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The brain is an extremely complex organ that continues to amaze researchers in neuroscience. It houses several important glands and is responsible for controlling movements, recalling memories, and a multitude of other tasks in the human body. It is no surprise that there is tremendous interest in keeping the brain healthy. Previously separate schools of research that focused on psychological or biological functions of the brain have now merged into more complex areas of research that combine multiple disciplines of science, such as psychoneurobiology and psychoneuroimmunoendocrinology. It is clear from these multidisciplinary approaches that the brain (and spinal cord) are plastic systems capable of being rewired. The ability of the brain and connecting nervous systems to communicate with each other and the rest of the body and make alterations as needed are directly influenced by components of the diet. There is a fair amount of scientific literature detailing the effects of specific dietary components on the brain during development, aging, and various pathological conditions. There is much less information available on their role for normal, healthy, adult brain function. This article overviews the roles and limitations of a variety of nutrients promoted.
Assessing cognitive function
Research studies use various methods to determine cognitive performance. These methods range from answering questions that measure short-term memory to making decisions that affect reaction time. Changes in cognitive performance are assumed to de due to cerebral changes. Another assumption is that all of the subjects decline or improve at the same rate. It is also assumed that snapshots of cognition (that are called tests) within a clinical trial can document such effects. These assumptions may be flawed in several areas. There are multiple biological and social-psychological factors that influence cognitive changes during the life cycle (particularly during development). Individual responses to nutrient deficiencies may vary so that a given test may overlook significant changes in status, especially if it is outside the scope of the test, for example if only purchase co-enzyme q10 was assessed, improvements in memory may be missed. One way to deal with this is a battery of tests administered periodically over a fairly long time period so that changes are more likely to be measured.
When To Start A Dietary Intervention
A problem with research examining the effects of a particular supplement on cognitive development or decline is timing of the intervention. Subjects cant be forced to develop a disease, so research is left at the mercy of studying people after a diagnosis occurs. This means most research interventions do not occur until after the disease has reached a point that warrants a clinical diagnosis. The logical argument is to start the nutritional intervention earlier, when the people are healthy. The dilemma is that until earlier interventions are actually studied, the outcome is not really known. However, people at risk for a given condition may not want to wait until the research is done. Calcium and osteoporosis is an example where intervention early in life can make significant differences later in life. It seems logical to assume that other nutrients will have a similar effect on long-term health, but we often dont know for sure. From a practical point of view, if a supplement has safety data behind it, risks can be minimized as long as it is not abused, contraindications are considered, and the condition is monitored by a competent healthcare practitioner.
The Developing Brain and Cognitive Functions
Malnutrition is known to cause morphological and functional alterations in the cortical neurons of infants, which may partially explain the neuropsychological deficits in these children (1). Depending on the marker for brain function that is used, an argument could be made that any essential nutrient is also essential for brain development due to either direct or indirect effects. Therefore, only iron, a-linolenic acid, and folate/folic acid will be briefly discussed. Insufficient maternal intake of the essential mineral iron has detrimental effects on the infant, including impaired psychomotor development, immune responses, and muscular strength (2). Deficits in psychological function and alterations in electroencephalograph (EEG) readings are also found in children with iron deficiency anemia (3). This has led some groups to propose that high-risk iron deficiency anemia populations consume supplemental iron, however there is very little data on pregnancy outcomes for either mother or baby after supplementation (4). A prudent recommendation would be for monitoring of maternal iron stores to determine if iron supplementation is warranted.
The fatty acids a-linolenic acid (aLA) and linoleic acid (LA) are essential fatty acids in humans that play a structural role in cellular membranes (which influence the activities of membrane-linked molecules) and serve as precursors to second messengers. aLA serves as a precursor to docosahexaenoic acid (DHA). DHA is a polyunsaturated fatty acid (PUFA) present in high concentrations in the brain. Deficiencies in aLA lead to decreased levels of DHA in the brain (5). Since fetal plasma concentrations of fatty acids are highly correlated with maternal plasma concentrations (6), the implications are that maternal dietary intake influences fetal DHA levels. Also DHA concentrations decrease in formula-fed infants vs. breast-fed infants (7), implying that infant dietary intake also influences DHA levels. The provision of DHA in breast milk is only one reason why breast-feeding is encouraged by various health organizations. While it is generally accepted that fatty acid intake influences brain function, the underlying mechanisms have not been elucidated. Studies on formula-fed infants supplemented with DHA indicate no additional benefits on developmental markers (8, 9). Prudent strategies should emphasize sufficient quantities of aLA and DHA in the maternal diet and encourage breast-feeding of the infant.
Folic acid has been heavily researched with respect to brain development due to the incidence of neural tube defects during and after folate-deficient pregnancies. In 1991 a landmark study clearly demonstrated a decrease in neural tube defects in high-risk pregnancies after supplementation with folic acid (10). This has led to recommendations from the American Academy of Pediatrics Committee on Genetics that healthy women consume 0.4 mg of folic acid per day, while high-risk populations consume 4 mg per day (11). Since an ideal supplementation strategy would start one month prior to pregnancy and many pregnancies are unplanned, routine supplementation is often encouraged. Apart from a reduction in the incidence of neural tube defects and possible low birth weights, there is not enough evidence to evaluate whether folate supplementation has any further maternal or fetal effects on clinical outcomes (12). While there is no doubt that folic acid is important for the developing nervous system, little is known about the mechanisms. Folate is involved in 1-carbon metabolism methylation reactions, and maintenance of neuronal and glial membranes. A folate deficiency could impair DNA, protein, or lipid synthesis leading to altered neuronal growth and development resulting in neural tube defects.
Other nutrients that have been implicated during development of the brain and spinal cord include zinc, iodine, and choline. Numerous animal studies have demonstrated that zinc and choline are vital to brain health (13, 14). However a recent review concludes There is insufficient evidence to evaluate fully the affect of zinc supplementation during pregnancy (13). Ingestion of cooked chicken egg yolks appears to supply sufficient choline for maternal and fetal needs, making supplementation unnecessary unless eggs are not part of the diet (14). Iodine deficiency results in a global loss of 10-15 IQ points at a population level and constitutes the worlds greatest single cause of preventable brain damage and mental retardation (15). Given the variety of nutrients that appear to be involved in brain development, it may seem wise for women to ingest a multivitamin/mineral (MVM) supplement routinely for prevention. However, there is limited research on the effects of a MVM supplement during pregnancy. Some papers have stated that outside of iron and folic acid, there is little benefit for ingestion of additional nutrients (16). However, one study has indicated that a supplement containing 60 mg of iron, 250 mg of folate, and 15 mg zinc improves maternal zinc status and may improve fetal neurobehavioral development (17). Given the risks of being nutrient deficient versus the risks of developing a nutrient toxicity, in the final analysis it seems that prenatal vitamins would be worth the risk, as it is unlikely that doses as mentioned above would pose side effects to the mother or baby.
Studies examining relationships between micronutrients and cognitive functions have also been done with adolescents. Biscuits fortified with iron (5 mg ferrous fumarate), iodine (60 mg potassium iodate), and b-carotene (2.1 mg), and a sugar-based cold drink providing ~90 mg vitamin C with 60 mg potassium iodate were given to 6-11 year old children from a poor rural community for five days per week for 43 weeks (18). Significant improvements were reported in the micronutrient status for the supplemented group, including fewer missed school days, but no effects were found on cognitive function or short-term memory. In another study administering iron (650 mg of ferrous sulphate) twice daily to non-anemic high school girls for 8 weeks, both verbal learning and memory improved (19). Another study administered a high dose MVM supplement to adolescents for 12 months and found an improvement in cognitive functioning for females but not males (20). Collectively, it appears that these studies indicate that multiple vitamins and minerals may be involved in cognitive functions. Ideally the diet would be varied enough to meet the requirements for all of these nutrients, but in poor, uneducated, or inappropriately supervised environments, children will most likely not receive adequate nutrient intakes. Under these conditions, supplementation with a MVM may be prudent. For the healthy child with a normal micronutrient status, there is little evidence that additional supplementation is warranted in order to improve cognitive function.
The Adult Brain and Cognitive Functions
A variety of supplements are marketed as capable of improving brain functions, such as short term-memory. Many of these claims are based on studies using clinical populations. Many of these agents work by increasing levels of one or more neurotransmitters (NTs) in the brain. The presence of high concentrations of these agents leads to an increase in NT production that results in improved brain functions. NTs are molecules that allow neurons to send electrical signals to other cells and/or neurons. This simplistic overview, however, underscores the fact that all components of the metabolic pathway must be present for significant elevations in NT levels to occur. A generalized critique against dietary supplements is that key ingredients for the metabolic pathways are often missing or the doses are too low to be effective. The following section takes this into account and will outline key nutrients to complete the metabolic pathway for NT production.
Tryptophan (Try) is an essential amino acid that can serve as precursor for serotonin production. Numerous studies have demonstrated that Try availability to brain neurons influences the production of serotonin (21). The changes in serotonin levels can produce changes in sleep and mood patterns. While Try ingestion appeared to have promise, the effects are rather subtle when compared to potent drugs. Recent evidence indicates that Try depletion does not affect mood, memory, anxiety, and attention (22). It is conceivable that small segments of the population may be affected by Try fluctuations to a greater extent. Effective doses of Try supplementation studies range from 6-10 grams per day or 70-100 mg per kg of body mass. Regardless, Try is no longer available off-the-shelf due to outbreaks years ago of eosiniphilia myalgia syndrome (EMS), an increase in eosinophils with myalgia.
Another amino acid used to increase specific NTs is tyrosine. Tyrosine is converted into L-dopa, dopamine, norepinephrine, and then into epinephrine. Research on the effects of tyrosine in diseased populations has not been very promising. Research on healthy subjects appears to have more benefit. Ingestion of doses ranging from 100-150 mg per kg of body mass elevated catecholamines and improved cognitive function during stressful conditions (23, 24). Usually these doses are divided into three smaller doses taken during the day between 8 AM to 5 PM. Given the number of steps involved in the conversion of tyrosine into epinephrine, there appear to be several points at which the process can be halted due to insufficient cofactors. Ascorbic acid, pyridoxine, and S-adenosyl-methionine are agents that are also involved in the production of epinephrine from tyrosine. While ingestion of all these agents simultaneously appears to have theoretical support, this strategy has limited scientific evidence to support it would work any better than the ingestion of tyrosine alone. The development of amino acid imbalances leading to other complications is the primary concern for long-term tyrosine ingestion (or other amino acids). Whether the initial benefits experienced in healthy individuals are maintained chronically also requires further research.
Choline, CDP-choline, and lecithin have been promoted as potential memory boosters. There is evidence that in specific clinical situations, choline levels may be lower and hence a therapeutic effect may be achieved by administering the aforementioned supplements. In patients who require long-term total parenteral nutrition (TPN), choline levels may be lower than normal (it is not included in the TPN formula) and both verbal and visual memory may be impaired. Adding 2 g of choline chloride to their TPN regimen may improve verbal and visual memory (25). These findings are contrasted by lack of an effect of an oral challenge of 50 mg/kg of choline bitartrate on brain choline metabolites (26). This would suggest that choline supplementation would have little effect on normal subjects. Whether this holds true for other forms of choline and/or delivery methods requires further research.
The Aging Brain and Cognitive Functions
With aging there is increased prevalence of atrophic gastritis with hypochlorhydria or achlorhydria in 20-50% of the elderly (depending on the diagnosis and definition used) (27). The physiological consequences include altered gastric secretions and nutrient absorption. This partially explains why B vitamin deficiencies are common in the elderly. These deficiencies are associated with various neurological and behavioral dysfunctions. Healthy elderly subjects with low intakes or blood concentrations of folate, vitamin B-12, riboflavin, and vitamin C scored poorly on memory tests (28). While some studies indicate a beneficial effect of supplementation with B vitamins in the elderly (29), most studies generally indicate that supplementation of B vitamins has minimal effects, if any, on memory and other cognitive functions (30, 31). Homocysteine levels are high during inadequate folate and vitamin B-12 intakes and thus serve as a marker for these nutrients. While previous studies linked high homocysteine levels in elderly people with cognitive dysfunction, recent evidence indicates there is no correlation between the two (32). It is thought that B vitamin supplementation may have the greatest effect on the cognitive functions of healthy older adults who have had low plasma concentrations of B vitamins for less than one year. In pathological conditions or when B vitamin deficiency (especially folate) has persisted for longer than one year, it may simply be too late to reverse impairments in brain neurons. If severe deficiencies are allowed to persist, atrophy of brain regions may occur such as the atrophy of the neocortex that occurs with folate deficiency in Alzheimer disease (33). Regardless of whether or not B vitamins improve existing cognitive performance, if blood concentrations are low, further cognitive impairments can develop. Given the poor food intakes and poor nutrient absorption of this population, supplementation with a MVM would seem prudent.
During normal aging and various neuropathologies, there is evidence of increased oxidative stress in the brain (34). Ingestion of known antioxidants such as vitamin C, vitamin E, selenium, coenzyme Q10, n-acetyl-cysteine (NAC), lipoic acid, flavonoids, and other phytonutrients have been promoted to reduce free radical damage and prevent declines in cognitive function. While numerous animal studies support the above claims, research on humans is more limited. One study indicated that among people aged 65 and older, higher ascorbic acid and beta-carotene plasma levels are associated with better memory performance (35). Another study indicated that decreasing serum levels of vitamin E per unit of cholesterol were consistently associated with increasing levels of poor memory, while serum levels of vitamins A and C, beta- carotene, and selenium were not associated with poor memory performance (36). These epidemiological studies are correlative and other factors may have impacted the findings. Collectively they do tend to support that higher antioxidant concentrations are associated with a higher performance on memory tests. Unfortunately, there is insufficient information to recommend exact doses and nutrient combinations or at what stage of the life cycle an antioxidant intervention should be implemented. 400 IUs of vitamin E and 500 mg of vitamin C appear safe doses for daily consumption in older adults. Additional antioxidant benefits can be achieved from generous consumption of spinach, blueberries, grapes, onions, and strawberries as part of the diet.
Acetyl-L-carnitine (ALC) is a unique compound that offers potential in a variety of areas. Orally ingested ALC is absorbed and readily crosses the blood-brain barrier. Animal studies indicate that it can improve neuronal energetics and repair mechanisms while modifying acetylcholine production in the brain and spinal cord. Positive results have been found in various clinical pathologies including HIV, Alzheimers dementia, depression in the elderly, and peripheral neuropathy (37-41). ALC structurally resembles acetylcholine. co-enzyme q10 it can mimic a variety of neurotransmitters and is involved mitochondrial metabolism. The multiple roles of this molecule indicate that is has widespread potential in a variety of clinical conditions as well as counteracting declines in ALC levels that occur with aging. Doses as high as 3 g/d taken in 1 g doses tid have been safely tested, with nausea being the most common side effect. While it appears safe and has many theoretical applications, more research is needed to determine appropriate dosing strategies and timing of intervention protocols. There is little scientific evidence thus far that it can enhance brain function in normal healthy people, although an argument could be made that it may prevent the decline in memory that occurs with aging.
Phosphatidylserine (PS) and S-adenosyl-methionine (SAM) are additional supplements with potential for the aging brain. Research using middle-aged rats indicates that PS derived from soy lecithin or bovine cortex can improve cognitive function (42). Research on humans indicates that 300 mg/d can also improve cognitive function in the elderly (43). Long-term studies indicate that PS is safe. Animal studies indicate that SAM can prevent brain neuronal cell death and minimize oxidative stress. A meta-analysis of various studies on humans indicated that SAM has few side effects and may be a potentially useful treatment against depression with oral doses up to 1,600 mg/d (44).
Combining nutrients
Given that many of the agents overviewed have the potential to act synergistically, it could be theoretically predicted that any improvements in cognitive function would be potentiated. Research on rats with brain lesions determined the combination of vitamin B-12 with egg phosphatidylcholine worked better than either separately for improving memory in the Morris water maze task (45). A seven-step complementary medical program was developed that included:
1. Nutritional modification: A 15% fat diet.
2. Nutrient supplementation of 800 IU vitamin E (part of a MVM package), PS 300 mg/day, coenzyme-Q-10 100 mg/day, and ALC 750-1500 mg/day.
3. Herbs: Ginkgo Biloba 120 mg/day.
4. Medication: Deprenyl 5-10 mg/day.
5. Hormone Replacement: 50-100 mg of either DHEA or Pregnenolone, both precursors of estrogen, were prescribed.
6. Mental training: Headline discussions etc. enhance dendritic sprouting.
7. Mind/Body Exercises: Aerobic reconditioning, stress management via meditation and yoga.
The program was found to have a potent therapeutic impact in patients with age-associated memory impairment (46). These results, while rather limited (i.e. a study on rats and an abstract), do point to the potential of nutrient mixes that may safely and effectively be used to maintain and/or prevent declines in brain function.
References upon request.
Thomas Incledon, PhD(c), RD, LD/N, NSCA-CPT, CSCS, RPT has been involved in research on how to enhance health and human performance for over 17 years and is considered one of the worldwide leading experts on effective health and performance strategies. He is the Chief Executive Officer of Human Health Specialists. Tom can be reached at tom@thomasincledon.com or (480) 883-7240. Visit our websites at http://www.ThomasIncledon.com, http://www.HumanPerformanceSpecialists.com, http://www.HumanHealthSpecialists.com
