Plasma Abeta, homocysteine, and cognition: the Vitamin Intervention for Stroke Prevention (VISP) trial.
BACKGROUND
Amyloid-beta protein (Abeta) 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 Abeta levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation-induced reduction of tHcy influences plasma Abeta 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 Abeta with 40 (Abeta40) and 42 (Abeta42) 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 Abeta40 but not Abeta42 concentrations. There was no difference in the change in Abeta40, Abeta42 (p = 0.40, p = 0.35), or the Abeta42/Abeta40 ratio over time (p = 0.86) between treatment groups. Abeta 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 Abeta40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Abeta, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Abeta40, they may be regulated by independent mechanisms.
Viswanathan
A
A
Hemorrhagic Stroke Research Program, Massachusetts General Hospital Stroke Research Center, 175 Cambridge Street, Suite 300, Boston, MA 02114, USA. aviswanathan1@partners.org
Raj
S
S
Greenberg
S M
SM
Stampfer
M
M
Campbell
S
S
Hyman
B T
BT
Irizarry
M C
MC
D000368:Aged; D016229:Amyloid beta-Peptides / Q000097:blood* / Q000737:chemistry; D003071:Cognition / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015536:Down-Regulation; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage; D006710:Homocysteine / Q000097:blood* / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D009994:Osmolar Concentration; D010446:Peptide Fragments / Q000097:blood*; D011736:Pyridoxine / Q000008:administration & dosage; D020521:Stroke / Q000517:prevention & control*; D017211:Treatment Failure; D014805:Vitamin B 12 / Q000008:administration & dosage; D014803:Vitamin B Complex / Q000008:administration & dosage; D014815:Vitamins / Q000008:administration & dosage / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D014815:Vitamins; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D006710:Homocysteine; D014803:Vitamin B Complex; D005492:Folic Acid; D011736:Pyridoxine; D014805:Vitamin B 12