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个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色物质破坏，在理解额纹状体脑网络下降的潜在作用。该提案建立在一个理论方向上，即对认知和潜在大脑网络的许多影响通常归因于高级衰老的发展过程可能与神经病理学过程有关;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，并检查其与衰老过程中的行为的关系。为此目的进行的培训将以候选人以前的经验为基础，并为以后的目标奠定基础。第二个目的是测试特定的神经病理是否与额纹状体网络的中断有关。为此目的的培训将发展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，并描述这三种年龄相关神经病理学之间的横截面关系。第三个目的是测试是否神经病理学预测的纵向变化额纹状体网络。为此目的的培训将发展候选人在纵向分析方法方面的专业知识，并将进一步促进候选人的长期目标，即确定衰老过程中观察到的认知和神经变化所涉及的机制途径。将通过利用与已资助的项目一起收集的数据以及通过添加拟在拟议项目中收集的新数据来获得三种脑部病理学的标志物。多巴胺能功能在衰老过程中下降，其程度不像在帕金森病中观察到的那样严重，将通过多巴胺转运的PET成像来测量。淀粉样蛋白积聚将通过淀粉样蛋白斑块的PET成像来测量，淀粉样蛋白斑块是阿尔茨海默病的标志性病理学。白色物质的完整性，通常破坏血管性痴呆，将使用结构磁共振成像（MRI）进行测量。在马萨诸塞州总医院提供的培训允许获得资源和导师在许多必要的技术，以候选人的培训和职业目标的目标。每个神经病理学过程的关系中断额纹状体脑网络将进行检查，以确定是否年龄相关的减少，这个网络的完整性可以追溯到特定的影响神经病理学。使用纵向数据，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。这些目标的完成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。这项研究与潜在的未诊断神经病理学和大脑网络破坏的筛查相关，这可能有助于早期诊断年龄相关的神经退行性变，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.