Description

	• Several nutritional factors play a role in cerebral metabolism and function.
	• These factors include carbohydrates such as glucose, proteins, amino acids (precursors of nucleic acids), and vitamins and minerals, which enter the brain through the blood-brain barrier.
	• The microbiota-gut-brain axis is a bidirectional pathway, through which the gastrointestinal tract exerts an influence on cerebral nutrition and function.
	• Advances in omics have enabled an understanding of interactions between genes and nutrition that is useful for elucidating the pathomechanism of several neurologic disorders.
	• Neurologic disorders due to malnutrition may be treatable.

Role of nutritional factors in cerebral metabolism and function. The brain requires several nutrients to perform properly. Nutrition of the brain depends on the supply of essential substances from the rest of the body as it cannot manufacture its own nutrients. The nutrition of the body depends mainly on diet, the constituents of which may affect brain function.

The nutritional environment for the optimal development and function of the CNS has not been properly defined. Several studies, both experimental and clinical, are in progress to study the role of nutrition in the nervous system from infancy to senescence. In addition to conventional laboratory studies, several technologies are being incorporated into these investigations, including genomics, proteomics, brain imaging, and molecular biomarkers. PET and MRI data have been used to calculate brain glucose utilization from birth to adulthood and reveal that brain glucose demand relates inversely to body growth from infancy to puberty, and the data have shown that the high costs of human brain development require compensatory slowing of body growth rate (32).

Brain imaging tools, including MRI, electroencephalography/magnetoencephalography, near-infrared spectroscopy, PET and single-photon emission computerized tomography, are important for observational studies as well as randomized controlled trials investigating nutritional effects on the human brain. Nutritional factors that are of importance in brain function are discussed briefly here.

Role of blood-brain barrier in cerebral nutrition. Several disease processes, including inflammation, genetic predisposition, autoimmunity, and mitochondrial dysfunction affect the function of blood-brain barrier, which is the site of regulation of entry into the brain of substances involved in cerebral nutrition, eg, glucose, insulin, folic acid, leptin, and proteins and amino acids such as tyrosine and valine. There is unidirectional flow of cerebral phospholipids into the brain.

Microbiota-gut-brain axis. This bidirectional communication occurs through many pathways, including:

	• The main neuroanatomical communication between the enteric nervous system, which directly innervates the gastrointestinal tract, and the CNS is provided by the vagus nerve (parasympathetic input) and spinal nerves (sympathetic input).
	• The gastrointestinal tract produces numerous hormones and signaling molecules that cross the blood-brain barrier to affect the brain centers that regulate appetite, metabolic control, and behavioral pathways.
	• Intestinal microbiota play a role in regulating CNS levels of brain-derived neurotrophic factor, which is a key molecule involved in synaptic and structural plasticity, learning, and memory.
	• Intestinal microbiota can synthesize vitamins that have an important role in the brain.

Gut microbiota changes have an impact on several neurologic disorders, including neurodevelopmental disorders such as autism spectrum disorder, psychiatric disorders (eg, major depressive disorder, anxiety, and schizophrenia), and neurodegenerative disorders (36).

Glucose. Glucose and oxygen are constantly required for cerebral metabolism. The entry of other nutrients into the brain is limited by regulation of uptake at the blood-brain barrier. Lipid is taken up slowly by diffusion. Fatty acids account for only a small amount of the energy supply in the adult brain, as evidenced by their respiratory quotient of 0.97. Amino acid breakdown accounts for less than 10% of total brain energy requirements. Under some circumstances, the brain can utilize ketone bodies to a limited extent. Glucose remains the most important substance that the brain can convert to energy. Circulating glucose concentrations regulate many brain functions, which include learning and memory. Much of the evidence for this comes from experiments assessing stress-related release of epinephrine with subsequent increases in blood glucose concentrations. At least 10 other nutrients are directly involved in this conversion of glucose into energy: (1) thiamin, (2) riboflavin, (3) niacin, (4) pyridoxine, (5) pantothenic acid, (6) magnesium, (7) manganese, (8) iron, (9) phosphates, and (10) lipoic acid.

In normal adults with normal diets, glucose supply to the CNS is sufficient. In glucose deficiency, GABA levels may increase during the changeover phase to utilize alpha-ketoglutarate. GABA, because of its inhibiting effect on neurons, may be responsible for the "minimal brain dysfunction." It is possible that psychological changes may occur before the total oxygen and glucose consumption of the brain shows a measurable decrease. In certain circumstances, particularly in patients with senile dementia, glucose utilization by the brain is reduced even at normal glucose levels.

Glycogen. Brain glycogen stored in astrocytes provides lactate as an energy source to neurons through monocarboxylate transporters to maintain neuronal functions such as hippocampus-regulated memory formation (34). Adenosine triphosphate (ATP) in the brain, maintained by glycogen, is a possible defense mechanism for neurons in the exhausted brain.

Insulin. This hormone is needed for normal brain function, including learning and memory. Insulin may act by chaperoning glucose into brain neurons. Glucose utilization in the brain in dementia is shown to be increased by mixed glucose and insulin infusions. Insulin increases the transfer of glucose across the blood-brain barrier unless hypoglycemia is present.

Hypoglycemia. The essential biochemical abnormality in hypoglycemia is a critical lowering of the blood glucose level. It is a pathophysiological state and not a disease. The normal fasting serum glucose level in a healthy adult is 70 to 105 mg/dL. Performance starts to deteriorate between 60 and 70 mg/dL. Hypoglycemia of this slight degree can occur following exhaustive physical activity. When serum glucose levels fall to 50 to 60 mg/dL, hyperkinesia with tremor and obvious aggressive behavior can occur. Impairment of cerebral function occurs when the serum glucose level falls to 45 mg/dL. It is manifested by reduced intellectual capacity, irritability, and convulsions. The oxygen consumption of the brain decreases when the glucose level falls to 20 mg/dL. Even in cases of extreme hypoglycemia, the brain can utilize the glucose provided by carbohydrate stores. At a delayed rate of oxygen consumption, these last for approximately 1 to 1.5 hours. At the 10 mg/dL level, however, coma sets in, and there may be irreversible injury to the brain if the level is not raised by the administration of glucose.

Glucose is indispensable for the brain, which is the only organ besides the heart that suffers severe functional and structural disorders under hypoglycemia. Hypoglycemia disrupts cell-to-cell communication. The pathophysiology of cerebral dysfunction in hypoglycemia is not fully elucidated. Hypoglycemia reduces oxygen uptake and increases cerebral blood flow. A reduction of glutamate and GABA occurs, whereas an increase of aspartate and ammonia levels takes place. Ammonia accumulation that occurs prior to coma may contribute to symptoms of severe hypoglycemia. It is questionable whether depletion takes place or inadequate production of high-energy phosphate compounds. The brain may utilize some nonglucose substrates, such as ketones, lactate, and pyruvate, when glucose levels fall. Hypoglycemia also activates adrenal glands and the autonomic nervous system to induce a compensatory neoglucogenesis. In the face of prolonged hypoglycemia, the nonglucose substrates are not adequate to protect the integrity of the neurons. Reactive hypoglycemia (postprandial) occurs after ingestion of glucose-rich foods and is aggravated by fructose or leucine intolerance as well as in galactosemia. Various causes of fasting hypoglycemia are:

A. Overutilization of glucose
	1. Accidental or intentional overdose of insulin 2. Oral antidiabetic agents (eg, tolbutamide) 3. Neoplasms that secrete insulin or insulin-like material 4. Antibodies to endogenous insulin 5. Hypermetabolic states (eg, sepsis) 6. Carnitine deficiency
B. Underutilization of glucose
	1. Endocrine deficiencies (eg, growth hormone) 2. Enzyme disorders of metabolic pathways (eg, Krebs cycle) 3. Acute liver disease 4. Drug-induced (eg, sulfonylureas) 5. Severe malnutrition

In postprandial hypoglycemia, symptoms occur within 6 hours of the ingestion of glucose-rich food and are mainly those of catecholamine release such as shaking, sweating, anxiety, palpitations, and weakness. Signs of CNS dysfunction are rare. Acute hypoglycemia most commonly results from the action of insulin preparations, and presenting symptoms are malaise, restlessness, hunger, nervousness, and ataxia. Seizures may occur. These symptoms are usually relieved promptly by the administration of glucose. Subacute hypoglycemia is usually of the fasting type. It causes a slowing of the thought processes, amnesia, and gradual impairment of consciousness. EEG abnormalities occur, but correlation with the clinical picture is imprecise. Hypoglycemic encephalopathy is like hypoxic encephalopathy, and the major disturbances occur in the cerebral cortex. Chronic hypoglycemia is rare and is usually due to an insulin-secreting tumor. It is characterized by deterioration of personality, memory, and behavior that may resemble dementia. These symptoms are not promptly relieved by the administration of glucose. Clinical improvement is gradual after removal of the source of exogenous insulin.

Administration of glucose produces the following effects:

	• Mental performance. It has been hypothesized that glucose administration will improve mental performance in the same way that it improves muscular performance. Improvements in simple thinking tests have been attributed to glucose. Possible mechanisms of a glucose-induced increase in mental performance are those due to a nutritive effect, an effect on neurotransmitters, a GABA shunt pathway, and memory storage-processing.
	• Effect on neurotransmitters. Single doses of glucose, mainly via insulin, increase plasma levels of tryptophan, which is a precursor of the neurotransmitter serotonin. Single doses of tryptophan have an effect like that of glucose.
	• Memory enhancement. Glucose consumption has been reported to enhance attention and learning in students, but neither face and word recognition nor working memory was influenced by treatment with glucose. Initial evidence suggests that glucose or a metabolite may activate release of the neurotransmitter acetylcholine in rats when they are engaged in learning. Consequently, the issue of nutrition and cognition becomes increasingly important because circulating glucose concentrations have substantial effects on the brain and cognitive functions.

Amino acids. Most of the amino acids serve as brain nutrients, and all are ultimately delivered to the brain by the blood stream. The factors that control the availability of amino acids to the brain are the cerebral blood flow, the blood-brain barrier, and the plasma levels of amino acids. Circulating amino acids are transported across the blood-brain barrier by one of the transport mechanisms, which have an affinity for either neutral, basic, or acidic amino acids. The proximity of the plasma amino acid concentration and blood-brain barrier transport and Km (affinity of the enzyme for the substrate) forms the basis of competition between amino acid and blood-brain barrier sites. An important pathway of brain amino acid metabolism may be under nutritional control in protein synthesis. The proximity of the rates of influx of essential amino acids into the brain, and the rate of amino acid incorporation into the proteins, suggests that cerebral protein synthesis is a substrate-limited pathway. It is speculated that the supply of branched-chain amino acids may control protein synthesis in the brain like the way the branched-chain amino acids do in the muscles.

Normal homeostatic responses tend to prevent drastic changes in the plasma amino acid concentration following dietary ingestion of disproportionate amounts of amino acids. If the amount exceeds the capacity of the homeostatic mechanism, toxic effects may be seen.

Brain tryptophan and tyrosine pools are determined by the relative plasma levels of these two amino acids as well as other large neutral amino acids, and their fluctuations after a protein meal depend on circadian rhythms. The ability of the elderly to absorb tryptophan into the brain is in part dependent on its concentration (free and bound) and the ratio of its concentration to that of other amino acids (phenylalanine, tyrosine, leucine, isoleucine, and valine) that compete for the same transport mechanism. Several neurologic disorders can occur due to disturbances in amino acid transport and metabolism.

Neurotransmitters. The amount of a neurotransmitter present in the brain is determined by the following factors:

• The number of neurons that contain the neurotransmitter • The number of synaptic terminals or boutons (intracellular loci of neurotransmitter molecules) • The number of neurotransmitter molecules present in each bouton

The first two factors are probably influenced by diet in developing animals but are fixed during adult life. The number of molecules present in each bouton (and, thus, in the neurons) may depend on dietetic factors. Choline and lecithin administration has been shown to increase brain choline and acetylcholine levels. The effect of diet on brain catecholamine concentration is not as apparent as in the case of acetylcholine. Serotonin is formed in the neurons from L-tryptophan. The rate of 5-hydroxytryptamine synthesis is normally controlled by tryptophan availability.

Nutrients that affect brain neurotransmitter synthesis and function are shown in Table 1.

Table 1. Nutrients that Affect Brain Neurotransmitter Synthesis and Function

Carbohydrates
	Glucose
	• Function
		- energy metabolism - regulator of precursor supply - acetyl coenzyme A production
	• Site of regulation
		- blood-brain barrier - tryptophan hydroxylase - choline acetyltransferase
	• Neurotransmitters
		- 5-hydroxytryptamine - acetylcholine
Protein: essential amino acids
	Tryptophan
	• Function
		- NT precursor
	• Site of regulation
		- blood-brain barrier - tryptophan hydroxylase
	• Neurotransmitters
		- norepinephrine 5-hydroxytryptamine
	Tyrosine
	• Function
		- NT precursor
	• Site of regulation
		- blood-brain barrier - tyrosine hydroxylase
	• Neurotransmitters
		- norepinephrine - dopamine
	Valine
	• Function
		- NT precursor
	• Site of regulation
		- blood-brain barrier
	• Neurotransmitters
		- 5-hydroxytryptamine
	Leucine and Isoleucine
	• Function
		- competitive inhibitors
	• Site of regulation
		- tryptophan hydroxylase - tyrosine hydroxylase
	• Neurotransmitters
		- norepinephrine - dopamine
	Histidine
	• Function
		- NT precursor
	• Site of regulation
		- histidine decarboxylase
	• Neurotransmitters 77
		- histamine
	Threonine
	• Function
		- NT precursor
	• Site of regulation
		- serine transhydroxymethylase
	• Neurotransmitters
		- glycine - taurine
	Lipid: phosphatidyl
	• Function
		- NT precursor - choline acetyltransferase - acetylcholine
Vitamins
	Nicotinamide
	• Function
		- enzyme cofactor (NAD and NADH)
	• Site of regulation
		- tryptophan pyrrolase (liver)
	• Neurotransmitters
		- 5-hydroxytryptamine
	Vitamin B6 (pyridoxine)
	• Function
		- enzyme cofactors (transamination, deamination, and decarboxylation reactions)
	• Site of regulation
		- tyrosine decarboxylase - histidine decarboxylase - glutamic acid decarboxylase
	• Neurotransmitters
		- norepinephrine - dopamine - GABA - serotonin
	Folic acid/B12
	• Function
		- enzyme cofactor (transmethylation reactions)
	• Site of regulation
		- catechol-0-methylatransferase - blood-brain barrier
	• Neurotransmitters
		- norepinephrine - dopamine
	Vitamin C (ascorbic acid)
	• Function
		- enzyme cofactor - dopamine-beta-hydroxylase - dihydropterin reductase - DA-adenylcyclase
	• Neurotransmitters
		- norepinephrine - dopamine
	Vitamin E (tocopherol)
	• Function
		- antioxidant and free radical scavenger - brain prostaglandin synthesis
	• Site of regulation
		- mitochondrial, microsomal, and synaptosomal subcellular fractions of the brain
	• Neurotransmitters
		- GABA - glutamate
Minerals
	Calcium
	• Function
		- precursor hydroxylation and NT release
	• Site of regulation
		- tryptophan hydroxylase - tyrosine hydroxylase
	• Neurotransmitters
		- 5-hydroxytrptamine
	Iron
	• Function
		- cofactor (BH4)
	• Site of regulation
		- tryptophan hydroxylase - tyrosine hydroxylase
	• Neurotransmitters
		- norepinephrine - dopamine
	Copper
	• Function
		- enzyme cofactor
	• Site of regulation
		- dopamine-beta-hydroxylase
	• Neurotransmitters
		- norepinephrine - dopamine

Neurotransmitters. The ability of the brain to synthesize monoamine neurotransmitters may normally be regulated by the availability of the precursor amino acid, which further depends on the meal composition: proteins increase it, whereas carbohydrates lower it. The effect is evidenced by a change in the concentration of branched-chain amino acids, rather than the level of precursor amino acid. To some extent, control of brain monoamine neurotransmitter synthesis is dependent on the level and change in branched-chain amino acids.

In animal experiments, acetylcholine synthesis has been shown to be sensitive to conditions that impair carbohydrate oxidation. Existing evidence provides that impaired carbohydrate oxidation and impaired cholinergic function exist in the brains of patients with Alzheimer disease.

Amino acids. Except tryptophan, tyrosine, histidine, and threonine, the fluctuations of amino acid concentration in the brain over the normal range do not appear to influence neurotransmitter synthesis. The amino acids that function directly as neurotransmitters are nonessential amino acids such as glutamic acid, aspartic acid, and GABA. Metabolic controls within the neurons are thought to regulate their production for release for neural transmission purposes.

Choline. This is crucial for sustaining life because it modulates the basic signaling processes within cells, and it is a structural element in membranes. Choline metabolism is closely interrelated with the metabolism of methionine and folate. Choline is present in some foods normally consumed by humans such as egg yolk, meat, fish, legumes, and cereals. It is largely absent in fruits and vegetables. Although it is well documented that administered choline is incorporated into acetylcholine, the ability of the supplemental choline to increase the synthesis and release of acetylcholine has been questioned. Acute or chronic choline supplementation does not by itself enhance the levels of acetylcholine in the brain under normal conditions.

Various sources of choline for acetylcholine synthesis within the cholinergic nerve terminals are:

• De novo synthesis • Uptake after hydrolysis of acetylcholine • Flux across the blood-brain barrier

The blood-brain barrier allows unidirectional diffusion of choline and cannot sustain a concentration gradient. Lecithin consumption raises blood choline levels by diminishing the brain-to-blood concentration gradient, thereby slowing choline's efflux from the brain. The amount of lecithin that needs to be ingested to modify neurotransmitter synthesis is large because it is a nutrient.

Choline in cholinergic neurons has two fates: (1) it is a constituent of phosphatidylcholine and other phospholipids, and (2) it is used as a precursor for the synthesis of acetylcholine. It is hypothesized that the brain generates free choline for acetylcholine synthesis from an endogenous phosphatidylcholine pool, which has a rapid turnover and is used as a choline source. This pool probably accounts for 1% of the brain phosphatidylcholine and may or may not be quantitatively significant within the cholinergic terminals; however, its synthesis is activated when neuronal firing is accelerated.

After entering the brain, radioactively marked choline is quickly metabolized to acetylcholine and phosphatidylcholine. Acetylcholine and phospholipid metabolism in the brain is dependent on a rapid choline transport system across the blood-brain barrier. In addition to diffusion, there appear to be two transport systems, one with low affinity for choline and the other with high affinity. The high affinity choline system in the brain tissue requires the presence of sodium and is confined to cholinergic nerve terminals; most of the choline transported by this system is converted to acetylcholine. The low-affinity transport system is found in other tissues like erythrocytes. Alterations of activity in cholinergic neurons in vivo are followed by parallel changes in sodium dependent, high-affinity choline uptake in vivo. Labeled choline studies have shown that stimulation of acetylcholine release by high potassium concentration leads to higher uptake and acetylation of choline.

Choline supply is vital during critical periods in brain development. The normal human diet provides sufficient choline to sustain healthy organ function; however, vulnerable populations, such as the growing infant, the pregnant or lactating woman, and the patient fed intravenously, may develop choline deficiency. Administration of choline to experimental animals usually does not show any evidence of improvement in tasks requiring memory. However, choline supplementation attenuates the behavioral effects of pentobarbital by increasing cerebral glucose metabolism. It is possible that the enhanced level of functional neuronal activity mediates both the increased locomotor activity and the resistance of the animals to the sedative and hypnotic effect of pentobarbital.

Taurine. Taurine is one of the most abundant amino acids in the brain and has an inhibitory neurotransmitter function. It exerts a wide variety of actions throughout the body. Elevated levels of biomarkers of endoplasmic reticulum stress induced by excitotoxicity, as well as infarct size in animal models of stroke, significantly decline after taurine administration, suggesting that taurine may exert a neuroprotective function (20).

Carnitine. Carnitine (3-hydroxy-4-N-trimethylaminobutyric acid) is a naturally occurring essential metabolite that plays a key role in the transport of fatty acids from the cytosol into the mitochondrial matrix of beta-oxidation. It can be synthesized from lysine molecules that have been incorporated into protein. Carnitine metabolism is minimal, and most of it is excreted unchanged. Carnitine deficiency may result from dietary restriction of carnitine and lysine. The metabolism of carnitine is linked to acetylcholine as acetylcarnitine favors the synthesis of acetylcholine. Carnitine acetyltransferase is a key mitochondrial enzyme in acetyl-CoA metabolism; thus, the availability and removal of acetyl-CoA (a substrate of choline acetyltransferase) may be critical factors in the regulation of intraneural acetylcholine synthesis.

Omega-3 polyunsaturated fatty acids. These are essential components of the central nervous system and their role in learning and memory is well recognized. Diets rich in polyunsaturated fatty acids lead to significant changes in expression of several genes in the central nervous system and study of these might provide an insight to their beneficial effect. The omega-3 fatty acids are essential dietary nutrients, and one of their important roles is providing the fatty acid with 22 carbons and 6 double bonds, known as docosahexaenoic acid (DHA), for nervous tissue growth and function with a key role in vision, neuroprotection, and successful aging. Epidemiological studies have linked low maternal DHA to increased risk of poor child neural development. Intervention studies have shown that improving maternal DHA nutrition decreases the risk of poor infant and child visual and neural development. DHA is retained and concentrated in the nervous system, particularly in photoreceptors and synaptic membranes. DHA signalolipidomics includes uncovering of signaling pathways regulated by DHA including neuroprotectin D1, thus, providing opportunities for developing treatment of neurologic disorders such as Alzheimer disease (02).

Vitamins. The neurologic effects of some vitamin deficiency states are well known, but the role of vitamins in neuronal metabolism under normal dietary conditions is not as well understood. Vitamins of the B-complex group, particularly B1, B6, and B12, are the most important, followed by A and E, which are involved in neuronal metabolism. Both vitamin E and vitamin C have antioxidant roles. Vitamin D is now recognized as playing an important role in the central nervous system.

Disorders of the nervous function are not simply a matter of vitamin deficiency; associated signs of malnutrition are present as well. Total starvation does not lead to vitamin deficiency syndromes. A certain amount of food is necessary for production of these syndromes. Alcohol is an important factor in causing nutritional diseases of the nervous system due to these three mechanisms:

(1) Displacing food in the diet (2) Adding carbohydrate calories (3) Impairing absorption of vitamins from the gastrointestinal tract

Vitamin deficiency frequently results from the effects of medications. Although the clinical picture of gross vitamin deficiency is well recognized, little attention has been paid to the effect of suboptimal vitamin status on human behavior.

Thiamine (B1). In addition to its metabolic role as a coenzyme, thiamine also plays a role in nerve conduction as well as in ion transport. Thiamine deficiency leads to a decline in the putative transmitters’ glutamate and aspartate, probably due to the entry of pyruvate into the tricarboxylic cycle. A relative excess of carbohydrates in the diet relative to thiamine, favors the development of thiamine deficiency states such as Wernicke encephalopathy. This syndrome is by no means confined to alcoholics, but can also occur in anorexia nervosa, gastric plication, hyperemesis gravidarum, and prolonged fasting (conditions that are all associated with poor intake of vitamins). The cholinergic system has been implicated in the pathophysiology of thiamin deficiency because acetylcholine synthesis and synaptic transmission are decreased. This suggests a link between beriberi amnesia, Wernicke encephalopathy, and senile dementia.

Niacin. This name describes two compounds: (1) nicotinic acid and (2) nicotinamide. It is the precursor of two coenzymes, nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, that function in a variety of oxidation-reduction reactions. The causes of deficiency include corn as a diet staple, alcohol, and certain drugs such as isonicotinic acid hydrazide and the anticancer agent 6-mercaptopurine. The classical symptoms of niacin deficiency, or pellagra, are dermatitis, diarrhea, and dementia. The most clearly defined neurologic manifestations are cerebral. Initially taking place is apathy, mental dullness, and impairment of memory. These may progress to an acute psychosis. Symptoms can be reversed by treatment with niacinamide.

Vitamin B12 (cyanocobalamin). Vitamin B12 is essential for the normal maturation of erythrocytes, and its deficiency is associated with pernicious anemia (megaloblastic). Vitamin B12 is required as a coenzyme of methylmalonyl-CoA mutase in the CNS, and a lack of this factor leads to an increase in tissue levels of methylmalonyl-CoA and its precursor propionyl-CoA. As a result of this, nonphysiological fatty acids containing an odd number of carbon atoms are synthesized and incorporated into the neural lipids and phospholipids. Deficiency of this vitamin also produces disorders of the nervous system such as peripheral neuropathies, subacute combined degeneration of the posterior and lateral columns of the spinal cord, and disturbances of mental function.

B12 deficiency may be manifested by memory dysfunction years before hematological or spinal cord symptoms appear. Cobalamin deficiency has been reported in elderly patients with recent onset of cognitive deficits, and significant improvement has been noted in cognitive function after the start of B12 therapy. Low vitamin B12 status should be further investigated as a modifiable cause of brain atrophy and of likely subsequent cognitive impairment in the elderly. Supplementation of dietary B12 may have neuroprotective effects in those with low levels of this vitamin.

Folic acid. This is the common name for a family of compounds called "folates." Folic acid deficiency is due to a depletion in folic acid reserves such as those that occur during pregnancy, from increased demands, from decreased intake (as in the elderly), due to the action of certain drugs, and due to decreased absorption due to gastrointestinal disturbances. Folic acid deficiency is aggravated by deficiencies of vitamin C, iron, and B12. Although folate deficiency produces megaloblastic anemia, neurologic symptoms are rarely reported. The biochemical basis of symptoms common to both B12 and folate deficiency is the induction of a functional folate deficiency by B12 deprivation. Folate therapy has been shown to improve neuropathy and neuropsychological function in patients with decreased folate concentrations in the serum and CSF. Deficiency of folate has no effect on cerebral glucose utilization, whereas glucose metabolism is suppressed in B12 deficiency; therefore, folate metabolism seems to be regulated by vitamin B12. Controversy regarding the role of B12 and folate in the etiology of dementia as well as the success or failure of replacement therapy is not yet settled.

Folic acid deficiency has been linked to neural tube defects that occur during early pregnancy; these are preventable if a woman consumes adequate folic acid daily before conception and throughout the first trimester of her pregnancy. The United States Public Health Service recommends that all women capable of becoming pregnant consume 400 micrograms of folic acid daily. This fortification regimen increases red-cell folate levels by approximately 50% and, thus, should prevent many folate-related neural-tube defects.

Cerebral folate deficiency, which can result from blood-brain barrier dysfunction, affects the metabolic functions of folate within the brain. Folate is needed to synthesize purines and thymidylate and for the remethylation of homocysteine to methionine. Methionine is a precursor of S-adenosylmethionine, which is required for synthesis of neurotransmitters. Folate is transported across the blood-brain barrier to the CSF at the choroid plexus by receptor-mediated endocytosis, and this process is mediated by folate receptor alpha in an adenosine triphosphate-dependent manner. Because of the difference in folate concentration in the CSF relative to the blood, CSF folate levels indicate brain folate status independent of indicators of whole-body folate status (19).

Vitamin D. Apart from its important role in bone health, vitamin D has several other functions in the human body. The receptor for vitamin D as well as the enzymes necessary for synthesizing bioactive 1,25-dihydroxyvitamin D are expressed in the brain, and hypovitaminosis D is associated with abnormal development and function of the brain (27). Hypovitaminosis D has been linked to several neurologic disorders, including multiple sclerosis, cognitive decline in the elderly, and Alzheimer disease. Vitamin D deficiency has been reported to be more common in patients with Parkinson disease than in healthy control subjects (16).

Vitamin E. As an antioxidant, vitamin E scavenges free radicals in the nervous system. Neurologic dysfunction due to vitamin E deficiency may result from lack of antioxidant protection in susceptible tissues. Vitamin E has been used therapeutically in many neurologic disorders wherein oxidative stress is implicated in pathophysiology, such as in neurodegenerative disorders.

Foods rich in vitamin E (eg, wheat germ oil, almonds, hazelnuts, and walnuts) have shown protective properties in Alzheimer disease. However, evidence for other neurodegenerative disorders and for biomarkers of neurodegeneration is lacking. Interventional studies in humans were unable to substantiate the promise of the therapeutic potential of vitamin E regarding neurodegenerative diseases, which may be due to interindividual differences in vitamin E metabolism (43). Personalization of vitamin E appears to be a worthwhile pursuit for future studies.

Minerals and trace elements.

Iron. In animal experiments, early iron deficiency irreversibly affected brain iron content and distribution, resulting in neurotransmitter and behavioral alterations. Iron deficiency in rats altered postsynaptic responses to serotonin as well as to dopamine. The mechanism is not known, but it is possible that iron deficiency can affect both brain function and behavior and lead to a decline of cognitive function.

Even though extrapolation of animal data is often misleading, iron-deficiency anemia is consistently associated with psychomotor delays in infancy. The areas most involved are language and body balance. In these infants, iron therapy, in most cases, was not sufficient to reverse psychological effects even after complete correction of hematological measures. Low consumption of foods rich in bioavailable iron, such as meat (particularly red meat), and high consumption of foods rich in inhibitors of iron absorption, such as phytate, certain dietary fibers, and calcium, cause iron deficiencies. Neuropsychologic impairment is one of several potential outcomes of this deficiency.

Copper. Copper is a metallic cofactor of dopamine-beta-carboxylase. Although it is present in the brain in reasonably high concentration, it is affected by nutritional status, particularly during development. Copper metabolism is altered in Wilson disease, with obvious neurologic and behavioral sequelae.

Zinc. It is abundant in the brain tissue and has an impact on brain function. In zinc deficiency, lipid composition and essential fatty acid concentrations are altered in the brain. Zinc deficiency affects neuronal protein synthesis and can cause disturbances in the hippocampal areas. Zinc deficiency is an important health problem and may lead to impairment of neuropsychological function.

Magnesium. Magnesium plays an essential role in cellular physiology and is involved in the activation of about 300 enzymes including those catalyzing energy-producing and energy-consuming reactions. It is a cell membrane stabilizer. In the extracellular space, magnesium competes with calcium to reduce calcium entry into cells. The magnesium ion blocks the N-methyl-D-aspartate channel in a voltage dependent fashion, but electrophysiologically extracellular magnesium behaves as a noncompetitive NMDA antagonist. The exact mode of action of magnesium is not known. It has a protective role against oxygen free radicals. Extracellular magnesium ion is a natural NMDA channel blocker.

Magnesium deficiency can affect a variety of neural enzyme systems, cerebral excitability, and deficiency states of other key nutrients. Hypomagnesemia is more frequent than hypermagnesemia and is usually compounded by a deficiency of other vitamins and minerals. Magnesium deficiency is due to deficient intake absorption or increased excretion. If a large amount of magnesium flows out from the CNS, a critical level is reached below which neurologic dysfunction occurs. Early signs of magnesium deficiency are decreased mentation, fatigue, and lethargy. Abnormalities of magnesium metabolism have been reported in depression and alcoholism.

Calcium. It has an important role in the functions of the CNS. Ionized calcium may play a role in synaptic plasticity. Increasing calcium availability has been shown to ameliorate age-related deficits in neurotransmission. Hypercalcemia is a manifestation of several systemic disorders. CNS symptoms of hypercalcemia include impaired mental function, loss of memory for recent events, depression, somnolence, and even coma.

Iodine. A deficiency of this element as a precursor to goitrous hypothyroidism affects fetal brain maturation, which leads to mental handicaps for the infants as they grow.

Role of the brain in control of body weight. Role of the brain in regulating the hunger, nutrient intake, control of body weight and obesity are important issues. A role for autophagy in hypothalamic agouti-related peptide (AgRP) neurons has been demonstrated in the regulation of food intake and energy balance (29). Starvation-induced hypothalamic autophagy mobilizes neuron-intrinsic lipids to generate endogenous free fatty acids, which in turn regulate AgRP levels. During starvation neurons of the hypothalamus respond to nutrient shortages by autophagy or set off a cascade to make the organism crave more food, which explains the difficulty in dieting approaches to control of weight gain. Regulation of hypothalamic autophagy could form the basis for effective intervention in obesity.

Neuroendocrine control of body weight. Neuroregulators found in various parts of the brain have an important role in controlling food intake, and the disturbance of neuroregulators may lead to obesity. Neuropeptide Y can initiate feeding for energy needs, opioid peptides can provide the rewarding aspects of eating, and corticotropin releasing factor can affect stress-induced eating. Neuropeptide Y not only increases eating; it also decreases energy expenditure in brown fat and increases enzymatic activity associated with fat storage in white fat, resulting in obesity.

Considerable evidence demonstrates the importance of leptin in the control of energy homeostasis and feeding behavior. The hormones leptin and insulin are secreted in direct proportion to the size of the adipose mass. During states of negative energy balance, the adipose mass contracts, and less insulin and leptin are secreted and reach the brain. As a result of this, the anabolic pathways are disinhibited and the catabolic pathways are suppressed, leading to increased food intake and energy storage. Conversely, during a state of positive energy balance, the adipose mass expands, leptin and insulin concentrations increase, and the resulting output from the brain favors less food intake, which finally leads to reduction of adipose mass. These feedback circuits help to stabilize the body weight under normal circumstances.

Leptin receptors are found in several regions of the brain implicated in the regulation of energy balance, and the administration of exogenous leptin can alter the function of the hypothalamic-pituitary-adrenal axis. The hypothalamus contains multiple neuronal systems that are important in the regulation of the energy homeostasis. Feeding-related signals from the adipose tissue, the gut, and the brain are integrated in the hypothalamus. The circulating leptin and insulin signals penetrate the blood-brain barrier and stimulate receptors on neurons in the hypothalamus. Satiety signals generated by the ingested food enter the caudal brainstem and influence reflexes related to the acceptance or rejection of the food. Satiety information is relayed to the hypothalamus where it is integrated with cognitive information and adiposity signals. Increased activity of the satiety signals enhances the ability of the satiety signals to terminate a meal. The central melanocortin may be involved in integrating long-term adipostatic signals from leptin and insulin.

Brain, nutrition, and genes. Advances in genomics and epigenomics have enabled an understanding of interactions between genes and nutrition that is useful for understanding the pathomechanism of several neurologic disorders resulting from interactions between environmental and genetic factors (14). Gene expression, single nucleotide polymorphisms, and copy number variations may help in determining individual responses to nutrition.

Brain disorders caused by malnutrition. Common brain disorders caused by malnutrition are:

• Cognitive impairment • Cerebral atrophy • Mental deficiency • Depression • Cerebrovascular disease • Protein-calorie malnutrition (Kwashiorkor) • Polyneuropathy with optic neuropathy • Altered responsiveness to psychoactive drugs

Malnutrition and cognitive impairment in the elderly. Various studies show an association between nutritional status and cognitive function in the elderly. Those with low blood levels of riboflavin, folic acid, vitamin B12, and vitamin C perform poorly on cognitive tests. Most of these elderly persons live independently in their own homes and it is possible that poor nutrition may be due to cognitive impairment (eg, they may forget to take vitamin pills or prepare proper meals). In other words, poor nutrition and cognitive impairment interact. Correlation of plasma nutritional biomarkers with psychometric and imaging indices of brain health in the elderly Oregon Brain Aging Study cohort accounted for 17% of the variation in cognitive test scores and 37% of the variation in brain size (05). A pattern of high plasma levels of vitamins B1, B2, B6, B12, C, D, and E and folate or high plasma omega-3 fatty acids were each associated with greater brain volume and better cognitive function. The Québec Longitudinal Study on Nutrition and Successful Aging uncovered an association between higher serum vitamin K1 levels and better verbal episodic memory in the elderly (41).

Malnutrition has been suggested to play a role in the pathogenesis of Alzheimer disease, and oral nutritional supplements may improve cognitive function in these patients. Thus far, no nutritional intervention has been proved to be effective in reducing the risk or severity of Alzheimer disease. However, several large randomized controlled trials are underway to test the effectiveness of several nutrients (11).

Gut microbiota and brain development. The human gut is also a "microbial organ" composed of trillions of organisms that metabolize various diets and influence brain development (23). Cognitive abnormalities seen in children with undernutrition are partly related to immaturity of their persistent gut microbiota. An implication of this concept is that optimization of nutritional recommendations can promote healthy brain development.

Neurologic sequelae of malnutrition due to gastrointestinal procedures. Various surgical procedures for obesity such as gastric bypass can result in chronic nutritional deficiency of minerals and vitamins with neurologic sequela. A patient with gait disturbances and neuropathy due to copper deficiency was reported less than 2 years following a Roux-en-Y gastric bypass, and improvement occurred within 2 months of copper supplementation (39). Patients with small bowel resection who are on long-term parenteral therapy may develop various neurologic disorders, the most common being cerebral atrophy. This may be due to inadequate intake of essential nutrients in the parenteral nutrition.

Cerebral atrophy. This may develop in patients with intestinal failure. Patients with small bowel resection who are on long-term parenteral therapy may develop various neurologic disorders, the most common being cerebral atrophy. This may be due to inadequate intake of essential nutrients in the parenteral nutrition.

Nutrition and cognitive development. A study on Korean children and adolescents found significant correlations between nutrition and cognitive function, which were rigorously measured by computer-based cognitive function tests and visual continuous performance tests (31). Sources of good nutrition such as vitamins B1, B6, and C, rice with mixed grains, and mushrooms were positively correlated with better cognitive function, whereas processed carbohydrates such as white rice and noodles or fast food were negatively correlated with cognition.

Malnutrition and mental deficiency. Experimental studies on nonhuman species have shown conclusively that malnutrition retards mental development. No such studies have been done on humans, but compelling evidence is available that advances the notion that malnutrition during the first year of life is a contributing factor to mental deficiency. This is believed to be due to inadequate myelination during the period of active brain growth. Protein and vitamin B1 deficiencies appear to be the most significant factors. Maternal deprivation in early postnatal life, which is associated with malnutrition of the newborn, leads to a significant decrease in acetylcholine levels in the developing brain, resulting in decreased learning ability throughout life.

Malnutrition in infancy and impairment of intellectual development. Malnutrition during a sensitive period may result in disease in adult life, and studies strongly suggest the development of the brain and retina can be affected. This may be due to the lack of essential fatty acids and particularly involves premature babies born at a time when cell membrane development is especially vulnerable. These findings must be viewed with caution, as genetic and environmental influences can be important as well. A plethora of reasons support breast feeding over formula feeds, including improved cognition and visual function. For example, breast milk contains docosahexanoic acid and arachidonic acid essential for normal brain development, which is often absent or in short supply in formula feeds.

The traditional concepts about the importance of nutrition in brain development during the first 2 years are being modified. Brain growth in undernourished children is not terminated abruptly after this period, but rather, it is put on hold. Growth of the brain may resume even if nutrition improves by the age of 3 or so. According to the concepts, malnutrition alters intellectual development by interfering with overall health as well as the child's energy level, rate of motor development, and rate of growth. Poverty and a lack of an intellectually stimulating environment are additional factors that retard intellectual development. Some controversy exists concerning the role that micronutrients play in psychomotor and cognitive development; a causal relation is sometimes difficult to establish. Although conclusive evidence stipulates that iodine deficiency during intrauterine life causes cretinism, the role of iodine supplementation in the cognitive development of school-age children is less clear; however, some of the relations are well established. Iron-deficient anemic children are at high risk of poor behavioral development; evidence of the benefit of iron treatment in these children is reasonably good.

The consequences of proper nutritional management of the brain play out over a lifetime from conception to adulthood even though the human brain may account for 50% of the body's basal nutritional requirement during childhood (22).

Depression. Depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency. Conversely, borderline low or deficient serum or red blood cell folate levels are detected in 15% to 38% of adults diagnosed with depressive disorders. Low folate levels have been linked to poorer antidepressant response to selective serotonin reuptake inhibitors.

Vitamin deficiency as a risk factor for stroke. The findings of a multicenter case-controlled study in Europe reveal a link between stroke and low circulating levels of vitamin B6 and folate. Insufficient intake of these two nutrients is already linked to high levels of hyperhomocysteinemia, which is already recognized to be a risk factor for stroke. In this study, the investigators measured the plasma levels of total homocysteine, red cell folate, vitamin B6, and vitamin B12 in patients with documented vascular disease (coronary artery disease, peripheral vascular disease, and stroke) and compared the findings to those in age- and sex-matched control subjects without any evidence of vascular disease. They found that vitamin B6 levels were lower in patients with vascular disease than in the healthy controls and that study participants in the lowest 20th percentile were almost twice as likely to have heart disease and stroke as those with high levels of vitamin B6. Folate levels were also low in those with vascular disease and subjects with folate levels in the lowest 10th percentile were about 1.5 times as likely to have heart disease or stroke as those with higher levels of this nutrient. This association may be related partly to the effect of folates on homocysteine metabolism. The mechanism of the risk of stroke associated with vitamin B6 deficiency may also be related to the promotion of the formation of blood clots.

Protein-calorie malnutrition (kwashiorkor). Protein-calorie malnutrition is a problem not only in poor, Third World countries where kwashiorkor is common; it is also found in some hospitalized patients with a long duration of stay in developed countries.

Dietary amino acids play a precursor role in neurotransmitter synthesis (tyrosine for norepinephrine and tryptophan for serotonin) and their turnover decreases with protein deficiency. EEG shows diminution of voltage and excessive slow-rhythm activity. Children with kwashiorkor have psychomotor and mental retardation. Whether this is due to dietary factors alone or also due to social deprivation is not certain. Severe protein calorie malnutrition in the first year of life causes severe intellectual deficits. In the second year of life, it may produce mental retardation, but usually does not.

Polyneuropathy with optic neuropathy. An epidemic outbreak of peripheral neuropathy was reported in Cuba in 1992 to 1993 (46). Clinical forms included retrobulbar optic neuropathy, sensory and dysautonomic peripheral neuropathy, dorsolateral myeloneuropathy, sensorineural deafness, dysphonia and dysphagia, spastic paraparesis, and mixed forms. An intensive search for neurotoxic agents, particularly organophosphorus esters, chronic cyanide, and trichloroethylene intoxication, yielded negative results. Treatment of patients with B-group vitamins and folate produced rewarding results. There were no deaths, and most patients improved significantly; less than 0.1% of the patients had residual sequelae. Supplementation of multivitamins to the entire Cuban population curbed the epidemic. Overt malnutrition was not present, but a deficit of micronutrients, particularly thiamin, cobalamin, folate, and sulfur amino acids, appears to have been a primary determinant of this epidemic. Although such an epidemic has not been reported again, advances in genome-wide sequencing, whole exome sequencing, homozygosity mapping, and segregation analysis for novel disease-causing gene discovery have revealed that hereditary polyneuropathy with optic atrophy is due to mutations in the PDXK gene that encodes for a pyridoxal kinase, which converts inactive B6 to the active cofactor pyridoxal 5'-phosphate (PLP). Variants in PDXK cause impaired vitamin B6 metabolism like that in axonal Charcot-Marie-Tooth disease, which responds to pyridoxal 5'-phosphate supplementation, and the plasma pyridoxal 5'-phosphate levels can be monitored by high performance liquid chromatography (09; 30).

Age-related macular degeneration. Epidemiologic studies indicate important contributions of dietary patterns to the risk for age-related macular degeneration. There is a functional interaction between dietary carbohydrates, the metabolome, including microbial cometabolites, and features of age-related macular degeneration (47). These findings suggest that a simple dietary intervention may be useful for halting the progression of age-related macular degeneration.

Altered responsiveness to psychoactive drugs. A considerable amount of data show that malnourished animals react to drugs differently from controls, which suggests that the altered behavioral expression of these animals could be partly explained by the alterations in the brain function following malnutrition. Reactivity of malnourished animals to psychoactive drugs acting through GABAergic, catecholaminergic, serotonergic, opioid, and cholinergic neurotransmitter systems is important. Altered responsiveness to psychoactive drugs in malnourished animals may be especially relevant to understanding the consequences of malnutrition in human populations.

Clinical applications

• Nutrition-based interventions are used in the management of neurologic disorders.

In addition to determining the role of nutritional disturbances in neurologic disorders, several nutrition-based interventions are used in the management of some of these. The ESPEN guidelines for nutrition therapy in patients with neurologic diseases offers 88 recommendations for use in clinical practice for amyotrophic lateral sclerosis, Parkinson disease, stroke, and multiple sclerosis, where management of oropharyngeal dysphagia plays a pivotal role (08).

Nutrition and cognition function in extreme physical exertion. The combination of optimal nutrition with physical exercise is generally recognized to be beneficial for cognitive function. Exercise has been promoted as a prevention for neurodegenerative diseases and the positive influence on cognition is attributed to an increase in the brain-derived neurotrophic factor. Several cross-sectional and longitudinal studies have shown that a higher intake of flavonoids from food may be associated with a better evolution of cognition (35). Extreme physical exertion, however, places extra stress on the human body, and may require nutritional modification.

Stress-related disorders. Chronic stress with failure of adaptation may lead to illness, partly through changes in nutritional behavior, because physiological and psychological stress responses are affected by food choice and food ingredients, which affect a broad range of neuroendocrine and related psychological processes (50). Dietary modification may provide a means to modify susceptibility to stress-related disorders.

Nutrition and mental function in the elderly. A glucose drink has been shown to improve memory in persons with poor glucose regulation and cognition. Like glucose, early morning consumption of cereal can improve performance on some cognitive tests in the elderly subjects. Dietary carbohydrates, such as potatoes, have been shown to enhance cognition in subjects with poor memory and impaired pancreatic beta cell function independently of plasma glucose. Results on tests of memory are better after a full meal compared to only drinking a glass of water. Results of animal studies suggest that a high-fat, carbohydrate-poor diet may impair brain function over time. High-fat diets may hinder brain function by promoting insulin resistance. The link between high-fat diets and impaired brain function appears to be diabetes, as diabetics often suffer a decline in certain mental functions such as long-term memory.

Results of various experimental studies indicate that increasing dietary intake of fruits and vegetables high in antioxidant activity may be an important component of a healthy living strategy designed to maximize neuronal and cognitive functioning into old age. Diets rich in antioxidants such as those found in fruits, nuts, vegetables, and spices may lower age-related cognitive declines and the risk of developing neurodegenerative disease (28). A high adherence to the Mediterranean diet has been associated with slower cognitive decline and reduced risk of conversion of mild cognitive impairment to Alzheimer disease (18).

Nutritional prophylaxis neurologic disorders. No standard dietary regimens are available for neurologic diseases comparable to those for cardiovascular and renal disorders. Dietary measures are sometimes directed at metabolic disorders with neurologic manifestations or at-risk factors for neurologic diseases. One example is the specific dietary measures that are to be followed for the prevention of cerebrovascular disease.

Caloric restriction. Animal studies suggest that caloric intake may be the primary effector for many hormonal, metabolic, physiologic, and behavioral responses that coordinate reproductive strategy to apparent availability of food. Calorically restricted rodents have significantly longer reproductive and total life spans than their ad libitum-fed controls and exhibit a spectrum of biochemical and physiologic alterations that characterize their adaptation to reduced intake. Dietary calorie intake restriction can increase the resistance of neurons in the brain to dysfunction and death in experimental models of Alzheimer disease, Parkinson disease, Huntington disease, and stroke. The mechanism underlying the beneficial effects of dietary restriction involves stimulation of the expression of neurotrophic factors, which may protect neurons by inducing the production of proteins that suppress oxidative radical production, stabilize cellular calcium homeostasis, and inhibit apoptotic biochemical cascades. Dietary restriction also increases numbers of newly generated neural cells in the adult brain, suggesting that this dietary manipulation can increase the brain's capacity for plasticity and self-repair. Dietary restriction, even when started in old age, can be beneficial not only to retard age-related functional decline, but also to restore functional activity.

Control of nutritional risk factors for cerebrovascular disease. Control of nutritional risk factors for stroke, such as hypertension, atherosclerosis, and hyperlipidemia, are important.

Hypertension. Nonpharmacologic interventions for hypertension include nutritional measures such as weight reduction, salt restriction, and potassium supplementation. These measures have been shown to reduce both systolic and diastolic levels in older patients with borderline hypertension. A vegetarian diet is associated with decreased risk of early death from cerebrovascular disease. In Japan, the incidence of hypertension is higher in areas where people consume less protein and more salt in their diet. An increase in protein and a restriction in salt have been recommended as preventive measures. Dietary therapeutic measures are an important adjunct to the drug therapy of hypertension.

Dietary factors influencing fibrinolysis and hemorrheology. The fibrinolytic system in humans is affected by nutritional factors. Obese persons have reduced fibrinolytic activity. Dietary restriction, sufficient to induce rapid weight loss in obese subjects, has been observed to be associated with an increase in plasma fibrinolytic activity. A vegetarian diet poor in arachidonic acid, does not inhibit platelet aggregation or thromboxane production, but does so when it is combined with eicosapentaenoic acid. A diet rich in eicosapentaenoic acid leads to changes in hemostatic and other parameters that are consistent with overall antithrombotic effect.

Dietary measures against hyperlipidemia. These are the most important measures against lipidemia. The emphasis is on a low-fat diet containing unsaturated fatty acids of plant origin. The lowering of cholesterol esters after eating plant fats contrasts with the rise in cholesterol ester levels in blood after eating animal (saturated) fats; however, an excess of vegetable oils can lead to an increase in plasma triglyceride levels.

Correction of vitamin deficiency. Clinical trials have been proposed to test the long-term effects of the correction of deficiencies of vitamin B6, B12, and folate in preventing cardiovascular disease and stroke.

Dietary antioxidants. Oxidative stress and systemic inflammation are involved in the pathogenesis of ischemic stroke. Findings of an Italian population-based study suggest that dietary antioxidants may play a role in reducing the risk of cerebral infarction but not hemorrhagic stroke (15).

Prevention of neurologic disorders in infancy. Knowledge of nutritional factors that influence development of the nervous system can be used for the prevention of neurologic disorders in infancy. Nutritional strategies to optimize brain growth and development in a preterm infant include assessment of status at birth, aggressive provision of nutrients that are critical in this time period, control of non-nutritional factors that impede brain growth, and repletion of nutrient deficits (42). Choline is mentioned as example of an important nutrient.

Choline. Choline is critical for normal development of the fetus brain during pregnancy and lactation (periods when maternal reserves of choline are depleted). Variations in choline intake by the mothers influence memory performance of their offspring. These observations are important for planning ideal dietary intake for mothers and their children. The National Academy of Sciences (United States) has identified choline as a required nutrient for humans and recommended daily intake amounts. Choline, or its metabolites, assure the structure of cell membranes and directly affect nerve signaling, cell signaling, and lipid transport and metabolism.

Nutritional therapy for neurologic disorders. Several naturally occurring dietary constituents are precursors for neurotransmitters and are used in the treatment of brain diseases. The consideration of nutrients as therapeutic agents has led to the following question: "When large doses of a nutrient separated from other constituents of food that are its usual source are given to people specifically to treat a disease or a condition, does the nutrient therapy become a drug?" The boundary between a nutritional or physiological dose and therapeutic dose may be difficult to establish. When a healthy diet containing factors such as omega-3 fatty acids and curcumin is combined with physical exercise, a synergistic beneficial effect in neuronal recovery occurs, as both approaches elevate levels of molecules important for synaptic plasticity, such as a brain-derived neurotrophic factor (21).

Nutritional psychiatry. There is a strong association between malnutrition and the exacerbation of mood disorders, including anxiety and depression, as well as other neuropsychiatric conditions. An overview of the emerging field of nutritional psychiatry concludes that an experimental medicine approach and understanding of pathomechanisms are required to provide solid evidence on which to base future recommendations about nutrition for mental health (01).

Nutritional approaches to memory impairment. Several widely marketed nonprescription compounds claimed to be memory enhancers and treatments for age-related memory decline. Some of these have undergone double-blind placebo-controlled studies. These include phosphatidylserine, phosphatidylcholine, citicoline, piracetam, vinpocetine, acetyl-L-carnitine, and antioxidants such as vitamin E.

Choline as a precursor of acetylcholine for treatment of dementia. Choline is a precursor of acetylcholine, and lecithin is a dietary source of acetylcholine. The rationale for attempting to improve cognitive function by increasing the intake of cholinergic precursors can, under certain conditions, lead to an increase in brain choline levels and, hence, in synthesis and (presumably) release of acetylcholine. Choline does not improve memory impairment in otherwise healthy elderly subjects. Several controlled clinical trials have been conducted, but the efficacy of choline in treating patients with Alzheimer disease has been disappointing.

Nutritional aspects of Parkinson disease. Tyrosine, tryptophan, and glutamic acid as dietary precursors of neurotransmitters are reported to produce modest improvement in some studies and negative results in others. The ability of the elderly to absorb tryptophan shows a wide variation. Subnormal serum levels of tryptophan have been demonstrated in Parkinson disease patients with mental symptoms as well as in patients with senile dementia.

Certain amino acids compete with L-dopa in the intestine and at the blood-brain barrier and, thus, daytime protein restriction may improve fluctuations in motor ability in patients with Parkinson disease; however, protein restriction diet can contribute to weight loss, nutritional deficiencies and cognitive impairment if it is not controlled adequately. Further studies are required to clarify how medication, such as L-dopa, may affect motor fluctuations, nutritional status, and cognitive ability in combination with different diets.

Nutritional aspects of Alzheimer disease. Brains of patients with Alzheimer disease contain fewer and smaller synapses and have reduced levels of synaptic proteins, membrane phosphatides, choline, and docosahexaenoic acid. Brain phosphatidylcholine rise considerably in experimental animals fed a cocktail containing omega-3 fatty acids, uridine, and choline, indicating the potential of this as therapy in Alzheimer disease. Several nutritional products are in clinical trials for Alzheimer disease.

Nutritional therapy in demyelinating disorders. Essential fatty acid deficiency has been well studied for the important role of C22:6 (a C18:3 metabolite) in vision system development. The observation that dietary fatty acids can affect membrane composition led to the use of modified diets in some CNS pathological conditions. Several nutritional compounds, mostly polyunsaturated fatty acids and vitamin D, have been investigated as a possible treatment in multiple sclerosis, but their role in the treatment remains to be confirmed (25).

Creatine. Creatine monohydrate is an amino acid produced naturally in the body from the proteins arginine, glycine, and methionine. Creatine is converted (phosphorylated) to phosphocreatine by the enzyme creatine kinase. Phosphocreatine in turn buffers the concentration in cells of ATP (adenosine triphosphate), the basic energy source for living cells. ATP is formed when creatine combines with ADP (adenosine diphosphate). When the energy in ATP is used, it becomes ADP again and needs to be regenerated back to ATP by phosphocreatine. Phosphocreatine regenerates ADP by transferring a phosphate group to it. Creatine supplementation increases phosphocreatine levels, which in turn increase ATP (energy) levels that nourish the brain. Creatine breaks down into creatinine, a waste product processed by the kidneys and excreted in the urine.

Creatine kinase and its substrates creatine and phosphocreatine constitute an intricate cellular energy buffering and transport system connecting sites of energy production (mitochondria) with sites of energy consumption, and creatine administration stabilizes the mitochondrial creatine kinase and inhibits opening of the mitochondrial transition pore. Creatine, one of the most common food supplements used by individuals at almost every level of athleticism, promote gains in performance, strength, and fat-free mass. Experimental findings have demonstrated that creatine affords significant neuroprotection against ischemic and oxidative insults. Clinical studies conducted in patients with amyotrophic lateral sclerosis did not find evidence of a beneficial effect of creatine monohydrate on survival or disease progression in patients with amyotrophic lateral sclerosis.

Ketogenic diet. The rationale of ketogenic diet, a type of low-carbohydrate and low-calorie diet, for control of seizures is based on the experimental evidence that diet-induced ketosis raises the threshold for seizures in mice. The anticonvulsant effect of ketogenic diet withstood the test of time but declined in usage with the introduction of anticonvulsant medications; however, a resurgence of interest has taken place in the ketogenic diet for the management of intractable seizures, particularly in infants and children. Ketogenic diet has been shown to reduce seizures in mice by increasing activation of adenosine A1 receptors (24). Adenosine deficiency may be relevant to human epilepsy because hippocampal tissue resected from patients with intractable epilepsy has demonstrated increased adenosine kinase (33).

The adult human brain uses ketone bodies as the principal substrate during starvation, resulting in a decrease in brain glucose consumption. Ketogenic diets are rich in carbohydrate content and poor in protein content and can have adverse effects on the brain. Besides ketogenic diets, other dietary approaches that have been investigated include a diet enriched in polyunsaturated fatty acids and even calorie restriction, but further studies are necessary to evaluate these.

Ketogenic diet is neuroprotective because ketones promote mitochondrial energy production and membrane stabilization. Ketogenic diet slows the progression of disease in a transgenic mouse model of amyotrophic lateral sclerosis, probably due to the ability of ketone bodies to promote ATP synthesis and bypass inhibition of complex I in the mitochondrial respiratory chain. The clinical significance of this is not known. Ketogenic diet has also been investigated as an approach to delay the effects of aging. Increases in the level of ketone body D-β-hydroxybutyrate βOHB, which is known as an endogenous and specific inhibitor of class I histone deacetylases, by administration of exogenous βOHB or fasting or calorie restriction, was shown to confer significant protection against oxidative stress in mice (49). Identification of a link between caloric restriction and protection from oxidative stress opens a variety of avenues to neuroprotection in age-related diseases such as Alzheimer disease. A phase I/II randomized clinical trial examined the feasibility of using a modified Atkins diet (very low carbohydrates and extra fat) to induce ketogenesis in persons with early Alzheimer disease and the effect of this diet on memory and other clinical outcomes (06). The preliminary data suggest that the generation of even trace ketones might enhance episodic memory and patient-reported vitality in early Alzheimer disease.

Nutritional measures for neurodegenerative disorders. Oxidative stress has been implicated in the pathogenesis of neurodegenerative disorders. Several studies have shown that antioxidants can block neuronal death in vitro and in animal models of neurodegenerative diseases. Clinical data also suggest that nutritional antioxidants might have some protective effect against the progression of Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis. However, no nutritional intervention has so far proved to be effective in reducing the risk or severity of Alzheimer disease or any dementia (11). Several large randomized clinical trials are in progress. Results of these trials may provide the evidence to make more definite recommendations, either for or against, specific nutrition approaches to reduce the impact of or control Alzheimer disease.

Nutritional approach to neuroinflammation. Inflammation is a hallmark of several neurologic disorders and serves different functions, including protection of uninjured neurons, removal of degenerating neuronal debris, and assistance in recovery. The dietary ratio of arachidonic acid to docosahexaenoic acid may affect neurodegeneration associated with acute neural trauma and neurodegenerative diseases (17).

Nutritional support for traumatic brain injury. Early nutritional support is recommended for patients with traumatic brain injury. Enteral nutrition started within 48 hours following injury is associated with better survival, recovery, and outcome of traumatic brain injury patients, particularly in those with a Glasgow Coma score of 6-8 (10). Results of studies in humans suggest that supplementation with omega three fatty acids, vitamin D, branched chain amino acids, and zinc may be helpful for recovery from traumatic brain injury (13). A retrospective study suggests that patients with traumatic brain injury who receive immune-enhancing nutrition containing additives such as glutamine, arginine, and omega-3 fatty acids are more likely to have increased prealbumin levels reflecting improved nutrition during their hospital stay and may show some reduction in rates of infections (40). Results of a prospective randomized control trial indicate that early enteral nutrition (plus parenteral nutrition) treatment, by enhancing nutritional status, can promote the recovery of the immune function, decrease complications, and improve clinical outcomes in patients with severe traumatic brain injury (37).

Nutritional support for the stroke patient. Malnutrition is common in stroke patients. A study has shown that acute stroke patients were not meeting nutritional requirements and losing body weight (44). Malnutrition in this study was associated with lower energy and protein intakes and increased length of hospital stay. The enriched environment alone showed no effect on nutritional intake.

A stroke patient may have difficulty in oral feeding due to impairment of consciousness or dysphagia. Nasal tube feeding or gastrostomy may be used for supplementing intravenous fluid therapy. Results of a study have shown that the evidence-based practice of continuous nasal feeding in stroke patients is an effective method to provide adequate nutrition and reduce gastrointestinal complications (48).

Vitamins and megavitamin therapy. The role of vitamin therapy, such as thiamin in relieving symptoms of thiamine deficiency, is well known. Thiamine plays an important role in Wernicke-Korsakoff syndrome. The progression of the acute syndrome can be stopped by a timely injection of a large dose of thiamine; however, thiamine has not been proven to be effective in other dementias such as Alzheimer disease.

The only accepted indications for vitamin therapy are for treatment of specific deficiency syndromes. The role of megadoses of vitamins to treat neurologic disorders by increasing the concentration of vitamins in the brain remains unproved. Vitamins, themselves, have no neuropharmacologic action. Megadoses of these substances can also over activate vitamin-dependent enzymes, which leads to reverse metabolic dysregulation (ie, deficiency of enzyme substrates and accumulation of enzyme products); thus, megavitamin therapy can cause indirect neurotoxicity.

Trace elements and minerals.

Magnesium. Ionized magnesium is a sedative that depresses the function of the CNS and the cardiovascular system. This is the basis for its use in toxemias of pregnancy. It has been suggested that systemically administered magnesium sulfate can block NMDA receptors in the brain and afford neuronal protection in cerebral ischemia and seizures. Clinical trials have not shown efficacy in stroke.

Iron. Iron-deficiency anemia during infancy may be associated with irreversible adverse effects on cognitive performance. Careful follow-up studies of these infants at 5 to 6 years of age shows that cognitive disadvantages persist as assessed with a comprehensive set of psychological tests that reliably predict future competence; thus, if once anemia ensues, even timely and adequate iron therapy seems to be ineffective in reversing these behavioral and cognitive disadvantages, the only practical way to approach this problem is by prevention of iron deficiency in infancy. An attempt should be made to prevent iron deficiency with adequate food fortification strategies or by supplementing targeted population groups.

Beneficial neurologic effects of caffeine. Caffeine, a common dietary constituent, is the most widely used stimulant in the world. Epidemiological evidence implies that caffeine has a neuroprotective effect in Parkinson disease. The stimulant effects of caffeine are mediated through its antagonistic properties on adenosine A2A receptors that are concentrated in the dopamine rich areas of the brain. Adenosine decreases dopaminergic neurotransmission by means of antagonistic interactions between adenosine A2A receptors and dopamine receptors. The blockade of these receptors can, thus, facilitate dopaminergic transmission by stimulating dopamine release and by potentiating the effects of dopamine receptor stimulation. The beneficial effect of caffeine also points to the potential usefulness of developing adenosine A2A receptors as therapeutic agents for Parkinson disease.

Personalized nutrition for neurologic disorders. A randomized study has demonstrated that personalized nutrition support delivered using biotechnology can improve dietary intake in adults with significantly greater changes observed in dietary intakes for those receiving a higher level of personalized support, which included the Australian Eating Survey dietary feedback (45). Progressive age-related reductions in muscle mass and strength (sarcopenia) can cause substantial morbidity. Based on available data, individualized dietary and supplemental interventions may add to the benefits of exercise on muscle mass and strength (12). Nutritional therapy should be personalized in management of the neurologic patient.