B-Vitamin Supplements May Slow Brain Atrophy in MCI

Susan Jeffrey

September 24, 2010

September 24, 2010 — Results of a new randomized trial of high-dose B vitamins, including B12, B6, and folic acid, suggest the rate of brain atrophy may be slowed by treatment in elderly people with mild cognitive impairment (MCI).

The effect of supplementation related to baseline homocysteine levels, said A. David Smith, professor emeritus of pharmacology and founding director of the Oxford Project to Investigation Memory and Aging (OPTIMA) at the University of Oxford, United Kingdom, lead author of the study.

Overall, B vitamins given at a dose high enough to reduce homocysteine by 31.7% in this trial had a "pretty dramatic effect" on the rate of brain atrophy also of about 30% compared with placebo, Dr. Smith told Medscape Medical News.

The effect was greater among those in the highest quartile for homocysteine levels. "The treatment actually reduced the rate of shrinkage by 53%, which is a huge effect," he said. "We were absolutely delighted with this strong result."

Their findings from the trial known as VITACOG were published in the September issue of PLoS One.

Steady Atrophy With Aging

Neuroimaging studies have established that even in the healthy elderly, the brain is shrinking at a rate of about 0.5% per year, Dr. Smith said. In those with Alzheimer's disease, the rate is accelerated to about 2.5% per year, and those with MCI fall somewhere in between, with an intermediate rate of about 1%.

Homocysteine has been confirmed by his group and others as a risk factor for brain atrophy, as well as cognitive impairment and dementia.

"Since homocysteine levels can be regulated by B vitamins, because they are the main cofactors in the enzymes involved in metabolizing homocysteine, the question is, 'If you lower homocysteine by giving B vitamins, will you reduce the rate of shrinkage of the brain?'" he said.

VITACOG was a single-center, randomized, double-blind, controlled trial of high-dose B vitamins vs placebo in 271 subjects older than 70 years with a diagnosis of MCI. Of these, 187 volunteered to have cranial magnetic resonance imaging (MRI) scans at the start and finish of the study.

Treatment was a combination of 0.8 mg/day of folic acid, 0.5 mg/day of vitamin B12, and 20 mg/day of vitamin B6 or placebo, given for 24 months. The dose of B12 was up to 300 times higher than recommended daily allowances in most countries to try and counter the poorer absorption in elderly people, he noted.

The primary outcome measure was change in the rate of whole-brain atrophy assessed by serial volumetric MRI.

Of the 187 patients undergoing neuroimaging, 168 completed both scans, 85 in the treatment group and 83 in the placebo group.

The rate of brain atrophy was found to be significantly less in those receiving treatment, the study authors report.

Table. VITACOG: Mean Rate of Brain Atrophy Per Year

Endpoint B Vitamins Placebo P Value
Mean rate of brain atrophy per year, % 0.76 (0.63 – 0.90) 1.08 (0.94 – 1.22) .001


They found a significant interaction of treatment with baseline homocysteine levels; among those with a baseline homocysteine level greater than 13 μmol/L, brain atrophy was 53% lower with treatment (P = .001). No interaction was seen baseline folate or vitamin B12 levels.

Effect on Cognition?

Of course, the big question is whether this reduction in the pace of brain atrophy translates into effects on maintaining cognition, Dr. Smith said. The trial was not powered to detect effects on cognition, but they have explored these data and found in a post hoc analysis that a greater rate of atrophy was associated with lower final cognitive test scores.

An additional analysis on cognitive outcomes in VITACOG was presented in July during the Alzheimer's Association's International Conference on Alzheimer's Disease in Honolulu, Hawaii.

In addition to imaging, subjects underwent neuropsychological testing in the domains of episodic and semantic memory, executive function, and selective attention at baseline and after 2 years of treatment.

After controlling for age, sex, education, and apolipoprotein E ε4 status, there was no overall difference between treated and placebo groups, Dr. Smith said.

"But in those who started with a high level of homocysteine in the placebo group, the test scores declined over 2 years, whereas in the treated group they didn't decline at all; absolutely steady," Dr. Smith said. "So here we have a hint that even in this relatively small trial there was a statistically significant cognitive effect."

Safety data showed no concerns, but he emphasized that the trial was short and included relatively few patients. Results of another cardiovascular trial, the Norwegian Vitamin Trial (NORVIT), which had about 7000 participants taking B vitamins for up to 8 years, showed a cancer signal with treatment, although this risk appeared to be confined to smokers.

NORVIT also looked at cognitive outcomes, however, and showed no effect of B vitamins in improving cognitive performance over 2 years in otherwise healthy elderly subjects (N Engl J Med. 2006;354:2764-2772, 2817-2819).

"What we'd like to do next is maybe a bigger trial of about 1000 people where the endpoint is a clinical one, conversion from MCI to dementia, Alzheimer's mainly," Dr. Smith. They are currently planning such a trial, but he anticipates funding it will be a problem because there is no pharmaceutical interest.

"For the bigger trial we need a lot more money, and I don't think we're going to find it easily, frankly," he said.

Small Numbers, No Surprise

Asked for comment on these findings, William Thies, PhD, chief medical and scientific officer at the Alzheimer's Association in Chicago, Illinois, said the results were interesting but not surprising.

"There's been a lot of work done on lowering homocysteine levels, and some of it is positive and some of it isn't," Dr. Thies said. "This data I think is pretty consistent with what most people think is true, and that is, if your homocysteine level is high, getting it down can have an effect."

But homocysteine levels for most people are not high particularly where mandatory folate supplementation is in effect, he notes. "We have lots of places where people's diet is so supplemented with B vitamins and folate, it's probably pretty hard to get a population-wide association with this kind of treatment effect."

In addition, the study is still relatively small. "That's a way to start, but it's certainly far from the end," Dr. Thies added. "I would think that there probably needs to be replication, certainly in other laboratories because there are a variety of techniques for measuring hippocampal volume, so that's something we'd like to see done in several different ways to see if you get the same kind of results."

The study was supported by grants from the Charles Wolfson Charitable Trust, Medical Research Council, Alzheimer's Research Trust, Henry Smith Charity, John Coates Charitable Trust, Thames Valley Dementias, and Neurodegenerative Diseases Research Network of the National Institute for Health Research, United Kingdom, and the Sidney and Elizabeth Corob Charitable Trust, and Med AB/Recip AB, Solna, Sweden. Dr. Smith is named as an inventor on 2 patents held by the University of Oxford on the use of folic acid to treat Alzheimer's disease; under the university's rules he could benefit if the patent is exploited. He also reports having in the past received speaking honoraria from Recip AB, the company that donated the vitamin tablets, and from Axis-Shield, the company that makes the equipment used to assay homocysteine. Disclosures for other coauthors appear in the original article.

PLoS ONE. Published online September 1, 2010.


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