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Effect of Suvorexant on Alzheimer's Disease Biomarkers

Suvorexant 对阿尔茨海默病生物标志物的影响

基本信息

批准号：
10584093
负责人：
Brendan Patrick Lucey
金额：
$ 159.55万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-15 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10584093
关键词：
Acute Adult Adverse effects Affect Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Alzheimer’s disease biomarker Amyloid Amyloid beta-42 Amyloid beta-Protein Amyloid beta-Protein Precursor Amyloid deposition Animal Model Biological Biological Markers Blood Cerebrospinal Fluid Cessation of life Chronic Cognition Cognitive Data Dementia Deposition Dose Drug Kinetics FDA approved Hour Human Immune response Immunologic Markers Impaired cognition Individual Inflammatory Intercellular Fluid Liquid substance Measures Mediating Mus Nerve Degeneration Neuropeptides Participant Pathogenesis Pharmacodynamics Phase Phosphorylation Site Placebos Plasma Polysomnography Prevention approach Prevention trial Primary Prevention Process Production Protein Isoforms Proteins Protocols documentation Puncture procedure Randomized Reporting Safety Sampling Secondary Prevention Senile Plaques Sleep Sleep Deprivation Sleep Wake Cycle Sleep disturbances Sleeplessness Spinal Puncture Synapses Target Populations Tauopathies Testing Transgenic Mice Treatment Effectiveness Venous Wakefulness abeta deposition amyloid pathology antagonist design feasibility testing human old age (65+)hyperphosphorylated tau hypocretin innovation modifiable risk primary outcome receptor response safety assessment sleep quality success synaptic function tau Proteins tau aggregation tau-1 treatment effect trial design

项目摘要

PROJECT SUMMARY Sleep disturbances are increasingly recognized as a risk factor for Alzheimer’s disease (AD) and a marker for Alzheimer’s disease pathology. The sleep-wake cycle affects the cerebrospinal fluid (CSF) concentrations of proteins critical to Alzheimer’s disease pathogenesis. We recently reported that overnight sleep disruption increases CSF amyloid-β (Aβ) levels by ~30% via increased production/release. Orexins (also called hypocretins) are wake-promoting neuropeptides. Chronic administration of a dual orexin receptor antagonist (DORA) to increase sleep in amyloid precursor protein (APP) transgenic mice decreased both the soluble concentration of Aβ in interstitial fluid and amyloid plaque formation. Our preliminary data shows that a DORA, suvorexant, acutely decreases the ratio of phosphorylated tau-181 (pT181) to unphosphorylated tau-181 (T181) in CSF. Although previous studies examined sleep-mediated changes in CSF Aβ and tau over hours, it is unknown how chronic administration of DORAs affect plasma and CSF tau, phosphorylated tau (p-tau), Aβ, and other Alzheimer’s disease fluid biomarkers in individuals with Alzheimer’s pathology. In this project, we will test the hypothesis that chronic treatment with suvorexant for 6 months will decrease CSF pT181/T181 and other CSF and plasma AD biomarkers. In this project, we will use an innovative adaptive trial design to test the potential of chronic treatment with suvorexant for secondary prevention of Alzheimer’s disease. 200 cognitively normal, amyloid-positive adults with symptomatic insomnia age ≥65 years will be randomized to receive placebo or suvorexant for 6 months. Each participant will undergo polysomnography as well as lumbar and venous puncture to sample CSF and blood at baseline, 3 months, and 6 months. We will test the hypothesis that chronic treatment with suvorexant will decrease CSF pT181/T181 as well as determine the effect on CSF plasma Aβ, CSF and plasma tau, other forms of CSF and plasma p-tau, and CSF markers for immune response (microglial function), synaptic function, and non-tau measures of neuronal degeneration. Optimal trial design is essential prior to launching a full secondary prevention trial with a maximum chance of success. This study will provide critical information for designing Alzheimer’s disease secondary prevention trial using suvorexant obtaining data on pharmacokinetics, safety, and chronic effects of suvorexant on multiple soluble Alzheimer’s disease biomarkers.

项目总结