The structural and functional connectome across Alzheimer's disease subtypes

 描述(申请人提供)：现在很清楚，阿尔茨海默病不是一种单一的现象，它可以根据其遗传来源分为不同的亚型，每种亚型可能有不同的致病级联，因此对治疗的反应可能不同。人类连接组计划(HCP)方案提供了全面描述这些AD亚型的影像和临床表型的独特机会。通过将HCP方案应用于全穿透性常染色体显性AD(A431E PSEN1或V717I APP突变导致的ADAD)高危人群，结合使用新型配体18F-T807的tau正电子发射断层扫描(PET)成像，我们将能够检验tau病理以跨突触方式沿着可定义的神经路径传播的假设。将HCP方案应用于这一独特的人群，将提供检验AD病因学中tau跨突触扩散的假设的机会，并提供区分AD亚型的病理过程的机会，从而为治疗方法提供参考。由于与PSEN1相关的AD可以表现为痉挛性瘫痪，这是一种容易评估的表型，我们将能够将中枢神经系统传导时间的神经生理参数与HCP中的连通性测量联系起来，有助于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)确定常染色体显性AD突变(由于PSEN1和APP基因的特定突变引起的ADAD)可能揭示不同病理表型的神经变性过程中连接(结构、功能和连接)和脑灌注(ASL)MRI的差异。3)确定早期AD(由于PSEN1和APP突变)和迟发性AD(负载，是否与APOE e4等位基因相关)之间的连接和脑血流灌注MRI差异。4)确定ADAD和TMS负荷时运动通路中枢传导时间改变的连接基础。这项研究将利用具有A431E PSEN1和V717I APP突变的人之间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Mestizo起源相关的TE连接组的可变性，这一群体在阿尔茨海默氏症和其他神经科学研究中通常代表不足。最后，通过将HCP表型分析协议翻译成西班牙语并将其应用于这一人群，我们将创建一个数据库，以便将来能够对拉丁裔进行更多的研究，拉美裔在美国人口中的比例越来越高。

 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.