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: 9988329
• 负责人: JASMEER P CHHATWAL
• 金额: $ 84.71万
• 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/9988329
• 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; 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; Structure; 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.

项目总结/文摘: