Homocisteina

Homocysteine-Lowering by B Vitamins Slows the Rate of
Accelerated Brain Atrophy in Mild Cognitive Impairment:
A Randomized Controlled Trial
A. David Smith1,2*., Stephen M. Smith3, Celeste A. de Jager1, Philippa Whitbread1, Carole Johnston1,2,
Grzegorz Agacinski1, Abderrahim Oulhaj1, Kevin M. Bradley4, Robin Jacoby5, Helga Refsum1,2,6.
1 Oxford Project to Investigate Memory and Ageing(OPTIMA), University of Oxford, Oxford, United Kingdom, 2 University Department of Pharmacology and Department
of Physiology, Anatomy & Genetics, University of Oxford, Oxford, United Kingdom, 3 Department of Clinical Neurology, Oxford Centre for Functional Magnetic Resonance
Imaging of the Brain, University of Oxford, Oxford, United Kingdom, 4 Department of Radiology and Nuclear Medicine, OxfordRadcliffe Hospitals NHS Trust, Oxford,
United Kingdom, 5 University Department of Psychiatry, University of Oxford, Oxford, United Kingdom, 6 Department of Nutrition, Institute of Basic Medical Sciences,
University of Oslo, Oslo, Norway

Abstract
Background: An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from
cognitive decline. Homocysteineis 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
treatedwith 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 ofbrain 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 mmol/L was 53% lower in the active treatment group (P = 0.001). A greater
rate of atrophy was associated with a lower finalcognitive 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
Citation: Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, et al. (2010) Homocysteine-Lowering by BVitamins Slows the Rate of Accelerated Brain
Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS ONE 5(9): e12244. doi:10.1371/journal.pone.0012244
Editor: Ashley I. Bush, Mental Health Research Institute of Victoria, Australia
Received May 27, 2010; Accepted July 22, 2010; Published September 8, 2010
Copyright: ß 2010 Smith et al. This is an open-access article distributed...