The structural and functional connectome across Alzheimer's disease subtypes

 描述（由申请人提供）：现在清楚的是，阿尔茨海默病不是单一的现象，并且可以根据其遗传起源将其分为亚型，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）方案提供了全面表征这些AD亚型的成像和临床表型的独特机会。通过将HCP方案应用于具有完全渗透性常染色体显性AD（由于A431 E PSEN 1或V717 I APP突变导致的ADAD）风险的人，结合使用新型配体18 F-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病理学以跨突触方式沿沿着可定义的神经通路传播的假设。将HCP方案应用于该独特人群将提供检验AD病因学中tau跨突触扩散假设的机会，并提供区分AD亚型中病理过程的机会，从而为治疗方法提供信息。由于PSEN 1相关AD可表现为痉挛性下肢轻瘫，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中的连接性测量相关联，从而帮助理解该特征并验证HCP测量。我们提出了以下具体目标：1）进行网络分析，将使用tau PET测量的神经元缠结的皮质沉积序列与白色物质通路和临床状态相关联。2)识别常染色体显性AD突变（由于PSEN 1和APP基因的特定突变导致的ADAD）导致的神经退行性变期间的连接组（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AD（由于PSEN 1和APP突变）和晚期AD（LOAD，与APOE e4等位基因相关或无关）之间的连接组和脑灌注MRI差异。4)使用TMS识别ADAD和LOAD中运动通路中中枢传导时间变化的连接组学基础。这项研究将利用A431 E PSEN 1和V717 I APP突变的相关性来估计连接组MRI中突变相关的变异性。它还将提供机会，探索与墨西哥梅斯蒂索起源相关的te连接体的变异性，这是一个在阿尔茨海默氏症和其他神经科学研究中通常代表性不足的人群。最后，通过采用西班牙语的HCP表型分析方案并将其应用于该人群，我们将创建一个数据库，以便将来在拉丁美洲人中进行更多的研究，拉丁美洲人是美国人口的一个不断增长的部分。

 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.