self Promotion and Health Passport Tool Initiative (CP-CHAMP). Robertson, D., Patricia, H., Pan, Z., Carollo, J. (2016). Cerebral palsy adult transition study (CPAT): Health passport consultation follow-up study. Archives of Physical Medicine and Rehabilitation, 97 (10). https://doi.org/10.1016/j.apmr.2016. 08.231; Schwartz, J. K., Carmen, C.-L., Heyn, P. C. (2018). Health self management. In: J. M. Prasher, Vee P. Prasher (Ed.), Physical health of adults with intellectual and developmental disabilities (pp. 345–358). Springer. https://doi.org/10.1007/978-3-319-90083-4_17.)

We propose that clinicians ask thorough questions to the patient to evaluate their current health status, including questions regarding eating habits, physical activity, and falls (Table 2). This health evaluation should be corroborated by a caregiver or partner. The provider should also conduct routine physical examinations to assess grip strength, waist: hip ratio, and metabolic markers for MS, if suspected.

Summary and future research CP is the most common motor disorder of childhood. While not a progressive condition, CP presents significant challenges in motor function that may increase the rates of secondary negative outcomes into adulthood. Individuals with CP frequently suffer from inadequate nutrition, as well as increased rates of cardiovascular disease (CVD) and metabolic syndrome (MS). Secondary motor conditions such as dysphagia, difficulty communicating, poor muscle tone, and reduced mobility may contribute to low nutritional status and obesity, including normal-weight obesity. Low bone density may result, which can be exacerbated by limited physical activity and commonly

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Table 2 Clinical wellness recommendations for providers of adult CP patients. Wellness recommendations for healthcare providers treating patients with CP

Questionnaire Nutrition

Physical activity

Mental health History of falls

Risky behavior Physical examination Obesity

Strength

Metabolic markers for MS Gross motor function Kidney function Bone density

a

Metric

Intervention

Mininutritional assessment, CHAMP tool, or similar

Provide customized dietary recommendations, and/or refer to a dietitian or nutritionist Provide literature on recommended physical activity, refer to a physical therapist or exercise program, if desired Refer to a mental health specialist

a

CDC guidelines (2018), with modifications per ability, or CP-CHAMP tool (Robertson et al., 2016) Provide depression and anxiety screen Ask about the number of falls in last year, or provide History of Falls Questionnaire (Talbot, Musiol, Witham, & Metter, 2005) or similar Inquire into risky behaviors, e.g., driving without a seat belt, drug and alcohol use, sexual behaviors

Waist:hip ratio, waist circumference, and/or BMIb

Grip strength, Medical Research Council Manual Muscle Testing scale Fasting glucose test, blood pressure measurements, lipid panel GMFCS examination eGFR (note that serum creatinine may not be appropriate; more research needed) DEXA scan

Provide literature for fall prevention and reduction

Provide literature and/or refer for counseling

Provide nutritional and/or exercise literature for fat reduction, if appropriate; use in the diagnosis of MS Monitor for frailty; provide strength training recommendations, if appropriate Monitor and/or diagnose for MS, CVD Use GMFCS to assist in appropriate physical activity recommendations Refer to nephrologist

Provide strength training literature, assess for possible nutritional deficiencies, determine if any medications affecting BMD

Questionnaire to be corroborated by a partner, family member, or caregiver. BMI may not always be appropriate for individuals with CP and other disabilities.

b

Nutrition and adult with cerebral palsy

prescribed medications. Although current evidence points to increased rates of obesity and malnutrition in this population, research is lacking into appropriate interventions, particularly among adults. There is an urgent need for evidence-based recommendations on these interventions to improve the quality of life for both young and aging individuals with CP.

Applications to other neurological conditions Central nervous system disability: Individuals with other neurological conditions impacting muscle tone may experience many of the same difficulties in nutrition as those with CP. The most common cause of dysphagia, which can exacerbate difficulties in obtaining adequate nutrition, is an underlying central nervous system disability, followed by epilepsy (Bae et al., 2014). TBI: Traumatic brain injury (TBI) is a major cause of death and disability within the United States. Consequences of TBI may resemble certain aspects of CP, including motor dysfunction, cognitive defects, and other neurobehavioral symptoms (Wilson et al., 2017). Frailty, cognitive impairment, and other age-associated conditions: The CP phenotypes of poor muscle tone and problems with cognition have been compared to the elderly population, particularly with frailty. Individuals with CP experience accelerated symptoms of biological aging, including a loss of bone and muscle mass, mild cognitive impairment, and an increase in heart disease (Ng et al., 2021). Physical frailty can be considered a neuromuscular condition and is associated with reductions in total brain volume, muscle mass, strength, and function (Hassan, Imani, & Duque, 2019). One study found that young adults with CP displayed similar neurocognitive function to seniors with mild cognitive impairment (mean ages, 24.97  5.29 and 71.28  6.03 years, respectively) (Ng et al., 2021).

Other components of interest Gastrostomy and other feeding interventions: Children and adults with CP often experience difficulties sucking and swallowing food and may experience gagging or aspiration of liquids. Feeding tubes including gastrostomy or jejunostomy may be inserted to increase nutritional intake and alleviate problematic symptoms. However, there are not yet any clinical trials investigating the relationship between feeding tube use and nutritional status in individuals with CP (Gantasala, Sullivan, & Thomas, 2013). Vitamin D and iron supplementation: A majority of children and adolescents with moderate-severe CP were found to have insufficient serum vitamin D and ferritin (Le Roy et al., 2021). Due to the frequency of these deficiencies in CP, it may be

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recommended to perform blood tests assessing levels of these nutrients. However, studies are lacking into the benefit of supplementation and proper dosing for individuals with CP.

Mini-dictionary of terms Gross Motor Functional Classification System (GMFCS): A tool to categorize the everyday motor functions of individuals with CP into levels I through V. A higher GMFCS score indicates an increased need for assistance with daily movements, such as walking or sitting. Metabolic syndrome: Metabolic syndrome (MS) refers to a constellation of metabolic markers often associated with CVD and some cancers. MS markers include obesity, hyperglycemia, hypercholesterolemia/hypertriglyceridemia, and hypertension. Precise clinical guidelines for CP differ across health organizations. Oropharyngeal dysphagia: Describes difficulties in swallowing, which may include gagging, swallowing, choking, and drooling. Dysphagia may exacerbate difficulties in obtaining adequate nutrition and contribute to a reduced enjoyment of eating and quality of life. Bone density or bone mineral density: A measurement of bone mineral content at a specific bone location. Bone density is usually measured by a dual-energy X-ray absorptiometry (DEXA) scan. A low bone density increases the risk of fracture and is associated with frailty. Normal-weight obesity: A body-fat percentage above the recommended values, but with normal BMI measurements.

Key facts of metabolic syndrome in adult cerebral palsy: Implications for diet Key facts of cerebral palsy • • • • •

Cerebral Palsy (CP) affects 3–4 out of every 1000 live births and is the most common motor disorder of childhood. CP is caused by damage or injury to one or more specific areas of the brain that occurs during fetal development, the perinatal period, or infancy. CP causes lifelong challenges including increased risks of obesity, high cholesterol, sarcopenia, insulin resistance, and metabolic syndrome. Although not a progressive disorder, motor and cognitive effects may worsen into adulthood. Adults with CP often do not meet nutritional guidelines or physical activity guidelines, and research is lacking in clinical interventions to meet this need.

Nutrition and adult with cerebral palsy

Key facts of metabolic syndrome • • •

• •

Metabolic syndrome (MS) refers to a constellation of metabolic markers often associated with CVD and some cancers. MS markers include obesity, hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and hypertension. Precise clinical guidelines for CP differ across health organizations, including the World Health Organization (WHO), International Diabetes Foundation (IDF), and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). MS is strongly correlated with an increased risk of developing CVD and type II diabetes. Recent research suggests adults with CP may be at an increased risk of developing MS.

Key facts of nutritional interventions for CP • • •

• • •

Individuals with CP are at an increased risk of nutritional deficiencies and malnutrition. Problems with motor control, dysphagia, and communication may contribute to nutritional problems. Nutritional deficiencies may be further exacerbated by prescriptions commonly prescribed to individuals with CP, including proton-pump inhibitors and anticonvulsants. Nutritional deficiencies may exacerbate bone loss, weight problems, and overall quality of life. BMI may not be an appropriate measurement for individuals with CP, due to low muscle tone masking an overfat phenotype. Routine dietary assessments and a wholistic approach to nutrition and wellness are recommended.

Summary points • •

•

Cerebral palsy (CP) causes lifelong challenges including increased risks of obesity, high cholesterol, sarcopenia, insulin resistance, and metabolic syndrome (MS). MS is significantly associated with the development of cardiovascular disease, type II diabetes, and some cancers. Markers for MS include obesity, hyperglycemia, hypercholesterolemia/hypertriglyceridemia, and hypertension. Individuals with CP are at a significantly increased risk of nutritional deficiencies and malnutrition.

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• • •

Problems with motor control, dysphagia, and communication may contribute to nutritional problems. Screening for nutritional deficiencies may help improve dietary outcomes for adults with CP. Further research is needed into nutritional interventions for adults with CP, particularly clinical trials and evidence-based reviews.

References Alberti, K. G., & Zimmet, P. Z. (1998). Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabetic Medicine, 15(7), 539–553. https://doi.org/10.1002/(SICI)1096-9136(199807) 15:73.0.CO;2-S. Bae, S. O., Lee, G. P., Seo, H. G., Oh, B. M., & Han, T. R. (2014). Clinical characteristics associated with aspiration or penetration in children with swallowing problem. Annals of Rehabilitation Medicine, 38(6), 734–741. https://doi.org/10.5535/arm.2014.38.6.734. Bax, M., Goldstein, M., Rosenbaum, P., Leviton, A., Paneth, N., Dan, B., et al. (2005). Proposed definition and classification of cerebral palsy, April 2005. Developmental Medicine and Child Neurology, 47(8), 571–576. https://doi.org/10.1017/s001216220500112x. Brown, M. C., Marciniak, C. M., Garrett, A. M., & Gaebler-Spira, D. J. (2021). Diet quality in adults with cerebral palsy: A modifiable risk factor for cardiovascular disease prevention. Developmental Medicine and Child Neurology, 63(10), 1221–1228. https://doi.org/10.1111/dmcn.14913. Carlon, S. L., Taylor, N. F., Dodd, K. J., & Shields, N. (2013). Differences in habitual physical activity levels of young people with cerebral palsy and their typically developing peers: A systematic review. Disability and Rehabilitation, 35(8), 647–655. https://doi.org/10.3109/09638288.2012.715721. Carter, D. R., & Tse, B. (2009). The pathogenesis of osteoarthritis in cerebral palsy. Developmental Medicine and Child Neurology, 51(Suppl 4), 79–83. https://doi.org/10.1111/j.1469-8749.2009.03435.x. Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities. (2019). Available from: https://www.cdc.gov/ncbddd/disabilityandhealth/data-highlights.html (Retrieved 27.1.2019). Edvinsson, S. E., & Lundqvist, L. O. (2016). Prevalence of orofacial dysfunction in cerebral palsy and its association with gross motor function and manual ability. Developmental Medicine and Child Neurology, 58(4), 385–394. https://doi.org/10.1111/dmcn.12867. Eek, M. N., Tranberg, R., & Beckung, E. (2011). Muscle strength and kinetic gait pattern in children with bilateral spastic CP. Gait & Posture, 33(3), 333–337. https://doi.org/10.1016/j.gaitpost.2010.10.093. Gantasala, S., Sullivan, P. B., & Thomas, A. G. (2013). Gastrostomy feeding versus oral feeding alone for children with cerebral palsy. Cochrane Database of Systematic Reviews, 7, CD003943. https://doi.org/ 10.1002/14651858.CD003943.pub3. Gross Motor Function Classification System (GMFCS). (2018). Cerebral Palsy Alliance. Available from: https://cerebralpalsy.org.au/our-research/about-cerebral-palsy/what-is-cerebral-palsy/severity-ofcerebral-palsy/gross-motor-function-classification-system/ (Retrieved 23.01.2022). Grundy, S. M., Cleeman, J. I., Daniels, S. R., Donato, K. A., Eckel, R. H., Franklin, B. A., et al. (2005). Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute scientific statement: Executive summary. Critical Pathways in Cardiology, 4(4), 198–203. https://www.ncbi.nlm.nih.gov/pubmed/18340209. Haak, P., Lenski, M., Hidecker, M. J., Li, M., & Paneth, N. (2009). Cerebral palsy and aging. Developmental Medicine and Child Neurology, 51(Suppl 4), 16–23. https://doi.org/10.1111/j.1469-8749. 2009.03428.x. Hassan, E. B., Imani, M., & Duque, G. (2019). Is physical frailty a neuromuscular condition? Journal of the American Medical Directors Association, 20(12), 1556–1557. https://doi.org/10.1016/j.jamda.2019.10.019.

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Via, M. (2012). The malnutrition of obesity: Micronutrient deficiencies that promote diabetes. ISRN Endocrinology, 2012, 103472. https://doi.org/10.5402/2012/103472. Viitasalo, A., Lakka, T. A., Laaksonen, D. E., Savonen, K., Lakka, H. M., Hassinen, M., et al. (2014). Validation of metabolic syndrome score by confirmatory factor analysis in children and adults and prediction of cardiometabolic outcomes in adults. Diabetologia, 57(5), 940–949. https://doi.org/10.1007/s00125014-3172-5. Vij, S. C., Wadih, K., Myers, J. B., Emilio, P., Herts, B., & Wood, H. (2016). Assessing renal function in adult myelomeningocele patients: Correlation between volumetric- and creatinine-based measurements. Journal of Clinical Nephrology and Renal Care, 2(1). https://doi.org/10.23937/2572-3286.1510003. Whitney, D. G., & Oliverio, A. L. (2021). The association between kidney disease and mortality among adults with cerebral palsy-a cohort study: It is time to start talking about kidney health. Frontiers in Neurology, 12, 732329. https://doi.org/10.3389/fneur.2021.732329. Whitney, D. G., Schmidt, M., Bell, S., Morgenstern, H., & Hirth, R. A. (2020). Incidence rate of advanced chronic kidney disease among privately insured adults with neurodevelopmental disabilities. Clinical Epidemiology, 12, 235–243. https://doi.org/10.2147/CLEP.S242264. Whitney, D. G., Wolgat, E. M., Ellenberg, E. C., Hurvitz, E. A., & Schmidt, M. (2021). The paradoxical relationship between severity of cerebral palsy and renal function in middle-aged adults: Better renal function or inappropriate clinical assessment? Disability and Rehabilitation, 1–7. https://doi.org/ 10.1080/09638288.2021.1890841. Wiley, M. E., & Damiano, D. L. (1998). Lower-extremity strength profiles in spastic cerebral palsy. Developmental Medicine and Child Neurology, 40(2), 100–107. https://doi.org/10.1111/j.1469-8749.1998. tb15369.x. Wilson, L., Stewart, W., Dams-O’Connor, K., Diaz-Arrastia, R., Horton, L., Menon, D. K., et al. (2017). The chronic and evolving neurological consequences of traumatic brain injury. Lancet Neurology, 16(10), 813–825. https://doi.org/10.1016/S1474-4422(17)30279-X. Wood, E., & Rosenbaum, P. (2000). The gross motor function classification system for cerebral palsy: A study of reliability and stability over time. Developmental Medicine and Child Neurology, 42(5), 292–296. https://doi.org/10.1017/s0012162200000529. Yi, Y. G., Oh, B. M., Seo, H. G., Shin, H. I., & Bang, M. S. (2019). Dysphagia-related quality of life in adults with cerebral palsy on full oral diet without enteral nutrition. Dysphagia, 34(2), 201–209. https://doi.org/ 10.1007/s00455-018-09972-7. Zimmet, P., Magliano, D., Matsuzawa, Y., Alberti, G., & Shaw, J. (2005). The metabolic syndrome: A global public health problem and a new definition. Journal of Atherosclerosis and Thrombosis, 12(6), 295–300. https://doi.org/10.5551/jat.12.295.

Further reading Hettler, B. (2020). The six dimensions of wellness. National Wellness Institute. https://nationalwellness.org/ resources/six-dimensions-of-wellness/. Heyn, P. C., Tagawa, A., Pan, Z., Thomas, S., & Carollo, J. J. (2019). Prevalence of metabolic syndrome and cardiovascular disease risk factors in adults with cerebral palsy. Developmental Medicine and Child Neurology, 61(4), 477–483. https://doi.org/10.1111/dmcn.14148. Oliveira, T., Carollo, J. J., Robertson, D., Zhaoxing, P., & Heyn, P. (2014). Incidence of epilepsy in adults with cerebral palsy and secondary health outcomes: A review and proposed feasibility study [Review]. Neurological Disorders, 2(6). https://doi.org/10.4172/2329-6895.1000188.

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CHAPTER 17

Gut microbiota characteristics in children with cerebral palsy Yinhu Li and Shuai Cheng Li

Department of Computer Science, City University of Hong Kong, Hong Kong, China

Abbreviations 5-HT AD CP FODMAP GABA GBA GLP-1 GM GPR IBS LPS PD SCFAs Treg

5-hydroxytryptophan Alzheimer’s disease cerebral palsy fermentable oligosaccharides, disaccharides, monosaccharides, and polyols γ-aminobutyric acid gut-brain axis glucagon-like peptide one gut microbiome G protein-coupled receptors inflammatory bowel syndrome lipopolysaccharide Parkinson’s disease short-chain fatty acids T regulatory cells

Introduction Cerebral palsy (CP) refers to a syndrome disease caused by nonprogressive brain injuries and developmental defects during the fetus or infancy (Graham et al., 2016; Rosenbaum et al., 2007). Due to the persistent central dyskinesia and postural development abnormalities, the patients often manifested movement and behavioral disorders (Fig. 1) (O’Shea, 2008; Sadowska, Sarecka-Hujar, & Kopyta, 2020). Since limited by behavioral dysfunctions, high proportions of CP children lack sufficient physical exercise and suffer from gastrointestinal disorders and nutrition problems (Gonzalez Jimenez, Diaz Martin, Bousono Garcia, & Jimenez Trevino, 2010; Rogers, 2004). We learned from previous reports that the gut microbiome (GM) participated in food digestion and nutrient absorption in hosts. The disordered GM emerged in patients with gastrointestinal diseases, such as refractory constipation, recurrent abdominal distension, and gastroesophageal reflux (Avelar Rodriguez, Popov, Ratcliffe, & Toro Monjaraz, 2020; Hills Jr. et al., 2019; Shi et al., 2019). Hence, we would like to review the nutrient absorption and gastrointestinal health Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00005-2

Copyright © 2023 Elsevier Inc. All rights reserved.

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Fig. 1 The common complications present in CP children.

in CP children from the perspective of GM. Besides the digestive and nutritional problems, CP children also suffered from other neurologic diseases commonly, such as sensory disorder, cognitive impairment, and epilepsy (Gajewska, Sobieska, & Samborski, 2014; Peduzzi, Defontaine, & Misson, 2006). Increasing studies have reported the interactions between the GM and the brain activity through the gut-brain axis (GBA) and described the GM characteristics in patients with a variety of neurological diseases, such as autism, depression, Alzheimer’s disease (AD), and Parkinson’s disease (PD) (Cryan, O’Riordan, Sandhu, Peterson, & Dinan, 2020; Martin, Osadchiy, Kalani, & Mayer, 2018; Sharon, Sampson, Geschwind, & Mazmanian, 2016). Therefore, GM could improve our understanding of the pathogenesis of CP and its concomitant diseases, providing the basis of adjuvant intervention for the rehabilitation and treatment of CP.

GM and nutritional absorption in CP children As an important place for food digestion and nutritional absorption, the gastrointestinal tract provides an ideal habitat environment for the growth of microorganisms, which interact with different systems in hosts (Fig. 2) (Schmidt, Raes, & Bork, 2018). According to the

Gut microbiota and cerebral palsy

Fig. 2 Associations between GM and human health.

abundance of bacteria in GM, we can divide them into the majority bacteria and the minority bacteria (Lynch & Pedersen, 2016; Yatsunenko et al., 2012). The majority bacteria play an essential role in GM balance, such as Bacteroides, Prevotella, Ruminococcus, Bacillus, and Bifidobacterium, which mainly belong to obligate anaerobic bacteria (Lynch & Pedersen, 2016; Yatsunenko et al., 2012). In contrast, the minority bacteria are potentially responsible for the host diseases, including Escherichia, Shigella, and Streptococcus, mainly from aerobic or facultative anaerobic bacteria (Lynch & Pedersen, 2016; Yatsunenko et al., 2012). GM participates in the nutritional absorption mainly in the following two methods: (a) GM synthesizes and metabolizes nutrients for host usage; and (b) GM-secreted metabolites regulate the nutritional absorption by interacting with the neuro and endocrine systems in hosts (Valdes, Walter, Segal, & Spector, 2018). Firstly, some bacteria in GM could synthesize and metabolize various nutrients in the gut, such as vitamin B12, vitamin D, vitamin K, and amino acids (Boran et al., 2020; Dodd et al., 2017; Waterhouse et al., 2019). In addition, part of intestinal bacteria could ferment undigested carbohydrates in the gastrointestinal tract, produce short-chain fatty acids (SCFAs) such as propionic and butyric acids, and participate in liver energy metabolism, fat generation, sugar metabolism, etc. (Valdes et al., 2018). Moreover, GM-secreted SCFAs can be recognized by the G protein-coupled receptors 41 and 43 (GPR41 and GPR43) located in the dendritic cells in the intestinal mucosa, stimulating the release of glucagon-like peptide one (GLP-1), promoting the synthesis of insulin, and regulating the level of blood glucose (Tolhurst et al., 2012). Nevertheless, GM also affects the human immune system tightly, affecting gastrointestinal health and nutritional absorption indirectly (Rooks & Garrett, 2016). GM-derived lipopolysaccharide (LPS) could stimulate the development and maturation of intestinal mucosaassociated immune systems, inducing the secretion of mucins in goblet cells and maintaining the integrity of the intestinal mucosal barrier (Rooks & Garrett, 2016).

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Since liquid food is the primary food source for CP children with behavioral disorders, our previous study discovered that the GM in the CP children contained decreased Prevotella and Bacteroidetes, which could metabolize dietary fiber or degrade plant-derived protein (Fig. 3) (Huang et al., 2019). From Dongfang Li et al.’s research, we learned that specific species in Bacteroidetes could metabolize dietary fiber and revert the Fe3+ into Fe2+ in the intestinal tract, and Fe2+ participates in the hemoglobin, myoglobin, cytochrome, and enzyme synthesis (Li et al., 2019). Therefore, the findings indicate that GM affects the absorption of nutrients in CP children. In addition, the GM in CP children also lacks probiotics such as Faecalibacterium and Lactobacillus in their intestines compared to that in healthy children (Huang et al., 2019). Previous studies revealed that the bacteria could secret butyric and lactic acids by metabolizing dietary fiber ( Joseph, Depp, Shih, Cadenhead, & Schmid-Schonbein, 2017). These SCFAs could maintain the intestinal mucosa integrity and repress the growth of pathogens (Rooks & Garrett, 2016). Generally, these studies suggested that diet habits affect GM in CP children, while GM affects nutrient absorption in hosts through its metabolites in turn (Rooks & Garrett, 2016). Meanwhile, the findings also imply that GM can be a potential therapeutic target for the treatment of CP children by applying a personalized diet or probiotics.

GM and neurologic regulations in CP children Increasing studies reveal that GM interacts with the gastrointestinal tract and associates with brain activity through the GBA (Cryan et al., 2020; Martin et al., 2018; Sharon et al., 2016). GBA refers to the two-way information communications between the gastrointestinal tract and the brain, which involves the immune, vagus nerve, and neuroendocrine systems (Martin et al., 2018). In the GBA, GM plays an important role as a bridge, and the interactions between the brain and GM accompany the entire life of humans (Martin et al., 2018). At the early stage of life, GM affects brain development by secreting metabolites and neuro-signal transmissions and imposes a long-term impact on the occurrences of adult neurological diseases (Niemarkt et al., 2019). From previous reports, we know that GM could synthesize various neuroactive compounds, such as 5hydroxytryptophan (5-HT, also known as serotonin), dopamine, gamma-aminobutyric acid, and short-chain fatty acids (Liu, Zhang, & Ai, 2021; Strandwitz et al., 2019; Valles-Colomer et al., 2019). Among these bacterial metabolites, 5-HT is one of the pleasure perception neurotransmitters essential for emotion regulation in humans (Liu et al., 2021). Mireia Valles-Colomer et al. have reported that the patients with depressive disorders exhibited depleted Akkermansia, Alistipes, and Roseburia, which were associated with the secretion of 5-HT (Valles-Colomer et al., 2019). Moreover, 5-HT (e.g., Prozac, Zoloft, and Celexa) is the primary target for treating depression (Valles-Colomer et al., 2019). As an important inhibitory neurotransmitter, GM produced γ-aminobutyric acid (GABA) linked with the mood, anxiety, and depression states

Fig. 3 The GM features in healthy and CPE children. In the heatmap, the contributions of the top 10 genera on 37 KEGG level II functional categories were detected in CPE and healthy groups, respectively. The deeper red square means that the genera contribute to the functional category, while the deeper blue square means that the functional category obtained less contribution from the genera. In the box plot, we compared the pathways between CPE and healthy groups. *, **, and *** stand for the P-value smaller than .05, .01, and .001, respectively. Functional classifications of KEGG level I were suggested by different colors, while the blue and red boxes represented healthy and CPE groups, respectively. CPE means the CP with epilepsy.

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in hosts, and Bacteroides and Parabacteroides species in GM are responsible for the production of GABA (Strandwitz et al., 2019). Hence, GM is considered the “second brain” of humans due to its close relationships with the neurological system. In previous research, we have investigated the characteristics of GM in CP children (Fig. 3) (Huang et al., 2019). Compared with healthy children, the CP patients exhibited altered bacterial compositions, such as the decreased Anaerostipes and Faecalibacterium (Huang et al., 2019). The decreased Anaerostipes and Faecalibacterium sp. would aggregate neuroinflammation and lead to the increased risks of other neuro-diseases, since the SCFAs could stimulate Treg cells’ differentiation (Treg) and secrete butyrate to relieve inflammation burdens (Yamawaki et al., 2018). In addition, the bacterial co-occurrence network was altered in the CP patients under the changed GM features (Huang et al., 2019). For example, Bacteroides exhibited antagonistic relationships with Bifidobacterium and Lactobacillus (Huang et al., 2019). Regarded as probiotics, Bifidobacterium and Lactobacillus could repress the overgrowth of pathogens and improve epithelial integrity (O’Mahony et al., 2005; Zhao et al., 2020). With overgrowth of Bacteroides induced by liquid diet, the CP patients contained decreased Bifidobacterium and Lactobacillus, which expose the hosts to an increased risk of digestive diseases (O’Mahony et al., 2005; Zhao et al., 2020). Moreover, the functional analysis indicated that Bacteroides would increase the risks of immunologic and neurologic diseases in hosts (Huang et al., 2019). Generally, GM plays a vital role in the human nervous system’s development, regulation, and response. In addition, the dysbiotic GM in CP children might involve in the co-occurrence of other neurological diseases.

GM and gastrointestinal complications in CP children Due to the long-term lack of physical exercises, repeated antibiotic applications, and oropharyngeal dysfunction, most CP children present with gastrointestinal disorders (Fig. 1) (Gonzalez Jimenez et al., 2010). Around 75% of the CP children suffer from refractory constipation. In Chassard et al.’s study, the patients with constipation exhibited significantly enriched sulfate-reducing bacteria, such as Enterobacteriaceae (Chassard et al., 2012). Conversely, levels of Bifidobacteria and Lactobacillus decreased obviously (Chassard et al., 2012). With mouse models, the researchers confirmed the influences of Lactobacillus sp. on gut motility. Lactobacillus sp.-secreted metabolites interact with afferent sensory nerves in the gut and affect the stool frequency through GBA (Zegarra-Ruiz et al., 2019). As for Bifidobacteria, the randomized controlled trials have proved that the bacteria could shorten the colonic transit time and improve gastrointestinal health. Guerra et al.’s study applied a dairy product enriched with Bifidobacterium longum in 59 students for 5 weeks and assessed their stool frequency and defecation pain (Guerra et al., 2011; Marteau et al., 2002). Although gastrointestinal disorder was relieved in both the treated and control groups, the students treated with Bifidobacterium longum

Gut microbiota and cerebral palsy

exhibited an additional improvement in stool frequency and defecation pain (Guerra et al., 2011). Besides constipation, severe CP children fed with liquid food also suffer from gastroesophageal reflux, recurrent abdominal distension, and even gastrointestinal bleeding, and GM is closely related to these gastrointestinal diseases (Hills Jr. et al., 2019; Shi et al., 2019). With these findings, we summarized that GM is associated with the occurrences of gastrointestinal disorders, and the administration of probiotics, prebiotics, or specified diets provides strategies for symptom improvements in CP children (Fig. 4).

Applications to other neurological conditions GM and neurologic complications in CP children Epilepsy is another common comorbidity in CP children, with a high incidence of 25%– 45% (Rosenbaum et al., 2007). Epileptic seizure refers to the brain neurons’ sudden abnormal electric discharges, leading to transient brain dysfunction (Arnold & Dodson, 1996). Therefore, epileptic seizure aggravates brain injury in CP patients (Sellier et al., 2012). Since the ketogenic diet exhibits smaller side effects and remarkable efficacy, the diet has become the primary therapy for the treatment of epilepsy (Ulamek-

Fig. 4 The strategies to reshape GM in humans.

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Koziol, Czuczwar, Januszewski, & Pluta, 2019). Previous studies have indicated that the ketogenic diet was sufficient in seizure control in 50%–80% of refractory epilepsy children. It could decrease the frequency of seizures to 10% in 30% of refractory epilepsy children and eliminate seizures in 10%–20% of the patients (Olson et al., 2018). As a type of food with high fat and low carbohydrate, the ketogenic diet regulates the brain and neural pathways mainly through GM (Olson et al., 2018). As a critical factor bridging the ketogenic diet and central nervous system in epilepsy children, GM plays an essential role in controlling seizures in CP children (Olson et al., 2018). Since diet was the main contributor in determining the microorganism compositions of GM (David et al., 2014), the ketogenic diet could alter the GM components, regulate the secretion of neural pathway-related metabolites in GM, and prevent abnormal neuron electric activities, such as seizure (Olson et al., 2018). Previous studies have revealed that the GM in children with refractory epilepsy changed significantly after ketogenic diet treatment (Olson et al., 2018; Zhang et al., 2018). The abundance of Bacteroides, Prevotella, and Bifidobacteria increased after ketogenic treatment, accompanied by decreased Cronobacter (Zhang et al., 2018). Olson et al. also reported that the abundances of Akkermansia muciniphila and Parabacteroides sp. increased significantly in children with refractory epilepsy after the ketogenic diet (Olson et al., 2018). By decreasing γ-glutamyl amino acids in the gut and promoting GABA secretion in the brain, these two bacteria were the key factors in reducing the frequency of seizures (Olson et al., 2018). To verify the roles of two bacteria in epileptic control, the researchers conducted a ketogenic diet on sterile epileptic mouse models (Olson et al., 2018). The experiment exhibited that Akkermansia muciniphila and Parabacteroides sp. must be provided to the aseptic epileptic mouse models simultaneously during the ketogenic diet treatment. Otherwise, seizures cannot be controlled effectively in the mice (Olson et al., 2018). These results suggested that clinical treatment based on GM shed light on the amelioration of epilepsy and other neurological complications in CP children.

Other components of interest Personalized diet, GM, and CP treatment Diet emerges as one of the most relevant environmental factors affecting GM configuration in a reproducible manner (Fig. 4) (David et al., 2014). In the former parts, we have introduced the impacts of liquid food on the GM composition in CP children (Huang et al., 2019), summarized the influences of probiotics on the remission of constipation (O’Mahony et al., 2005), and illustrated the relationships between ketogenic diet, GM alteration, and seizures controlling (Ulamek-Koziol et al., 2019). However, humans from different regions or with different ages have different diet habits (Yatsunenko et al., 2012), so the nutrient compositions, such as the contents and ratios of carbon and water, protein, lipids, and dietary fiber, differ from each other. In De Filippo et al.’s study, they

Gut microbiota and cerebral palsy

have reported the GM compositions between the children living in rural African village and the children living in the developed European urban with the same age (De Filippo et al., 2010). Composed of starch, animal protein, plant polysaccharides, sugar, fat, and fiber differentially, the diets from these two cohorts shaped the GM with specific characteristics: The African children exhibited enriched Actinobacteria and Bacteroidetes, whereas more abundant Firmicutes and Proteobacteria existed in European children (De Filippo et al., 2010). Moreover, the African children contained higher abundant SCFA-producing bacteria (e.g., Prevotella, Butyrivibrio, and Treponema) than European children, corresponding to the higher levels of butyrate and propionate (De Filippo et al., 2010). SCFAs could activate Treg differentiation and protect the intestine from inflammations (Dalile, Van Oudenhove, Vervliet, & Verbeke, 2019). Hence, the study indicated the close correlations between food diet, GM, and intestinal health in children. Therefore, a personalized diet provides a potential strategy for the reshipment of GM in CP children, assisting the improvement of their health and the prevention of comorbidities. More than that, identical dietary interventions in GM composition and host metabolism are personal-specific (Kolodziejczyk, Zheng, & Elinav, 2019). Given that GM is affected by many factors, such as genetic makeup, exercises, meal times, and sleep times (Fig. 5) (Zeevi et al., 2015), the GM and physiologic response varies in people to the same

Fig. 5 Factors affect the GM composition. This pie chart divided the factors into two types: The factors that can be and cannot be regulated humanly were marked with orange and blue colors, respectively.

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meals. In a random clinical trial from Chumpitazi et al., the researchers have enrolled the children with inflammatory bowel syndrome (IBS) for the low fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAP) diet intervention and identified the GM differences between the responders and nonresponders (Chumpitazi et al., 2015). The GM in FODMAP responder contained higher Bacteroides, Ruminococcaceae, and Faecalibacterium prausnitzii, which are capable of saccharolytic metabolism (Chumpitazi et al., 2015). In contrast, the nonresponders harbored abundant Turicibacter, which required the supplements of maltose and 5-ketogluconate for growth (Chumpitazi et al., 2015). With such discoveries, the prediction of metabolic responses to a specific diet in hosts can be achieved based on the GM composition and other personal features. In Zeevi et al.’s study, the researchers have developed a machine learning algorithm to predict the postprandial glycemic response in people by integrating their GM, dietary, and body parameters (Zeevi et al., 2015). Notably, the model exhibited accurate predictions on the postprandial glycemic responses in an independent test (Zeevi et al., 2015). The discoveries also inspire us that the GM-combined machine learning model could predict the consequences of personalized diet on clinical symptoms, assisting in designing customized diets for the CP children (Fig. 6).

Mini-dictionary of terms •

•

Gut microbiome: All the microorganisms colonized in the human gut, including bacteria, fungi, archaea, and viruses. The microorganisms in the gut microbiome interact with each other and are associated with human health. Gut-brain axis: Gut-brain axis refers to the system composed of the gut and brain. Through the hormonal metabolites and neurologic signals, gut and brain

Fig. 6 The design of personalized diet for GM and clinical regulation.

Gut microbiota and cerebral palsy

• •

•

communicate with each other and regulate hosts’ emotional responses, metabolism, immune system, brain development, etc. Probiotics: The live microorganisms that benefit human health, such as the species in Bifidobacterium, Lactobacillus, and Bacillus subtilis. Prebiotics: The edible substances that promote the growth and metabolism of probiotics selectively, such as fructose oligosaccharide, galactose oligosaccharide, and inulin. Inflammatory bowel syndrome: Inflammatory bowel syndrome refers to gastrointestinal disorders with persistent or intermittent attacks, and the patients are mainly manifested with abdominal pain, abdominal distension, diarrhea, etc.

Key facts • • •

• •

Gut microbiome affects nutrient absorption and immune regulation in cerebral palsy children through metabolites secretion. Gut microbiome secreted neuro-related metabolites associate with the mood responses and nervous system development in cerebral palsy children. Interventions to gut microbiome in cerebral palsy children could relieve their gastrointestinal complications, such as gastroesophageal reflux, recurrent abdominal distension, constipation, etc. Gut microbiome-based clinical treatment shed light on the amelioration of epilepsy and other neurological complications in cerebral palsy children. Personalized diet is an essential strategy in restoring gut microbiome balance in cerebral palsy children, assisting in the improvement of their health and the prevention of comorbidities.

Summary points • • • • •

Disordered GM weakens the nutrient absorption ability of the intestinal tract in CP children. Disordered GM exposed the intestinal tract to higher inflammations risks and affected the neurodevelopment in CP children. Dysbiotic GM increased the risks of gastrointestinal and neurologic complications in CP children. Personalized diets, prebiotics, and probiotics provided strategies for GM reshaping, which is beneficial for health improvement and comorbidities prevention in hosts. GM and machine learning algorithms enable the prediction of the clinical outcomes of a specific diet in people, assisting in designing personalized diets for CP children.

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CHAPTER 18

Swallowing problems: Major components of nutritional deficits in adults with cerebral palsy You Gyoung Yia,b a

Department of Rehabilitation Medicine, Seoul National University Hospital, Seoul, South Korea Department of Rehabilitation Medicine, Seoul National University College of Medicine, Seoul, South Korea

b

Abbreviations CP EDACS DDS GMFCS MACS CFCS BMI BMD VFSS SWAL-QOL FOIS BMI GERD

cerebral palsy eating and drinking ability classification system dysphagia disorder survey gross motor function classification system manual ability classification system communication function classification system body mass index bone mineral density. videofluoroscopy swallowing study swallowing quality of life functional oral intake scale body mass index gastroesophageal reflux disease

Introduction Adults and children with cerebral palsy (CP) have a high prevalence of problems in their swallowing function (Balandin, Hemsley, Hanley, & Sheppard, 2009; Samuels & Chadwick, 2006; Sheppard, 2002; Yi, Oh, Seo, Shin, & Bang, 2019). Individuals with CP are usually evaluated as children to assess any swallowing problems using videofluoroscopy swallowing study (VFSS) (Arvedson, 2000, 2008; Van Den Engel-Hoek et al., 2014) or the Dysphagia Disorder Survey (DDS) (Calis et al., 2008; Scott, 2014; Sheppard, 2002). As individuals transition into adulthood, the dietary patterns established in childhood usually remain unaltered without adequate examination and treatment (Bagatell, Chan, Rauch, Thorpe, et al., 2017; Nieuwenhuijsen, Donkervoort, Nieuwstraten, An, & Donkervoort, 2009; Seo et al., 2018; Young, 2007). Adults with CP, even those who maintain the same dietary way, may experience gradual changes in their swallowing and mealtime capabilities (Balandin et al., 2009; Sheppard, 2002). Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00009-X

Copyright © 2023 Elsevier Inc. All rights reserved.

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One prior qualitative study regarding swallowing difficulty in adults with CP reported that adults with CP can experience gradual changes in their swallowing ability from 30 years of age (Balandin et al., 2009). Considering the consequence of aspiration risk on general health, swallowing problem is a challenging issue across all CP populations. Dysphagia symptoms are frequent and can also have a profound effect on swallowingrelated quality of life (QOL) in adults with CP (Yi, Oh, et al., 2019). The Eating and Drinking Ability Classification System (EDACS) is a recently developed, complementary addition to the CP functional classification system to contribute another dimension to the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS) (Benfer et al., 2017b; Scott, 2014; Sellers, Mandy, Pennington, Hankins, & Morris, 2014; Tschirren et al., 2018). As a measure of dysphagia and independence of eating, the EDACS uses five distinct levels to reflect the “safety (aspiration and choking)” and “efficiency (amount of food and time taken to eat)” and a three-level scale to depict the level of assistance required to bring food or liquid into the mouth (independent, requires assistance, and totally dependent). This method was developed for children aged
3 years and also validated in adults with CP (Hyun, Yi, & Shin, 2021; Sellers et al., 2014). According to the EDACS, nutritional supplements should be considered in adults with CP as swallowing problems are associated with health status, sarcopenia (Peterson, Zhang, Haapala, Wang, & Hurvitz, 2015; Tosi, Maher, Moore, Goldstein, & Aisen, 2009; Verschuren et al., 2018), low body mass index (BMI) (3,9), bone mineral density (BMD) (Peterson et al., 2015), and aspiration lung disease (Arvedson, 2013; Balandin et al., 2009; Thomson et al., 2016; Weir et al., 2007). In this chapter, swallowing problems throughout the life span and the classification systems used to describe swallowing problems in people with CP are discussed.

Swallowing problems in individuals with cerebral palsy: A lifelong problem Individuals with CP experience several health issues associated with neurological disorders (Krigger, 2006; Mutch, Alberman, Hagberg, Kodama, & Perat, 1992). The prevalence of dysphagia symptoms in children with CP is approximately 58%–90% (Dahl, Thommessen, Rasmussen, & Selberg, 1996; Fung et al., 2002; Reilly, Skuse, & Poblete, 1996; Stallings, Charney, Davies, & Cronk, 1993). Feeding problems are associated with poor health status and growth in children with CP (Fung et al., 2002; Stallings et al., 1993). Children with oropharyngeal dysphagia at 18–24 months of life showed low Z-scores for weight and BMI at 36 months of age (Benfer et al., 2016). In children with CP, silent aspiration is significantly associated with developmental delay, neurologic impairment, enteral feeding, and aspiration lung disease (Weir, McMahon, Taylor, & Chang, 2011). As life expectancy in children with CP is extended by treatments such

Swallowing problems in adults with cerebral palsy

as gastrostomy tubes and nutritional supplements, CP is no longer considered to be limited to childhood (Hemming, Hutton, & Pharoah, 2006; Himmelmann & Sundh, 2015; Oskoui, 2012; Westbom, Bergstrand, Wagner, & Nordmark, 2011; Young, 2007). In some children, swallowing problems are chronic and persist in adulthood (Sheppard, 2002). Adults and children with CP have a high prevalence of swallowing difficulties (Balandin et al., 2009; Balandin & Morgan, 1997; Yi, Oh, et al., 2019; Seo et al., 2018; Sheppard, 2002). Eating and swallowing, which are not always associated with gross motor function, are other dimensions of challenging conditions in adults with CP (Hyun et al., 2021). Dysphagia can present as oral, oropharyngeal, and/or esophageal phase disorders (Arvedson, 2013; Benfer et al., 2016, 2017a; Edvinsson & Lundqvist, 2016; Seo et al., 2018; Serel Arslan, Demir, & Karaduman, 2018). The process of introduction and maintenance of food or liquid in the mouth, oral preparation and oral transport of the food, and pharyngeal transport requires inclusive motor function, which may be difficult for adults with CP (East, Nettles, Vansant, & Daniels, 2014; Erasmus, Van Hulst, Rotteveel, Willemsen, & Jongerius, 2012; Peterson Haak, Hidecker, Li, & Paneth, 2014; Sheppard, 2002; Somerville et al., 2008). Difficulties with eating and swallowing can occur unexpectedly, and in these patients, the symptoms may be disproportionate to their other disabilities. Dysphagia in CP can occur due to abnormal neurological maturation, motor impairment, poor intraoral sensations, or esophageal motility disorders and can be exacerbated by gastroesophageal reflux disease (Calis et al., 2008; Davis et al., 2016; Durvasula, O’Neill, & Richter, 2014). If nutritional intake is insufficient due to dysphagia in persons with CP, weight loss can be induced by affecting development (Samson-Fang & Stevenson, 2000; Sullivan et al., 2006; Troughton & Hill, 2001). In addition, pneumonia or chronic lung disorders due to aspiration may occur (Arvedson, 2013; Erasmus et al., 2012).

Characteristics of dysphagia symptoms and their impact on quality of life in adults with cerebral palsy In children with CP, many studies have reported changes in swallowing function according to disease etiology, age, and functional status (Arvedson, 2013; Benfer et al., 2016; Edvinsson & Lundqvist, 2016; Reilly et al., 1996; Senner, Logemann, Zecker, & Gaebler-Spira, 2004; Weir et al., 2011; Yilmaz, Basar, & Gisel, 2004). In contrast, limited studies have demonstrated such problems in adults with CP (Balandin et al., 2009; Yi, Oh, et al., 2019; Seo et al., 2018; Yi, Jung, & Bang, 2019). Balandin et al. interviewed 32 adults with CP and reported that adults with CP more than 30 years of age showed limited experience in mealtime, anxiety due to prolonged mealtime duration, reduced social interaction, and restricted food choices. They also reported that these problems

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worsened gradually as the patients became older (Balandin et al., 2009). Recently, knowledge of the severity and frequency of dysphagia symptoms and their impact on participation and QOL have broadened the understanding of CP manifestations in community-dwelling adults with CP (Yi, Oh, et al., 2019). In a previous study, among pharyngeal symptoms in adults with CP, choking on food was the most frequently reported problem, followed by coughing and choking on liquid (Table 1) (Yi, Oh, et al., 2019). Among oral symptoms, chewing problems were the most frequent, followed by food dribbling from the mouth or sticking to the mouth, in adults with CP (Yi, Oh, et al., 2019). Swallowing-related QOL also worsened with age (Yi, Oh, et al., 2019). Mealtime duration was also longer in adults with CP than in healthy adults, and individuals who required more time to eat a meal had low BMI (Yi, Oh, et al., 2019).

Nutritional problems and sarcopenia in adults with cerebral palsy Nutritional factors are contributing factors to the development of sarcopenia in adults with CP (Verschuren et al., 2018). Swallowing problems and physical and mental disorders that limit activities such as buying and cooking food are commonly observed reasons for nutritional deficits in individuals with CP (Rempel, 2015). Although adequate dietary protein and vitamin D intake can be an important key factor in preventing sarcopenia in individuals with CP, swallowing problems can hamper nutritional intake in this population. Swallowing disorders result in poor ability to not only swallow food and drinks safely but also eat an adequate amount to maintain body weight (Stewart, 2003). In a previous study, the average meal time was longer in adults with CP than in healthy adults, and low BMI was observed in people with CP who required more than 45 min to eat a meal (Yi, Oh, et al., 2019). Individuals with CP are also at an increased risk of hypovitaminosis D-induced osteopenia and bone metabolism disorders (Cremer, Hurvitz, & Peterson, 2017; Peterson, Haapala, Chaddha, & Hurvitz, 2014; Verschuren et al., 2018; Whitney et al., 2018; Yi, Jung, & Bang, 2019). Considering the role of malnutrition in the pathology of sarcopenia, appropriate intake/supplementation of musculoskeletal nutrients including protein, vitamin D, calcium, phosphorus, and magnesium is important to prevent muscle loss (21,62). In addition to increasing the total amount of protein or essential amino acids during meals, increasing the rate of the amino acid lysine in low protein intake can help reduce the anabolic response due to aging (Casperson, Sheffield-Moore, Hewlings, & Paddon-Jones, 2012; Verschuren et al., 2018).

Table 1 Prevalence of dysphagia symptoms in adults with cerebral palsy (N ¼ 117). Symptom

Almost always

Often

Sometimes

Hardly ever

Never

Converted scorea

7 (6.0) 8 (6.8) 2 (1.7)

33 (28.2) 24 (20.5) 26 (22.0)

50 (42.7) 42 (35.9) 54 (46.2)

20 (17.1) 34 (29.1) 24 (20.5)

7 (6.0) 9 (7.7) 11 (9.4)

47.2 52.6 53.4

5 (4.3)

22 (18.8)

52 (44.4)

26 (22.2)

12 (10.3)

53.8

2 (1.7)

21 (17.9)

50 (42.7)

30 (25.6)

14 (12.0)

57.1

4 (3.4)

19 (16.2)

46 (39.3)

36 (30.8)

12 (10.3)

57.1

3 (2.6)

6 (5.1)

31 (26.5)

47 (40.2)

30 (25.6)

70.3

18 (15.4)

23 (19.7)

29 (24.8)

35 (29.9)

12 (10.3)

50.0

9 (7.7)

26 (22.2)

28 (23.9)

37 (31.6)

17 (14.5)

55.8

2 (1.7)

22 (18.8)

43 (36.8)

37 (31.6)

13 (11.1)

57.9

11 (9.4) 0 (0)

17 (14.5) 6 (5.1)

25 (21.4) 33 (28.2)

45 (38.5) 45 (38.5)

19 (16.2) 33 (28.2)

59.4 72.4

5 (4.3)

25 (21.4)

39 (33.3)

35 (29.9)

13 (11.1)

55.6

5 (4.3)

22 (18.8)

43 (36.8)

34 (29.1)

13 (11.1)

56.0

Pharyngeal symptoms

Choking on food Coughing Choking on liquid Coughing out food or liquid stuck in the mouth Having to clear the throat Food sticking in the throat Gagging Oral symptoms

Chewing problems Food or liquid dribbling from the mouth Food sticking in the mouth Drooling Food or liquid coming out through the nose Salivary symptoms

Thick saliva or phlegm Excess saliva or phlegm

Prevalence is expressed as frequency (percentage). a Dysphagia symptom scores are shown after conversion to a 0–100 scale, with lower scores indicating symptoms with stronger effect on quality of life. From Yi, Y. G., Oh, B. M., Seo, H. G., Shin, H. I., & Bang, M. S. (2019). Dysphagia-related quality of life in adults with cerebral palsy on full oral diet without enteral nutrition. Dysphagia, 34 (2), 201–209. https://doi.org/10.1007/s00455-018-09972-7, with permission.

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Assessment of dysphagia in adults with cerebral palsy Individuals with CP have a high incidence of GERD and dysphagia. Symptoms of dysphagia generally include food left in the mouth, prolonged eating time, coughing, gagging, or throat clearing during or after a meal, gurgly voice, and failure to consume the entire meal (Stewart, 2003). Sheppard et al. reported that BMI is a strong predictor of the severity of dysphagia in individuals with mental retardation. They reported that the lower BMI in this population is associated with suffering from dysphagia (Sheppard, Liou, Hochman, Laroia, & Langlois, 1988). In line with this study, the Nutrition and Swallowing Checklist, a screening tool for nutritional and swallowing risks in individuals with intellectual disability, was developed in 2003 (Stewart, 2003). The DDS is a test of functional capabilities developed and standardized for adults with lifelong disabilities (Calis et al., 2008; Sheppard, 2002). It is designed to be sensitive to developmental disabilities and has been widely used to evaluate dysphagia in children and adults with CP (Sheppard et al., 1988). Although screening tools for swallowing difficulties and undernutrition in children with CP have been recently validated, these tools are not widely used for clinical and research purposes (Bell et al., 2019). A VFSS dynamically visualizes the phases of swallowing (Arvedson, 2013). It is generally accepted as the gold standard for evaluating dysphagia (Kim et al., 2014). The videofluoroscopic dysphagia scale was developed to measure these VFSS findings as quantitative scores objectively. The videofluoroscopic dysphagia scale has been reported to be valid in stroke (Chun et al., 2011) and in various etiologies (Kim et al., 2014).

Use of the eating and drinking ability classification system in people with cerebral palsy The EDACS (Fig. 1) was developed in response to the need to evaluate dysphagia in individuals with CP. It is complementary to the GMFCS, MACS, and CFCS (Table 2) to comprehensively evaluate the functional performance of individuals with CP. As a measure of dysphagia and independence in eating, the EDACS employs a five-level ordinal scale (Table 2) to identify key features of safety (aspiration and choking) and efficiency (amount of food and time taken to eat) and a three-level scale to depict the level of assistance required to bring food or fluid to the mouth (independent, requires assistance, and totally dependent). EDACS was developed for children with CP and has high inter-rater reliability between professionals and between parents and professionals. It was initially validated in children with CP based on its correlation with the GMFCS (Sellers et al., 2014). Recently, several studies have demonstrated the high reliability and validity of the EDACS in older children including preschool-aged children, and adults with CP (Benfer et al., 2017b; Hyun et al., 2021; Scott, 2014; Tschirren et al., 2018).

Swallowing problems in adults with cerebral palsy

Eating and Drinking Ability Classification System - Algorithm Is the individual able to swallow food and drink without risk of aspiration?

Is the individual able Yes to bite and chew on hard lumps of food without a risk of choking? Yes

No

Is the individual able to eat a meal in the same time as peers? Yes

Level I Eats and drinks safely and efficiently

No

Level III Eats and drinks with some limitations to safety; there maybe limitations to efficiency.

No

Yes

Level IV Eats and drinks with significant limitations to safety.

Can risks of aspiration be managed to eliminate harm to the individual? No

Level V Unable to eat or drink safely - tube feeding may be considered to provide nutrition.

Level II Eats and drinks safely but with some limitations to efficiency.

Fig. 1 Algorithm for eating and drinking ability classification system. (Clinical algorithm of classifying eating and drinking ability classification system from www.edacs.org.)

The EDACS has adequate inter-rater reliability in adults aged >22 years with CP (Hyun et al., 2021). It can be rated through interviews by professionals and caregivers or by self-report (Hyun et al., 2021) in the adult population. Written instructions from developers are provided in the EDACS manual in multiple languages and can be found on their official website (www.edacs.org).

Nutritional supplements according to the eating and drinking ability classification system in adults with cerebral palsy EDACS level V is defined as the inability to eat or drink safely, and tube feeding is often considered to provide nutrition in such cases. In persons with EDACS level V, administration of adequate calories should be performed by tube feeding, and nutritional supplements, including protein, calcium, vitamin D, magnesium, and phosphorus, could also be considered. EDACS levels III and IV indicate that people cannot eat and drink safely. According to their BMI and severity of sarcopenia, musculoskeletal supplements can be provided and fluid modification, chopping, or grinding of food can be considered. In people with EDACS level II, mealtime duration can be evaluated as efficiency is the main problem. As nutritional deficit and chronic immobilization increase the risk of metabolic syndrome

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Table 2 The five levels of functional classification systems for cerebral palsy. Level

GMFCS

MACS

CFCS

EDACS

I

Walks without limitations

Handles objects easily and successfully

Eats and drinks safely and efficiently

II

Walks with limitations

III

Walks using a handheld mobility device

Handles most objects but with somewhat reduced quality and/or speed or achievement Handles objects with difficulty; needs help to prepare and/or modify activities

Sends and receives with familiar and unfamiliar partners effectively and efficiently Sends and receives with familiar and unfamiliar partners but may need extra time

IV

Self-mobility with limitations; may use powered mobility Transported in a manual wheelchair

V

Handles a limited selection of easily managed objects in adapted situations Does not handle objects and has severely limited ability to perform even simple actions

Eats and drinks safely with some limitations to efficiency

Sends and receives with familiar partners effectively, but not with unfamiliar partners Inconsistently sends and/or receives even with familiar partners

Eats and drinks with significant limitations to safety

Seldom effectively sends and receives, even with familiar partners

Unable to eat or drink safely— tube feeding may be considered to provide nutrition

Eats and drinks with some limitations to safety; there may be limitations to efficiency

GMFCS: Gross Motor Function Classification System, MACS: Manual Ability Classification System, CFCS: Communication Function Classification System, EDACS: Eating and Drinking Ability Classification System. From Hyun, S. E., Yi, Y. G., & Shin, H. I. (2021). Reliability and validity of the eating and drinking ability classification system in adults with cerebral palsy. Dysphagia, 36(3), 351–361. https://doi.org/10.1007/s00455-020-10141-y with permission.

and osteoporosis, individuals with EDACS level
III should regularly undergo BMD assessment to evaluate the need for adequate nutritional supplements (Tosi et al., 2009).

Application in other neurological conditions In adults with other childhood-onset disabilities, the GMFCS or EDACS level may reflect their motor function and nutritional status. Persons with childhood-onset

Swallowing problems in adults with cerebral palsy

disabilities are likely to have decreased functional levels and poor nutritional status since childhood. Tube feeding or nutritional supplementation can be considered according to ambulation status or EDACS level. In these populations, regular nutritional checkups, evaluation of dietary conditions, BMD assessment, and evaluation of muscle mass are required.

Other components of interest In this chapter, we describe the swallowing disorder in individuals with cerebral palsy and how we can measure the swallowing function. Studies have also shown that nutritional status in individuals with cerebral palsy is also associated with their motor function, which can be evaluated using the Gross Motor Function Classification System. Ambulatory status is associated with bone health and nutritional status, which affects the amount and type of required nutritional supplements. Anticonvulsant use, gonadal status, and use of percutaneous endoscopic gastrostomy feeding are also associated with sarcopenia and bone health in this population. Clinical studies have also shown that adequate physical exercise can also prevent osteopenia and sarcopenia in this population. It has also been reported that nutritional supplementation combined with a back extensor strengthening exercise was effective in spinal sarcopenia.

Mini-dictionary of terms • • • • •

Hypovitaminosis: A vitamin level that is below normal. It can be caused by several conditions including inadequate nutrition of vitamins. Sarcopenia: Loss of skeletal muscle mass or poor muscle quality associated with aging, malnutrition, decreased activity levels, and diseases such as malignancies. Musculoskeletal nutrients: Protective nutrients that are important for musculoskeletal health. Dysphagia: Difficulty in swallowing. Aspiration: Passage of materials below the vocal folds.

Key facts on dysphagia in adults with cerebral palsy Adults and children with cerebral palsy (CP) have a high prevalence of problems in swallowing function. Among the pharyngeal symptoms reported by adults with CP, choking on food was the most frequently reported problem, followed by coughing and choking on liquid. Among oral symptoms, chewing problems were the most frequent, followed by food dribbling from the mouth or sticking to the mouth, in adults with CP.

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Nutritional factors are some of the most important contributing factors to the development of sarcopenia in adults with CP. Individuals with CP have an increased risk of hypovitaminosis D-induced osteopenia and impaired bone metabolism. The Eating and Drinking Ability Classification System is a reliable and valid tool for evaluating the ability of adults to chew and swallow, the food or fluid texture manageable by them, changes in breathing associated with swallowing, choking symptoms, and the level of assistance required to bring food or liquids into the mouth. Nutritional supplements can be considered according to the Eating and Drinking Ability Classification System in adults with cerebral palsy.

Summary points • • •

• • •

•

In adults with cerebral palsy, dysphagia symptoms are frequent and can have a profound effect on swallowing-related quality of life. The Eating and Drinking Ability Classification System is a reliable and valid tool for classifying eating, drinking, and swallowing abilities in adults with cerebral palsy. As in children with cerebral palsy, in adults with cerebral palsy, the Eating and Drinking Ability Classification System can be rated either using interviews by professionals/ caregivers or by self-report. Videofluoroscopy swallowing study and the Dysphagia Disorders Survey can be used to evaluate swallowing function in adults with cerebral palsy. Individuals with CP also have an increased risk of hypovitaminosis D-induced osteopenia and impaired bone metabolism. Appropriate intake/supplementation of musculoskeletal nutrients, including protein, calcium, vitamin D, magnesium, and phosphorus, is important for preventing muscle loss. Nutritional supplements can be considered according to the Eating and Drinking Ability Classification System and other evaluation results in adults with cerebral palsy.

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Himmelmann, K., & Sundh, V. (2015). Survival with cerebral palsy over five decades in western Sweden. Developmental Medicine and Child Neurology, 57(8), 762–767. https://doi.org/10.1111/dmcn.12718. Hyun, S. E., Yi, Y. G., & Shin, H. I. (2021). Reliability and validity of the eating and drinking ability classification system in adults with cerebral palsy. Dysphagia, 36(3), 351–361. https://doi.org/10.1007/ s00455-020-10141-y. Kim, J., Oh, B. M., Kim, J. Y., Lee, G. J., Lee, S. A., & Han, T. R. (2014). Validation of the videofluoroscopic dysphagia scale in various etiologies. Dysphagia, 29(4), 438–443. https://doi.org/10.1007/s00455014-9524-y. Krigger, K. W. (2006). Cerebral palsy: An overview. American Family Physician, 73(1), 91–100. Mutch, L., Alberman, E., Hagberg, B., Kodama, K., & Perat, M. V. (1992). Cerebral palsy epidemiology: Where are we now and where are we going? Developmental Medicine and Child Neurology, 34(6), 547–551. https://doi.org/10.1111/j.1469-8749.1992.tb11479.x. Nieuwenhuijsen, C., Donkervoort, M., Nieuwstraten, W., An, C., & Donkervoort, M. (2009). Experienced problems of young adults with cerebral palsy: Targets for rehabilitation care. Archives of Physical Medicine and Rehabilitation, 90(11), 1891–1897. https://doi.org/10.1016/j.apmr.2009.06.014. Oskoui, M. (2012). Growing up with cerebral palsy: Contemporary challenges of healthcare transition. Canadian Journal of Neurological Sciences, 39(1), 23–25. https://doi.org/10.1017/s0317167100012634. Peterson Haak, L. M., Hidecker, M. J. C., Li, M., & Paneth, N. (2014). Cerebral palsy and aging. Developmental Medicine and Child Neurology, 51(Suppl. 4), 16–23 (0 4). Peterson, M. D., Haapala, H. J., Chaddha, A., & Hurvitz, E. A. (2014). Abdominal obesity is an independent predictor of serum 25-hydroxyvitamin D deficiency in adults with cerebral palsy. Nutrition and Metabolism, 11, 22. https://doi.org/10.1186/1743-7075-11-22. Peterson, M. D., Zhang, P., Haapala, H. J., Wang, S. C., & Hurvitz, E. A. (2015). Greater adipose tissue distribution and diminished spinal musculoskeletal density in adults with cerebral palsy. Archives of Physical Medicine and Rehabilitation, 96(10), 1828–1833. https://doi.org/10.1016/j.apmr.2015.06.007. Reilly, S., Skuse, D., & Poblete, X. (1996). Prevalence of feeding problems and oral motor dysfunction in children with cerebral palsy: A community survey. Journal of Pediatrics, 129(6), 877–882. https://doi.org/ 10.1016/s0022-3476(96)70032-x. Rempel, G. (2015). The importance of good nutrition in children with cerebral palsy. Physical Medicine and Rehabilitation Clinics of North America, 26(1), 39–56. https://doi.org/10.1016/j.pmr.2014.09.001. Samson-Fang, L. J., & Stevenson, R. D. (2000). Identification of malnutrition in children with cerebral palsy: Poor performance of weight-for-height centiles. Developmental Medicine and Child Neurology, 42(3), 162–168. https://doi.org/10.1017/s0012162200000293. Samuels, R., & Chadwick, D. D. (2006). Predictors of asphyxiation risk in adults with intellectual disabilities and dysphagia. Journal of Intellectual Disability Research, 50(5), 362–370. https://doi.org/10.1111/j.13652788.2005.00784.x. Scott, S. (2014). Classifying eating and drinking ability in people with cerebral palsy. Developmental Medicine and Child Neurology, 56(3), 201. https://doi.org/10.1111/dmcn.12380. Sellers, D., Mandy, A., Pennington, L., Hankins, M., & Morris, C. (2014). Development and reliability of a system to classify the eating and drinking ability of people with cerebral palsy. Developmental Medicine and Child Neurology, 56(3), 245–251. https://doi.org/10.1111/dmcn.12352. Senner, J. E., Logemann, J., Zecker, S., & Gaebler-Spira, D. (2004). Drooling, saliva production, and swallowing in cerebral palsy. Developmental Medicine and Child Neurology, 46(12), 801–806. https://doi.org/ 10.1017/s0012162204001409. Seo, H. G., Yi, Y. G., Choi, Y.-A., Leigh, J., Yi, Y., Kim, K., et al. (2018). Oropharyngeal dysphagia in adults with dyskinetic cerebral palsy and cervical dystonia: A preliminary study. Archives of Physical Medicine and Rehabilitation, 1–7. Serel Arslan, S., Demir, N., & Karaduman, A. A. (2018). Both pharyngeal and esophageal phases of swallowing are associated with recurrent pneumonia in pediatric patients. The Clinical Respiratory Journal, 12(2), 767–771. https://doi.org/10.1111/crj.12592. Sheppard, J. J. (2002). Swallowing and feeding in older people with lifelong disability. Advances in Speech Language Pathology, 4(2), 119–121. https://doi.org/10.1080/14417040210001669341.

Swallowing problems in adults with cerebral palsy

Sheppard, J. J., Liou, J., Hochman, R., Laroia, S., & Langlois, D. (1988). Nutritional correlates of dysphagia in individuals institutionalized with mental retardation. Dysphagia, 3(2), 85–89. https://doi.org/ 10.1007/BF02412425. Somerville, H., Tzannes, G., Wood, J., Shun, A., Hill, C., Arrowsmith, F., et al. (2008). Gastrointestinal and nutritional problems in severe developmental disability. Developmental Medicine and Child Neurology, 50(9), 712–716. https://doi.org/10.1111/j.1469-8749.2008.03057.x. Stallings, V. A., Charney, E. B., Davies, J. C., & Cronk, C. E. (1993). Nutrition-related growth failure of children with quadriplegic cerebral palsy. Developmental Medicine and Child Neurology, 35(2), 126–138. https://doi.org/10.1111/j.1469-8749.1993.tb11614.x. Stewart, L. (2003). Development of the nutrition and swallowing checklist, a screening tool for nutrition risk and swallowing risk in people with intellectual disability. Journal of Intellectual and Developmental Disability, 28(2), 171–187. https://doi.org/10.1080/1366825031000106945. Sullivan, P. B., Alder, N., Bachlet, A. M., Grant, H., Juszczak, E., Henry, J., et al. (2006). Gastrostomy feeding in cerebral palsy: Too much of a good thing? Developmental Medicine and Child Neurology, 48(11), 877–882. https://doi.org/10.1017/S0012162206001927. Thomson, J., Hall, M., Ambroggio, L., Stone, B., Srivastava, R., Shah, S. S., et al. (2016). Aspiration and non-aspiration pneumonia in hospitalized children with neurologic impairment. Pediatrics, 137(2), e20151612. https://doi.org/10.1542/peds.2015-1612. Tosi, L. L., Maher, N., Moore, D. W., Goldstein, M., & Aisen, M. L. (2009). Adults with cerebral palsy: A workshop to define the challenges of treating and preventing secondary musculoskeletal and neuromuscular complications in this rapidly growing population. Developmental Medicine and Child Neurology, 51(Suppl. 4), 2–11. https://doi.org/10.1111/j.1469-8749.2009.03462.x. Troughton, K. E., & Hill, A. E. (2001). Relation between objectively measured feeding competence and nutrition in children with cerebral palsy. Developmental Medicine and Child Neurology, 43(3), 187–190. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/11263689 https://doi.org/10.1111/j.14698749.2001.tb00185.x. Tschirren, L., Bauer, S., Hanser, C., Marsico, P., Sellers, D., & van Hedel, H. J. A. (2018). The eating and drinking ability classification system: Concurrent validity and reliability in children with cerebral palsy. Developmental Medicine and Child Neurology, 60(6), 611–617. https://doi.org/10.1111/dmcn.13751. Van Den Engel-Hoek, L., Erasmus, C. E., Van Hulst, K. C. M., Arvedson, J. C., De Groot, I. J. M., & De Swart, B. J. M. (2014). Children with central and peripheral neurologic disorders have distinguishable patterns of dysphagia on videofluoroscopic swallow study. Journal of Child Neurology, 29(5), 646–653. https://doi.org/10.1177/0883073813501871. Verschuren, O., Smorenburg, A. R. P., Luiking, Y., Bell, K., Barber, L., & Peterson, M. D. (2018). Determinants of muscle preservation in individuals with cerebral palsy across the lifespan: A narrative review of the literature. Journal of Cachexia, Sarcopenia and Muscle, 9(3), 453–464. https://doi.org/10.1002/ jcsm.12287. Weir, K., McMahon, S., Barry, L., Ware, R., Masters, I. B., & Chang, A. B. (2007). Oropharyngeal aspiration and pneumonia in children. Pediatric Pulmonology, 42(11), 1024–1031. https://doi.org/10.1002/ ppul.20687. Weir, K. A., McMahon, S., Taylor, S., & Chang, A. B. (2011). Oropharyngeal aspiration and silent aspiration in children. Chest, 140(3), 589–597. https://doi.org/10.1378/chest.10-1618. Westbom, L., Bergstrand, L., Wagner, P., & Nordmark, E. (2011). Survival at 19 years of age in a total population of children and young people with cerebral palsy. Developmental Medicine and Child Neurology, 53(9), 808–814. https://doi.org/10.1111/j.1469-8749.2011.04027.x. Whitney, D. G., Hurvitz, E. A., Ryan, J. M., Devlin, M. J., Caird, M. S., French, Z. P., et al. (2018). Noncommunicable disease and multimorbidity in young adults with cerebral palsy. Clinical Epidemiology, 10, 511–519. https://doi.org/10.2147/CLEP.S159405. Yi, Y. G., Jung, S. H., & Bang, M. S. (2019). Emerging issues in cerebral palsy associated with aging: A physiatrist perspective. Annals of Rehabilitation Medicine, 43(3), 241–249. https://doi.org/10.5535/ arm.2019.43.3.241.

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Yi, Y. G., Oh, B. M., Seo, H. G., Shin, H. I., & Bang, M. S. (2019). Dysphagia-related quality of life in adults with cerebral palsy on full oral diet without enteral nutrition. Dysphagia, 34(2), 201–209. https://doi.org/ 10.1007/s00455-018-09972-7. Yilmaz, S., Basar, P., & Gisel, E. G. (2004). Assessment of feeding performance in patients with cerebral palsy. International Journal of Rehabilitation Research, 27(4), 325–329. https://doi.org/ 10.1097/00004356-200412000-00013. Young, N. L. (2007). The transition to adulthood for children with cerebral palsy: What do we know about their health care needs? Journal of Pediatric Orthopedics, 27(4), 476–479. https://doi.org/10.1097/01. bpb.0000271311.87997.e7.

Further reading Mus-Peters, C., Huisstede, B., Noten, S., Hitters, M., van der Slot, W., & van den Berg-Emons, R. (2019). Low bone mineral density in ambulatory persons with cerebral palsy? A systematic review. Disability and Rehabilitation, 41(20), 2392–2402. https://doi.org/10.1080/09638288.2018.1470261. Pavithran, J., Puthiyottil, I. V., Narayan, M., Vidhyadharan, S., Menon, J. R., & Iyer, S. (2019). Observations from a pediatric dysphagia clinic: Characteristics of children at risk of aspiration pneumonia. Laryngoscope, 129(11), 2614–2618. https://doi.org/10.1002/lary.27654.

PART V

Dietary neurotoxins

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CHAPTER 19

Dietary neurotoxins: An overview Ojaskumar D. Agrawala,b and Yogesh A. Kulkarnia a

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM’s NMIMS, Mumbai, Maharashtra, India Vivekanand Education Society’s College of Pharmacy, Chembur (E), University of Mumbai, Mumbai, India

b

Abbreviations 5-MOP 8-MOP ADHD FDA FFDCA MAO NMDA PAHs Se

5-methoxypsoralen 8-methoxypsoralen attention-deficit/hyperactivity disorder Food and Drug Administration The Federal Food Drug and Cosmetic Act monoamine oxidase N-methyl-D-aspartic acid polycyclic aromatic hydrocarbons selenium

Introduction A number of food items containing toxins that are produced as a result of processing or handling, as naturally occurring constituents, or as unwanted adverse reactions to those foods are comparatively low (Dolan, Matulka, & Burdock, 2010). Many a time, the consumption of beverages and foods leads to intoxication and disease. The various reasons can be attributed to it like the presence of toxic substances naturally in the food, microbial toxins, residue of different types, or maybe contaminants present in the food or beverages (Costa, Guizzetti, Costa-Mallen, & Vitalone, 2002). The chances of toxicity because of eating food containing toxins are relatively less; rather, chances of toxicity are due to contamination with toxic substances, overconsumption, or an allergy to that particular food (Dolan et al., 2010). As the standard literature had mentioned, monosodium glutamate was reported with severe adverse side effects mainly in experimental animals including induction of diabetes, hepatotoxic effects, obesity, neurotoxic effects, and genotoxic effects (Kazmi, Fatima, Perveen, & Malik, 2017). It is always advisable to use normal salt instead of monosodium glutamate as it may be reported and associated with severe side effects. A young child’s nervous system can show hazardous effect on the consumption of excitotoxic food additives (Olney, 1981, 1984). Non-nutritional additives in food play a vital role in attention-deficit/hyperactivity disorder (ADHD). The calculation of these additives is based upon the analysis of content in food items and approximate ratio of absorption from the gut (Lau, McLean, Williams, & Howard, 2006). Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00037-4

Copyright © 2023 Elsevier Inc. All rights reserved.

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Glutamate is considered as the most commercially added excitotoxin that can freely penetrate brain areas and immediately destroy the available neurons by hyperactivating the NMDA Glu receptor. In shellfish, the high content of domoic acid causes food poisoning that causes brain damage and memory impairment. A neurodegenerative disease called neurolathyrism occurs due to the ingestion of legumes (Olney, 1994). Recent findings pertaining to the potential role of excitotoxic mechanisms in developmental neuropathology need to be reviewed with special emphasis on hypoxic–ischemic and related forms of neuropathology, which appear to be mediated through NMDA receptors (Olney, 1993). Some amino acids such as glutamate and aspartate and some of their structural analogs are neurotransmitter candidates, all of which have both neuroexcitatory and neurotoxic activities (Olney, 1982). Preliminary evidence that domoate powerfully induces a kainate-like seizure-brain damage syndrome in experimental animals further supports the involvement of kainate receptors in domoate neurotoxicity (Olney, 1990). Stegink and co-researchers have reported that very large doses of aspartame (or its components—aspartate, phenylalanine, and methanol) produce deleterious effects in sensitive animal species (Stegink, 1987). For some neurotoxins that are classified as classical neurotoxins like snake venom, bacterial toxins, and heavy metals, the mechanism by which they are mediated is relatively known; also, their antidotes are generally available. Food additives, manufacturing components, and air pollutants are classified as atypical neurotoxins, and they showed the effect on the nervous system, which is not easy to detect and may be extended for a long period (Tseng, 2021).

Regulatory accommodation Foods must have hedonic, nutritional, and satiety value, and because of this, it is considered as edible; otherwise, there would be no additional benefit to consume these foods at a cost (Dolan et al., 2010). The Federal Food Drug and Cosmetic Act (FFDCA) defined the term “food” as (a) articles used for food or drink for humans or other animals, (b) chewing gum, and (c) articles used for components of any such article.

Factors driving the acceptance of certain foods A small subset of plant volatile metabolites was sensed by humans and animals. These volatiles provide essential and sensory cues for the information about the nutritional status of the particular foods (Goff & Klee, 2006). For example, particular odor profile of tomatoes like grassy tomato, normal tomato, and green tomato is derived from trans-hexenal,

Dietary neurotoxins: An overview

cis-3-hexenal, and cis-3-hexenol along with some visual cues, and this will encourage repeated or overconsumption of a pleasing food (Dolan et al., 2010).

Incorporation of toxins during growth, processing, or storage Contaminants from environment Methylmercury in seafood Ingestion and exposure to elemental mercury are comparatively rare. Inhalation of fumes of mercury led to the deterioration of mental health, which is called “mad hatter syndrome” (Waldron, 1973, 1983). Exposure to methylmercury may result in ataxia, neurological paraesthesia, hearing defects, dysarthria, and death. Also, for the newborn baby, the developmental delay was reported if the mother was previously exposed to methylmercury (Carrington & Bolger, 2002). Selenium in grain In food chain, the selenium enters by microorganisms and plants, which convert inorganic selenium (Se) to organically bound form (Sors, Ellis, & Salt, 2005). Selenosis is the selenium toxicity caused due to excessive intake of selenium-containing food (approx. 3–6 mg of selenium per day) (Yang, Wang, Zhou, & Sun, 1983). The general symptom of selenosis includes deformity, loss of hair, and loss of nails. Some symptoms include diarrhea, increase in blood selenium levels, bodily secretions that have garlic-like odor, fatigue, peripheral neuropathy, irritability, and skin lesions (Reilly, 2018).

Naturally formed substances Furocoumarins The furocoumarins represent a major family of natural food constituents with photomutagenic and phototoxic properties. These are mainly found in the plants that belong to the Umbelliferae (parsnip, parsley, celery, carrots) and Rutaceae (citrus fruits) families. These furocoumarins are regarded as natural pesticides as they will be produced by plants in response to stress, and this will help the plants defend against bacteria, viruses, insects, fungi, and animals (Wagstaff, 1991). As reported by Aucja and Stewart, the most three active furocoumarins in developing photodermatitis are 5-methoxypsoralen (5-MOP, bergapten), psoralen, and 8-methoxypsoralen (8-MOP, methoxsalen or xanthotoxin) (Aucja & Stewart, 1991). When exposed to the near UV light that ranges from 320 to 380 nm, the abovementioned three furocoumarins that are in linear fashion can adduct with DNA cross-links and DNA. This photoaddition resulted in cell death, chromosome aberrations, and mutations (Ashwood-Smith, Ceska, Chaudhary, Warrington, & Woodcock, 1986). As reported by Dunnick, when exposed to ultraviolet radiation, 8-MOP and 5-MOP produce skin tumors in animals (Dunnick, 1989).

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Lectins in legumes A legume mainly contains glycoproteins, and the presence of lectins has been reported in a higher proportion. Legumes include soybeans, black beans, kidney beans, lima beans, and lentils, and some grain products are the best examples of them ( Jones, 1992; Shibamoto & Bjeldanes, 1993). Lectins can bind reversibly with carbohydrates without changing their covalent structure ( Jones, 1992). Lectins have the ability to bind and agglutinate with RBCs, and considering this property, it was used to detect the blood group; hence, lectins are generally called hemagglutinins. Lectins can bind strongly to the mucosal cells and interfere with the absorption of nutrients from the intestine (Omaye, 2004). Lectins have the ability to produce intestinal malabsorption in the existence of enteric bacteria, and it was proposed that lectin toxicity is linked to supporting the growth of the bacteria in the gastrointestinal tract (Banwell, Boldt, Meyers, & Weber, 1983). The report suggested that when isolated lectins from black beans and soybeans were fed to rats, they retarded the growth; moreover, lectins from kidney beans cause death in around two weeks when fed to experimental rats (Omaye, 2004). For the availability of lectins in food, FDA has mentioned catering practices before the consumption of legumes (Buhler, 2004). Oxalic acid The oxalic acid is found in varied proportions in tea, rhubarb, purslane, parsley, spinach, broccoli, asparagus, Brussels sprouts, lettuce, celery, cauliflower, cabbage, beets, celery, coffee, peas, potatoes, beans, berries, and carrots (Deshpande, 2002; Jones, 1992) (Fig. 1). This is an organic acid, which can bind easily with calcium and any other minerals and decreases their bioavailability by making it insoluble in the intestine. Also, it has been reported that taking food that contains more amount of oxalates may decrease bone growth and can cause renal toxicity, kidney stones, diarrhea, vomiting, impaired blood clotting, convulsions, and coma ( Jones, 1992). Inside the kidney, the oxalates play an important role in the development of stones and it was supported by documented evidence that more than 60% of kidney stones reported showed the presence of calcium oxalate (Finkielstein & Goldfarb, 2006). Safrole Chemically safrole is 1-allyl-3,4-methylenedioxybenzene and is found majorly in aromatic oils of cinnamon—Cinnamomum verum, nutmeg—Myristica fragrans, and

Fig. 1 Structure of oxalic acid.

Dietary neurotoxins: An overview

camphor—Cinnamomum camphora and is also present in the oil of sassafras—Sassafras albidum (McGuffin, 1997). The most common use of safrole was in foods and flavor root beer. At around a concentration of 1% in the diet, safrole may produce bone marrow depletion, testicular atrophy, weight loss, and malignant tumors in experimental rats (Homburger & Boger, 1968). The report published by National Toxicological Program, United States, mentioned carcinogenicity in experimental animals, and safrole is evidently anticipated to be a human carcinogen (National Toxicology Program, 2004). The mechanism may involve cytochrome P450 catalyzed hydroxylation of safrole to 10 -hydroxysafrole; further, it was metabolized to electrophiles, which are highly reactive and easily bind to DNA (Wislocki, Miller, Miller, McCoy, & Rosenkranz, 1977). Sassafras is still popular among herbal teas and other preparations. For humans, 0.66 mg/kg is considered to be a hazardous dose ( Jones, 1992; Tony, 2009) (Fig. 2). Myristicin Myristicin or methoxysafrole is one of the naturally occurring acaricides and insecticides generally found in mace and nutmeg, which belongs to the Myristica spp. in different concentrations. It is also reported that dill, celery parsley, carrot, and black pepper are also having varied proportions of myristicin (Deshpande, 2002; Hallstrom & Thuvander, 1997) (Fig. 3). Myristicin is a weak inhibitor of monoamine oxidase (MAO), and it is structurally related to mescaline. It may cause some psychotropic effects like feeling of irresponsibility euphoria and freedom; also, in some cases, increased alertness has been reported. Some unpleasant indications like tremor, nausea, fear, tachycardia, and anxiety have also been reported (Hallstrom & Thuvander, 1997). FDA has not issued any guidelines pertaining to the availability of myristicin in normal food. Consumption of more than 5 g of nutmeg, which corresponds to 1–2 mg per kg body weight myristicin, has reported toxicological symptoms, which are similar to that of intoxication caused by the consumption of alcohol (Hallstrom & Thuvander, 1997).

Fig. 2 Structure of safrole.

Fig. 3 Structure of myristicin.

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Tomatine in tomatoes The different parts of plants like stems, leaves, and unripe fruits of tomato plant contain steroidal alkaloids known as α-tomatine, which contains two molecules of D-glucose along with D-galactose and D-xylose. The report suggested that tomatine has toxic effects on different types of fungi, and considering this property, it is acting as a natural fungicide as it forms a complex with membrane sterol of fungi, thereby causing membrane disruption (Arneson & Durbin, 1968). As such, no evidence has been reported that tomatine is having harmful effect on humans. Also, FDA has not laid down any regulations and guidelines for the amount of tomatine in food (Rick, Uhlig, & Jones, 1994). The content of tomatine does not reduce on deep-frying or microwaving; also, delayed ripen fruits have a similar concentration of tomatine as normally ripen fruits (Friedman & Levin, 1995). Prussic acid in peach pits, apple, and cherry Prussic acid, which is also known as hydrocyanic acid, is produced when cyanogenic glycosides found in peach pits, apple, cherry, leaves, oak moss, or any other plant parts are degraded when coming into contact with enzyme beta-glycosidase. This enzyme releases the cyanide from the glycoside, which results in the prevention of utilization of oxygen by body’s cells, and this will end up in tissue damage and cellular necrosis. Clinical sign of prussic acid poisoning includes trembling, rapid breathing, coordination, and, in some extreme cases, cardiac or respiratory arrest (Fig. 4).

Substances formed because of product abuse Glycoalkaloids in potatoes (chaconine and solanine) α-Solanine and α-chaconine are the glycoalkaloids used as natural pesticides that are formed in potatoes. The report showed that α-solanine is also found in apples, eggplant, cherries, bell peppers, tomatoes, and sugar beets (Shibamoto & Bjeldanes, 1993; Tice, 1998). The sugar molecule in the trisaccharide portion is the only difference between α-solanine and α-chaconine (Surak, 1978). The concentration of α-chaconine and α-solanine in potato tuber will vary depending upon the storage conditions. The synthesis of these compounds is initiated and stimulated by mechanical injury and aging (Dinkins & Peterson, 2008; Tice, 1998). Potatoes on exposure to light in the marketplace or in the field result in the concentration of glycoalkaloids, which is not suitable for human consumption. Solanine concentration in green potatoes has been increased up to sevenfold ( Jones, 1992) (Figs. 5 and 6).

Fig. 4 Structure of prussic acid.

Dietary neurotoxins: An overview

Fig. 5 Structure of alpha-chaconine.

Fig. 6 Structure of alpha-solanine.

The major factors of α-solanine and α-chaconine acute toxicity are as follows: They act as inhibitors of acetylcholinesterase and disrupt the cell membrane. Glycoalkaloids at dose of 01–05 mg/kg showed toxicity in humans and dose of 03 to 06 mg/kg showed toxicity in humans (Tice, 1998). The various symptoms of toxicity include increased sensitivity, itchiness in the neck region, and drowsiness; few gastrointestinal symptoms include vomiting, nausea, abdominal pain, diarrhea, and labored breathing (Shibamoto & Bjeldanes, 1993). Furocoumarin in parsnips The report has stated that spoiled, older, and diseased parsnips have been freely available in markets and in grocery stores, which may contain furocoumarin content of more than 2000% as compared to that of fresh parsnips (Ceska, Chaudhary, Warrington, Poulton, & Ashwood-Smith, 1986). Totally five furocoumarins are present in the parsnip roots, viz. angelicin, 5-methoxypsoralen (5-MOP), 8-methoxypsoralen (8-MOP), isopimpinellin, and psoralen. Reported furocoumarin concentration in freshly harvested roots is less than 2.5 mg/kg at around 18°C for up to 50 days. If stored at around 4°C, the report showed that an increase in concentration has been reported up to 40 mg/kg. If stored at room temperature, a dramatic increase up to 566 mg/kg has been reported (Ostertag, Becker, Ammon, Bauer-Aymanns, & Schrenk, 2002) (Figs. 7–11).

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Fig. 7 Structure of angelicin.

Fig. 8 Structure of 5-methoxypsoralen.

Fig. 9 Structure of 8-methoxypsoralen.

Fig. 10 Structure of isopimpinellin.

Fig. 11 Structure of psoralen.

Infection caused by fungus has also been reported to augment the furocoumarin synthesis around 150-fold in carrots (Wagstaff, 1991).

Substances produced because of processing Polycyclic aromatic hydrocarbons Obtained from the unburned and incomplete combustion of the fossil fuels like coal, oil, and wood, polycyclic aromatic hydrocarbons (PAHs) are formed, which are carcinogenic in nature. The food chain is the main entry gate for PAHs from environmental contaminants or from processed foods. Various foods that contain the highest proportions of

Dietary neurotoxins: An overview

PAHs include smoked or cooked fish or meat, cured or smoked cheese, roasted coffee, and tea. Exposure to excessive heat or direct contact with flame stimulates the synthesis of PAHs in meat, fish, or other foods (Park & Penning, 2009). Also, few reports have stated PAH proportions are affected by type of wood, temperature, and oxygen concentration in smoked foods. On oral exposure in rats, three PAHs, namely dibenz[a,h]anthracene, benzo[a]pyrene, and benz[a]anthracene, are found carcinogenic (FAO/WHO, 2005) (Figs. 12–14). Acrylamide A number of starch-containing food products like bakery products, bread, potato products like French fries, chips, and bread that are fried or baked at 120°C temperature or more contain acrylamide. It is also found in coffee and cocoa-based products (Mills, Mottram, & Wedzicha, 2009) (Fig. 15). The toxicological effect of acrylamide was neurotoxicity in humans, which was observed in the person who was occupationally exposed to high levels (Exon, 2006).

Fig. 12 Structure of dibenz[a,h]anthracene.

Fig. 13 Structure of benzo[a]pyrene.

Fig. 14 Structure of benz[a]anthracene.

Fig. 15 Structure of acrylamide.

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Acrylamide exposure can be reduced by keeping away from deep-fried foods, cooking French fries at relatively lower temperatures up to light yellow color, soaking potato slices before cooking, and toasting bread to a lighter color (Mills et al., 2009). Furan Furan is a by-product of thermal treatment and high-energy carbohydrate. The products of meat and vegetables that are available in jars and cans like sauces, gravy, pastas, baby foods, soups, and brewed coffee particularly contain very high proportions of furans (Carthew, Di Novi, & Setzer, 2010). Though the production of furan in food is still underway to understand, it is reported that it can be produced from organic acid, vitamin C, reducing sugars, amino acid, polyunsaturated fatty acids, and carotenes in the presence of heat (Bolger, Tao, & Dinovi, 2009) (Fig. 16). It is reported that furan is clastogenic and mutagenic in various in vitro mammalian cell assays, and this may cause damage to chromosomes in mice, and also, carcinogenic report has been reported on mice and rats on oral administration (Carthew et al., 2010; Cordelli et al., 2010; Leopardi et al., 2010; Moser, Foley, Burnett, Goldsworthy, & Maronpot, 2009).

Summary •

• •

Diet is one of the contributors to the exposure of environmental agents and neurotoxic compounds in humans and participates in the etiology of few neurodegenerative and neuropsychiatric disorders in humans. In this chapter, we have underlined different aspects of the problems relating foodborne neurotoxicants to human neurotoxicity. Toxic compounds may occur naturally, may be produced as a reaction of constituents, or may be present in the form of residue. They may assist in toxicity and eventually result in neurotoxicity.

Mini-dictionary Toxins: A poison of plant or animal origin, especially one produced by or derived from microorganisms and acting as an antigen in the body. Neurotoxins: A poison that acts on the nervous system. Genotoxicity: The property of chemical agents that damage the genetic information within a cell causing mutations, which may lead to cancer.

Fig. 16 Structure of furan.

Dietary neurotoxins: An overview

Dysarthria: Difficult or unclear articulation of speech that is otherwise linguistically normal. Paraesthesia: An abnormal sensation. Ataxia: The loss of full control of bodily movements.

Key facts • •

•

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Neurotoxicity occurs when exposure to natural or manmade toxic substances (neurotoxicants) alters the normal activity of the nervous system. This process can eventually interrupt and disrupt or even kill neurons. These are the key cells that transmit and process signals in the brain and other parts of the nervous system. Neurotoxicity can result from exposure to substances used in radiation treatment, chemotherapy, organ transplants, and drug therapies and as well as exposure to heavy metals such as mercury and lead, certain pesticides, foods and food additives, industrial and/or cleaning solvents, naturally occurring substances, and cosmetics. Symptoms may appear immediately after exposure or be delayed. They may include loss of memory, limb weakness or numbness, headache, vision, and/or intellect, sexual dysfunction, and cognitive and behavioral problems.

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Dietary neurotoxins: An overview

Lau, K., McLean, W. G., Williams, D. P., & Howard, C. V. (2006). Synergistic interactions between commonly used food additives in a developmental neurotoxicity test. Toxicological Sciences, 90, 178–187. [Internet]. [cited 2021 Jun 23]; Available from: https://pubmed.ncbi.nlm.nih.gov/16352620/. Leopardi, P., Cordelli, E., Villani, P., Cremona, T. P., Conti, L., De Luca, G., et al. (2010). Assessment of in vivo genotoxicity of the rodent carcinogen furan: Evaluation of DNA damage and induction of micronuclei in mouse splenocytes. Mutagenesis, 25, 57–62. [Internet]. [cited 2021 Jun 28]; Available from: https://academic.oup.com/mutage/article/25/1/57/1354500. McGuffin, M. (1997). American herbal products association’s botanical safety handbook (2nd ed.). CRC Press. [cited 2021 Jun 25]. [place unknown]: Available from: https://books.google.co.in/books? hl¼en&lr¼&id¼UdcZ2bttXaMC&oi¼fnd&pg¼PR19&dq¼McGuffin,+M.+American+Herbal+ Product+Association’s+Botanical+Safety+Handbook%3B+CRC+Press:+Boca+Raton,+FL,+USA,+ 1997%3B+pp.+149–152.&ots¼4t8F9TKkO7&sig¼GsDlQatNxhrXBqeTBOPLVfyjoX. Mills, C., Mottram, D. S., & Wedzicha, B. L. (2009). In R. H. Stadler, & D. R. Lineback (Eds.), Polyaromatic hydrocarbons (Part 2.1), process-induced food toxicants: occurrence, formation, mitigation, and health risk. Hoboken, NJ, USA: John Wiley & Sons. [Internet]. [place unknown]: [cited 2021 Jun 28]. Available from: https://books.google.co.in/books?hl ¼en&lr ¼&id¼ 6cty8fU3v68C&oi ¼ fnd&pg¼ PR5&dq ¼Mills, +C.%3B+Mottram,+D.S.%3B+Wedzicha,+B.L.+Acrylamide+(Part+2.1).+In+Process-Induced +Food+Toxicants.+Occurrence,+Formation,+Mitigation,+and+Health+Risks%3B+Stadler,+R.H., +Lineba. Moser, G. J., Foley, J., Burnett, M., Goldsworthy, T. L., & Maronpot, R. (2009). Furan-induced doseresponse relationships for liver cytotoxicity, cell proliferation, and tumorigenicity (furan-induced liver tumorigenicity). Experimental and Toxicologic Pathology, 61, 101–111. [Internet]. [cited 2021 Jun 28]; Available from: https://linkinghub.elsevier.com/retrieve/pii/S0940299308001048. National Toxicology Program. (2004). NTP 11th report on carcinogens. Report on Carcinogens, 11, 1–11. [Internet]. [cited 2021d Jun 25]; Available from http://toxnet.nlm.nih.gov/. Olney, J. W. (1981). Excitatory neurotoxins as food additives: An evaluation of risk. Neurotoxicology, 2, 163–192. [Internet]. [cited 2021e Jun 23]; Available from: https://pubmed.ncbi.nlm.nih.gov/ 15622732/. Olney, J. W. (1982). The toxic effects of glutamate and related compounds in the retina and the brain. Retina, 2, 341–359. [Internet]. [cited 2021f Jun 23]; Available from: https://pubmed.ncbi.nlm.nih.gov/ 6152914/. Olney, J. W. (1984). Excitotoxic food additives—Relevance of animal studies to human safety. Neurobehavioral Toxicology and Teratology, 6, 455–462. [Internet]. [cited 2021 Jun 23]; Available from: https:// pubmed.ncbi.nlm.nih.gov/6152304/. Olney, J. W. (1990). Excitotoxicity: an overview. Canada Diseases Weekly Report, 16(Suppl 1), 47–57. discussion 57. [Internet]. [cited 2021g Jun 23]; Available from: https://pubmed.ncbi.nlm.nih.gov/ 1966279/. Olney, J. W. (1993). Role of excitotoxins in developmental neuropathology. APMIS. Supplementum, 40, 103–112. [Internet]. [cited 2021h Jun 23]; Available from: https://pubmed.ncbi.nlm.nih.gov/8311990/. Olney, J. W. (1994). Excitotoxins in foods. Neurotoxicology, 15, 535–544. [place unknown]; [cited 2021 Jun 23]; [internet]. Available from: https://pubmed.ncbi.nlm.nih.gov/7854587/. Omaye, S. T. (2004). Food and nutritional toxicology. CRC Press. [cited 2021i Jun 25]. [place unknown]: Available from: https://www.taylorfrancis.com/books/mono/10.1201/9780203485309/foodnutritional-toxicology-stanley-omaye. Ostertag, E., Becker, T., Ammon, J., Bauer-Aymanns, H., & Schrenk, D. (2002). Effects of storage conditions on furocoumarin levels in intact, chopped, or homogenized parsnips. Journal of Agricultural and Food Chemistry, 50, 2565–2570. [Internet]. [cited 2021 Jun 27]; Available from: https://pubs.acs.org/doi/abs/ 10.1021/jf011426f. Park, J. H., & Penning, T. M. (2009). In R. H. Stadler, & D. R. Lineback (Eds.), Polyaromatic hydrocarbons (Part 2.8), process-induced food toxicants: Occurrence, formation, mitigation, and health risk. Hoboken, NJ, USA: John Wiley & Sons. [place unknown]: [Internet]. [cited 2021 Jun 28]. Available from: https:// books.google.co.in/books?hl¼en&lr¼&id¼6cty8fU3v68C&oi¼fnd&pg¼PR5&dq¼Park,+J.-H.%3B +Penning,+T.M.+Polyaromatic+Hydrocarbons+(Part+2.8).+In+Process-Induced+Food+Toxicants. +Occurrence,+Formation,+Mitigation,+and+Health+Risks%3B+Stadler,+R.H.,+Linebac.

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CHAPTER 20

Alcohol consumption induces oxidative damage, neuronal injury, and synaptic impairment: Consequences for the brain health Margrethe A. Olesen and Rodrigo A. Quintanilla

Laboratory of Neurodegenerative Diseases, Instituto de Ciencias Biom
edicas, Facultad de Ciencias de la Salud, Universidad Auto´noma de Chile, Santiago, Chile

Abbreviations AD ADH ALDH AMPA ApoE4 APP CCR2 CNS DSMdV EPSC FAS fMRI GABA GFAP Iba1 IC ICU IL IPSC LTP MCP-1 MWM N2a-APP cells NF-Κβ NMDA PD TNFα VTA

Alzheimer’s disease alcohol dehydrogenase aldehyde dehydrogenase α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid apolipoprotein E4 amyloid precursor protein CdC chemokine receptor 2 central nervous system diagnostic and Statistical Manual of Mental Disorders excitatory postsynaptic excitatory current fetal alcohol syndrome functional magnetic resonance gamma-aminobutyric acidic glial fibrillary acidic protein ionized calcium-binding adapter molecule 1 inferior colliculus hospital critical care unit interleukin mediated inhibitory postsynaptic currents long-term potentiation monocyte chemoattractant protein-1 Morris water maze mouse neuroblastoma cell line expressing wild-type human amyloid precursor protein nuclear factor-Κβ N-methyl-D-aspartate Parkinson’s disease tumor necrosis factor-alpha ventral tegmental area

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00043-X

Copyright © 2023 Elsevier Inc. All rights reserved.

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Introduction Alcohol is a common drug socially accepted to celebrate ceremonies, parties, and sports victories and alleviate emotional and mood stress (Moss, 2013). Notably, the social costs of alcohol abuse are incredibly high due to the increase in the number of accidental deaths, elevated spending on healthcare resources, and even disruption of family life (Bouchery, Harwood, Sacks, Simon, & Brewer, 2011). Furthermore, alcohol consumption contributes to the pathogenesis of several diseases that reduces life span, including cardiac failure, liver diseases, pancreatitis, and the impairment of brain function (Rehm, 2011). Also, alcohol-attributable neuropsychiatric diseases are essential contributors to the global burden being 33.7% in men and 27.3% in women (Rehm, 2011). Evidence has shown that different brain areas are severely affected by ethanol: the prefrontal cortex, hippocampus, hypothalamus, amygdala, and cerebellum (Harper, 1998). Ethanol toxicity appears to contribute to several neurological disorders, including Alzheimer’s disease (AD) and Parkinson’s disease (PD) (Brust, 2010; Peng et al., 2020). In this context, ethanol-treated rats for 40 weeks presented cerebellar degeneration and Purkinje cell damage, which affect neuronal communication (Dlugos & Pentney, 1997). Also, our research work has evidenced defects in hippocampal function, dendritic spine loss, oxidative damage, and mitochondrial impairment in juvenile ethanol-treated rats (Mira, Lira, Quintanilla, & Cerpa, 2020). Other studies in alcoholic subjects showed a prefrontal cortex vulnerability to alcohol consumption, leading to cognitive and synaptic impairment (Loheswaran et al., 2017). In this context, other reports have indicated that ethanol toxicity triggers neurotransmitter deficiency such as NMDA, glutamate, dopamine, and serotonin (Ward, Lallemand, & de Witte, 2009). These severe defects compromise cognitive performance as attention, learning, and memory and even destabilize the psycho-emotional state of persons (Farr, Scherrer, Banks, Flood, & Morley, 2005; Jedema et al., 2011; Kato, Tsuji, Miyagawa, Takeda, & Takeda, 2013). In recent years, evidence has suggested that ethanol can cause “ethanol-related dementia” in the absence of other diseases such as hepatic damage, cerebral trauma, or nutritional deficiency (Brust, 2010). This feature has been proposed since that ethanol is strongly considered a risk factor to induce neurotoxicity and cognitive impairment (Brust, 2010). In fact, in vivo models exposed to ethanol have shown neuropathological changes associated with learning and memory impairment (Tapia-Rojas, Torres, & Quintanilla, 2019; Wang, Lee, Hui, Michaelis, & Choi, 2019). Also, alcoholic patients showed neuronal dysfunction in different brain regions, such as the prefrontal cortex and hippocampus (Harper, 1998). Therefore, alcohol induces brain impairment and vulnerability, and these negative features may persist over time, affecting neuronal functions throughout adult life. This chapter will discuss the toxic effects of ethanol and how it contributes to brain injury. Then, we will describe the different types of alcohol consumption and how these impact neurochemical balance and affect cognitive performance.

Alcohol consumption induces neurodegeneration

Alcohol toxicity Alcohol is metabolized mainly in the liver by different enzymes, including aldehyde dehydrogenase (ALDH), alcohol dehydrogenase (ADH), cytochrome P450, and catalase (Zakhari, 2006). In addition, alcohol metabolization generates acetaldehyde, which is considered a highly toxic compound associated with tissue damage (Zakhari, 2006). Although alcohol is a legal drug widely consumed and accepted worldwide, its abuse has generated significant health concerns due to its contribution to different diseases (Parry, Patra, & Rehm, 2011). Among the group of diseases in which alcohol intake is considered to impact are cancer (Meadows & Zhang, 2015), cardiovascular diseases (Toma, Par
e, & Leong, 2017), liver diseases (Ohashi, Pimienta, & Seki, 2018), and pancreatitis (Clemens et al., 2016). Interestingly, excessive alcohol consumption has also been considered a risk factor in stroke (Reynolds et al., 2003), psychiatric illnesses (Petrakis, Gonzalez, Rosenheck, & Krystal, 2002), and dementia (Koch et al., 2019). Due to maladaptive alcohol consumption patterns and associated damage in society, criteria to catalog alcohol use disorders are defined in the Diagnostic and Statistical Manual of Mental Disorders (DSMdV) (Witkiewitz, Litten, & Leggio, 2019). DSM-V describes several features related to alcohol intake, including difficulties in controlling drinking, not being able to reduce or stop drinking, neglect of activities or failure to comply with responsibilities, drinking despite physical and psychological problems, alcohol consumption in larger quantities, and recurrent alcohol consumption in dangerous situations (Grant et al., 2015). Also, according to the World Health Organization (OMS), 3 million deaths per year worldwide are due to alcohol consumption, which represents 5.3% of all deaths (OMS, 2011). Furthermore, a meta-analysis carried out between the years 1991 and 2010 determined that the highest mortality risk of alcohol was for those with consumption above 40 g/day ( Jayasekara, English, Room, & MacInnis, 2014). These studies showed an increased proportion between alcohol consumption over time and mortality risk ( Jayasekara et al., 2014). Also, in 2016, it was determined that 32.5% of people worldwide were active alcohol users, where 25% correspond to women and 39% to males, and in total, these percentages represent 2.4 billion people worldwide (Griswold et al., 2018). Notably, a study conducted in France in 2017 reported that alcoholic women have a 13–20 times greater risk to suffer liver disease, while men have a 16 times greater risk of developing liver cirrhosis and liver cancer, which were associated with two-thirds of deaths in people with alcoholic disorders (Schwarzinger, Thi
ebaut, Baillot, Mallet, & Rehm, 2017). Among the toxic effects of alcohol in the body, the most common liver diseases are induced by fatty liver accumulation and cirrhosis (Rasineni & Casey, 2012; Roerecke et al., 2019). Nowadays, several studies have proposed linking excessive alcohol consumption and central nervous system (CNS) damage (Cservenka & Brumback, 2017). Ethanol is a small molecule that crosses the blood–brain barrier interfering with neuronal

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Fig. 1 Ethanol consumption affects the brain. Ethanol is metabolized to acetaldehyde (A) by the liver. Metabolized ethanol crosses the blood–brain barrier (B), targeting different brain structures such as the prefrontal cortex, hippocampus, amygdala, and hypothalamus, inducing the toxicity of neuronal cells (C and D). In addition, neuronal dysfunction induced by ethanol intake produced an imbalance between the release of inhibitory (GABA) and excitatory (glutamate) neurotransmitters (E). These events could trigger an excitotoxicity response produced by an accumulation of glutamate, which contributes to the impairment of synaptic plasticity and, consequently, reduced cognitive performance (F) such as memory, attention, and executive function, leading finally to mortality (G).

function and triggering uncontrolled behavioral responses such as aggression and impulsiveness (Oscar-Berman & Marinkovi
c, 2007) (Fig. 1). In addition, ethanol could induce changes in the fluidity of the neuronal membrane affecting the ion’s transport, such as calcium, thus impairing neuronal function (Leonard, 1986). In this context, it has been demonstrated that alcohol-induced negative consequences in the neuronal activity not only affect the inhibitory responses principally in the front-temporal cortex (Gan et al., 2014), but also reduce excitatory activity in the medial prefrontal cortex in ethanol-treated rats and induced executive function and attention defects (Hughes, Crofton, Buckley, Herman, & Morrow, 2020; Kroener et al., 2012). Complementary studies in ethanol-treated mice showed a loss in the number of dendritic spines in hippocampal neurons (Lescaudron, Jaffard, & Verna, 1989). Also, the primary culture of

Alcohol consumption induces neurodegeneration

cortical neurons showed that ethanol treatment affected the neuronal viability and morphology, which induced a negative effect on synaptic vesicle activity and contributed to the apoptotic process (Guadagnoli, Caltana, Vacotto, Gironacci, & Brusco, 2016). Interestingly, we showed that alcohol consumption from early age induced significant damage to the hippocampus, which persists as age advances (Tapia-Rojas et al., 2018). Furthermore, other studies have described that rats exposed to high doses of ethanolinduced decreased antioxidant defenses such as catalase and glutathione peroxidase activity with a concomitant increase in oxidative damage (Flora, Gautam, & Kushwaha, 2012). Complementarily, these studies showed an increase in the expression levels of apoptotic markers such as Bax, cytochrome C, caspase-3, and p53 and a reduction in Bcl-2 expression, which were associated with neuronal damage (Flora et al., 2012). Interestingly, another study demonstrated that the expression of apolipoprotein E4 (ApoE4) (a genetic risk factor for AD) exacerbates neuronal damage induced by alcohol toxicity in vitro (Li & Cheng, 2018). In this study, N2a-APP cells (mouse neuroblastoma cell line expressing wild-type human amyloid precursor protein (APP)) were treated with ethanol and ethanol + Apoe4 increasing alcohol-induced neuronal toxicity, enhancing apoptosis, oxidative stress, and, consequently, decreasing neuronal viability (Li & Cheng, 2018). Therefore, excessive alcohol consumption could have a synergic mechanism increasing the risk of dementia and neurodegeneration.

Alcohol affects brain function It is well-accepted that alcohol consumption induces defects in neurons and glial cells along with cognitive damage and neurodegeneration (de la Monte & Kril, 2014). For instance, studies from Farr et al. showed that ethanol-treated mice showed deficits in learning and long-term memory (Farr et al., 2005). Similarly, ethanol treatment can induce an increase in the anxiety behavior along with an elevated neuroinflammatory response by the increase of interleukin-6 (IL-6), tumor necrosis factor-alpha (TNFα), monocyte chemoattractant protein-1 (MCP-1), and thus receptor CdC chemokine receptor 2 (CCR2) expression (Xu et al., 2021) (Fig. 2). Furthermore, ethanol consumption induced synaptic transmission defects by preventing the induction of LTP (long-term potentiation), which finally affects neuronal plasticity (Mira et al., 2020). Furthermore, in the next section, we will discuss several ways alcohol consumption could induce neurodegeneration and contribute to brain injury.

Hangover A hangover is defined as the set of unpleasant physical and mental symptoms experienced the next day after an episode of excessive alcohol intake (Verster, Scholey, van de Loo, Benson, & Stock, 2020). This process is characterized by presenting symptoms such as

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Fig. 2 Alcohol (ethanol) use induced a neuroinflammatory response. The ethanol-induced inflammatory response is widely observed in the brain (A). This process is produced by releasing inflammatory cytokines from microglial and astrocytic cells activated after brain injury induced by ethanol (B). Here, oxidative stress and DNA damage are also observed (C). In addition, the release of pro-inflammatory cytokines induced by ethanol has been observed, including IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and TNFα. Additionally, nuclear factors (NF-Kβ), IBA1, and GFAP also increase their expression in response to ethanol treatment (C).

headache, diarrhea, anorexia, poor sense of overall well-being, fatigue, nausea, and tremors (Gauvin et al., 1997; Wiese, Shlipak, & Browner, 2000). Also, other studies have shown that hangovers could have negative influences on daily life activities. For example, driving in hangover states increases the risk of injury and mortality (Mackus et al., 2017). Moreover, several reports have indicated that hangovers contribute to cognitive impairment affecting activities like psychomotor performance, executive function, attention, and memory (Prat, Adan, P
erez-Pa`mies, & Sa`nchez-Turet, 2008). In this context, studies with neuroimaging techniques, like functional magnetic resonance (fMRI), showed increased brain blood flow and activation in the orbital frontal, temporal, and hippocampus during the hangover period (Howland, Rohsenow, McGeary, Streeter, & Verster, 2010). Furthermore, hangover effects trigger changes in neurotransmitter levels, including gamma-aminobutyric acidic (GABA), glutamate, dopamine, serotonin, and the endocannabinoid system (Palmer et al., 2019). Glutamate

Alcohol consumption induces neurodegeneration

is the primary excitatory neurotransmitter in the brain (Zhou & Danbolt, 2014). When glutamate is released into the synaptic cleft, it exerts its action by binding to postsynaptic receptors such as both NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3hydroxy-5-methyl-4-isoxazole propionic acid) receptors (Riedel, Platt, & Micheau, 2003). NMDA and AMPA receptors are essential to LTP generation inducing synaptic plasticity and allowing the acquisition, coding, and storage of information (Hunt & Castillo, 2012; Martinez Jr. & Derrick, 1996). At the same time, GABA is a major inhibitory neurotransmitter that hyperpolarizes the cell membrane and inhibits neuronal excitability and activity (Li & Xu, 2008). In this context, the balance between inhibitory and excitatory neurotransmission is affected by hangover, reducing GABA levels and increasing glutamate availability, leading to excitotoxicity (Crews et al., 2005; Palmer et al., 2019). On the other hand, evidence indicated that hangover induces pro-inflammatory cytokines such as IL-2, IL-4, IL-5, IL-6, IL-10, and TNFα (Karadayian, Busso, Feleder, & Cutrera, 2013). Interestingly, microglial activation induced by IL-10 and TNFα because of a hangover may lead to symptomatic consequences such as nausea, vomiting, headache, and depression (Karadayian et al., 2013; Palmer et al., 2019). In addition, hangover states promote detrimental effects in the left and right hemispheres (Kim, Yoon, Lee, Choi, & Go, 2009). For example, patients suffering from hangover symptoms showed defects in cortical function such as fine motor speed, spatial-based movement, visual activity and naming, phonemic discrimination, relational concepts, and general verbal intelligence (Kim et al., 2009). Altogether, the hangover state promotes neurochemical changes, neuroinflammation, and imbalance of neurotransmitters affecting behavior and cognitive abilities. As a result, the hangover period could trigger symptoms that may limit the quality of daily life and even endanger the person’s life.

Binge drinking Binge drinking is characterized by heavy ethanol consumption in a short time (1–2 h), followed by a period of abstinence (Courtney & Polich, 2009). It is accepted that binge drinking is even more prevalent in adolescents and young adults (Fauci et al., 2019). The study of binge drinking in adolescents has caused great interest since during this life stage young brain is maturating and is more vulnerable to changes induced by alcohol (Squeglia, Jacobus, & Tapert, 2014). Also, this early alcohol consumption could trigger a dependence behavior that persists during the adult stages (Spear, 2015; Tapia-Rojas et al., 2019; Vargas, Bengston, Gilpin, Whitcomb, & Richardson, 2014). Brain development remains highly active during adolescence; therefore, this period is crucial for forming and consolidating new neuronal circuits (Mira, Lira, Tapia-Rojas, et al., 2020). In this context, studies in young rats submitted to binge ethanol drinking

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protocol showed a decrease in learning and memory recognition after one week of ethanol treatment (Tapia-Rojas, Carvajal, et al., 2018). Furthermore, animals subjected to the same binge drinking protocol presented synaptic plasticity injury, where LTP (primary cellular mechanism underlying learning and memory) and synaptic strength were significantly reduced, suggesting an abnormal neurotransmitter release (Tapia-Rojas, Carvajal, et al., 2018). Also, hippocampal tissue of animals submitted to binge drinking protocol showed an inflammatory response induced by increased pro-inflammatory cytokine expressions such as IL-1β, IL-6, and TNFα (Tapia-Rojas, Carvajal, et al., 2018). Also, an increase in nuclear factor-Κβ (NF-Κβ), microglial activator (ionized calcium-binding adapter molecule 1 (iba1)), and glial fibrillary acidic protein (GFAP, expressed by activated astrocytes) was also observed in the hippocampal tissue of young binge ethanol treatment rats (Tapia-Rojas, Carvajal, et al., 2018). Previous studies suggested that the brain is more susceptible to alcohol consumption during adolescence than in the adult stages (Markwiese, Acheson, Levin, Wilson, & Swartzwelder, 1998). Binge drinking can negatively modulate neurotransmitter function and synaptic trigger dysfunction and induce cognitive performance impairment (Ward et al., 2009). In this context, it has been shown that binge drinking promotes an increase in GABA release, induces excitotoxicity by excessive glutamate release, and also increases dopamine and serotonin levels (Ward et al., 2009). These effects can lead to abnormal brain responses such as anxiety, motivation loss, attention loss, and memory defects (Ward et al., 2009). Moreover, a study on young university students showed that binge drinking affected executive function as working memory and attentional capacity, dependent on the prefrontal cortex (Crego et al., 2009). Additionally, in vivo studies showed that spatial memory acquisition is also affected in young rats exposed to binge ethanol drinking by increasing the escape latency in Morris water maze (MWM) tests (Markwiese et al., 1998). Another study in adolescent rats submitted to binge drinking presented negative consequences in the excitability of pyramidal neurons in the prefrontal cortex generating negative changes and working memory deficits (Salling et al., 2018). Additionally, binge drinking contributed to neuronal morphology changes in the CA1 hippocampus as dendritic spines density was reduced along with an increase in neuroinflammation and astrocyte activation by an increase in GFAP expression (Mira, Lira, Quintanilla, & Cerpa, 2020). Altogether, these studies suggest that binge drinking contributes to brain damage affecting neuronal and cognitive performance.

Chronic ethanol consumption Chronic ethanol consumption could lead to neuropsychiatric diseases since alcohol can induce mental and physical symptoms (Tapia-Rojas, P
erez, Jara, Vergara, & Quintanilla, 2018). In this condition, ethanol intake is uncontrolled, and the subject develops a

Alcohol consumption induces neurodegeneration

dependency on alcohol, generating negative consequences against health and social life (Varlinskaya, Truxell, & Spear, 2014). Evidence suggested that chronic ethanol consumption produces neurobiological changes (Mehta, 2016). In this context, studies in vivo have shown that chronic ethanol consumption triggers severe synaptic transmission defects in different brain regions, including the frontal cortex, hippocampus, and amygdala (Fleming, Manis, & Morrow, 2009; Hughes et al., 2020; Pleil et al., 2015). Interestingly, studies in rats showed that the orbitofrontal cortex, medial prefrontal cortex, and motor cortex were affected by chronic ethanol intake producing microglial activation and neuronal loss, which extends into subcortical areas of the brain (Charlton et al., 2019). Similarly, other studies showed that in rats’ medial prefrontal cortex and dentate gyrus, ethanol treatment reduced neuron action potential, affecting the ability to release neurotransmitters (Avchalumov et al., 2021). In addition, several reports have revealed that the prefrontal cortex of chronic ethanol-treated rats presents a reduced frequency of GABA-mediated inhibitory postsynaptic currents (IPSC), negatively affecting the neuronal activity (Hughes, Bohnsack, O’Buckley, Herman, & Morrow, 2019). These detrimental effects induced by chronic ethanol consumption also have been observed in the hippocampus, where glutamatergic and GABAergic neurons were negatively affected, increasing the neurochemical imbalance and excitotoxicity (Zorumski, Mennerick, & Izumi, 2014). Rats’ hippocampal toxicity produced by chronic ethanol consumption increases synaptic excitability in the CA1 region and induces changes in synaptic protein expression where the AMPA receptor GluA2 subunit was increased (Ewin et al., 2019). These neurotoxic effects may also be promoted by neuroadaptive changes in NMDA receptors in the hippocampus (Nelson, Ur, & Gruol, 2005). Furthermore, other studies showed a deficit in synaptic transmission mediated by NMDA receptor in CA1 hippocampus of rats exposed to chronic ethanol treatment finding significant participation of NMDA receptor subunits, NR2A and NR2B subunits, therefore, promoting impairment of LTP formation (Nelson et al., 2005). Neurochemical changes produced by chronic ethanol consumption contribute to cognitive function deficiency (Farr et al., 2005). In this context, the spatial memory of mice was affected by chronic ethanol consumption (Wang et al., 2018). For example, mice exposed to chronic ethanol consumption at a concentration between 19% and 29% showed spatial memory loss by the MWM, observing an increased latency compared to the control group ( Wang et al., 2018). Also, these results were associated with chronic ethanol-induced apoptosis in the hippocampus of mice C57BL/6, which is dependent on the ethanol concentration (Wang et al., 2018). On the other hand, anxiety behavior is also contributed by chronic alcohol consumption (Kliethermes, 2005). Also, this type of consumption can negatively modulate the synaptic function observed in the amygdala of rats (Lack, Diaz, Chappell, DuBois, & McCool, 2007). These studies showed an increase in NMDA receptors and the high glutamatergic response of basolateral amygdale of rats and, therefore, enhanced neuronal excitability (Lack et al., 2007).

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Ethanol withdrawal Ethanol withdrawal is a condition that occurs after abrupt and intentional cessation of alcohol consumption (Bayard, McIntyre, Hill, & Jr, 2004). The symptoms include hyperactivity, tremor, insomnia, nausea or vomiting, hallucinations, psychomotor agitation, and anxiety, affecting social and occupational skills (Bayard et al., 2004). Approximately 76.3% of people worldwide present ethanol withdrawal, 42% are admitted to hospital critical care unit (ICU), and 1.8% of persons die each year ( Jesse et al., 2017). Abrupt cessation of alcohol intake results in neuronal hyperexcitability, contributing to neuropsychiatric symptoms such as delirium (Kattimani & Bharadwaj, 2013). Hyperexcitability following ethanol withdrawal is produced by an increased release of glutamate and sensitivity of NMDA receptors in the hippocampus of rats (Hendricson et al., 2007). CA1 hippocampal neurotoxicity of rats by ethanol withdrawal increased excitatory postsynaptic excitatory currents (EPSCs) and enhanced action potential evoked negatively modulating synaptic activity (Hendricson et al., 2007). These toxic effects were accompanied by a significant increase in NR1, NR2A, and NR2B subunit expression, indicating maladaptive consequences in response to withdrawal (Hendricson et al., 2007). Interestingly, spinal cord motor neurons of rats exposed to ethanol withdrawal showed a limited contribution of AMPA receptors in neuronal hyperexcitability (Li & Kendig, 2003). However, NMDA receptors were significantly associated with neuronal hyperactivity during ethanol withdrawal in neuron motor of rats (Li & Kendig, 2003). On the other hand, tonic–clonic seizure (convulsive movement followed by contract muscle and consciousness loss) also is a symptom contributed by ethanol withdrawal (N’gouemo & Rogawski, 2006; Stafstrom & Carmant, 2015). Neurons of the inferior colliculus (IC) play a critical role in the tonic–clonic seizure event in rats subject to ethanol withdrawal (Akinfiresoye, Miranda, Lovinger, & N’Gouemo, 2016). In this context, IC neurons of rats subject to ethanol withdrawal showed downregulation in α1B subunit expression levels of N-type calcium channel associated with the vulnerability of IC neurons and induce seizure episodes (N’Gouemo, Yasuda, & Morad, 2006). Depressive behavioral symptoms are observed in mice following ethanol withdrawal and have shown an increase in immobility time, increased feeding latency, and reduced saccharin consumption, considered depressive symptoms in mice (Skuza, 2013). Dopaminergic neurons are associated with depressive behavior and participate in reward and motivation (Arias-Carrio´n, Stamelou, Murillo-Rodrı´guez, Men
endez-Gonza´lez, & P€ oppel, 2010; Dunlop & Nemeroff, 2007; Wise, 2004). However, in depressive rats, a decrease in action potential and hyperpolarization of dopaminergic neurons were observed and associated with demotivation of these animals (Zhong et al., 2018). The ventral tegmental area (VTA), known as the midbrain, contains most dopaminergic neurons, mainly GABAergic (Mesman & Smidt, 2020). Ethanol withdrawal significantly decreases the activity of dopaminergic neurons in rats VTA (Bailey et al., 1998) since

Alcohol consumption induces neurodegeneration

ethanol withdrawal depresses the GABA neurotransmitter release and, therefore, attributes to depression in rats (Fu et al., 2019). Neurochemical imbalance contributes to cognitive performance damage, which persists in ethanol withdrawal (Farr et al., 2005). Interestingly, forty-eight patients (29 male and 19 female) with ethanol withdrawal diagnostic were evaluated with a neuropsychological measure to determine the impact on cognitive function (Loeber et al., 2010). Results of the neuropsychological testing showed that ethanol withdrawal negatively impacted attention, executive function, and memory loss (Loeber et al., 2010). Similarly, ethanol 20%-treated rats showed reduced acquisition and retention of short- and longterm memory in T-maze during the ethanol withdrawal period (Farr et al., 2005). Furthermore, ethanol withdrawal in rats significantly contributed to acquisition, codification, and spatial memory loss (Santucci, Cortes, Bettica, & Cortes, 2008). In this study, rats with ethanol withdrawal were subject to MWM for eight days, and this group showed an increase in escape latency, which lasted until the last day of the test (Santucci et al., 2008). Therefore, the neurochemical imbalance and cognition damage induced by ethanol remain after the withdrawal period harming the person’s quality of life.

Fetal alcohol syndrome Pregnancy is a critical stage during development where CNS is formed (Rice & Barone Jr, 2000). In this process, neurons proliferate from the outer germ layer (ectoderm) into specific brain regions to fulfill their function, respectively (O’Rahilly & M€ uller, 1994; Sidman & Rakic, 1973). Currently, alcohol consumption among pregnant women has been dramatically increasing (Dejong, Olyaei, & Lo, 2019). This maternal behavior causes excellent concern since ethanol easily crosses the placenta, directly affecting the development of the fetal CNS (Dejong et al., 2019). In this context, fetal alcohol syndrome (FAS) is a disease caused during pregnancy due to exposed alcohol by the mother (Williams, Smith, & Abuse, 2015). Globally, FAS prevalence is estimated to be 7.7/1.000 habitats, whereas in South Africa (111.1/1.000 habitants), Croatia (53.3/1.000 habitants), and Ireland (47.5/1.000 habitants), there was a high prevalence (Lange et al., 2017). For many years, evidence has reported that FAS induced injury in the CNS where intrauterine growth deficiency and microcephaly have been observed (a tiny brain for body size) (West, Chen, & Pantazis, 1994). Complementary studies showed an abnormal cortical thickness, reduced cerebral volume, among other malformations leading to several neuropathologic defects such as mental retardation, hypotonia, coordination diminished, hyperactivity, and behavioral problems (Brust, 2010). Also, complementary studies have shown that small doses of alcohol during embryonic development by the mother induce a significant deterioration in the newborn child’s cognitive capacity (Cudd, 2005).

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Evidence has reported that children with FAS presented a reduction in frontal lobes volume, correlated with neuropsychological damages such as executive function and attention loss (Nunez, Roussotte, & Sowell, 2011). In the same context, FAS produced a reduced mass in the parietal lobe in charge of the visuospatial activity, highlighting white matter deficiency (Nunez et al., 2011). Also, FAS induced other abnormalities in the temporal lobe in charge of memory, learning, auditory processing, and language comprehension with an abnormal increase in gray matter and reduced white matter (Nunez et al., 2011). Importantly, studies in vivo showed that ethanol treatment of postnatal rats (5–7 days) promoted apoptosis, which correlated with a reduction in cortical activity and the impairment of neuronal function from the first week postnatal (Lebedeva et al., 2017). In the same context, studies using an in vitro model of rat embryonic midbrain cells exposed to ethanol for 96 h result in cytotoxicity in a concentration-dependent manner finding elevated Bcl-2 and p53 expression levels both contributing to apoptotic responses (Lee et al., 2005). Furthermore, these studies observed oxidative stress and an increase in DNA damage in ethanol-treated cells compared to the control group (Lee et al., 2005). Other studies have suggested that the hippocampus of mice exposed to ethanol intake during embryonic stages exhibits a reduced number of neurons and abnormal dendritic spine density (Berman & Hannigan, 2000). The neuronal plasticity is also affected in FAS since it has been observed that LTP decreased in rats’ hippocampus, triggering learning and memory difficulty (Izumi et al., 2005; Medina, 2011). Glutamatergic receptors such as NMDA and AMPA receptors are crucial to neuronal connection during brain development, finding an abnormal increase in NMDA and reduced AMPA receptors in hippocampus and neocortex of rats (Bellinger, Davidson, Bedi, & Wilce, 2002; Toso et al., 2005). Altogether, these studies suggest that FAS induces significant neuronal plasticity and function abnormalities, contributing to morphological and functional deficits in the infant’s brain.

Alcohol consumption contributes to the pathogenesis of different neurological diseases Effects of alcohol on the brain have been of great interest since they can negatively modulate and promote different neurological alterations (Pervin & Stephen, 2021). For example, studies in cultured cortical neurons showed chronic ethanol treatment-induced cell vulnerability, increased oxidative stress, reduced antioxidant defenses, neuroinflammation, and apoptosis (Maffi et al., 2008). Furthermore, the neurochemical imbalance is also affected by excessive alcohol consumption inducing the release of excessive glutamate and transient opening of NMDA receptor triggering excitotoxicity observed in neurodegenerative diseases such as AD and PD (Beal, 1998; Bhave, Ghoda, & Hoffman, 1999; Uribe et al., 2012). These negative changes are associated with depression, cognitive

Alcohol consumption induces neurodegeneration

defects, and brain atrophy in alcoholic patients (Tateno & Saito, 2008). In this context, neuroimaging studies in alcoholic patients showed brain mass loss, more significant in the hippocampus, a spectrum evidenced in AD patients (Agartz, Momenan, Rawlings, Kerich, & Hommer, 1999). Moreover, evidence suggested that reduced hippocampal seizure would be promoted by ethanol-induced CA1 cell pyramidal dysfunction and aberrant hippocampal circuit (Bonthius, Woodhouse, Bonthius, Taggard, & Lothman, 2006).

Conclusions The studies discussed here indicate that our brain is highly vulnerable to alcohol toxicity either during neurodevelopment or during maturity. Brain dysfunction due to alcohol intake is due to the neurochemical imbalance in different brain regions contributing to abnormal responses in cognitive abilities and behavior. Findings discussed here suggest that ethanol consumption types like a hangover, chronic ethanol consumption, binge drinking, or ethanol intake during pregnancy promote the damage of neuronal connectivity and contribute to synaptic plasticity impairment. These negative changes in our brain function may play an essential role in the onset and development of alcohol dependency.

Summary points • • • • •

Ethanol is a toxic compound that affects different brain areas, principally the prefrontal cortex and hippocampus. Excessive alcohol consumption during adolescence induced neuronal damage until mature ages. Alcohol consumption induces inflammatory responses activating microglial and astrocytic mechanisms releasing pro-inflammatory cytokines. Excessive alcohol intake triggers neuronal dysfunction, destabilizes neuronal excitatory and inhibitory balance, and consequently cognitive deficit. Ethanol consumption is associated with neurological disorders such as AD and PD.

Other components of interest • •

Ethanol induces mitochondrial impairment in the brain. Binge drinking in adolescents induces mitochondrial dysfunction, cognitive decline, and glial activation in the hippocampus.

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Key facts • • • • •

The brain presents a significant vulnerability to ethanol. Ethanol induces neurotoxic effects. Ethanol promotes neurochemical imbalance. Excessive alcohol consumption is associated with cognitive damage during adolescence. Ethanol induces neurodegeneration and impairs brain function.

Mini-dictionary of terms •

•

• • • •

Cognitive abilities: It refers to multiple mental processes promoting learning, memory attention, reasoning, problem resolution, decision-making, perception, understanding, judgment, among others. Neurotoxicity: It occurs when exposure to toxic compounds induces adverse effects in central or peripheric nervous system activity, inducing inflammatory cascade and triggering neuronal dysfunction. Neuronal plasticity: Neurons can structurally and functionally modify in response to internal and external stimuli. Neuropathology: It refers to a clinical and scientific discipline that studies nervous system diseases either by biopsy or by autopsies examination. Synapses: This process establishes the communication between neurons, allowing the passage of electrical and chemical signals in response to a nerve impulse. Neurotransmitter: Chemical molecule released by neuronal depolarization into other neuronal cells (postsynaptic zone) to form the synapses and induce the information to target different as muscle and gland.

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Further reading Blitzer, R. D., Gil, O., & Landau, E. M. (1990). Long-term potentiation in the rat hippocampus is inhibited by low concentrations of ethanol. Brain Research, 537(1–2), 203–208. https://doi.org/10.1016/00068993(90)90359-j. Liew, H.-K., Cheng, H.-Y., Huang, L.-C., Li, K.-W., Peng, H.-F., Yang, H.-I., et al. (2016). Acute alcohol intoxication aggravates brain injury caused by intracerebral hemorrhage in rats. Journal of Stroke and Cerebrovascular Diseases, 25(1), 15–25. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.08.027. Ramachandran, V., Watts, L. T., Maffi, S. K., Chen, J., Schenker, S., & Henderson, G. (2003). Ethanolinduced oxidative stress precedes mitochondrially mediated apoptotic death of cultured fetal cortical neurons. Journal of Neuroscience Research, 74(4), 577–588. https://doi.org/10.1002/jnr.10767. Skike, C. E. V., Goodlett, C., & Matthews, D. B. (2019). Acute alcohol and cognition: Remembering what it causes us to forget. Alcohol, 79, 105–125. https://doi.org/10.1016/j.alcohol.2019.03.006. Teng, S. X., & Molina, P. E. (2014). Acute alcohol intoxication prolongs neuroinflammation without exacerbating neurobehavioral dysfunction following mild traumatic brain injury. Journal of Neurotrauma, 31(4), 378–386. https://doi.org/10.1089/neu.2013.3093.

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CHAPTER 21

Dietary effects of lead as a neurotoxicant Ericka Cabañasa, George B. Cruza, Michelle A. Vasquezb, Jewel N. Josepha, Evan G. Clarkea, Asma Iqbalc, Bright U. Emenikeb, Wei Zhud, Patrick Cadeta, Narmin Mekawye, Abdeslem El Idrissie, Morri E. Markowitzf,g, and Lorenz S. Neuwirthd a

Department of Biology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States Department of Chemistry & Physics, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States c Department of Counseling and Clinical Psychology, Teachers College, Columbia University, New York, NY, United States d Department of Psychology, SUNY Neuroscience Research Institute, SUNY Old Westbury, Old Westbury, NY, United States e Department of Biology, Center for Developmental Neuroscience, The College of Staten Island (CUNY), Staten Island, NY, United States f Children’s Hospital at Montefiore, The University Hospital for Albert Einstein College of Medicine, Bronx, NY, United States g SUNY Neuroscience Research Institute, Old Westbury, NY, United States b

Abbreviations AB ANOVA ASV BLL BLM Ca2+ CaM CB CDC CDI Cldn 1 Cldn 5 CNS EDTA GI HA KO Pb2+ Pb2+/Ca2+ PMCA PND PTH SEM SI US VDR VSCC

Alcian blue analysis of variance anodic stripping voltammetry blood lead level basolateral membrane calcium calmodulin calbindin Center for Disease Control and Prevention Ca2+-dependent inactivation claudin 1 claudin 5 central nervous system ethylenediaminetetraacetic acid gastrointestinal system hyaluronic acid knockout lead lead/calcium competition plasma membrane Ca2+ ATPase postnatal day parathyroid hormone standard error of the mean small intestine United States Vitamin-D receptor voltage-sensitive calcium channels

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00016-7

Copyright © 2023 Elsevier Inc. All rights reserved.

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WHO μg/dL

World Health Organization microgram per deciliter

Introduction In the United States, the Centers for Disease Control and Prevention (CDC) has been unable to identify a blood lead level (BLL) threshold below which children are not susceptible to lead (Pb2+)-induced neurobehavioral and cognitive deficits. According to the World Health Organization (WHO, 2010), 15–18 million children in developing countries have suffered brain damage as a result of Pb2+ exposure, and this may occur in part, due to Pb2+ gut-brain interactions. Postnatally, it is possible that biochemical determinants occurring within the developing GI tract are the main site of Pb2+ uptake, whereby children will absorb higher percentages of the amounts of ingested Pb2+ than adults (Sharma & Barber, 2014). Historically, BLLs of 50–70 μg/dL were associated with intestinal symptoms of constipation, epigastric pain, nausea, indigestion, and anorexia (Hernberg, 1975), whereas symptoms were worse at higher BLLs (Hernberg, 1976). Given these reports, Morton, Partridge, and Blair (1985) first described molecular pathways of intestinal Pb2+ uptake. Further studies examined the different toxicokinetics of Pb2+ GI absorption that were dependent on its formation of a lipid-soluble, lipid-insoluble, or both types of Pb2+ complexes (for review, see Mushak, 1991). However, despite these important contributions, the literature at that time was mostly restricted to evaluations of the effects of moderate to high BLLs, i.e.,
20 μg/dL, and included studies across different species, dosing regimens, Pb2+ formulations, and the developmental time-periods of Pb2+ exposure. Furthermore, they lacked assessment of the GI effects across the duodenum, jejunum, and ileum and did not assess the effects of low BLLs in addition to any possible interactions by sex. Ultimately, the consequences of Pb2+ on the GI tract as it relates to the potential gut-brain interactions across the life span and how sex might serve as an effect modifier require further elucidation. Animal research shows that developmental Pb2+ exposure impedes the remodeling of synapses in neurons causing learning and memory deficits (Schneider, Anderson, Talsania, Mettil, & Vadigepalli, 2012). This suggests that organogenesis is vulnerable to adverse effects of Pb2+ exposure which may persist throughout postnatal development with consequences continuing into adulthood (Sharma & Barber, 2014). Similarly, Pb2+induced disruptions during the GABA-shift can cause alterations in the excitation-toinhibition balance in the brain between immature and mature GABAergic neurons as a contributing risk factor for causing developmental neuropathologies (Neuwirth, 2014; Neuwirth & El Idrissi, 2021; Neuwirth, Emenike, et al., 2019; Neuwirth, Kim, et al., 2019; Neuwirth, Masood, Anderson, & Schneider, 2019; Neuwirth, Phillips, & El Idrissi, 2018; Neuwirth et al., 2017). Moreover, these risk factors may also contribute to early forms of neurodegenerative diseases such as Alzheimer’s and Parkinson’s diseases (Cory-Slechta, 1995; Land & Rubin, 2017).

Dietary effects of lead as a neurotoxin

Notably, Pb2+ can inhibit the evoked release of neurotransmitters by reducing calcium (Ca2+) influx into presynaptic nerve terminals via Ca2+/Pb2+ competition (Neuwirth, 2014; Simons, 1993). Essentially, the ability of Pb2+ to mimic or displace Ca2+ (Kerper & Hinkle, 1997) can inform our understanding about both normal and pathophysiological states not just within the central nervous system (CNS) but also in elucidating how Ca2+/Pb2 competition might occur in other systems as well, such as the GI. The consequences of this Ca2+/Pb2 competition may help us to better understand Pb2+ absorption, bioavailability, toxicokinetics, and Pb2+ body burden accumulation (Garza, Vega, & Soto, 2006). In turn, understanding the molecular mechanism(s) of GI Pb2+ absorption may provide new insights regarding earlier BLL screening to proactively assess for childhood neuropathological disorders through gut-brain interactions (for review, see Neuwirth, 2018). The GI system is unique in its intestinal epithelial stem cells (IESCs) which produce progenitor cells that can differentiate into the cells required for normal GI physiological functions. However, the signals that regulate these distinct populations of IESCs emanating from the crypts could also alter their structure-function physiological relationships and are less understood (for review, see Umar, 2010). Studies have shown that IESCs require cytoplasmic Ca2+-dependent activity to regulate the metabolic and proliferative signals within the intestines (Na´szai & Cordero, 2016), which may facilitate the maturation of IESCs through vitamin D-dependent Ca2+-binding proteins at the brush border of the villi activity (Marche, Cassier, & Mathieu, 1980). Given that Ca2+/Pb2 interactions are well described, it is possible that Pb2+ exposure may alter such structure-function relationships.

Gastrointestinal structure-function relationships The intestinal tract is an elegant system in which two key structures (i.e., the villi and the crypts of Lieberk€ uhn) allow for the movement of nutrients across the mucosa of the intestines. The villi are composed of thin epithelium and large surface areas (i.e., brush borders) that have a highly efficient absorptive capacity for a range of nutrients. The crypts receive the nutrients that are guided by the villi peristalsis. Additionally, the crypts are the source of the progenitor villous cells. Several types of cells develop here with functions that include: host defense (e.g., Paneth cells), hormone production (e.g., such as gastrin, secretin, and cholecystokinin), and enterocytes for nutrient absorption. Interspersed in the villi are goblet cells that produce and secrete mucins. The mucins are viscous and consist of highly glycosylated proteins and a complex electrolytic solution that covers the villi. It functions to prevent against villi shearing, to trap and eliminate undesirable molecules, and to increase the absorption of nutrients from the diet. When secreted, mucins are highly compact but can expand up to 500-fold in size nearly instantly in a Ca2+-dependent manner (Ambort et al., 2012). When considering the IESCs proliferating from the crypts, it is important to understand the relationship between these progenitor cells and the villi regarding cellular proliferation as an adaptive mechanism that occurs as a function of age, sex, and selective pressures brought on by consequences of the environment and dietary food sources as

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well as availability or lack thereof. For example, when dietary sources of food become scarce, this may cause a survival-dependent adaptive structure-function compensatory mechanism by which more progenitors are created to increase nutrient loading in the short time-period in which food resources are available. As such, these physical structural adaptations may augment the physiological activities that promote survival.

Gastrointestinal pathways and Ca2+ absorption The start of Pb2+ toxicity begins with Pb2+ entry into the body. For children, this is almost always via ingestion of Pb2+-containing materials. Multiple mechanisms for Pb2+ absorption likely exist. One such mechanism is via Ca2+-dependent pathways. As such, Ca2+ is absorbed through transcellular and paracellular mechanisms. Transcellular Ca2+ absorption is a saturable vitamin D-dependent pathway that is upregulated when plasma Ca2+ levels are low and occur predominantly in the proximal intestine in humans. Molecularly, the transcellular pathway is dependent on voltage-sensitive Ca2+ channels (VSCCs) located on the luminal side of the intestinal enterocytes. One main channel type is the Ca2+ transport protein 1 (CaT1, also called TRPV6), which is located mainly in the duodenum and upper jejunum and is highly selective for Ca2+. Further, it is part of three key events that permit Ca2+ absorption: (1) luminal Ca2+ enters the enterocytes in the microvillus border at the apical membrane through CaT1; (2) upon entry, the Ca2+ binds to calbindin-D9k and crosses the cytoplasm; and (3) extrusion of Ca2+ to the extracellular space through the basolateral membrane against an electrochemical gradient requires a plasma membrane Ca2+ ATPase (PMCA; Frick & Bushinsky, 2003; Kalkwarf, Specker, Heubi, Vieira, & Yergey, 1996). Thus, Pb2+ may utilize all parts of this pathway to gain absorption through the enterocyte to then enter the bloodstream disrupting other organ systems. The paracellular transport may be less regulated by hormonal vitamin D but is found throughout the intestine (Di Mari, Mifflin, & Powell, 2005; Houser & Tansey, 2017; Prozialeck, Grunwald, Dey, Reuhl, & Parrish, 2002). The availability of the paracellular Ca2+ pathway, which consists of claudins (Cldn) 2,12, and 15 that act as permissive pores found within the tight junctions between enterocytes that permit Ca2+ entry, may also allow for Pb2+ absorption, although this potential mechanism is less well studied.

Pb2+ uptake in the duodenum While the aforementioned mechanisms for possible Pb2+ diffusion through Ca2+ channels are likely, the transcellular capacity is not a constant in all intestinal sections. In situ hybridization of rat intestinal RNA demonstrated the following gradient of expression throughout the intestine: in the small intestine, high levels of CaT1 RNA were present in the duodenum, low levels in the proximal jejunum, and an absence of expression in the ileum (Frick & Bushinsky, 2003). These levels indicate that if CaT1 is the principal

Dietary effects of lead as a neurotoxin

epithelial Ca2+ channel, then the duodenum is the site of the highest transcellular Ca2+ uptake (Arshad & Visweswariah, 2013; Bressler, Kim, Chakraborti, & Goldstein, 1999). However, whether the CaT1 distribution shares a specific relationship with microvilli size remains to be elucidated. Notably, Mayhew and Middleton (1985), using stereological and electron microscopy techniques on 8-month-old Lister rat’s intestines (animal sex was not specified), showed evidence that the volumes, lengths (cm), and surface areas of the villi and microvilli structures change in size as a function of body weight and metabolic demand; hence, the size of the villi was greatest in the duodenum and formed a decreasing gradient through the intestine to the ileum. The villous crypts did not change in structural size along the intestinal length (Mayhew & Middleton, 1985).

Pb2+/Ca2+ competition alters Ca2+ channel uptake A second Ca2+ channel, Cav1.3, has been postulated that allows for GI and CNS cell Ca2+ absorption. Additionally, Pb2+ has been shown to disrupt Cav1.3 via a calmodulin (CaM)dependent pathway (see the following). As such, CaM is a crucial intermediary Ca2+ activated intracellular molecule that is ubiquitously distributed in cells with many cytoplasmic and nuclear effects. Like many other Ca2+-binding proteins, it has a higher affinity for Pb2+ than for Ca2+ (Chao, Bu, & Cheung, 1995; Diaz de Barboza, Guizzardi, & de Talamoni, 2015; Habermann, Crowell, & Janicki, 1983). These Pb2+ influences on CaM have also been reported to occur within GI cells (Fullmer, Edelstein, & Wasserman, 1985). Normally, Ca2+-activated CaM must associate with Cav1.3 and requires L-type VSCCs located in the apical membrane of the enterocyte for Ca2+-dependent inactivation (CDI), and this function may be altered when Pb2+ displaces Ca2+. To further evaluate the effects of Pb2+ toxicokinetics, it is necessary to bear in mind that Pb2+ is involved in disrupting multiple Ca2+ signaling pathways. For instance, Pb2+ will inhibit Ca2+ efflux through the plasma membrane Ca2+ ATPase (PMCA) pump, which may result in excitotoxic Ca2+ accumulation (Sharma, Singh, & Siddiqi, 2014; Simons, 1993). These Pb2+ effects on pathways common to many cell types beyond the intestinal enterocytes (e.g., CaM and Cav1.3) are also found in neurons where they may also induce an imbalance between neuronal excitation and inhibition (Drew, Spence, & Johnston, 1990; Habermann et al., 1983; Neuwirth & El Idrissi, 2021; Neuwirth, 2014; Neuwirth et al., 2018; Silbergeld, Hruska, Miller, & Eng, 1980; Silbergeld, Miller, Kennedy, & Eng, 1979; Struzy nska & Rafaowska, 1994). Altogether, functional Cav1.3 and CaM are both crucial in regulating Ca2+ absorption, neuronal activity, protection against neurodegenerative diseases, and potentially gut-brain interactions, all of which may be detrimentally affected by Pb2+.

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Vitamin-D metabolism increases intestinal Pb2+ absorption Low extracellular Ca2+ levels result in increased parathyroid hormone (PTH) production and circulating levels. In turn, PTH induces the renal production of 1,25-dihydroxyvitamin D calcitriol, the activated hormonal form of vitamin D. Calcitriol promotes the production of the proteins that facilitate enterocyte transcellular Ca2+ absorption described earlier. The vitamin D receptor (VDR) is required for calcitriol actions. Moreover, VDR knockout (KO) mice were observed to have a decrease in duodenal Ca2+ absorption and a diminished expression of CaT1, and calbindin-D9k (CB9k; Schwaller, 2010). Research conducted on rats exposed to 0.2% Pb2+ acetate via drinking water from postnatal days (PND) 1–21 showed a decrease in 1,25(OH)2D levels and an increase in VDR immunostaining in the brain at PND 30; serum levels were also measured via immunoassay and were also low (Rahman, Al-Awadi, & Khan, 2018). The precursor molecule, 25-hydroxyvitamin D, was also lower when compared to controls. The results from this study determined that differences in 1,25(OH)2D serum levels in the Pb2+-exposed rats were not due to vitamin D intake, were age-independent, and were suggested to be due to altered hepatic 25-hydroxylase activity, i.e., to decrease the conversion of vitamin D to 25(OH)D, the main circulatory metabolite. In turn, this would decrease the availability of substrate for renal 1-alpha hydroxylation for calcitriol production. Additionally, the observed reduction in circulating 1,25(OH)2D serum levels with increasing Pb2+ may be related to Pb2+‘s multiple effects on the heme pathway enzymes (i.e., 1-alpha vitamin D hydroxylase is a heme-containing molecule). Thus, low 1,25(OH)2D may be a secondary effect due to insufficient heme production and the increase in the VDR levels may be a compensatory effort in response to Pb2+ toxicity.

Pb2+ neurotoxicity through the paracellular pathway Tight junctions consist of several Claudins including Claudin 1 (Cldn 1) and Claudin 5 (Cldn 5) that are regulated by transcellular calbindin (CB) proteins (Tsukita, Furuse, & Itoh, 2001). Additionally, Cldn 1 and Cldn 5 have clear sealing functions that might also affect Ca2+ transport, as they influence general paracellular permeability and may also be targets of metal toxicity (Mitic, Van Itallie, & Anderson, 2000). Furthermore, the effects of Pb2+ exposure and tight junctions of the blood-brain barrier (BBB) were evaluated through qRT-PCR and Western blot analyses which confirmed that Pb2+ exposure decreased the mRNA as well as the membrane and cytosolic protein levels of Cldn 1 (Shi & Zheng, 2007; Song et al., 2014). These data on claudins and the BBB data may provide useful insight as to whether and how ingested Pb2+ disrupts the tight junctions of the GI tract as well. Notably, an impairment of the tight junctions will cause GI epithelial damage. It may damage the mucin-secreting goblet cells that are important factors in providing a

Dietary effects of lead as a neurotoxin

protective mucin barrier over the GI epithelium (Sharma & Barber, 2014). Alternatively, if the tight junctions are impaired by Pb2+ exposure, the goblet cells may secrete more mucins as a compensatory mechanism to slow the absorption of Pb2+. Altogether, the interdependence of tight junctions and the mucous barrier serve to regulate paracellular permeability, ion gradients, and serve as a protective mechanism against toxicants that might also include dietary metallotoxicants such as Pb2+. Further, sex-dependent effects of IESCs have shown females to have more cellular proliferation than males in the crypts (Zhou, Davis, Li, Nowak, & Dailey, 2018), which updates the work done by Mayhew and Middleton (1985) which lacked sex comparisons. These observations would suggest that Pb2+ exposure may have sex-specific effects that modify the IESCs and subsequently alter both the structure and physiology of the GI tract that could impact Pb2+ absorption with adverse consequences for the CNS. In order to investigate this question, the present study sought to histologically evaluate the rat’s GI regarding the villi and crypts, as well as the villi epithelial cells’ height and width’s structural changes in response to early neurodevelopmental Pb2+ treatment and sex-dependent differences to better understand the gut-brain interactions following Pb2+ exposure.

Assessing the effects of Pb2+ on the GI gradient through histological Alcian blue staining The Alcian blue (AB) stain is used to differentiate between neutral and weakly acidic sulfated mucosubstances, hyaluronic acid (HA), and sialomucins as a routine stain for GI biopsies (Carson, 1996) using the following steps: 3-min wash with dH2O, 3-min incubation in 3% glacial acetic acid (GAA; [CH3CO2H]), 30-min incubation in 3% GAA + AB, rinsed quickly with 2–3 dips in 3% GAA, 10-min wash with running warm tap water, rinse quickly with 2–3 dips in dH2O, 5-min incubation to counterstain with nuclear fast red, 1-min wash in running warm, followed by dehydration in 95% ethanol (ETOH) for 1 min, 95% ETOH for 1 min, 100% ETOH 1 min, xylene 1 min, xylene 1 min, and coverslipped with 3 drops of Permount mounting medium (Daigger Scientific, Buffalo Grove, IL) allowed to dry and were later imaged on a compound microscope. This provides researchers with the ability to examine each GI sample through a subsequent imaging analysis to evaluate a number of pathological, morphological, and spatial relationships of these tissues (e.g., of which the duodenum (see Fig. 1), the proximal SI (see Fig. 2), and the distal SI (see Fig. 3) can be parsed for assessing gradients across the GI of Pb2+-exposed rats as a function of sex: Peri-22 (150 ppm) rats had MBLLs ¼ 10.24 μg/dL (SD ¼ 4.32, SEM ¼ 1.53) and the Peri-22 (1000 ppm) rats had MBLLs ¼ 30.16 μg/dL (SD ¼ 13.04, SEM ¼ 4.61), respectively.

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Peri-22 (1000 ppm)

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40 X

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Fig. 1 Structural comparisons of the duodenum as a function of sex and Pb2+ exposure. Representative cross sections of the duodenum for control (0 ppm) rats (left panel), Peri-22 (150 ppm) rats (middle panel), and Peri-22 (1000 ppm) rats (right panel). Vertically, each panel vertically shows the males on the left and the females on the right, and horizontally, the magnifications are shown at 4  (upper panel), 10 (middle panel), and 40  (lower panel). The Peri-22 (150 ppm) rats show greater staining for weakly sulfated mucosubstances, hyaluronic acid, and sialomucins (purple).

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Male

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Fig. 2 Structural comparisons of the proximal small intestine as a function of sex and Pb2+ exposure. Representative cross sections of the proximal small intestine for control (0 ppm) rats (left panel), Peri-22 (150 ppm) rats (middle panel), and Peri-22 (1000 ppm) rats (right panel). Vertically, each panel vertically shows the males on the left and the females on the right, and horizontally, the magnifications are shown at 4 (upper panel), 10 (middle panel), and 40 (lower panel). There appears to be equal staining for weakly sulfated mucosubstances, hyaluronic acid, and sialomucins (purple).

Peri-22 (150 ppm)

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Male

Peri-22 (1000 ppm)

Female

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40 X

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Fig. 3 Structural comparisons of the distal small intestine as a function of sex and Pb2+ exposure. Representative cross sections of the distal small intestine for control (0 ppm) rats (left panel), Peri-22 (150 ppm) rats (middle panel), and Peri-22 (1000 ppm) rats (right panel). Vertically, each panel vertically shows the males on the left and the females on the right, and horizontally, the magnifications are shown at 4 (upper panel), 10 (middle panel), and 40 (lower panel). The Peri-22 (150 ppm) rats show greater staining for weakly sulfated mucosubstances, hyaluronic acid, and sialomucins (purple).

Dietary effects of lead as a neurotoxin

Sex-dependent effects between control male and female rat’s gastrointestinal villi and crypt gradients Through the use of AB histological staining, control male and female rats’ GI villi gradient showed that there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 5.605, P < .01**, η2p ¼ 0.384 for the villi height (Fig. 4A). In contrast, the control male and female rats’ GI crypt gradient showed a significant effect of the Gastrointestinal Gradient F(2) ¼ 3.391, P < .05*, η2p ¼ 0.274, a significant effect of Sex F(1) ¼ 17.767, P < .001###, η2p ¼ 0.497, and a significant Gastrointestinal Gradient X Sex interaction F(2,1) ¼ 5.666, P < .01‡‡, η2p ¼ 0.382 (Fig. 5A). Further, there was a statistically significant Gastrointestinal Gradient X Sex interaction F(2,1) ¼ 10.206, P < .001‡‡‡, η2p ¼ 0.531 within and between the duodenum, proximal SI, and distal SI for the crypt width (Fig. 5B).

Pb2+ exposure effects on the male rat’s gastrointestinal villi and crypt gradients Similarly, by employing the AB histological staining technique, the effects of Pb2+ exposure could be examined on the GI gradient of both the villi and the crypts. The control (0 ppm), Peri-22 (150 ppm), and Peri-22 (1000 ppm) male rat’s showed that there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 4.418, P < .05*, η2p ¼ 0.247 for the villi height (Fig. 6A). For the crypt depth, there was a significant effect of Gastrointestinal Gradient F(2) ¼ 3.302, P < .05*, η2p ¼ 0.197 (Fig. 7A). For the crypt width, there was a significant effect of Gastrointestinal Gradient F(2) ¼ 7.392, P < .01**, η2p ¼ 0.354; a significant effect of Treatment F(2) ¼ 6.131, P < .01††, η2p ¼ 0.312; and a significant Gastrointestinal Gradient X Treatment interaction F(2,2) ¼ 7.087, P < .001‡‡‡, η2p ¼ 0.354 (Fig. 7B).

Pb2+ exposure effects on the female rat’s gastrointestinal villi and crypt gradients In contrast to the males, the same AB histological staining technique was used to examine the effects of Pb2+ exposure on the female’s GI gradient of both the villi and the crypts. The control (0 ppm), Peri-22 (150 ppm), and Peri-22 (1000 ppm) female rats showed that there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 18.020, P < .001***, η2p ¼ 0.572; a significant effect of Treatment F(2) ¼ 4.676, P < .01††, η2p ¼ 0.257; and a significant Gastrointestinal Gradient X Treatment interaction F(2,2) ¼ 3.587, P < .01‡‡, η2p ¼ 0.257 for the villi height (Fig. 8A). For the villi width, there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 7.411, P < .01**, η2p ¼ 0.354 and a significant Gastrointestinal Gradient X Treatment interaction F(2,2) ¼ 4.126, P < .01‡‡, η2p ¼ 0.379 (Fig. 8B). For the villi epithelial thickness, there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 25.925, P < .001***, η2p ¼ 0.658 and a significant Gastrointestinal

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Gastrointestinal Villi Gradient Male

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Fig. 4 Gastrointestinal villi structural differences between control males and females. Representative samples from the duodenum, proximal and distal SI for the villi height (A), width (B), and epithelial thickness (C) between control male and female rats. The effects of Gastrointestinal Gradient differences are noted as (*) P < .05 and P < .01.

Dietary effects of lead as a neurotoxin

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Fig. 5 Gastrointestinal crypt structural differences between control males and females. Representative samples from the duodenum, proximal and distal SI for the crypt depth (A) and width (B) between control male and female rats. The effects of Gastrointestinal Gradient differences are noted as (*) and the effects of sex are noted as (#).

Gradient X Treatment interaction F(2,2) ¼ 4.550, P < .01‡‡, η2p ¼ 0.403 (Fig. 8C). For the crypt depth, there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 31.858, P < .001***, η2p ¼ 0.702 (Fig. 9A). For the crypt width, there was a significant effect of the Gastrointestinal Gradient F(2) ¼ 20.719, P < .001***, η2p ¼ 0.605 and a significant Gastrointestinal Gradient X Treatment interaction F(2,2) ¼ 2.880, P < .05‡, η2p ¼ 0.299 (Fig. 9B). These AB histological data provide new evidence to consider how developmental Pb2+ exposure via dietary intake (i.e., food and water consumption) may pose

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Fig. 6 Gastrointestinal villi structural differences between control and Pb2+-exposed males. Representative samples from the duodenum, proximal and distal SI for the villi height (A), width (B), and epithelial thickness (C) between control (0 ppm), Peri-22 (150 ppm), and Peri-22 (1000 ppm) male rats. The effects of Gastrointestinal Gradient differences are noted as (*) with statistical values noted as P < .05, P < .01, and P < .001.

Dietary effects of lead as a neurotoxin

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Fig. 7 Gastrointestinal crypt structural differences between control and Pb2+-exposed males. Representative samples from the duodenum, proximal and distal SI for the crypt depth (A) and width (B) between control (0 ppm), Peri-22 (150 ppm), and Peri-22 (1000 ppm) male rats. The effects of Gastrointestinal Gradient differences are noted as (*), the effects of Treatment are noted as (†), and the Gastrointestinal Gradient X Treatment interactions are noted as (†) with statistical values noted as P < .05, P < .01, and P < .001.

different sex-dependent vulnerabilities that may shed light on prior models of GI metallotoxicity.

Revisiting early models of gastrointestinal Pb2+ uptake in a modern low-level exposure paradigm Morton et al. (1985) provided the original reports of Pb2+ uptake from the intestinal lumen. Since then, several studies reported that Pb2+ uptake in the GI tract is optimal in the duodenum (Barton, 1984; Conrad & Barton, 1978; Edlestein, Fullmer, & Wasserman, 1984; Flanagan, Hamilton, Haist, & Valberg, 1979; Henning & Cooper, 1988; Henning & Leeper, 1984), the jejunum (Hussein, Coghill, Milne, &

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Fig. 8 Gastrointestinal villi structural differences between control and Pb2+-exposed females. Representative samples from the duodenum, proximal and distal SI for the villi height (A), width (B), and epithelial thickness (C) between control (0 ppm), Peri-22 (150 ppm), and Peri-22 (1000 ppm) female rats. The effects of Gastrointestinal Gradient differences are noted as (*), the effects of Treatment are noted as (†), and the Gastrointestinal Gradient X Treatment interactions are noted as (†) with statistical values noted as P < .05, P < .01, and P < .001.

Dietary effects of lead as a neurotoxin

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Fig. 9 Gastrointestinal crypt structural differences between control and Pb2+-exposed females. Representative samples from the duodenum, proximal and distal SI for the crypt depth (A) and width (B) between control (0 ppm), Peri-22 (150 ppm), and Peri-22 (1000 ppm) female rats. The effects of Gastrointestinal Gradient differences are noted as (*), the effects of Treatment are noted as (†), and the Gastrointestinal Gradient X Treatment interactions are noted as (†) with statistical values noted as P < .05, P < .01, and P < .001.

Hopwood, 1984), and the ileum (Henning & Leeper, 1984). These observations follow the Ca2+ gradient across the GI tract. In addition, these portions of the intestine may have increased vulnerability for Pb2+ uptake when dietary nutrients are low. As a consequence of increased Pb2+ absorption, increased organ deposition and toxicity could ensue, while the brain appears to be uniquely vulnerable to even low levels of Pb2+. From these early reports, Mushak (1991) wrote a seminal review describing the possible uptake mechanisms of Pb2+ through the intestine but failed to consider the possible influence of

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sex. The functional consequences of these observed Pb2+-induced changes remain to be determined.

Pb2+ exposure-induced sex-based differences in gastrointestinal absorption Since sex can influence proliferation rates of IESCs in the GI tract (Zhou et al., 2018), it is plausible that Pb2+ exposure may serve as an effect modifier of sex on GI development, for example, on Ca2+ uptake and handling. This is an area in need of investigation, especially at low-level Pb2+ exposures. Although these early studies provided significant insight regarding Pb2+ effects on the GI tract, our understanding of Pb2+ toxicokinetics (e.g., absorption rates, distribution, metabolism, and elimination) as a function of both low- and high-level Pb2+ exposures remain limited. Furthermore, these early studies did not explore the mechanisms underlying Pb2+ GI pathophysiology, which in turn, might improve our understanding of developmentally related gutbrain interactions. In addition to questions of altered absorption characteristics, other GI functions should be considered. For example, the gut is an endocrine organ that produces multiple hormones such as gastrin, secretin, and cholecystokinin. Is GI hormonal signaling altered by Pb2+? It has extensive innervation for both afferent and efferent conduction pathways; is this modified by the observed morphologic differences? Future studies in this area will be critical to aid our understanding as to the structure-function relationship across the GI gradient, as well as across ages and between sexes. There are a number of gaps within the literature that may be circumvented and perhaps initially and systematically approached through a preliminary histological analysis in relation to early neurodevelopmental Pb2+ exposure. First, BLLs differed by nearly 20 μg/dL at PND 22 between 150 and 1000 ppm exposures. However, at neither exposure dosage was there a BLL difference by sex. One month later, at PND 55, BLLs were below the detection limit, i.e., 3.33 μg/dL. Histological examination of the GI occurred at PND 55. Despite the lack of a BLL differences at this age, sex-specific effects in GI tract histological structural changes in villi height and crypt depths were observed. These observations suggest that these maturation- as well as sex-dependent alterations in Peri-22,150 and 1000 ppm females within the GI tract histology potentially occurred after the cessation of Pb2+ exposure. This observation, in turn, raises an important question of whether persistent Pb2+ ingestion (i.e., continuing after PND 22) would have contributed to eventual differences in BLLs as a function of sex. If this were the case, then it would be expected that sex-dependent differences in Pb2+ absorption from the gut would have related neurochemical alterations within the brain.

Dietary effects of lead as a neurotoxin

The role of developmental time-periods of Pb2+ exposure on potential gut-brain interactions Prior studies using either similar developmental time-periods of Pb2+ exposure (CorySlechta, 1995; Jiang, Zhang, & Li, 1956) or the exact exposure conditions as in the present study (Neuwirth, Kim, et al., 2019) reported alterations in the rat brain’s neurochemistry (i.e., specifically, dopamine, glutamate, acetylcholine, GABA, and taurine) following neurodevelopmental Pb2+ exposure. An alternative hypothesis is possible, namely, that the observed differences in GI tract structural anatomy as a function of sex may not affect either nutrient or Pb2+ absorption and therefore, might not have any influence on the CNS through gut-brain interactions. Notably, from these reports, only Neuwirth, Kim, et al. (2019) evaluated both sexes and observed sex-dependent differences in neurotransmitter levels within the prefrontal cortex and hippocampus (e.g., Pb2+-exposed males showed elevated DA levels and Pb2+-exposed females showed elevated glutamate levels). In considering the observed GI sex-dependent differences from the present study, control male and female age-matched (PND 55) rats exhibited different heights of the villi and depths of the crypts across the GI tract from the duodenum to the ileum (Figs. 4A and 5A). This provides supporting evidence that GI Ca2+ gradients exist, may be sensitive to Pb2+/Ca2+ competition, and may further be influenced by the developmental time-period of Pb2+ exposure, concentration of Pb2+, and sex. Along these lines, Fig. 5A provides evidence of a sex-dependent effect whereby the crypt depth in females was nearly 2–3 times larger in the small intestine when compared to males (Fig. 5A). The functional significance of a deeper crypt in females may serve to increase a faster metabolism of tissue as an evolutionary adaptive/compensatory mechanism for reproductive needs as they relate to renewing/regenerating intestinal villi and may also serve to optimize nutrient absorption consistent with other reports (Hamedi, Resaian, & Shomali, 2011; Saeid, Mohamed, & Al-Baddy, 2013). In contrast, these sex-dependent effects observed in the control rats were further exaggerated in the Pb2+-exposed rats, with females showing greater structural differences than males that may also be additively driven by monthly/cyclic hormonal-dependent processes. The male perinatal Pb2+-exposed rats, exhibited similar effects regardless of treatment of 150 and 1000 ppm, that altered the structural features of the villi and the crypts across the GI tract with persistent changes observed 1-month following the cessation of Pb2+ exposure. In contrast, the female perinatal Pb2+-exposed rats showed significant GI effects that were dose-dependent. Clear sex-dependent effects were observed to be modified by Pb2+ exposure. If a gut-brain interaction does exist as a function of Pb2+ exposure and sex, then these findings would suggest that females would be more likely to have increased altered brain neurotransmitter profiles over males. This would be incongruent with the clinical literature that shows males’ neurotransmitter profiles are more likely to

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be altered. Extrapolation to humans always requires caution. In clinical cases, one may not know the origin or duration of patients’ Pb2+ exposure (i.e., whether they were gestational, perinatal, or later postnatal). This limits our ability to draw precise developmental time-period comparisons. Thus, the observation described herein should be restricted to perinatal Pb2+ exposures. Many of the animal model studies on Pb2+ exposure have not equally evaluated sex-dependent effects with associated neurotransmitter function or physiological activity, and in the absence of such data, it is not possible to eliminate the possibility of a sex-dependent difference/vulnerability for gut effects of Pb2+ on the CNS. Figs. 1–3 provide evidence for supporting a possible functional alteration of the GI that is associated with the Pb2+ exposure with an increased histological staining for HA and sialomucins (purple staining). This suggests that Pb2+ exposure increased the Ca2+-dependent secretion of these molecules in response to Pb2+/Ca2+ competition 1-month following the cessation of Pb2+ exposure. For example, if Pb2+ exposure weakens the GI tight junctions (i.e., through disrupting claudins), it will cause less restriction for Pb2+ uptake, absorption, and distribution within the circulatory system, thereby increasing the organisms’ BLL. This may in turn cause a compensatory mechanism by which the increased secretions of HA and sialomucins occur to reduce the diffusion of Pb2+ uptake when tight junctions weaken. Further, if claudins in general are highly vulnerable to Pb2+ exposure as shown in the weakening of the BBB and the renal system epithelial tissues, then perhaps GI claudin vulnerability may increase Pb2+ uptake. This in turn would increase other organ Pb2+ levels, of which the CNS is most vulnerable to low-level Pb2+ exposures.

Conclusion Additional data have been provided to support the argument that sex-dependent differences in the GI structure of the villi and crypts can occur in response to developmental Pb2+ exposure in female and male rats. Presumably, these are adaptations to facilitate sex-specific needs for nutrient intake at PND 55 as they are at an age optimal for reproduction and/or may co-occur during the monthly/cyclic hormonal events. Further, perinatal Pb2+ exposure was observed to cause persistent GI structural changes to both the villi and the crypts with males showing equal aberrations when exposed to 150 and 1000 ppm. In contrast, female rats exhibited dose-dependent structural changes to both the villi and the crypts. The patterns of the GI gradient also differed based on Pb2+ exposure and sex and did not present with a uniform pattern. The present study showed that the GI tract is not only a major pathway that is underexplored for how Pb2+ enters into the body, but it may also be a critical target organ for Pb2+ effects; thus, establishing a gut-brain pathway to guide future work in the field. The pathophysiological consequences for the organism, especially

Dietary effects of lead as a neurotoxin

to the CNS, of these observed Pb2+ by sex effects on the GI tract require further exploration at low-level Pb2+ exposures.

Mini-dictionary of terms • • • • •

Perinatal. Referring to exposures that begin 1 month prior to breeding and ceasing postbirth at PND 22. Gastrointestinal gradient. Referring to the duodenum to the proximal and distal SI. Proximal SI. Referring to the jejunum. Distal SI. Referring to the ileum. Toxicokinetics. Referring to the absorption, distribution, metabolism, and elimination of a toxic compound, chemical, or agent that enters an organism’s body directly or indirectly effecting any organ system.

Summary points • • •

•

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Control female rats have sex-dependent differences in the duodenum and proximal SI crypt depth when compared to control male rats. Perinatal Pb2+ exposure caused sex-dependent and gastrointestinal gradient differences in the crypts for males. Perinatal Pb2+ exposure caused sex-dependent and gastrointestinal gradient differences in both the crypts and the villi structures that were more pronounced in females observed at PND 55. The persistent structural changes to the gastrointestinal system induced by perinatal low-level Pb2+ exposure warrant further investigation to elucidate gut-brain pathophysiological interactions. Low-level Pb2+ exposure in the CNS causes neurotoxicity, but similar levels of Pb2+ exposure in the gastrointestinal system have been understudied and overlooked.

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CHAPTER 22

Environmental toxicants (OPs and heavy metals) in the diet: What are their repercussions on behavioral/ neurological systems? Caridad López-Graneroa, Michael Aschnerb, and Fernando Sánchez-Santedc a

Department of Psychology and Sociology, Faculty of Social and Human Sciences, University of Zaragoza, Teruel, Spain Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States c Department of Psychology, Centro de Investigacio´n en Salud/ Universidad de Almerı´a (CEINSA/UAL), Almerı´a, Spain b

Abbreviations ALS CAT CPF CSN DFP DLT FAO GPx GSH OPs ROS SOD TEPP WHO

amyotrophic lateral sclerosis catalase chlorpyrifos central nervous system diisopropylfluorophosphate deltamethrin Food and Agriculture Organization of the United Nations glutathione peroxidase glutathione organophosphates reactive oxygen species superoxide dismutase tetraethyl pyrophosphate World Health Organization

Introduction Organophosphate compounds (OPs) and potentially toxic elements (heavy metals) as environmental-pollutant agents in the diet Food is a complex part of the human environment (Rodricks, Turnbull, Chowdhury, & Wu, 2020). The food we consume may contain hundreds of chemical compounds; these substances can be natural or added components, which in turn may render the food hazardous, both for humans and ecosystems. This is the case when toxic elements, including organophosphate (OPs) and heavy metal compounds, permeate the water and food chain. The uncontrolled use of OPs and potentially toxic elements leads to their bioaccumulation in food chains, increasing the risk for human exposures and leading to their persistence in the ecosystem. Environmental contamination and its effect on population Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00038-6

Copyright © 2023 Elsevier Inc. All rights reserved.

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health are currently one of the most important public health issues. The impact of environmental toxicants is a serious challenge to society. Since all we eat can interfere with the behavioral system, it is necessary to identify the toxic compounds for human health. Therefore, this chapter provides an overview of the adverse impact of environmental agents on the nervous system and the behavioral output. The environmental toxicants discussed in this chapter include OPs and heavy metals (Costa, Cole, Garrick, Marsillach, & Furlong, 2017). The origin of these environmental toxic substances can be natural or due to anthropogenic sources ( Jan et al., 2015). Road transport, agriculture, water distribution systems and aquatic environment, additives, electronic applications, power plants, industry, combustion of fossil fuel, mining, and homes are the largest emitters of environmental pollutants in the industrialized world as well as developing countries (Ali, Khan, & Ilahi, 2019; Costa, 2020; Grant, 2020; Hu, Sunderland, & Grandjean, 2020). Many developed countries, including those in Europe, have failed to keep these environmental agents under control. These agents not only pose a threat to human life and health but also have economic repercussions since their exposure and ensuing health problems increase medical expenses, reduce worker productivity, and damage the biological ecosystem (Fabisiak, 2020). The risks of OP and heavy metal exposure stem from their accumulation in the environment, thus contaminating the food chain and the water consumption system (Costa et al., 2017; Grant, 2020; Hu et al., 2020). Even though the environmental toxicants are capable of penetrating into the organism by different routes of absorption including dermal and inhalation routes (Costa et al., 2017; Eaton et al., 2008), the oral OP (Lo´pez-Granero et al., 2013; Lo´pez-Granero et al., 2016) and heavy metal exposures (Antunes dos Santos et al., 2016) from dietary sources are the main health threat to humans. Several classes of environmental agents may reach both the food chain and water distribution. These elements are OPs and heavy metals, including cadmium, lead, copper, manganese, arsenic, and mercury among others (Alengebawy, Abdelkhalek, Qureshi, & Wang, 2021; Ali et al., 2019). Once inside the organism, several of these environmental agents may pose a risk to the central nervous system (CNS) affecting cognitive, emotional, and motor systems (dos Santos et al., 2018; Lo´pez-Granero, Cardona, et al., 2013; Lo´pez-Granero et al., 2016). These repercussions are linked to neurological conditions during the neurodevelopmental and neurodegenerative processes including an imbalance of redox straus (dos Santos et al., 2018; Green & Planchart, 2018). Finally, this chapter provides data on the beneficial effects of antioxidant dietary supplements in the prevention of neurodegenerative disorders.

From the origin to the diet: The input Organophosphate compounds used as pesticides for food pest control The history of OPs dates back to France when, in 1854, Clermont synthesized the first OP compound called tetraethyl pyrophosphate (TEPP). Almost 80 years later, the

Environmental toxicants: Diet and behavior

German Schrader synthesized a series of OP compounds in search of pesticides (Costa, 2006). However, the imminent arrival of World War II led to the main intention of these compounds being used as chemical weapons, mainly due to the low cost of production, such as tabun, sarin, and soman (Martı´n Rubı´, Y
elamos Rodrı´guez, La´ynez Bretones, & Co´rdoba Esca´mez, 2001). Later on, other agents were developed, such as diisopropylfluorophosphate (DFP) (Martı´n Rubı´ et al., 2001), and used in the Iran-Iraq War (1980–88) and in the terrorist attacks in Japan in 1995 (Nishiwaki et al., 2001). While the original intent was to use these agents in the military arena, their use was extended to other areas: in medicine as therapeutic agents (Abou-Donia, 1992) in the treatment of diseases where the cholinergic function is inadequate (Giacobini, 2004) in the industry (Pope, 1999) and in the domestic environment, as antiparasitic (Maroni, Colosio, Ferioli, & Fait, 2000). Despite the multifaceted nature of OPs, the most widespread and known use at present is relative to their application as pesticides used for the control of insects that affect both public health and agriculture and gardening (Costa, 2020). Along with insecticides, herbicides, and fungicides, the use of pesticides promotes the opportunity for international exchange of fruits and vegetables throughout the year, without climatic barriers that depend on the availability of a certain food. This practice sometimes without rigid control has led to environmental and human risks, which require changes in agriculture, at a cost to human health (Richardson, Fitsanakis, Westerink, & Kanthasamy, 2019). Addressing acute toxicity, Thundiyil (2008) classified exposures to OPs as intentional, accidental, and occupational. Occupational poisonings include the largest number of people, mainly in developing countries where the vast majority of the workforce is engaged in agriculture. The World Health Organization (WHO) defines a pesticide “as any substance, or a mixture of substances of chemical or biological ingredients intended for repelling, destroying, or controlling any pest, or regulating plant growth” (FAO & WHO, 2016). According to the WHO, around three million people are poisoned per year by pesticides. Since the first Recommended Classification of Pesticides by Hazard, in 1975, referring only to their acute toxicity, a large number of investigations have also demonstrated their chronic dietary health hazards. Therefore, in 2013, the Food and Agriculture Organization of the United Nations (FAO) considered pesticides highly hazardous and capable of causing severe irreversible damage to health or the environment (FAO & WHO, 2016). Accordingly, dietary exposure is the main source of nonoccupational exposure from trace levels of OPs on food products and contaminated water (Costa, 2020; Eaton et al., 2008; Lo´pez-Granero, Cardona, et al., 2013; Lo´pez-Granero et al., 2016). This chapter focuses on chronic or low-dose exposure via diet to environmental toxic agents as well as their effects on behavior.

Potentially toxic elements in the food and drinking water The presence of heavy metals in nature is a known fact. Even when their source is not anthropogenic, their bioaccumulation in the environment occurs naturally leading to health consequences in human populations where their food is adulterated with metals.

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Some authors have alluded to their presence in the food chain, causing severe damage to human health (Ali et al., 2019). However, since “all metals/elements are toxic in certain forms and in sufficiently high doses” (Hodson, 2004) taking into account the recent controversy around the term heavy metal, it has been decided to use both terms, heavy metals and potentially toxic elements along with this chapter (Pourret & Hursthouse, 2019). Also, the concept of heavy metals has been loosely used. It seems that density is the main characteristic of heavy metals along with relative atomic mass and atomic number (Ali & Khan, 2018; J€arup, 2003; Kim, Kim, & Kumar, 2019). Therefore, heavy metal is defined as a metallic element, which contains a density of more than 5 g/cm3 compared to the water (Kim et al., 2019; Tchounwou, Yedjou, Patlolla, & Sutton, 2012) and is having an atomic number (Z) greater than 20 (Ali & Khan, 2018) (Fig. 1). The environment requires essential elements for its natural well-being. Although these trace elements are considered essential at low concentrations, exposure to nonessential metals can severely damage the health of the population and the ecosystem even at low concentrations (Kim et al., 2019). These elements can be classified as essential and nonessential heavy metals. The essential classification group includes examples such as zinc, copper, iron, and cobalt. On the other hand, nonessential elements contain

Fig. 1 Schematic indicating the overview of the chapter. The figure shows how environmental pollution (OPs and heavy metals) enters the organism leading to behavioral abnormalities during early and later life stages.

Environmental toxicants: Diet and behavior

cadmium, mercury, arsenic, lead, and chromium among others, although arsenic (is a metalloid) is included in heavy metal classifications due to similarities in physical and chemical properties (Kim et al., 2019). WHO has indicated the risk to human health is the greatest upon exposure to cadmium, lead, mercury, and arsenic as the main threats to humans (World Health Organization and Regional Office for Europe, 2007). The history of the use of heavy metals goes back thousands of years. For example, in ancient times, lead has been used for building, water pipes, additive for wine, and food utensils. Also, it has been reported that mercury as a therapeutic remedy for the pain of teeth and syphilis was also used in prehistoric cave paintings for red color. Some reputed painters have used cadmium as pigments for paints (Hubbard, 2005; J€arup, 2003). Nowadays, the exposure to potentially toxic elements continues, more in less-developed countries. Exposure to these toxic elements has increased due to the industrial, agricultural, mining, smelting, domestic, and technological activities, refineries, coal burning, and petroleum combustion among others (Tchounwou et al., 2012). Specifically, cadmium is used for the production of alloys, pigments, and batteries (Tchounwou et al., 2012), is also present in phosphate fertilizers, and is higher in cigarette-smoking persons ( J€arup, 2003). Lead, for example, is derived from fossil fuel burning, mining, batteries, ammunitions, solders, pipes, and devices to shield X-rays (Tchounwou et al., 2012). Mercury is used in switches, thermostats, batteries, and dentistry (dental amalgams), for the control of fungi in grain seeds, and for the production of caustic soda among other industrial activities (Tchounwou et al., 2012). It is worth mentioning that mercury can be metabolized to methylmercury in aquatic systems and thus accumulates in the marine food chain (intake of fish and seafood products) (Costa et al., 2017; Hu et al., 2020; J€arup, 2003).

The impact of environmental toxic elements on the behavior system: The output The intake of food and water contaminated by OPs and heavy metals can alter human behavior, affecting cognitive, emotional, and motor daily activities. Behavior is a complex system comprising different biochemical functions and activities and it has been repeatedly indicated as one of the neurological functions affected after exposure to OPs or environmental elements (Antunes dos Santos et al., 2016; Lo´pez-Granero, Cardona, et al., 2013; Lo´pez-Granero et al., 2016). Behavior is the product of various functions: associative, motor, and sensory. The neurotoxicity of environmental elements can adversely affect one or more of these functions, leading to damage to learning and memory processes, anxiety, depression behavior, and motor impairment (Alengebawy et al., 2021; Deiana, Platt, & Riedel, 2011; Lo´pez-Granero, Cardona, et al., 2013; Lo´pez-Granero et al., 2016).

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It is well established that CNS is particularly vulnerable during development (Antunes dos Santos et al., 2016) and pregnant mothers are more susceptible to environmental adverse effects. Children have a special vulnerability to environmental pollutants. The Committee on Pesticides in the Diets of Infants and Children have established this link because children are more exposed to the toxic elements; however, they possess less metabolic ability and more years to develop a chronic disease (Costa, 2020; National Research Council (US) Committee on Pesticides in the Diets of Infants and Children, 1993). Nonetheless, the consequences during the adult stage are also relevant. The behavioral alterations of OPs and heavy metals can be chronic, leading to long-term consequences that persist as a consequence of chronic exposure to small doses prolonged over time (Antonelli, Pallar
es, Ceccatelli, & Spulber, 2017; Debes, Weihe, & Grandjean, 2016; Eaton et al., 2008; Lo´pez-Granero et al., 2014). Furthermore, early exposures may unmask only during later stages of life given the redundancy within the CNS, which may compensate for initial insults (Antonelli et al., 2017).

Behavioral disabilities and OP exposure via diet The effects of OPs are especially evident during the development. Some studies have observed a relationship between the intake of OPs and intellectual deficits in children not directly exposed to the toxin (Laporte, Gay-Qu
eheillard, Bach, & Vill
egier, 2018). It has been indicated the presence of chlorpyrifos (CPF) in the umbilical cord blood in children (Rauh et al., 2012). The Stanford-Binet copying test showed a decreased score, suggesting deficits in visual function in Ecuadorian children whose mothers had an occupational history of pesticide exposure during pregnancy (Grandjean, Harari, Barr, & Debes, 2006). Also, higher concentrations of urinary metabolites of OPs have been observed in children diagnosed with attention deficit/hyperactivity disorder in the United States (Bouchard, Bellinger, Wright, & Weisskopf, 2010). Experiential studies in animals point in the same direction. In a study with rat dams administered with 1 mg/kg/day of CPF during gestation and lactation via gavage, neonatal rats were tested in a behavioral battery at a different life stage. The results indicated alterations in sensorimotor function in male neonates as well as a deficit of noveltyseeking behavior in juveniles from mothers exposed to CPF (Laporte et al., 2018). Neurobehavioral effects in adult rats also have been reported after repeated exposure to oral environmental elements such as CPF (Moser et al., 2005; Samsam, Hunter, & Bushnell, 2005). CPF is used for a variety of purposes in agriculture and industry (Maroni et al., 2000; Pope, 1999). These initial studies indicate that chronic exposure to doses of 5 mg/kg/day of CPF showed higher latencies to reach the platform and thigmotaxis in a spatial task in the Morris water maze after 1 year of treatment in rats (Moser et al., 2005). These data point to spatial learning and anxiety alterations as consequences of intake of CPF. On the other hand, Lo´pez-Granero et al. (2013) and Lo´pez-Granero, Cardona, et al. (2013) evaluated the repercussions of the behavior of the intake of OPs.

Environmental toxicants: Diet and behavior

These authors found that dietary CPF induced damage in the spatial working memory and higher impulsive choice even once the intake of OP was finalized. Similarly, rats were administered 5 mg/kg/day CPF for 6 months during adult age and evaluated in the behavioral system 7 months after the diet ended. The authors indicated behavioral disturbances such as long-term spatial memory and anxiety effects in animals exposed to dietary CPF (Lo´pez-Granero et al., 2016).

Behavioral disabilities and heavy metal exposure via diet In relation to the potentially toxic element or heavy metal exposure, epidemiological studies have noted an association between lead and neurobehavioral disorders and learning deficits in children (Miranda et al., 2007). In this sense, aluminum, lead, mercury, and arsenic have been related to a deterioration of autism-spectrum disorder symptoms. These symptoms include learning deficits, attention deficits, hyperactivity and impulsivity, autistic behaviors, delinquency, anxiety, depression, and sleep disorders (Agency for Toxic Substances and Disease Registry, 2020). Evens et al. (2015) observed that lead below 10 μg/dL was inversely associated with poor school performance and reduced scores on reading and math tests in children (Evens et al., 2015). In addition, concentrations of lead above 100 μg/dL have been associated with deficits in attention, language, memory, and cognitive flexibility (Alengebawy et al., 2021; Pfadenhauer, Burns, Rohwer, & Rehfuess, 2014). Elevated concentrations of copper have been associated with working memory and attention deficits in children (Zhou et al., 2015). The working memory system is able to retain and use information recently acquired and therefore is essential for the academic performance. Likewise, cadmium provokes adverse effects in the CNS even at low concentrations (Liu, Cai, Liu, Chen, & Wang, 2019; Wang & Du, 2013) in children in southwestern Spain measured in urine and hair samples (Rodrı´guez-Barranco et al., 2014). A recent study by Wang, Zhang, Abel, Storm, and Xia (2018) has demonstrated damage in olfactory learning and memory in adult mice exposed to 3 mg/L of cadmium via drinking water for 20 weeks (Wang et al., 2018). Neurological disturbances, cognitive disabilities, and behavioral alterations in children and adults exposed to cadmium have also been reported (Liu et al., 2019). As well, arsenic exposure has been associated with deficits in cognitive abilities in children living in rural Bangladesh (Hamadani et al., 2011). In this study, the authors found impairment in cognitive function at 5 years of age based on urinary arsenic (drinking water exposure) using the Wechsler Preschool and Primary Scale of Intelligence. Moreover, it seems that the adverse effects on the CNS observed during the childhood can endure to adult age (Tanaka, Tsukuma, & Oshima, 2010). These authors analyzed adults who survived to the incident of arsenic-contaminated dry milk happened in Japan in 1955. Tanaka and collaborators observed an increased prevalence of neurological disease during adult life (Tanaka et al., 2010).

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Methylmercury is also a developmental neurotoxicant produced by biomethylation of inorganic mercury present in the aquatic environment and is capable of accumulating in large concentrations in the food chain (Antunes dos Santos et al., 2016). Therefore, diets consisting largely of fish and seafood may be dangerous for human health. Early exposure to methylmercury may lead to neurological alterations such as cognitive and motor dysfunction (Antunes dos Santos et al., 2016). In addition, methylmercury affects emotional behavior; in this sense, some studies have observed depressive-like behavior in the MeHg-exposed male offspring (Onishchenko et al., 2007). Studies of the population in the Faroe Islands have observed negative effects on the cognitive functions such as verbal memory, language and attention processes, and motor activities in children after maternal methylmercury exposure (Grandjean et al., 1997). Also, elevated levels of mercury in hair were associated with a lower performance in visuospatial working memory, semantic knowledge, and phonological verbal fluency in children in the areas of the Brazilian Amazon region (dos Santos-Lima et al., 2020). These alterations may persist during adult age. Debes et al. (2016) exanimated in the same-birth cohort at 22 years and observed that the cognitive deficits still remain for a long time after a maternal seafood diet (Debes et al., 2016). In this sense, the last publications underline the concept that prenatal environmental exposure to toxic pollutants might determine the vulnerability to disease in adulthood (Antonelli et al., 2017). Although manganese is essential for human health, it is in turn toxic when the daily dietary intake exceeds the adequate concentrations (Peres et al., 2016). It is estimated a correct value of 5.32–14.03 ng Mn/mg protein in the brain; however, an excess value of 15.96 ng Mn/mg protein in the human brain can be dangerous for the health (Bowman & Aschner, 2014). Also, manganese may cause behavioral alterations during both development and adult life. Briefly, manganese affects spatial memory, working memory, and attention systems as well as impulsivity behavior (Peres et al., 2016; Schneider, Williams, Ault, & Guilarte, 2015; Vez
er et al., 2005).

Neurodegenerative pathologies and chronic environmental toxicant exposure: The role of oxidative stress and antioxidants It is well established that manganese exposure can cause motor alterations and produce symptoms similar to Parkinson’s disease (Racette, 2014). An association between cognitive impairment and Alzheimer’s disease linked to copper exposure has also been advanced (Squitti et al., 2014). Furthermore, both experimental and epidemiological studies reported an association between OP exposure and Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) (Sa´nchez-Santed, Colomina, & Herrero Herna´ndez, 2016). Oxidative stress has been suggested as a key to understanding different neurological diseases (Singh, Kukreti, Saso, & Kukreti, 2019). Both OPs and metals can alter multiple mechanisms, with oxidative stress being a major one (Costa, 2017). In fact, the combination of OPs and other xenobiotics such as pesticides has demonstrated a decrease in the immune system activity via oxidative stress (Singh et al., 2019).

Environmental toxicants: Diet and behavior

Therefore, it seems that some environmental pollutants are involved in physiological mechanisms that can directly affect cognition and emotional symptoms (dos Santos, Lo´pez-Granero, et al., 2018; Lo´pez-Granero, Can˜adas, et al., 2013; Lo´pez-Granero, Cardona, et al., 2013; Lo´pez-Granero et al., 2016) by causing oxidative stress disruption (Sa´nchez-Santed et al., 2016; Singh et al., 2019). In this sense, experimental studies have shown that environmental pollutants can readily traverse the blood-brain barrier and cause alterations in the oxidative stress system along with a systemic inflammation impacting adversely the CNS (Singh et al., 2019). The inflammatory and oxidative stress response caused by environmental pollution is similar to that in aging. Oxidative stress acts producing an imbalance between oxidant and antioxidant agents due to excess production of reactive oxygen species (ROS) along with an insufficient antioxidant defense system (Singh et al., 2019). Both oxidative stress and inflammatory cytokines possess the quality to alter brain function, increasing the risk for behavioral disorders and CNS pathologies (Lo´pez-Granero, Ferrer, dos Santos, Barrasa, & Aschner, 2020). Definitely, recent studies have paid much attention to oxidative stress and inflammatory profiles as a central key to understanding many CNS diseases. What kind of environmental elements is able to influence the oxidative stress system and lead to neurodegenerative disorders? A final toxic effect of several environmental elements in food depends on the interaction between these elements in a mixture (Cao et al., 2012). Several publications have observed this phenomenon upon oral OP exposure. In a recent study, young adult male rats were administered the combination of two low levels of pesticides, CPF and deltamethrin (DLT), by gastric gavage for 120 days (Uchendu, Ambali, Ayo, & Esievo, 2018). The results showed elevated levels of oxidative stress along with decreased activities of serum antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Another interesting result from this study is that the observed oxidative stress was ameliorated by oral 60 mg/kg of alpha-lipoic acid, a strong antioxidant. Alpha-lipoic acid is relevant for its function of the cleaning of ROS and the recovery of antioxidant enzymes including vitamins C and E and glutathione (Wollin & Jones, 2003). Similarly, other authors have found that malathion OP compounds elevate the levels of oxidative stress after the oral route of exposure along with reducing antioxidant substances (Akbel, Arslan-Acaroz, Demirel, Kucukkurt, & Ince, 2018). Again, in this study, it has been demonstrated the therapeutic role of some antioxidant elements. Resveratrol was able to ameliorate malathion toxicity in rats. Also, it has been noted that dietary flavonoids exert a protective effect against the observed oxidative stress after oral administration of dichlorvos, an OP compound (Cao et al., 2012). Vitamin E has protective effects in rodent models of manganese-induced neurodegeneration (Peres et al., 2016). In fact, vitamin E supplementation is orally administered to Alzheimer’s disease patients because of its effects on lipid peroxidation (Chiurchiu`, Orlacchio, & Maccarrone, 2016). It is well established that exposure to lead, aluminum,

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mercury, manganese, copper, and cadmium, to name a few, leads to an imbalance in redox status, increasing the levels of oxidative stress (Singh et al., 2019). Copper can induce oxidative stress facilitating the aggregation of β-amyloid in the Alzheimer’s model (Chiurchiu` et al., 2016). The antioxidant glutathione (GSH) is the main target of some heavy metals ( Jan et al., 2015). Several neuronal and glial culture studies have informed a link between decreased GSH levels and the presence of oxidative stress after methylmercury exposure (Kaur, Aschner, & Syversen, 2006). Also, arsenic is characterized by oxidative stress and changes in SOD and CAT antioxidant enzymes in in vitro and in vivo conditions ( Jan et al., 2015). Similarly, low levels of lead are capable of causing oxidative damage inducing free radical generation and modifying antioxidant defense systems of cells (Ahamed & Siddiqui, 2007). Authors mark that even low levels of lead exposure might be responsible for many neurodegenerative diseases.

Conclusions Environmental pollutants such as OPs and heavy metals are present in a multitude of applications including industry, homes, and agriculture. Even if their source is natural or anthropogenic, their bioaccumulation in materials, earth, and water may resent a serious problem for human health and the ecosystem, especially when these elements reach the food chain and water distribution in uncontrolled proportions. The literature establishes how their toxicity affects the CNS, leading to damage to cognitive, emotional, and motor impairments. While the adverse effects of OPs and heavy metals have been observed at all life stages, they are particularly evident during the neurodevelopmental period. Children show behavioral disabilities associated with environmental exposure. In addition, adverse effects on the behavioral system may last into adulthood and senescence. Several studies have corroborated the protective effects of antioxidants such as alpha-lipoic acid, vitamin E, resveratrol, and flavonoids, to name a few. Therefore, this chapter attempted to address the repercussions of dietary toxicants on human health.

Applications to other neurological conditions In this chapter, we discuss behavioral disabilities and changes in the oxidative stress system following the exposure to organophosphates (OPs) and heavy metals during development and adult life. Both epidemiological and clinical studies have demonstrated reduced performance in learning and memory functions, attention process, hyperactivity/ impulsivity, anxiety, depression behavior, and motor impairment upon environmental exposure to these toxics substances (Alengebawy et al., 2021; Deiana et al., 2011; Lo´pez-Granero, Cardona, et al., 2013; Lo´pez-Granero et al., 2016). Also, higher

Environmental toxicants: Diet and behavior

concentrations of these compounds is are associated with oxidative stress and altered redox homeostasis (Sa´nchez-Santed et al., 2016; Singh et al., 2019). These behavioral and molecular changes have been linked to several neurological disorders, such as attention deficit/hyperactivity disorder in children, Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis (ALS) (Sa´nchez-Santed et al., 2016). It seems that the imbalance of the oxidative stress system and inappropriate apoptosis is the mechanistic basis for multiple neurological conditions (Radi, Formichi, Battisti, & Federico, 2014). Some studies have indicated that alpha-lipoic acid is relevant for the attenuation of ROS and the recovery of antioxidant enzymes, including vitamins C and E, and glutathione (Wollin & Jones, 2003). An antioxidant diet might have protective effects against environmental pollutants and their ensuing behavioral alterations. In this context, antioxidant supplementation could be appropriate with strong support for their pharmacological efficacy in neurodegenerative and developmental disorders. Therefore, antioxidant-enriched nutritional diets have been proposed as a therapeutic remedy to mitigate the alterations induced by environmental pollutants. This chapter underlines the relevance of antioxidant nutritional interventions as part of the pharmacological treatments for neurological disorders.

Other components of interest In this chapter, we describe the toxic effects on human health in an attempt to address the repercussions of dietary toxicants on the population. Dietary exposure to chlorpyrifos induces cognitive and emotional alterations along with changes in oxidative stress status (Lo´pez-Granero et al., 2014, 2016; Lo´pez-Granero, Cardona, et al., 2013). Lead, copper, cadmium, arsenic, mercury, and manganese have negative effects on cognition, emotional, and motor functions (Agency for Toxic Substances and Disease Registry, 2020). These alterations may persist throughout adult age (Debes et al., 2016; Grandjean et al., 2006). Also, this chapter relates the benefits of an antioxidant diet to the neurotoxicity induced by OPs and heavy metals. Antioxidant-enriched nutritional diets improve cognition by restoring the balance of the oxidative system including vitamins C and E, and glutathione (Peres et al., 2016; Wollin & Jones, 2003). Resveratrol and dietary flavonoids were able to ameliorate dichlorvos and malathion toxicity in rats (Akbel et al., 2018; Cao et al., 2012). Vitamin E protects against metal-induced toxicity (Peres et al., 2016). Even vitamin E supplementation is used in Alzheimer’s disease patients because of its effects on lipid peroxidation (Chiurchiu` et al., 2016). These studies underline the relevance of the antioxidant nutrient diet in preventing and treating neurotoxicity induced by OPs and heavy metals which accumulate in the ecosystem and adulterate water and food chains.

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Key facts of OPs and heavy metals • •

•

•

• • •

The food and water we consume may contain OPs and heavy metals. OPs and heavy metals can impact the nervous system and the behavioral output, including learning and memory processes, anxiety, depression behavior, and motor impairment. Studies suggest that OPs and heavy metals contribute to neurological conditions such as attention deficit/hyperactivity and autism disorders in children and Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis in adults. Neurotoxicity induced by OPs and heavy metals induces increased oxidative stress concomitantly with decreased activities of serum antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), to name a few. Early exposures to OPs and heavy metals may unmask only during later stages of life, given the redundancy within the central nervous system. Antioxidant-enriched nutritional diets including vitamins C and E, glutathione, resveratrol, and flavonoid substances mitigate the effects of OPs and heavy metals. Antioxidant dietary consumption has been proposed as a therapeutic remedy for OP and heavy metal toxicity.

Mini-dictionary of terms •

•

•

• •

Organophosphates. Chemical substances used mainly as insecticides for pest control. They affect the CNS leading to aberrant consequences for human health. Examples of these compounds include chlorpyrifos, diisopropylfluorophosphate, parathion, and dichlorvos, among others. Heavy metals. Metallic chemical element with high density. They can pose a human health risk even at low exposures. Examples of these potentially toxic elements include mercury, lead, copper, arsenic, manganese, and cadmium, among others. Behavior. The manifestation of an organism in response to a stimulus or elements of its environment. These responses can include associative, motor, and sensory functions. Oxidative stress. Disequilibrium between free radical levels and antioxidant response in the organism. Antioxidant. Compounds capable of delaying or preventing molecular oxidation and therefore act to mitigate oxidative stress processes. Examples of these compounds include vitamin C, vitamin E, and glutathione (GSH).

Summary points • •

All the foods that we intake contain hundreds of chemical compounds. OP and heavy metal dietary exposures are a motive for health threats to humans.

Environmental toxicants: Diet and behavior

• • • • •

Their toxic properties pose a risk to the CNS inducing different behavioral and molecular alterations. OP and heavy metal toxicities are linked to neurological conditions during the neurodevelopmental and neurodegenerative processes. OP- and heavy metal-induced behavioral alterations can promote long-term consequences that persist in time. Oxidative stress is a key to understanding different neurological diseases upon environmental pollutant exposures. Diets rich in antioxidants can mitigate neurodegenerative disorders induced by environmental pollutants.

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PART VI

Epilepsy

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CHAPTER 23

Hypercholesterolemic diet and status epilepticus Romildo de Albuquerque Nogueira∗, Edbhergue Ventura Lola Costa, Jeine Emanuele Santos da Silva, and Daniella Tavares Pessoa

Laboratory of Theoretical, Experimental and Computational Biophysics, Department of Animal Morphology and Physiology, Rural Federal University of Pernambuco, Recife, Pernambuco, Brazil

Abbreviations 24-OHC 27-OHC AMPAR ApoA-I ApoB ApoE ApoJ BBB BCSFB CA1 CA2 CA3 CKD CNS ECoG GABA GLUT 1 HDL KD LDL MAD NMDAR NPC1L1 PSD95 PSS PUFA SCN1A VLDL

∗

24-hydroxycholesterol 27-hydroxycholesterol alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor apolipoprotein A-I apolipoprotein B apolipoprotein E apolipoprotein J blood-brain barrier blood cerebrospinal fluid barrier cornu ammonis 1 cornu ammonis 2 cornu ammonis 3 classical ketogenic diet central nervous system electrocorticography gamma-aminobutyric acid glucose transporter-1 high-density lipoprotein ketogenic diet low-density lipoprotein modified Atkins diet N-methyl-D-aspartate receptor Niemann-Pick-type C1-like 1 postsynaptic density protein 95 poststroke seizure polyunsaturated fatty acid sodium channel protein type 1 subunit alpha very low-density lipoprotein

In Absentia Contact Person: Marliete Maria Soares da Silva, Department of Animal Morphology and Physiology, Rural Federal University of Pernambuco, Av. Dom Manoel de Medeiros, s/n, Dois Irma˜os, Recife, PE, CEP 52171-900, Brazil. Phone: +55 81 33206390.

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00025-8

Copyright © 2023 Elsevier Inc. All rights reserved.

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Introduction Western countries incorporate a lifestyle based on the consumption of a high-calorie diet (Christ, Lauterbach, & Latz, 2019) which is represented by a high intake of saturated fat, sucrose, and low fiber intake (Statovci, Aguilera, MacSharry, & Melgar, 2017). This diet has a great impact on human health, increasing the occurrence of metabolic diseases, such as diabetes and obesity (Statovci et al., 2017; Zin€ ocker & Lindseth, 2018), and inducing metaflammation (Christ et al., 2019). This diet also can be associated with a risk factor for atherosclerotic cardiovascular disease (Escola`-Gil et al., 2011) and promote effects on brain function (Lo´pez-Taboada, Gonza´lez-Pardo, & Conejo, 2020). The Western diet, in addition to containing saturated fatty acid, also contains cholesterol (Escola`-Gil et al., 2011). Cholesterol is substantial to the organism (R€ ohrl & Stangl, 2018; Vicente, Sampaio, Ferrari, & Torres, 2012), and, therefore it is produced by several body cells (Zampelas & Magriplis, 2019), moreover to be obtained by foods (Luo, Yang, & Song, 2020; P€ uschel & Henkel, 2018). About 25% of the body’s cholesterol can be found in the central nervous system (CNS) (Cartocci, Servadio, Trezza, & Pallottini, 2017). The presence of this cholesterol percentage has its importance to the brain. This lipid plays an essential role in good brain activity performance (Benarroch, 2008; Ermilova & Lyubartsev, 2019). Nevertheless, when there is a cholesterol homeostasis imbalance, it can likely result in serious problems in the cerebral activity causing diseases (Loera-Valencia et al., 2021; Merino-Serrais et al., 2019; Zhang et al., 2015). Some studies have pointed the implications of a cholesterol-rich diet on brain activity (Brooks, Dykes, & Schreurs, 2017; Zhang et al., 2018). Thus, this chapter aims to describe the implications of cholesterol in brain activity, discussing the effects of a hypercholesterolemic diet on epileptic seizures.

Neurological aspect What is epilepsy? Epilepsy is a global disease that affects millions of people worldwide, with a large number of epileptic individuals living in low- and middle-income countries. It is a chronic neurological disease, characterized by repeated seizures or by one seizure with a strong potential for recurrence or diagnosis of an epilepsy syndrome (Espinosa-Jovel, Toledano, Aledo-Serrano, Garcı´a-Morales, & Gil-Nagel, 2018; Guerreiro, 2016). Temporal lobe epilepsy, whose recurrent partial seizures are generated in the hippocampus, is one of the very common forms in humans (Crepel & Mulle, 2015). The CNS activity is played by several neurotransmitters. Some of them have an inhibitory action, such as GABA, while others possess an excitatory function, for instance, glutamate, which is the major excitatory neurotransmitter (Hanada, 2020). The imbalance

Cholesterol and epileptic seizure

between the inhibitory and excitatory neurotransmissions can cause epileptic seizures (Yang et al., 2018). The breakdown of balance on inhibition and excitation mechanisms in the brain is going to result in excessive discharge of action potentials capable of promoting a seizure. This process that initiates the seizures in epilepsy is known as ictogenesis (Bamikole et al., 2019; Silva & Cabral, 2008). An epileptic seizure is a transient behavioral alteration of signs and/or symptoms caused by exacerbated atypical or synchronous neuronal activity in the CNS (Devinsky et al., 2018; Falco-Walter, Scheffer, & Fisher, 2018). A seizure is a paroxysmal change of neuronal activity due to excessive and hypersynchronous firing of brain neurons. “Epileptic seizure” is a term that must be used to differentiate a seizure resulting from abnormal neuronal firings from a nonepileptic seizure, such as a psychogenic seizure (Stafstrom & Carmant, 2015). In epilepsy, the seizures are classified according to the cerebral-onset location (focal, generalized, or unknown) and the degree of consciousness (aware or impaired awareness). The focal onset can be motor or nonmotor and also be focal to bilateral tonicclonic. Both generalized onset and unknown can be motor (tonic-clonic or another motor) and nonmotor (Falco-Walter et al., 2018).

Possible causes of epilepsy Epilepsy can have several causes (Fig. 1), so it may be classified by etiology: genetic, such as SCN1A-related epilepsies; metabolic, such as GLUT 1 deficiency; structural, such as stroke; infectious, such as bacterial or viral brain infections; immunologic, such as autoimmune encephalitis; in addition to unknown etiologies (Devinsky et al., 2018). An example of genetic etiology is somatic mosaicism (individual with two distinct genetic materials) that causes some focal epileptogenic lesions (Ellis, Petrovski, & Berkovic, 2020). Another example, genes associated with epilepsy have a functional connection with an imbalance between excitation and disinhibition, with many of these genes encoding ion channels responsible for controlling the excitability of neurons. Regarding the type of genetic mutation and type of neurons in which the ion channels are expressed, the dysfunction of the channels linked to epilepsy can promote a lot of excitement or little inhibition. This event can occur in a sodium channel of the inhibitory neuron, and the channel dysfunction will lead to reduced inhibition and increased excitability of the neuronal network, generating seizures (Bamikole et al., 2019). Poststroke seizure (PSS) is a complication of stroke and a common structural cause of seizures in the elderly population. PSS may be early onset which results from an acute neuronal injury, followed by glutamate-mediated excitotoxicity, altered ion channel function, and blood barrier rupture, while late-onset PSS may be secondary to a gliotic scar with alteration in membrane properties, chronic inflammation, neurodegeneration, changed synaptic plasticity, possibility of generating hyperexcitability, and increased synchronization of neuronal activities (Xu, 2019).

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Fig. 1 Cause of epilepsy. The illustration shows the possible causes of epilepsy.

Infections by microorganisms can cause severe complications in the CNS. Seizures can result from infections and infestations, even after the patient has recovered from an illness. Some viruses (e.g., herpes simplex), bacterial infections (e.g., bacterial meningitis), parasitosis (e.g., cerebral toxoplasmosis), and fungal (e.g., candidiasis) can be associated with seizures or epilepsy (Vezzani et al., 2016). Epilepsy may be related to autoimmune disorders. Probably, there is an autoimmune basis in individuals who present antiepileptic drug-resistant seizures. In systemic lupus erythematosus, patients have antiphospholipid antibodies that possibly promote immune-mediated cortical damage. Observation in mutations involving sodium channels in generalized epilepsy with febrile convulsions which supposes the autoimmune action on ion channels may be underlying some epileptic disorders (Greco et al., 2016).

Nutritional aspects Dietary cholesterol and its metabolism by the peripheral system Cholesterol can be obtained from the diet (Luo et al., 2020; P€ uschel & Henkel, 2018) or synthesized by the cells of vertebrate animals (Zampelas & Magriplis, 2019), being

Cholesterol and epileptic seizure

essential for humans. It is a precursor of steroid hormones (aldosterone, cortisone, progesterone, testosterone, etc.), vitamin D, and bile acids; moreover, it is present in the cell membrane (R€ ohrl & Stangl, 2018; Vicente et al., 2012). The cholesterol in the diet is absorbed via NPC1L1 protein on the apical surface of the enterocytes and incorporated in the chylomicrons (Luo et al., 2020). Then, chylomicrons are released in the bloodstream and reach the liver cells where are absorbed via receptor-mediated endocytosis (P€ uschel & Henkel, 2018). In the liver, the main site where cholesterol synthesis occurs, the cholesterol in the hepatocytes binds to specific apolipoproteins (ApoB) resulting in VLDLs that can transport sterol in the blood plasma. VLDLs, when in the bloodstream, generate LDLs which can be absorbed by peripheral cells for endocytosis. Excess cholesterol still can generate HDLs with apolipoprotein A-I (apoA-I), which is free of lipids or low in lipids, produced by the liver, intestine, and also the pancreas. The excess cholesterol undergoes esterification by the action of the acyl-coenzyme A: cholesterol acyltransferase, so cholesterol esters are stored as cholesterol reservoirs in cytosolic lipid droplets or are released as one of the main constituents of plasma lipoproteins (chylomicrons, VLDLs, LDLs, and HDLs). HDLs are moved from peripheral tissues back to the liver and intestine, where cholesterol is recycled or eliminated through bile acids (Luo et al., 2020). HDL is a crucial source of cholesterol to organs where cholesterol is used to produce steroid hormones (R€ ohrl & Stangl, 2018). Fig. 2 shows a scheme of the cholesterol dynamics in the peripheral system. The body regulates the synthesis of cholesterol to complete what is ingested in the diet, as the surplus cholesterol must be excreted since it cannot be used as energy. The mammalian cells keep cholesterol homeostasis by regulating its synthesis, uptake, and export. The cholesterol biosynthesis occurs in the endoplasmic reticulum from acetate, having 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR) as an important enzyme responsible for the synthesis of mevalonate, which is converted to squalene, later to lanosterol and then to cholesterol. The formed cholesterol leaves the endoplasmic reticulum toward the plasma membrane, where it is distributed by the vesicular and nonvesicular transport mechanism (Luo et al., 2020; Martı´n, Pfrieger, & Dotti, 2014; R€ ohrl & Stangl, 2018).

Cholesterol metabolism in the central nervous system Even though the liver assumes a large role in the cholesterol distribution to the peripheral system, several tissues are capable of synthesizing it and the brain is one of these organs (Wang, Garruti, Liu, Portincasa, & Wang, 2017; Zhang & Liu, 2015). The blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) in the CNS enable the brain cholesterol metabolism to be separate from peripheral cholesterol metabolism (Courtney & Landreth, 2016; Vitali, Wellington, & Calabresi, 2014).

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Fig. 2 Cholesterol dynamics in the peripheral system. The dietary cholesterol is absorbed and the chylomicrons, containing cholesterol, are formed in the enterocytes and absorbed by hepatocytes. Cholesterol synthesis can occur in the liver, intestine, and other peripheral tissues. Cholesterol binds to ApoB, resulting in VLDLs, or apoA-I, generating HDLs. VLDLs and HDLs transport the cholesterol in the bloodstream, and VLDLs generate LDLs which can be absorbed by peripheral cells. The HDLs are moved from peripheral tissues back to the liver and intestine. The cholesterol can be eliminated through bile acids (liver) or used in steroid hormones and vitamin D production.

Almost 25% of the body’s cholesterol is in the brain (Cartocci et al., 2017; Yoon, Flores, & Kim, 2016). It is found in the myelin sheath that is formed by oligodendrocytes to surround the axons, in addition to being an important constituent in the membranes of astrocytes and neurons (Cartocci et al., 2017; Zhang & Liu, 2015). The peripheral cholesterol transport mediated by lipoproteins to the brain is blocked by the BBB, thereby that most of the cholesterol in the CNS is synthesized in situ. The brain has cholesterol regulatory mechanisms that differ from those in the periphery. Cholesterol transfer mechanisms are similar between the brain and peripheral tissues. Apolipoproteins in the brain have distinct characteristics in relation to those of the periphery, the main ones being ApoE, ApoJ, and ApoA-I (Yoon et al., 2016). Although cholesterol is unable to cross the BBB and BCSFB, a hydroxylated cholesterol metabolite, 24S-hydroxycholesterol (24S-OHC), formed in neuronal cells by the enzyme CYP46A1, can pass from the brain to peripheral circulation. There is 27-hydroxycholesterol (27-OHC), an oxysterol produced by the cells of the body through the enzyme CYP27A1, also capable of crossing the BBB, as shown in Fig. 3. The presence of 27-OHC in the CNS is basically of extracerebral origin because the

Cholesterol and epileptic seizure

Fig. 3 CNS cholesterol dynamics. Despite neurons synthesizing cholesterol, astrocytes make it available to neurons from apoE. 24-OHC, formed in neuronal cells by the enzyme CYP46A1, is a cholesterol homeostasis regulator in the brain and it can pass from this last to the peripheral circulation, as a way of removal. 27-OHC is produced by the body cells through the enzyme CYP27A1 and is also capable of crossing both BBB and BCSFB.

brain has a very low production of this oxysterol (Vitali et al., 2014). The removal of cholesterol from the brain is enabled by the transformation of cholesterol into 24-OHC oxysterol. 24-OHC and other oxysterols are the main regulators of cholesterol homeostasis in the brain (Benarroch, 2008). Astrocytes make cholesterol available to neurons, although neurons are supposed to synthesize it (Benarroch, 2008). The synthesis of cerebral cholesterol also involves enzymes present in these cells (Martı´n et al., 2014; Zhang & Liu, 2015).

Role of cholesterol in the brain Cholesterol is a molecule with four hydrocarbon steroidal rings between the hydroxyl group and hydrocarbon chain. The presence of the hydroxyl group gives it an amphipathic property (de Oliveira Andrade, 2016). The organization of the cholesterol molecule in the cell lipid bilayer appears to create cholesterol-enriched domains known as lipid rafts. The formation of these domains is due to different interactions of cholesterol with saturated and unsaturated lipids in the cellular membrane (Ermilova & Lyubartsev, 2019). Lipid rafts also contain many specific proteins and may be involved with signaling in a variety of cellular processes (de Oliveira Andrade, 2016). They have been found at synapses; thus, probably problems in cholesterol metabolism can be reflected in pre- and

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postsynaptic activities (Egawa, Pearn, Lemkuil, Patel, & Head, 2016). Cholesterol is an important component in membrane lipid rafts in neurons and astrocytes. In addition to being important in brain development, cholesterol plays an important function in neuronal activity, regulating cell signaling pathways, gene transcription, and the availability of bioactive steroids (Benarroch, 2008). Cholesterol is substantial to maintain the membrane structure and the physicochemical properties essential for the good functional performance of cells (Ermilova & Lyubartsev, 2019). Its interaction with adjacent lipids allows it to regulate bilayer stiffness, fluidity, and permeability (Luo et al., 2020), in addition to maintaining the cell membrane integrity (Zampelas & Magriplis, 2019). Cholesterol synthesized by neighboring glial cells is taken for neurons to ensure plasticity and cellular function (Courtney & Landreth, 2016). Therefore, the cholesterol present in the cell membranes ends up being important to regulate neurotransmission (Grouleff, Irudayam, Skeby, & Schiøtt, 2015).

Merging neurological and nutritional aspects Measuring the brain activity of rats fed a hypercholesterolemic diet and submitted to the status epilepticus Experiments were carried out in our laboratory aimed to study the effect of a hypercholesterolemic diet (25% lard and 75% standard diet for rats) on brain electrical activity in male Wistar rats under basal conditions and submitted to the status epilepticus by the use of pilocarpine. The animals fed with this diet had a cholesterol level significantly higher than the control animals, showing the effectiveness of the diet (Nogueira, Pessoa, da Silva, & Costa, 2019). The histological analysis showed the presence of cell death, cytoplasmic vacuolation, and destructuration of cell layers in animals submitted to status epilepticus, mainly in the hippocampal areas CA1, CA2, and CA3. In addition, neuronal necrosis and the presence of gitter cells were also observed. The hypercholesterolemic diet had no effect on the lesions observed in animals with status epilepticus. Animals in status epilepticus without and with a hypercholesterolemic diet presented similar cell lesions (Nogueira et al., 2019). In electrophysiological experiments, the ECoG of brain electrical activity was recorded in control animals (basal condition) and animals submitted to the status epilepticus, both animal groups being fed without and with a hypercholesterolemic diet. The ECoG was analyzed through its power spectrum. The power spectrum makes it possible to measure the contribution of different frequency components that make up the time series of the ECoG signal. Then, the average power value of each rhythm that makes up the ECoG signal (delta, theta, alpha, and beta) can be accurately measured. This technique is shown in Fig. 4. A scheme with different characteristics of the brain waves can be seen in Fig. 5.

Cholesterol and epileptic seizure

Fig. 4 Signal acquisition and data processing. The ECoG recording device allows capturing the signal of brain activity from electrodes implanted directly into the cortex of the rat, and the ECoG signal is conducted to the computer (A). The brain waves are generated from the ECoG signal (B) and the average power for each wave is calculated (C).

The animals fed with the hypercholesterolemic diet and submitted to status epilepticus showed higher average power values of a beta wave, the fastest wave, than animals submitted to status epilepticus with a standard diet. The animals in status epilepticus with a hypercholesterolemic diet also showed higher values of alpha wave in relation to animals receiving a standard diet. This means that induction to the status epilepticus elicited a more pronounced excitatory effect in animals fed with a hypercholesterolemic diet (Nogueira et al., 2019). The animals only fed with the hypercholesterolemic diet (without induction to the status epilepticus) showed higher average power values of beta wave and lower average power values of delta wave, slower wave, when compared to beta wave and delta wave of control animals (standard diet). Thereby, the hypercholesterolemic diet promoted an increase in cerebral excitability. The average power values of alpha and theta waves did not present significant statistical differences (Nogueira et al., 2019).

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Fig. 5 Brain waves. The illustration shows each brain wave with its respective frequency range and its physiological characteristics.

Evaluating the effects of a hypercholesterolemic diet on status epilepticus The hypercholesterolemic diet promoted an increase in the average power of beta waves, and these values still were higher when the rats were submitted to status epilepticus than control animals. This indicates that the hypercholesterolemic diet promoted an increase in cerebral excitability. These results mean that the status epilepticus induced by pilocarpine triggered a more pronounced excitatory response in animals fed the hypercholesterolemic diet. Therefore, the diet favored a greater severity of the status epilepticus (Nogueira et al., 2019). A rise in cholesterol of neurons in the hippocampus, after suppressing the expression of the enzyme CYP46A1, leads to neuronal death and also generates epileptiform synchronies, according to Chali et al. (2015). However, our histological results did not reveal lesions resulting exclusively from the hypercholesterolemic diet, meaning that there was no increase in the level of cholesterol that could cause apparent damage to the hippocampal areas (Nogueira et al., 2019). Dufour, Liu, Gusev, Alkon, and Atzori (2006) worked with whole-cell patch-clamp recording in hippocampal brain slices of rats fed a cholesterol-enriched diet and suggested a long-lasting alteration in presynaptic functions due to an elevated paired-pulse ratio in glutamatergic synapses and GABAergic synapses. Moreover, they observed that cholesterol was able to modulate the postsynaptic function which was displayed by a lower ratio

Cholesterol and epileptic seizure

of NMDAR- and AMPAR-mediated currents in the cells of rats fed a cholesterol diet. Cholesterol has a large action on NMDAR, furthermore other effects on synaptic properties, which becomes an important regulator of synaptic transmission (Korinek et al., 2020). The NMDAR and AMPAR are glutamate ionotropic receptors, and glutamate is mainly responsible for excitatory neurotransmission in the brain. Moreover, NMDAR and AMPAR must be involved in the ictogenesis process (Hanada, 2020). Some authors suggested that the levels of 27-OHC in the brain can be increased by dietary cholesterol (Brooks et al., 2017; Zhang et al., 2018). Merino-Serrais et al. (2019) displayed that an elevated concentration of 27-OHC impairs the neuronal morphology, implicating in synaptic structural alterations. Dietary cholesterol may have some influence on 27-OHC synthesis, and the increase in the level of this oxysterol causes hippocampal synaptic plasticity changes (Loera-Valencia et al., 2021). We also suggest that 27-OHC modulates the cholesterol metabolism in the brain (Zhang et al., 2015) and this should affect NMDAR, AMPAR, and also GABAergic receptors (Dufour et al., 2006; Korinek et al., 2020). These alterations may directly cause an increase in the excitatory neurotransmission or elicit instability in the excitatory and inhibitory mechanisms in the CNS. Thus, diet cholesterol had an effect on neuronal excitability and intensified status epilepticus as identified in our results.

Applications to other neurological conditions Although cholesterol is essential for CNS, our study displayed a more pronounced excitatory activity in animals fed the hypercholesterolemic diet and in status epilepticus. Hypercholesterolemia has been related to neurodegenerative diseases (Cartocci et al., 2017). Thus, some studies reveal that disturbances in the brain cholesterol metabolism can impair normal neuronal functions, being the cause of some diseases (Brooks et al., 2017; Merino-Serrais et al., 2019; Wang et al., 2019; Zhang et al., 2015, 2018). Since the presence of 27-OHC in the brain can be associated with dietary cholesterol (Brooks et al., 2017; Zhang et al., 2018), this oxysterol is able to modulate the cholesterol metabolism, reducing the expression of HMGC-R and receptor of LDL in the rat brain, damaging the cognitive process (Zhang et al., 2015). Wang et al. (2019) have described the 27-OHC neurotoxic effect, thus being deleterious for structural and functional plasticity in hippocampal neurons. Merino-Serrais et al. (2019) have suggested a probable connection between hypercholesterolemia and neurodegeneration from concentration excess of 27-OHC that ends up decreasing the PSD-95 level, an important postsynaptic protein for synaptic support and plasticity. Moreover, 27-OHC is able to reduce hippocampal spine density, essential postsynaptic structures in the process of memory and cognition (Merino-Serrais et al., 2019).

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A study performed by Brooks et al. (2017) with rabbits fed with a cholesterol-rich diet showed an elevation of serum cholesterol; these animals also presented an increased 27-OHC level in both plasma and hippocampus. This study also revealed that increased levels of neurodegeneration in CA1/2 and CA3 of the hippocampus were associated with a cholesterol-rich diet; in addition, these animals presented alterations in hippocampus estrogen receptor expression and reduction of both postsynaptic maker PSD-95 and hippocampal mitochondria. These results may help elucidate a likely mechanism related to the development of Alzheimer’s disease. Zhang et al. (2018) carried out a study with rats fed a cholesterol diet with or without 27-OHC synthetase inhibitor, concluding that the cholesterol diet was able to cause a rise in the level of 27-OHC that may promote the production and deposition of β-amyloid peptides in the brain. According to these authors, 27-OHC may impair the memory and learning of rats; furthermore, this oxysterol may be involved in lysosome function and cholesterol metabolism. Fig. 6 shows the possible effects of dietary cholesterol action on the brain from the increase in 27-OHC.

Fig. 6 Possible effects of dietary cholesterol action on the brain. Raising dietary cholesterol may promote an increase in 27-OHC, resulting in various effects on the brain.

Cholesterol and epileptic seizure

A study performed by Chen, Yin, Cao, Hu, and Xiao (2018) showed that a cholesterol-rich diet had harmful and protective effects on the brains of aged mice. The authors observed that this diet neither did aggravate the spatial cognitive deficits nor increase hippocampus neuronal degeneration. This diet had promoted pro- and antiinflammatory effects, as well as, implicated in the expression rise of presynaptic proteins (synaptophysin and growth-associated protein-43) in the hippocampus. These results show that studies still must be conducted to clarify if hypercholesterolemia is really associated with Alzheimer’s disease since some studies showed an evident association between LDL cholesterol serum concentrations and increased risk for Alzheimer’s disease (Sa´izVazquez, Puente-Martı´nez, Ubillos-Landa, Pacheco-Bonrostro, & Santaba´rbara, 2020). Paul et al. (2017) observed that mice with hypercholesterolemia presented a depletion of dopamine in the striatum and serotonin in the cortex. The authors concluded that the depletion of cortex and striatum biogenic amines was provoked by a cholesterol-rich diet; this depletion can be observed in the Parkinson’s disease pathology. However, the cohort study of statin-free individuals showed that there was a low Parkinson’s disease risk indicated by increased concentrations of LDL and total cholesterol among men over time (Rozani et al., 2018). This evidence points to the need for further studies to elucidate whether cholesterol is a villain or hero in the story of disease’s physiopathology.

Other components of interest Unlike cholesterol which contributes to status epilepticus, the use of diets enriched in different lipids has contributed to help in the treatment of this disease. The ketogenic diet (KD) is a nonpharmacological treatment developed by physician Dr. Russel M. Wilder in 1920 that has presented beneficial effects for children and teenagers with epileptic seizures (Dashti et al., 2006; Lima, Sampaio, & Damasceno, 2015). This diet can produce ketonemia, containing a high-fat and low-carbohydrate ratio. A less-restricted KD was developed in 1972 by cardiologist Dr. Robert C. Atkins, which is also high in fat and low in carbohydrates. There are other KD therapies such as medium-chain triglyceride oil diet and low glycemic index treatment, whose ratios of fat to carbohydrate and protein (1:1) are similar to the modified Atkins diet—MAD (Sampaio, 2016). Both classical KD (CKD) and MAD have been used as treatments for drug-resistant seizures in children and also in adults with refractory epilepsy (Cervenka, Patton, Eloyan, Henry, & Kossoff, 2016). CKD has 4 g of fat ratio to 1 g of carbohydrates and proteins (4:1). The fat will provide about 90% of the daily caloric intake while the carbohydrates will provide about 2%. MAD is a less-restrictive option than CKD that limits net carbohydrates to 10–20 g/day but allows an ad libitum fat intake (Cervenka et al., 2016). In addition to the 4:1 ratio, another commonly used ratio to control seizures is 3:1. A smaller ratio (2:1) can also be made when the treatment is introduced (Lima et al., 2015). Besides KD by enteral route,

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a study done by Chiusolo et al. (2016) has shown that intravenous KD may be a temporary alternative for patients with partial or total intestinal failure who need KD. According to Armeno, Verini, Araujo, Reyes, and Caraballo (2019), patients with parenteral KD may have a good response despite a lower ketogenic ratio for this route. Various works evidence the effectiveness of KD in a wide range of epilepsies, decreasing the seizures or allowing patients to be free of certain seizures. This diet may contribute to the control for periods of severe seizure exacerbation or in the catastrophic onset of epileptic encephalopathy episodes. Furthermore, KD provides an alternative energy source to the brain, and it is recommended for children that have glucose-1 transporter defects or pyruvate dehydrogenase deficiency (McTague & Cross, 2013). The anticonvulsant activity of KD must be certainly related to its lipid components. The PUFA that can be found in KD would be a strong candidate to show the anticonvulsant properties, due to eicosapentaenoic acid and docosahexaenoic acid possessing antiinflammatory activity. However, Dupuis, Curatolo, Benoist, and Auvin (2015) have observed that the pro-inflammatory cytokine levels were lower in rats submitted to the KD, besides a reduction in the circulating level of arachidonic acid and long-chain n-3 PUFA. Although Pessoa, da Silva, Costa, and Nogueira (2017) showed that the supplementation with omega-3 did not promote a significant difference in brain electrical activity in rats with status epilepticus, it reduced neuronal damages. A plausible explanation for the understanding of the KD anticonvulsant property would be the ketone body generation by this diet which may increase membrane potential hyperpolarization, raise gamma-aminobutyric acid synthesis, as well as reduce the release of norepinephrine, glutamate, or adenosine (Sampaio, 2016).

Mini-dictionary of terms Brain waves are oscillating electrical voltages in the brain measured by frequency and range from very slow to very fast. Each wave correlates with different behavioral states. EEG is the record of brain electrical activity, obtained through electrodes placed on the patient’s head and connected to an electrical current amplifier that increases the amplitude of the brain’s electrical signal thousands of times. The amplifier is connected to a computer, in which the oscillations of the electric current are digitized and can be analyzed by the doctor or researcher. EEG is the most used test in the diagnosis of epilepsy. ECoG, similar to EEG, is the recording of the electrical signal from the brain, but with the electrodes placed directly on the cerebral cortex. Both EEG and ECoG are records of the voltage of brain electrical activity as a function of time. ECoG power spectrum is a graph of the power in the function of the frequency. Mean power is the integral (area) of this graph and can be calculated in a range of frequency (fs, fe) as follows:

Cholesterol and epileptic seizure

ðf e Eω ¼

fs

jF ðf Þj2 df ðf e df fs

The mean power obtained in the power spectrum allows us to estimate the contribution of different brain rhythms in the ECoG signal. Gitter cells are cells that phagocyte dead neurons.

Key facts of epilepsy • • • • •

Epilepsy is a chronic neural condition that affects people of all ages. This disease is characterized by recurrent epileptic seizures that can vary from brief inattention or muscle spasms to severe and prolonged seizures. About 50 million people have epilepsy, making it the most prevalent neurological disease in the world. When correctly diagnosed and treated, approximately 70% of patients can live without recurrent seizures. People with epilepsy and their families suffer from discrimination and stigma in many parts of the world.

Summary points 1. Cholesterol plays an essential role in the good performance of brain activity, and an imbalance of cholesterol homeostasis can cause neural diseases. 2. The imbalance between the inhibitory and excitatory neurotransmissions can cause epileptic seizures. 3. The mammalian cells keep homeostasis of cholesterol by the regulation of its synthesis, uptake, and export. 4. BBB and BCSFB in the CNS enable the brain cholesterol metabolism to be separate from peripheral cholesterol metabolism. 5. The transformation of cholesterol into oxysterol 24-OHC allows the elimination of the first one in the brain. 6. Cholesterol plays a crucial role in maintaining the membrane structure and the physicochemical properties necessary for the proper functioning of the cell. 7. The hypercholesterolemic diet had no effect on the lesions observed in animals with status epilepticus. Both animals in status epilepticus with a standard and with a hypercholesterolemic diet presented similar cell lesions.

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8. The animals fed with the hypercholesterolemic diet and submitted to status epilepticus showed higher average power values of beta waves than animals submitted to status epilepticus with a standard diet. This means that pilocarpine elicited a more pronounced excitatory effect in animals fed with a hypercholesterolemic diet. 9. We suggested that 27-OHC modulates the cholesterol metabolism in the brain and this should affect NMDAR, AMPAR, and also GABAergic receptors. Therefore, these alterations may directly cause an increase in the excitatory neurotransmission or elicit instability in the excitatory and inhibitory mechanisms in the CNS. Thus, diet cholesterol had an effect on neuronal excitability and intensified status epilepticus as identified in our results.

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R€ ohrl, C., & Stangl, H. (2018). Cholesterol metabolism—Physiological regulation and pathophysiological deregulation by the endoplasmic reticulum. Wiener Medizinische Wochenschrift, 168, 280–285. Rozani, V., Gurevich, T., Giladi, N., El-Ad, B., Tsamir, J., Hemo, B., et al. (2018). Higher serum cholesterol and decreased Parkinson’s disease risk: A statin-free cohort study. Movement Disorders, 33, 1298–1305. Sa´iz-Vazquez, O., Puente-Martı´nez, A., Ubillos-Landa, S., Pacheco-Bonrostro, J., & Santaba´rbara, J. (2020). Cholesterol and Alzheimer’s disease risk: A meta-meta-analysis. Brain Sciences, 10, 386. Sampaio, L. P. D. B. (2016). Ketogenic diet for epilepsy treatment. Arquivos de Neuro-Psiquiatria, 74, 842–848. Silva, A. V. D., & Cabral, F. R. (2008). Ictog^enese, epileptog^enese e mecanismo de ac¸a˜o das drogas na profilaxia e tratamento da epilepsia. Journal of Epilepsy and Clinical Neurophysiology, 14, 39–45. Stafstrom, C. E., & Carmant, L. (2015). Seizures and epilepsy: An overview for neuroscientists. Cold Spring Harbor Perspectives in Medicine, 5, a022426. Statovci, D., Aguilera, M., MacSharry, J., & Melgar, S. (2017). The impact of western diet and nutrients on the microbiota and immune response at mucosal interfaces. Frontiers in Immunology, 8, 838. Vezzani, A., Fujinami, R. S., White, H. S., Preux, P. M., Bl€ umcke, I., Sander, J. W., et al. (2016). Infections, inflammation and epilepsy. Acta Neuropathologica, 131(2), 211–234. Vicente, S. J., Sampaio, G. R., Ferrari, C. K., & Torres, E. A. (2012). Oxidation of cholesterol in foods and its importance for human health. Food Reviews International, 28, 47–70. Vitali, C., Wellington, C. L., & Calabresi, L. (2014). HDL and cholesterol handling in the brain. Cardiovascular Research, 103, 405–413. Wang, Y., An, Y., Zhang, D., Yu, H., Zhang, X., Wang, Y., et al. (2019). 27-hydroxycholesterol alters synaptic structural and functional plasticity in hippocampal neuronal cultures. Journal of Neuropathology & Experimental Neurology, 78, 238–247. Wang, H. H., Garruti, G., Liu, M., Portincasa, P., & Wang, D. Q. H. (2017). Cholesterol and lipoprotein metabolism and atherosclerosis: Recent advances in reverse cholesterol transport. Annals of Hepatology, 16, S27–S42. Xu, M. Y. (2019). Poststroke seizure: Optimising its management. Stroke and Vascular Neurology, 4, e000175. Yang, Y., Tian, X., Xu, D., Zheng, F., Lu, X., Zhang, Y., et al. (2018). GPR40 modulates epileptic seizure and NMDA receptor function. Science Advances, 4, eaau2357. Yoon, H., Flores, L. F., & Kim, J. (2016). MicroRNAs in brain cholesterol metabolism and their implications for Alzheimer’s disease. Biochimica et Biophysica Acta (BBA)—Molecular and Cell Biology of Lipids, 1861, 2139–2147. Zampelas, A., & Magriplis, E. (2019). New insights into cholesterol functions: A friend or an enemy? Nutrients, 11, 1645. Zhang, J., & Liu, Q. (2015). Cholesterol metabolism and homeostasis in the brain. Protein & Cell, 6, 254–264. Zhang, X., Lv, C., An, Y., Liu, Q., Rong, H., Tao, L., et al. (2018). Increased levels of 27-hydroxycholesterol induced by dietary cholesterol in brain contribute to learning and memory impairment in rats. Molecular Nutrition & Food Research, 62, 1700531. Zhang, D. D., Yu, H. L., Ma, W. W., Liu, Q. R., Han, J., Wang, H., et al. (2015). 27-hydroxycholesterol contributes to disruptive effects on learning and memory by modulating cholesterol metabolism in the rat brain. Neuroscience, 300, 163–173. Zin€ ocker, M. K., & Lindseth, I. A. (2018). The Western diet–microbiome-host interaction and its role in metabolic disease. Nutrients, 10, 365.

CHAPTER 24

Low glycemic index therapy: What it is and how it compares to other epilepsy diets Vishal Sondhia and Sheffali Gulatib a

Department of Pediatrics, Armed Forces Medical College, Pune, India Center of Excellence & Advanced Research on Childhood Neurodevelopmental Disorders, Child Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India b

Abbreviations AD ALS GI KD LGIT MAD PD

Alzheimer’s disease amyotrophic lateral sclerosis glycemic index ketogenic diet low glycemic index therapy modified Atkins diet Parkinson’s disease

History Hippocrates first described a dietary approach for epilepsy treatment. He narrated an account of a man whose seizures were controlled by fasting, and he wrote of fasting “purifications” as a cure for seizures (Hippocrates, 400 BC). The first scientific account of fasting in epilepsy appeared in 1911 when Drs Marie and Guelpa described a cyclical fasting regime of 4 days of fasting and purges followed by 4 days of a vegetarian diet (Guelpa & Marie, 1911). Of the 20 patients studied, 15 could not adhere to the diet for more than one cycle, while the remaining five had a significant reduction in seizure burden. However, despite the improvement, the long-term compliance with protocol was limited. Hence, they concluded that “their regimen was too difficult for most adults to follow” (Guelpa & Marie, 1911). Dr. Geyelin of New Year Presbyterian studied this phenomenon extensively in the 1910s and 1920s. He observed a 10-year-old boy with refractory epilepsy, becoming cured after four fasts over 4 months under the care of osteopath Dr. Conklin. Dr. Geyelin then treated a 9-year-old boy with a 3-day fast. With these encouraging observations, he started treating an increasing number of patients with increasing lengths of fasting and reported his observations in 1921. He reported that 26 patients with epilepsy Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00047-7

Copyright © 2023 Elsevier Inc. All rights reserved.

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(ages 3–35 years) underwent intermittent fasting, 22 had seizure remission by the 10th day of fasting, and 18/26 had marked improvement one year following fasting and had no further seizures (Geyelin, 1921). Concurrently, Dr. Conklin advocated gut rest and starved his patients for up to 25 days. In 1922, he reported 90% success in seizure reduction in children 50% seizure reduction after 6 months (Kossoff, Krauss, McGrogan, & Freeman, 2003). Similar successful outcomes have been reported in subsequent retrospective/prospective/randomized studies. Auvin and colleagues, in their review of 7 prospective and two retrospective studies, summarized the efficacy of MAD as follows: the proportion of patients with >50% seizure reduction after 1 month: 51/87 (59%), after 3 months: 73/152 (48%), and after 6 months: 46/119 (39%) (Auvin, 2012). A randomized controlled trial of the use of MAD for the treatment of drugresistant epilepsy from our center demonstrated that the proportion of patients with >90% seizure reduction (30% vs. 7.7%, P ¼ 0.005) and that with>50% seizure reduction (52% vs. 11.5%, P < 0.001) was significantly higher in the MAD group than in the control group after 3 months (Sharma, Sankhyan, Gulati, & Agarwala, 2013). However, despite excellent results in reducing seizure burden, MAD administration is associated with a side-effect profile nearly similar to KD, with some of the adverse events like long QT syndrome being life-threatening (Kossoff et al., 2018; Sharma et al., 2013).

Low glycemic index therapy Jenkins, in 1981, developed a concept for describing glucose availability potential of various food items ( Jenkins et al., 1981). He reported that both the quantity and quality of ingested food determined an individual’s blood glucose change and captured this idea under the terminology glycemic index (GI). The GI is a numerical value assigned to foods based on how slowly or how quickly those foods cause an increase in blood glucose levels. GI values are compared with a standard reference value of glucose and are influenced by the rate of digestion and absorption of food components. GI calculation follows the following methodology. First, ten individuals consume a test food that contains 50 g of glucose. Their postprandial glucose levels are measured serially at predefined time intervals, and an area under the curve is constructed. Subsequently, the same ten individuals, at a different time point, consume 50 g of glucose. And their postprandial blood glucose is charted similarly at predefined time intervals over 2 h. For each individual, the area under the curve for the test food is divided by the area under the curve for glucose. The average of the ten quotients thus obtained determines the GI for that food item (Brand-Miller, Colagiuri, & Foster-Powell, 2006; Neal, 2012). The foods with complex carbohydrates that require prolonged digestion and those absorbed slowly have a lower GI value. Typically, foods higher in fiber and acidity have a lower GI. The other factors that impact the GI of food include its ripeness, processing and fiber content of the food, and its cooking method. In addition, the presence of other macronutrients like fat or protein that delay gastric emptying further lowers the GI of foods (Kumada, Miyajima, Hiejima, Nozaki, & Hayashi, 2013; Neal, 2012).

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Low GI foods are defined as foods with a GI less than 50, which maintain a reasonably stable blood glucose level. Low glycemic index therapy (LGIT) diet has been used for several decades to manage diabetes mellitus, obesity, polycystic ovary syndrome, and cardiac disorders (Kumada et al., 2013). Its role in intractable epilepsy was first demonstrated in the early 2000s by researchers from Boston and has been described in detail later (Pfeifer & Thiele, 2005).

LGIT: Concept and composition The classic KD is a low-carbohydrate regime. The observation that blood glucose level stays stable while on a low-carbohydrate regimen led to the suggestion that administration of a diet based on low GI carbohydrates can ensure this glucose stability and allow a more liberal ketogenic protocol. Hence, this alternative KD from Boston allows a liberal daily intake of carbohydrates (40–60 g per day), provided that the GI of carbohydrates is restricted to less than 50 (Kumada et al., 2013; Pfeifer & Thiele, 2005). In LGIT, the typical calorie proportions are as follows: fat ¼ 60–65%, protein ¼ 20–30%, and carbohydrates ¼ 10–15%. The calories and fluids are not restricted. Hence, the result is a diet that is more palatable, less rigid, and maintains a ketogenic ratio of almost 1:1. The foods are based on portion sizes and hence need not be weighed either. The GI values of some foods can be found in the literature; however, unfortunately, GI data are not readily available for all foods. Figure 1 illustrates the typical dietary proportions in LGIT as compared to the clinical KD and MAD. Table 1 outlines the diet protocols for classical KD, MAD, and LGIT.

Mechanism of action The cellular basis of the effectiveness of the LGIT has not been established. Three possible mechanisms have been hypothesized for the KD and similar alternative diets like the LGIT: (a) stabilization of blood and brain glucose levels; (b) the provision of alternative energy substrates in the form of ketone bodies; and/or (c) the antiseizure  antiinflammatory action of the metabolic products like ketone bodies and polyunsaturated fatty acids (Bough & Rho, 2007; Kim, Petrou, & Reid, 2014). Triheptanoin is a triglyceride containing heptanoate that is metabolized to produce intermediates of the citric acid cycle capable of anaplerosis. Triheptanoin-supplemented diet reduces seizure burden in the mouse model by 40%, suggesting that anaplerosis could be an important underlying mechanism for the KD (Kim, Borges, Petrou, & Reid, 2013; Kim et al., 2014). Kim and colleagues have demonstrated that a low GI diet has a similar impact on seizure burden, but the same effect is not seen when glucose levels are controlled with insulin (Kim et al., 2013). This suggests that rapid blood (and brain) glucose fluctuations may be associated with increased seizure propensity.

LGIT and epilepsy

Table 1 Protocols for ketogenic diet, modified Atkins diet, and low glycemic index therapy diet. Protocol for ketogenic diet

Carbohydrate-free medications where possible (switch from syrups to tablets) Carbohydrate: 0.4). The scheme of classical KD includes three isocaloric main meals and one or more snacks. Substitutions between fats and carbohydrates should be done in each meal and snack to maintain a constant ketogenic ratio. All foods must be strictly weighed. Adherence to weights and consumption of only known foods are essential; small variations can alter the balance of the ketogenic ratio and affect ketone body levels. Special attention should be paid to avoid drugs, homeopathic products, vitamin supplements, and even toothpastes and mouthwashes containing sugars.

Medium-chain triglyceride (MCT) diet and modified MCT diet Medium-chain triglycerides (MCTs) are triglycerides with two or three saturated fatty acids consisting of 6–12 carbon atoms, such as caproic, caprylic, capric, and lauric acids. They are extensively present in milk, coconut oil, and some oils extracted from seeds. Unlike triglycerides with long-chain saturated fatty acids (LCTs, with more than 12 carbon atoms), MCTs can be directly absorbed by the intestinal mucosa and are discharged directly into the portal system and transported to the liver, without passing through the lymphatic system. They subsequently undergo β-oxidation after having entered into the mitochondrion without the intervention of carnitine. MCTs are more ketogenic than their LCT counterparts because their metabolism generates more ketone bodies per unit of produced energy. The original MCT diet that was elaborated in the 1970s was based on the replacement of foods rich in long-chain fatty acids with medium-chain fatty acids. This strategy allowed patients to consume more carbohydrates and proteins without remarkable

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changes in the induction of ketosis. The initial MCT diet consisted of approximately 71% of the caloric intake from medium-chain fatty acids, 10% from protein, and 19% from carbohydrates (Runyon & So, 2012). The rapid absorption of the prescribed quote of MCTs in the gastrointestinal tract resulted in a high frequency of various side effects including abdominal pain, diarrhea, nausea, and vomiting. For this reason, it was proposed a modified MCT diet including 30% of the caloric intake as mediumchain triglycerides, 40%–50% as long-chain triglycerides, 10%–20% as protein, and 5%–10% as carbohydrates (Runyon & So, 2012). Other authors demonstrated that an amount of MCTs between 40% and 50% of total caloric intake appears to be well tolerated and produces an acceptable state of ketosis (Miranda, Turner, & Magrath, 2012).

Modified Atkins diet (MAD) The Atkins diet became popular in the Western countries for the treatment of obesity in the 1970s and it is based on a drastic reduction in carbohydrates and a high intake of protein and fat. This diet results in a certain degree of ketosis, forcing the body to burn mainly lipids for energy (lipolysis). The modified Atkins diet (MAD) differs from the Atkins diet in three aspects: (1) the induction phase of the diet, during which carbohydrates are limited, is maintained indefinitely; (2) lipid intake is encouraged (not just allowed); (3) weight loss is not the goal to be achieved (Kossoff & Dorward, 2008). The modified Atkins diet has a macronutrient ratio of 1:1. Carbohydrates are reduced to 10 g/day in children and 15 g/day in adults (increasing to 15–20 g/day after 1–3 months). There is no protein restriction, and fat intake is favored (Kossoff & Dorward, 2008; Miranda et al., 2012). It can be easily started on an outpatient regimen; it is more palatable, less restrictive, and better tolerated by adolescents and adults.

Low glycemic index treatment (LGIT) The creation of the low glycemic index treatment (LGIT) diet allowed to formulate a diet that was more palatable and acceptable to patients than the classic KD (Pfeifer & Thiele, 2005). The LGIT diet induces lower levels of ketosis than classical KD. However, it restricts carbohydrates to those with a low glycemic index (< 50) resulting in a postprandial reduction in blood glucose and insulin levels. These metabolic changes may have an additional anticonvulsant effect (Miranda et al., 2012). The LGIT diet provides about 10% of the caloric intake in the form of carbohydrates with a low glycemic index (40–60 g/day), 50%–60% as lipids, and about 20% as proteins (Miranda et al., 2012).

Ketogenic diet and epilepsies

Evaluation of candidates for ketogenic diet A thorough assessment should be obtained, before starting KD, to check the suitability of the dietary intervention as a treatment option for the patient as well as to rule out preexisting contraindications (Tables 2 and 3) (Kossoff et al., 2018). The baseline monitoring includes: Table 2 Preliminary evaluation and monitoring scheme for the follow-up of patients on ketogenic diet. Advised pre-KD evaluation Essential

Follow-up Essential

Blood tests

– Complete blood count with platelets – Electrolyte profile – Serum liver tests – Serum kidney tests (including albumin, blood urea nitrogen, and creatinine) – Fasting lipid profile – Glucose levels – Serum acylcarnitine profile – Vitamin D levels – Antiseizure drug levels (if applicable)

Blood tests

Urine tests

– Urinalysis (to assess urinary calcium excretion and hematuria) – Creatinine ratio – EEG (to identify possible candidates for surgery) – MRI of brain (to identify possible candidates for surgery)

Urine tests

Instrumental tests

Recommended

Blood tests

Urine tests

– Complete blood count with platelets – Electrolyte profile – Serum liver tests – Serum kidney tests (including albumin, blood urea nitrogen, and creatinine) – Fasting lipid profile – Glucose levels – Serum acylcarnitine profile – Vitamin D levels – Antiseizure drug levels (if applicable) – Urinalysis (to assess urinary calcium excretion and hematuria) – Creatinine ratio – EEG (when clinically indicated and at KDT discontinuation consideration) – Dual-energy X-ray absorptiometry—DEXA (after 2 years on the KD)

Recommended

– Vitamins A, E, and B12 levels – Zinc, selenium, and copper levels – Folate and ferritin levels – Serum amino acid profile (if diagnosis unclear) – Urine organic acid profile (if diagnosis unclear)

Blood tests (6 months, then every 12 months)

– Vitamins A, E, and B12levels – Zinc, selenium, and copper levels – Folate and ferritin levels

Continued

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Table 2 Preliminary evaluation and monitoring scheme for the follow-up of patients on ketogenic diet—cont’d Advised pre-KD evaluation

Instrumental tests

– ECG (strongly recommended if there is a personal or family history of heart disease) – Renal ultrasounds (if there is a personal or family history of kidney stones)

Follow-up

Instrumental tests

– ECG (when clinically indicated) – Renal ultrasounds (after 12 months)

The table summarizes the preliminary steps to evaluate candidates for ketogenic diet and the diagnostic protocol for the follow-up of patients under this dietary regimen. Adapted from Kossoff, E. H., Zupec-Kania, B. A., Auvin, S., Ballaban-Gil, K. R., Bergqvist, A. G. C., Blackford, R., Buchhalter, J. R., Caraballo, R. H., Cross, J. H., Dahlin, M. G., Donner, E. J., Guzel, O., Jehle, R. S., Klepper, J., Kang, H.-C., Lambrechts, D. A., Liu, Y. M. C., Nathan, J. K., Nordli, D. R., … Wirrell, E. C. (2018). Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the international ketogenic diet study group. Epilepsia Open, 3(2), 175–192. https://doi.org/10.1002/epi4.12225.

Table 3 Contraindications of ketogenic diet. Absolute

• • • • • • • • • • •

Carnitine deficiency (primary) Carnitine palmitoyltransferase (CPT) I or II deficiency Carnitine translocase deficiency b-oxidation defects Medium-chain acyl dehydrogenase deficiency (MCAD) Long-chain acyl dehydrogenase deficiency (LCAD) Short-chain acyl dehydrogenase deficiency (SCAD) Long-chain 3-hydroxyacyl-CoA deficiency Medium-chain 3-hydroxyacyl-CoA deficiency Pyruvate carboxylase deficiency Porphyria

Relative

• • • •

Inability to maintain adequate nutrition Surgical focus identified by neuroimaging and video-EEG monitoring Parent or caregiver noncompliance Propofol concurrent use (risk of propofol infusion syndrome may be higher)

Contraindications to the use of KD. Adapted from Kossoff, E. H., Zupec-Kania, B. A., Auvin, S., Ballaban-Gil, K. R., Bergqvist, A. G. C., Blackford, R., Buchhalter, J. R., Caraballo, R. H., Cross, J. H., Dahlin, M. G., Donner, E. J., Guzel, O., Jehle, R. S., Klepper, J., Kang, H.-C., Lambrechts, D. A., Liu, Y. M. C., Nathan, J. K., Nordli, D. R., … Wirrell, E. C. (2018). Optimal clinical management of children receiving dietary therapies for epilepsy: Updated recommendations of the international ketogenic diet study group. Epilepsia Open, 3(2), 175–192. https://doi.org/10.1002/epi4.12225.

Ketogenic diet and epilepsies

– Physical examination to evaluate weight, height, BMI, and head circumference in infants. – Nutritional status evaluation to assess food allergies/intolerances or feeding problems and to find out cultural/religious preferences. – Blood and urine tests to exclude metabolic disorders or deficiencies that are contraindications to KD and to assess any complicating comorbidities such as dyslipidemia, liver disease, or chronic metabolic acidosis. – Instrumental tests as essential examinations of patients who are possible surgical candidates (Stainman, Turner, Rubenstein, & Kossoff, 2007) or as optional examinations in the presence of a personal or family history of kidney stones or cardiomyopathy.

Monitoring children on ketogenic diet During the first weeks after the diet initiation, clinicians should frequently have a contact with the caregivers by phone, e-mails, or other telemedicine tools. Periodic follow-up visits should be scheduled at 1, 3, 6, 9, and 12 months during the first year of KD, and every 6 months afterward. It is well established that controlling ketosis (blood β-hydroxybutyrate (BHB) concentrations) is the most consistent metabolic biomarker of adherence to KD. However, it has been recently shown that ketosis correlates to seizure control at 3 months (Lambrechts et al., 2017), but no more at 6 and 12 months (Wijnen et al., 2017). Despite unclear clinical evidence of usefulness, most pediatric neurology centers monitor blood BHB (recommended levels ¼ 4–6 mmol/L) (Schoeler & Cross, 2016). Therefore, the most important parameters to assess KD efficacy remain seizure control and other clinical outcomes. However, if BHB levels are lower than expected and the child shows a poor response, a brief but detailed food diary (3–5 days) may be useful to adjust the diet implementation. An AED dosage adjustment is currently not recommended while applying KD and the neurologist should avoid altering the AED therapy unless necessary, even if there is no rapid seizure reduction. Otherwise, it could be difficult to determine the diet effect on epilepsy. The potential interactions between KD and other antiepileptic treatments should be strictly monitored. A recent prospective study highlighted that MAD might reduce the plasma concentration of some AEDs up to 10% (e.g., valproate, carbamazepine, lamotrigine, topiramate, lacosamide, and clobazam) even if other authors have failed to demonstrate relevant pharmacokinetic interactions (Kverneland et al., 2019). Other authors reported a seizure frequency reduction (SFR) higher than 50% with the combination of KD with zonisamide while a less favorable response was reported when the combined AEDs were phenobarbital or valproate (Morrison, Pyzik, Hamdy, Hartman, & Kossoff, 2009; Spilioti et al., 2016).

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Adverse effects and tolerability Short-term adverse effects usually occur within the first few weeks of dietary therapy. The most common ones are gastrointestinal (GI) disturbances, such as constipation or diarrhea, nausea and vomiting, abdominal pain, or gastroesophageal reflux. These GI adverse effects are reported in at least 15% (Sourbron et al., 2020) and up to 50% (Phillips, 2019) of children on KD. Other less common short-term adverse effects include dehydration, hypoglycemia, metabolic acidosis, lethargy, irritability, and anorexia. As these complications depend on the metabolic shift induced by KD, they should be expected and should not lead to discontinuation of treatment. Furthermore, most of these conditions can be treated by dietary adjustments (e.g., increasing fluid, salt, and fiber intake) (Kossoff et al., 2018) or drugs (e.g., laxatives, antiemetics, or H2-blockers). Severe adverse effects, such as respiratory failure, thrombocytopenic purpura, cardiomyopathy, and pancreatitis, have been reported in no more than 0.5% of children on KD (Cai et al., 2017). Among the long-term adverse effects, hyperlipidemia, low HDL (high-density lipoprotein), and high LDL (low-density lipoprotein) are reported in up to 60% of children. This increase is usually transient (normalizing within 12 months) and responsive to simple dietary adjustments (e.g., increasing flaxseed or olive oil in exchange of saturated fats, or supplementing with MCT oil or L-carnitine) (Kossoff et al., 2018). KD has been reported to have a potential negative effect on children’s growth even if the results of several studies are inconclusive and inconsistent, due to an inadequate length of observation periods and differences in diets and populations. Overall, more than 12 months on KD have been associated with a negative impact on a child’s growth (Cai et al., 2017). Adjustments in caloric intake might help to compensate for this effect. An old study suggested that KD may reduce bone mineral content, despite supplementation with calcium and vitamin D, with worse results for younger children and subjects with lower BMI (Bergqvist, Schall, Stallings, & Zemel, 2008). Due to this risk of osteopenia, it could be useful to realize a bone density scan every 2 years. Patients on KD may present with hypercalciuria, urinary acidification, and low citrate excretion resulting in a potential ureteral stone formation, especially when the fluid intake is low. The risk of urolithiasis might be increased if a concurrent treatment with carbonic anhydrase inhibitors (acetazolamide, topiramate, and zonisamide) is used. A study reported kidney stones in 13 out of 195 children on classical KD without an evident correlation with the use of topiramate or zonisamide (Sampath, Kossoff, Furth, Pyzik, & Vining, 2007). In another cohort of 93 children on KD, 6 children developed urolithiasis, of whom 3 were also on zonisamide and 1 on topiramate (Paul et al., 2010).

Ketogenic diet and epilepsies

Despite inconclusive evidence, many centers propose periodic renal ultrasound in children in which KD is combined with carbonic anhydrase inhibitors. Moreover, an adequate hydration and supplementation with oral citrates (potassium citrate is usually preferred over sodium citrate) may help to reduce the risk of kidney stones. Some authors reported that children on KD may have higher arterial stiffness parameters, which might contribute to develop atherosclerosis later in life even if the collected data are inconclusive (Sourbron et al., 2020).

Ketogenic diet in pediatric drug-resistant epilepsies A recent meta-analysis reviewed the evidence from high-quality randomized controlled trials concerning two of the most common KD regimes in children and adolescents (classic KD and MAD) and highlighted a seizure frequency reduction (SFR) higher than 50% in 35%–56.1% of the patients receiving the dietary intervention versus 6–18.2% of the controls (Sourbron et al., 2020). Another meta-analysis evidenced that classical KD did not differ significantly from MAD in short- and long-term SFR and that, overall, the number of children and adolescents achieving seizure freedom increases over time during KD (Rezaei, Abdurahman, Saghazadeh, Badv, & Mahmoudi, 2019). A 6-week treatment period is considered sufficient to determine the success or the failure of the diet. Previous studies reported that 75% of children respond to KD treatment within 14 days (Kossoff et al., 2008), while complete seizure freedom requires at least 3–18 months in KD-responders (Taub, Kessler, & Bergqvist, 2014). Furthermore, there is also evidence that children younger than 2 years of age tend to respond better to KD, given that seizure freedom is most often achieved and maintained in younger patients (Zarnowska, 2020). Moreover, tolerability and compliance are also generally better in infants even if good results were also obtained in more recent trials involving adolescents and adults (Kishk et al., 2021). It should be considered that the effectiveness of KD is not limited to seizure control. KD has proven positive effects on motor and language development, attention and global cognition, and sleep quality by increasing REM (rapid eye movement) sleep (Hallb€ oo €k, Lundgren, & Rosen, 2007; van Berkel, Ijff, & Verkuyl, 2018). Different studies have shown that the efficacy of KD may be predicted in specific genetic conditions. For instance, it is well documented that patients with developmental and epileptic encephalopathy due to SCN1A, SCN2A, KCNQ2, or STXBP1 pathogenic variants tend to respond effectively to KD, while CDKL5encephalopathy is typically associated with an evident ineffectiveness (Schoeler et al., 2018).

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Ketogenic diet as gold standard therapy: GLUT-1 deficiency syndrome and pyruvate dehydrogenase deficiency KD represents the first choice’s treatment for two different disorders of brain energy metabolism: GLUT-1 deficiency syndrome (Glut1DS) and pyruvate dehydrogenase deficiency (PDHD) (Klepper et al., 2020; Sofou et al., 2017). In these disorders, KD provides an alternative energy source to glucose (e.g., ketone bodies) to support both brain development and normal neuronal function contributing to seizure control and mitigating other clinical symptoms (Gavrilovici & Rho, 2021). Glut1DS is due to a defect in the glucose transporter (GLUT-1) encoded by the SLC2A1 gene on chromosome 1p34.2. The impaired glucose transport over the blood–brain barrier leads to decreased glucose concentration in the cerebrospinal fluid (hypoglycorrhachia) but without hypoglycemia. Despite the exact pathogenic mechanism is not yet fully understood, it has been hypothesized that the reduced availability of glucose in the developing brain causes an impaired maturation of thalamo-cortical metabolism resulting in epileptogenic cascades (Pascual et al., 2007). Glut1DS shows a wide phenotypic variability. The most notable clinical features are early-onset pharmaco-resistant seizures (Figs. 2 and 3 show an illustrative case) or epileptic and developmental encephalopathy, acquired microcephaly, persistent or paroxysmal movement disorders (spasticity, ataxia, dystonia, chorea, tremor, paroxysmal eye-head movements, and paroxysmal exercise-induced dyskinesia), and cognitive impairment (from learning disabilities to severe intellectual disability) (Klepper et al., 2020). KD should be started as soon as possible, after the diagnosis, as it constantly results in the reduction (31%) or disappearance (52%) of the seizures. Movement disorders (82%) and cognitive issues (59%) also improve in most of the cases (Schwantje, Verhagen, van

Fig. 2 Diffuse spike and waves discharges associated with axial myoclonic jerks in a 12-year old with GLUT-1 deficiency.

Ketogenic diet and epilepsies

Fig. 3 Diffuse spike and waves discharges induced by 1-Hz intermittent photostimulation in the same patient of the previous figure.

Hasselt, & Fuchs, 2020). In Glut1DS, KD is recommended at least until puberty but it can also be used in adulthood because of its effectiveness (Veggiotti & De Giorgis, 2014). PDHD is a mitochondrial disorder caused by mutations of the PDHA1 gene on chromosome Xp22.1. This gene encodes the E1α subunit of a multienzyme complex that catalyzes the irreversible decarboxylation of pyruvate to acetyl-CoA, which is essential for the synthesis of citrate, the first substrate in the citric acid cycle. The deficient activity of this subunit impairs the pyruvate dehydrogenase complex leading to pyruvate accumulation. Pyruvate is massively converted to lactate through the lactic acid cycle and reduces citrate production, resulting in a reduction of energy production in the mitochondrial matrix (Bhandary & Aguan, 2015). Signs and symptoms of PDHD may appear anytime between neonatal period and early adulthood, but usually, the first signs begin during infancy. The most common clinical features include developmental delay (57% of the patients); hypotonia/hypertonia (46%); seizures (26%); microcephaly (22%); ataxia (19%); signs of motor dysfunction including spasticity, ptosis, and choreoathetoid movements (14.5%); and respiratory distress (14%) (Patel, O’Brien, Subramony, Shuster, & Stacpoole, 2012). A recent longitudinal cohort study on pediatric patients with PDHD reported a reduction (100%) or a disappearance (>50%) of seizures within 1 year after KD initiation (Sofou et al., 2017). A recent MRI study demonstrated the association of reversible basal ganglia lesions with clinical improvement after the beginning of KD (Shelkowitz, Ficicioglu, Stence, Van Hove, & Larson, 2020). There are differential age-specific recommendations for KD in Glut1DS and PDHD (Kossoff et al., 2018): – In Glut1DS, classic KD typically provides higher levels of ketosis and should be preferred in infants and preschool children;

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– In school-age children, adolescents and adults, MAD can be a good alternative, especially in noncompliant patients; – LGIT provides inadequate levels of ketosis and it is not recommended for both diseases.

Ketogenic diet in the intensive care units Super-refractory status epilepticus (SRSE) is defined as a status epilepticus persisting at least 24 h after the beginning of anesthesia (Hirsch et al., 2018). It is associated with high morbidity and mortality. A recent retrospective cohort study investigated safety, tolerability, and effectiveness of KD in 29 pediatric patients in the intensive care unit (ICU) (Worden, Abend, & Bergqvist, 2020). Two initiation protocols were implemented: most patients were started on a gradual KD starting with a low carbohydrate/fat ratio (e.g., 2:1) at full calories, then increasing the ratio daily by 0.5–1; conversely, some other patients were started at the goal ketogenic ratio and advancing calories until reaching the appropriate caloric need in three days (Worden et al., 2020). Serum glucose, BHB, and electrolytes were measured every 4–6 h. Ketosis was reached in a median of 1 day after initiation (while high levels of BHB 4 mmol/L were achieved in a median of 4 days). (Worden et al., 2020). Although starvation is no longer a routine approach to KD initiation, fasting might be useful in these critically ill patients, given the need for rapid seizure control (ketosis achieved around two days sooner) (Bergqvist, Schall, Gallagher, Cnaan, & Stallings, 2005). All patients experienced at least one KD-related adverse effect (being hypoglycemia the most common one), but they were all easily treatable (Worden et al., 2020). About 65% of the patients wean off anesthetic infusions within two weeks, while 25% achieved seizure freedom (Worden et al., 2020). The authors also reported that at the 1-year follow-up, 67% of survived patients remained on KD, and seizure freedom was sustained in 27% of them (Worden et al., 2020). Initiation of KD in a pediatric ICU setting is therefore feasible, safe, and useful to manage SRSE and epileptic encephalopathies. However, general hinders to its implementation are lack of trained dieticians, lack of experience with KD, or need for propofol infusion, which is contraindicated during KD (Baumeister et al., 2004).

Applications to other neurological conditions The contribution to cellular homeostasis—improving mitochondrial function, decreasing oxidative stress and pro-apoptotic factors, and inhibiting inflammatory mediators— makes any disease influenced by disorders in cellular energy metabolism theoretically amenable to the KD.

Ketogenic diet and epilepsies

There is growing evidence that ketone bodies have broad neuroprotective effects through several possible mechanisms including antioxidative stress actions, maintaining energy supply, modulating the activity of deacetylation and inflammatory responses. These effects may result in the slowing of brain aging and degeneration with positive repercussions in Alzheimer’s and Parkinson’s diseases. Other potential fields of application for ketogenic diet may include amyotrophic lateral sclerosis, stroke, cancer, mitochondrial disorders, traumatic brain injury (reducing long-term consequences, such as epilepsy), mood disorders and major depression (due to hypothesized mood stabilizing properties), autism spectrum disorder (autism-related aggression or anxiety), and medically refractory migraines (Rho & Stafstrom, 2012).

Other components of interest The necessity of a supplementation with micronutrients in children on ketogenic was largely highlighted in the last decades. Chin recently reported the case of a 2-year-old female, who presented with anemia and neutropenia due to a copper deficiency during the transition from a formula-based ketogenic diet to a pureed food-based ketogenic diet (Chin, 2018). These hematological manifestations were solved with a copper supplementation. Another case with a low serum copper without hematological manifestations was reported by Caraballo et al. (2011) in a cohort of 216 patients on ketogenic diet suggesting that copper deficiency is an extremely rare complication. Despite its rarity, an adequate monitoring of blood cell count and serum and urinary copper levels should be carefully considered during the follow-up of patients on KD because copper deficiency may also worsen the neurological status. Copper is an essential cofactor for the biosynthesis of monoamine neurotransmitter and its deficiency may also result in symptoms such as lower limb paresthesia and gait abnormalities including sensory ataxia or spasticity (Chin, 2018). The introduction of a multivitamin integrator, also including minerals, is strongly recommended during the switch to pureed food–based ketogenic diet (Christodoulides et al., 2012) and the presence of copper into the administered products should be assessed.

Mini-dictionary of terms •

Ketogenic diet: high-lipid, adequate-protein, low-carbohydrate dietary regimen that induces a chronic state of ketosis and/or other metabolic conditions in which ketone bodies—acetoacetate (ACA) and β-hydroxybutyrate (BHB)—are used as energy sources.

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Epilepsy: Disorder of the brain characterized by an enduring predisposition to generate epileptic seizures, and by the neurobiological, cognitive, psychological, and social consequences of this condition. Drug-resistant epilepsy: Type of epilepsy in which it is observed the failure of adequate trials of two tolerated and appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom. Super-refractory status epilepticus: Continuous or recurrent seizures without normalization of consciousness lasting for 24 h or more despite administration of an intravenous anesthetic, or recurrence of status epilepticus on weaning of intravenous treatment Epileptic and developmental encephalopathy: A condition in which a genetically determined condition has developmental consequences arising directly from the effect of the genetic mutation, in addition to the effect of the frequent epileptic activity on development.

Key facts •

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Ketogenic diet (KD) is a high-lipid, adequate-protein, low-carbohydrate dietary regimen that induces a metabolic condition in which ketone bodies are used as energy sources. KD has several proposed antiepileptogenic properties, although the detailed underlying mechanisms remain not completely understood. KD is the first therapeutic choice in GLUT-1 deficiency and pyruvate dehydrogenase deficiency syndromes, but it is also effective in other pediatric drug-resistant epilepsies. There are several variants of KD, including the classic KD, the medium-chain triglyceride diet, the modified Atkins diet, and the low glycemic index treatment. Potential candidates for KD should be thoroughly assessed before starting the dietary treatment, to check its suitability as well as to rule out preexisting contraindications. During the first weeks after the diet initiation, the clinician should be frequently in contact with the caregivers; then periodic follow-up visits should be scheduled at 1, 3, 6, 9, and 12 months during the first year of KD, and every 6 months afterward.

Summary points • •

This chapter focuses on applications of ketogenic diet as a treatment for pediatric epilepsy, describing its four main variants. Recent studies supported the safety and the efficacy of KD also in adults and in the pediatric intensive care settings.

Ketogenic diet and epilepsies

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The classic ketogenic diet has a macronutrient ratio of 4 or 3 to 1 (i.e., 4 or 3 g of lipids to 1 g of protein and carbohydrates) with more than 90% of the caloric intake being provided as lipids, mainly long-chain triglycerides (LCTs). The MCT diet was based on the replacement of foods rich in long-chain fatty acids with medium-chain fatty acids. The features of modified Atkins diet include a macronutrient ratio of 1:1 a reduction of carbohydrates to 10 g/day in children and 15 g/day in adults, no protein restriction, and support of fat intake. The LGIT diet provides about 10% of the caloric intake in the form of carbohydrates with a glycemic index below 50 (40–60 g/day), 50%–60% as lipids, and about 20% as proteins. Ketogenic diet requires a periodic follow-up, by a multidisciplinary team of dedicated child neurologists and dietitians, to assess its efficacy on seizures and to prevent its potential side effects on growth and nutrition.

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Olson, C. A., Vuong, H. E., Yano, J. M., Liang, Q. Y., Nusbaum, D. J., & Hsiao, E. Y. (2018). The gut microbiota mediates the anti-seizure effects of the ketogenic diet. Cell, 173(7), 1728–1741.e13. https:// doi.org/10.1016/j.cell.2018.04.027. Pascual, J. M., Wang, D., Hinton, V., Engelstad, K., Saxena, C. M., Van Heertum, R. L., et al. (2007). Brain glucose supply and the syndrome of infantile neuroglycopenia. Archives of Neurology, 64(4), 507–513. https://doi.org/10.1001/archneur.64.4.noc60165. Patel, K. P., O’Brien, T. W., Subramony, S. H., Shuster, J., & Stacpoole, P. W. (2012). The spectrum of pyruvate dehydrogenase complex deficiency: Clinical, biochemical and genetic features in 371 patients. Molecular Genetics and Metabolism, 105(1), 34–43. https://doi.org/10.1016/j.ymgme.2011.09.032. Paul, E., Conant, K. D., Dunne, I. E., Pfeifer, H. H., Lyczkowski, D. A., Linshaw, M. A., et al. (2010). Urolithiasis on the ketogenic diet with concurrent topiramate or zonisamide therapy. Epilepsy Research, 90(1–2), 151–156. https://doi.org/10.1016/j.eplepsyres.2010.04.005. Pfeifer, H. H., & Thiele, E. A. (2005). Low-glycemic-index treatment: A liberalized ketogenic diet for treatment of intractable epilepsy. Neurology, 65(11), 1810–1812. https://doi.org/10.1212/01. wnl.0000187071.24292.9e. Phillips, M. C. L. (2019). Ketogenic diet therapies in children and adults with epilepsy. Epilepsy - Advances in Diagnosis and Therapy. https://doi.org/10.5772/intechopen.83711. Rezaei, S., Abdurahman, A. A., Saghazadeh, A., Badv, R. S., & Mahmoudi, M. (2019). Short-term and long-term efficacy of classical ketogenic diet and modified Atkins diet in children and adolescents with epilepsy: A systematic review and meta-analysis. Nutritional Neuroscience, 22(5), 317–334. https://doi.org/ 10.1080/1028415X.2017.1387721. Rho, J. M., & Stafstrom, C. E. (2012). The ketogenic diet as a treatment paradigm for diverse neurological disorders. Frontiers in Pharmacology, 3. https://doi.org/10.3389/fphar.2012.00059. Runyon, M. A., & So, T. Y. (2012). The use of ketogenic diet in pediatric patients with epilepsy. Review article. ISRN Pediatrics, 2012, 1–10. https://doi.org/10.5402/2012/263139. Sampath, A., Kossoff, E. H., Furth, S. L., Pyzik, P. L., & Vining, E. P. G. (2007). Kidney stones and the ketogenic diet: Risk factors and prevention. Journal of Child Neurology, 22(4), 375–378. https://doi. org/10.1177/0883073807301926. Schoeler, N. E., & Cross, J. H. (2016). Ketogenic dietary therapies in adults with epilepsy: A practical guide. Practical Neurology, 16(3), 208–214. https://doi.org/10.1136/practneurol-2015-001288. Schoeler, N. E., Leu, C., Balestrini, S., Mudge, J. M., Steward, C. A., Frankish, A., et al. (2018). Genomewide association study: Exploring the genetic basis for responsiveness to ketogenic dietary therapies for drug-resistant epilepsy. Epilepsia, 59(8), 1557–1566. https://doi.org/10.1111/epi.14516. Schwantje, M., Verhagen, L. M., van Hasselt, P. M., & Fuchs, S. A. (2020). Glucose transporter type 1 deficiency syndrome and the ketogenic diet. Journal of Inherited Metabolic Disease, 43(2), 216–222. https://doi. org/10.1002/jimd.12175. Shelkowitz, E., Ficicioglu, C., Stence, N., Van Hove, J., & Larson, A. (2020). Serial magnetic resonance imaging (MRI) in pyruvate dehydrogenase complex deficiency. Journal of Child Neurology, 35(2), 137–145. https://doi.org/10.1177/0883073819881940. Simeone, T. A., Simeone, K. A., Stafstrom, C. E., & Rho, J. M. (2018). Do ketone bodies mediate the antiseizure effects of the ketogenic diet? Neuropharmacology, 133, 233–241. https://doi.org/10.1016/j. neuropharm.2018.01.011. Sofou, K., Dahlin, M., Hallb€ oo €k, T., Lindefeldt, M., Viggedal, G., & Darin, N. (2017). Ketogenic diet in pyruvate dehydrogenase complex deficiency: Short- and long-term outcomes. Journal of Inherited Metabolic Disease, 40(2), 237–245. https://doi.org/10.1007/s10545-016-0011-5. Sourbron, J., Klinkenberg, S., van Kuijk, S. M. J., Lagae, L., Lambrechts, D., Braakman, H. M. H., et al. (2020). Ketogenic diet for the treatment of pediatric epilepsy: Review and meta-analysis. Child’s Nervous System, 36(6), 1099–1109. https://doi.org/10.1007/s00381-020-04578-7. Spilioti, M., Pavlou, E., Gogou, M., Katsanika, I., Papadopoulou-Alataki, E., Grafakou, O., et al. (2016). Valproate effect on ketosis in children under ketogenic diet. European Journal of Pediatric Neurology, 20(4), 555–559. https://doi.org/10.1016/j.ejpn.2016.04.003. Stainman, R. S., Turner, Z., Rubenstein, J. E., & Kossoff, E. H. (2007). Decreased relative efficacy of the ketogenic diet for children with surgically approachable epilepsy. Seizure, 16(7), 615–619. https://doi. org/10.1016/j.seizure.2007.04.010.

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PART VII

Headaches and migraines

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CHAPTER 26

The value of fruit and vegetable consumption in pediatric migraine Soodeh Razeghi Jahromia,∗, Shadi Ariyanfara, Pegah Rafieea, and Mansoureh Toghab a

Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran b Department of Nutrition, Headache Department, Iranian Center of Neurological Research, Neuroscience Institute Tehran University of Medical Sciences, Sina Hospital, Tehran, Iran

Abbreviations CGRP TNF-α NF-κB LPS IL-6 TRPA1 ICHD3 USDA DASH LGD GPx MDA GDNF BDNF PPAR AMPK NPY BMI

calcitonin gene-related peptide tumor necrosis factor-α nuclear factor kappa-B lipopolysaccharides interlukin-6 transient receptor potential ankyrin 1 international classification of headache disorder 3 United States Department of Agriculture dietary approach to stop hypertension low-glycemic diet glutathione peroxidase malondialdehyde glia-derived neurotrophic factor brain-derived neurotrophic factor proliferator-activator receptor AMP-activated protein kinase. neuropeptide Y body mass index

Introduction The estimated prevalence of headache and mean prevalence of migraine in pediatric agegroup are 54.4%–58.4% and 7.7%–9.1%, respectively (Philipp et al., 2019; Yamanaka et al., 2020). During childhood, migraine headache largely affects academic function and the quality of life (Recober et al., 2019). ∗

In Absentia Contact Person: Nasim Rezaeimanesh, Multiple sclerosis Research Centre, Neuroscience Institute, Tehran University of Medical Sciences, Iran, Telephone, Fax: +98 2166347582, Email: [email protected].

Diet and Nutrition in Neurological Disorders https://doi.org/10.1016/B978-0-323-89834-8.00026-X

Copyright © 2023 Elsevier Inc. All rights reserved.

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Frequent migraine attacks inquire prolonged use of prophylactic drugs such as betablockers, tricyclic antidepressants, antiepileptics, antihistamines, or calcium channel blockers with expected different side effects. In addition to medical therapy, studies pointed to nonmedicinal therapies such as endurance exercise, stress management, enough and proper sleep, and a regular meal plan (Yamanaka et al., 2020). Two out of three adult migraineurs report an influence of diet on their migraine activity. However, nutritional therapies are not standard procedures in migraine prophylaxis (Kelman, 2007). Studies on nutritional intervention in pediatric migraine are even rarer. The pathophysiology of migraine headache is not fully understood, though inflammation, oxidative stress, and disrupted energy metabolism were implicated in painful migraine manifestation. The activation of different arrays of cell types such as mast cells and macrophages that contribute to the creation of an inflammatory state via the release of various substances (named TNF-α and IL-6) could stimulate the trigeminovascular system. Trigeminovascular system is responsible for the manifestation of pain in migraine (Lukacs et al., 2017). Disturbances in the glucose-insulin metabolism have an essential role in the energy supply of the CNS and were hypothesized as having a potential pathophysiological correlation in migraine as early as 1935 (Gray & Burtness, 1935). Evans et al. stated that women with migraine attacks had a poorer diet quality in which the consumption of vegetables and fruits was markedly lower than nonmigraineurs (Evans et al., 2015). Dietary fiber found in fruits and vegetables is metabolized by the intestinal microbiota into short-chain fatty acids (SCFAs). SCFAs regulate gut immunity and consequently systemic immunity. Moreover, fruits and vegetables often have a low glycemic index. Low glycemic foods can favorably affect migraine by modifying energy and particularly glucose metabolism and consequently cortical spreading depolarization and transient receptor potential ankyrin 1 (TRPA1)-induced CGRP release. Since vegetables and fruits are considered main sources of dietary antioxidants, vitamin E, vitamin C, minerals, carotenoids, and flavonoids, numerous studies have suggested that they are effective in different chronic diseases (Okoli et al., 2019). The pathogenesis of various chronic diseases such as migraine involves inflammation (Raymond & Morrow, 2020) as various inflammatory mediators are known to be associated with the development and persistence of migraine (Torres-Ferru´s et al., 2020). According to the results of a meta-analysis, a higher intake of vegetables and fruits is accompanied by lower levels of inflammatory indices like TNF-a (Hosseini et al., 2018). Furthermore, vegetable and fruit intake can inversely affect obesity by reducing the energy-dense food intake (Ledoux, Hingle, & Baranowski, 2011). Potentially, obesity and overweight have a greater impact on pediatric migraine than trigger foods (Eidlitz-Markus & Toldo, 2017). Current available evidence suggest a beneficial role for dietary fiber in adults with a migraine headache (Arzani et al., 2020). However, evidence about the relationship between dietary fiber intake and pediatric migraine is rare. Also, as fruits and vegetables

Fruits, vegetables, and pediatric migraine

can positively affect inflammatory processes, energy metabolism, and weight, it can be proposed that a higher intake of these food items might reduce the odds of pediatric migraine. Up to the best of our knowledge, our study about the association between fruit and vegetable intake and migraine in children and adolescents provides the first data suggesting this promising new approach to migraine prophylaxis in this age-group. In the current chapter, we aim to go through the results of the mentioned study and other available evidence.

Review of the available studies and discussion Review of the available studies In a descriptive study by Mirzababaei et al. on 266 women with migraine headaches, severe headache (VAS: 8–10) was 46% less prevalent in individuals with the greatest adherence to a DASH diet, which is characterized by high fruit and vegetable intake. The frequency of moderate headache (VAS: 4–7) was also 36% lower in this group compared to the individuals with the lowest adherence (Mirzababaei et al., 2018). Similarly, in a clinical trial by Evcili et al., 350 migraineurs were assigned to (1) a lowglycemic diet (LGD) which is a high-fiber diet group and (2) prophylactic medication group receiving amitriptyline, flunarizine, and propranolol (n ¼ 1:1). After one month, the attack frequency decreased significantly in both groups. After three months, headache € gu € intensity was reduced significantly by LGD as well (Evcili, Utku, O €n, & Ozdemir, 2018). The protective role of fruits and vegetables against headaches was detected in another observational study, which was conducted on 83,214 university students. According to the study, fruit and vegetable consumption resulted in a 30% and 16% reduction in the odds of primary headaches, respectively (Mansouri et al., 2020).

Discussion The impairment of oxidant/antioxidant balance is seen in children with migraines, caused by elevated levels of glutathione peroxidase (GPx) and malondialdehyde (MDA) activity (Vurucu et al., 2013). Dietary fibers are metabolized by the intestinal microbiota to SCFA (i.e., acetoacetate, butyrate, and propionate) (Collins, 2014). SCFAs regulate gut immunity and consequently systemic immunity. Butyrate mediates the induction of regulatory T-cells in the colon and consequently modulates its function. Butyrate imposes this effect by inhibiting the activity of histone deacetylases. SCFAs are crucial in maintaining gut barrier integrity. For example, butyrate facilitates the expression of tight junction protein including occludin protein, claudin-2, occludin, and zonula (Peng, He, Chen, Holzman, & Lin, 2007; Wang et al., 2012). Butyrate can also alleviate hypoxia-inducible factor (HIF), which is crucial for decreasing the gut permeability to toxins and preserving gut barrier integrity (Noble, Hsu, & Kanoski, 2017).

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Besides affecting gut/systemic immunity, SCFAs produced by bacteria in the distal colon reach the CNS via circulation. In CNS, SCFAs exhibit neuroprotective properties. For instance, sodium butyrate, the salt of butyrate, promotes cell proliferation and differentiation in the dentate gyrus and stimulates the expression of glia-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF). Butyrate also imposes an antiinflammatory effect in the brain by reducing the synthesis of TNF-α, caused by the endotoxin lipopolysaccharide (LPS) via the suppression of nuclear factor κB (Noble et al., 2017). SCFAs have been reported to enhance the AMPK activity in the liver and muscles (Sandhu et al., 2017). The induction of AMPK increases the activity of peroxisome proliferation-activated receptor co-activator-1a and consequently peroxisome proliferator-activator receptor (PPAR) (Sandhu et al., 2017). PPAR-α suppresses NO synthase (He-min, Guo-Rong, Qiu, Xiang, & Suli, 2015). The release of CGRP rapidly occurs following the NO generation which is of great importance as (De Logu, Nassini, Landini, & Geppetti, 2019) PPARα activation could prevent CGRP release, too (Le May et al., 2000). Furthermore, migraine pathophysiology is closely linked to the central and peripheral pathways involved in obesity. High levels of pro-inflammatory agents [namely neuropeptide Y (NPY) and CGRP] which are correlated with abdominal obesity are also in association with pain manifestation in migraine sufferers. Based on the study of Harshely et al., a decreased level of BMI resulted in a significant improvement in pediatric migraine (Razeghi Jahromi et al., 2018). Cancer, cardiovascular disease, and all-cause mortality have a reverse correlation with various types of vegetable and fruit intake, especially green leafy vegetables (Aune et al., 2017). A higher amount of vegetable and fruit intake is associated with lower levels of inflammation, cholesterol, and blood pressure. Recent studies on pediatrics showed that higher consumption of vegetables and fruits is protective against chronic diseases (SavoieRoskos, Wengreen, & Durward, 2017). Moreover, in children with less fruit and vegetable intake, insulin sensitivity is lower. Evidence indicated an inverse relationship between dietary vegetable and fruit intake and low-grade inflammation. Results of a study performed by Almeida et al. revealed that consumption of a variety of vegetables can decrease low-grade inflammation in adolescents. In line with their investigation, children with a higher intake of vegetables had significantly lower levels of IL-6 (Almeidade-Souza et al., 2018). The bioactive elements in plant-based foods (e.g., flavonoids and carotenoids) possess anti-inflammatory properties (Yu et al., 2018). In a study on 285 adolescents (aged 15), a diet rich in vegetables and fruits that is abundant in antioxidants, flavonoids, and folate is accompanied by a reduction in oxidative stress and inflammation. Accordingly, evidence supported the inverse relationship between flavonoid (quercetin and kaempferol) intake and oxidative stress. Also, quercetin, the flavonoid in grapes, was reported to reduce the TNF-α and IL-6 levels (Holt et al., 2009). A high level of vegetable intake improves anti-inflammatory responses by a reduction in TNF-α and IL-6

Fruits, vegetables, and pediatric migraine

concentration (Hosseini et al., 2018). The antioxidant properties of plant-derived foods are also attributed to the polyphenolic content of vegetables and fruits. These compounds impose their effect through altering inflammatory pathways or the expression of the proinflammatory mediator genes (e.g., IL-6 and TNF-α). Additionally, polyphenols also positively affect the production of anti-inflammatory compounds such as IL-4 and IL-10 ( Joseph, Edirisinghe, & Burton-Freeman, 2016). Neuroinflammation is known as a key factor in different neurological diseases including migraine (Lukacs et al., 2017). The elevated expression of IL-1β and TNF-α in plasma and CSF of migraineurs is correlated with the activation of neuroinflammatory responses in painful episodes of migraine (Ramachandran, 2018). The release of CGRP from the endings of sensory nerves has been linked to the activation of various immune cell types (including mast cells, T-cells, and macrophages), which is consequently followed by the release of IL-6 and TNF-α, as well as the induction of an inflammatory state (Lukacs et al., 2017).

Results of our study In our study from an Iranian headache research center, we studied 100 children (aged between 7 and 14) with a diagnosis of migraine, and 190 matched controls. All logistic regression models have illustrated an inverse relationship between dietary vegetable or fruit consumption and the odds of pediatric migraine. The first model, adjusted for gender and age, caused a nonsignificant decrease in the odds of having a headache in the second and third tertiles of fruit and vegetable intake compared to the first tertile. Further adjustment for total energy intake and BMI resulted in a significant relationship between a higher intake of fruits (Table 1) and vegetables (Table 2) with declined odds of migraine in the second tertile of vegetable and the third tertile of fruit intake. By adjusting for all confounders, we noticed a 70% and 50% reduction in odds of migraine by increasing the consumption of fruits and vegetables to 578/8 g/week and 218/9 g/week in the second tertile of fruits and vegetables compared to the first tertile, respectively. Likewise, adjustment for gender and age in the first model demonstrated a nonsignificant result in the second, third, and fourth quartiles of dietary fiber intake. Accordingly, in the second model that is fully adjusted for all confounders, a 72% decline in odds of migraine was noticed by an elevated level of fiber intake to 46/4 g/week in the fourth quartile of dietary fiber (Table 3).

Conclusion Taken together, these findings propose a role for dietary fiber and antioxidant sources including fruits and vegetables in decreasing the risk of developing a headache in susceptible children. Additionally, mounting evidence exists in favor of the protective role of vitamins and minerals against migraine (Okoli et al., 2019).

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Table 1 The association of migraine with fruit consumption (ORs (95% CI)). Variable

First tertile

Second tertile

Third tertile

Fruit intakeb (g/week) No. of cases/controls Modelc

196.2 (303.9) 39/5 1

422.1 (305.9–576.8) 33/6 0.83 (0.45–1.551)

818.8 (578.8)

Modeld

1

0.58 (0.30–1.12)

Modele

1

0.62 (0.32–1.23)

28/6 0.68 (0.36–1.28) 0.31 (0.14–0.69) 0.30 (0.13–0.71)

P-trenda

0.24