Connectome-based spread of neurodegenerative processes in Alzheimer's disease

项目摘要/摘要 阿尔茨海默病(AD)的特征是存在β-淀粉样斑块和含有tau的神经原纤维 缠结和神经元丢失；然而，对神经退行性疾病的发展和扩散知之甚少 流程。神经成像的最新进展使检测阿尔茨海默病的主要特征成为可能 使用正电子发射断层扫描(PET)和磁共振成像(MRI)的病理生理级联， 使研究人员能够跟踪疾病在体内的发展。 候选人与环境。候选人的职业目标是成为一名独立的调查员和领导者 影像研究阐明阿尔茨海默病(AD)的发病机制并提高精确度 为个别病人量身定做的医疗工具。在这次K奖期间，候选人将扩展他的专业知识 在多模式神经成像方面接受额外的连通性分析培训，并将获得以下专业知识 网络科学和数学建模。这套新技能将使他能够从事创新研究 测试关于AD病理传播的假说的项目。候选人将有权访问大型数据集 拥有最先进的PET和MRI数据；他将与一个由世界知名导师组成的多学科团队合作 以及具有成像、行为神经学、生物工程、病理学和 统计数据。加州大学旧金山分校记忆和衰老中心的特殊资源和多样化的科学社区 将为候选人的培训提供理想的环境，并将促进他未来的成功成长 独立调查员。 研究项目。本文提出的研究项目旨在使用纵向人体神经成像来测试 由基础科学提供信息的疾病模型，假设i)tau起源于焦点区域(“震中”)和 通过预先存在的连接在整个大脑中进行，并且ii)tau触发局部神经元丢失。 分析将依赖于带有tau病理的放射性示踪剂的PET和结构MRI来测量脑萎缩，a 阿尔茨海默病早期临床阶段(轻度认知障碍或痴呆)患者神经元丢失的代用品 到公元后)。候选人将使用已建立的网络扩散模型来量化成像异常 顺应并沿着大脑结构连接体前进。具体地说，他将使用这个扩散模型来 推断以前的疾病状态，即确定单个患者的tau中心(目标1)，并预测未来tau的传播 (目标2)。基准tau-PET随后将用于预测未来的脑萎缩(目标3)。国家-国家的组合使用 最先进的多模式成像和数学建模不仅允许候选人测试假设 有关疾病传播机制的信息，但也将为制定针对患者的措施提供信息 疾病进展对设计更有效的临床试验的影响。

PROJECT SUMMARY/ABSTRACT Alzheimer’s Disease (AD) is characterized by the presence of β-amyloid plaques, tau-containing neurofibrillary tangles, and neuronal loss; yet, little is known about the development and spread of neurodegenerative processes. Recent progress in neuroimaging has enabled the detection of the main features of the AD pathophysiological cascade using positron emission tomography (PET) and magnetic resonance imaging (MRI), allowing researchers to track the development of the disease in vivo. Candidate & environment. The candidate’s career goal is to become an independent investigator and lead imaging research to elucidate the mechanisms underlying Alzheimer’s disease (AD) and develop precision medicine tools tailored towards individual patients. During this K award, the candidate will extend his expertise in multimodal neuroimaging by receiving additional training in connectivity analyses and will acquire expertise in network science and mathematical modeling. This new skill set will allow him to pursue innovative research projects testing hypotheses about the spread of AD pathology. The candidate will have access to large datasets of state-of-the-art PET and MRI data; he will be working with a multi-disciplinary team of world-renowned mentors and collaborators with expertise spanning imaging, behavioral neurology, bioengineering, pathology and statistics. The exceptional resources and diverse scientific community at the UCSF Memory and Aging Center will provide an ideal environment for the candidate’s training and will foster his growth as a future successful independent investigator. Research project. The research project proposed herein aims to use longitudinal human neuroimaging to test a disease model informed by basic science, postulating that i) tau originates in focal areas (“epicenters”) and progresses throughout the brain via pre-existing connections, and that ii) tau triggers local neuronal loss. Analyses will rely on PET with a radiotracer for tau pathology and structural MRI to measure brain atrophy, a proxy for neuronal loss, in patients in the early clinical stages of AD (mild cognitive impairment or dementia due to AD). The candidate will use an established network diffusion model to quantify how imaging abnormalities conform to and progress along the brain structural connectome. Specifically, he will use this diffusion model to infer prior disease states, i.e. identify tau epicenters in individual patients (Aim 1), and to predict future tau spread (Aim 2). Baseline tau-PET will then be used to predict future brain atrophy (Aim 3). The combined use of state- of-the-art multimodal imaging and mathematical modeling will not only allow the candidate to test hypotheses about mechanisms of disease spread, but will also inform the development of patient-tailored measures of disease progression with implications for the design of more efficient clinical trials.