In a study on elderly subjects with increased dementia risk, researchers at the University of Oxford showed that high-dose B-vitamin treatment can slow the atrophy of specific brain regions that are a key component of the Alzheimer's disease (AD) process and that are associated with cognitive decline.

The prevention of AD is a major public health challenge, and many promising therapies have already failed in late-stage clinical trials. A progressive disease, AD destroys memory and other important mental functions and is the most common cause of dementia. In order to treat at-risk people before they develop the major symptoms of dementia, scientists are increasingly turning to alternative approaches.

One approach is to modify nongenetic risk factors such as lowering elevated plasma homocysteine with B vitamins. Critical nutrients, B vitamins are necessary to help avoid many health problems.


Risk Factors

Elevated plasma homocysteine has been identified as a risk factor for vascular disease and potentially for dementia and depression as well. The most common cause of elevated homocysteine levels is deficiency of folate or vitamin B(12). To investigate the effect of B-vitamin treatment on elderly volunteers with memory complaint, the Oxford researchers analyzed data over a period of 24 months from a randomized, controlled trial (VITACOG).

The MRI scans of participants - 76 receiving placebo and 80 receiving B vitamins - showed no differences in baseline gray matter volume. And, over the two-year period, both treatment groups were found to have lost gray matter. In fact, atrophy was found in similar areas encompassing medial temporal, lateral temporoparietal, and occipital regions, as well as the anterior and posterior cingulate cortex.

Yet, further direct comparison between the two groups revealed a significant effect of treatment. Compared to the placebo group, subjects receiving B vitamins (specifically, folic acid 0.8 mg, vitamin B12 0.5 mg, vitamin B6 20 mg) showed a significant reduction of atrophy in posterior brain regions, including bilateral hippocampus and parahippocampal gyrus, retrosplenial precuneus, lingual and fusiform gyrus, as well as in the cerebellum.

"There is ... clear anatomical and functional evidence for the role of the cerebellum in cognitive and behavioral functions, and particularly for autobiographical memory and working memory," wrote the authors.

The posterior brain regions and the cerebellum are among those most affected in Alzheimer's disease as well as in mild cognitive impairment subjects who later develop AD. In the regions showing significant treatment effect, the average loss of gray matter over two years was 3.7 percent in the placebo group compared with only 0.5 percent in the B-vitamin group.

In order to investigate the interplay between treatment and baseline tHcy, researchers further divided participants into two groups according to baseline tHcy: those with measurements below and above the median. Previously it has been shown that higher plasma tHcy levels are related to smaller global brain volume and white matter volume, smaller amygdala and hippocampus, and faster reduction in overall brain size.

Researchers discovered participants with high tHcy in the placebo group had greater gray matter atrophy compared to those with low tHcy.

In contrast, among the subjects receiving B vitamins, there was no difference in atrophy between participants with low and high baseline tHcy. No significant effect of B-vitamin treatment was found in the participants with low baseline tHcy. However, the B-vitamin treatment over two years had a marked beneficial effect in reducing gray matter atrophy in those with high tHcy - from 5.2 percent down to 0.6 percent.

In the high-tHcy group, B vitamins reduced atrophy in similar regions as seen in the total group. The reduced atrophy also extended to anterior regions including the anterior cingulate cortex and piriform cortex, as well as prefrontal areas.


Differentiated Memory

To more precisely delineate which regions of the brain were associated with cognitive decline, the researchers analyzed the changes over time in gray matter volume and changes in their scores on neuro-psychological tests for all 156 participants. In particular, the researchers explored the relationship between gray matter loss and decline in measures of global brain function, decline in measures of episodic memory, and decline in measures of semantic memory.

Gray matter loss was significantly associated with worsening of global functioning test scores, which was most pronounced bilaterally in the amygdalohippocampal complex and entorhinal cortex. Decreases in episodic memory and semantic memory test scores were associated with increased gray matter loss in the left hippocampus and entorhinal cortex.


Source: Douaud G, Refsum H, de Jager CA, et al. Preventing Alzheimer ' s disease-related gray matter atrophy by B-vitamin treatment. PNAS. 2013.