Does Donepezil Treatment Slow the Progression of Hippocampal Atrophy in Patients With Alzheimer’s Disease?

Osaka University, Suika, Ōsaka, Japan
American Journal of Psychiatry (Impact Factor: 12.3). 05/2005; 162(4):676-82. DOI: 10.1176/appi.ajp.162.4.676
Source: PubMed


The only approved pharmacological approach for the symptomatic treatment of Alzheimer's disease in Japan is the use of a cholinesterase inhibitor, donepezil hydrochloride. Recent in vivo and in vitro studies raise the possibility that cholinesterase inhibitors can slow the progression of Alzheimer's disease. The purpose of the present study was to determine whether donepezil has a neuroprotective effect in Alzheimer's disease by using the rate of hippocampal atrophy as a surrogate marker of disease progression.
In a prospective cohort study, 54 patients with Alzheimer's disease who received donepezil treatment and 93 control patients with Alzheimer's disease who never received anti-Alzheimer drugs underwent magnetic resonance imaging (MRI) twice at a 1-year interval. The annual rate of hippocampal atrophy of each subject was determined by using an MRI-based volumetric technique. Background characteristics, age, sex, disease duration, education, MRI interval, apolipoprotein E (APOE) genotype, and baseline Alzheimer's Disease Assessment Scale score were comparable between the treated and control groups.
The mean annual rate of hippocampal volume loss among the treated patients (mean=3.82%, SD=2.84%) was significantly smaller than that among the control patients (mean=5.04%, SD=2.54%). Upon analysis of covariance, where those confounding variables (age, sex, disease duration, education, MRI interval, APOE genotype, and baseline Alzheimer's Disease Assessment Scale score) were entered into the model as covariates, the effect of donepezil treatment on hippocampal atrophy remained significant.
Donepezil treatment slows the progression of hippocampal atrophy, suggesting a neuroprotective effect of donepezil in Alzheimer's disease.

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    • "Donepezil hydrochloride (HCl) is a chemically unique, piperidine-based acetylcholinesterase inhibitor that has shown cognitive and functional benefit in the treatment of mild, moderate, and severe AD dementia in multiple randomized controlled trials [9]. In addition to its symptomatic effects on memory and cognition, donepezil has demonstrated some effects on the cellular and molecular system level associated with AD in nonclinical studies that may contribute to the significant changes observed on hippocampus in patients with mild moderate AD dementia treated with donepezil [10] [11]. In subjects with MCI, the effect of donepezil is less clearly understood. "
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    ABSTRACT: To study the effect of donepezil on the rate of hippocampal atrophy in prodromal Alzheimer's disease (AD). A double-blind, randomized, placebo-controlled parallel group design using donepezil (10 mg/day) in subjects with suspected prodromal AD. Subjects underwent two brain magnetic resonance imaging scans (baseline and final visit). The primary efficacy outcome was the annualized percentage change (APC) of total hippocampal volume (left + right) measured by an automated segmentation method. Two-hundred and sixteen only subjects were randomized across 28 French expert clinical sites. In the per protocol population (placebo = 92 and donepezil = 82), the donepezil group exhibited a significant reduced rate of hippocampal atrophy (APC = -1.89%) compared with the placebo group (APC = -3.47%), P < .001. There was no significant difference in neuropsychological performance between treatment groups. A 45% reduction of rate of hippocampal atrophy was observed in prodromal AD following 1 year of treatment with donepezil compared with placebo. Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
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    • "Previous studies demonstrated that AChE inhibitors, such as donepezil and galantamine, exert a protective effect via the nicotinic acetylcholine receptor (nAChR)-mediated cascade [21,22]. In addition, it has been reported that AChE inhibitors inhibit the progress of brain atrophy in AD [23], indicating the attenuation of neuronal death in the brain of the patients. "
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    • "The neuropathology of AD includes widespread neuronal cell loss, neurofibrillary tangles (such as aggregation of tau proteins), and senile plaques (including extracellular aggregates of amyloid ␤-peptides) starting in the entorhinal cortex and limbic areas during the early stages of the disease, followed by spreading to other parts of the cortex (Braak and Braak, 1991). Recently, several studies have suggested that pharmacological treatment of mild cognitive impairment and early AD can slow the development of the disease (Hashimoto et al., 2005; Pietrzik and Behl, 2005). "
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