Skip to main content Accessibility help
×
×
Home

Information:

  • Access
  • Cited by 38
  • Cited by
    This article has been cited by the following publications. This list is generated based on data provided by CrossRef.

    Krishnaveni, GV Kumaran, Kalyanaraman Krishna, Murali Sahariah, Sirazul Chandak, Giriraj Kehoe, Sarah Jones, Alexander Bhat, Dattatray Danivas, Vijay Srinivasan, Krishnamachari Suguna Shanthi, J Karat, SC Barker, Mary Osmond, Clive Yajnik, Chittaranjan and Fall, Caroline 2018. Life course programming of stress responses in adolescents and young adults in India: Protocol of the Stress Responses in Adolescence and Vulnerability to Adult Non-communicable disease (SRAVANA) Study. Wellcome Open Research, Vol. 3, Issue. , p. 56.

    Mazzio, Elizabeth and Soliman, Karam F. A. 2018. Genomics-Driven Healthcare. p. 263.

    Laidley, Thomas and Conley, Dalton 2018. The Effects of Active and Passive Leisure on Cognition in Children: Evidence from Exogenous Variation in Weather. Social Forces, Vol. 97, Issue. 1, p. 129.

    Caffrey, Aoife Irwin, Rachelle E McNulty, Helene Strain, J J Lees-Murdock, Diane J McNulty, Breige A Ward, Mary Walsh, Colum P and Pentieva, Kristina 2018. Gene-specific DNA methylation in newborns in response to folic acid supplementation during the second and third trimesters of pregnancy: epigenetic analysis from a randomized controlled trial. The American Journal of Clinical Nutrition, Vol. 107, Issue. 4, p. 566.

    Wang, Xinyan Li, Wen Li, Zhenshu Ma, Yue Yan, Jing Wilson, John X and Huang, Guowei 2018. Maternal Folic Acid Supplementation During Pregnancy Promotes Neurogenesis and Synaptogenesis in Neonatal Rat Offspring. Cerebral Cortex,

    Hauta-alus, Helena H Korkalo, Liisa Freese, Riitta Ismael, Carina and Mutanen, Marja 2018. Urban and rural dietary patterns are associated with anthropometric and biochemical indicators of nutritional status of adolescent Mozambican girls. Public Health Nutrition, Vol. 21, Issue. 6, p. 1057.

    Wang, Xinyan Li, Wen Li, Shou Yan, Jing Wilson, John X. and Huang, Guowei 2018. Maternal Folic Acid Supplementation During Pregnancy Improves Neurobehavioral Development in Rat Offspring. Molecular Neurobiology, Vol. 55, Issue. 3, p. 2676.

    McKee, Sarah E and Reyes, Teresa M 2018. Effect of supplementation with methyl-donor nutrients on neurodevelopment and cognition: considerations for future research. Nutrition Reviews, Vol. 76, Issue. 7, p. 497.

    Caffrey, Aoife McNulty, Helene Irwin, Rachelle E. Walsh, Colum P. and Pentieva, Kristina 2018. Maternal folate nutrition and offspring health: evidence and current controversies. Proceedings of the Nutrition Society, p. 1.

    Mendonça, Nuno Jagger, Carol Granic, Antoneta Martin-Ruiz, Carmen Mathers, John C Seal, Chris J and Hill, Tom R 2018. Elevated Total Homocysteine in All Participants and Plasma Vitamin B12 Concentrations in Women Are Associated With All-Cause and Cardiovascular Mortality in the Very Old: The Newcastle 85+ Study. The Journals of Gerontology: Series A, Vol. 73, Issue. 9, p. 1258.

    Chakraborty, S. Chopra, M. Mani, K. Giri, A. K. Banerjee, P. Sahni, N. S. Siddhu, A. Tandon, N. and Bharadwaj, D. 2018. Prevalence of vitamin B12 deficiency in healthy Indian school-going adolescents from rural and urban localities and its relationship with various anthropometric indices: a cross-sectional study. Journal of Human Nutrition and Dietetics, Vol. 31, Issue. 4, p. 513.

    Shavlovskaya, O. A. 2018. Neuroprotectors in the correction of cognitive impairment. Zhurnal nevrologii i psikhiatrii im. S.S. Korsakova, Vol. 118, Issue. 9, p. 130.

    Parada, Francisco J. 2018. Understanding Natural Cognition in Everyday Settings: 3 Pressing Challenges. Frontiers in Human Neuroscience, Vol. 12, Issue. ,

    Kemse, Nisha Sundrani, Deepali Kale, Anvita and Joshi, Sadhana 2017. Maternal Micronutrients, Omega-3 Fatty Acids and Gene Expression of Angiogenic and Inflammatory Markers in Pregnancy Induced Hypertension Rats. Archives of Medical Research, Vol. 48, Issue. 5, p. 414.

    Moore, K. O'Shea, M. Hughes, C. F. Hoey, L. Ward, M. and McNulty, H. 2017. Current evidence linking nutrition with brain health in ageing. Nutrition Bulletin, Vol. 42, Issue. 1, p. 61.

    Thaler, Lea and Steiger, Howard 2017. Neuroepigenomics in Aging and Disease. Vol. 978, Issue. , p. 93.

    Gougeon, Laura Payette, Hélène Morais, José A. Gaudreau, Pierrette Shatenstein, Bryna and Gray-Donald, Katherine 2017. A prospective evaluation of the depression–nutrient intake reverse causality hypothesis in a cohort of community-dwelling older Canadians. British Journal of Nutrition, Vol. 117, Issue. 07, p. 1032.

    Bahari-Javan, Sanaz Varbanov, Hristo Halder, Rashi Benito, Eva Kaurani, Lalit Burkhardt, Susanne Anderson-Schmidt, Heike Anghelescu, Ion Budde, Monika Stilling, Roman M. Costa, Joan Medina, Juan Dietrich, Detlef E. Figge, Christian Folkerts, Here Gade, Katrin Heilbronner, Urs Koller, Manfred Konrad, Carsten Nussbeck, Sara Y. Scherk, Harald Spitzer, Carsten Stierl, Sebastian Stöckel, Judith Thiel, Andreas von Hagen, Martin Zimmermann, Jörg Zitzelsberger, Antje Schulz, Sybille Schmitt, Andrea Delalle, Ivana Falkai, Peter Schulze, Thomas G. Dityatev, Alexander Sananbenesi, Farahnaz and Fischer, André 2017. HDAC1 links early life stress to schizophrenia-like phenotypes. Proceedings of the National Academy of Sciences, Vol. 114, Issue. 23, p. E4686.

    Khezri, Marzieh Beigom Nasseh, Nahid and Soltanian, Ghodratollah 2017. The comparative preemptive analgesic efficacy of addition of vitamin B complex to gabapentin versus gabapentin alone in women undergoing cesarean section under spinal anesthesia. Medicine, Vol. 96, Issue. 15, p. e6545.

    Kumar, Neeraj 2017. Nutrients and Neurology. CONTINUUM: Lifelong Learning in Neurology, Vol. 23, Issue. 3, p. 822.

    ×

Actions:

      • Send article to Kindle

        To send this article to your Kindle, first ensure no-reply@cambridge.org is added to your Approved Personal Document E-mail List under your Personal Document Settings on the Manage Your Content and Devices page of your Amazon account. Then enter the ‘name’ part of your Kindle email address below. Find out more about sending to your Kindle. Find out more about sending to your Kindle.

        Note you can select to send to either the @free.kindle.com or @kindle.com variations. ‘@free.kindle.com’ emails are free but can only be sent to your device when it is connected to wi-fi. ‘@kindle.com’ emails can be delivered even when you are not connected to wi-fi, but note that service fees apply.

        Find out more about the Kindle Personal Document Service.

        Emerging roles for folate and related B-vitamins in brain health across the lifecycle
        Available formats
        ×

        Send article to Dropbox

        To send this article to your Dropbox account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Dropbox.

        Emerging roles for folate and related B-vitamins in brain health across the lifecycle
        Available formats
        ×

        Send article to Google Drive

        To send this article to your Google Drive account, please select one or more formats and confirm that you agree to abide by our usage policies. If this is the first time you use this feature, you will be asked to authorise Cambridge Core to connect with your <service> account. Find out more about sending content to Google Drive.

        Emerging roles for folate and related B-vitamins in brain health across the lifecycle
        Available formats
        ×
Export citation

Abstract

Nutrition plays a fundamental role in supporting the structural and functional development of the human brain from conception, throughout early infancy and extending into later life. A growing body of evidence suggests that folate and the metabolically related B-vitamins are essential for brain health across all age groups, owing to their specific roles in C1 metabolism and particularly in the production of S-adenosylmethionine, a universal methyl donor essential for the production of neurotransmitters. Emerging, though not entirely consistent, evidence suggests that maternal folate status throughout pregnancy may influence neurodevelopment and behaviour of the offspring. Furthermore optimal B-vitamin status is associated with better cognitive health in ageing. Of note, a recent clinical trial provided evidence that supplementation with folic acid and related B-vitamins over a 2-year-period reduced global and regional brain atrophy, as measured by MRI scan in older adults. In terms of potential mechanisms, the effects of these B-vitamins on cognitive health may be independent or may be mediated by nutrient–nutrient and/or relevant gene–nutrient interactions. Furthermore, a new area of research suggests that the in utero environment influences health in later life. Folate, an important cofactor in C1 metabolism, is indirectly involved in DNA methylation, which in turn is considered to be one of the epigenetic mechanisms that may underlie fetal programming and brain development. The present review will explore the evidence that supports a role for folate and the related B-vitamins in brain health across the lifecycle, and potential mechanisms to explain such effects.

Brain development is subject to complex lifelong processes of interactions between genetic and environmental factors. Although many environmental factors contribute to brain development, nutrition is of particular importance through the role that nutrients play in specific metabolic pathways and structural components( 1 ). It is known, for example, that a dietary deficiency during critical periods of development can result in permanent changes to the brain( 2 ). Of particular importance are folate and the related B-vitamins that are involved in C1 metabolism and in the production of S-adenosylmethionine (SAM), a universal methyl donor required for various reactions, including the production of neurotransmitters( 3 ). 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 lifecycle( 4 ).

This review will explore the evidence linking maternal folate status with neurocognitive development in the offspring and will consider the associated explanatory mechanisms. In addition, the roles of B-vitamins and relevant genetic interactions in relation to cognitive health in older adults will also be examined.

The role of folate and related B-vitamins in C1 metabolism

Folate, a substrate of various enzyme reactions, along with vitamins B12, B6 and riboflavin in their co-factor forms, are involved in C1 metabolism, which comprises a network of interrelated biochemical pathways that donate and regenerate C1 units, including methyl groups (Fig. 1). Within the folate cycle tetrahydrofolate acquires a carbon unit from serine in a vitamin B6-dependent reaction, which subsequently forms 5, 10-methylenetetrahydrofolate. The latter is involved in the synthesis of thymidine, which in turn is incorporated into DNA or it is converted to 5-methyltetrahydrofolate which participates in a riboflavin (i.e. FAD)-dependent reaction, catalysed by the enzyme methylenetetrahydrofolate reductase (MTHFR). 5-Methyltetrahydrofolate then serves as single carbon donor, feeding into the C1 pathway by donating its methyl group to homocysteine to form methionine, via the vitamin B12-dependent enzyme methionine synthase. Methionine is a precursor for the synthesis of SAM, a methyl donor required for the methylation of DNA, proteins, chromosomes and phospholipids, production of myelin and the synthesis and activation of neurotransmitters, including catecholamine and serotonin( 5 ). Upon donating its methyl group, SAM is converted to S-adenosylhomocysteine and homocysteine, which can be further metabolised in the transsulphuration pathway to form cysteine, a B6-dependent process, or remethylated back to methionine.

Fig. 1. (colour online) C1 metabolism. PLP, pyridoxal 5 phosphate; MTHFR, methylenetetrahydrofolate reductase; DMG, dimethylglycine; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate. (Adapted from Clarke et al.( 85 ))

It is important to note that some genetic factors may affect the function of enzyme activity, leading to disturbances in B-vitamin absorption, transport and uptake. Of particular interest is the common 677C→T polymorphism in the gene coding for MTHFR, and this polymorphism is an important genetic determinant of plasma homocysteine. Individuals with the homozygous mutant MTHFR 677TT genotype have reduced MTHFR enzyme activity. Homozygosity for this polymorphism alters B-vitamin requirements and has been linked to a number of degenerative diseases, including cognitive dysfunction( 6 ).

C1 metabolism, B-vitamins and early brain health

The role of folate in fetal brain development

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( 7 ). 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 for the expansion of maternal blood volume( 8 ). 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 μg folic acid/d from preconception until the end of the first trimester of pregnancy( 11 , 12 ). 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 d post-conception); however, little is known as to whether continuing folic acid usage throughout pregnancy confers any long-term beneficial effects to the offspring.

There is a growing body of evidence from observational and experimental studies, suggesting that nutrition in utero 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 via their participation in transcription, nucleotide synthesis, neurotransmitter production and methylation processes, including DNA methylation( 13 ).

Evidence linking maternal folate status with offspring cognitive performance

In recent years, the association between maternal folate and/or related B-vitamin status with later cognitive performance of the offspring has become a topic of interest. To date most of the literature in this area is derived from observational (Table 1) and animal studies. Given the recognised protection of folic acid in the prevention of neural tube defect during early fetal development, the majority of these studies reported peri-conceptional use of folic acid by women and are focused in the early stages pregnancy. Only a few studies have investigated maternal folate status in the second and third trimesters of pregnancy, i.e. after the recommended period, in relation to later cognitive performance of the child, and no available human evidence has addressed this question in a randomised trial in pregnancy.

Table 1. Observational studies investigating the association between maternal folate status with cognitive performance of the offspring

FA, folic acid; GW, gestational week; PPVT, Peabody Picture Vocabulary Test; WRAVMA, Wide Range Assessment of Visual Motor Abilities; DDST, Denver Development Screening Test; MSCA, McCarthy Scales of Children's Abilities; KABCTM -II, Kaufman Assessment Battery, 2nd edition; Bayley-III, Bayley Scales of Infant and Toddler Development, 3rd edition.

A number of human studies have shown positive associations between self-reported folic acid supplement use during the first trimester of pregnancy and cognitive performance of the child( 15 , 17 19 ). Julvez et al. ( 15 ) demonstrated that folic acid use in pregnancy was associated with improved neurodevelopment, verbal performance and motor development in children aged 4 years. Similarly, a large longitudinal study (n 1210) examined the association between maternal intake of methyl donor nutrients, including folate and vitamin B12, during the first trimester of pregnancy in relation to the cognitive performance of the offspring. The authors estimated that each 600 μg/d increment in total folate intake (from food and supplements combined) was associated with a 1·6 point higher score in cognitive performance in the child, assessed at age 3 years( 19 ). Likewise, another observational study indicated significantly higher verbal comprehension, vocabulary development and communication skills in Greek children born to mothers taking high dose folic acid (5 mg/d) in pregnancy, compared with those whose mothers did not take supplements( 18 ). Most notably, evidence from a large prospective study (n 38 954) in the US-linked maternal folic acid supplement use from 4 to 8 weeks after conception with a reduced risk of severe language delay evaluated by self-reported parental questionnaires assessing the grammar of the child, at age 3 years( 17 ).

During the growth spurt in pregnancy (about 24–42 gestational weeks), the developing brain, owing to the sequence of developmental stages, including neuronal proliferation and myelination, is particularly vulnerable to adequate nutrition( 20 ). Throughout the late fetal and early postnatal periods areas such as the hippocampus, auditory and visual cortices and the striatum undergo rapid growth by morphogenesis and synaptogenesis which makes them functionally active( 21 ). All nutrients are important for brain development, but it is proposed that certain nutrients, including folate, have greater effects during the late fetal development. Only a few studies, however, have investigated the impact of maternal folate status in the later stages of pregnancy on the child's neurodevelopment. Nearly 40 years ago, Gross et al. ( 14 ) reported that children born to mothers with diagnosed megaloblastic anaemia during the third trimester of pregnancy had abnormal neurodevelopment and lower intellectual abilities compared with infants born to mothers with optimal folate status. Several decades later a study investigating the impact of maternal blood folate, B12 and homocysteine concentrations, at 30 gestational weeks, in relation to cognitive performance of 9–10-year-old children (n 536), showed that higher maternal folate status during late pregnancy predicted better cognitive performance in children( 16 ). No association was observed for maternal B12 or homocysteine status on the overall cognitive ability of the children( 16 ).

To date no randomised controlled trial (RCT) has investigated the effect of maternal folate status during the later stages of pregnancy and subsequent cognitive performance of the offspring. A pilot study (n 39), conducted by our group, examined the effect of folic acid supplementation in the second and third trimester of pregnancy and subsequent cognitive performance of the child. The novel results showed that children (aged 3 years) born to mothers supplemented with folic acid, scored significantly higher in the cognitive domain of the Bayley's development assessment( 22 ). These highly promising results from this RCT now need to be confirmed on a larger scale.

Mechanistic studies in animal models also provide evidence that prenatal folate deficiency may be causally related to adverse structural changes in the brain( 23 , 24 ). Craciunescu et al. ( 24 ) reported that the offspring of rats fed a folic acid deficient diet during days 11 and 17 of gestation (i.e. corresponding to mid- and late stages of human pregnancy), had a reduction in progenitor cells in the fetal neocortex (an area responsible for complex behaviours, including cognition) suggesting that the developing fetal brain is vulnerable to maternal folate deficiency, which may adversely affect cognitive performance in the later life( 24 ). Similarly, another study showed that gestational B-vitamin deficiency resulted in an accumulation of homocysteine with ‘concomitant apoptosis’ in selective brain areas, the cerebellum, striatum and hippocampus, which altered motor function and learning and memory abilities in rats( 25 ).

Evidence regarding the impact of maternal folate status on the offspring neurodevelopment is further strengthened by genetic studies. The common 677C→T polymorphism in the gene coding for the folate metabolising enzyme MTHFR is an important genetic determinant of plasma homocysteine and individuals homozygous for the polymorphism (MTHFR 677TT genotype), are prone to low folate status and elevated plasma homocysteine concentrations. Recent studies from Mexico, where the frequency of the MTHFR 677TT genotype is reported to be the highest in the world( 26 ), showed that the maternal MTHFR 677TT genotype is a predictor of poor child neurodevelopment( 27 ) especially in combination with low maternal folate intake (<400 μg/d) during the first trimester of pregnancy( 28 ). However, research in this area is limited and further studies are required to investigate whether children born to mothers genetically susceptible to impaired folate status are more at risk of impaired neurodevelopment.

Not all studies support the association between maternal folate status and the neurodevelopment of the child. A Hungarian RCT investigating pregnant women consuming a multi-vitamin containing folic acid (0·8 mg/d) before conception until the second month of pregnancy did not find any evidence of improved ‘mental development’ of children aged 6 years( 29 ). The present study, however, was primarily designed to investigate the effect of folic acid on neural tube defects during the very early stages of pregnancy. Likewise a longitudinal study found no evidence of an association between maternal blood folate status (low ≤11 nmol v. normal >11 nmol/l) in the later stages of pregnancy (19, 26 and 37 gestational weeks) and cognitive performance of children aged 5 years( 30 ). Possible reasons to explain these inconsistencies may include the influence of socio-economic status, a well-known confounder for cognitive development and which could potentially confound any effect of folic acid( 30 ). Furthermore, the studies by Dobo & Czeiel( 29 ) and Tamura et al. ( 30 ) used a multi-vitamin approach, rather than folic acid alone; an approach, which again could impact the findings.

Overall, the observational and animal evidence appears to be supportive for a role of maternal folate status in later cognitive performance of the child. Aside from cognitive health, there are also studies linking low maternal folate status with higher offspring behavioural( 31 ), inattention and hyperactivity problems( 32 ) and emotional problems( 33 ), which warrant further investigation. It is important to note however that much of the observational evidence is based on self-reported folic acid usage, usually during the early fetal development stages( 15 , 17 19 ), with only a few studies exploring the effect of supplementation during later stages of pregnancy( 14 , 16 ) and none doing so using a RCT. 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 required to more fully investigate the potential effect of folate throughout pregnancy and to determine if the effect is specific to certain stages of pregnancy or perhaps the effect is mediated throughout all trimesters of pregnancy.

Other evidence supporting folate status in relation to brain health in the young

The effect of dietary and blood folate status on cognitive performance has also been investigated in young children and adolescents. A recent study by Strand et al. ( 34 ) reported that low plasma folate and vitamin B12 concentrations were associated with poorer cognitive performance, measured in children aged 12–18 months. Furthermore, an investigation of Swedish adolescents (age 15 years) showed that higher dietary folate intakes was positively associated with academic achievements( 35 ). Nguyen et al. ( 36 ) also reported that higher serum folate measured in children aged 6–16 years was associated with higher performance in reading and also in block design in participants from the National Health and Nutrition Examination Survey III cohort in the USA.

C1 metabolism, B-vitamins and brain health in ageing

Cognitive dysfunction and dementia

Cognitive dysfunction is a common problem among the ageing population and ranges in severity from mild cognitive impairment to more progressive types of dementia; the latter referring to a state in which the disease is sufficient to impair normal way of living( 37 , 38 ). Although some degree of cognitive decline is considered a normal and an unpreventable aspect of ageing, the development of dementia and Alzheimer's disease is attributable to diseases of the brain, resulting in changes to the brain structure sufficient to interfere with normal life activities. Globally an estimated 35·6 million people suffer from dementia, affecting 7 % of individuals aged over 65 years and 30 % of those over 80 years( 39 ). Given the increase in life expectancy, these figures are expected to double worldwide by 2025( 39 ) and represents a major public health challenge for future generations.

As brain changes start to progress long before the diagnosis of dementia is overt, it is important to find early biomarkers that would enable timely interventions to delay the onset or slow the progression of the disease( 40 ). Well-established non-modifiable risk factors include increasing age, family history and genetic factors. However, evidence has now amassed from long-term epidemiological studies linking potentially modifiable lifestyle factors, including smoking status, physical inactivity and nutritional factors with cognitive dysfunction. 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.

Evidence linking B-vitamins with brain health in ageing

The majority of epidemiological studies generally support an association between suboptimal status of folate, the metabolically related B-vitamins or elevated concentrations of the metabolite homocysteine with cognitive dysfunction in older adults. Indeed, a review by Smith ( 41 ) some years ago reported that 90 out of 100 published cross-sectional and prospective studies showed a link between elevated homocysteine and/or low B-vitamins concentrations with cognitive dysfunction. Most of these studies have focused on elevated plasma homocysteine concentrations( 42 46 ), and/or a combination of suboptimal status of folate and vitamin B12 ( 47 54 ) and to a much lesser extent on vitamin B6 ( 55 , 56 ). To the authors’ knowledge, no published study thus far has focused on riboflavin alone as a potential contributor to cognitive health. Notably, there are a number of limitations associated with these studies; typically, only one cognitive assessment tool was used, rather than a battery of tests providing information for multiple cognitive domains; depression and anxiety (known confounders) are not measured and there is a lack of data on vitamin supplement usage, all of which can limit the reliability of reported results.

It is also important to take into consideration recent concerns regarding mandatory folic acid fortification and the potential ‘masking’ effect of vitamin B12 deficiency among older adults. In B12 deficiency, the activity of methionine synthase is reduced; therefore 5, methyltetrahydrofolate cannot be converted to tetrahydrofolate (the active form of folate) and becomes trapped in an unusable form. Evidence from the National Health and Nutrition Examination Survey reported that although higher folate was generally associated with better cognitive health, a combination of high plasma folate (>59 nmol/l) with low plasma B12 (<148 pmol) and elevated methylmalonic acid (a B12-specific functional biomarker), was actually associated with poorer cognitive performance compared with individuals with normal concentrations of these biomarkers( 57 ). Furthermore, Moore et al. ( 58 ) showed participants with high red cell folate and low serum B12 were three times more likely to have impaired cognitive performance. In contrast, however, analysis from the Hordaland Health study failed to confirm this association in their analysis( 59 ). The disagreement between studies is possibly linked to the relatively small sample of participants with the combination of high folate and low B12 status available for analysis in these studies. In addition, high and low status of folate and B12 is defined differently among various published studies.

Following the positive associations from epidemiological evidence a number of RCT have investigated the potential benefits of B-vitamin supplementation on cognitive health (Table 2). Many of these trials however were of insufficient power and duration to detect an effect or included participants with existing optimal B-vitamin status or with advanced dementia, where a beneficial effect is not likely( 60 , 62 , 67 70 ).

Table 2. Summary of randomised trials assessing the effect of B-vitamin treatment on cognitive function in older adults

FA, folic acid; hcy, homocysteine; AD, Alzheimer's disease; MCI, mild cognitive impairment.

Notably, two similarly designed homocysteine-lowering trials have yielded conflicting results. The Folic Acid and Carotid Intimamedia Thickness (FACIT) trial found that supplementation with 800 μg folic acid/d over 3 years in healthy adults’ (n 818) improved global cognitive function, in particular memory, information processing speed and sensorimotor speed( 61 ). In contrast, a 2-year trial also conducted in healthy individuals (n 276) supplemented with a combination of folate (1000 μg/d), B12 (500 μg/d) and B6 (10 mg/d) or placebo, reported no significant effect on cognitive performance, across the eight cognitive assessments used( 60 ). Although these studies were of similar design, sufficiently powered, had comparable baseline cognitive scores and used similar exclusion criteria, it is important to note the difference in the baseline folate status of participants between these two trials. The baseline folate (12 nmol/l) was lower in the FACIT trial compared with the McMahon study (baseline folate 22·6 nmol/l), which may suggest that any benefits of folic acid on cognitive health in ageing may arise from correcting suboptimal folate status, whereas supplementing with additional folic acid to those with optimal status may not provide any further benefit to cognitive function. More recently, a significant improvement in overall cognitive performance was found following a 2-year intervention with B-vitamins in participants with elevated psychological distress( 64 ). 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 interventions.

The strongest evidence to date originates from the VITACOG trial in Oxford, in which patients with mild cognitive impairment (without dementia) were supplemented with folic acid (800 μg/d), B12 (500 μg/d) and B6 (20 mg/d) or placebo over a 2-year period. The results reported that supplementation with B-vitamins slowed the rate of cognitive decline, assessed by questionnaire-based cognitive tests( 63 ). 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 %( 65 ). The effect was greatest in participants with the highest baseline homocysteine concentrations (>13 μmol/l), among whom an overall reduction of brain atrophy rate of 53 % was reported, while no effect was found in those in the bottom quartile (≤9·5 μmol/l)( 65 ). Moreover, when a subsample of VITACOG cohort were further analysed, the investigators reported that B-vitamin treatment reduced the cerebral atrophy, by as much as 7-fold, specifically in grey matter areas of the brain vulnerable to Alzheimer's disease, including bilateral hippocampus and cerebellum( 66 ). Finally, when participants were analysed by quartiles for brain shrinkage, it was reported that participants with the highest rate of brain shrinkage displayed the most cognitive decline( 71 ). Importantly, folate, vitamin B12 and vitamin B6 are all required to lower concentrations of homocysteine and perhaps it is the combination of B-vitamins, and not a monotherapy B-vitamin approach, which is required to optimise C1 metabolism. This research has paved the way for future RCT in this area; more research is however warranted in both healthy and cognitively impaired groups to investigate the proposed effect further.

In summary, results from large observational studies conducted in healthy and cognitively impaired cohorts provide strong evidence of a possible relationship between suboptimal B-vitamin status, elevated homocysteine (independently or as a marker of B-vitamin status) and cognitive dysfunction. At present the most promising evidence supporting a cause and effect relationship comes from the VITACOG trial( 63 , 65 , 66 , 71 ). These findings now require replication in other population groups to confirm the role played by B-vitamins in cognitive health. If cognitive dysfunction can in fact be slowed or prevented by B-vitamins, in healthy older people, then this could offer a cost-effective preventative public health strategy in ageing populations.

Potential mechanisms linking B-vitamins with brain health

Potential mechanism explaining the role of B-vitamins in early brain development

B-vitamins appear to have direct roles on brain development and maintenance, through their involvement in C1 metabolism. A new emerging area of research concerns the role of epigenetics, which is broadly defined as the ‘heritable changes in gene function that cannot be explained by changes in the DNA sequence’( 72 ). Epigenetic alternations in utero may have the potential to programme diseases in adulthood. Studies have recently begun to investigate whether epigenetic modification, through nutritional interventions, can influence an individual's health in later life. DNA methylation is the most widely studied epigenetic mechanism and occurs through C1 metabolism, which is dependent on folate and several cofactors, including the related B-vitamins.

A number of animal studies have addressed the issue of maternal folate status and subsequent epigenetic effect on the offspring. Waterland & Jirlte( 73 ) demonstrated that in pregnant agouti mice a high methyl diet, resulted in offspring with mottled brown coats, which were less obesogenic and less prone to diseases. Interestingly, methyl donor supplementation of agouti pregnant dams appeared to not only affect the fetus, but also the subsequent generation, suggesting that the maternal diet may influence several generations( 74 ). Recently, Cho et al. ( 75 ) also provided evidence of the epigenetic effects of folate supplementation in pregnancy and showed that a high folate diet throughout pregnancy and weaning resulted in dams less exposed to an obseogenic phenotype. Collectively, these studies show that restriction in folate can influence DNA methylation in the offspring and in turn influence gene expression and disease related phenotypes.

The results from human studies, although limited, are also generally supportive of the effect of folate on epigenetic processes. Evidence from the Dutch Hunger Winter study has shown that malnutrition (in this case because of extreme famine) during pregnancy may induce permanent epigenetic changes in IGF2 ( 76 , 77 ). Recent studies suggest that IGF2 epigenetic changes in utero are associated with long-term metabolic health risk in human subjects( 77 ). The results from Steegers-Theunissen et al.( 78 ) showed that reported maternal folic acid supplement usage was associated with an increased methylation (4·5 %) of IGF2 differentially methylated region of the offspring, 17 months after delivery. Moreover, maternal SAM concentrations were related to the offspring IGF2 differentially methylated region's methylation levels, indicating that the maternal environment had a greater influence on the methylation of IGF2 in the offspring( 78 ). In further support, results from an observational study (n 913) investigating the effect of folic acid use after the recommended 12 gestational weeks, reported that supplement use was associated with significant, albeit small, elevation in IGF2 methylation and reduced methylation in paternally expressed 3 (PEG3) and LINE-1( 79 ). No effect was observed before 12 weeks gestation; perhaps suggesting an epigenetic effect of folate occurred during the later stages of pregnancy. Considering that IGF2 is involved in placental and fetal development and PEG3 is a gene highly expressed in the brain and also involved in the development of the fetal hypothalamus( 80 , 81 ), alterations in the methylation of these genes may subsequently exert influence on their expression, which in turn might have an impact on the offspring's brain development. However, further studies are required to expand on the current knowledge of nutrition and disease prevention through epigenetic mechanisms.

Potential mechanism explaining the role of B-vitamins with brain health in ageing

Mechanisms linking B-vitamins and cognitive health in ageing are speculative and several hypotheses have been suggested. Folate and vitamin B12 are required for the production of SAM, which in turn is required for various methylation reactions and adequate production of neurotransmitters. Deficiencies in these vitamins may lead to disturbances in important methylation reactions, which may affect pathways associated with cognitive health. It is also proposed that deficiencies in folate, vitamins B12 and B6 can disrupt the remethylation of homocysteine to methionine, resulting in hyperhomocysteinemia. Studies have linked elevated plasma homocysteine concentrations with atrophy of the hippocampus; an area of the brain required for memory consolidation( 82 ). It is therefore suggested that high homocysteine concentrations may have direct neurotoxic effects, resulting in apoptosis and possibly impairing pathways associated with cognition( 64 , 83 ). In addition, optimal B6 status plays an important role in brain health through its essential role in transamination and decarboxylation reactions required for the metabolism of several neurotransmitters, including serotonin, γ-aminobutyric acid, dopamine, noradrenaline and histamine( 84 ).

Conclusion

Given the importance of C1 metabolism in a wide array of processes, including the production of neurotransmitters and DNA methylation, it is not surprising that disturbances in this cycle may have profound effects on both the developing and ageing brain. Mechanistically it is clear that folate and the related B-vitamins are critical for brain function throughout the lifecycle. Some important questions, however, still need to be considered. The potential role between maternal folate status during pregnancy and later neurodevelopment of the offspring needs to be explored through well-designed RCT. A clearer understanding of the role of folate in early brain health will help to inform future policies in relation to folic acid recommendations in pregnancy. Compelling evidence from epidemiological studies and RCT show that there is a strong association between suboptimal B-vitamin status and/or elevated homocysteine with an increased risk of cognitive dysfunction in older adults. Further research from well-conducted RCT which includes brain-imaging techniques is warranted to shed light on some fundamental questions. In conclusion, current evidence suggests that folate and the metabolically related B-vitamins may be important contributors to brain health across the lifecycle. Improving knowledge of potential epigenetic mechanisms during pregnancy and postnatal life will help provide the important mechanistic links between B-vitamins and brain health.

Financial Support

This work was supported by the funding from the Northern Ireland Department for Employment and Learning which funded the PhD studentship for C. M. G. The Northern Ireland Department for Employment and Learning had no role in the design, analysis or writing of this article.

Conflict of Interest

None.

Authorship

C. M. G. drafted the manuscript. K. P., H. McN. and J. J. S. critically revised the manuscript for important intellectual content. All authors have read and approved the final manuscript.

References

1. Georgieff, MK (2007) Nutrition and the developing brain: nutrient priorities and measurement. Am J Clin Nutr 85, 614S620S.
2. Anjos, T, Altmäe, S, Emmett, P et al. (2013) Nutrition and neurodevelopment in children: focus on NUTRIMENTHE project. Eur J Nutr 52, 18251842.
3. Dominguez-Salas, P, Cox, SE, Prentice, AM et al. (2012) Maternal nutritional status, C1 metabolism and offspring DNA methylation: a review of current evidence in human subjects. Proc Nutr Soc 71, 154165.
4. van de Rest, O, van Hooijdonk, LWA, Doets, E et al. (2012) B Vitamins and n-3 fatty acids for brain development and function: review of human studies. Ann Nutr Metab 60, 272292.
5. Schaevitz, L, Berger-Sweeney, J & Ricceri, L (2014) One-carbon metabolism in neurodevelopmental disorders: using broad-based nutraceutics to treat cognitive deficits in complex spectrum disorders. Neurosci. Biobehav Rev (Epublication ahead of print version)
6. Ford, AH, Flicker, L, Hankey, GJ et al. (2012) Homocysteine, methylenetetrahydrofolate reductase C677T polymorphism and cognitive impairment: the health in men study. Mol Psychiatry 17, 559566.
7. McNulty, B, Pentieva, K, Marshall, B et al. (2011) Women's compliance with current folic acid recommendations and achievement of optimal status for preventing neural tube defects. Hum Reprod 26, 15301536.
8. McNulty, H, McPartlin, JM, Weir, DG et al. (1993) Folate catabolism is increased during pregnancy in rats. J Nutr 123, 10891093.
9. Czeizel, AE & Dudás, I (1992) Prevention of the first occurrence of neural-tube defects by periconceptional vitamin supplementation. N Engl J Med 327, 18321835.
10. MRC Vitamin Study Research Group (1991) Prevention of neural tube defects: results of the Medical Research Council Vitamin Study. Lancet 338, 131137.
11. Centers for Disease Control Prevention (1992) Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. Morb Mortal Wkly Rep 41, 18.
12. Department of Health (1992) Folic acid and the prevention of neural tube defects. Report from an expert advisory group No.1. London: Department of Health.
13. Reynolds, E (2006) Vitamin B12, folic acid, and the nervous system. Lancet Neurol 5, 949960.
14. Gross, RL, Newberne, PM & Reid, JVO (1974) Adverse effects on infant development associated with maternal folic acid deficiency. Nutr Rep Intern 10, 241248.
15. Julvez, J, Fortuny, J, Mendez, M et al. (2009) Maternal use of folic acid supplements during pregnancy and four-year-old neurodevelopment in a population-based birth cohort. Paediatr Perinat Epidemiol 23, 199206.
16. Veena, SR, Krishnaveni, GV, Srinivasan, K et al. (2010) Higher maternal plasma folate but not Vitamin B-12 concentrations during pregnancy are associated with better cognitive function scores in 9- to 10-year-old children in South India. J Nutr 140, 10141022.
17. Roth, C, Magnus, P, Schjølberg, S et al. (2011) Folic acid supplements in pregnancy and severe language delay in children. J Am Med Assoc 306, 15661573.
18. Chatzi, L, Papadopoulou, E, Koutra, K et al. (2012) Effect of high doses of folic acid supplementation in early pregnancy on child neurodevelopment at 18 months of age: the mother-child cohort ‘Rhea’ study in Crete, Greece. Public Health Nutr 15, 17281736.
19. Villamor, E, Rifas-Shiman, SL, Gillman, MW et al. (2012) Maternal intake of methyl-donor nutrients and child cognition at 3 years of age. Paediatr Perinat Epidemiol 26, 328335.
20. Isaacs, EB (2013) Neuroimaging, a new tool for investigating the effects of early diet on cognitive and brain development. Front Hum Neurosci 7, 445.
21. Thompson, RA & Nelson, CA (2001) Developmental science and the media. Early brain development. Am Psychol 56, 515.
22. Pentieva, K, McGarel, C, McNulty, B et al. (2012) Effect of folic acid supplementation during pregnancy on growth and cognitive development of the offspring: a pilot follow-up investigation of children of FASSTT study participants. Proc Nutr Soc 71, E139.
23. Whitley, JR, O'Dell, BL & Hogan, AG (1951) Effect of diet in maze learning in second generation rats; folic acid deficiency. J Nutr 45, 153160.
24. Craciunescu, CN, Brown, EC, Mar, MH et al. (2004) Folic acid deficiency during late gestation decreases progenitor cell proliferation and increases apoptosis in fetal mouse brain. J Nutr 134, 162166.
25. Blaise, SA, Nédélec, E, Schroeder, H et al. (2007) Gestational Vitamin B deficiency leads to homocysteine-associated brain apoptosis and alters neurobehavioral development in rats. Am J Pathol 170, 667679.
26. Wilcken, B, Bamforth, F, Li, Z et al. (2003) Geographical and ethnic variation of the 677C>T allele of 5, 10 methylenetetrahydrofolate reductase (MTHFR): findings from over 7000 newborns from 16 areas worldwide. J Med Genet 40, 619625.
27. Pilsner, JR, Hu, H, Wright, RO et al. (2010) Maternal MTHFR genotype and haplotype predict deficits in early cognitive development in a lead-exposed birth cohort in Mexico City. Am J Clin Nutr 92, 226234.
28. del Río Garcia, C, Torres- Sanchez, L, Chen, J et al. (2009) Maternal MTHFR 677C>T genotype and dietary intake of folate and vitamin B(12): their impact on child neurodevelopment. Nutr Neurosci 12, 1320.
29. Dobó, M & Czeizel, AE (1998) Long-term somatic and mental development of children after periconceptional multivitamin supplementation. Eur J Pediatr 157, 719723.
30. Tamura, T, Goldenberg, RL, Chapman, VR et al. (2005) Folate status of mothers during pregnancy and mental and psychomotor development of their children at five years of age. Pediatrics 116, 703708.
31. Roza, SJ, van Batenburg-Eddes, T, Steegers, EAP et al. (2010) Maternal folic acid supplement use in early pregnancy and child behavioural problems: the Generation R Study. Br J Nutr 103, 445452.
32. Schlotz, W, Jones, A, Phillips, DIW et al. (2010) Lower maternal folate status in early pregnancy is associated with childhood hyperactivity and peer problems in offspring. J Child Psychol Psychiatry 51, 594602.
33. Steenweg-de Graaff, J, Roza, SJ, Steegers, EAP et al. (2012) Maternal folate status in early pregnancy and child emotional and behavioral problems: the Generation R Study. Am J Clin Nutr 95, 14131421.
34. Strand, TA, Taneja, S, Ueland, PM et al. (2013) Cobalamin and folate status predicts mental development scores in North Indian children 12–18 mo of age. Am J Clin Nutr 97, 310317.
35. Nilsson, TK, Yngve, A, Bottiger, AK et al. (2011) High folate intake is related to better academic achievement in Swedish adolescents. Pediatrics 128, E358E365.
36. Nguyen, CT, Gracely, EJ & Lee, BK (2013) Serum folate but not Vitamin B-12 concentrations are positively associated with cognitive test scores in children aged 6–16 years. J Nutr 143, 500504.
37. Graham, JE, Rockwood, K, Beattie, BL et al. (1997) Prevalence and severity of cognitive impairment with and without dementia in an elderly population. Lancet 349, 17931796.
38. McNulty, H & Scott, JM (2008) Intake and status of folate and related B-vitamins: considerations and challenges in achieving optimal status. Br J Nutr 99, S48S54.
39. Alzheimer's Society UK (2013) Statistics; available at https://www.alzheimers.org.uk/statistics
40. Kivipelto, M, Ngandu, T, Laatikainen, et al. (2006) Risk score for the predicition of dementia risk in 20 years among middle-aged people: a longitudinal, population-based study. Lancet Neurol 5, 735741.
41. Smith, AD (2008) The worldwide challenge of the dementias: a role for B vitamins and homocysteine? Food Nutr Bull 29, 2 Suppl, S143S172.
42. Ravaglia, G, Forti, P, Maioli, F et al. (2003) Homocysteine and cognitive function in healthy elderly community dwellers in Italy. Am J Clin Nutr 77, 668673.
43. Ford, AH, Flicker, L, Singh, U et al. (2013) Homocysteine, depression and cognitive function in older adults. J Affect Disord 151, 646651.
44. Allam, M, Fahmy, E, Elatti, SA et al. (2013) Associations between total plasma homocysteine level and cognitive functions in elderly Egyptian subjects. J Neurol Sci 322, 8691.
45. Seshadri, S, Beiser, A, Selhub, J et al. (2002) Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med 346, 476483.
46. Miller, JW, Green, R, Ramos, MI et al. (2003) Homocysteine and cognitive function in the Sacramento Area Latino Study on Ageing. Am J Clin Nutr 78, 441447.
47. Ramos, MI, Allen, LH, Mungas, DM et al. (2005) Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr 82, 13461352.
48. Campbell, AK, Jagust, WJ, Mungas, DM et al. (2005) Low erythrocyte folate, but not plasma B-12 or homocysteine, is associated with dementia in elderly Latinos. J Nutr Health Aging 9, 3943.
49. de Lau, LML, Refsum, H, Smith, AD et al. (2007) Plasma folate concentration and cognitive performance: Rotterdam Scan Study. Am J Clin Nutr 86, 728734.
50. Duthie, SJ, Whalley, LJ, Collins, AR et al. (2002) Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr 75, 908913.
51. Kado, DM, Karlamangla, AS, Huang, MH et al. (2005) Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of successful aging. Am J Med 118, 161167.
52. Nurk, E, Refsum, H, Tell, Gs et al. (2005) Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study. Ann Neurol 58, 847857.
53. Haan, MN, Miller, JW, Aiello, AE et al. (2007) Homocysteine, B vitamins, and the incidence of dementia and cognitive impairment: results from the Sacramento Area Latino Study on Aging. Am J Clin Nutr 85, 511517.
54. Hooshmand, B, Solomon, A, Kåreholt, I et al. (2012) Associations between serum homocysteine, holotranscobalamin, folate and cognition in the elderly: a longitudinal study. J Intern Med 271, 204212.
55. Riggs, KM, Spiro, A III, Tucker, K et al. (1996) Relations of vitamin B-12, vitamin B-6, folate, and homocysteine to cognitive performance in the Normative Aging Study. Am J Clin Nutr 63, 306314.
56. Moorthy, D, Peter, I, Scott, TM et al. (2012) Status of Vitamins B-12 and B-6 but not of folate, homocysteine, and the methylenetetrahydrofolate reductase C677T polymorphism are associated with impaired cognition and depression in adults. J Nutr 142, 15541560.
57. Morris, MS, Jacques, PF, Rosenberg, IH et al. (2007) Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortification. Am J Clin Nutr 85, 193200.
58. Moore, EM, Ames, D, Mander, AG et al. (2014) Among vitamin B12 deficient older people, high folate levels are associated with worse cognitive function: combined data from three cohorts. J Alzheimers Dis 39, 661668.
59. Doets, EL, Ueland, PM, Tell, GS et al. (2014) Interactions between plasma concentrations of folate and markers of vitamin B12 status with cognitive performance in elderly people not exposed to folic acid fortification: the Hordaland Health Study. Br J Nutr 111, 10851095.
60. McMahon, JA, Green, TJ, Skeaff, CM et al. (2006) A controlled trial of homocysteine lowering and cognitive performance. N Engl J Med 354, 27642772.
61. Durga, J, van Boxtel, MPJ, Schouten, EG et al. (2007) Effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomised, double blind, controlled trial. Lancet 369, 208216.
62. Aisen, PS, Schneider, LS, Sano, M et al. (2008) High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. J Am Med Assoc 300, 17741783.
63. de Jager, CA, Oulhaj, A, Jacoby, R et al. (2012) Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: a randomized controlled trial. Int J Geriatr Psychiatry 27, 592600.
64. Walker, JG, Batterham, PJ, Mackinnon, AJ et al. (2012) Oral folic acid and vitamin B-12 supplementation to prevent cognitive decline in community-dwelling older adults with depressive symptoms-the Beyond Ageing Project: a randomized controlled trial. Am J Clin Nutr 95, 194203.
65. Smith, AD, Smith, SM, de Jager, CA et al. (2010) Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial. PLoS ONE 5, e12244.
66. Douaud, G, Refsum, H, de Jager, CA et al. (2013) Preventing Alzheimer's disease-related gray matter atrophy by B-vitamin treatment. Proc Natl Acad Sci USA 110, 95239528.
67. Lewerin, C, Matousek, M, Steen, G et al. (2005) Significant correlations of plasma homocysteine and serum methylmalonic acid with movement and cognitive performance in elderly subjects but no improvement from short-term vitamin therapy: a placebo-controlled randomized study. Am J Clin Nutr 81, 11551162.
68. Pathansali, R, Mangoni, AA, Creagh-Brown, B et al. (2006) Effects of folic acid supplementation on psychomotor performance and hemorheology in healthy elderly subjects. Arch Gerontol Geriatr 43, 127137.
69. Eussen, SJ, de Groot, LC, Joosten, LW et al. (2006) Effect of oral vitamin B12 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 84, 361370.
70. Kwok, T, Lee, J, Law, CB et al. (2011) A randomized placebo controlled trial of homocysteine lowering to reduce cognitive decline in older demented people. Clin Nutr 30, 297302.
71. de Jager, CA (2014) Critical levels of brain atrophy associated with homocysteine and cognitive decline. Neurobiol Aging 35, Suppl. 2, S35S39.
72. Russo, VEA, Martienssen, RA & Riggs, AD (1996) Epigenetic Mechanisms of Gene Regulation. Cold Springs Harbor, New York: Cold Springs Harbor Laboratory Press.
73. Waterland, RA & Jirtle, RL (2003) Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol 23, 52935300.
74. Cropley, JE, Suter, CM, Beckman, KB et al. (2006) Germ-line epigenetic modifications of the murine Avy allele by nutritional supplementation. Proc Natl Acad Sci USA 103, 1730817312.
75. Cho, CE, Sánchez-Hernández, D, Reza-López, SA et al. (2013) High folate gestational and post-weaning diets alter hypothalamic feeding pathways by DNA methylation in Wistar rat offspring. Epigenetics 8, 710719.
76. Roseboom, TJ, Painter, RC, van Abeelen, AFM et al. (2011) Hungry in the womb: what are the consequences? Lessons from the Dutch famine. Maturitas 70, 141145.
77. Heijmans, BT, Tobi, EW, Stein, AD et al. (2008) Persistent epigenetic differences associated with prenatal exposure to famine in humans. Proc Natl Acad Sci USA 105, 1704617049.
78. Steegers-Theunissen, RP, Obermann-Borst, SA, Kremer, D et al. (2009) Periconceptional maternal folic acid use of 400 μg per day is related to increased methylation of the IGF2 gene in the very young child. PLoS ONE 4, 15.
79. Haggarty, P, Hoad, G, Campbell, DM et al. (2013) Folate in pregnancy and imprinted gene and repeat element methylation in the offspring. Am J Clin Nutr 97, 9499.
80. Ivanoca, E & Kelsey, G (2011) Imprinted genes and hypothalamic function. J Mol Endocrinol 47, R67R74.
81. Keverne, B (2009) Monoallelic gene expression and mammalian evolution. BioEssays 31, 13181326.
82. den Heijer, T, Vermeer, SE, Clarke, R et al. (2003) Homocysteine and brain atrophy on MRI of non-demented elderly. Brain 126, 170175.
83. Clarke, R, Smith, AD, Jobst, KA et al. (1998) Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimer disease. Arch Neurol 55, 14491455.
84. di Salvo, ML, Contestabile, R & Safo, MK (2011) Vitamin B6 salvage enzymes: mechanism, structure and regulation. Biochim Biophys Acta 1814, 15971608.
85. Clarke, M, Ward, M, Strain, JJ et al. (2014) B-vitamins and bone health and disease: the current evidence. Proc Nutr Soc 73, 330339.