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

基本信息

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
项目类别：
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&apos s Disease Alzheimer&apos 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&apos s disease rapid eye movement recruit tau Proteins tau aggregation therapeutic target therapy design β-amyloid burden

项目摘要

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.

项目摘要/摘要：根据动物和有限的人类数据，睡眠中断与清除率降低和 b-淀粉样蛋白和 tau 蛋白的产生增加，这两种蛋白质以聚集形式代表阿尔茨海默病的标志性病理学也有许多不同的睡眠参数。与记忆巩固和慢性睡眠中断密切相关，会增加记忆障碍的风险然而，尽管有数据表明睡眠障碍与阿尔茨海默病的病理学有关。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) 的病程以及睡眠的哪些方面可能是干预的目标。在这种情况下，我们建议直接检查睡眠中断的演变与体内进展的关系利用表明 tau 蛋白病理学、认知能力下降和网络功能障碍的数据。在阿尔茨海默病前驱期，积累可能相当快，我们将重点关注这些研究我们认为睡眠结构紊乱与 MCI 增加密切相关。新皮质 tau 蛋白病理学和认知障碍，无论是横向还是纵向。睡眠中断会导致先前与睡眠有关的大脑网络的连接性减弱记忆力和认知能力下降，这种网络失调可能部分介导睡眠中断对认知的影响总之，这些研究将增进对机制的理解。更广泛地说，这些研究的数据将揭示睡眠、认知和阿尔茨海默病之间的联系。通过识别来改变早期阿尔茨海默病的睡眠，为干预研究的设计提供重要信息睡眠中断的哪些具体方面与 b-淀粉样蛋白和 tau 蛋白病理学关系最密切（潜在治疗目标），评估 MCI 中睡眠的哪些方面随时间变化，以及变化的程度纵向多导睡眠图和体动记录仪可以测量与阿尔茨海默病相关的睡眠中断的各个方面疾病。