RCT Targeting Cognition in Early Alzheimer's Disease by Improving Sleep withTrazodone (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能力的随机对照试验

• 批准号: 10857885
• 负责人: Barry David Greenberg
• 金额: $ 9.95万
• 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/10857885
• 关键词: Affect; Alzheimer' s Disease; Amyloid; Antidepressive Agents; Benign; Cognition; Cognitive; Cross-Over Trials; Dementia; Development; Disease; Disease Progression; Double-Blind Method; Elderly; FDA approved; Functional Magnetic Resonance Imaging; Hippocampus; Home; Impaired cognition; Impairment; Link; Measures; Memory; Observational Study; Outcome; Pathogenesis; Pathogenicity; Patient Self-Report; Pattern; Performance; Persons; Pharmaceutical Preparations; Phase; Placebo Control; Placebos; Polysomnography; Process; Randomized; Research Personnel; Rest; Safety; Sleep; Sleep disturbances; Slow-Wave Sleep; Testing; Time; Trazodone; actigraphy; amnestic mild cognitive impairment; blood-based biomarker; effective therapy; executive function; improved; improvement on sleep; mild cognitive impairment; neuropsychiatric symptom; off-label use; poor sleep; prevent; primary outcome; processing speed; prodromal Alzheimer' s disease; response; risk mitigation; secondary outcome; side effect; tau Proteins; trial comparing

Project Summary - Abstract 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 - 摘要 据估计，美国有 580 万人患有痴呆症，这一数字预计 除非有有效的治疗方法来预防或预防，否则到 2050 年将增加到 1400 万。 显着减缓疾病进程。睡眠问题在 AD 期间很常见 从前驱阶段开始的连续体。在观察性研究中，睡眠受到干扰 与 AD 发病机制和随后出现的轻度认知障碍 (MCI) 相关 失智。共同研究员 Bakker 博士研究了模式分离（PS；一项记忆任务） 涉及编码的最早阶段，这对于新记忆的形成至关重要） 任务相关功能 MRI (fMRI) 范式，确定 PS 受损与 遗忘性MCI（aMCI）中海马激活增加。因为睡眠不好可能会 与海马体激活增加相关，改善睡眠是潜在的目标 对 AD 的认知和疾病进展产生积极影响。曲唑酮是一种仿制药 抗抑郁药广泛用于标签外治疗睡眠障碍，特别是改善睡眠障碍 波睡眠（SWS）被证明是影响致病性的关键睡眠阶段 机制。虽然它已被证明可以改善 AD 患者的睡眠并可能缓解 尽管存在 MCI 的风险，但其对睡眠的影响尚未在 MCI 中得到严格研究。 在其良好的安全性的支持下，我们提出了严格的双盲、安慰剂- 在 100 名患有前驱症状的受试者中进行曲唑酮的对照、随机交叉试验 AD/aMCI 和睡眠投诉。每个治疗阶段将持续四个星期，其中包括两周 各相之间的冲洗。睡眠将通过家庭睡眠测试来测量，包括 多导睡眠图、体动记录仪和自我报告。海马功能和兴奋性将 通过使用 PS 的任务相关功能磁共振成像进行评估。主要结果将是检查 曲唑酮与睡眠参数的关联。我们假设曲唑酮会改善 总睡眠时间和 SWS 时间比例。次要结果包括评估 通过任务相关的功能磁共振成像，曲唑酮对 1) PS 和海马激活的影响，其中 假设曲唑酮会改善 PS 表现并减少海马激活； 2）更广泛的认知领域，假设曲唑酮会改善 其他记忆任务、执行功能和处理速度的表现； 3） 神经精神症状，假设曲唑酮治疗会改善这些症状。 我们还将评估淀粉样蛋白和 tau 蛋白的血液生物标志物，作为探索性结果 评估它们与睡眠和曲唑酮认知反应的关系。