Preventing Alzheimer’s disease-related gray matter atrophy by B-vitamin treatment
Edited by Marcus E. Raichle, Washington University in St. Louis, St. Louis, MO, and approved March 29, 2013 (received for review January 29, 2013)
Abstract
Is it possible to prevent atrophy of key brain regions related to cognitive decline and Alzheimer’s disease (AD)? One approach is to modify nongenetic risk factors, for instance by lowering elevated plasma homocysteine using B vitamins. In an initial, randomized controlled study on elderly subjects with increased dementia risk (mild cognitive impairment according to 2004 Petersen criteria), we showed that high-dose B-vitamin treatment (folic acid 0.8 mg, vitamin B6 20 mg, vitamin B12 0.5 mg) slowed shrinkage of the whole brain volume over 2 y. Here, we go further by demonstrating that B-vitamin treatment reduces, by as much as seven fold, the cerebral atrophy in those gray matter (GM) regions specifically vulnerable to the AD process, including the medial temporal lobe. In the placebo group, higher homocysteine levels at baseline are associated with faster GM atrophy, but this deleterious effect is largely prevented by B-vitamin treatment. We additionally show that the beneficial effect of B vitamins is confined to participants with high homocysteine (above the median, 11 µmol/L) and that, in these participants, a causal Bayesian network analysis indicates the following chain of events: B vitamins lower homocysteine, which directly leads to a decrease in GM atrophy, thereby slowing cognitive decline. Our results show that B-vitamin supplementation can slow the atrophy of specific brain regions that are a key component of the AD process and that are associated with cognitive decline. Further B-vitamin supplementation trials focusing on elderly subjets with high homocysteine levels are warranted to see if progression to dementia can be prevented.
Data Availability
Data deposition: The preprocessed structural imaging scans used in this paper can be found at www.fmrib.ox.ac.uk/analysis/VB/.
Acknowledgments
The authors thank all participants in the trial and the entire OPTIMA team, Dr. Joe Ramsey for advice on the use of Tetrad, and Dr. Rita Marasco for help on the visual inspection of the scans. This work 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), Sidney and Elizabeth Corob Charitable Trust and Meda AB/Recip (Solna, Sweden). Meda AB/Recip supplied the vitamin and placebo tablets.
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Cover image: Pictured are microbubbles with small fluorophores called “molecular rotors” embedded in their surface. Neveen A. Hosny et al. developed a method to directly measure the viscosity of a microbubble using a molecular rotor whose fluorescence lifetime is directly related to the viscosity of its surroundings. The study found that viscosity varied widely across a population of microbubbles and was influenced by their composition and manufacturing process. Microbubbles have potential utility as contrast agents for ultrasound and other imaging techniques, and a better understanding of their viscosity and surface properties could help optimize their production for use in imaging. See the article by Hosny et al. on pages 9225–9230. Image courtesy of Neveen A. Hosny and Graciela Mohamedi.
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Data Availability
Data deposition: The preprocessed structural imaging scans used in this paper can be found at www.fmrib.ox.ac.uk/analysis/VB/.
Submission history
Published online: May 20, 2013
Published in issue: June 4, 2013
Keywords
Acknowledgments
The authors thank all participants in the trial and the entire OPTIMA team, Dr. Joe Ramsey for advice on the use of Tetrad, and Dr. Rita Marasco for help on the visual inspection of the scans. This work 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), Sidney and Elizabeth Corob Charitable Trust and Meda AB/Recip (Solna, Sweden). Meda AB/Recip supplied the vitamin and placebo tablets.
Notes
This article is a PNAS Direct Submission.
Authors
Competing Interests
Conflict of interest statement: A.D.S. is named as inventor on three patents held by the University of Oxford on the use of B vitamins to treat Alzheimer’s disease or mild cognitive impairment (US6008221, US6127370, and PCT/GB2010/051557); H.R. is named as inventor on Patent PCT/GB2010/051557. Under the University of Oxford’s rules, they could benefit financially if the patents are exploited.
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