Evaluating the disease-modifying potential of a sleep intervention for Alzheimer's Disease outcomes

摘要 可以减缓阿尔茨海默病（AD）进展的治疗可以显着减轻护理负担。睡眠 干预可能是具有这种疾病缓解潜力的治疗方法之一。来自动物模型的证据 提示睡眠和AD病理生理学之间存在双向关系， 破坏可以促进淀粉样蛋白β（Aβ）的积累及其聚集成斑块和下游 相反，AD病理生理学可以用睡眠剂逆转。许多 动物模型的关键发现转化为疾病的人类模型，例如Aβ的昼夜变化 （清醒时较高，睡眠时较低），睡眠时Aβ向脑脊液（CSF）的清除率降低 剥夺和破坏，以及正常老化和正常老化的Aβ昼夜节律减弱， Aβ斑块。流行病学研究补充了这些较小样本的发现，以表明睡眠和昼夜节律 中断可以预测4-6年内的MCI/AD事件。然而，其他证据表明这些预测 通常与老化不良一致，可能不是AD特异性的。有效的实验研究 睡眠辅助可以解决这些问题。褪黑素改善睡眠，长期使用安全记录良好 在非随机研究中， MCI患者中。然而，褪黑激素是否影响Aβ级联反应中的生物标志物尚不清楚。的 拟议的实用试验将测试5毫克褪黑激素对记忆和AD生物标志物结果的疗效， 使用MCI+和MCI-至活性的分层随机化， 安慰剂组使用短期纵向框架。将通过活动记录仪观察参与者， 在日常生活中客观地跟踪睡眠和昼夜节律，持续两个月， 阶段#1，以AD生物标志物的CSF采样和简短的认知测试结束。以下分层 随机分组后，将对受试者进行另外两个月的随访，并在 睡眠干预阶段#2，也以AD生物标志物的CSF采样和简短的认知测试结束。 第3阶段长期随访将褪黑激素治疗延长至9个月，无需活动记录监测， 结束于AD生物标志物的CSF采样和认知测试。密集的，重复的，客观的抽样， 现实世界中的睡眠和昼夜节律功能以及这些客观评估与AD的耦合 在褪黑激素治疗两个月之前和之后的生物标志物取样将允许方法学上的 严格评估褪黑激素是否具有改善疾病的治疗潜力。项目的具体目标 是围绕着一个中心预测组织的，即情景记忆的改善将滞后于 生物标志物的改善将介导睡眠改善对情景记忆的影响。 研究结果将探讨先前报道的睡眠/昼夜节律功能与AD结局的关系 谈谈这些干预措施减缓疾病进展的潜力。

Abstract Treatments that can slow Alzheimer's disease (AD) progression can reduce care burden significantly. Sleep interventions may be among treatments with such disease-modifying potential. Evidence from animal models suggests there is a bi-directional relationship between sleep and AD pathophysiology such that sleep disruptions can facilitate amyloid beta (Aβ) accumulation and its aggregation into plaques and downstream formation of tau-tangles, and conversely, that AD pathophysiology can be reversed with sleep agents. Many key findings from animal models translate to human models of the disease, such as diurnal variation in Aβ (higher in wakefulness, lower in sleep), reduced clearance of Aβ to cerebrospinal fluid (CSF) in sleep deprivation and disruption, and weakening of the Aβ circadian rhythm with both normative aging and those with Aβ plaques. Epidemiologic studies supplement these smaller sample findings to indicate sleep and circadian disruptions can predict incident MCI/AD over 4-6 years. However, other evidence suggests these predictions are consistent with poor aging in general and may not be specific to AD. Experimental studies with efficacious sleep aids can address these questions. Melatonin improves sleep, has a good safety record for long-term use among older adults, and improves cognitive outcomes over a 9-month period in non-randomized studies among MCI patients. However, whether melatonin affects biomarkers in the Aβ-cascade is unknown. The proposed pragmatic trial will test efficacy of 5mg of melatonin on both memory and AD-biomarker outcomes in the spectrum of preclinical to prodromal AD using stratified randomization of MCI+ and MCI- to active and placebo arms using a short-term longitudinal framework. The participants will be observed with actigraphy to objectively track both sleep and circadian rhythm in daily life for a two month period in the sleep-as-usual phase#1, ending with CSF sampling of AD biomarkers and brief cognitive testing. Following stratified randomization, participants will be followed for another two-month period with actigraphic monitoring in the sleep-intervention-phase#2, also ending with CSF sampling of AD biomarkers and brief cognitive testing. Phase#3 long-term follow-up will extend the melatonin treatment to 9 months without actigraphic monitoring, ending with CSF sampling of AD biomarkers and cognitive testing. Dense, repeated, objective sampling of both sleep and circadian function in the real-world and the coupling of those objective assessments with AD biomarker sampling both prior to and after two-months of melatonin treatment will permit a methodologically rigorous evaluation of whether melatonin has disease-modifying treatment potential. Project's specific aims are organized around the central prediction that improvements in episodic memory will lag those seen in biomarkers, and that biomarker improvements will mediate the effects of improved sleep on episodic memory. Findings will address whether previously reported associations of sleep / circadian function with AD outcomes speak to the potential of these interventions to slow disease progression.