Journal of Alzheimer's disease : JAD
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Randomized Controlled Trial Multicenter Study Comparative Study Clinical Trial
Memantine in behavioral variant frontotemporal dementia: negative results.
We tested the efficacy and tolerability of one-year treatment with memantine (10 mg bid) in behavioral variant frontotemporal dementia (bvFTD). BvFTD patients aged 45 to 75 years, with a Mini-Mental Status Examination (MMSE) score ≥19, were enrolled in a national, randomized, double-blind, placebo-controlled (DBPC), Phase II trial. The primary endpoint was the CIBIC-Plus (Clinician's Interview-Based Impression of Change Plus Caregiver Input). ⋯ This is the first DBPC trial in a large group of bvFTD patients involving neuroprotective treatment. A multinational study with a larger number of patients is now needed in order to verify the results of our study. The trial is registered with ClinicalTrials.gov; number NCT 00200538.
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Review
Membrane anchored and lipid raft targeted β-secretase inhibitors for Alzheimer's disease therapy.
β-secretase, a key enzyme involved in amyloid-β generation, is an attractive candidate for Alzheimer's disease therapy. Transition-state inhibitors of β-secretase are designed to achieve specificity. However, these inhibitors bind only to the active conformation of the enzyme and as the active β-secretase is sequestered in subcellular compartments, new strategies have to be implemented. ⋯ In addition, membrane-anchoring of soluble inhibitors reduces the dimensionality of the inhibitor and consequently increases the inhibitor concentration at the target membrane plane. Such inhibitors have great potential in terms of substrate selectivity and reduced side effects. Not only for β-secretase, this strategy could be applied for many membrane targets that are localized either at the plasma membrane or in the endocytic compartments.
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Multicenter Study Clinical Trial
Sustained effects of once-daily memantine treatment on cognition and functional communication skills in patients with moderate to severe Alzheimer's disease: results of a 16-week open-label trial.
The present study evaluated the effects of once-daily memantine (20 mg) treatment on cognition and communication in patients with moderate to severe Alzheimer's disease (AD). In a multicenter, single-arm open-label study, outpatients diagnosed with AD (MMSE < 20; n = 97) were titrated from 5 mg to 20 mg once-daily memantine over 4 weeks. Once-daily memantine treatment (20 mg) was then continued for 8 weeks, followed by a 4-week wash-out period. ⋯ ADCS-ADL19 total scores showed only slight increases from baseline, and CGI-C indicated that the majority of patients experienced an improvement or stabilization of the disease after 12 weeks. At least one Treatment-Emergent Adverse Event was reported by 38 (39.2%) patients. In patients with moderate to severe AD, once-daily memantine (20 mg) treatment significantly improved cognition and functional communication and was found to have a favorable safety and tolerability profile.
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The aim of this study was to predict cognitive performance on the basis of the cerebrospinal fluid (CSF) biomarkers total tau (T-tau) and amyloid-β₄₂ (Aβ₄₂) in controls and patients at various impairment levels. Previous studies have found an association of CSF T-tau levels with cognitive symptoms, but it has been difficult to relate Aβ to cognition, and it has thus been hypothesized that Aβ reaches a plateau level prior to cognitive symptoms. A comprehensive battery of neuropsychological tests was subjected to factor analysis to yield aggregated cognitive domains. ⋯ For patients with dementia (n = 100), the most pronounced impacts of Aβ₄₂ were found in episodic memory and visuospatial functioning, while T-tau was substantially associated with episodic memory. Our results suggest that cognition is related to CSF biomarkers regardless of impairment level. Aβ₄₂ is associated with cognitive functions from a potentially early to a later disease phase, and T-tau is more indicative of performance in a later disease phase.
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Amyloid-β (Aβ) is the core component of amyloid plaques of Alzheimer's disease (AD). The effects of Aβ include damage to neuronal plasma membrane, disruption of Ca(2+) homeostasis, and alterations of neurotrophic factor levels. The aim of this study was to determine the effects of Aβ treatment on vitamin D receptor (VDR), L-type voltage sensitive calcium channels A1C (LVSCC A1C), NGF, and observing the effects of vitamin D treatment on Aβ induced alterations in primary cortical neurons. ⋯ Administration of vitamin D to this model protected neurons by preventing cytotoxicity and apoptosis, and also by downregulating LVSCC A1C and upregulating VDR. Additionally, vitamin D brought NGF expression to a state of equilibrium and did not show its apoptosis inducing effects. Consequently, prevention of Aβ toxicity which was one of the major component of AD type pathology by vitamin D treatment and understanding how Aβ effects vitamin D related pathways, might open up new frontiers in clarifying molecular mechanisms of neurodegeneration and provide basis for novel perspectives in both preventing and treating AD.