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

基本信息

批准号：
9145149
负责人：
JOHN M RINGMAN
金额：
$ 96.21万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
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/9145149
关键词：
Adopted Affect Age Alleles Alzheimer&apos s Disease Amyloid Beta A4 Precursor Protein Cerebrum Characteristics Clinical Clinical Pathways Databases Dementia Deposition Disease Electrophysiology (science)Etiology Failure Future Genes Genetic Genotype Health 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 connectome demented disorder subtype insight mutational status neurophysiology novel presenilin-1 tau Proteins white matter

项目摘要

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种单一现象，它可以根据其遗传起源分为不同的亚型，每种亚型可能具有不同的致病级联，因此可能对治疗产生不同的反应。连接组项目 (HCP) 方案通过将 HCP 方案应用于有完全渗透性常染色体显性 AD 风险的人群，提供了全面表征这些 AD 亚型的影像和临床表型的独特机会。（由于 A431E PSEN1 或 V717I APP 突变引起的 ADAD）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 病理学在跨突触中传播的假设将 HCP 协议应用于这个独特的群体将为测试 tau 蛋白跨突触传播的假设提供机会。由于 PSEN1 相关的 AD 可能出现痉挛性截瘫（一种易于评估的表型），因此我们将能够将中枢神经的神经生理学参数联系起来。系统传导时间到 HCP 中的连接测量，有助于了解这一特征并验证 HCP 测量结果：1）执行与测量的神经原纤维缠结的皮质沉积序列相关的网络分析。使用 tau PET 来了解白质通路和临床状态 2) 识别由于常染色体显性 AD 突变（由于 PSEN1 和 APP 中的特定突变而导致的 ADAD）导致的神经变性期间的连接组（结构性、功能性和连接性）和脑灌注 (ASL) MRI 差异。 3) 确定早期 AD（由于 PSEN1 和 APP 突变）和晚期 AD（LOAD，与 AD 相关或无关）之间的连接组和脑灌注 MRI 差异4) 使用 TMS 确定 ADAD 和 LOAD 运动通路中枢传导时间变化的连接组基础本研究将利用 A431E PSEN1 和 V717I APP 突变人群之间的相关性来估计连接组 MRI It 中与突变相关的变异性。还将提供探索与墨西哥梅斯蒂索血统相关的连接组变异性的机会，该群体在阿尔茨海默氏症和其他疾病中的代表性不足最后，通过将 HCP 表型分析协议采用西班牙语并将其应用于该人群，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。