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

睡眠和食欲素：从临床前到轻度症状阿尔茨海默病进展的潜在标志

• 批准号: 10622500
• 负责人: Brendan Patrick Lucey
• 金额: $ 21.6万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-01-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622500
• 关键词: Affect; African American population; Age; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer’s disease biomarker; Amyloid; Amyloid beta-Protein; Animal Model; Animals; Apnea; Biological Markers; Brain; Brain Injuries; Cellular Phone; Cerebrospinal Fluid; Clinical; Clinical Trials; Clinical Trials Design; Cognition; Cognition Disorders; Cognitive; Cognitive deficits; Cross-Sectional Studies; Data; Dementia; Development; Disease Progression; Early Diagnosis; Elderly; Electroencephalography; Frequencies; Future; Goals; Human; Image; Impaired cognition; Individual; Intercellular Fluid; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Monitor; Mus; Narcolepsy; Neuronal Injury; Neurons; Neuropsychological Tests; Neurotransmitters; Not Hispanic or Latino; Participant; Pathogenesis; Pathology; Pharmaceutical Preparations; Polysomnography; Positron-Emission Tomography; Prognosis; Prognostic Marker; REM Sleep; Race; Research; Rodent; Senile dementia; Severities; Signs and Symptoms; Sleep; Sleep Disorders; Sleep Stages; Sleep disturbances; Spinal Puncture; Stage II Sleep; Symptoms; Synapses; System; Tauopathies; Testing; Time; Wakefulness; Work; abeta accumulation; abeta deposition; amyloid imaging; apolipoprotein E-4; cognitive performance; cognitive testing; cohort; comparison control; demented; healthy aging; human old age (65+); hypocretin; imaging biomarker; indexing; individual response; mild cognitive impairment; minimally invasive; molecular pathology; neuroinflammation; neuron loss; non rapid eye movement; novel; novel therapeutics; pre-clinical; progression marker; rapid eye movement; rate of change; sex; sleep quality; tau Proteins; tau aggregation; tau-1

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.

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， 其次是tau蛋白病、神经元和突触损失以及认知障碍。阿尔茨海默病的存在 大脑中没有临床症状的疾病病理被称为“临床前”阿尔茨海默病，并开始 至少在症状出现前 10-15 年出现。一旦认知障碍开始出现 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 在 tau 蛋白病的早期阶段，当神经元丢失时，Aβ 沉积没有神经元损伤的证据，然后 认知缺陷开始出现。可靠地区分有或没有的个体的这种转变 认知障碍对于以下方面至关重要：1）预测预后； 2) 筛选和监测个人的反应 阿尔茨海默病临床试验； 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要么是侵入性的（腰椎穿刺），要么是昂贵的（淀粉样蛋白 PET）。基于 根据我们在动物和人类身上的数据，我们建议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方法来评估从临床前到临床前的转变 有症状的阿尔茨海默病，也是对新疗法有反应的功能标志物。工作于 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： 睡眠量和质量可能会调节 Aβ 沉积和/或睡眠参数的变化可能表明 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 发作性睡病。最近的横断面研究将较高的脑脊液食欲素水平与轻度认知障碍相关 与对照组相比，以及中度和重度阿尔茨海默病。这些发现表明食欲素 可用于早期检测阿尔茨海默病，但是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学测试尚不清楚。在这项研究中，我们 假设纵向测量认知正常和轻度的睡眠参数和脑脊液食欲素 痴呆症患者将有助于检测整体睡眠标记和食欲系统的变化 从临床前阿尔茨海默病发展到轻度症状的早期脑损伤标志物 阿尔茨海默病。