Tracking Tau with In Vivo Braak Staging: Longitudinal Analysis of Tau Pathology and Functional Sequelae in Cognitively Healthy Older Adults

使用体内 Braak 分期追踪 Tau：认知健康老年人 Tau 病理学和功能性后遗症的纵向分析

• 批准号: 9395664
• 负责人: Theresa M. Harrison
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9395664
• 关键词: Accounting; Adult; Affect; Aging; Alzheimer' s Disease; American; Amyloid beta-Protein; Amyloid deposition; Anatomy; Area; Autopsy; Behavior; Behavioral; Behavioral Symptoms; Binding; Biological Assay; Biological Markers; Brain; Cessation of life; Clinical; Clinical Trials Design; Cognition; Cognitive; Cohort Studies; Data; Dementia; Deposition; Diagnosis; Disease; Distant; Early Intervention; Effectiveness; Elderly; Environment; Functional Imaging; Functional Magnetic Resonance Imaging; Goals; Hippocampus (Brain); Human; Image; Impaired cognition; Impairment; Individual; Intervention; Light; Link; Measures; Medial; Mediating; Memory; Outcome; Participant; Pathogenesis; Pathology; Performance; Phase; Population; Positron-Emission Tomography; Process; Proxy; Research; Research Personnel; Risk; Scanning; Severities; Severity of illness; Spinal Tap; Staging; Symptoms; Temporal Lobe; Terminal Disease; Time; Tissues; Tracer; Work; abeta accumulation; abeta deposition; base; density; design; effective intervention; entorhinal cortex; follow-up; in vivo; longitudinal analysis; longitudinal dataset; longitudinal positron emission tomography; mild cognitive impairment; multimodality; neuropathology; normal aging; novel; novel strategies; pathological aging; potential biomarker; pre-clinical; prevent; radiotracer; tau Proteins; tau aggregation; therapy design

Project Summary Interventions designed to delay or prevent Alzheimer's disease (AD) are more likely to be effective if delivered early in the course of the disease before clinical symptoms emerge. To identify individuals who are in the pre- symptomatic or preclinical phase of AD the processes underlying early pathogenesis must be better understood. Recently developed tau-specific positron emission tomography (PET) tracers are allowing researchers to shed light on this critical neuropathology, which previously could only be examined post-mortem or by proxy measures from a spinal tap. Braak staging, a framework for staging tau pathology in post-mortem tissue based on density and topology of tau, may now be used to stage tau pathology in vivo. The current proposal is designed to elucidate the temporal dynamics of AD pathology, especially tau, and associated functional connectivity changes in cognitively healthy older adults. Specifically, longitudinal PET imaging of both beta-amyloid and tau along with task-free functional MRI will be used to 1) characterize the extent and spread of tau pathology using in vivo Braak staging, 2) examine the effect of tau pathology in Braak regions on local functional coherence and 3) determine how tau pathology in medial temporal lobe (MTL) affects functional connectivity to the retrosplenial cortex, which is anatomically connected (mono-synaptic) to MTL and essential to normal memory function. The relationship of tau pathology, functional connectivity changes and early changes in memory function will also be explored. The progression and severity of tau pathology are associated with disease severity (cognition) across the mild cognitive impairment (MCI)-dementia spectrum. It is critical, therefore, to elucidate the temporal dynamics of tau progression in aging and to examine possible mechanisms underlying the link between tau and cognitive decline. In this proposal both local and distant functional connectivity will be explored to better understand the downstream effects of tau on brain function. The Braak staging framework, which was originally derived from cross-sectional data, is an essential component of neuropathological diagnosis of AD. The current proposal will apply a recently developed in vivo Braak staging approach to longitudinal data for the first time. Findings from the studies described here will be novel and high impact. Furthermore, the outcomes of this proposal will contribute to efforts to differentiate normal aging from pathological aging-related trajectories. The accurate identification of individuals with preclinical AD will be critical to effective delivery and assessment of early intervention approaches. 1

项目摘要 旨在延迟或预防阿尔茨海默病（AD）的干预措施如果实施， 在临床症状出现之前的病程早期。为了确定谁是在前- AD的症状或临床前阶段，早期发病机制的基础过程必须更好 明白最近开发的tau特异性正电子发射断层扫描（PET）示踪剂允许 研究人员试图揭示这种重要的神经病理学，以前只能在死后进行检查 或者通过脊椎穿刺的替代测量。Braak分期，用于在死后对tau病理进行分期的框架 基于tau的密度和拓扑结构的组织现在可用于对体内tau病理进行分期。当前 该提案旨在阐明AD病理学的时间动力学，特别是tau蛋白，以及相关的 认知健康的老年人的功能连接变化。具体而言，纵向PET成像 β-淀粉样蛋白和tau蛋白与无任务功能MRI一起沿着将用于1）表征 使用体内Braak分期检测tau病理学的传播，2）检测Braak区域中tau病理学对 局部功能相干性和3）确定内侧颞叶（MTL）中的tau病理如何影响 与压后皮质的功能连接，压后皮质在解剖学上与MTL连接（单突触）， 对正常记忆功能至关重要tau蛋白病理学、功能性连接变化和 还将探讨记忆功能的早期变化。tau病理学的进展和严重程度是 与轻度认知障碍（MCI）-痴呆谱中的疾病严重程度（认知）相关。它 因此，关键是要阐明衰老过程中tau蛋白进展的时间动力学，并研究可能的 tau蛋白和认知能力下降之间联系的潜在机制。在这项提案中，无论是本地还是远程 将探索功能连接，以更好地了解tau蛋白对脑功能的下游影响。 Braak分期框架，最初来自横截面数据，是一个重要的 AD的神经病理学诊断的组成部分。目前的建议将适用于最近开发的体内 Braak分期方法首次用于纵向数据。这里描述的研究结果将 新颖，影响力大。此外，本提案的结果将有助于区分 正常衰老与病理衰老相关的轨迹。准确识别个人 临床前AD对于早期干预方法的有效实施和评估至关重要。 1