'B' Sharp? Alzheimer's Disease and B Vitamins
Abstract & Commentary
By Russell H. Greenfield, MD, Editor
Source: Smith AD, et al. Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: A randomized controlled trial. PLoS One 2010;5:e12244.
Synopsis: Results of this methodologically sound trial strongly suggest that moderate-dose B vitamin therapy has a protective effect against the rapidly progressive brain atrophy commonly seen in elderly people with mild cognitive impairment (MCI). The intervention was safe and effective over a 2-year time frame, and shows promise for slowing the inexorable progression of MCI to frank dementia.
The researchers behind this british single-center, randomized, controlled, double-blind trial sought to determine whether high-dose B vitamin supplementation could slow the rate of brain atrophy in subjects age 70 years or older with mild cognitive impairment (MCI) over a 2-year period. The data come from what has been called the VITACOG trail.
Elderly people with concerns about their memory were recruited for screening through local advertisements. Inclusion criteria included a diagnosis of MCI with corroborative results on tools such as the Telephone Interview of Cognitive Status, Modified (TICS-M) and Mini-Mental State Exam (MMSE). Exclusion criteria included a prior diagnosis of dementia, recent stroke, or the taking of high-dose B vitamin therapy (those using low-dose B vitamins were permitted to continue and participate in the study). Subjects were randomized to receive either placebo or high-dose B vitamin therapy (0.8 mg folic acid, 0.5 mg cyanocobalamin. and 20 mg pyridoxine HCL). Tablets were provided at time of initial study entry and subsequently by mail at 6-month intervals.
Volumetric cranial MRI scans were performed at baseline and at trial's end (2 years). An automated, quantitative, proven method (SIENA) was used to measure rate of whole brain atrophy, the main outcome of interest. Primary analysis focused only on those subjects for whom a technically good MRI was available both at baseline and at ~24-month follow-up (n = 83 placebo, n = 85 B vitamins group). All subject analyses were adjusted for age because the factor was strongly associated with rate of brain atrophy.
Secondary outcomes included adverse events, withdrawals, compliance, changes in biochemical markers, and cognitive and depression scores (the authors will be reporting results of the latter in a separate publication). Total homocysteine and plasma vitamin levels were determined and compliance levels defined.
At the end of the trial, adherence to protocol was noted to be good as determined by the number of returned tablets and plasma vitamin concentrations. A total of 48 subjects were lost to follow-up (n = 20 in placebo group). No significant difference in adverse effects was found save for a slightly lower number of subjects in the active group who lost vibration sense.
Plasma total homocysteine increased by 7.7% in the placebo group and decreased by 31.7% in the active group. The rate of brain atrophy slowed significantly with B vitamin therapy, being 29.6% less than the rate determined for placebo group subjects. A significant interaction was found between baseline homocysteine levels and treatment effect in the placebo group, with higher homocysteine levels associated with a higher rate of brain atrophy. As plasma homocysteine concentrations decreased, the rate of brain atrophy likewise decreased. In addition, the rate of brain atrophy slowed as concentrations of folate and B12, but not B6, increased. On the other hand, those subjects whose folate and B12 levels decreased over the two-year period were found to be at increased risk for brain atrophy. Of note, subjects in the placebo group with a prior history of stroke or TIA at baseline had an increased rate of brain atrophy compared to people without such a history; the rate of brain atrophy was slowed in subjects with a history of CVA or TIA who received B vitamin therapy.
When total homocysteine results were divided into quartiles, no effect of B vitamin therapy was detectable for those in the lowest quartile (total homocysteine < 9.5 mmol/L), whereas there was a 53.3% decrease in brain atrophy rate in those subjects in the highest quartile (>13.0 mmol/L) treated with B vitamins. Treatment effect was thus greatest for those with the highest baseline homocysteine levels.
In a post hoc analysis the researchers found that final cognitive test scores were positively correlated with rate of brain atrophy.
The researchers concluded that the accelerated brain atrophy seen in elderly people with MCI can be slowed with high-dose B vitamin treatment that lowers homocysteine levels, potentially slowing progression to Alzheimer's disease or other forms of dementia.
Commentary
The authors note that between 14-18% of people older than age 70 years, or approximately 5 million people in the United States, have MCI , and about half will go on to develop dementia. They also note that while elderly people typically experience significant and progressive brain atrophy, even those who are cognitively healthy, a much-accelerated form of brain atrophy occurs with Alzheimer's disease. An intermediate pace of brain atrophy is seen in people with MCI, but a more rapid rate is characteristic of subjects with MCI who convert to Alzheimer's disease. Effective means to reduce the rate of brain atrophy might slow progression to Alzheimer's disease.
Experts believe the number of cases of Alzheimer's disease likely will rise dramatically within the next decade. Preventive interventions are urgently needed because there is no cure for the disease. The prescription aids currently available only slow the progression of cognitive dysfunction, not halt or reverse it. Unfortunately, there is scant evidence on effective preventive strategies. Following a Mediterranean-style diet appears to offer some protection, and regular physical and mental exercise, and perhaps the use of specific anti-inflammatory agents, all show at least a modicum of promise, but there is little agreement on tactics beyond these basics.
A great deal of study has already taken place regarding homocysteine and homocysteine-lowering therapies, especially B vitamin therapy, and select disorders. Research into the use of B vitamin therapy to reduce cardiovascular risk largely has not met high expectations, but elevated homocysteine levels are a recognized risk factor for brain atrophy, cognitive impairment, and Alzheimer's disease, and it is well-accepted that plasma levels of homocysteine can be lowered through dietary administration of B vitamins. It appears, however, that a beneficial effect can be anticipated only for those with a high baseline total homocysteine concentration (> 9.5 mmol/L). It is noteworthy that the current study took place in the United Kindgom, where fortification of foods with folic acid is not mandatory.
Prior studies have shown that the rate of whole brain atrophy in MCI correlates with cognitive decline as measured by several different tests, including MMSE, and that the rate of atrophy may be a major determinant of final MMSE and TICS-M scores. The authors' data regarding cognitive and depression scores should be very interesting and, hopefully, compelling.
This well-done study raises hopes that moderately high-dose folic acid and B12 therapy, though perhaps not pyridoxine, may offer some protection against rapid brain atrophy in elderly people with MCI. The intervention appears to be safe and to have a meaningful clinical effect. Yes, more data are required, but for elderly patients with MCI, B vitamin therapy should be a therapeutic consideration, save for the presence of a specific contraindication.
Results of this methodologically sound trial strongly suggest that moderate-dose B vitamin therapy has a protective effect against the rapidly progressive brain atrophy commonly seen in elderly people with mild cognitive impairment (MCI). The intervention was safe and effective over a 2-year time frame, and shows promise for slowing the inexorable progression of MCI to frank dementia.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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