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      Neuropsychiatric signs and symptoms of Alzheimer's disease: New treatment paradigms

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          Abstract

          Neuropsychiatric symptoms (NPSs) are hallmarks of Alzheimer's disease (AD), causing substantial distress for both people with dementia and their caregivers, and contributing to early institutionalization. They are among the earliest signs and symptoms of neurocognitive disorders and incipient cognitive decline, yet are under-recognized and often challenging to treat. With this in mind, the Alzheimer's Association convened a Research Roundtable in May 2016, bringing together experts from academia, industry, and regulatory agencies to discuss the latest understanding of NPSs and review the development of therapeutics and biomarkers of NPSs in AD. This review will explore the neurobiology of NPSs in AD and specific symptoms common in AD such as psychosis, agitation, apathy, depression, and sleep disturbances. In addition, clinical trial designs for NPSs in AD and regulatory considerations will be discussed.

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          Most cited references118

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          Sleep drives metabolite clearance from the adult brain.

          The conservation of sleep across all animal species suggests that sleep serves a vital function. We here report that sleep has a critical function in ensuring metabolic homeostasis. Using real-time assessments of tetramethylammonium diffusion and two-photon imaging in live mice, we show that natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of β-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.
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            The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia

            Neurology, 44(12), 2308-2308
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              Nonpharmacological Therapies in Alzheimer’s Disease: A Systematic Review of Efficacy

              Introduction: Nonpharmacological therapies (NPTs) can improve the quality of life (QoL) of people with Alzheimer’s disease (AD) and their carers. The objective of this study was to evaluate the best evidence on the effects of NPTs in AD and related disorders (ADRD) by performing a systematic review and meta-analysis of the entire field. Methods: Existing reviews and major electronic databases were searched for randomized controlled trials (RCTs). The deadline for study inclusion was September 15, 2008. Intervention categories and outcome domains were predefined by consensus. Two researchers working together detected 1,313 candidate studies of which 179 RCTs belonging to 26 intervention categories were selected. Cognitive deterioration had to be documented in all participants, and degenerative etiology (indicating dementia) had to be present or presumed in at least 80% of the subjects. Evidence tables, meta-analysis and summaries of results were elaborated by the first author and reviewed by author subgroups. Methods for rating level of evidence and grading practice recommendations were adapted from the Oxford Center for Evidence-Based Medicine. Results: Grade A treatment recommendation was achieved for institutionalization delay (multicomponent interventions for the caregiver, CG). Grade B recommendation was reached for the person with dementia (PWD) for: improvement in cognition (cognitive training, cognitive stimulation, multicomponent interventions for the PWD); activities of daily living (ADL) (ADL training, multicomponent interventions for the PWD); behavior (cognitive stimulation, multicomponent interventions for the PWD, behavioral interventions, professional CG training); mood (multicomponent interventions for the PWD); QoL (multicomponent interventions for PWD and CG) and restraint prevention (professional CG training); for the CG, grade B was also reached for: CG mood (CG education, CG support, multicomponent interventions for the CG); CG psychological well-being (cognitive stimulation, multicomponent interventions for the CG); CG QoL (multicomponent interventions for PWD and CG). Conclusion: NPTs emerge as a useful, versatile and potentially cost-effective approach to improve outcomes and QoL in ADRD for both the PWD and CG.
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                Author and article information

                Contributors
                Journal
                Alzheimers Dement (N Y)
                Alzheimers Dement (N Y)
                Alzheimer's & Dementia : Translational Research & Clinical Interventions
                Elsevier
                2352-8737
                05 August 2017
                September 2017
                05 August 2017
                : 3
                : 3
                : 440-449
                Affiliations
                [a ]Hurvitz Brain Sciences Program, Sunnybrook Research Institute and Departments of Psychiatry and Pharmacology, University of Toronto, Toronto, Canada
                [b ]Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA
                [c ]Department of Psychiatry, University of California, San Diego, CA, USA
                [d ]Department of Medicine, University of California, San Diego, CA, USA
                [e ]Interdisciplinary Brain Center, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
                [f ]Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK
                [g ]University of Exeter, Exeter, UK
                [h ]Department of Health Promotion, School of Public Health, Sackler Faculty of Medicine and Minerva Center for the Interdisciplinary Study of End of Life, Tel Aviv University, Tel Aviv, Israel
                [i ]Department of Psychiatry, Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada
                [j ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins Medicine Institutes, Baltimore, MD, USA
                [k ]Bracket Global, Wayne, PA, USA
                [l ]Department of Neurology, Hope Center for Neurological Disorders, and Knight Alzheimer Disease Research Center, Washington University School of Medicine, St. Louis, MO, USA
                [m ]Center for Brain Health, NYU Langone Medical Center, New York, NY, USA
                [n ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA
                [o ]Eisai, Inc., Woodcliff Lake, NJ, USA
                [p ]Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA
                [q ]Banner Alzheimer's Institute, Phoenix, AZ, USA
                [r ]Elverson, PA, USA
                [s ]Alzheimer's Association, Chicago, IL, USA
                [t ]Department of Neurology, Brigham and Women's Hospital, Harvard University School of Medicine, Boston, MA, USA
                [u ]Voyager Therapeutics, Cambridge, MA, USA
                Author notes
                []Corresponding author. Tel.: +1-4164806100; Fax: +1-4164806022. krista.lanctot@ 123456sunnybrook.ca
                Article
                S2352-8737(17)30045-8
                10.1016/j.trci.2017.07.001
                5651439
                b47b6df6-bede-4a46-9620-fe9b0c4c8b3a
                © 2017 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Review Article

                alzheimer's disease,neuropsychiatric symptoms,trial design,delusions,hallucinations,agitation,apathy,depression,sleep disturbance

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