This review found insufficient evidence to assess the effects of B vitamin supplementation on cognitive function. The authors' conclusions appear appropriately cautious in view of the poor methodological quality and small sample sizes of many of the included studies.

To assess the effects and safety of B vitamins and of berries and their constituents in preventing or reversing age-related neurocognitive disorders, in particular Alzheimer's disease (AD) and Parkinson's disease (PD). In addition to a review of human intervention studies, the report included reviews of evidence from in vitro or animal studies and from studies of associations between B vitamin levels and neurocognitive outcomes. These are not discussed further in this abstract.

MEDLINE and CAB Abstracts were searched from inception to early 2005; the search terms were reported in an appendix available on the Internet. The searches were limited to peer-reviewed publications in English. Additional references were sought by contacting experts and checking the reference lists of selected included articles, reviews and meta-analyses.

Study designs of evaluations included in the review

Randomised controlled trials (RCTs), non-randomised controlled trials (CCTs) and prospective cohort studies were eligible for inclusion. Case reports were excluded from the review.

Specific interventions included in the review

Studies of vitamins B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B12 (cyanocobalamin) and folate, singly or in combination, were eligible for inclusion. Studies of multivitamins that included vitamins other than B vitamins were excluded. Studies of 12 named types of berries and their constituents were also eligible, but none were found. The duration of treatment in the included studies ranged from 1 to 12 months. Studies evaluating the effect of B6 on Parkinsonian symptoms and L-dopa levels in patients treated with L-dopa were excluded from the review.

Participants included in the review

Studies of adults were eligible for inclusion. The participants in the included studies were people with normal cognitive function and patients with neurodegenerative disorders, primarily AD or PD. Studies of participants with the following conditions were excluded from the review: mental retardation including Down's syndrome, Wernicke's encephalopathy, subacute combined degeneration, vascular dementia, acute encephalopathy, mixed causes of dementia where separate analyses for disease types were not available, peripheral neuropathy, and other lower motor neurodegeneration not related to PD. Also excluded were studies of non-applicable populations such as young diabetic patients.

Outcomes assessed in the review

The included studies were required to report diagnosis or severity of AD, PD other age-related cognitive disorder or cognitive impairment, or the results of a test of cognitive function. The included studies reported the outcomes of a wide range of different tests and scales.

How were decisions on the relevance of primary studies made?

The authors did not state how the papers were selected for the review, or how many reviewers performed the selection.

Studies were rated A (low risk of bias), B (some risk of bias but not enough to invalidate the results) or C (significant bias that may invalidate the results) using a generic checklist applicable to varying study designs. At least two reviewers assessed validity; when there was disagreement, one or two additional reviewers assessed the study and a consensus was reached. The studies were also rated as high, medium or low for applicability to the population of interest, i.e. people at risk of or diagnosed with age-related neurodegenerative disorders, particularly AD or PD.

One reviewer extracted the data using a standardised data extraction form and a second reviewer checked the extraction. Data on tests of cognitive function were used to derive the change from baseline in the intervention and control groups and the difference in change from baseline between the groups (net change); for uncontrolled studies, within-group change from baseline was calculated. Reported 95% confidence intervals and standard errors were used to determine whether changes were statistically significant.

How were the studies combined?

The studies were combined in a detailed narrative, grouped by intervention.

How were differences between studies investigated?

Differences between the studies in terms of interventions and study quality were discussed in the text.

Thirty-one studies (n=1,352) were included in the review. These comprised three RCTs, one CCT and one uncontrolled cohort study of vitamin B1 (n=79); two RCTs of vitamin B6 (n=151); five RCTs, one CCT and seven uncontrolled cohort studies of vitamin B12 (n=492); three RCTs and two uncontrolled cohort studies of folate (n=168); and three RCTs and three uncontrolled cohort studies of combinations of B vitamins (n=462).

One study was graded A for quality, seven were graded B, and the remainder C. There was weak evidence of a possible benefit of vitamin B1 supplementation in improving, or slowing deterioration of, cognitive function in people with AD. One out of two studies of vitamin B6 suggested a beneficial effect on one measure of cognitive function in people with normal cognitive function. There was weak and inconsistent evidence suggesting a possible benefit of intramuscularly injected vitamin B12 in people recently diagnosed with AD or cognitive impairment. Studies of folate gave contradictory results in cognitively normal and impaired participants. There was no benefit of folate supplementation in a study of patients with PD. Treatment with combinations of B vitamins was of no benefit overall. Ten studies reported on adverse events, of which eight reported none. Small numbers of adverse events were reported in one study with vitamin B1 and one with folate.

There is insufficient evidence to assess the effects of B vitamin supplementation on cognitive function.

This review addressed a clear question and inclusion criteria for the interventions and outcomes were clear. Inclusion criteria for the participants were broad, but this was addressed to some extent by rating the included studies for applicability to the populations of most interest. The search involved a narrow range of databases and the restriction to published papers in English means that the review could be at risk of publication and language bias; the risk of publication bias was not assessed. The range of criteria used for the quality assessment appeared appropriate and study quality was taken into account in the narrative synthesis. Extensive details of the included studies were provided in the text, tables and appendices. Appropriate methods were used to minimise bias and errors in the quality assessment and data extraction, although it was unclear whether this also applies to the study selection process of the review. The data were synthesised narratively, which seems appropriate in view of the variety of interventions, participants, outcomes and outcome scales in the review. The authors' conclusions appear appropriately cautious in view of the poor methodological quality and small sample sizes of many of the included studies.

Practice: The authors did not state any implications for practice.

Research: The authors stated that further large prospective studies are required to assess the effects of B vitamin supplementation on neurocognitive function; studies should evaluate regimens that could be followed and afforded by most people.

Agency for Healthcare Research and Quality, contract number 290-02-0022.

Balk EM, Raman G, Tatsioni A, Chung M, Lau J, Rosenberg IH. Vitamin B6, B12, and folic acid supplementation and cognitive function: a systematic review of randomized trials. Arch Intern Med 2007;167:21-30.

This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn.