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)进展的治疗方法可以显著减轻护理负担。沉睡 干预措施可能是具有这种改变疾病潜力的治疗方法之一。来自动物模型的证据 提示睡眠与阿尔茨海默病的病理生理之间存在双向关系 干扰可促进淀粉样β蛋白(Aβ)积聚并聚集到斑块和下游 形成tau缠结，反之，阿尔茨海默病的病理生理可以被安眠剂逆转。许多 来自动物模型的关键发现转化为人类模型的疾病，例如Aβ的日变化 (清醒程度较高，睡眠程度较低)，睡眠中Aβ对脑脊液的清除减少 Aβ昼夜节律的剥夺、扰乱和减弱 一种β斑块。流行病学研究补充了这些较小的样本发现，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 通常与衰老不良相一致，可能不是AD特有的。灵芝口服液的实验研究 睡眠辅助器可以解决这些问题。褪黑素改善睡眠，长期使用有良好的安全记录 在非随机研究中，在9个月的时间内改善认知结果 在MCI患者中。然而，褪黑素是否会影响Aβ级联中的生物标记物尚不清楚。这个 拟议的实用试验将测试5毫克褪黑素对记忆和AD-生物标记物结果的疗效 应用MCI+和MCI-对活动期和非活动期的分层随机化的临床前到先兆AD的频谱 使用短期纵向框架的安慰剂手臂。参与者将通过动作记录仪进行观察，以 在两个月的睡眠照常期间，客观地跟踪日常生活中的睡眠和昼夜节律 阶段1，结束于脑脊液对AD生物标志物的采样和简短的认知测试。遵循分层 随机化，参与者将被跟踪另一个为期两个月的期间，并在 睡眠干预-阶段2，也以脑脊液采样AD生物标记物和简短的认知测试结束。 第三阶段长期随访将褪黑素治疗延长至9个月，无需活动监测， 以脑脊液采样AD生物标记物和认知测试结束。密集的、重复的、客观的采样 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 在褪黑素治疗前和治疗两个月后进行生物标记物采样将在方法学上允许 严格评估褪黑素是否具有改善疾病的治疗潜力。项目的具体目标 围绕着中央预测进行组织，即情节记忆的改善将落后于 生物标志物，而生物标志物的改善将中介改善睡眠对情景记忆的影响。 研究结果将解决先前报道的睡眠/昼夜节律功能是否与AD结局相关 谈到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.