Does donepezil treatment slow the progression of hippocampal atrophy in patients with Alzheimer's disease?
ABSTRACT 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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ABSTRACT: Reduced phospholipase A2 (PLA2) activity and increased phosphorylation of glycogen synthase kinase 3B (GSK3B) participate in the production of beta-amyloid plaques and of neurofibrillary tangles, which are two neuropathological hallmarks of Alzheimer's disease (AD). Experimental evidences suggest a neuroprotective effect of the cholinesterase inhibitor donepezil in the treatment the disease. The aims of the present study were to evaluate in AD patients the effects of treatment with donepezil on PLA2 activity and GSK3B level. Thirty patients with AD were treated during 6 months with 10 mg daily of donepezil. Radio-enzymatic assays were used to measure PLA2 activity and Elisa assays for GSK3B level, both in platelets. Before treatment and after 3 and 6 months on donepezil, AD patients underwent a cognitive assessment and platelet samples were collected. Values were compared to a healthy control group of 42 sex- and age-matched elderly individuals. Before treatment, iPLA2 activity was lower in patients with AD as compared to controls (p < 0.001). At baseline, no differences were found in GSK3B level between both groups. After 3 and 6 months of treatment, we found a significant increase in iPLA2 activity (p = 0.015 and p < 0.001, respectively). iPLA2 increment was related to the cognitive improvement during treatment (p = 0.037). After 6 months, we found an increase in phosphorylated GSK3B (p = 0.02). The present findings suggest two possible mechanisms by which donepezil delays the progression of AD. The increment of iPLA2 activity may reduce the production of beta-amyloid plaques, whereas the phosphorylation of GSK3B inactivates the enzyme, reducing thus the phosphorylation of tau protein.European Archives of Psychiatry and Clinical Neuroscience 04/2015; DOI:10.1007/s00406-015-0600-6 · 3.36 Impact Factor
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ABSTRACT: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most frequent cause of dementia in elderly people. Current therapies are directed against the symptoms and at best slow down the progress of the disease in some cases. Thus, it is of particular importance to find drugs focusing on the origins of AD. Recent studies indicate that soluble oligomers (up to 12mers and higher) of Aβ1−42 are highly neurotoxic at nanomolar levels and probably a major cause for the symptoms of AD. Furthermore, structural similarity was found between the oligomers of several amyloidogenic proteins. A compound that inhibits Aβ aggregation in AD may therefore prevent aggregation in other amyloid diseases as well, with little or no modification to the compounds. These findings indicate that inhibition of oligomer aggregation is an appealing approach for AD drug research. In this study, we show the effects of a library of 18 chemical compounds, based on a 2-pyridone structure which is known to interfere with Aβ assembly, on the formation of oligomers. These molecules fulfil Lipinski’s rule of 5 and thereby should readily pass the blood brain barrier after application. Oligomers of Aβ1−42 were prepared in the absence and presence of these compounds and identified using Western blotting, dot blotting and atomic force microscopy. The toxicity of these preparations was determined by applying them onto neural cell lines and measuring the cell viability with MTT, WST-1 and resazurin based assays. The results indicate that several compounds decreased neurotoxicity of the oligomeric preparations by inhibition of aggregation. Despite the high variation in toxicity between the individual preparations we identified a compound offering both, low toxicity and stable oligomerization inhibiting potency, which will serve as a lead molecule for further development. Also we demonstrate an impact of the applied oligomerization protocol on cell viability. After further optimization we hope our method will prove to be a useful method for screening drug candidates directed against Aβ oligomers.09/2007, Degree: Magister rer. nat., Supervisor: Johannes Berger
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ABSTRACT: Weight loss has been described in 20% to 45% of patients with Alzheimer's disease (AD) and has been associated with adverse outcomes. Various mechanisms for weight loss in AD patients have been proposed, though none has been proven. This study aimed to elucidate a mechanism of weight loss in AD patients by examining the hypothesis that weight loss is associated with medial temporal lobe atrophy (MTA). Patients from the Frisian Alzheimer's disease cohort study (a retrospective, longitudinal study of 576 community-dwelling AD patients) were included when a brain MRI was performed on which MTA could be assessed. To investigate the hypothesis that weight loss is associated with MTA, we investigated whether the trajectory of body weight change depends on the severity of MTA at the time of diagnosis (that is baseline). We hypothesized that patients with more severe MTA at baseline would have a lower body weight at baseline and a faster decrease in body weight during the course of the disease. The generalized linear mixed model (GLMM) was used to determine the relationship of weight change trajectory with MTA severity. In total, 214 patients (median age 79 years, median MMSE 23, mean weight 73.9 kg) were included. Patients with moderate, severe or very severe MTA at baseline weighed 3.2 to 6.8 kg more than patients with no or mild MTA. During the 3.5 years, patients gained on average 1.7 kg in body weight, irrespective of the severity of their MTA at baseline. We found no evidence that MTA is associated with weight loss in AD patients. Moreover, contrary to what was expected, AD patients did not lose but gained weight during follow-up.Alzheimer's Research and Therapy 12/2015; 7(1). DOI:10.1186/s13195-015-0098-1 · 3.50 Impact Factor