Journal of Alzheimer's disease : JAD
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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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PET imaging of amyloid-β has recently emerged as a valuable biomarker to support the in vivo diagnosis of Alzheimer's disease (AD). So far, however, no tracer is available suitable for general clinical routine application. Florbetaben is a promising 18F-labeled amyloid-β-targeted PET tracer currently in Phase 2/3 clinical development. ⋯ Ongoing florbetaben PET trials deal with correlating the in vivo PET signal to post mortem histopathology evaluation, and with investigating the value of the tracer to predict progression to AD at the stage of mild cognitive impairment. The preclinical and clinical data currently available verify florbetaben as a safe and efficacious PET tracer suitable for detection of amyloid-β deposition in the brain. The results of the ongoing trials will contribute to current knowledge on the characteristics of florbetaben, and will help to determine the future potential of florbetaben PET imaging as a visual adjunct to supplement the routine clinical "AD diagnostic toolbox".
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A strong perception exists that elderly people are at risk for persistent cognitive deterioration lasting longer than six months following major surgery, particularly heart surgery. Furthermore, based on laboratory evidence, investigators hypothesize that surgery or anesthesia might precipitate incident dementia. Recent clinical studies have found that cognition might frequently be impaired within the first few months postoperatively, and that such impairment may be associated with death or debility. ⋯ There is evidence that most patients recover cognition in the long-term, and that for those who experience persistent decline, this is probably attributable to underlying undiagnosed neurological disease or other co-morbidities rather than to surgery or to anesthesia. There is currently minimal clinical evidence linking surgery or anesthesia to incident dementia. Rigorous clinical research is needed to resolve the controversy whether anesthesia or surgery is likely to cause persistent neurological decline or to precipitate dementia.
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Comparative Study
Episodic memory decline predicts cortical amyloid status in community-dwelling older adults.
Intra-individual decline in memory and cognition is characteristic of prodromal Alzheimer's disease (AD) and may allow detection of very early AD pathology. Episodic memory task scores on a brief computerized cognitive battery (CogState) were prospectively evaluated at baseline, and 3-, 6-, 9-, 12-, and 24-months post-baseline. Linear mixed models were conducted to compute age-adjusted slopes. ⋯ One of the memory decliners and none of the non-decliners fulfilled criteria for mild cognitive impairment, but the groups did not differ with respect to subjective memory impairment, neuropsychological evidence of episodic memory impairment, or MRI imaging abnormalities. Intra-individual decline in episodic memory can be detected using a brief computerized cognitive performance test optimized to detect change in community-dwelling non-demented older persons and appears predictive of the presence of cerebral amyloid in about half of these persons. This approach may help detect early prodromal AD pathology in wider-scale community screening programs.
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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.