Randomized, placebo-controlled trial of the effects of donepezil on neuronal markers and hippocampal volumes in Alzheimer's disease.
OBJECTIVE
The authors examined the effect of the acetylcholinesterase inhibitor donepezil on magnetic resonance markers of neurodegeneration in Alzheimer's disease.


METHODS
In this randomized, double-blind, placebo-controlled pilot study, 67 patients with mild to moderate Alzheimer's disease received 24 weeks of treatment with donepezil (5 mg/day for the first 28 days and 10 mg/day thereafter) or placebo. Patients were reevaluated at 6-week intervals to measure change from baseline in several outcome measures, including right, left, and total hippocampal volumes, measured with magnetic resonance imaging; brain concentrations of N-acetylaspartate, measured with proton magnetic resonance spectroscopy; and cognition, assessed with the Alzheimer's Disease Assessment Scale cognitive subscale.


RESULTS
At some interim assessments, mean normalized measures of N-acetylaspartate concentration tended to be higher in the donepezil-treated patients than in the patients who received placebo, but these differences were not significant at endpoint. At endpoint, the donepezil-treated patients had significantly smaller mean decreases in total and right hippocampal volumes and a smaller, nearly significant mean decrease in left hippocampal volume, compared with the placebo-treated patients. Mean Alzheimer's Disease Assessment Scale cognitive subscale scores were improved after treatment with donepezil, relative to placebo, at weeks 6, 12, 18, and 24.


CONCLUSIONS
These preliminary results suggest that donepezil may have a potentially protective effect in Alzheimer's disease. Larger, longer-term confirmatory studies of the medication's effects are warranted.
Department of Psychiatry, Duke University Medical Center, Durham, NC 27710, USA. krish001@mc.duke.edu
K Ranga Rama
KR
Krishnan
H Cecil
HC
Charles
P Murali
PM
Doraiswamy
Jacobo
J
Mintzer
Richard
R
Weisler
Xin
X
Yu
Carlos
C
Perdomo
John R
JR
Ieni
Sharon
S
Rogers
D000368:Aged; D000544:Alzheimer Disease / Q000175:diagnosis / Q000188:drug therapy* / Q000523:psychology; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000032:analysis; D015415:Biomarkers / Q000032:analysis*; D001923:Brain Chemistry / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000077265:Donepezil; D004311:Double-Blind Method; D005260:Female; D006624:Hippocampus / Q000033:anatomy & histology / Q000187:drug effects*; D006801:Humans; D007189:Indans / Q000494:pharmacology / Q000627:therapeutic use*; D007294:Inositol / Q000032:analysis; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D009474:Neurons / Q000737:chemistry; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D010919:Placebos; D011569:Psychiatric Status Rating Scales; D012720:Severity of Illness Index; D016896:Treatment Outcome
D015415:Biomarkers; D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D010919:Placebos; D001224:Aspartic Acid; D007294:Inositol; D000077265:Donepezil; C000179:N-acetylaspartate