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      In Alzheimer’s Disease, 6-Month Treatment with GLP-1 Analog Prevents Decline of Brain Glucose Metabolism: Randomized, Placebo-Controlled, Double-Blind Clinical Trial

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          Abstract

          In animal models, the incretin hormone GLP-1 affects Alzheimer’s disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of Aβ and raise, or prevent decline of, glucose metabolism (CMR glc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP-1 analog liraglutide ( n = 18), or placebo ( n = 20). We measured Aβ load in brain with tracer [ 11C]PIB (PIB), CMR glc with [ 18F]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients ( P = 0.04). Regional and global increases of PIB retention did not differ between the groups ( P ≥ 0.38). In placebo treated patients CMR glc declined in all regions, significantly so by the following means in precuneus ( P = 0.009, 3.2 μmol/hg/min, 95% CI: 5.45; 0.92), and in parietal ( P = 0.04, 2.1 μmol/hg/min, 95% CI: 4.21; 0.081), temporal ( P = 0.046, 1.54 μmol/hg/min, 95% CI: 3.05; 0.030), and occipital ( P = 0.009, 2.10 μmol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum ( P = 0.04, 1.54 μmol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMR glc after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMR glc that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the Aβ load or cognition measures, for which the study was underpowered.

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          Most cited references 49

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          Advancing research diagnostic criteria for Alzheimer's disease: the IWG-2 criteria.

          In the past 8 years, both the International Working Group (IWG) and the US National Institute on Aging-Alzheimer's Association have contributed criteria for the diagnosis of Alzheimer's disease (AD) that better define clinical phenotypes and integrate biomarkers into the diagnostic process, covering the full staging of the disease. This Position Paper considers the strengths and limitations of the IWG research diagnostic criteria and proposes advances to improve the diagnostic framework. On the basis of these refinements, the diagnosis of AD can be simplified, requiring the presence of an appropriate clinical AD phenotype (typical or atypical) and a pathophysiological biomarker consistent with the presence of Alzheimer's pathology. We propose that downstream topographical biomarkers of the disease, such as volumetric MRI and fluorodeoxyglucose PET, might better serve in the measurement and monitoring of the course of disease. This paper also elaborates on the specific diagnostic criteria for atypical forms of AD, for mixed AD, and for the preclinical states of AD. Copyright © 2014 Elsevier Ltd. All rights reserved.
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            Alzheimer's disease: the amyloid cascade hypothesis

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              An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers.

              Defective brain insulin signaling has been suggested to contribute to the cognitive deficits in patients with Alzheimer's disease (AD). Although a connection between AD and diabetes has been suggested, a major unknown is the mechanism(s) by which insulin resistance in the brain arises in individuals with AD. Here, we show that serine phosphorylation of IRS-1 (IRS-1pSer) is common to both diseases. Brain tissue from humans with AD had elevated levels of IRS-1pSer and activated JNK, analogous to what occurs in peripheral tissue in patients with diabetes. We found that amyloid-β peptide (Aβ) oligomers, synaptotoxins that accumulate in the brains of AD patients, activated the JNK/TNF-α pathway, induced IRS-1 phosphorylation at multiple serine residues, and inhibited physiological IRS-1pTyr in mature cultured hippocampal neurons. Impaired IRS-1 signaling was also present in the hippocampi of Tg mice with a brain condition that models AD. Importantly, intracerebroventricular injection of Aβ oligomers triggered hippocampal IRS-1pSer and JNK activation in cynomolgus monkeys. The oligomer-induced neuronal pathologies observed in vitro, including impaired axonal transport, were prevented by exposure to exendin-4 (exenatide), an anti-diabetes agent. In Tg mice, exendin-4 decreased levels of hippocampal IRS-1pSer and activated JNK and improved behavioral measures of cognition. By establishing molecular links between the dysregulated insulin signaling in AD and diabetes, our results open avenues for the investigation of new therapeutics in AD.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                24 May 2016
                2016
                : 8
                Affiliations
                1Institute of Biomedicine, Aarhus University Aarhus, Denmark
                2Department of Nuclear Medicine and PET Center, Aarhus University Hospital Aarhus, Denmark
                3Department of Neuroscience and Pharmacology, University of Copenhagen Copenhagen, Denmark
                4Dementia Clinic, Department of Neurology, Aarhus University Hospital Aarhus, Denmark
                5Department of Endocrinology, Aarhus University Hospital Aarhus, Denmark
                6Department of Clinical Biochemistry, Aarhus University Hospital Aarhus, Denmark
                7Center for Diabetes Research and Department of Clinical Pharmacology, Copenhagen University Hospital Gentofte and Rigshospitalet Copenhagen, Denmark
                Author notes

                Edited by: Naoyuki Sato, Osaka University, Japan

                Reviewed by: Christian Hölscher, Lancaster University, UK; Ramesh Kandimalla, Emory University, USA

                *Correspondence: Jørgen Rungby, jr@ 123456farm.au.dk
                Article
                10.3389/fnagi.2016.00108
                4877513
                27252647
                04a87cc4-1b8e-474e-9dba-19e9cb792192
                Copyright © 2016 Gejl, Gjedde, Egefjord, Møller, Hansen, Vang, Rodell, Brændgaard, Gottrup, Schacht, Møller, Brock and Rungby.

                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: 2, Tables: 4, Equations: 1, References: 48, Pages: 10, Words: 0
                Categories
                Neuroscience
                Original Research

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