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Plasma Aβ, homocysteine, and cognition

The Vitamin Intervention for Stroke Prevention (VISP) trial

From the Memory Disorders Unit (A.V., S.R., S.M.G., B.T.H., M.C.I.) and Stroke Service (A.V., S.M.G.), Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston; Harvard School of Public Health (M.S.), Boston; Department of Biostatistics (S.C.), Collaborative Studies Coordinating Center, University of North Carolina at Chapel Hill, Stroke Prevention and Atherosclerosis Research CenterI. is currently affiliated with WW Epidemiology, GlaxoSmithKline, Research Triangle Park, NC.

Address correspondence and reprint requests to Dr. Anand Viswanathan, Hemorrhagic Stroke Research Program, Massachusetts General Hospital Stroke Research Center, 175 Cambridge Street, Suite 300, Boston, MA 02114 aviswanathan1{at}partners.org

Background: Amyloid-beta protein (Aβ) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Aβ levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation–induced reduction of tHcy influences plasma Aβ levels in the Vitamin Intervention in Stroke Prevention (VISP) study.

Methods: Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Aβ with 40 (Aβ40) and 42 (Aβ42) amino acids were measured at baseline and at the 2-year visit.

Results: tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Aβ40 but not Aβ42 concentrations. There was no difference in the change in Aβ40, Aβ42 (p = 0.40, p = 0.35), or the Aβ42/Aβ40 ratio over time (p = 0.86) between treatment groups. Aβ measures were not associated with cognitive change.

Conclusions: This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Aβ40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Aβ, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Aβ40, they may be regulated by independent mechanisms.

Abbreviations: Aβ = amyloid-beta; AD = Alzheimer disease; BMI = body mass index; DBP = diastolic blood pressure; MMSE = Mini-Mental State Examination; mRS = modified Rankin Scale; NIHSS = NIH Stroke Scale; SBP = systolic blood pressure; tHcy = total homocysteine; VISP = Vitamin Intervention in Stroke Prevention study.

Supported by NIH grants 5K23NS046327-04, P50AG05134, and 5R01AG026484-02 (Massachusetts General Hospital), the Harvard Center for Neurodegeneration and Repair, and NIH grant 5T32NS048005-05 (Harvard School of Public Health).

Disclosure: Michael Irizarry is a stock and options-holding employee of GlaxoSmithKline. No pharmaceutical funding was used in this study.

Received July 3, 2008. Accepted in final form October 8, 2008.

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				A. Viswanathan High-Dose B Vitamin Supplementation as a Disease-Modifying Therapy in Alzheimer Disease Arch Neurol, April 1, 2009; 66(4): 520 - 522. [Full Text] [PDF]