RCT Targeting Cognition in Early Alzheimer's Disease by Improving Sleep with Trazodone (Rest)

通过曲唑酮（休息）改善睡眠来针对早期阿尔茨海默病认知的随机对照试验

• 批准号: 10477205
• 负责人: Barry David Greenberg
• 金额: $ 74.83万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10477205
• 关键词: Acute; Affect; Alleles; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid deposition; Animal Model; Animals; Antidepressive Agents; Attention; Benign; Biological Markers; Brain; Cerebrospinal Fluid; Cognition; Cognitive; Cross-Over Trials; Data; Dementia; Development; Disease; Disease Progression; Double-Blind Method; Drug Targeting; Elderly; FDA approved; Family Caregiver; Functional Magnetic Resonance Imaging; Health Care Costs; Hippocampus (Brain); Home; Human; Impaired cognition; Impairment; Individual; Insecta; Intercellular Fluid; Link; Measures; Mediating; Memory; Modification; Morbidity - disease rate; Observational Study; Outcome; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patient Self-Report; Pattern; Performance; Persons; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Polysomnography; Process; Public Health; Quality of life; Randomized; Research Personnel; Rest; Risk; Rodent; Safety; Sleep; Sleep Deprivation; Sleep Fragmentations; Sleep disturbances; Slow-Wave Sleep; Study models; Surrogate Markers; Testing; Therapeutic; Time; Trazodone; Wakefulness; actigraphy; amnestic mild cognitive impairment; apolipoprotein E-4; base; blood-based biomarker; cognitive performance; cognitive task; cost; disability; effective therapy; executive function; follow-up; glymphatic system; hemodynamics; improved; informant; interstitial; magnetic resonance imaging biomarker; mild cognitive impairment; neuropsychiatric symptom; off-label use; phase III trial; poor sleep; prevent; primary outcome; processing speed; prodromal Alzheimer' s disease; relating to nervous system; response; secondary outcome; side effect; sleep onset; symptom treatment; tau Proteins; tau-1; therapy development; trial comparing; vigilance

PROJECT SUMMARY It is estimated that 5.8 million people are afflicted by dementia in the US, a number projected to increase to 14 million by 2050 unless effective therapies are available that prevent or significantly slow the disease process. Sleep complaints are common throughout the AD continuum beginning with prodromal stages. In observational studies, disturbed sleep has been linked to AD pathogenesis and subsequent development of mild cognitive impairment (MCI) and dementia. Co-investigator Dr. Bakker has studied pattern separation (PS; a memory task involved with the earliest stages of encoding that is essential to formation of new memories) in a task related functional MRI (fMRI) paradigm, determining that impaired PS is associated with increased hippocampal activation in amnestic MCI (aMCI). Because poor sleep may be associated with increased hippocampal activation, improving sleep is a potential target for positively affecting cognition and disease progression in AD. Trazodone is a generic antidepressant widely used off-label to treat sleep disturbance, particularly enhancing slow wave sleep (SWS) that is evidenced to be a critical sleep phase influencing pathogenic mechanisms. While it has been demonstrated to improve sleep in AD and potentially mitigate the risk of developing MCI, its effect on sleep has not been rigorously studied in MCI. Supported by its benign safety profile, we propose a rigorous double-blind, placebo-controlled, randomized crossover trial of trazodone in 100 subjects with prodromal AD/aMCI and sleep complaints. Each treatment phase will last four weeks with a two-week washout between phases. Sleep will be measured by home sleep testing including polysomnography, actigraphy, and self-report. Hippocampal function and excitability will be assessed by task-related fMRI employing PS. The primary outcome will be to examine the association of trazodone with sleep parameters. We hypothesize that trazodone will improve total sleep time and proportion of time in SWS. Secondary outcomes include assessment of trazodone's effect on 1) PS and hippocampal activation by task-related fMRI, with the hypothesis that trazodone will improve PS performance and decrease hippocampal activation; 2) a broader range of cognitive domains, with the hypothesis that trazodone will improve performance on other memory tasks, executive function, and processing speed; 3) neuropsychiatric symptoms with the hypothesis that they will improve with trazodone treatment. We will also assess blood- based biomarkers of amyloid and tau, as exploratory outcomes to assess their association with sleep and cognitive responses to trazodone.

项目摘要 据估计，美国有580万人受到痴呆症的困扰，预计这一数字将增加到14 到2050年，除非有有效的疗法可预防或大大减慢疾病过程，否则百万。 在整个AD连续体中，睡眠投诉是从前驱阶段开始的。在 观察性研究，干扰的睡眠与AD发病机理有关，随后的发展 轻度认知障碍（MCI）和痴呆症。 Bakker博士共同研究已经研究了模式分离（PS； 与编码最早阶段有关的记忆任务，这对于形成新记忆至关重要） 与任务相关的功能性MRI（fMRI）范式，确定PS受损与增加有关 Amnestic MCI（AMCI）中的海马激活。因为睡眠不佳可能与增加有关 海马激活，改善睡眠是积极影响认知和疾病的潜在目标 AD的进展。曲唑酮是一种通用抗抑郁药，广泛使用的标签以治疗睡眠障碍， 特别是增强慢波睡眠（SWS），这证明是一个关键的睡眠阶段 致病机制。虽然已经证明它可以改善AD的睡眠并有可能减轻 在MCI中尚未严格研究其对睡眠的影响，其对睡眠的影响尚未进行。由良性支持 安全性概况，我们提出了一项严格的双盲，安慰剂对照的，随机的跨界试验 曲唑酮在100受试者中，有前瞻性AD/AMCI和睡眠投诉。每个治疗阶段将持续 四个星期，两期之间进行了两周的冲洗。睡眠将通过家庭睡眠测试来衡量 包括多摄影，动作法和自我报告。海马功能和兴奋性将是 通过使用PS的任务相关的功能磁共振成像评估。主要结果是检查 带有睡眠参数的曲唑酮。我们假设曲唑酮将改善总睡眠时间和比例 SWS的时间。次要结果包括评估曲唑酮对1）PS和海马的影响 通过任务相关的fMRI激活，假设曲唑酮将改善PS性能并降低 海马激活； 2）更广泛的认知领域，假设曲唑酮将会 提高其他内存任务，执行功能和处理速度的性能； 3）神经精神病学 症状的假设是，曲唑酮治疗将改善。我们还将评估血液 基于淀粉样蛋白和Tau的生物标志物，作为评估其与睡眠和睡眠的关联的探索结果 对曲唑酮的认知反应。