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

基本信息

批准号：
9816243
负责人：
Jorge Sepulcre
金额：
$ 41.66万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9816243
关键词：
Affect Aging Alzheimer disease detection Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid Amyloid Proteins 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 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 dementia care effective intervention genetic information genetic profiling graph theory imaging genetics in vivo molecular imaging multimodality neuroimaging neuroimaging marker neuronal circuitry next generation novel pre-clinical relating to nervous system spatiotemporal tau Proteins tau aggregation tau mutation tool transcriptome

项目摘要

Project Summary (Abstract) The progression phenomenon of abnormal tau and amyloid- (A) 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 A 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 A-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 A 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.

项目概要（摘要）异常 tau 蛋白和淀粉样蛋白- (A) 蛋白沿神经元回路的进展现象是了解阿尔茨海默病 (AD) 病理学的基础至关重要个体晚期发展的风险。 AD 的发病与生物和遗传特征有关，这些特征赋予了异常和进行性的易感性大脑中 tau 蛋白和 A 的积累。多模式神经影像和遗传生物标志物的最新进展。为检测 AD 的早期阶段并研究其网络性质和遗传提供了新的前景然而，该领域的一个主要研究挑战是整合和执行。因此，迫切需要新的策略。检测 tau 相关和 A 相关积累的传播途径和遗传机制人类大脑的进展和个体神经影像学概况的详细描述的组合。遗传脆弱性风险将提供增强的 AD 轨迹的可检测性。通过重点识别 tau 和 A 沉积物的体内扩散途径来应对这些新出现的挑战以及哈佛衰老大脑老年参与者纵向样本中的遗传脆弱性研究 (HABS)。在目标 1 中，我们将开发定制的图论指标来检测病理进展。在 Aim2 中，我们将重点关注构建个性化的 PET 图像中的网络级别。使用 PET 成像根据病理进展和扩散模式制定分期框架，我们将在目标 3 中，我们将描述与 HABS 相关的遗传脑转录组（由艾伦人脑图谱协助）在本提案结束时，我们将能够检测和识别早期和识别。体内分子成像和遗传特征赋予老年人 AD 易感性。