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：
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
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/10442358
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 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&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：基于动物和有限的人类数据，睡眠中断与清除率下降有关增加B-淀粉样蛋白和TAU的产生，蛋白质以汇总形式代表两者在阿尔茨海默氏病中看到的标志性病理。许多不同的睡眠参数也是与记忆巩固和慢性睡眠中断密切相关，增加了记忆障碍的风险老年人。但是，将睡眠中断与阿尔茨海默氏病病理学和记忆力障碍，我们对睡眠中断如何演变的明显差距仍然存在轻度认知障碍的过程（MCI）以及睡眠的哪些方面可能是干预的目标。在这个上下文，我们建议直接检查与体内进展有关的睡眠破坏的演变 tau病理学，认知能力下降和网络功能障碍。利用表明tau的数据在阿尔茨海默氏病前代疾病期间，积累可能非常迅速，我们将把这些研究重点放在患有MCI的人。我们假设被干扰的睡眠体系结构将与增加密切相关新皮层tau病理和认知障碍，无论是横截面还是纵向。此外，我们假设睡眠中断导致以前链接到的大脑网络中的连通性降低记忆表现和认知能力下降，并且该网络失调可能部分介导睡眠破坏对认知的影响。这些研究将共同提高对机械的理解睡眠，认知和阿尔茨海默氏病之间的联系。更广泛地，这些研究的数据将批判性地告知介入研究的设计，以修改阿尔茨海默氏病的早期睡眠干扰睡眠的哪些特定方面最紧密地与B-淀粉样蛋白和TAU病理相关（潜力）治疗靶标），评估MCI的睡眠随时间变化的哪些方面以及多大程度上纵向多个术语和行程学可以衡量与阿尔茨海默氏症相关的睡眠中断的各个方面疾病。