Professor David Kennedy, Director of the Brain, Performance and Nutrition Research Centre, Northumbria University, Newcastle-upon-Tyne, United Kingdom
To date, most research on B vitamins and the brain has concentrated on folate acid, B12 and B6, and their role in serum homocysteine reduction. Professor David Kennedy is the Director of the Brain, Performance and Nutrition Research Centre and Professor of Biological Psychology at Northumbria University, Newcastle upon Tyne, UK, and believes that the situation is much more complicated and requires a study of the intertwining effects of all eight B vitamins (thiamine B1, riboflavin B2, niacin B3, pantothenic acid B5, B6, folate B9 and B12). In his new review paper (1), he confirms that all eight B vitamins are involved in brain function, including energy production, synthesis and repair of DNA and RNA, genomic and non-genomic methylation, and the synthesis of a wide variety of neurochemicals and signalling molecules.
Professor Kennedy states that most of the clinical studies involving B vitamins and cognition have been designed around the “homocysteine hypothesis”. It can be observed that the onset of dementia is accompanied by a rise in levels of homocysteine in the body and a deficiency of folate and vitamin B12. As an example, this week, a new study from Korea (2) of a cohort of 48 people in care homes with mild cognitive impairment has shown that an “unspecified” cocktail of B vitamins enabled the intervention arm to achieve significantly improved results when assessed by the Mini Mental State Examination Test and a decrease in their serum homocysteine levels. Another recent paper provides evidence that B vitamin intervention only has a positive effect on cognition if the patient is not deficient in marine omega-3 fatty acids(3), suggesting that the role of nutrition is more complex than first thought.
Professor Kennedy believes that concentrating on the “homocysteine hypothesis” has led to both the observational and the intervention trial concentrating on just three B vitamins that reduce homocysteine serum levels, namely folate, vitamin B6 and vitamin B12. It has been hypothesized that homocysteine has detrimental effects on brain function through increasing oxidative stress, inhibition of methylation reaction, increased damage to DNA, and neurotoxicity. Sadly, the results from clinical trials using nutritional interventions targeted at reducing serum homocysteine results have been very inconsistent as regards measures of cognition. A meta-analysis from 2010 involving 39,107 participants of 17 trials (4) and a newer 2015 meta-analysis involving 47,429 participants of 12 trials (5) concluded that although interventions of folate (with vitamin B6 and vitamin B12) did indeed reduce serum homocysteine levels, the vitamins provided no protection against cardiovascular, cerebrovascular or all-cause mortality. The evidence suggests that homocysteine levels are actually a simple biomarker related to circulating levels of vitamins or progress of the relevant disease.
Professor Kennedy points out that one unfortunate consequence of the “homocysteine hypothesis” is that clinical research has focused on folate, B6 and B12 and has almost totally ignored the remaining five B vitamins. This is sometimes quite illogical, for example, flavoproteins derived from riboflavin have a direct effect on the status of folate, B6 and B12 levels. Indeed, riboflavin is involved in several key enzymesresponsible for homocysteine metabolism. Niacin is an important co-factor for key enzymes in the folate/tetrahydrobiopterin and methionine cycles, and indeed all the remaining B vitamins play important roles in the interlinked folate/methionine and citric acid cycles. Participation in these highly energy-generating pathways is very important for the brain, which accounts for 20% of the body’s total energy expenditure despite only comprising 2% of its weight.
Each individual B vitamin is actively transported across the blood-brain barrier. Though daily turnover varies from 8 to 100%, their actual levels are tightly regulated by multiple homeostatic mechanisms in the brain (6). Professor Kennedy details the important metabolic function of each B vitamin in relation to the brain (1). He notes that the importance of each B vitamin can be “illustrated by the neurological and psychiatric symptoms commonly associated with deficiency in any of these eight vitamins”. He believes all the B vitamins are individually good for cognitive health, but also function even better together. Further, the B vitamins also work in concert with other vitamins, minerals and micronutrients. Hence, the current reliance on clinical interventions with purely folic acid, B6 and B12 seems misguided.