Tracking the origin of tau pathology

追踪 tau 病理学的起源

• 批准号: 10573194
• 负责人: Heidi Irma Jacobs
• 金额: $ 79.33万
• 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: 2019-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573194
• 关键词: Address; Adult; Age; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animals; Apolipoprotein E; Area; Atrophic; Autopsy; Binding; Biological Markers; Brain; Brain Stem; Cell Density; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive aging; Cohort Studies; Complement; Data; Dedications; Deposition; Development; Diffusion; Discrimination; Early Diagnosis; Early Intervention; Emotional; Enrollment; Female; Functional Imaging; Genetic Carriers; Goals; Hippocampus; Human; Image; Imaging Techniques; Impaired cognition; Individual; Lateral; Lesion; Ligands; Longevity; Longitudinal cohort; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Memory; Memory Loss; Methods; Neocortex; Noise; Participant; Pathology; Pathway interactions; Patients; Pattern; Persons; Pharmacologic Substance; Phase; Pittsburgh Compound-B; Positron-Emission Tomography; Preventive; Proteins; Public Health; Reporting; Research; Research Personnel; Resolution; Risk; Role; Signal Transduction; Site; Testing; Time; Tracer; Visualization; With laterality; Work; abeta accumulation; abeta deposition; age related; aging brain; apolipoprotein E-4; brain abnormalities; cognitive testing; connectome; entorhinal cortex; healthy aging; in vivo; innovation; locus ceruleus structure; middle age; mild cognitive impairment; neocortical; neuromelanin; neuropathology; normal aging; novel; pre-clinical; prodromal Alzheimer' s disease; sex; tau Proteins; tau aggregation; tau mutation; white matter; young adult; β-amyloid burden; Address; Adult; Age; Age Years; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid beta-Protein; Animals; Apolipoprotein E; Area; Atrophic; Autopsy; Binding; Biological Markers; Brain; Brain Stem; Cell Density; Clinical; Clinical Trials; Cognition; Cognitive; Cognitive aging; Cohort Studies; Complement; Data; Dedications; Deposition; Development; Diffusion; Discrimination; Early Diagnosis; Early Intervention; Emotional; Enrollment; Female; Functional Imaging; Genetic Carriers; Goals; Hippocampus; Human; Image; Imaging Techniques; Impaired cognition; Individual; Lateral; Lesion; Ligands; Longevity; Longitudinal cohort; MRI Scans; Magnetic Resonance Imaging; Measures; Mediating; Memory; Memory Loss; Methods; Neocortex; Noise; Participant; Pathology; Pathway interactions; Patients; Pattern; Persons; Pharmacologic Substance; Phase; Pittsburgh Compound-B; Positron-Emission Tomography; Preventive; Proteins; Public Health; Reporting; Research; Research Personnel; Resolution; Risk; Role; Signal Transduction; Site; Testing; Time; Tracer; Visualization; With laterality; Work; abeta accumulation; abeta deposition; age related; aging brain; apolipoprotein E-4; brain abnormalities; cognitive testing; connectome; entorhinal cortex; healthy aging; in vivo; innovation; locus ceruleus structure; middle age; mild cognitive impairment; neocortical; neuromelanin; neuropathology; normal aging; novel; pre-clinical; prodromal Alzheimer' s disease; sex; tau Proteins; tau aggregation; tau mutation; white matter; young adult; β-amyloid burden

ABSTRACT The hallmark neuropathologic lesions of Alzheimer's disease (AD) are amyloid-beta (Aβ) and tau deposits. These deposits can be observed in clinically normal adults, on average 20 years before the onset of cognitive impairment. Despite considerable advance in imaging and biomarkers, researchers are not yet able to identify individuals expected to accumulate pathology prior to showing any pathology. As clinical trials are moving to earlier intervention a more accurate selection of participants at risk for accumulating AD pathology will be crucial. The overarching goal of this proposal is to evaluate in vivo locus coeruleus (LC) integrity as a gauge discerning cognitive aging from preclinical AD based on its very early associations with Aβ, tau accumulation patterns and trajectories of cognitive decline. The overall scientific premise for our goal is that autopsy studies indicated that the first tau lesions can be detected in the LC in 80% of the 40-year old cases, and LC integrity correlates with cognition, even in persons with no pathology. The recent development of tau tracers and novel methods to visualize the LC in detail provide now the opportunity to investigate associations between LC integrity, age, Aβ, tau and cognition. The central hypothesis is that LC integrity can predict regional tau accumulations and cognitive decline in individuals with lower levels of Aβ, already at midlife. Serial Aβ and tau PET measures, serial 3T MRI, serial cognitive assessments and dedicated baseline 7T LC-MRI scans will be collected in individuals between 36-56 years old carefully selected from the Human Connectome Project. This data will be leveraged to another longitudinal cohort, the Harvard Aging Brain Study and our existing patient studies. Three specific areas that could potentially identify individuals on a trajectory to preclinical AD will be addressed: 1) to identify cross-sectional associations between age, sex and LC integrity for individuals at different stages of Aβ and tau pathology and different cognitive impairment levels, which will contribute to the assessment of LC integrity as a biomarker for AD pathology (Aim 1); 2) the quantification of the range of LC integrity levels that predict regional tau accumulation and memory decline in clinically normal individuals, which will elucidate the spatial tau patterns associated with LC integrity and may help in discerning individuals on a trajectory of cognitive aging versus those towards preclinical AD (Aim 2); 3) to investigate underlying mechanisms of spread of pathology by relating structural connectivity and functional activity during a sensitive memory task to rates of tau accumulation (Aim 3). The research proposed in this application is innovative because it moves early detection to a younger adult group (<60 years), which will provide information on the role of LC integrity in preclinical AD and in cognitive aging. In addition, establishing potential mechanisms of pathology progression will be relevant for the development of new pharmaceuticals. Ultimately, being able to discern normal age-related from AD-related trajectories has a significant potential to move early detection and intervention to time frames where Aβ is low or not yet detectable, rendering preventive trials more successful.

抽象的 阿尔茨海默氏病（AD）的标志性神经病理病变是淀粉样蛋白β（Aβ）和TAU沉积物。 这些沉积物可以在临床正常的成年人中观察到，平均在认知开始前20年 损害。尽管成像和生物标志物方面有很大进步，但研究人员仍无法识别 个人期望在显示任何病理之前积累病理。随着临床试验的移动 较早的干预措施更准确选择有累积AD病理风险的参与者将是 至关重要的。该提案的总体目标是评估体内基因座（LC）的完整性作为仪表 根据临床前广告的认知衰老，其与Aβ的早期关联，tau积累的早期关联 认知能力下降的模式和轨迹。我们目标的总体科学前提是尸检研究 表明可以在80％的40％的病例中检测到第一个TAU病变，LC完整性 即使在没有病理的人中，也与认知有关。 tau示踪剂和小说的最新发展 现在详细可视化LC的方法提供了研究LC之间关联的机会 完整性，年龄，Aβ，TAU和认知。中心假设是LC完整性可以预测区域tau Aβ水平较低的个体的积累和认知能力下降已经在中年。串行Aβ和TAU PET测量，串行3T MRI，串行认知评估和专用基线7T LC-MRI扫描将是 在人类Connectome项目中精心挑选的36-56岁的个人中收集。这 数据将被利用到另一个纵向队列，哈佛大学衰老的大脑研究和我们现有的患者 研究。可能会在临床前广告轨迹上识别个体的三个特定领域将是 地址：1）确定个人年龄，性别和LC完整性之间的横截面关联 Aβ和TAU病理的不同阶段以及不同的认知障碍水平，这将有助于 评估LC完整性作为AD病理学的生物标志物（AIM 1）； 2）LC的范围 预测临床正常个体的区域tau积累和记忆下降的诚信水平， 这将阐明与LC完整性相关的空间TAU模式，并可能有助于辨别个人 在认知衰老与临床前AD的轨迹上（AIM 2）； 3）调查基础 敏感的结构连通性和功能活性通过敏感 记忆任务到tau积累的速率（目标3）。本应用程序中提出的研究是创新的 因为它会提早转移到年轻人群体（<60年），这将提供有关 LC完整性在临床前AD和认知衰老中的作用。另外，建立潜在机制 病理进展将与新药物的开发有关。最终，能够 与广告相关的轨迹识别与年龄相关的正常年龄相关的较大潜力可以移动早期检测和 干预Aβ低或尚未检测到的时间范围，使预防试验更成功。