Journal of Alzheimer's disease : JAD
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Randomized Controlled Trial
Effect of donepezil on cognition in severe Alzheimer's disease: a pooled data analysis.
To better characterize response to donepezil in patients with severe AD, Severe Impairment Battery (SIB) data were pooled from four donepezil clinical trials (N=904). Changes in SIB total and domain scores from baseline to week 24 were compared between placebo and donepezil treatment groups (observed case analysis). Analyses were stratified by baseline severity (Mini-Mental State Examination [MMSE] scores 1-5, 6-9, 10-12 and 13-17) to allow investigation of responses at different stages of cognitive impairment. ⋯ Change in total SIB score correlated significantly with change in measures of activities of daily living and global status. These results indicate that donepezil provides cognitive benefits in patients with severe AD, including those most markedly impaired. The treatment effect size and correlation between improvements in SIB scores and functional and global outcome measures suggest the drug-placebo differences are clinically meaningful.
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Review
Protective role of methylene blue in Alzheimer's disease via mitochondria and cytochrome c oxidase.
The key cytopathologies in the brains of Alzheimer's disease (AD) patients include mitochondrial dysfunction and energy hypometabolism, which are likely caused by the accumulation of toxic species of amyloid-beta (Abeta) peptides. This review discusses two potential approaches to delay the onset of AD. The first approach is use of diaminophenothiazines (e.g., methylene blue; MB) to prevent mitochondrial dysfunction and to attenuate energy hypometabolism. ⋯ Osmolytes may inhibit the formation of Abeta species in vivo, thus preventing the formation of soluble oligomers. Osmolytes are efficient antioxidants that may also increase neural resistance to Abeta. The potential significance of combining MB and osmolytes to treat AD are discussed.
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Comparative Study
The outcome of elderly patients with cognitive complaints but normal neuropsychological tests.
Elderly patients may present with prominent cognitive complaints and have performances in neuropsychological tests within the normal range for the age and education, and thus do not fulfill the criteria for mild cognitive impairment (MCI). There is insufficient evidence to support the clinical decision in these cases ("pre-MCI"). Forty-three subjects, 11 controls, 15 "pre-MCI," and 17 MCI, were followed for about three and half years with neuropsychological testing and magnetic resonance imaging including volumetric measurements of the hippocampus and amygdala. ⋯ In contrast, all control subjects remained stable and had no volumetric decreases. As expected, MCI patients underwent significant deterioration in several neuropsychological tests, often progressed to Alzheimer's disease, and showed decreases both in total hippocampal and amygdalar volumes. Elderly people presenting with cognitive complaints may be in an initial phase of a degenerative disorder and should be followed clinically, even if they have normal neuropsychological tests.
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Amyloid-β (Aβ) peptide-induced impairment of hippocampal synaptic plasticity is considered an underlying mechanism for memory loss in the early stages of Alzheimer's disease and its animal models. We previously reported inhibition of long-term potentiation (LTP) and miniature excitatory postsynaptic currents by oligomeric Aβ(1-42) at hippocampal synapses. While multiple cellular mechanisms could be involved in Aβ-induced synaptic dysfunction, blockade of activity-dependent autophosphorylation of Ca2+ and calmodulin-dependent protein kinase II (CaMKII) appeared to be a major component of Aβ action in our studies. ⋯ Aβ-induced LTP impairment, however, was prevented when slices were co-treated with neurotrophin 4 (NT4). Western blotting and immunohistochemical analyses confirmed that treatment with NT4 or brain-derived neurotrophic factor, another trkB-acting neurotrophin, could oppose Aβ action, enhancing autophosphorylation of CaMKII, and AMPA receptor phosphorylation at a CaMKII-dependent site. These findings support the view that CaMKII is a key synaptic target of Aβ toxicity as well as a potential therapeutic site of neurotrophins for Alzheimer's disease.
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For studying rare hereditary Alzheimer's disease (AD), transgenic (Tg) animal models overexpressing amyloid-beta protein precursor (AbetaPP) followed by increased amyloid-beta (Abeta) formation are used. In contrast, sporadic AD has been proposed to start with an insulin-resistant brain state (IRBS). We investigated the effect of IRBS induced by intracerebroventricularly (icv) administered streptozotocin (STZ) on behavior, glycogen synthase kinase-3 (GSK) alpha/beta content, and the formation of AD-like morphological hallmarks Abeta and tau protein in AbetaPP Tg2576 mice. ⋯ A linear negative correlation was detected between Abeta42 and cognition, and between GSK-3alpha/beta ratio and aggregated Abeta40+42. No marked necrotic and apoptotic changes were observed. In conclusion, IRBS may aggravate AD-like changes such as behavioral and increase the formation of pathomorphological AD hallmarks via GSK-3alpha/beta pathway in AbetaPP-overexpressing mice.