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（由适用提供）：现在很明显，阿尔茨海默氏病不是一个单一现象，可以通过其遗传来源将其分为亚型，每种都可能具有不同的致病级联反应，因此对治疗的反应可能有所不同。 Human ConnectMe项目（HCP）协议提供了独特的机会，可以全面地表征这些AD亚型的成像和临床表型。 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途径。将HCP方案应用于该独特的人群将提供机会，以测试TAU在AD病因中的透射率传播的假设，并为区分AD亚型的病理过程提供了机会，从而为治疗方法提供了信息。由于PSEN1相关的AD可以带有一种易于评估的表型的痉挛性帕拉帕拉斯，因此我们将能够将中枢神经系统中枢神经系统传导时间的神经生理参数与HCP中的连通性测量相关联，从而帮助理解这种特征性和验证HCP测量。我们提出以下具体目的：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途径和临床状态进行测量。 2）在神经变性过程中，由于常染色体显性AD突变（PSEN1和APP基因的特异性突变引起的ADAD引起的），在神经退行性过程中识别连接组（结构，功能和连接）和脑灌注（ASL）MRI差异可能揭示了潜水员的病理表型。 3）确定早期AD（由于PSEN1和APP突变）和晚期发作（负载，与APOE E4等位基因相关联或与APOE E4等位基因相关）之间的AD AD（由于PSEN1和APP突变）之间的连接组和脑灌注MRI差异。 4）确定ADAD电动路径中心传导时间变化的连接不能进行，并使用TMS负载。这项研究将利用A431E PSEN1和V717I APP突变的人之间的相关性来估计连接组MRI中与突变相关的变异性。它还将提供机会探索与墨西哥混血儿相关的TE Con​​nectome的变异性，墨西哥混血儿是一个人群，通常在阿尔茨海默氏症和其他神经科学研究中代表不足。最后，通过将HCP表型方案采用到西班牙语中并将其应用于该人群中，我们将创建一个数据库，以在拉丁美洲人的越来越多的拉丁美洲人进行更多研究。