Summary

  • The brain requires a constant supply of micronutrients for energy metabolism of neurons and glial cells, neurotransmitter synthesis and action, nerve impulse propagation, and homocysteine metabolism. (More information)
  • Deficiencies in various micronutrients, especially the B vitamins, have adverse effects on cognition. (More information)
  • The developing brain may be particularly vulnerable to deficiencies in choline and essential fatty acids. (More information)
  • Due to conflicting studies, more research in needed to determine whether micronutrient supplementation affects attention-related cognitive functions. (More information)
  • Presently, there is little evidence that supplementation with B vitamins, antioxidant vitamins, choline, or omega-3 fatty acids will improve memory performance. (More information)
  • More research is needed to determine whether micronutrient supplementation has any effects on executive functioning (i.e., higher-order cognitive processes). (More information)
  • Some, but not all, studies have reported that micronutrient supplementation improves overall mood and psychological well-being. (More information)
  • It is not yet clear whether supplementation with B vitamins, antioxidants, or omega-3 fatty acids protects against age-related cognitive decline. (More information)
  • Several methodological issues (e.g., tests used to assess cognition, choice of study population, nature of the supplementation, study duration, etc.) may have contributed to the conflicting results observed in intervention studies. (More information)

Introduction

Good nutritional status is important for proper brain development and maintenance of normal cognitive function (1). Through unique biological functions, various micronutrients affect brain function. This article discusses the roles of key micronutrients, including the B vitamins, antioxidant vitamins, and certain essential minerals, in cognitive function. When appropriate, research on the role of other compounds, such as essential fatty acids and choline, is also presented. The cognitive effects of micronutrient deficiencies are discussed, and the effects of micronutrient supplementation on the broad areas of attention, memory, executive functions, mood, as well as age-related cognitive decline are covered.

Basic Needs for Cognitive Performance

Energy metabolism of neurons and glial cells

The human brain is a highly metabolically active tissue that depends on a constant supply of glucose to meet its energy needs. In fact, the brain accounts for approximately 25% of total body glucose utilization at rest, despite representing only 2% of adult body weight (2, 3). Blood glucose levels must be maintained at all times to avoid hypoglycemia and to supply the brain with its preferential fuel. During the initial stages of fasting, blood glucose levels are maintained through the breakdown of liver glycogen and then through the process of gluconeogenesis—the production of glucose from non-carbohydrate precursors, such as amino acids. The B vitamin biotin is required for a key enzyme in the gluconeogenic pathway (4). While glucose is the obligatory fuel, ketone bodies can also be used by the brain when glucose supply is inadequate, such as during prolonged fasting or starvation. However, ketone bodies are acidic, and very high levels of these compounds in the blood are toxic and may result in ketoacidosis (5). Thus, glucose is the preferred and normal energy substrate of the brain.

Glucose oxidation in the brain requires certain micronutrients as cofactors. For instance, forms of several B vitamins, including thiamin, riboflavin, niacin, and pantothenic acid, as well as the compound lipoic acid, are utilized in reactions that completely metabolize glucose to carbon dioxide and water (3). Additionally, the nutritionally essential minerals, magnesium, iron, and manganese are required for the complete metabolism of glucose; these micronutrients are utilized as cofactors, substrates, or components of enzymes in glycolysis and the citric acid cycle (6, 7). Moreover, generation of cellular energy in the form of ATP by the electron transport chain requires the vitamins, riboflavin and niacin; iron contained in iron-sulfur clusters; and the endogenously synthesized compound, coenzyme Q10 (8).

Cerebral blood supply

At rest, the brain receives approximately 15% of cardiac output (9). Proper cerebral blood supply is necessary to deliver oxygen, glucose and other macronutrients, and the required micronutrients for proper cognitive function. Nutrition has a role in maintaining optimal blood supply to the brain. For instance, insufficiency of several dietary components increases the risk of developing stroke, a pathological condition that results from impaired cerebral blood supply; see "Stroke" in the Disease Index.

Neurotransmitter synthesis

A neurotransmitter is a chemical released from a nerve cell that transmits an impulse to another nerve cell or an effector cell, such as a muscle cell. Neurotransmitters have either excitatory or inhibitory effects; the type of effect is dependent on the receptor on the receiving cell (10). Neurotransmitters can be broadly divided into two main classes: small amino acids (e.g., γ aminobutyric acid [GABA], glutamate, aspartate, and glycine) and biogenic amines (e.g., dopamine, epinephrine, norepinephrine, serotonin, histamine, and acetylcholine) (11).

In addition to various amino acids, several B vitamins, including thiamin, riboflavin, niacin, vitamin B6, folate, and vitamin B12, are needed as cofactors for the synthesis of neurotransmitters. Moreover, vitamin C is required for synthesis of norepinephrine (3), and the mineral zinc is important for proper function of GABA, aspartate, and norepinephrine (12). Further, choline is a precursor for the neurotransmitter acetylcholine (13).

Neurotransmitter binding to receptors

Neurotransmitters function by binding to receptors on the cell membrane of the neuron releasing the neurotransmitter (i.e., presynaptic neuron) or to receptors on the cell membrane of the receiving cell (i.e., the postsynaptic neuron). Receptor binding can either mediate the opening of ion channels or cause metabolic changes within the cell (3, 14). Specifically, direct action on ion channels results from neurotransmitter binding to receptor sites on the membrane of postsynaptic neurons. This binding causes the gate-like ion channels to open, which allows ions to flow into the cell (10). Influx of positively charged ions into the postsynaptic neuron can have excitatory effects by depolarizing the membrane; membrane depolarization can cause a nerve impulse or action potential if a certain threshold is reached within the neuron. This is commonly referred to as “neuronal firing.” In contrast, influx of negatively charged ions can have inhibitory effects by hyperpolarizing the membrane and thus preventing neuronal firing (15). In addition to direct effects on ion channels, neurotransmitters may bind to G-protein coupled receptors, thereby eliciting cell-signaling effects that could result in metabolic changes (e.g., alterations in activity of various enzymes) within a postsynaptic cell (14).

Vitamins could possibly influence binding of neurotransmitters to postsynaptic receptors. For instance, an in vitro study showed that two forms of vitamin B6, pyridoxal and pyridoxal phosphate, inhibited the binding of GABA to postsynaptic receptors (16). Also, a rat study associated vitamin B6 deficiency during fetal development and lactation with changes in the number and binding of dopamine receptors (17).

Nerve impulse propagation

The speed at which nerve impulses (action potentials) are propagated is influenced by the myelination of the nerve (18). Myelination refers to the process in which nerves acquire a myelin sheath—the insulating layer of tissue made up of lipids and proteins that surrounds nerve fibers. This sheath acts as a conduit in an electrical system, allowing rapid and efficient transmission of nerve impulses (10).

Certain micronutrients can affect the propagation of nerve impulses. In particular, adequate intake of both folate and vitamin B12 is important in maintaining the integrity of the myelin sheath, and thiamin is needed for maintenance of the nerve’s membrane potential and for proper nerve conductance (3). Additionally, iron has an important role in the development of oligodendrocytes, the cells in the brain that produce myelin (19).

Homocysteine metabolism

Homocysteine is a sulfur-containing amino acid that is an intermediate in the metabolism of another sulfur-containing amino acid, methionine. Elevated homocysteine levels in the blood (i.e., hyperhomocysteinemia) may be a risk factor for cardiovascular disease and could also be linked to dementia and Alzheimer’s disease (20, 21). The amount of homocysteine in the blood is regulated by at least three vitamins: folate, vitamin B6, and vitamin B12 (Figure 1). Additionally, the nutrient choline is also involved in homocysteine metabolism. The choline metabolite, betaine, can also provide a methyl group for the conversion of homocysteine to methionine.

Figure 1. Involvement of B Vitamins in Homocysteine Metabolism. S-adenosyl homocysteine is formed during S-adenosyl methionine-dependent methylation reactions, and the hydrolysis of S-adenosyl homocysteine results in homocysteine. Homocysteine may be remethylated to form methionine in a reaction that requires both folate and vitamin B12. Alternately, homocysteine may be metabolized to the amino acid, cysteine, in reactions catalyzed by two vitamin B6-dependent enzymes.

Consequences of Select Micronutrient Deficiencies

Thiamin

Thiamin (vitamin B1) deficiency, like deficiencies in several of the B vitamins, has negative cognitive effects. Adequate intake of thiamin is important for reactions in the brain that metabolize carbohydrates, lipids, and amino acids. For instance, phosphorylated forms of thiamin, including thiamin diphosphate (TDP) and thiamin pyrophosphate (TPP), are required cofactors for enzymes of glycolysis, the citric acid cycle, and the pentose phosphate pathway (22). Additionally, thiamin triphosphate (TTP) may be involved in neuronal membrane functions and nerve impulse (action potential) generation, but the exact biochemical role of TTP is still not well understood (22, 23). Severe thiamin deficiency, which is rare in industrialized nations, except in patients with chronic alcoholism, HIV-AIDS, or gastrointestinal conditions that impair vitamin absorption (23), results in the condition called beriberi, of which there are many forms that involve neurological symptoms. The dry and wet forms of beriberi involve peripheral neuropathy, whereas cerebral beriberi can lead to neuronal cell death and the clinical conditions of Wernicke's encephalopathy and Korsakoff's psychosis, especially in those who chronically abuse alcohol (22, 24). For more information about the various forms of thiamin deficiency, see the article on Thiamin.

Niacin

The niacin (vitamin B3) coenzymes, NAD and NADP, are needed for several redox and other reactions in the body (see the article on Niacin). Severe niacin deficiency, known as pellagra, has been historically associated with poverty and consumption of a diet predominantly based on corn, which is low in bioavailable niacin (25, 26). Today, the condition is uncommon, but it can occur in cases of chronic alcoholism and in individuals with malabsorption syndromes (27). Among other symptoms, pellagra is characterized by dementia. Neurologic symptoms of pellagra include headache, fatigue, apathy, depression, ataxia, poor concentration, delusions, and hallucinations, which can lead to confusion, memory loss, psychosis, and eventual death (27).

Pantothenic acid

Pantothenic acid (vitamin B5) is required as a component of coenzyme A (CoA), a coenzyme needed for the oxidative metabolism of glucose and fatty acids and for the biosynthesis of fatty acids, cholesterol, steroid hormones, the hormone melatonin, and the neurotransmitter acetylcholine. A form of the vitamin (4'-phosphopantetheine) is also required for the activity of acyl carrier protein, which is needed for the synthesis of fatty acids (28), including phospholipids and sphingolipids. Phospholipids are important structural components of cell membranes, and the sphingolipid, sphingomyelin, is a component of the myelin sheath that enhances nerve transmission (29). Naturally occurring pantothenic acid deficiency in humans is very rare and has been observed only in cases of severe malnutrition (30). Therefore, most information regarding the vitamin deficiency comes from experimentally induced states in laboratory animals. Such studies have found that select deficiency in pantothenic acid causes demyelination (destruction or loss of the myelin sheath) and peripheral nerve damage (13). In humans, pantothenic acid deficiency has been induced experimentally by co-administering a pantothenic acid antagonist and a pantothenic acid-deficient diet. Participants in this experiment complained of headache, fatigue, insomnia, intestinal disturbances, and numbness and tingling of their hands and feet (31). In another study, participants who were fed only a pantothenic acid-free diet did not develop clinical signs of deficiency, although some appeared listless and complained of fatigue (32).

Vitamin B6

A form of vitamin B6, pyridoxal 5'-phosphate (PLP), is a required coenzyme for the biosynthesis of several neurotransmitters, including GABA, dopamine, norepinephrine, and serotonin (3). The vitamin has a number of other biological functions (see the article on Vitamin B6). Vitamin B6 concentrations in the brain are about 100 times higher than levels in the blood; thus, it is not surprising that vitamin B6 deficiency has neurologic effects (13). Severe deficiency of vitamin B6 is uncommon, but alcoholics are thought to be most at risk due to low dietary intakes and impaired metabolism of the vitamin. In the early 1950s, seizures were observed in infants as a result of severe vitamin B6 deficiency caused by an error in the manufacture of infant formula. Additionally, abnormal electroencephalogram (EEG) patterns have been noted in some studies of vitamin B6 deficiency. Other neurologic symptoms noted in severe vitamin B6 deficiency include irritability, depression, and confusion (33).

Biotin

Biotin (vitamin B7) is required as a cofactor for carboxylase enzymes that are important in the metabolism of fatty acids and amino acids. Overt biotin deficiency is quite rare but has been documented in patients on prolonged intravenous feeding (parenteral nutrition) without biotin supplementation; in individuals consuming high amounts of raw egg white that contains avidin, which binds biotin and prevents its absorption; and in those with hereditary disorder, biotinidase deficiency (34). In adults, neurologic symptoms of biotin deficiency include depression, lethargy, hallucinations, and numbness and tingling of the extremities (35).

Vitamin B12

Vitamin B12 deficiency, which affects 10-15% of adults over the age of 60, is frequently associated with neurological problems. Compared to younger individuals, this vitamin deficiency is more common in older adults because of the higher prevalence of food-bound vitamin B12 malabsorption (atrophic gastritis) and the higher incidence of the autoimmune condition, pernicious anemia (39). Hematological changes, including elevated blood levels of homocysteine and methylmalonic acid, are diagnostic of vitamin B12 deficiency; however, approximately 25% of cases include neurological symptoms as the only clinical indicator of vitamin B12 deficiency (40, 41). Such neurologic symptoms of vitamin B12 deficiency include numbness and tingling of the extremities, especially the legs; difficulty walking; concentration problems; memory loss; disorientation; and dementia that may or may not be accompanied by mood changes (41). In some cases, the dementia and other neurologic symptoms caused by vitamin B12 deficiency can be reversed by vitamin treatment (42), but reversibility seems to be dependent upon the duration of the associated neurologic complications (41). While the biochemical mechanisms underlying the neurological effects of vitamin B12 deficiency are not understood, the vitamin deficiency is known to damage the myelin sheath covering cranial, spinal, and peripheral nerves (42, 43).

Vitamin C

Vitamin C accumulates in the central nervous system, with neurons of the brain having especially high levels (44). In addition to its well-known antioxidant functions, vitamin C has a number of non-antioxidant functions. For instance, the vitamin is required for enzymatic reaction that synthesizes the neurotransmitter norepinephrine from dopamine. Another non-antioxidant action of vitamin C in the brain is in the reduction of metal (e.g., iron, copper) ions (44). Further, vitamin C may also be able to regenerate vitamin E (45), an important lipid-soluble antioxidant. Vitamin C deficiency causes oxidative damage to macromolecules (lipids, proteins) in the brain (13). Severe vitamin C deficiency, called scurvy, is a potentially fatal disease. However, in scurvy, vitamin C is retained by the brain for neuronal function, and eventual death from the disease is more likely due to lack of vitamin C for collagen synthesis (44). Collagen is an important structural component of blood vessels, tendons, ligaments, and bone.

Vitamin D

The vitamin D receptor is expressed in brain tissue (46), and vitamin D is known to be important for normal brain development and function (47). Accordingly, vitamin D deficiency may impair cognitive abilities. Vitamin D deficiency is a major problem worldwide, with an estimated one billion people having insufficient or deficient levels of circulating 25-hydroxyvitamin D (48). Aging is associated with a reduced capacity to synthesize vitamin D in the skin upon sun exposure (49). Thus, older adults may be more vulnerable to vitamin D deficiency and any untoward effects on cognition. Some studies in older adults have either linked lower 25-hydroxyvitamin D levels with measures of poor cognitive performance (50-53) or higher 25-hydroxyvitamin D levels with measures of better cognitive performance (54, 55). However, a recent systematic review of five observational studies concluded that the association between 25-hydroxyvitamin D concentrations and cognitive performance is not yet clear (56). More research, especially from randomized controlled trials, is needed to determine whether vitamin D deficiency has adverse effects on cognition.

Vitamin E

The α-tocopherol form of vitamin E is an important lipid-soluble antioxidant. In the brain and other tissues, α-tocopherol has a key role in preventing oxidant-induced lipid destruction and is therefore vital in maintaining the integrity of cell membranes. Accordingly, vitamin E deficiency causes lipid peroxidation in brain tissues (57). Severe vitamin E deficiency results mainly in neurological symptoms, including impaired balance and coordination (ataxia), injury to the sensory nerves (peripheral neuropathy), muscle weakness (myopathy), and damage to the retina of the eye (pigmented retinopathy). For this reason, people who develop peripheral neuropathy, ataxia, or retinitis pigmentosa should be screened for vitamin E deficiency (58). The developing nervous system appears to be especially vulnerable to vitamin E deficiency. For instance, children who have with severe vitamin E deficiency from birth and are not treated with vitamin E rapidly develop neurological symptoms. In contrast, individuals who develop malabsorption of vitamin E in adulthood may not develop neurological symptoms for ten to 20 years. It should be noted, however, that symptomatic vitamin E deficiency in healthy individuals who consume diets low in vitamin E has never been reported (58, 59).

Calcium

Calcium ions are important intracellular signals that regulate a number of physiological processes, including neuronal gene expression, neuronal secretion of neurotransmitters into synapses, and synaptic plasticity (reviewed in 60). Normal blood levels of calcium are maintained even when dietary intake of calcium is inadequate because the skeleton provides a large reserve of the mineral. Thus, effects of dietary calcium inadequacy would primarily result in negative effects to bone health. Interestingly, changes in calcium homeostasis in the brain may contribute to the cognitive decline associated with normal aging and possibly to the development of neurodegenerative disorders (61, 62).

Iodine

Iodine is required for the synthesis of thyroid hormones that regulate a number of physiological processes, including growth, development, metabolism, and reproduction (63, 64). In addition, thyroid hormones are important for myelination of the central nervous system, which mostly occurs before and shortly after birth (64, 65). Because iodine is critical for normal development of the brain, deficiency of this mineral during critical periods, such as during fetal development or during early childhood, can have deleterious effects on cognition. The most extreme cognitive effect of developmental iodine deficiency is irreversible mental retardation; milder cognitive effects include various neurodevelopmental deficits, including intellectual impairment (66, 67). For more information on iodine deficiency, which is now accepted as the most common cause of preventable brain damage in the world, see the article on Iodine.

Iron

Iron is an essential component of hundreds of proteins and enzymes involved in various aspects of cellular metabolism, including those involved in oxygen transport and storage, electron transport and energy generation, and DNA synthesis (see the article on Iron). Iron is needed for proper development of oligodendrocytes (the brain cells that produce myelin) (19), and the mineral is also a required cofactor for several enzymes that synthesize neurotransmitters (68). Accordingly, iron deficiency during various stages of brain development has detrimental consequences. Pregnant women are at increased risk of iron deficiency because iron requirements are significantly increased during pregnancy due to increased iron utilization by the developing fetus and placenta and because of blood volume expansion (69). Maternal iron deficiency has serious consequences for the woman and the fetus (70). Animal studies have shown that maternal iron deficiency results in decreased iron concentrations in the brain and permanent changes in cognitive performance and behavior in the offspring (71). In humans, iron deficiency during perinatal stages results in persistent deficits in learning and memory (reviewed in 60). Moreover, iron deficiency in later stages of development, such as during childhood, may be associated with impaired cognitive development (see the article on Iron). While iron is essential for brain function, it is toxic to neurons at high concentrations (60).

Magnesium

Magnesium is required for more than 300 metabolic reactions in the body, many being important for normal brain function (see the article on Magnesium). Magnesium deficiency in healthy individuals who are consuming a balanced diet is uncommon because the mineral is abundant in both plant and animal foods and because the kidneys are able to limit urinary excretion of magnesium when intake is low. However, magnesium deficiency has been induced experimentally and results in neurologic and muscular symptoms that include tremor, muscle spasms, and tetany (72). In fact, enzymes involved in neuromuscular activity (i.e., the ATPase enzymes that transport of sodium, potassium, and calcium ions) are apparently most sensitive to magnesium deficiency (69).

Selenium

Selenium is required for glutathione peroxidases (GPx)—important antioxidant enzymes in the brain and other tissues. GPx reduce potentially damaging reactive oxygen species (ROS), such as hydrogen peroxide and lipid hydroperoxides, to harmless products like water and alcohols by coupling their reduction with the oxidation of glutathione (Figure 2) (73, 74). Selenium deficiency has been associated with decreased GPx activity in the brain of laboratory animals (75); thus, selenium deficiency may be linked to a reduced antioxidant capacity in the brain.

Figure 2. Glutathione Oxidation Reduction (Redox) Cycle. One molecule of hydrogen peroxide is reduced to two molecules of water, while two molecules of glutathione (GSH) are oxidized in a reaction catalyzed by the selenoenzyme, glutathione peroxidase. Oxidized glutathione may be reduced by the flavin adenine dinucleotide (FAD)-dependent enzyme, glutathione reductase.

Zinc

Zinc is present at high levels in the brain where it has catalytic, structural, and regulatory roles in cellular metabolism (see the article on Zinc). In the brain, most of the zinc ion is tightly bound to proteins, but free zinc is present in synaptic vesicles and has a role in neurotransmission mediated by glutamate and GABA (76). Experimentally induced zinc deficiency in humans has been shown to impair measures of mental and neurologic function (77). Deficiency of the mineral during critical periods of cognitive development can be more devastating. For instance, zinc deficiency during fetal brain development can cause congenital malformations, and zinc deficiency during later stages of brain development have been associated with deficits in attention, learning, memory, and neuropsychological behavior (13, 78, 79). On the other hand, cellular release of zinc in the brain can mediate neuronal apoptosis and may be pathologically associated with Alzheimer’s disease and amyotrophic lateral sclerosis (ALS) (80). Thus, intracellular zinc levels in the brain are homeostatically regulated.

Choline

Choline can be synthesized by the body in small amounts, but dietary intake is needed to maintain health. Thus, choline is considered to be an essential nutrient for humans (81). Choline and its metabolites have a number of vital biological functions (see the article on Choline) (82-84). With respect to cognitive function, choline is needed for myelination of nerves and is a precursor for acetylcholine—an important neurotransmitter involved in muscle action, memory, and other functions. Choline is also used in the synthesis of the phospholipids, phosphatidylcholine and sphingomyelin, which are structural components of cell membranes and precursors for certain cell-signaling molecules. Studies in laboratory rats have shown that choline deficiency during the perinatal period results in persistent memory and other cognitive deficits (85).

Essential fatty acids

Omega-3 and omega-6 fatty acids are polyunsaturated fatty acids (PUFA), meaning they contain more than one cis double bond (86). The essential fatty acids include α-linolenic acid (ALA), an omega-3 fatty acid, and linoleic acid (LA), an omega-6 fatty acid. ALA and LA cannot be synthesized by humans and thus must be obtained from the diet; dietary intake recommendations set by the Institute of Medicine are for ALA and LA (see the article on Essential Fatty Acids) (86). The long-chain omega-6 fatty acid, arachidonic acid (AA), can be synthesized from LA. Additionally, two long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), can be synthesized from ALA, but their synthesis may be insufficient under certain conditions, such as during pregnancy and lactation (87, 88).

Excluding adipose tissue, tissue of the nervous system has the greatest concentration of lipids in the human body (89). Lipids found in the human body include fatty acids, phospholipids, triglycerides, and cholesterol. Omega-3 and omega-6 PUFA are incorporated into phospholipids, where they not only serve structural roles in cell membranes of the nervous system, but also affect membrane fluidity, flexibility, permeability, as well as the activities of membrane-associated enzymes and receptors (13, 90). Through these effects, omega-3 and 6 PUFA play several important roles in vision and nervous system function. DHA is selectively incorporated into retinal and neuronal cell membranes (91, 92), suggesting it plays important roles in vision and nervous system function. The phospholipids of the brain's gray matter contain high proportions of DHA and AA, indicating they are important to central nervous system function (93). Brain DHA content may be particularly important, since animal studies have shown that depletion of DHA in the brain can result in learning deficits. It is not clear how DHA affects brain function, but changes in DHA content of neuronal cell membranes could alter the function of ion channels or membrane-associated receptors, as well as the availability of neurotransmitters (94).

In general, essential fatty acid deficiency (i.e., deficiency of both ALA and LA) has been observed only in patients with chronic fat malabsorption, cystic fibrosis, or those on parenteral nutrition without PUFA (86, 95) (see the article on Essential Fatty Acids). Clinical manifestations of essential fatty acid deficiency primarily include skin effects (i.e., dermatitis), but negative hematologic effects and impaired immunity have also been seen in humans (96). Decreased physical growth in infants and children is also associated with essential fatty acid deficiency. The developing brain may be especially vulnerable to the effects of deficiencies in essential fatty acids (97). Since phospholipids of certain brain regions are enriched with DHA and AA, omega-3 or omega-6 PUFA deficiency during brain development could have lasting effects on visual and cognitive function (13). For instance, studies in laboratory rodents have found that dietary omega-3 PUFA deficiency impaired measures of cognitive performance through influencing the dopamine neurotransmitter system in the frontal cortex region of the brain (98). Omega-3 PUFA deficiency during fetal development has also been shown to have untoward effects on visual function (reviewed in 99, 100).

Effects of Micronutrient Supplementation

Compared to the consequences of micronutrient deficiencies, considerably less is known regarding the cognitive effects of micronutrient supplementation. Many of the intervention trials conducted to date have examined whether supplementation with B vitamins might attenuate the cognitive decline associated with normal aging. Other trials have looked at whether micronutrient supplementation improves specific measures of cognitive performance, including attention, memory, and various executive functions. These and other cognitive functions are interrelated; for example, memory of new information is dependent on proper attention (101). Additionally, cognitive performance can be affected by other factors, including one’s overall mood (101). A summary of randomized controlled trials (RCTs) on these cognitive parameters is presented below.

Attention

Attention is the mental process of selectively concentrating on information while excluding extraneous information. Proper attention is needed for higher-order cognitive abilities; thus, deficits in attention can profoundly affect learning and behavior (102). While there are different types of attention (i.e., selective, divided, sustained) (101), neuropsychological tests measure attention to either visual or auditory stimuli (102).

A few trials have assessed the effect of multivitamin/mineral supplementation on attention, with most being conducted in school-aged children. Yet, a one-year placebo-controlled, double-blind trial that provided ten times the recommendation of nine vitamins was carried out in 127 healthy young adults (aged 17-27 years) (103). Compared to baseline measurements, the multiple vitamin supplementation was associated with improvements on two assessments of attention in women but not in men; however, the differences between the vitamin and placebo groups were not statistically different at any of the measured timepoints (3 months, 6 or 9 months, and 12 months) (103). In a 14-month randomized, double-blind, placebo-controlled trial that administered a daily micronutrient-fortified beverage (details lacking) or placebo to 608 children (aged 6-15 years) in India, micronutrient supplementation was linked to improved scores on one measure of attention and concentration (Knox Cube test) but not on another assessment (Letter Cancellation test) (104). Another trial administered a micronutrient-fortified (vitamins A, B6, B12, C, and folate and the minerals, iron and zinc) drink, a drink fortified with docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), a drink fortified with the micronutrients and omega-3 fatty acids, or placebo for six days a week for 12 months to 644 school-aged children in Australia and Indonesia (105). This trial reported that the various treatments had no effect on attention compared to placebo, despite some improvements in nutrient status (105). Most recently, a randomized, double-blind, placebo-controlled trial in 81 children (8-14 years) residing in the UK found that use of a daily multivitamin/mineral supplement, containing most vitamins as well as iron, copper, zinc, calcium, and magnesium, was associated with an increase in accuracy on one attention task (Arrows Flankers test) throughout the 12-week study (106). Thus, trials conducted to date are conflicting and more research is needed to determine the effect of micronutrient supplementation on attention in children or adults.

Memory

Memory refers to one’s ability to encode, organize, and store new information and recall the information on demand. Other cognitive functions, such as learning, reasoning, and language, are dependent on a functioning memory (107). Experimental methods that assess memory functions often measure the speed or accuracy of response to a certain task (101). To date, there have been few clinical trials that have examined the effects of supplemental micronutrients on aspects of memory. Most of the research is observational and concerns blood levels of B vitamins or antioxidant vitamins and memory performance.

Some, but not all, observational studies have found that elderly individuals with lower status of folate and/or vitamin B12 may have poorer memory performance, especially episodic memory (i.e., memory of events, times, and places) (108-111). In addition, one study found that higher plasma levels of vitamin B6 were associated with better performance on two measures of memory performance (112). Some observational studies in elderly people have also found that lower blood levels of vitamin C or vitamin E to be associated with poorer performance on cognitive tests of memory (109, 113, 114). Vitamins C and E are the two antioxidant vitamins. While overt deficiencies in specific vitamins have cognitive effects (see Consequences of Select Micronutrient Deficiencies), correcting subclinical deficiencies through supplementation could possibly improve aspects of memory.

However, clinical trials on the effect of supplemental B vitamins or antioxidant vitamins on memory performance are limited and their findings are inconclusive. Elevated homocysteine levels in the blood may be linked to dementia and Alzheimer’s disease (21). Vitamin B6, folate, and vitamin B12 regulate the amount of circulating homocysteine (see Figure 1 above), and a deficiency of any of these B vitamins can lead to hyperhomocysteinemia, a condition treated through B vitamin supplementation. A three-year randomized, double-blind, placebo-controlled trial in 818 older adults (aged 50-70 years) with elevated homocysteine levels but normal serum vitamin B12 levels found that folic acid supplementation (800 mcg/day) lowered homocysteine levels and improved measures of memory performance (115). However, a one-year randomized, double-blind, placebo-controlled trial in 253 elderly (≥65 years) adults with elevated homocysteine levels found that B vitamin supplementation (1,000 mcg/day of folate, 10 mg/day of vitamin B6, and 500 mcg/day of vitamin B12) did not improve measures of cognitive function, including memory, despite lowering homocysteine levels (116). Additionally, a randomized, double-blind, placebo-controlled trial in 162 elderly people (≥70 years) with mild vitamin B12 deficiency found that vitamin B12 supplementation for 24 weeks, alone or in combination with folic acid, did not improve memory performance (117). Another trial found that vitamin B6 supplementation (20 mg/day of pyridoxine hydrochloride) for three months improved memory, especially long-term memory, in 38 healthy elderly men (70-79 years) compared to 38 men of similar age who received a placebo (118). Further, a placebo-controlled trial in 211 healthy adult women of varying ages found that B vitamin supplementation (750 mcg/day of folic acid, 75 mg/day of vitamin B6, or 15 mcg/day of vitamin B12) only slightly improved some measures of memory function (119). Thus, results of intervention trials of B vitamin supplementation are conflicting.

Because normal aging is associated with increased free radical-induced damage in the body and also with memory loss, antioxidant supplementation might slow age-related memory declines (120). Randomized controlled trials (RCTs) of antioxidant supplementation that evaluate memory functions are needed to evaluate this hypothesis. Some of the existing trials have examined whether vitamin E supplements might slow the cognitive decline associated with certain neurodegenerative diseases, such as Parkinson’s disease or Alzheimer’s disease, although few have conducted specific assessments of memory. One trial examined the effect of using vitamin E supplements (for a mean of 14 months) on memory performance in patients with early, untreated Parkinson’s disease. Specifically, performance on digit span and various recall tasks did not differ between the 174 patients who were given 2,000 IU/day of synthetic α-tocopherol (equivalent to 900 mg/day of RRR-α-tocopherol) and the 174 patients who were administered a placebo (121). Another trial evaluated whether the same dose of α-tocopherol, when provided for two years, could possibly treat moderately severe Alzheimer’s disease. Compared to use of a placebo (84 patients) in this trial, use of α-tocopherol (85 patients) significantly slowed progression of Alzheimer's dementia, evidenced by significant improvements on the Blessed Dementia Scale and time to institutionalization (122). However, α-tocopherol supplementation did not affect scores on the Alzheimer’s Disease Assessment Scale and the Mini-Mental State Examination, which in part involve assessment of memory performance (122). For more information on the use of vitamin E in the treatment of Alzheimer’s disease, see the article on Vitamin E. Overall, there is currently little evidence from RCTs that antioxidant supplementation improves memory performance in individuals with neurodegenerative conditions. More research is needed to determine the effects of antioxidant supplements on memory in healthy individuals.

Choline is an essential nutrient that has a number of vital biological functions (see the article on Choline). Increased dietary intake of choline very early in life can diminish the severity of memory deficits in aged rats. Choline supplementation of the mothers of unborn rats, as well as rat pups during the first month of life, leads to improved performance in spatial memory tests months after choline supplementation has been discontinued (123). A review by McCann et al. discusses the experimental evidence from rodent studies regarding the availability of choline during prenatal development and cognitive function in the offspring (124). It is not clear whether findings in rodent studies are applicable to humans. More research is needed to determine the role of choline in the developing brain and whether choline intake is useful in the prevention of memory loss or dementia in humans. Trials evaluating the therapeutic use of choline supplementation for memory loss in patients with Alzheimer’s disease have mainly reported no memory-related benefits (reviewed in 125). Additionally, there is little evidence that choline improves memory in elderly individuals without dementia (126).

Further, omega-3 fatty acid supplementation could possibly help prevent or treat neurological disorders associated with memory loss like Alzheimer’s disease. Docosahexaenoic acid (DHA; 22:6n-3), the major omega-3 fatty acid in the brain, appears to be protective against the development of Alzheimer's disease and other types of dementia (see the article on Essential Fatty Acids(127). Although results of studies in animal models have been promising (reviewed in 128), it is not yet known whether DHA supplementation can help treat Alzheimer's disease in humans. Recently, a randomized, double-blind, placebo-controlled trial in 295 patients with Alzheimer’s disease found that DHA supplementation (2 grams/day) for 18 months was not effective in slowing cognitive decline (129).

Executive functions

Executive functions refer to several higher-order cognitive processes, such as reasoning, planning, strategic thinking, problem solving, and multitasking (101, 130, 131). Specific examples of executive functions include shifting between two behaviors, inhibiting habitual behaviors, updating information, and planning (131). Such executive functions are experimentally assessed by employing cognitive tasks like the Wisconsin card-sorting test, the Stroop color-word test, or verbal fluency tests (102, 132). Certain cognitive tasks measuring one executive function may assess other cognitive functions as well (131).

To date, few studies have examined the effects of micronutrient supplementation on executive functioning. In a randomized, double-blind, placebo-controlled trial in 216 healthy women (25-50 years old), supplementation with a daily multivitamin/mineral for nine weeks was associated with a significant increase in speed and accuracy of performance on the Stroop color-word test (133). Overall, micronutrient supplementation in this trial was associated with increased accuracy of performance on a battery of tests assessing multitasking (133). Yet, a randomized, double-blind, placebo-controlled trial in 215 men (35-55 years old) found that daily supplementation with B vitamins (at 3 to 13 times the current RDA, except for folic acid, which was included at a dose equivalent to the RDA), vitamin C (500 mg/day), zinc (10 mg/day), and magnesium (100 mg/day) for 33 days had no effect on measured performance of executive functions, including the Stroop color-word test, the peg-and-ball task, and the Wisconsin card-sorting task (134). Additionally, a one-year placebo-controlled trial in adults aged 65 years and older found that daily supplementation with a multivitamin/mineral did not benefit cognitive performance on a verbal fluency test—an assessment in which participants were asked to list words starting with a certain letter in a designated time period (135). Further, a placebo-controlled trial in 152 elderly adults (aged 70-80 years) with mild cognitive impairment reported that B vitamin supplementation (50 mg/day of vitamin B6, 5 mg/day of folic acid, and 0.4 mg/day of vitamin B12) for one year did not improve performance on a similar test of verbal fluency (136). More research is needed to determine whether micronutrient supplementation has any effects on executive functioning in various populations.

Mood and psychological well-being

Deficiencies in select micronutrients, mainly certain B vitamins, have been linked to depression. Thus, micronutrient supplementation, especially in individuals with overt or marginal deficiencies, could possibly improve overall mood state and psychological well-being. Most studies discussed in this section were conducted in healthy individuals. It is important to note that mood state is commonly assessed by self-rating scales, such as self-administered questionnaires, which are not objective measurements (101).

Several studies in people of varying ages have evaluated whether taking a daily multivitamin/mineral supplement is associated with changes in mood state or psychological well-being. A randomized, double-blind, placebo-controlled in 129 young healthy adults found that taking a supplement that contained ten times the daily intake recommendations for nine different vitamins (vitamin A, thiamin, riboflavin, niacin, vitamin B6, folic acid, vitamin B12, vitamin C, vitamin E) for one year improved one self-assessment of mood, i.e., being “more agreeable” (137). Trials conducted more recently have been of much shorter duration, typically lasting about one to three months. For instance, a double-blind, placebo-controlled study in 80 healthy men, aged 18 to 42 years, found that use of a multivitamin/mineral supplement for 28 days was associated with reductions in the subjective measures of anxiety and perceived stress (138). In this study, the dosage of B vitamins and vitamin C was 3 to 12 times the current US RDA, zinc was contained at an amount almost the RDA, and the supplement also contained fractions of the RDA for calcium and magnesium (138). More recently, a randomized, double-blind, placebo-controlled trial in 215 men, aged 35 to 55 years, examined the effects of supplemental B vitamins (at 3 to 13 times the current RDA, except for folic acid which was included at a dose equivalent to the RDA), vitamin C (500 mg/day), and the minerals, zinc (10 mg/day), calcium (100 mg/day), and magnesium (100 mg/day) on mood and perceived stress (134). Compared to placebo, men who took the multiple vitamin-mineral supplement for 33 days had significantly improved ratings on one (vigor-activity score) of the six components of the Profile of Mood States (POMS) scale, significantly reduced subjective stress as measured by the Perceived Stress Scale, and significantly improved self-ratings of mental tiredness prior to and following a battery of cognitively demanding tasks (134). Additionally, in a 30-day placebo-controlled trial in 300 adults (aged 18-65 years), supplementation with the B vitamins (at doses of about 3 to 13 times the RDA, excluding folic acid), vitamin C (1,000 mg/day), calcium (100 mg/day), and magnesium (100 mg/day) was associated with significant improvements in various scores of psychological stress compared to a placebo (139). However, a trial in 216 healthy women (25-50 years old) found little benefit of a multivitamin/mineral supplement; micronutrient supplement use for nine weeks had no effect on several measures of mood, including a health survey, a fatigue survey, and the POMS assessment, but was associated with a reduction in perceived physical tiredness on a computerized assessment of multi-tasking (133). Further, a randomized, double-blind, placebo-controlled trial in 81 healthy children, aged 8 to 14 years, reported that supplementation with a daily multivitamin/mineral for 12 weeks had no effect on various measures of mood (106). Interestingly, a small trial in 30 premenopausal women found that daily multivitamin supplementation for ten weeks did not improve overall mood, but when the supplement also contained 7 mg/day of zinc (RDA=8 mg/day), the authors noted significant improvements in two components of POMS: the anger-hostility and the depression-dejection scores (140).

In addition to zinc, supplementation with other single nutrients may impact mood. In one study of 127 young mean age, 20.3 years) women, supplementation with a high dose of thiamin (50 mg/day; 45 times the current RDA) for two months was linked to improvements in self-reported mood, including the feeling of being more clear-headed (141). Two trials in acutely hospitalized patients have shown that short-term (around 7 days) vitamin C supplementation increased concentrations of ascorbic acid in plasma and leukocytes and led to 34-35% improvements in mood state, as measured by POMS (142, 143).

Deficiencies in other micronutrients, including vitamin B6, vitamin B12, and omega-3 fatty acids, have been linked to depression (see the Disease Index), and vitamin D deficiency has also been associated with negative effects on mood (51, 144). However, it is not known whether supplementation with these nutrients improves overall mood or depressive symptoms in those with depression.

Most of the abovementioned studies were conducted in individuals presumed to be healthy. Given that fact that a significant percentage of the general population does not consume adequate dietary levels for several micronutrients (145), a daily multivitamin/mineral supplement could help improve micronutrient status and possibly have some cognitive and other health benefits. However, more research is needed to determine whether multivitamin/mineral or single nutrient supplements improve mood state, psychological stress, and overall mental function.

Age-related cognitive decline

Normal aging is associated with mild cognitive impairments that are caused by various neuroanatomical changes, including alterations in brain receptors, myelin dystrophy, loss of dendritic spines, and changes in nerve transmission (146). Good nutritional status is known to be important for normal cognitive functioning, but the role of diet in the prevention of age-related cognitive decline is not well understood. Adequate dietary intake of B vitamins, antioxidant vitamins, essential minerals, and omega-3 fatty acids may help protect against the cognitive decline associated with normal aging (1). However, it is not known whether supplemental intake of these nutrients would result in additional benefits. Intervention trials are limited, and the findings of available trials are inconsistent. Overall, little benefit has been observed with micronutrient or omega-3 fatty acid supplementation. Cognitive effects could possibly depend on baseline nutritional status, i.e., any benefits of micronutrient supplementation might only be realized in individuals with micronutrient deficiencies and not in those with adequate micronutrient status. Another important factor is a person’s age at time of intervention, as nutritional interventions should ideally start at or before the observed cognitive decline (146). This section reviews the findings of clinical trials using B vitamins, antioxidant vitamins, and omega-3 fatty acids as possible therapeutics for normal cognitive aging. Studies in individuals with dementia and other related pathologies are not covered in this article.

Deficiencies in many of the B vitamins results in negative cognitive effects (see Consequences of Select Micronutrient Deficiencies), and a number of studies have linked lower blood levels of B vitamins with some cognitive impairments (147-154). Vitamin B6, folate, and vitamin B12 regulate blood levels of homocysteine (see Homocysteine metabolism and Figure 1 above)—an amino acid derived from methionine that may be associated with cognitive decline (155). However, evidence that B vitamin supplementation lowers the risk of cognitive decline is lacking. Three recent systematic reviews and a meta-analysis all concluded that short-term supplementation with folic acid, with or without other B vitamins, does not improve age-related cognitive decline or overall cognition and that trials of longer duration are needed (21, 156-158).

Because age-related cognitive decline has been linked to free radical-induced oxidative damage in the brain (159, 160), antioxidant supplements might help protect against cognitive aging. Prospective cohort studies have reported that vitamin C intake from supplements (161, 162) or vitamin E intake from food and supplements (161) was associated with some protection against cognitive decline. However, randomized controlled trials are needed to determine whether antioxidant supplements slow or prevent age-related cognitive decline. One randomized, double-blind, placebo-controlled trial found no evidence that a daily antioxidant supplement containing 12 mg of β-carotene, 500 mg of vitamin C, and 400 mg of vitamin E, when taken for up to 12 months, improved mental performance in elderly people (163). Another placebo-controlled trial in older adults at high risk of dementia found that supplementation with vitamin C (200 mg/day) and vitamin E (500 mg/day) for 12 weeks did not alter any of the measured cognitive functions despite nonsignificantly lowering levels of
F2-isoprostanes—biomarkers of lipid peroxidation in vivo. Large-scale trials of longer duration are needed to understand whether antioxidant supplementation might help prevent age-related cognitive decline. For more information on micronutrients and phytochemicals related to cognitive decline or neurodegenerative diseases, see the article on Micronutrients for Older Adults.

Cognitive decline has been linked to decreased levels of docosahexaenoic acid (DHA) in the brain (164). DHA is a long-chain omega 3-fatty acid found in oily fish (see the article on Essential Fatty Acids). Several observational studies have associated higher intakes of fish with benefits related to cognitive performance (165, 166) and cognitive decline (167, 168), as well as with lower risks of some types of dementia, including Alzheimer’s disease (166, 169-171). Additionally, one prospective cohort study reported an inverse association between omega-3 fatty acid content of red blood cell membranes (an indicator of omega-3 fatty acid intake) and cognitive decline (172). Thus, supplementation with DHA and perhaps other long-chain omega-3 fatty acids may help maintain cognition during aging and could possibly help protect against age-related cognitive decline. To date, clinical trials of omega-3 fatty acid supplementation have been mainly conducted in patients with vascular dementia, Alzheimer’s disease, or other brain pathologies (173, 174). Long-term intervention studies in healthy individuals or in those with mild cognitive impairment are needed. Results of the Older People And n-3 Long-chain polyunsaturated fatty acids (OPAL) study were recently published (175). In this trial, 748 cognitively healthy elderly adults, aged 70-79 years, were supplemented for two years with a combination of 500 mg/day of DHA and 200 mg/day of eicosapentaenoic acid or with a placebo containing olive oil. Cognitive function did not decline in either group over the two-year period (175), suggesting that longer intervention trials are needed to determine whether long-chain omega-3 fatty acids have utility in the prevention of age-related cognitive decline. A three-year trial of DHA supplementation (800 mg/day) in elderly adults without dementia is currently under way (see www.clinicaltrials.gov).

Conclusion

While we have a good understanding of the consequences of micronutrient deficiencies on cognition, we know considerably less about the cognitive effects of micronutrient supplementation. At present, there is little evidence that micronutrient supplementation provides cognitive benefits, with the reported benefits being mostly related to mood. To date, several of the randomized controlled trials (RCTs) have been conducted either in the elderly or in individuals with pathological conditions like Alzheimer’s disease. Therefore, there is a need for well-designed, large-scale, long-term RCTs in healthy adults, in individuals with micronutrient deficiencies, as well as in children—an age group undergoing rapid cognitive and brain development. Provision of micronutrients for several years may be required to observe any cognitive effects. Studies that measure micronutrient status in blood and correlate that with cognitive function are also needed to better assess the role of micronutrients on mental function. In general, supplementation with a broad range of micronutrients, rather than one or a selected few, would cover the micronutrient needs of more of the sample and would also be sensible given the well-known interactions among the various micronutrients with respect to cognition. While this approach may create complications in terms of attributing any demonstrated cognitive effects, assessment of the nutritional status at baseline and after supplementation will presumably help inform mechanistic questions.

Additionally, it is important to note that the available RCTs have utilized a plethora of cognitive tests to study the effects of micronutrient supplementation. A recent systematic review of 39 RCTs using supplemental micronutrients or phytochemicals found that the trials utilized 121 different cognitive tasks, thereby making it difficult for comparison among studies and for overall data interpretation (131). Thus, the field would benefit from more standardized and systematic approaches to study the effect of micronutrient supplementation on cognitive functions. Many of the paper and pencil questionnaires employed to assess cognitive abilities may not be sensitive enough to detect small changes that result from short-term interventions of micronutrient supplementation (101, 102). On the other hand, validated computer-based tests are becoming widely available; such tests ensure high sensitivity of measurement, both in terms of accuracy and speed of performance across various cognitive domains. Increased use of computerized cognitive assessments may aid in the ability to detect subtle changes that might result from micronutrient supplementation in healthy individuals.

Although it is not yet clear whether micronutrient supplementation has beneficial effects on various cognitive domains, it is well-established that micronutrient deficiencies, especially B vitamin deficiencies, have adverse effects on cognition. Eating a good diet is important for optimum health and prevention of chronic disease (see Healthy Eating in the LPI Rx for Health). US national surveys indicate that a significant proportion of Americans are not meeting the current recommended intakes for a number of micronutrients, including vitamin E, magnesium, vitamin A, and vitamin C. As part of its Rx for Health, the Linus Pauling Institute recommends a daily multivitamin/mineral supplement as nutritional insurance to meet micronutrient needs (see Supplements in the LPI Rx for Health).


Authors and Reviewers

Written in February 2011 by:
Victoria J. Drake, Ph.D.
Linus Pauling Institute
Oregon State University

Reviewed in February 2011 by:
Juerg Haller, Ph.D.
F. Hoffman-La Roche Ltd
Basel, Switzerland

This article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.

Copyright 2011-2015   Linus Pauling Institute


References

1.  Katz DL, Friedman RSC. Diet and cognitive function. Nutrition in clinical practice: a comprehensive, evidence-based manual for the practitioner. Philadelphia: Lippincott Williams & Wilkins; 2008:362-368.

2.  Brain energy metabolism. In: Squire L, Berg D, Bloom F, du Lac S, Ghosh A, Spitzer N, eds. Fundamental neuroscience. Amsterdam: Academic Press; 2008:271-293.

3.  Haller J. Vitamins and brain function. In: Lieberman HR, Kanarek RB, Prasad C, eds. Nutritional neuroscience. Boca Raton: CRC Press; 2005.

4.  Voet D, Voet JG. Other pathways of carbohydrate metabolism. Biochemistry. 2nd ed. New York: John Wiley & Sons, Inc.; 1995:599-625.

5.  Oh MS, Uribarri J. Electrolytes, water, and acid-base balance. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:180-181.

6.  Voet D, Voet JG. Glycolysis. Biochemistry. 2nd ed. New York: John Wiley & Sons, Inc.; 1995:443-483.

7.  Voet D, Voet JG. Citric acid cycle. Biochemistry. New York: John Wiley & Sons, Inc.; 1995:538-562.

8.  Voet D, Voet JG. Electron transport and oxidative phosphorylation. Biochemistry. 2nd ed. New York: John Wiley & Sons, Inc.; 1995:563-598.

9.  Clarke DD, Sokoloff L. Circulation and energy metabolism of the brain. In: Siegel GJ, ed. Basic neurochemistry: molecular, cellular and medical aspects. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 1999:637-669.

10.  Carter R, Aldridge S, Page M, Parker S. Brain anatomy. In: Frances P, ed. The human brain book. London: Dorling Kindersley; 2009:50-73.

11.  von Bohlen und Halbach O, Dermietzel R. Introduction. Neurotransmitters and neuromodulators: handbook of receptors and biological effects. Weinheim: Wiley-VCH; 2002:1-18.

12.  Chafetz MD. Zinc: a trace of nutrient action. Nutrition and neurotransmitters: the nutrient bases of behavior. Englewood Cliffs: Prentice-Hall, Inc.; 1990:187-210.

13.  Gibson GE, Blass JP. Nutrition and brain function. In: Siegel GJ, ed. Basic neurochemistry: molecular, cellular and medical aspects. Philadelphia: Lippincott Williams & Wilkins; 1999:692-709.

14.  Neurotransmitter receptors. In: Squire L, Berg D, Bloom F, du Lac S, Ghosh A, Spitzer N, eds. Fundamental neuroscience. 3rd ed. Amsterdam: Academic Press; 2008:181-203.

15.  Hille B, Cartterall WA. Electrical excitability and ion channels. In: Siegel GJ, ed. Basic neurochemistry: molecular, cellular and medical aspects. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 1999:119-137.

16.  Ebadi M, Klangkalya B, Deupree JD. Inhibition of GABA binding by pyridoxal and pyridoxal phosphate. Int J Biochem. 1980;11(3-4):313-317.  (PubMed)

17.  Guilarte TR, Wagner HN, Jr., Frost JJ. Effects of perinatal vitamin B6 deficiency on dopaminergic neurochemistry. J Neurochem. 1987;48(2):432-439.  (PubMed)

18.  Squire L, Berg D, Bloom F, du Lac S, Ghosh A, Spitzer N. Membrane potential and action potential. Fundamental neuroscience. 3rd ed. Amsterdam: Academic Press; 2008:111-132.

19.  Todorich B, Pasquini JM, Garcia CI, Paez PM, Connor JR. Oligodendrocytes and myelination: the role of iron. Glia. 2009;57(5):467-478.  (PubMed)

20.  Gerhard GT, Duell PB. Homocysteine and atherosclerosis. Curr Opin Lipidol. 1999;10(5):417-428.  (PubMed)

21.  Malouf R, Grimley Evans J. Folic acid with or without vitamin B12 for the prevention and treatment of healthy elderly and demented people. Cochrane Database Syst Rev. 2008;(4):CD004514.  (PubMed)

22.  Bates CJ. Thiamin. In: Bowman BA, Russell RM,eds. Present knowledge in nutrition. 9th ed. Volume 1. Washington, D.C.: ILSI Press; 2006:242-249.

23.  Butterworth RF. Thiamin deficiency and brain disorders. Nutr Res Rev. 2003;16(2):277-284.  (PubMed)

24.  Todd K, Butterworth RF. Mechanisms of selective neuronal cell death due to thiamine deficiency. Ann N Y Acad Sci. 1999;893:404-411.  (PubMed)

25.  Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. Am J Public Health. 2000;90(5):727-738.  (PubMed)

26.  Gregory JF, 3rd. Nutritional Properties and significance of vitamin glycosides. Annu Rev Nutr. 1998;18:277-296.  (PubMed)

27.  Hegyi J, Schwartz RA, Hegyi V. Pellagra: dermatitis, dementia, and diarrhea. Int J Dermatol. 2004;43(1):1-5.  (PubMed)

28.  Miller JW, Rogers LM, Rucker RB. Pantothenic acid. In: Bowman BA, Russell RM, eds. Present knowledge in nutrition. 9th ed. Volume 1. Washington, D.C.: ILSI Press; 2006:327-339.

29.  Brody T. Lipids. Nutritional biochemistry. 2nd ed. San Diego: Academic Press; 1999:311-378.

30.  Plesofsky-Vig N. Pantothenic acid. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern nutrition in health and disease. Philadelphia: Lippincott Williams & Wilkins; 1999:423-432.

31.  Hodges RE, Ohlson MA, Bean WB. Pantothenic acid deficiency in man. J Clin Invest. 1958;37(11):1642-1657.  (PubMed)

32.  Fry PC, Fox HM, Tao HG. Metabolic response to a pantothenic acid deficient diet in humans. J Nutr Sci Vitaminol (Tokyo). 1976;22(4):339-346.  (PubMed)

33.  Leklem JE. Vitamin B6. In: Machlin L, ed. Hanbook of vitamins. New York: Marcel Decker Inc.; 1991:341-378.

34.  Camporeale G, Zempleni J. Biotin. In: Bowman BA, Russell RM,eds. Present knowledge in nutrition. Volume 1. Washington, D.C.: ILSI Press; 2006:314-326.

35.  Mock DM. Biotin. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:482-497.

36.  Bailey LB, Gregory JF, 3rd. Folate metabolism and requirements. J Nutr. 1999;129(4):779-782.  (PubMed)

37.  Coppen A, Swade C, Jones SA, Armstrong RA, Blair JA, Leeming RJ. Depression and tetrahydrobiopterin: the folate connection. J Affect Disord. 1989;16(2-3):103-107.  (PubMed)

38.  Yudkoff M. Diseases of amino acid metabolism. In: Siegel GJ, ed. Basic neurochemistry: molecular, cellular, and medical aspects. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 1999:887-915.

39.  Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377.  (PubMed)

40.  Lindenbaum J, Healton EB, Savage DG, et al. Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1988;318(26):1720-1728.  (PubMed)

41.  Food and Nutrition Board, Institute of Medicine. Vitamin B12. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B6, vitamin B12, pantothenic acid, biotin, and choline. Washington, D.C.: National Academy Press; 1998:306-356.

42.  Healton EB, Savage DG, Brust JC, Garrett TJ, Lindenbaum J. Neurologic aspects of cobalamin deficiency. Medicine (Baltimore). 1991;70(4):229-245.  (PubMed)

43.  Stabler SP. Vitamin B12 In: Bowman BA, Russell RM, eds. Present knowledge in nutrition. Volume 1. Washington, D.C.: ILSI Press; 2006:302-313.

44.  Harrison FE, May JM. Vitamin C function in the brain: vital role of the ascorbate transporter SVCT2. Free Radic Biol Med. 2009;46(6):719-730.  (PubMed)

45.  Carr AC, Frei B. Toward a new recommended dietary allowance for vitamin C based on antioxidant and health effects in humans. Am J Clin Nutr. 1999;69(6):1086-1107.  (PubMed)

46.  Garcion E, Wion-Barbot N, Montero-Menei CN, Berger F, Wion D. New clues about vitamin D functions in the nervous system. Trends Endocrinol Metab. 2002;13(3):100-105.  (PubMed)

47.  McCann JC, Ames BN. Is there convincing biological or behavioral evidence linking vitamin D deficiency to brain dysfunction? Faseb J. 2008;22(4):982-1001.  (PubMed)

48.  Holick MF. Vitamin D deficiency. N Engl J Med. 2007;357(3):266-281.  (PubMed)

49.  Holick MF, Matsuoka LY, Wortsman J. Age, vitamin D, and solar ultraviolet. Lancet. 1989;2(8671):1104-1105.  (PubMed)

50.  Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly persons. Arch Intern Med. 2010;170(13):1135-1141.  (PubMed)

51.  Wilkins CH, Sheline YI, Roe CM, Birge SJ, Morris JC. Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults. Am J Geriatr Psychiatry. 2006;14(12):1032-1040.  (PubMed)

52.  Lee DM, Tajar A, Ulubaev A, et al. Association between 25-hydroxyvitamin D levels and cognitive performance in middle-aged and older European men. J Neurol Neurosurg Psychiatry. 2009;80(7):722-729.  (PubMed)

53.  Annweiler C, Schott AM, Allali G, et al. Association of vitamin D deficiency with cognitive impairment in older women: cross-sectional study. Neurology. 2010;74(1):27-32.  (PubMed)

54.  Przybelski RJ, Binkley NC. Is vitamin D important for preserving cognition? A positive correlation of serum 25-hydroxyvitamin D concentration with cognitive function. Arch Biochem Biophys. 2007;460(2):202-205.  (PubMed)

55.  Buell JS, Scott TM, Dawson-Hughes B, et al. Vitamin D is associated with cognitive function in elders receiving home health services. J Gerontol A Biol Sci Med Sci. 2009;64(8):888-895.  (PubMed)

56.  Annweiler C, Allali G, Allain P, et al. Vitamin D and cognitive performance in adults: a systematic review. Eur J Neurol. 2009;16(10):1083-1089.  (PubMed)

57.  MacEvilly CJ, Muller DP. Lipid peroxidation in neural tissues and fractions from vitamin E-deficient rats. Free Radic Biol Med. 1996;20(5):639-648.  (PubMed)

58.  Traber MG. Vitamin E. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:396-411.

59.  Traber MG. Vitamin E. In: Bowman BA, Russell RM,eds. Present knowledge in nutrition. Volume 1. Washington, D.C.: ILSI Press; 2006:211-219.

60.  Hidalgo C, Nunez MT. Calcium, iron and neuronal function. IUBMB Life. 2007;59(4-5):280-285.  (PubMed)

61.  Toescu EC, Verkhratsky A. The importance of being subtle: small changes in calcium homeostasis control cognitive decline in normal aging. Aging Cell. 2007;6(3):267-273.  (PubMed)

62.  Foster TC. Calcium homeostasis and modulation of synaptic plasticity in the aged brain. Aging Cell. 2007;6(3):319-325.  (PubMed)

63.  Hetzel BS, Clugston GA. Iodine. In: Shils ME, Olson JA, Shike M, Ross AC,eds. Modern nutrition in health and disease. Baltimore: Lippincott Williams & Wilkins; 1999:253-264.

64.  Dunn JT. What's happening to our iodine? J Clin Endocrinol Metab. 1998;83(10):3398-3400.  (PubMed)

65.  Food and Nutrition Board, Institute of Medicine. Iodine. Dietary reference intakes for vitamin A, vitamin K, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. Washington, D.C.: National Academy Press; 2001:258-289.

66.  Dunn JT. Iodine. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:300-311.

67.  Melse-Boonstra A, Jaiswal N. Iodine deficiency in pregnancy, infancy and childhood and its consequences for brain development. Best Pract Res Clin Endocrinol Metab. 2010;24(1):29-38.  (PubMed)

68.  Beard J. Iron. In: Bowman BA, Russell RM,eds. Present knowledge in nutrition. Volume 1. Washington, D.C.: ILSI Press; 2006:430-444.

69.  Brody T. Inorganic nutrients. Nutritional biochemistry. 2nd ed. San Diego: Academic Press; 1999:693-878.

70.  Gambling L, McArdle HJ. Iron, copper and fetal development. Proc Nutr Soc. 2004;63(4):553-562.  (PubMed)

71.  Kwik-Uribe CL, Golub MS, Keen CL. Chronic marginal iron intakes during early development in mice alter brain iron concentrations and behavior despite postnatal iron supplementation. J Nutr. 2000;130(8):2040-2048.  (PubMed)

72.  Rude RK, Shils ME. Magnesium. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Baltimore: Lippincott Williams & Wilkins; 2006:223-247.

73.  Arthur JR. The glutathione peroxidases. Cell Mol Life Sci. 2000;57(13-14):1825-1835.  (PubMed)

74.  Gladyshev VN. Selenoproteins and selenoproteomes. In: Hatfield DL, Berry MJ, Gladyshev VN, eds. Selenium: its molecular biology and role in human health. 2nd ed. New York: Springer; 2006:99-114.

75.  Sanchez V, Camarero J, O'Shea E, Green AR, Colado MI. Differential effect of dietary selenium on the long-term neurotoxicity induced by MDMA in mice and rats. Neuropharmacology. 2003;44(4):449-461.  (PubMed)

76.  Koh JY. Zinc and disease of the brain. Mol Neurobiol. 2001;24(1-3):99-106.  (PubMed)

77.  Henkin RI, Patten BM, Re PK, Bronzert DA. A syndrome of acute zinc loss. Cerebellar dysfunction, mental changes, anorexia, and taste and smell dysfunction. Arch Neurol. 1975;32(11):745-751.  (PubMed)

78.  Sandstead HH, Frederickson CJ, Penland JG. History of zinc as related to brain function. J Nutr. 2000;130(2S Suppl):496S-502S.  (PubMed)

79.  Bhatnagar S, Taneja S. Zinc and cognitive development. Br J Nutr. 2001;85 Suppl 2:S139-145.  (PubMed)

80.  Bitanihirwe BK, Cunningham MG. Zinc: the brain's dark horse. Synapse. 2009;63(11):1029-1049.  (PubMed)

81.  Blusztajn JK. Choline, a vital amine. Science. 1998;281(5378):794-795.  (PubMed)

82.  Zeisel SH. Choline: an essential nutrient for humans. Nutrition. 2000;16(7-8):669-671.  (PubMed)

83.  Zeisel SH, Niculescu MD. Choline and phosphatidylcholine. In: Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ, eds. Modern nutrition in health and disease. 10th ed. Philadelphia: Lippincott Williams & Wilkins; 2006:525-536.

84.  Food and Nutrition Board, Institute of Medicine. Choline. Dietary reference intakes for thiamin, riboflavin, niacin, vitamin B-6, vitamin B-12, pantothenic acid, biotin, and choline. Washington, D.C.: National Academy Press; 1998:390-422.

85.  Zeisel SH. Choline and brain development. In: Bowman BA, Russell RM,eds. Present knowledge in nutrition. Volume 1. Washington, D.C.: ILSI; 2006:352-360.

86.  Food and Nutrition Board, Institute of Medicine. Dietary fats: total fat and fatty acids. Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids. Washington, D.C.: The National Academies Press; 2002:422-541.

87.  Cunnane SC. Problems with essential fatty acids: time for a new paradigm? Prog Lipid Res. 2003;42(6):544-568.  (PubMed)

88.  Muskiet FA, Fokkema MR, Schaafsma A, Boersma ER, Crawford MA. Is docosahexaenoic acid (DHA) essential? Lessons from DHA status regulation, our ancient diet, epidemiology and randomized controlled trials. J Nutr. 2004;134(1):183-186.  (PubMed)

89.  Haag M. Essential fatty acids and the brain. Can J Psychiatry. 2003;48(3):195-203.  (PubMed)

90.  Stillwell W, Wassall SR. Docosahexaenoic acid: membrane properties of a unique fatty acid. Chem Phys Lipids. 2003;126(1):1-27.  (PubMed)

91.  SanGiovanni JP, Chew EY. The role of omega-3 long-chain polyunsaturated fatty acids in health and disease of the retina. Prog Retin Eye Res. 2005;24(1):87-138.  (PubMed)

92.  Su HM. Mechanisms of n-3 fatty acid-mediated development and maintenance of learning memory performance. J Nutr Biochem. 2010;21(5):364-373.  (PubMed)

93.  Innis SM. Perinatal biochemistry and physiology of long-chain polyunsaturated fatty acids. J Pediatr. 2003;143(4 Suppl):S1-8.  (PubMed)

94.  Chalon S, Vancassel S, Zimmer L, Guilloteau D, Durand G. Polyunsaturated fatty acids and cerebral function: focus on monoaminergic neurotransmission. Lipids. 2001;36(9):937-944.  (PubMed)

95.  Lepage G, Levy E, Ronco N, Smith L, Galeano N, Roy CC. Direct transesterification of plasma fatty acids for the diagnosis of essential fatty acid deficiency in cystic fibrosis. J Lipid Res. 1989;30(10):1483-1490.  (PubMed)

96.  Jeppesen PB, Hoy CE, Mortensen PB. Essential fatty acid deficiency in patients receiving home parenteral nutrition. Am J Clin Nutr. 1998;68(1):126-133.  (PubMed)

97.  Uauy R, Dangour AD. Nutrition in brain development and aging: role of essential fatty acids. Nutr Rev. 2006;64(5 Pt 2):S24-33; discussion S72-91.  (PubMed)

98.  Wainwright PE. Dietary essential fatty acids and brain function: a developmental perspective on mechanisms. Proc Nutr Soc. 2002;61(1):61-69.  (PubMed)

99.  Lauritzen L, Hansen HS, Jorgensen MH, Michaelsen KF. The essentiality of long chain n-3 fatty acids in relation to development and function of the brain and retina. Prog Lipid Res. 2001;40(1-2):1-94.  (PubMed)

100.  Wainwright PE. Do essential fatty acids play a role in brain and behavioral development? Neurosci Biobehav Rev. 1992;16(2):193-205.  (PubMed)

101.  Schmitt JA, Benton D, Kallus KW. General methodological considerations for the assessment of nutritional influences on human cognitive functions. Eur J Nutr. 2005;44(8):459-464.  (PubMed)

102.  Isaacs E, Oates J. Nutrition and cognition: assessing cognitive abilities in children and young people. Eur J Nutr. 2008;47 Suppl 3:4-24.  (PubMed)

103.  Benton D, Fordy J, Haller J. The impact of long-term vitamin supplementation on cognitive functioning. Psychopharmacology (Berl). 1995;117(3):298-305.  (PubMed)

104.  Vazir S, Nagalla B, Thangiah V, Kamasamudram V, Bhattiprolu S. Effect of micronutrient supplement on health and nutritional status of schoolchildren: mental function. Nutrition. 2006;22(1 Suppl):S26-32.  (PubMed)

105.  Osendarp SJ, Baghurst KI, Bryan J, et al. Effect of a 12-mo micronutrient intervention on learning and memory in well-nourished and marginally nourished school-aged children: 2 parallel, randomized, placebo-controlled studies in Australia and Indonesia. Am J Clin Nutr. 2007;86(4):1082-1093.  (PubMed)

106.  Haskell CF, Scholey AB, Jackson PA, et al. Cognitive and mood effects in healthy children during 12 weeks' supplementation with multi-vitamin/minerals. Br J Nutr. 2008;100(5):1086-1096.  (PubMed)

107.  Bjork EL, Bjork RA. Memory. San Diego: Academic Press, Inc.; 1996.

108.  Hassing L, Wahlin A, Winblad B, Backman L. Further evidence on the effects of vitamin B12 and folate levels on episodic memory functioning: a population-based study of healthy very old adults. Biol Psychiatry. 1999;45(11):1472-1480.  (PubMed)

109.  Goodwin JS, Goodwin JM, Garry PJ. Association between nutritional status and cognitive functioning in a healthy elderly population. JAMA. 1983;249(21):2917-2921.  (PubMed)

110.  Wahlin A, Hill RD, Winblad B, Backman L. Effects of serum vitamin B12 and folate status on episodic memory performance in very old age: a population-based study. Psychol Aging. 1996;11(3):487-496.  (PubMed)

111.  Ebly EM, Schaefer JP, Campbell NR, Hogan DB. Folate status, vascular disease and cognition in elderly Canadians. Age Ageing. 1998;27(4):485-491.  (PubMed)

112.  Riggs KM, Spiro A, 3rd, Tucker K, Rush D. Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr. 1996;63(3):306-314.  (PubMed)

113.  Perrig WJ, Perrig P, Stahelin HB. The relation between antioxidants and memory performance in the old and very old. J Am Geriatr Soc. 1997;45(6):718-724.  (PubMed)

114.  Perkins AJ, Hendrie HC, Callahan CM, et al. Association of antioxidants with memory in a multiethnic elderly sample using the Third National Health and Nutrition Examination Survey. Am J Epidemiol. 1999;150(1):37-44.  (PubMed)

115.  Durga J, van Boxtel MP, Schouten EG, et al. Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet. 2007;369(9557):208-216.  (PubMed)

116.  McMahon JA, Green TJ, Skeaff CM, Knight RG, Mann JI, Williams SM. A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med. 2006;354(26):2764-2772.  (PubMed)

117.  Eussen SJ, de Groot LC, Joosten LW, et al. Effect of oral vitamin B-12 with or without folic acid on cognitive function in older people with mild vitamin B-12 deficiency: a randomized, placebo-controlled trial. Am J Clin Nutr. 2006;84(2):361-370.  (PubMed)

118.  Deijen JB, van der Beek EJ, Orlebeke JF, van den Berg H. Vitamin B-6 supplementation in elderly men: effects on mood, memory, performance and mental effort. Psychopharmacology (Berl). 1992;109(4):489-496.  (PubMed)

119.  Bryan J, Calvaresi E, Hughes D. Short-term folate, vitamin B-12 or vitamin B-6 supplementation slightly affects memory performance but not mood in women of various ages. J Nutr. 2002;132(6):1345-1356.  (PubMed)

120.  McDaniel MA, Maier SF, Einstein GO. "Brain-specific" nutrients: a memory cure? Nutrition. 2003;19(11-12):957-975.  (PubMed)

121.  Kieburtz K, McDermott M, Como P, et al. The effect of deprenyl and tocopherol on cognitive performance in early untreated Parkinson's disease. Parkinson Study Group. Neurology. 1994;44(9):1756-1759.  (PubMed)

122.  Sano M, Ernesto C, Thomas RG, et al. A controlled trial of selegiline, alpha-tocopherol, or both as treatment for Alzheimer's Disease. The Alzheimer's Disease Cooperative Study. N Engl J Med. 1997;336(17):1216-1222.  (PubMed)

123.  Zeisel SH. Choline and phosphatidylcholine. In: Shils ME, Olson JA, Shike M, Ross AC, eds. Modern nutritition in health and disease. 9th ed. Baltimore: Lippincott Williams & Wilkins; 1999:513-523.

124.  McCann JC, Hudes M, Ames BN. An overview of evidence for a causal relationship between dietary availability of choline during development and cognitive function in offspring. Neurosci Biobehav Rev. 2006;30(5):696-712.  (PubMed)

125.  Becker RE, Giacobini E. Mechanisms of cholinesterase inhibition in senile dementia of the Alzheimer type: clinical, pharmacological, and therapeutic aspects. Drug Dev Res. 1988;12:163-195.

126.  Mohs RC, Davis KL, Tinklenberg JR, Hollister LE. Choline chloride effects on memory in the elderly. Neurobiol Aging. 1980;1(1):21-25.  (PubMed)

127.  van Marum RJ. Current and future therapy in Alzheimer's disease. Fundam Clin Pharmacol. 2008;22(3):265-274.  (PubMed)

128.  Hooijmans CR, Kiliaan AJ. Fatty acids, lipid metabolism and Alzheimer pathology. Eur J Pharmacol. 2008;585(1):176-196.  (PubMed)

129.  Quinn JF, Raman R, Thomas RG, et al. Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA. 2010;304(17):1903-1911.  (PubMed)

130.  Bellebaum C, Daum I. Cerebellar involvement in executive control. Cerebellum. 2007;6(3):184-192.  (PubMed)

131.  Macready AL, Butler LT, Kennedy OB, Ellis JA, Williams CM, Spencer JP. Cognitive tests used in chronic adult human randomised controlled trial micronutrient and phytochemical intervention studies. Nutr Res Rev.1-30.  (PubMed)

132.  Miyake A, Friedman NP, Emerson MJ, Witzki AH, Howerter A, Wager TD. The unity and diversity of executive functions and their contributions to complex "Frontal Lobe" tasks: a latent variable analysis. Cogn Psychol. 2000;41(1):49-100.  (PubMed)

133.  Haskell CF, Robertson B, Jones E, et al. Effects of a multi-vitamin/mineral supplement on cognitive function and fatigue during extended multi-tasking. Hum Psychopharmacol. 2010;25(6):448-461.  (PubMed)

134.  Kennedy DO, Veasey R, Watson A, et al. Effects of high-dose B vitamin complex with vitamin C and minerals on subjective mood and performance in healthy males. Psychopharmacology (Berl). 2010;211(1):55-68.  (PubMed)

135.  McNeill G, Avenell A, Campbell MK, et al. Effect of multivitamin and multimineral supplementation on cognitive function in men and women aged 65 years and over: a randomised controlled trial. Nutr J. 2007;6:10.  (PubMed)

136.  van Uffelen JG, Chinapaw MJ, van Mechelen W, Hopman-Rock M. Walking or vitamin B for cognition in older adults with mild cognitive impairment? A randomised controlled trial. Br J Sports Med. 2008;42(5):344-351.  (PubMed)

137.  Benton D, Haller J, Fordy J. Vitamin supplementation for 1 year improves mood. Neuropsychobiology. 1995;32(2):98-105.  (PubMed)

138.  Carroll D, Ring C, Suter M, Willemsen G. The effects of an oral multivitamin combination with calcium, magnesium, and zinc on psychological well-being in healthy young male volunteers: a double-blind placebo-controlled trial. Psychopharmacology (Berl). 2000;150(2):220-225.  (PubMed)

139.  Schlebusch L, Bosch BA, Polglase G, Kleinschmidt I, Pillay BJ, Cassimjee MH. A double-blind, placebo-controlled, double-centre study of the effects of an oral multivitamin-mineral combination on stress. S Afr Med J. 2000;90(12):1216-1223.  (PubMed)

140.  Sawada T, Yokoi K. Effect of zinc supplementation on mood states in young women: a pilot study. Eur J Clin Nutr. 2010;64(3):331-333.  (PubMed)

141.  Benton D, Griffiths R, Haller J. Thiamine supplementation mood and cognitive functioning. Psychopharmacology (Berl). 1997;129(1):66-71.  (PubMed)

142.  Evans-Olders R, Eintracht S, Hoffer LJ. Metabolic origin of hypovitaminosis C in acutely hospitalized patients. Nutrition. 2010;26(11-12):1070-1074.  (PubMed)

143.  Zhang M, Robitaille L, Eintracht S, Hoffer LJ. Vitamin C provision improves mood in acutely hospitalized patients. Nutrition. 2010. [E pub ahead of print  (PubMed)

144.  Barnard K, Colon-Emeric C. Extraskeletal effects of vitamin D in older adults: cardiovascular disease, mortality, mood, and cognition. Am J Geriatr Pharmacother. 2010;8(1):4-33.  (PubMed)

145.  Moshfegh A, Goldman J, Cleveland L. What We Eat in America, NHANES 2001-2002: Usual Nutrient Intakes from Food Compared to Dietary Reference Intakes. US Department of Agriculture, Agricultural Research Service. 2005.

146.  Shineman DW, Salthouse TA, Launer LJ, et al. Therapeutics for cognitive aging. Ann N Y Acad Sci. 2010;1191 Suppl 1:E1-15.  (PubMed)

147.  Robins Wahlin TB, Wahlin A, Winblad B, Backman L. The influence of serum vitamin B12 and folate status on cognitive functioning in very old age. Biol Psychol. 2001;56(3):247-265.  (PubMed)

148.  Whyte EM, Mulsant BH, Butters MA, et al. Cognitive and behavioral correlates of low vitamin B12 levels in elderly patients with progressive dementia. Am J Geriatr Psychiatry. 2002;10(3):321-327.  (PubMed)

149.  Quadri P, Fragiacomo C, Pezzati R, Zanda E, Tettamanti M, Lucca U. Homocysteine and B vitamins in mild cognitive impairment and dementia. Clin Chem Lab Med. 2005;43(10):1096-1100.  (PubMed)

150.  Quadri P, Fragiacomo C, Pezzati R, et al. Homocysteine, folate, and vitamin B-12 in mild cognitive impairment, Alzheimer disease, and vascular dementia. Am J Clin Nutr. 2004;80(1):114-122.  (PubMed)

151.  Lindeman RD, Romero LJ, Koehler KM, et al. Serum vitamin B12, C and folate concentrations in the New Mexico elder health survey: correlations with cognitive and affective functions. J Am Coll Nutr. 2000;19(1):68-76.  (PubMed)

152.  Ramos MI, Allen LH, Mungas DM, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2005;82(6):1346-1352.  (PubMed)

153.  Mooijaart SP, Gussekloo J, Frolich M, et al. Homocysteine, vitamin B-12, and folic acid and the risk of cognitive decline in old age: the Leiden 85-Plus study. Am J Clin Nutr. 2005;82(4):866-871.  (PubMed)

154.  Tucker KL, Qiao N, Scott T, Rosenberg I, Spiro A, 3rd. High homocysteine and low B vitamins predict cognitive decline in aging men: the Veterans Affairs Normative Aging Study. Am J Clin Nutr. 2005;82(3):627-635.  (PubMed)

155.  Del Parigi A, Panza F, Capurso C, Solfrizzi V. Nutritional factors, cognitive decline, and dementia. Brain Res Bull. 2006;69(1):1-19.  (PubMed)

156.  Wald DS, Kasturiratne A, Simmonds M. Effect of folic acid, with or without other B vitamins, on cognitive decline: meta-analysis of randomized trials. Am J Med. 2010;123(6):522-527 e522.  (PubMed)

157.  Jia X, McNeill G, Avenell A. Does taking vitamin, mineral and fatty acid supplements prevent cognitive decline? A systematic review of randomized controlled trials. J Hum Nutr Diet. 2008;21(4):317-336.  (PubMed)

158.  Balk EM, Raman G, Tatsioni A, Chung M, Lau J, Rosenberg IH. Vitamin B6, B12, and folic acid supplementation and cognitive function: a systematic review of randomized trials. Arch Intern Med. 2007;167(1):21-30.  (PubMed)

159.  Berr C, Balansard B, Arnaud J, Roussel AM, Alperovitch A. Cognitive decline is associated with systemic oxidative stress: the EVA study. Etude du Vieillissement Arteriel. J Am Geriatr Soc. 2000;48(10):1285-1291.  (PubMed)

160.  Reiter RJ. Oxidative processes and antioxidative defense mechanisms in the aging brain. Faseb J. 1995;9(7):526-533.  (PubMed)

161.  Morris MC, Evans DA, Bienias JL, Tangney CC, Wilson RS. Vitamin E and cognitive decline in older persons. Arch Neurol. 2002;59(7):1125-1132.  (PubMed)

162.  Paleologos M, Cumming RG, Lazarus R. Cohort study of vitamin C intake and cognitive impairment. Am J Epidemiol. 1998;148(1):45-50.  (PubMed)

163.  Smith A, Clark R, Nutt D, Haller J, Hayward S, Perry K. Anti-oxidant vitamins and mental performance of the elderly. Hum Psychopharmacol. 1999;14:459-471.

164.  Lukiw WJ, Bazan NG. Docosahexaenoic acid and the aging brain. J Nutr. 2008;138(12):2510-2514.  (PubMed)

165.  Nurk E, Drevon CA, Refsum H, et al. Cognitive performance among the elderly and dietary fish intake: the Hordaland Health Study. Am J Clin Nutr. 2007;86(5):1470-1478.  (PubMed)

166.  Kalmijn S, van Boxtel MP, Ocke M, Verschuren WM, Kromhout D, Launer LJ. Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology. 2004;62(2):275-280.  (PubMed)

167.  van Gelder BM, Tijhuis M, Kalmijn S, Kromhout D. Fish consumption, n-3 fatty acids, and subsequent 5-y cognitive decline in elderly men: the Zutphen Elderly Study. Am J Clin Nutr. 2007;85(4):1142-1147.  (PubMed)

168.  Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS. Fish consumption and cognitive decline with age in a large community study. Arch Neurol. 2005;62(12):1849-1853.  (PubMed)

169.  Kalmijn S, Launer LJ, Ott A, Witteman JC, Hofman A, Breteler MM. Dietary fat intake and the risk of incident dementia in the Rotterdam Study. Ann Neurol. 1997;42(5):776-782.  (PubMed)

170.  Barberger-Gateau P, Letenneur L, Deschamps V, Peres K, Dartigues JF, Renaud S. Fish, meat, and risk of dementia: cohort study. BMJ. 2002;325(7370):932-933.  (PubMed)

171.  Morris MC, Evans DA, Bienias JL, et al. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003;60(7):940-946.  (PubMed)

172.  Heude B, Ducimetiere P, Berr C. Cognitive decline and fatty acid composition of erythrocyte membranes--The EVA Study. Am J Clin Nutr. 2003;77(4):803-808.  (PubMed)

173.  Cederholm T, Palmblad J. Are omega-3 fatty acids options for prevention and treatment of cognitive decline and dementia? Curr Opin Clin Nutr Metab Care. 2010;13(2):150-155.  (PubMed)

174.  Fotuhi M, Mohassel P, Yaffe K. Fish consumption, long-chain omega-3 fatty acids and risk of cognitive decline or Alzheimer disease: a complex association. Nat Clin Pract Neurol. 2009;5(3):140-152.  (PubMed)

175.  Dangour AD, Allen E, Elbourne D, et al. Effect of 2-y n-3 long-chain polyunsaturated fatty acid supplementation on cognitive function in older people: a randomized, double-blind, controlled trial. Am J Clin Nutr. 2010;91(6):1725-1732.  (PubMed)