Sleep and Orexin: Potential Markers of Progression from Preclinical to Mildly Symptomatic Alzheimer's Disease

项目2项目概要 β淀粉样蛋白（Aβ）在大脑中的沉积是阿尔茨海默病发展的关键早期步骤， 随后是tau蛋白病、神经元和突触损失以及认知损害。存在阿耳茨海默 没有临床症状的脑中的疾病病理被称为“临床前”阿尔茨海默病， 在症状出现前至少10-15年发展。一旦认知障碍开始， 明显的神经元缺失因此，阿尔茨海默病研究的一个主要目标是确定从 Aβ沉积没有神经元损伤的证据，到tau蛋白病的早期阶段，当神经元丢失时， 认知缺陷开始发展。可靠地区分个体的这种转变， 认知障碍对于：1）预测预后; 2）筛选和监测个体的反应， 阿尔茨海默病临床试验;和3）指导阿尔茨海默病临床试验设计。目前的生物标志物 阿尔茨海默病病理学是侵入性的（腰椎穿刺）和/或昂贵的（淀粉样蛋白PET）。基于 我们在动物和人类的数据，我们建议睡眠的变化可以作为一个信息 临床前和症状性阿尔茨海默病的生物标志物。与阿尔茨海默病相关的睡眠变化 疾病病理学可以提供一种微创的方法来评估从临床前到 症状性阿尔茨海默病以及作为对新疗法有反应的功能性标志物。工作 啮齿动物和人类都强烈表明睡眠和阿尔茨海默病之间存在双向关系： 睡眠量和质量可以调节Aβ沉积和/或睡眠参数的变化可以指示 阿尔茨海默病病理学的进展。阿尔茨海默病介导的睡眠变化也可能 涉及食欲系统。食欲素是一种促进觉醒的神经递质，食欲素缺乏会导致 嗜睡症最近的横断面研究表明，脑脊液食欲素水平升高与轻度认知功能障碍相关 以及中度和重度阿尔茨海默病。这些发现表明， 可用于阿尔茨海默病的早期检测，但食欲素与不同睡眠的关系 参数、CSF阿尔茨海默病生物标志物和神经心理学测试未知。本研究 假设在认知正常和轻度认知障碍患者中， 痴呆个体将用于检测整体睡眠标记物和食欲素能系统的变化， 从临床前阿尔茨海默病进展到轻度症状的早期脑损伤标志物 老年痴呆症

Project 2 Project Summary Amyloid-β (Aβ) deposition in the brain is a key early step in the development of Alzheimer disease and is followed by tauopathy, neuronal and synaptic loss, and cognitive impairment. The presence of Alzheimer disease pathology in the brain without clinical symptoms is called “preclinical” Alzheimer disease and begins to develop at least 10-15 years prior to symptom onset. Once cognitive impairment begins, there is already marked neuronal loss. Therefore, a major goal of Alzheimer disease research is to identify the transition from Aβ deposition without evidence of neuronal injury to the early stages of tauopathy when neuronal loss and then cognitive deficts begin to develop. Reliably differentiating this transition in individuals with and without cognitive impairment is critical to: 1) predict prognosis; 2) screen and monitor response of individuals in Alzheimer disease clinical trials; and 3) guide Alzheimer disease clinical trial design. Current biomarkers of Alzheimer disease pathology are either invasive (lumbar puncture) and/or expensive (amyloid PET). Based on our data in both animals and humans, we propose that changes in sleep can serve as an informative biomarker of preclinical and symptomatic Alzheimer disease. Changes in sleep associated with Alzheimer disease pathology may provide a minimally invasive way to assess the transition from preclinical to symptomatic Alzheimer disease as well as be a functional marker that is responsive to new therapies. Work in both rodents and humans strongly suggests a bidirectional relationship between sleep and Alzheimer disease: the amount and quality of sleep may regulate Aβ deposition and/or changes in sleep parameters may indicate progression of Alzheimer disease pathology. Changes in sleep mediated by Alzheimer disease may also involve the orexinergic system. Orexin is a wake-promoting neurotransmitter and orexin deficiency results in narcolepsy. Recent cross-sectional studies associated higher CSF orexin levels with mild cognitive impairment as well as moderate and severe Alzheimer disease compared to controls. These findings suggest that orexin could be used for early detection of Alzheimer disease, however the relationship of orexin to different sleep parameters, CSF Alzheimer disease biomarkers, and neuropsychological testing is unknown. In this study, we hypothesize that longitudinally measuring sleep parameters and CSF orexin in cognitively normal and mildly demented individuals will serve to detect changes in global sleep markers and the orexinergic system as markers of brain injury at the very early progression from preclinical Alzheimer disease to mildly symptomatic Alzheimer disease.