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: 10700150
• 负责人: Barry David Greenberg
• 金额: $ 71.08万
• 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/10700150
• 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; 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; 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; blood-based biomarker; cognitive performance; cognitive task; cost; disability; effective therapy; executive function; follow-up; glymphatic system; hemodynamics; improved; improvement on sleep; informant; interstitial; memory consolidation; mild cognitive impairment; neural; neuropsychiatric symptom; off-label use; phase III trial; poor sleep; prevent; primary outcome; processing speed; prodromal Alzheimer' s disease; response; risk mitigation; 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580万人患有痴呆症，预计这一数字将增加到14 到2050年，除非有有效的治疗方法可以预防或显著减缓疾病进程。 从前驱期开始，睡眠问题在整个AD连续过程中很常见。在 观察性研究表明，睡眠障碍与AD的发病机制和随后的发展有关， 轻度认知障碍（MCI）和痴呆。合作研究者博士巴克研究了模式分离（PS; 一项涉及编码的最早阶段的记忆任务，这对新记忆的形成至关重要）， 任务相关功能性MRI（fMRI）范式，确定PS受损与PS增加相关， 遗忘型MCI（aMCI）海马激活。因为睡眠不好可能与增加 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。曲唑酮是一种通用的抗抑郁药，广泛用于治疗睡眠障碍， 特别是增强慢波睡眠（SWS），其被证明是影响睡眠质量的关键睡眠阶段， 致病机制虽然它已被证明可以改善AD患者的睡眠，并可能减轻 尽管它具有发展MCI的风险，但它对睡眠的影响尚未在MCI中进行严格的研究。以其良性的 安全性，我们提出了一个严格的双盲，安慰剂对照，随机交叉试验， 曲唑酮在100例前驱AD/aMCI和睡眠主诉受试者中的应用。每个治疗阶段将持续 四周，两个阶段之间有两周的洗脱期。睡眠将通过家庭睡眠测试来测量 包括多导睡眠描记、活动描记和自我报告。海马神经元的功能和兴奋性 采用PS进行任务相关fMRI评估。主要结果将是检查 曲唑酮与睡眠参数。我们假设曲唑酮将改善总睡眠时间和比例 时间在SWS次要结局包括评估曲唑酮对1）PS和海马的影响 通过任务相关的功能磁共振成像激活，假设曲唑酮将改善PS性能， 海马激活; 2）更广泛的认知领域，假设曲唑酮将 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 假设曲唑酮治疗会改善症状。我们还要评估血液- 基于淀粉样蛋白和tau的生物标志物，作为探索性结果，以评估其与睡眠的关联， 对曲唑酮的认知反应