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

项目摘要-摘要 据估计，美国有580万人患有痴呆症，预计这一数字将 到2050年增加到1400万人，除非有有效的治疗方法来预防或 显著延缓了疾病的进程。睡眠抱怨在整个AD中都很常见 从前驱阶段开始的连续统一体。在观察性研究中，睡眠受到干扰 与AD的发病机制和随后发生的轻度认知障碍(MCI)和 痴呆症。合作研究员巴克博士研究了模式分离(PS；记忆任务 与形成新记忆所必需的编码的最早阶段有关) 任务相关功能磁共振成像(FMRI)范式，确定受损的PS与 遗忘性MCI(AMCI)大鼠海马区激活增强。因为睡眠不佳可能是 与海马区激活增加有关，改善睡眠是一个潜在的目标 对阿尔茨海默病的认知和疾病进展有积极影响。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，特别是增强慢 波睡眠(SWS)被证明是影响致病因素的关键睡眠阶段 机械装置。虽然已经证明它可以改善AD患者的睡眠，并有可能缓解 发生MCI的风险及其对睡眠的影响在MCI中尚未得到严格的研究。 在其良性安全性的支持下，我们提出了一种严格的双盲安慰剂- 曲唑酮治疗100例先兆受试者随机对照交叉试验 AD/aMCI和睡眠抱怨。每个疗程为期四周，疗程为两周。 两个阶段之间的冲刷。睡眠将通过家庭睡眠测试来衡量，包括 多导睡眠描记、活动描记和自我报告。海马区的功能和兴奋性 通过使用PS的任务相关功能磁共振进行评估。主要结果将是检查 曲唑酮与睡眠参数的相关性。我们假设曲唑酮会有所改善 SWS的总睡眠时间和所占时间比例。次要结果包括评估 曲唑酮对1)PS和任务相关功能磁共振海马区激活的影响 假设曲唑酮将改善PS表现并降低海马区的激活； 2)更广泛的认知领域，假设曲唑酮将有所改善 在其他记忆任务、执行功能和处理速度上的表现；3) 神经精神症状，假设它们会通过曲唑酮治疗而改善。 我们还将评估基于血液的淀粉样蛋白和tau的生物标记物，作为对 评估它们与睡眠和曲唑酮认知反应的关系。

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.