“Brain development is subject to complex lifelong processes of interactions between genetic and environmental factors. Although many environmental factorscontribute to brain development, nutrition is of particular importance due to the role that nutrients play in specific metabolic pathways and structural components. It is known, for example, that nutrient deficiency during critical periods of development can result in permanent changes to the brain. Of particular importance are folate and the related B vitamins that are involved in one-carbon (C1) metabolism and the production of S-adenosylmethionine (SAM), a universal methyl donor required for various reactions, including the production of neurotransmitters. B vitamins are required for essential brain metabolic pathways and are fundamental in all aspects of brain development and maintenance of brain health throughout the life cycle (1).
Optimal folate status is essential throughout pregnancy for placental and fetal growth and development. During pregnancy there is a decline in maternal folate concentrations to approximately 50% of non-pregnant concentrations. This is partly owing to the increased folate requirements for rapid cell proliferation and tissue growth of the uterus and placenta, growth of the fetus, and the expansion of maternal blood volume. Irrefutable evidence has shown that supplementation with folic acid protects against both first occurrence (9) and recurrence (10) of neural tube defects, leading to government recommendations (which are in place worldwide) advising all women planning a pregnancy to consume 400 micrograms of folic acid per day from preconception until the end of the first trimester of pregnancy (2). This protective effect of folic acid supplementation relates to the early stages of pregnancy when the closure of the neural tube occurs (about 21–28 days post conception). There is a growing body of evidence from observational and experimental studies suggesting that in utero nutrition may affect later cognitive development in the offspring. As the fetal brain develops rapidly, poor maternal intake of key nutrients during pregnancy can influence the development of the structure and components of the brain. Folate and the metabolically related B vitamins are fundamental throughout brain development owing to their participation in transcription, nucleotide synthesis, and neurotransmitter production and methylation processes, including DNA methylation (3).
Many observational studies appear to support the role of adequate maternal folate status in contributing to later cognitive performance of the child (4-7). Aside from cognitive health, there are also studies linking low maternal folate status with higher offspring behavioral (8), inattention and hyperactivity problems (9), and emotional problems (10), which warrant further investigation. Considering that there is rapid structural and synaptic development in key areas of the brain (including the hippocampus) during the growth spurt in pregnancy, further studies are needed to more fully investigate the potential effect of folate during pregnancy and to determine if the effect is specific to certain stages of pregnancy or whether the effect is perhaps mediated throughout all trimesters of pregnancy. The effect of dietary and blood folate status on cognitive performance has also been investigated in young children and adolescents. A recent study reported that low plasma folate and vitamin B12 concentrations were associated with poorer cognitive performance, measured in children aged 12–18 months (11). Furthermore, an investigation of adolescents (aged 15 years) showed that higher dietary folate intake was positively associated with academic achievements (12). An observational study also reported that higher serum folate measured in children aged 6–16 years was associated with better reading performance in participants from the National Health and Nutrition Examination Survey III cohort in the USA (13).
Cognitive dysfunction is a common problem among the elderly and ranges in severity from mild cognitive impairment to more progressive types of dementia, the latter referring to a state in which the disease has advanced enough to disrupt a person’s normal way of living. Emerging evidence suggests that suboptimal status of folate and the metabolically related B vitamins and/or elevated homocysteine concentrations – owing to their essential roles in C1 metabolism – may be linked with cognitive dysfunction and dementia. A review reported that 90 out of 100 published cross-sectional and prospective studies showed a link between elevated homocysteine and/or low B vitamin concentrations and cognitive dysfunction (14). Most of these studies have focused on elevated plasma homocysteine concentrations, and/or a combination of suboptimal status of folate and vitamin B12, and to a much lesser extent on vitamin B6. Following the positive associations emerging from epidemiological research, a number of randomized controlled trials have investigated the potential benefits of B vitamin supplementation on cognitive health. Many of these trials, however, were of insufficient depth and duration to detect an effect or included participants with existing optimal B vitamin status or with advanced dementia, where a beneficial effect is unlikely. In addition, the majority of the reported intervention trials used questionnaire-based assessments of cognitive performance. Very few clinical trials have investigated the effect of B vitamins on cognitive dysfunction using direct methods such as brain imaging techniques, which may provide a more robust measure of long-term brain changes, including the impact of nutritional intervention.
The strongest evidence to date originates from the VITACOG trial, in which patients with mild cognitive impairment (without dementia) were supplemented with folic acid (800 micrograms/day), vitamin B12 (500 micrograms/day) and vitamin B6 (20 milligrams/day) or a placebo over a two-year period. The results reported that supplementation with B vitamins slowed the rate of cognitive decline, as assessed by questionnaire-based cognitive tests (15). Of greater importance is the fact that the same study also found that B vitamin treatment reduced brain atrophy, as measured by MRI scans, by approximately 30% (16). The effect was greatest in participants with the highest baseline homocysteine concentrations (above 13 micromoles/liter), among whom an overall reduction in brain atrophy occurrence of 53% was reported, while no effect was found in those in the bottom quartile (below 9.5 micromoles/liter). Moreover, when a subsample of the VITACOG cohort was further analyzed, the investigators reported that B vitamin treatment reduced cerebral atrophy by as much as sevenfold, specifically in gray matter areas of the brain vulnerable to Alzheimer’s disease, including the bilateral hippocampus and cerebellum. Finally, when participants were analyzed in quartiles for brain shrinkage, it was reported that participants with the highest rate of brain shrinkage displayed the greatest level of cognitive decline (17). Importantly, folate, vitamin B12, and vitamin B6 are all required to lower concentrations of homocysteine, and perhaps it is a combination of B vitamins rather than a monotherapy B vitamin approach that is required to optimize C1 metabolism.
More research is however needed for both healthy and cognitively impaired groups to investigate the suggested effect further. If cognitive dysfunction can in fact be slowed or prevented by B vitamins in healthy older people, then this could represent a cost-effective preventative public health strategy in ageing populations.”
Based on: McGarel C. et al. Emerging roles for folate and related B-vitamins in brain health across the lifecycle. Proceedings of the Nutrition Society. Published online November 2014.