B Vitamins Slows the Rate of Brain Atrophy in Mild Cognitive Impairment

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SOURCE:   PLoS One. 2010 (Sep 8); 5 (9): e12244

Smith AD, Smith SM, de Jager CA, Whitbread P, Johnston C, Agacinski G, Oulhaj A, Bradley KM, Jacoby R, Refsum H

Oxford Project to Investigate Memory and Ageing, University of Oxford, Oxford, United Kingdom. david.smith@pharm.ox.ac.uk

The Oxford Project to Investigate Memory and Ageing (OPTIMA) published the results of a key aspect of their study in the online journal Public Library of Science ONE in 2010. In this arm of the study, they investigated the effect of B-vitamin supplementation on various parameters of brain aging and associated cognitive function. The study group consisted of 168 individuals over the age of 70 with mild cognitive impairment.

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The treatment group was given daily supplementation of the following B vitamins: folic acid (800 mcg), vitamin B12 (500 mcg) and vitamin B6 (20 mg). The main outcome measured was change in rate of whole brain atrophy on MRI investigation after 24 months of supplementation compared to the placebo group.

Study results showed that the group taking the B-vitamin cocktail experienced a 30-percent slower rate of brain atrophy, on average, and in some cases patients experienced reductions as high as 53 percent. Greater rates of atrophy were associated with lower cognitive test scores.

The authors also observed that, in the control group, the the degree of atrophy was directly related to elevated homocysteine levels.

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 B(6) and B(12) 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 B(12) (0.5 mg/d) and vitamin B(6) (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.


In elderly, the brain shows significant progressive atrophy. The atrophy occurs even in cognitively healthy subjects [1] but is much accelerated in patients suffering from Alzheimer’s disease [2-5]. An intermediate rate of atrophy is found in people with mild cognitive impairment (MCI) [6-11]. Since the rate of brain atrophy is more rapid in subjects with MCI who convert to Alzheimer’s disease [5], it is important to identify factors that determine the rate of atrophy since reducing the rate of atrophy is likely to slow the conversion to Alzheimer’s disease. One such factor appears to be raised concentrations of plasma total homocysteine (tHcy). Moderately elevated concentrations of tHcy have been associated with an increased risk of dementia, notably Alzheimer’s disease, in many cross-sectional and prospective studies [12-16]. Raised tHcy is also associated with both regional and whole brain atrophy, not only in Alzheimer’s disease [12] but also in healthy elderly [17-21].

The tissue and plasma concentrations of homocysteine are largely determined by the body’s status of certain B vitamins (folate, B6 and B12), which are cofactors or substrates for enzymes involved in homocysteine metabolism [22]. The VITACOG trial reported here was designed to see if lowering tHcy concentrations by the administration of high doses of supplementary B vitamins (folic acid, vitamins B6 and B12) over two years would slow the rate of atrophy of the brain in elderly subjects with MCI. This group was chosen because they suffer from modestly increased rate of atrophy, making it possible to detect significant changes in rate of atrophy in a relatively small number of subjects followed for relatively short time. The chosen doses of vitamins lower tHcy levels by about 30% in populations from countries without mandatory folic acid fortification of flour [23].

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