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

项目2项目总结 淀粉样蛋白-β(A-β)在大脑中的沉积是阿尔茨海默病发展的关键早期步骤， 紧随其后的是紧张症、神经元和突触丧失，以及认知障碍。阿尔茨海默病的存在 大脑中没有临床症状的疾病病理称为临床前阿尔茨海默病，并开始 在症状出现前至少10-15年发病。一旦认知障碍开始，就已经有 明显的神经元丢失。因此，阿尔茨海默病研究的一个主要目标是确定从 无神经损伤证据的β沉积到肌萎缩侧索硬化症的早期，当神经元丢失时，然后 认知缺陷开始出现。可靠地区分有无此过渡的个人 认知障碍对以下方面至关重要：1)预测预后；2)筛查和监测患者的反应 3)指导阿尔茨海默病临床试验设计。目前的生物标记物 阿尔茨海默病的病理要么是侵入性的(腰椎穿刺术)，要么是昂贵的(淀粉样蛋白PET)。基于 我们在动物和人类中的数据表明，睡眠的变化可以作为一种信息 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 疾病病理学可能提供一种微创的方法来评估从临床前到 它不仅是阿尔茨海默病的症状，而且是对新疗法有反应的功能标记物。在.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： 睡眠的数量和质量可以调节β沉积和/或睡眠参数的变化可以指示 阿尔茨海默病的病理进展。阿尔茨海默病引起的睡眠变化也可能 牵涉到食欲素能系统。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，脑脊液增食欲素水平升高与轻度认知障碍有关 以及与对照组相比的中度和重度阿尔茨海默病。这些发现表明食欲素 可用于阿尔茨海默病的早期检测，但增食欲素与不同睡眠的关系 参数、脑脊液阿尔茨海默病生物标志物和神经心理测试尚不清楚。在这项研究中，我们 纵向测量认知正常和轻度患者的睡眠参数和脑脊液增食欲素的假设 痴呆症患者将用于检测全球睡眠标志物和食欲素能系统的变化 阿尔茨海默病从临床前发展到轻度症状非常早期的脑损伤标志物 阿尔茨海默病。

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.