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 references 118

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Sleep drives metabolite clearance from the adult brain.

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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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Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.

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Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease.

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Author and article information

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Krista L. Lanctôt

Journal

Journal ID (nlm-ta): Alzheimers Dement (N Y)

Journal ID (iso-abbrev): Alzheimers Dement (N Y)

Title: Alzheimer's & Dementia : Translational Research & Clinical Interventions

Publisher: Elsevier

ISSN (Electronic): 2352-8737

Publication date PMC-release: 05 August 2017

Publication date Collection: September 2017

Publication date (Electronic): 05 August 2017

Volume: 3

Issue: 3

Pages: 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

Publisher ID: S2352-8737(17)30045-8

DOI: 10.1016/j.trci.2017.07.001

PMC ID: 5651439

PubMed ID: 29067350

SO-VID: b47b6df6-bede-4a46-9620-fe9b0c4c8b3a

License:

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

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

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Abstract

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Alternative approaches to Alzheimer's Disease

Most cited references 118

Sleep drives metabolite clearance from the adult brain.

The Neuropsychiatric Inventory: Comprehensive assessment of psychopathology in dementia

Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.

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