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.
"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 . 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  . In subjects with MCI, the effect of donepezil is less clearly understood. "
"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 , indicating the attenuation of neuronal death in the brain of the patients. "
[Show abstract][Hide abstract] ABSTRACT: Tolerance to the analgesic effect of opioids is a pharmacological phenomenon that occurs after their prolonged administration. It has been shown that morphine-induced tolerance is associated with apoptosis in the central nervous system and neuroprotective agents which prevented apoptosis signaling could attenuate tolerance to the analgesic effects. On the other hand donepezil, an acetylcholinesterase inhibitor, has been reported to have neuroprotective effects. Therefore in this study, the effect of systemic administration of donepezil on morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord was evaluated. Various groups of rats received morphine (ip) and different doses of donepezil (0, 0.5, 1, 1.5 mg/kg/day). Nociception was assessed using tail flick apparatus. Tail flick latency was recorded when the rat shook its tail. For apoptosis assay other groups of rats received the above treatment and apoptosis was evaluated by in situ terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) method.
The results showed that administration of donepezil (0.5, 1, 1.5 mg/kg, ip) delayed the morphine tolerance for 9, 12 and 17 days, respectively. Furthermore pretreatment injection of donepezil attenuated the number of apoptotic cells in the cerebral cortex and lumbar spinal cord compared to the control group.
In conclusion, we found that systemic administration of donepezil attenuated morphine-induced tolerance and apoptosis in the rat cerebral cortex and lumbar spinal cord.
"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). "
[Show abstract][Hide abstract] ABSTRACT: Methods for the extraction of features from physiological datasets are growing needs as clinical investigations of Alzheimer's disease (AD) in large and heterogeneous population increase. General tools allowing diagnostic regardless of recording sites, such as different hospitals, are essential and if combined to inexpensive non-invasive methods could critically improve mass screening of subjects with AD. In this study, we applied two state of the art multiway array decomposition (MAD) methods to extract unique features from electroencephalograms (EEGs) of AD patients obtained from multiple sites. In comparison to MAD, spectral-spatial average filter (SSFs) of control and AD subjects were used as well as a common blind source separation method, algorithm for multiple unknown signal extraction (AMUSE), and singular value decomposition (SVD) coupled to tensor unfolding. We trained a feed-forward multilayer perceptron (MLP) to validate and optimize AD classification from two independent databases. Using a third EEG dataset, we demonstrated that features extracted from MAD outperformed features obtained from SSFs AMUSE in terms of root mean squared error (RMSE) and reaching up to 100% of accuracy in test condition. We propose that MAD maybe a useful tool to extract features for AD diagnosis offering great generalization across multi-site databases and opening doors to the discovery of new characterization of the disease.
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