MICRONUTRIENTS AND COGNITIVE FUNCTION
Victoria J. Drake, Ph.D.
Summary: Deficiencies of vitamins (B vitamins, vitamins C, D, and E) or minerals (calcium, iodine, iron, magnesium, selenium, and zinc) impair cognitive function. More research, including clinical trials, is necessary to determine if micronutrient supplementation improves cognitive abilities in healthy people, attenuates age-related cognitive decline, or improves mental function in patients with Alzheimer's disease.
Good nutritional status is imperative for normal cognition. Several micronutrients (vitamins and nutritionally essential minerals) have important biochemical roles in the brain and are needed for proper cognitive function. This article summarizes the basic needs of the brain for cognition, the cognitive effects of select micronutrient deficiencies, and the present knowledge regarding the cognitive effects of micronutrient supplementation.
Micronutrients are directly or indirectly involved in a number of cognitive processes that are dependent on energy metabolism in brain cells, blood supply to the brain, synthesis of neurotransmitters (chemicals that are released from a nerve cell and result in the transmission of an impulse to other cells), neurotransmitter binding to its receptors, nerve impulse propagation, and homocysteine metabolism.
The brain is a highly metabolically active tissue that needs a constant supply of glucose (sugar) to meet energy needs. Glucose metabolism in the brain requires several vitamins, including thiamin, riboflavin, niacin, and pantothenic acid, that function as enzyme cofactors in the oxidation of glucose to carbon dioxide and water. Certain minerals, such as magnesium, iron, and manganese, are also needed to complete the metabolism of glucose.
Proper blood supply to the brain is necessary to deliver oxygen, glucose, and macronutrients, as well as micronutrients, for normal cognitive function. Good nutrition can help maintain optimal blood supply to the brain and lower the risk of stroke—a pathological condition that results from impaired blood supply to the brain.
Amino acids and many of the B vitamins are needed to synthesize various neurotransmitters in the brain. In addition, vitamin C is required for the synthesis of the neurotransmitter norepinephrine, and the mineral zinc is needed for functioning of the neurotransmitters norepinephrine, aspartate, and gamma-aminobutyric acid (GABA). Vitamins could possibly affect neurotransmitter binding to receptors on neurons, thereby altering neurotransmission.
Micronutrients may indirectly influence nerve impulse propagation by affecting the integrity of the myelin sheath of nerves. The myelin sheath, composed of lipids and proteins, surrounds and insulates nerve fibers and functions as a conduit in an electrical system, allowing for rapid and efficient neurotransmission. Two B vitamins, folate and vitamin B12, are needed to maintain the integrity of the myelin sheath; therefore, these vitamins are important in nerve impulse propagation. Additionally, the B vitamin thiamin is required for maintenance of membrane potential and proper conductance of nerves. Furthermore, iron is required for the development of oligodendrocytes—myelin-producing cells of the brain.
Vitamin B6, folate, and vitamin B12, as well as the nutrient choline, are involved in the metabolism and reduction of homocysteine, a sulfur-containing compound produced in the metabolism of the amino acid methionine. Some studies have linked elevated levels of homocysteine with cognitive dysfunction found in dementia and Alzheimer's disease.
Phosphorylated forms of thiamin (vitamin B1) are required for reactions involved in the metabolism of carbohydrates, amino acids, and lipids, and one form of the vitamin has been implicated in membrane functions of neurons and in the generation of nerve impulses. Thus, inadequate intake of thiamin can negatively affect cognition. Severe thiamin deficiency causes beriberi; the dry and wet types of beriberi involve peripheral neuropathy, whereas cerebral beriberi can lead to cell death of neurons and the clinical conditions of Wernicke's encephalopathy and Korsakoff's psychosis, especially in those who abuse alcohol.
Niacin (vitamin B3) is needed for a number of redox reactions (reduction—"electron gain", oxidation—"electron loss") and other reactions in the body. 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. Today, the condition is uncommon but can occur in cases of chronic alcoholism and in individuals with malabsorption syndromes. Neurologic symptoms of pellagra include headache, fatigue, apathy, depression, ataxia, poor concentration, delusions, and hallucinations, which can lead to confusion, memory loss, psychosis, dementia, and death.
Pantothenic acid (vitamin B5) is needed for the oxidative metabolism of glucose and fats and also for synthesis of fats, cholesterol, steroid hormones, the hormone melatonin, and the neurotransmitter acetylcholine. Pantothenic acid deficiency is very rare and has been observed only in cases of severe malnutrition. However, deficiency of this vitamin has been induced experimentally in humans by co-administering a pantothenic acid antagonist and a pantothenic aciddeficient diet. Participants in this experiment complained of headache, fatigue, insomnia, intestinal disturbances, and numbness and tingling of their hands and feet.
Experimentally induced pantothenic acid deficiency in laboratory animals has been shown to cause loss of the myelin sheath and peripheral nerve damage.
Pyridoxal, pyridoxine, and pyridoxamine are collectively called vitamin B6, which is required for the biosynthesis of several neurotransmitters, including GABA, dopamine, norepinephrine, and serotonin. Severe deficiency of vitamin B6 is uncommon, but alcoholics are thought to be most at risk due to inadequate dietary intakes and impaired metabolism of the vitamin. Neurologic symptoms of severe vitamin B6 deficiency include irritability, depression, confusion, and seizures.
Biotin (vitamin B7) is required for carboxylase enzymes that are important in the metabolism of fatty acids and amino acids. While overt biotin deficiency is quite rare, deficiency of the vitamin has been observed in patients on prolonged intravenous feeding (parenteral nutrition) without biotin supplementation, in individuals consuming high amounts of raw egg white containing a protein that binds biotin and prevents its absorption, and in those with inherited disorders of biotin metabolism. Neurologic symptoms of biotin deficiency include depression, lethargy, hallucinations, and numbness and tingling of the extremities.
Folate (vitamin B9) is required for the metabolism of nucleic acids (DNA and RNA) and amino acids. The vitamin is also needed for the synthesis of several neurotransmitters, including norepinephrine, dopamine, and serotonin, and, along with vitamin B12, folate is required in the breakdown of norepinephrine and dopamine. Dietary folate deficiency in the absence of vitamin B12 deficiency does not cause neurologic symptoms. However, individuals with genetic disorders of folate metabolism have experienced seizures and progressive neurologic deterioration.
In humans, vitamin B12 is a required cofactor for two enzymes: methionine synthase, which is needed for the production of methionine from homocysteine, and L-methylmalonyl-CoA mutase, which is involved in crucial metabolic pathways. Vitamin B12 deficiency affects 10-15% of adults over the age of 60 years. It damages the myelin sheath of nerves and is frequently associated with neurological problems. Neurologic symptoms are the only clinical indicator of vitamin B12 deficiency in about 25% of cases. Such symptoms include numbness and tingling of the extremities, difficulty walking, problems with concentration, memory loss, disorientation, and dementia. Severe B12 deficiency is associated with pernicious anemia and, if untreated, can lead to "megaloblastic madness," characterized by delusions and hallucinations. Atrophic gastritis, an age-related condition resulting in diminished digestive factors, is often associated with decreased absorption of vitamin B12 from food.
Vitamin C accumulates in the central nervous system, with neurons of the brain having especially high levels. Vitamin C is an important antioxidant that is required for the synthesis of the neurotransmitter norepinephrine, the reduction of metal (e.g., iron, copper) ions in the brain, and for the regeneration of vitamin E. Vitamin C deficiency causes oxidative damage to lipids and proteins in the brain. Severe vitamin C deficiency, called scurvy, is potentially fatal. 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 the synthesis of collagen—an important structural component of blood vessels, tendons, ligaments, and bone. Vitamin C is also required for the conversion of dietary lysine to carnitine, a compound essential for energy production in the cells' mitochondria. Hence, scurvy is characterized by fatigue and depression in addition to physical manifestations.
Vitamin D is important for normal brain development and function, and vitamin D deficiency may impair cognitive abilities. Some studies in older adults have either linked lower 25-hydroxyvitamin D levels—the clinical indicator in the blood of vitamin D status&mdwith measures of poor cognitive performance or higher 25-hydroxyvitamin D levels with measures of better cognitive performance. However, the association between 25-hydroxyvitamin D concentrations and cognitive performance is not yet clear.
In the brain and other tissues, the alpha-tocopherol form of vitamin E is a key fat-soluble antioxidant that prevents lipid peroxidation and helps to maintain the integrity of cell membranes. Thus, vitamin E deficiency causes lipid peroxidation in brain tissues. 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).
Calcium ions are important intracellular signals that regulate a number of physiological processes, including neuronal gene expression and neuronal secretion of neurotransmitters. 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, dietary calcium inadequacy primarily affects bone health.
Iodine is required for the synthesis of thyroid hormones, which are important for myelination of the central nervous system. Iodine is critical for normal development of the brain; therefore, deficiency of this mineral during critical periods of fetal development or 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.
Iron is an essential component of hundreds of proteins and enzymes involved in various aspects of cellular metabolism. The mineral is needed for proper development of oligodendrocytes (the brain cells that produce myelin) and for several enzymes that synthesize neurotransmitters. Accordingly, iron deficiency during various stages of brain development has negative consequences. Maternal iron deficiency during pregnancy has serious consequences for the woman and the fetus, including permanent learning and memory deficits in the offspring. Iron deficiency during childhood may be associated with impaired cognitive development.
Magnesium is required for more than 300 metabolic reactions, many of which are important for normal brain function. Overt magnesium deficiency has been induced experimentally and results in neurologic and muscular symptoms that include tremor, muscle spasms, and tetany (involuntary muscle contractions). According to recent surveys, many Americans do not have an adequate intake of magnesium.
Selenium is required for glutathione peroxidases (GPx), important antioxidant enzymes in the brain and other tissues. Selenium deficiency has been associated with decreased GPx activity in the brains of laboratory animals and may be linked to a reduced antioxidant capacity in the brain.
Zinc is present at high levels in the brain, where it has catalytic, structural, and regulatory roles in cellular metabolism. 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. Experimentally induced zinc deficiency in humans has been shown to impair measures of mental and neurologic function. However, deficiency of the mineral during critical periods of cognitive development can be more devastating, causing congenital malformations or deficits in attention, learning, memory, and neuropsychological behavior.
Although not considered a vitamin, choline is an essential nutrient needed for myelination of nerves, synthesis of the neurotransmitter acetylcholine, and synthesis of various structural and cell-signaling molecules, including phospholipids (phosphatidylcholine and sphingomyelin) that are important components of cell membranes. Choline deficiency during the perinatal period in laboratory animals results in persistent memory and other cognitive deficits in offspring.
Compared to the consequences of micronutrient deficiencies, considerably less is known about the cognitive effects of micronutrient supplementation. Overall, there is currently little evidence that micronutrient supplementation provides cognitive benefits related to attention, memory, or executive functions (higher-order cognitive processes that include reasoning, planning, strategic thinking, problem solving, and multitasking). Some studies, however, have reported that multivitamin/mineral supplementation may benefit subjective measures of mood and psychological wellbeing. Additionally, evidence that supplementation with B vitamins or antioxidant vitamins prevents age-associated cognitive decline is largely lacking, although randomized controlled trials (RCTs) of longer duration are needed.
Linus Pauling was interested in the relationship of critical micronutrients and enzymes with mental function, including mental illness. He discussed the exquisite chemical sensitivity of the brain to vitamin deficiencies and addressed the theoretical basis for micronutrient supplementation to help treat mental illness in his seminal paper, Orthomolecular Psychiatry, published in 1968 in Science.
To date, many of the RCTs of micronutrient supplementation have employed elderly subjects or individuals with pathological conditions like Alzheimer's disease. Thus, there is a need for well-designed, largescale, long-term RCTs in healthy adults and in children. In addition, the available RCTs have used a number of different cognitive assessments; therefore, more standardized approaches would be useful to interpret evidence across studies. Studies that measure micronutrient status in blood and correlate that with cognitive function are also needed to better assess the role of micronutrients in cognition. Furthermore, intervention trials in individuals with micronutrient deficiencies are required to fully assess the role of micronutrient supplementation in populations with inadequate or marginal micronutrient status.
For more detailed information on micronutrients and cognition, see the article in the Micronutrient Information Center. This article was underwritten, in part, by a grant from Bayer Consumer Care AG, Basel, Switzerland.
Last updated July 2011