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

项目总结 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来预防或显著减缓疾病的进程，否则将有100万人死亡。 睡眠主诉在AD的整个过程中都很常见，从前驱症状开始。在……里面 观察性研究发现，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)和痴呆症。合作者巴克博士研究了模式分离(PS； 与编码的最早阶段有关的记忆任务，这对于形成新的记忆是必不可少的) 任务相关功能磁共振成像(FMRI)范式，确定PS受损与增加相关 遗忘性MCI(AMCI)患者的海马区激活。因为睡眠不佳可能与睡眠增加有关 海马体激活，改善睡眠是积极影响认知和疾病的潜在靶点 AD的进展。曲唑酮是一种非处方抗抑郁药，广泛用于治疗睡眠障碍， 特别是增强慢波睡眠(SWS)，这被证明是影响 致病机制。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，其对睡眠的影响在MCI中还没有得到严格的研究。由其良性的 安全性概况，我们提出了一项严格的双盲、安慰剂对照、随机交叉试验 曲唑酮治疗100例伴有前驱AD/aMCI和睡眠主诉的患者。每个治疗阶段都将持续 四周，在两个阶段之间有两周的冲刷。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。主要结果将是检查两者之间的关联 曲唑酮和睡眠参数。我们假设曲唑酮将改善总的睡眠时间和比例 在SWS中的时间。次要结果包括评估曲唑酮对PS和海马区的影响 任务相关功能磁共振的激活，假设曲唑酮将改善PS的表现并降低 海马区激活；2)更广泛的认知域，假设曲唑酮将 提高其他记忆任务的表现、执行功能和处理速度；3)神经精神病学 与曲唑酮治疗会改善症状的假设。我们还将评估血液- 基于淀粉样蛋白和tau的生物标记物，作为评估它们与睡眠和 对曲唑酮的认知反应。

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.