Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial

PLoS ONE

Sep 2010

DOI: 10.1371/journal.pone.0012244

Citations:764

Influential Citations:51

Interventional (Human) Studies

Enhanced Details

Methods

Single-center, randomized, double-blind, placebo-controlled trial in adults over 70 years with mild cognitive impairment (amnestic or non-amnestic) per Petersen criteria; 271 participants randomized; MRI sub-study included (n=187) with baseline and follow-up scans.

Intervention

Folic acid 0.8 mg/day; Vitamin B12 0.5 mg/day; Vitamin B6 20 mg/day; for 24 months; taken orally as tablets.

Results

High-dose B vitamins slowed brain atrophy over 2 years in older adults with MCI. Rate of whole-brain atrophy per year was 0.76% with active treatment vs 1.08% with placebo (29.6% slower; P=0.001). After additional covariate adjustment, 27.1% slower (0.78% vs 1.07%; P=0.003). In biologically compliant MRI participants (n=136), rate was 0.73% vs 1.06% (31.1% slower; P=0.004). The beneficial effect was greater in those with higher baseline homocysteine, with up to 53% slower atrophy in the top quartile (>13 μmol/L). No difference in serious adverse events between groups. Authors conclude that homocysteine-lowering B vitamins can slow accelerated brain atrophy in MCI and may delay progression to Alzheimer’s disease, but cognition was not powered in this trial and requires further study.

Limitations

Three-vitamins combination prevents identifying which vitamin is essential; trial powered for brain atrophy, not cognition; subgroup analyses have small samples; some interactions (stroke history, diabetes, aspirin use) require cautious interpretation; adherence varied; MRI analysis limited to subset (n=168), reducing generalizability; conducted in the UK without mandatory folic acid fortification.

Abstract

Background An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins. Objective To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159). Methods and Findings Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans. Results A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category. Conclusions and Significance The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease. Trial Registration Controlled-Trials.com ISRCTN94410159 show less