Linking Sleep Disruption to Tau Accumulation and Network Dysregulation in Early Alzheimer's Disease

睡眠中断与早期阿尔茨海默病中 Tau 蛋白积累和网络失调有关

• 批准号: 10442358
• 负责人: JASMEER P CHHATWAL
• 金额: $ 83.66万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10442358
• 关键词: Abeta synthesis; Alzheimer' s Disease; Alzheimer' s disease pathology; Amyloid; Amyloid beta-Protein; Animals; Architecture; Attention; Behavior; Biological Markers; Brain; Caregiver Burden; Chronic; Clinical; Cognition; Cognitive; Data; Deposition; Disease; Disease Progression; Equation; Evolution; Factor Analysis; Family health status; Frequencies; Functional Magnetic Resonance Imaging; Grouping; Healthcare Systems; Home; Human; Imaging Techniques; Impaired cognition; Individual; Inferior; Intervention; Intervention Studies; Link; Magnetic Resonance Imaging; Measurable; Measures; Mediating; Mediator of activation protein; Memory; Memory impairment; Modeling; Neuropsychological Tests; Neuropsychology; Participant; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Performance; Persons; Phase; Pittsburgh Compound-B; Polysomnography; Population; Positron-Emission Tomography; Production; Proteins; Public Health; Publishing; REM Sleep; Rest; Risk; Sleep; Sleep Apnea Syndromes; Sleep Architecture; Sleep disturbances; Specific qualifier value; Syndrome; Time; Visit; actigraphy; analysis pipeline; base; cognitive performance; cohort; design; disease natural history; human data; improved; in vivo; indexing; memory consolidation; mild cognitive impairment; molecular pathology; neocortical; network dysfunction; neural network; non rapid eye movement; poor sleep; prodromal Alzheimer' s disease; rapid eye movement; recruit; tau Proteins; tau aggregation; therapeutic target; therapy design; β-amyloid burden

Project Summary/Abstract: Based on animal and limited human data, sleep disruption has been linked to decreased clearance and increased production of b-amyloid and tau, proteins which in their aggregated forms represent the two hallmark pathologies seen in Alzheimer’s disease. A number of different sleep parameters have also been closely tied to memory consolidation and chronic sleep disruption increases the risk of memory impairment in older individuals. However, despite data linking sleep disruption to Alzheimer’s disease pathology and memory impairment, significant gaps remain in our understanding of how sleep disruption evolves over the course of Mild Cognitive Impairment (MCI) and what aspects of sleep may be targets for intervention. In this context, we propose to directly examine the evolution of sleep disruption in relation to the in vivo progression of tau pathology, cognitive decline, and network dysfunction. Leveraging data that suggest that tau accumulation may be quite rapid during prodromal Alzheimer’s disease, we will focus these studies on individuals with MCI. We hypothesize that disrupted sleep architecture will be closely related to increased neocortical tau pathology and cognitive impairment, both cross-sectionally and longitudinally. Further, we hypothesize that sleep disruption leads to diminished connectivity in brain networks previously linked to memory performance and cognitive decline, and that this network dysregulation may partially mediate the effects of sleep disruption on cognition. Together, these studies will improve understanding on mechanistic links between sleep, cognition, and Alzheimer’s disease. More broadly, the data from these studies will critically inform the design of interventional studies modifying sleep in early Alzheimer’s disease by identifying which specific aspects of disrupted sleep are most closely tied to b-amyloid and tau pathology (potential therapeutic targets), assessing which aspects of sleep change over time in MCI, and the extent to which longitudinal polysomnography and actigraphy can measure aspects of sleep disruption relevant to Alzheimer’s disease.

项目概要/摘要： 根据动物和有限的人类数据，睡眠中断与清除率降低有关， b-淀粉样蛋白和tau蛋白的产生增加，所述蛋白以其聚集形式代表两种 阿尔茨海默病的标志性病理。许多不同的睡眠参数也被 与记忆巩固和慢性睡眠中断密切相关， 老年人。然而，尽管有数据将睡眠中断与阿尔茨海默病病理学联系起来， 记忆障碍，我们对睡眠中断如何演变的理解仍然存在重大差距。 轻度认知障碍（MCI）的过程以及睡眠的哪些方面可能是干预的目标。在这 在这种背景下，我们建议直接研究睡眠中断的演变与体内进展的关系， tau蛋白病理学、认知能力下降和网络功能障碍。利用数据表明， 在前驱阿尔茨海默病期间，这种累积可能相当迅速，我们将把这些研究集中在 MCI患者。我们假设，睡眠结构的破坏与睡眠质量的增加密切相关。 新皮质tau病理学和认知损害，包括横截面和纵向。我们还 假设睡眠中断导致大脑网络的连接性减弱， 记忆表现和认知能力下降，这种网络失调可能部分介导了 睡眠中断对认知的影响。总之，这些研究将提高对机械的理解。 睡眠，认知和阿尔茨海默病之间的联系。更广泛地说，这些研究的数据将 批判性地告知干预性研究的设计，通过确定 睡眠中断的哪些特定方面与b-淀粉样蛋白和tau病理学最密切相关（潜在的 治疗目标），评估MCI中睡眠的哪些方面随时间变化，以及 纵向多导睡眠描记术和体动描记术可以测量与阿尔茨海默氏症相关的睡眠中断方面 疾病