The structural and functional connectome across Alzheimer's disease subtypes

阿尔茨海默病亚型的结构和功能连接组

• 批准号: 8969574
• 负责人: JOHN M RINGMAN
• 金额: $ 70.41万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-30 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8969574
• 关键词: APP gene; Adopted; Affect; Age; Alleles; Alzheimer' s Disease; Cerebrum; Characteristics; Clinical; Clinical Pathways; Databases; Dementia; Deposition; Disease; Etiology; Failure; Future; Genes; Genetic; Genotype; Human; Image; Impairment; Intervention; Late Onset Alzheimer Disease; Latino; Length; Ligands; Light; Magnetic Resonance Imaging; Measures; Mexican; Motor Pathways; Mutation; Nerve Degeneration; Neural Pathways; Neuraxis; Neurofibrillary Tangles; Pathologic Processes; Pathology; Pathway interactions; Perfusion; Persons; Phenotype; Population; Positron-Emission Tomography; Protocols documentation; Research; Risk; Spastic Paraparesis; Spin Labels; Synapses; Testing; Time; Transcranial magnetic stimulation; autosomal dominant mutation; base; clinical phenotype; disorder subtype; insight; neurophysiology; novel; presenilin-1; public health relevance; tau Proteins; white matter

 DESCRIPTION (provided by applicant): It is now clear that Alzheimer's disease is not a unitary phenomenon and that it can be divided into subtypes by their genetic origins, each of which may have distinct pathogenetic cascades and therefore may respond differentially to treatments. The Human Connectome Project (HCP) protocol provides the unique opportunity to comprehensively characterize imaging and clinical phenotypes of these AD subtypes. By applying the HCP protocol to persons at-risk for fully-penetrant autosomal dominant AD (ADAD due to either the A431E PSEN1 or V717I APP mutations) in conjunction with positron emission tomography (PET) imaging of tau using the novel ligand 18F-T807, we will be able to test the hypothesis that tau pathology spreads in a trans-synaptic manner along definable neural pathways. Applying the HCP protocol to this unique population will provide the opportunity to test the hypothesis of transynaptic spread of tau in the etiology of AD and provide the opportunity to differentiate pathological processes in subtypes of AD and therefore inform approaches to treatment. As PSEN1-related AD can present with spastic paraparesis, an easily assessed phenotype, we will be able to relate the neurophysiological parameters of central nervous system conduction time to connectivity measures in the HCP, helping to understand this characteristic and also validating HCP measures. We propose the following specific aims: 1) Perform network analyses relating the sequence of cortical deposition of neurofibrillary tangles measured using tau PET to white matter pathways and clinical status. 2) Identify connectomic (structural, functional, and connectional) and cerebral perfusion (ASL) MRI differences during neurodegeneration due to autosomal dominant AD mutations (ADAD due to specific mutations in the PSEN1 and APP genes) potentially revealing diverse pathological phenotypes. 3) Identify connectomic and cerebral perfusion MRI differences between AD of early (due to PSEN1 and APP mutations) and late onset (LOAD, associated or not with the APOE e4 allele). 4) Identify the connectomic bases for changes in central conduction times in motor pathways in ADAD and LOAD using TMS. This study will leverage the relatedness among persons with the A431E PSEN1 and V717I APP mutations to estimate mutation-associated variability in the connectome MRI. It will also provide the opportunity to explore variability of te connectome associated with Mexican Mestizo origin, a population typically under-represented in Alzheimer's and other neuroscientific research. Finally, by adopting the HCP phenotyping protocol into Spanish and applying it in this population, we will create a database to enable additional future studies in Latinos, a growing segment of the U.S. population.

 描述（由申请人提供）：现在很清楚，阿尔茨海默氏病不是一个单一的现象，它可以根据其遗传起源分为亚型，每种亚型可能具有不同的致病级联，因此可能对治疗有不同的反应。人类连接组计划 (HCP) 协议提供了独特的机会来全面表征这些 AD 亚型的成像和临床表型。通过将 HCP 方案应用于有完全渗透性常染色体显性 AD（ADAD 由于 A431E PSEN1 或 V717I APP 突变所致）风险的人，并结合使用新型配体 18F-T807 对 tau 进行正电子发射断层扫描 (PET) 成像，我们将能够检验 tau 病理学沿着可定义的神经网络以跨突触方式传播的假设。 途径。将 HCP 方案应用于这一独特人群将为检验 AD 病因中 tau 突触传播的假设提供机会，并提供区分 AD 亚型病理过程的机会，从而为治疗方法提供信息。由于 PSEN1 相关的 AD 可以表现为痉挛性截瘫，这是一种易于评估的表型，因此我们将能够将中枢神经系统传导时间的神经生理学参数与 HCP 中的连接测量联系起来，帮助了解这一特征并验证 HCP 测量。我们提出以下具体目标：1) 进行网络分析，将使用 tau PET 测量的神经原纤维缠结的皮质沉积序列与白质通路和临床状态联系起来。 2) 识别由于常染色体显性 AD 突变（由于 PSEN1 和 APP 基因的特定突变导致的 ADAD）导致的神经变性期间的连接组（结构、功能和连接）和脑灌注 (ASL) MRI 差异，可能揭示不同的病理表型。 3) 确定早期（由于 PSEN1 和 APP 突变）和晚期（LOAD，与 APOE e4 等位基因相关或无关）AD 之间的连接组和脑灌注 MRI 差异。 4) 使用 TMS 确定 ADAD 和 LOAD 中运动通路中心传导时间变化的连接组学基础。本研究将利用 A431E PSEN1 和 V717I APP 突变人群之间的相关性来估计连接组 MRI 中与突变相关的变异性。它还将提供探索与墨西哥混血裔血统相关的连接组变异性的机会，该群体在阿尔茨海默病和其他神经科学研究中通常代表性不足。最后，通过将 HCP 表型分析协议采用西班牙语并将其应用到该人群中，我们将创建一个数据库，以便在未来对拉丁裔（美国人口中不断增长的群体）进行更多研究。