Genetic Profiles of the Spatiotemporal Causality of Tau and Amyloid in the Elderly Brain

老年大脑中 Tau 蛋白和淀粉样蛋白的时空因果关系的遗传图谱

• 批准号: 10390455
• 负责人: Jorge Sepulcre
• 金额: $ 37.8万
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10390455
• 关键词: Affect; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid; Amyloid beta-Protein; Amyloidosis; Atlases; Biological; Biological Markers; Brain; Cerebrum; Clinical; Code; Cognitive; Custom; Data; Dementia; Deposition; Detection; Development; Diagnosis; Disease susceptibility; Early Diagnosis; Elderly; Epidemic; Etiology; Foundations; Functional disorder; Genes; Genetic; Genetic Markers; Genetic Predisposition to Disease; Genetic Risk; Genotype; Graph; Human; Impaired cognition; Impairment; Individual; Investigation; Joints; Late Onset Alzheimer Disease; Maps; Mediating; Methods; Modeling; Monitor; Nature; Network-based; Neurobiology; Neurology; Neurons; Neuropsychology; Neurosciences; Participant; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Persons; Phase; Phenotype; Positron-Emission Tomography; Predisposition; Preventive treatment; Proteins; Reporting; Research; Risk; Sampling; Staging; Study Subject; Symptoms; Synapses; System; Tauopathies; Tissues; United States; abeta accumulation; accurate diagnosis; aging brain; analytical tool; base; brain pathway; clinically relevant; cost estimate; dementia care; effective intervention; genetic information; graph theory; imaging genetics; in vivo; molecular imaging; multimodal neuroimaging; neuroimaging; neuroimaging marker; neuronal circuitry; next generation; novel; pre-clinical; relating to nervous system; spatiotemporal; tau Proteins; tau aggregation; tau mutation; tool; transcriptome

Project Summary (Abstract) The progression phenomenon of abnormal tau and amyloid-β (Aβ) proteins along neuronal circuits is critical to understand the foundations of Alzheimer's disease (AD) pathology. The individual risk to develop late onset AD relates to the biological and genetic profiles that confer susceptibility for abnormal and progressive accumulation of tau and Aβ in the brain. Recent advances in multi-modal neuroimaging and genetic biomarkers provide new prospects to detect very early stages of AD and to study its network nature and genetic underpinnings. However, a major research challenge in this field has been to integrate and perform comprehensive joint analysis of neuroimaging and genetic data. Thus, there is a critical need for new strategies to detect the spreading pathways and genetic mechanisms of tau-related and Aβ-related accumulation in the human brain. The combination of detailed descriptions of individual neuroimaging profiles of progression and genetic vulnerability risk will offer enhanced detectability of AD trajectories. This proposal purposes to solve these emerging challenges by focusing on identification of in vivo spreading pathways of tau and Aβ deposits and their genetic vulnerabilities in a longitudinal sample of elderly participants from the Harvard Aging Brain Study (HABS). In Aim 1, we will develop customized graph theory metrics to detect progression of pathology at the network level in cross-sectional and longitudinal PET images. In Aim2, we will focus on building individualized staging frameworks based on progression and spreading patterns of pathology using PET imaging, and we will correlate staging estimates with clinical and neuropsychological profiles. In Aim 3, we will characterize the genetic brain transcriptome –assisted by the Allen Human Brain Atlas- that are associated to the HABS neuroimaging spreading profiles. At the end of this proposal, we will be able to detect and identify the early and in vivo molecular imaging and genetic features that confer AD susceptibility in elderly individuals.

项目摘要（摘要） 沿神经元回路的异常TAU和淀粉样蛋白（Aβ）蛋白的进展现象是 了解阿尔茨海默氏病（AD）病理的基础至关重要。个人发展迟到的风险 发作广告与生物学和遗传特征有关，该生物学和遗传特征会导致对异常和进步的敏感性 tau和aβ在大脑中的积累。多模式神经影像学和遗传生物标志物的最新进展 提供新的前景来检测AD的早期阶段并研究其网络性质和遗传 基础。但是，该领域的重大研究挑战是整合和执行 神经影像和遗传数据的全面关节分析。这是对新策略的迫切需求 检测与tau相关的扩散途径和遗传机制和与Aβ相关的积累 人脑。单个神经影像学特征的详细描述和 遗传脆弱性风险将增强AD轨迹的可检测性。该建议目的解决 这些新出现的挑战是通过专注于识别Tau和Aβ沉积的体内扩散途径 以及他们在哈佛大学衰老大脑的老年参与者的纵向样本中的遗传脆弱性 研究（HAB）。在AIM 1中，我们将开发自定义的图理论指标，以检测病理的进展 横截面和纵向PET图像中的网络水平。在AIM2中，我们将专注于建立个性化的 使用PET成像基于病理的进展和病理传播模式的分期框架，我们将 将分期估计与临床和神经心理学概况相关。在AIM 3中，我们将表征 遗传脑转录组 - 与HABS相关的艾伦人脑大脑协助 神经影像扩散曲线。在本提案的结尾，我们将能够检测并确定早期和确定 体内分子成像和遗传特征，这些特征会在老年人中会导致AD敏感性。