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      Drug Development in Alzheimer’s Disease: The Contribution of PET and SPECT

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          Abstract

          Clinical trials aiming to develop disease-altering drugs for Alzheimer’s disease (AD), a neurodegenerative disorder with devastating consequences, are failing at an alarming rate. Poorly defined inclusion-and outcome criteria, due to a limited amount of objective biomarkers, is one of the major concerns. Non-invasive molecular imaging techniques, positron emission tomography and single photon emission (computed) tomography (PET and SPE(C)T), allow visualization and quantification of a wide variety of (patho)physiological processes and allow early (differential) diagnosis in many disorders. PET and SPECT have the ability to provide biomarkers that permit spatial assessment of pathophysiological molecular changes and therefore objectively evaluate and follow up therapeutic response, especially in the brain. A number of specific PET/SPECT biomarkers used in support of emerging clinical therapies in AD are discussed in this review.

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          Most cited references 354

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          Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis.

          Soluble oligomers are common to most amyloids and may represent the primary toxic species of amyloids, like the Abeta peptide in Alzheimer's disease (AD). Here we show that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomers regardless of sequence. The in vitro toxicity of soluble oligomers is inhibited by oligomer-specific antibody. Soluble oligomers have a unique distribution in human AD brain that is distinct from fibrillar amyloid. These results indicate that different types of soluble amyloid oligomers have a common structure and suggest they share a common mechanism of toxicity.
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            The cholinergic hypothesis of geriatric memory dysfunction.

            Biochemical, electrophysiological, and pharmacological evidence supporting a role for cholinergic dysfunction in age-related memory disturbances is critically reviewed. An attempt has been made to identify pseudoissues, resolve certain controversies, and clarify misconceptions that have occurred in the literature. Significant cholinergic dysfunctions occur in the aged and demented central nervous system, relationships between these changes and loss of memory exist, similar memory deficits can be artificially induced by blocking cholinergic mechanisms in young subjects, and under certain tightly controlled conditions reliable memory improvements in aged subjects can be achieved after cholinergic stimulation. Conventional attempts to reduce memory impairments in clinical trials hav not been therapeutically successful, however. Possible explanations for these disappointments are given and directions for future laboratory and clinical studies are suggested.
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              Tau-mediated neurodegeneration in Alzheimer's disease and related disorders.

              Advances in our understanding of the mechanisms of tau-mediated neurodegeneration in Alzheimer's disease (AD) and related tauopathies, which are characterized by prominent CNS accumulations of fibrillar tau inclusions, are rapidly moving this previously underexplored disease pathway to centre stage for disease-modifying drug discovery efforts. However, controversies abound concerning whether or not the deleterious effects of tau pathologies result from toxic gains-of-function by pathological tau or from critical losses of normal tau function in the disease state. This Review summarizes the most recent advances in our knowledge of the mechanisms of tau-mediated neurodegeneration to forge an integrated concept of those tau-linked disease processes that drive the onset and progression of AD and related tauopathies.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                31 March 2016
                2016
                : 7
                Affiliations
                1Laboratory for Radiopharmacy, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven Leuven, Belgium
                2Laboratory for Cognitive Neurology, Department of Neurosciences, KU Leuven Leuven, Belgium
                3Nuclear Medicine and Molecular Imaging, Department of Imaging and Pathology, KU Leuven Leuven, Belgium
                Author notes

                Edited by: Albert D. Windhorst, VU University Medical Center, Netherlands

                Reviewed by: Bashir M. Rezk, Southern University at New Orleans, USA; Carmen Gil, Centro de Investigaciones Biologicas (CIB–CSIC), Spain

                *Correspondence: Guy Bormans, guy.bormans@ 123456pharm.kuleuven.be

                This article was submitted to Experimental Pharmacology and Drug Discovery, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2016.00088
                4814730
                27065872
                Copyright © 2016 Declercq, Vandenberghe, Van Laere, Verbruggen and Bormans.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 11, Tables: 2, Equations: 0, References: 422, Pages: 27, Words: 0
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine

                alzheimer’s disease, pet, spect, drug development, biomarkers

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