Influence of Age-related Neuropathology on Functional Brain Networks

描述（由申请人提供）：拟议的研究探讨了三种与年龄相关的神经病理过程，即多巴胺功能障碍，淀粉样蛋白积累和白质破坏，在理解额纹状体脑网络衰退中的潜在作用。该建议建立在一个理论方向上，即通常归因于老年发展过程的认知和潜在大脑网络的许多影响可能与神经病理过程有关；研究计划的长期目标是使用多种方法彻底测试这一理论方向。第一个目的是表征额纹状体网络并研究其与衰老过程中行为的关系。这一目标的培训将建立在候选人以前的经验基础上，并将为以后的目标提供基础。第二个目的是测试特定的神经病变是否与额纹状体网络的破坏有关。为此目的培训将培养候选人在使用正电子发射断层扫描（PET）的分子成像技术方面的专业知识。短期目标包括获得PET技术的专业知识和表征这三种与年龄相关的神经病变之间的横断面关系。第三个目的是测试神经病理学是否能预测额纹状体网络的纵向变化。针对这一目标的培训将培养候选人在纵向分析方法方面的专业知识，并将进一步实现候选人的长期目标，即确定在衰老过程中观察到的认知和神经变化的机制途径。通过利用与已资助项目一起收集的数据以及在拟议项目中添加将收集的新数据，将获得三种脑病的标记。多巴胺能功能随着年龄的增长而下降，其程度不像帕金森病那样严重，将通过多巴胺转运的PET成像来测量。淀粉样蛋白积累将通过淀粉样斑块的PET成像来测量，淀粉样斑块是阿尔茨海默病的标志性病理。白质完整性，通常在血管性痴呆中被破坏，将使用结构磁共振成像（MRI）来测量。麻省总医院提供的培训允许获得资源和导师，以实现候选人的培训目标和职业目标所需的许多技术。每个神经病理过程与额纹状体大脑网络中断的关系将被检查，以确定该网络完整性的年龄相关减少是否可以追溯到神经病理学的特定影响。利用纵向数据，将评估每种神经病理学对额纹状体网络完整性随时间变化的影响。完成这些目标将增强对亚临床神经病理学在与年龄相关的脑网络完整性和相关认知能力下降中的作用的理解。这项研究对未确诊的神经病理学和脑网络破坏的潜在筛查具有重要意义，这可能有助于年龄相关神经退行性疾病的早期诊断，并允许开发用于评估介入治疗的生物标志物。

DESCRIPTION (provided by applicant): The proposed research examines the potential role of three age-related neuropathological processes, namely dopamine dysfunction, amyloid accumulation, and white matter disruption, in understanding declines in a frontostriatal brain network. The proposal builds upon a theoretical orientation that many effects on cognition and underlying brain networks often attributed to developmental processes of advanced aging may be associated with neuropathological processes; a long-term goal of the research program is thorough testing of this theoretical orientation using multiple methods. The first aim is to characterize the frontostriatal network and examine its relationship to behavior during aging. Training for this aim will build on the candidate's previous experience and will provide a foundation for the later aims. The second aim is to test whether specific neuropathologies are associated with disruption of the frontostriatal network. Training for this aim will develop the candidate's expertise in molecular imaging techniques using positron emission tomography (PET). Short- term goals include obtaining expertise in PET techniques and characterizing the cross-sectional relationship between these three age-related neuropathologies. The third aim is to test whether neuropathology predicts longitudinal change in the frontostriatal network. Training for this aim will develop the candidate's expertise in longitudinal analytic methods and will further the candidate's long-term goal of identifying mechanistic pathways involved in cognitive and neural change observed during aging. Markers of three brain pathologies will be obtained by leveraging data collected in conjunction with already funded projects and by adding new data to be collected in the proposed project. Dopaminergic function, which declines during aging to an extent not as severe as that observed in Parkinson's disease, will be measured with PET imaging of dopamine transport. Amyloid accumulation will be measured with PET imaging of amyloid plaques, a hallmark pathology of Alzheimer's disease. White matter integrity, commonly disrupted in vascular dementia, will be measured using structural magnetic resonance imaging (MRI). Training available at Massachusetts General Hospital allows access to resources and mentors in the many techniques necessary to the aims of the candidate's training and career goals. The relationship of each neuropathological process to disruption in a frontostriatal brain network will be examined to determine if age-related reductions in this network's integrity can be traced to specific influences of neuropathology. Using longitudinal data, the influence of each neuropathology on change in frontostriatal network integrity over time will be assessed. Completion of the aims will enhance understanding of the role of sub-clinical neuropathology in age-related declines of brain network integrity and associated cognitive abilities. This research holds relevance for potential screening for undiagnosed neuropathology and disruption of brain networks that may aid in early diagnosis of age-related neurodegeneration and allow development of biomarkers for evaluating interventional therapies.