Cognitive and clinical outcomes of homocysteine-lowering B-vitamin treatment in mild cognitive impairment: A randomized controlled trial
Homocysteine is a risk factor for Alzheimer's disease. In the first report on the VITACOG trial, we showed that homocysteine-lowering treatment with B vitamins slows the rate of brain atrophy in mild cognitive impairment (MCI). Here we report the effect of B vitamins on cognitive and clinical decline (secondary outcomes) in the same study.
This was a double-blind, single-centre study, which included participants with MCI, aged ≥ 70 y, randomly assigned to receive a daily dose of 0.8 mg folic acid, 0.5 mg vitamin B(12) and 20 mg vitamin B(6) (133 participants) or placebo (133 participants) for 2 y. Changes in cognitive or clinical function were analysed by generalized linear models or mixed-effects models.
The mean plasma total homocysteine was 30% lower in those treated with B vitamins relative to placebo. B vitamins stabilized executive function (CLOX) relative to placebo (P = 0.015). There was significant benefit of B-vitamin treatment among participants with baseline homocysteine above the median (11.3 µmol/L) in global cognition (Mini Mental State Examination, P < 0.001), episodic memory (Hopkins Verbal Learning Test-delayed recall, P = 0.001) and semantic memory (category fluency, P = 0.037). Clinical benefit occurred in the B-vitamin group for those in the upper quartile of homocysteine at baseline in global clinical dementia rating score (P = 0.02) and IQCODE score (P = 0.01).
In this small intervention trial, B vitamins appear to slow cognitive and clinical decline in people with MCI, in particular in those with elevated homocysteine. Further trials are needed to see if this treatment will slow or prevent conversion from MCI to dementia.
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- "However, it may be notable that this meta-analysis excluded any trials on people with cognitive impairment or dementia and therefore did not address the question of whether these B vitamins slowed cognitive decline. Of course, these demonstrations of a lack of efficacy have elicited a counter-commentary noting that the null findings may be due to a number of methodological factors, including: the study selection; the heterogeneity or insensitivity of the cognitive tests; the good, or bad, cognitive status of the participants at the studies' outsets; the duration of treatment; and the pooling of data obscuring the positive findings from more methodologically rigorous studies and those in sub-populations that are more likely to see benefits including those with poorer vitamin status[101,129130131. Examples of the latter include positive findings in groups suffering high levels of homocysteine at the outset[132,133]. It has also been notedthat more consistent evidence exists for lower vitamin B 12 status and higher homocysteine levels being associated with decreased brain volume[134,135]and increased white matter lesionsand for supplementation with homocysteine lowering B vitamins attenuating the rate of cerebral atrophy associated with dementia and age related cognitive impairment, particularly in those with higher homocysteine levels at the outset[137,138]. "
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ABSTRACT: The B-vitamins comprise a group of eight water soluble vitamins that perform essential, closely inter-related roles in cellular functioning, acting as co-enzymes in a vast array of catabolic and anabolic enzymatic reactions. Their collective effects are particularly prevalent to numerous aspects of brain function, including energy production, DNA/RNA synthesis/repair, genomic and non-genomic methylation, and the synthesis of numerous neurochemicals and signaling molecules. However, human epidemiological and controlled trial investigations, and the resultant scientific commentary, have focused almost exclusively on the small sub-set of vitamins (B₉/B12/B₆) that are the most prominent (but not the exclusive) B-vitamins involved in homocysteine metabolism. Scant regard has been paid to the other B vitamins. This review describes the closely inter-related functions of the eight B-vitamins and marshals evidence suggesting that adequate levels of all members of this group of micronutrients are essential for optimal physiological and neurological functioning. Furthermore, evidence from human research clearly shows both that a significant proportion of the populations of developed countries suffer from deficiencies or insufficiencies in one or more of this group of vitamins, and that, in the absence of an optimal diet, administration of the entire B-vitamin group, rather than a small sub-set, at doses greatly in excess of the current governmental recommendations, would be a rational approach for preserving brain health.
- "A recent clinical cohort trial showed that plasma homocysteine levels are inversely related to cognitive performance, but found no evidence that high plasma levels of folate gave significant protection against dementia. However, other studies showed treatment with vitamins B12 and B6 stabilised performance on the CLOX testand executive and planning function. The most recent Cochrane reviews reflect these heterogeneous and contradictory results, finding no significant effect overall for B vitamin treatment on cognitive function. "
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ABSTRACT: Nutritional factors can influence the risk of Alzheimer's disease and its rate of clinical progression, suggesting that the association between diet, nutrient status and cognitive function deserves more attention. The European Union Geriatric Medicine Society (EUGMS) working group “Healthy Brain Ageing and Cognition” supports the development of practical recommendations for nutritional strategy, focused predominantly on the preventive aspects of diet and nutrition on cognitive decline. Adopting a healthy lifestyle and avoiding nutritional deficiencies in young or midlife adults is essential and there is compelling evidence to justify recommending a Mediterranean diet as a way of achieving these goals. There is currently insufficient evidence to endorse the use of specific nutrients to promote healthy brain ageing. In addition, currently there is no generally applicable evidence to recommend the use of single-agent micronutrient supplementation at any stage of dementia or for prevention. Omega-3 fatty acids or specific medical foods may be considered for selected patients with early dementia. When signs of malnutrition are detected, correction of specific deficiencies is necessary to improve nutritional status. Individuals at risk of malnutrition should be advised to improve nutritional intake from dietary food sources and should avoid taking high doses of specific nutrients as supplements. Nutritional awareness, advice and intervention are important in the general management and follow-up of people with cognitive problems.
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- "As mentioned in the Introduction, trials of both omega-3 fatty acids and, separately, of B vitamins have given conflicting results regarding cognitive outcomes. Nevertheless, some previous studies have shown benefits of omega-3 fatty acid treatment alone on various types of memory[14,19], attention and processing speed, as well as global cognition, while trials with B vitamins have shown benefits on episodic memory, verbal fluency, and global cognition in people with high baseline tHcy[9,12]. We find here that this beneficial effect of B vitamin treatment on cognition only clearly occurs in those with a good omega-3 fatty acid status. "
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ABSTRACT: A randomized trial (VITACOG) in people with mild cognitive impairment (MCI) found that B vitamin treatment to lower homocysteine slowed the rate of cognitive and clinical decline. We have used data from this trial to see whether baseline omega-3 fatty acid status interacts with the effects of B vitamin treatment. 266 participants with MCI aged ≥70 years were randomized to B vitamins (folic acid, vitamins B6 and B12) or placebo for 2 years. Baseline cognitive test performance, clinical dementia rating (CDR) scale, and plasma concentrations of total homocysteine, total docosahexaenoic and eicosapentaenoic acids (omega-3 fatty acids) were measured. Final scores for verbal delayed recall, global cognition, and CDR sum-of-boxes were better in the B vitamin-treated group according to increasing baseline concentrations of omega-3 fatty acids, whereas scores in the placebo group were similar across these concentrations. Among those with good omega-3 status, 33% of those on B vitamin treatment had global CDR scores >0 compared with 59% among those on placebo. For all three outcome measures, higher concentrations of docosahexaenoic acid alone significantly enhanced the cognitive effects of B vitamins, while eicosapentaenoic acid appeared less effective. When omega-3 fatty acid concentrations are low, B vitamin treatment has no effect on cognitive decline in MCI, but when omega-3 levels are in the upper normal range, B vitamins interact to slow cognitive decline. A clinical trial of B vitamins combined with omega-3 fatty acids is needed to see whether it is possible to slow the conversion from MCI to AD.
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