MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA

项目2（格拉博斯基）：摘要 PD相关认知障碍和APOE或GBA遗传变异的基于MR的系统成像 新出现的证据表明，帕金森病（PD）认知障碍的变异性部分反映了 基本的生物异质性。我们假设这种差异是由不同的 妥协的内在皮层系统，功能性连接功能磁共振成像将证明具体的 神经生理学关系中的系统水平变化取决于特定的分子 疾病的司机。APOE ε4和GBA变异体是痴呆症的可靠遗传预测因子， 帕金森病，他们可能会改变认知障碍的概况，证明重点放在这些遗传- 定义的群体。我们将在APOE ε4中应用新的动态和已建立的功能连接fMRI方法 和GBA变体携带者以及健康对照受试者。这些分析将在实践中进行。 多巴胺能关闭状态。我们预计，APOE ε4不成比例地影响记忆相关系统， 包括默认模式网络的顶叶和颞叶成分，而GBA变体加速了 对内侧额壁和基底神经节中多巴胺能靶点的病理作用， 功能整合的额顶叶外侧网络使用相同的基因定义的参与者，我们将 测试假设，动态功能连接和网络内核分析，方法，我们有 开发的静息和任务状态功能磁共振成像，可以灵敏地预测的发展和进展， 认知功能障碍这些分析将使用多巴胺能神经元的fMRI数据进行。 药我们还将评估功能连接是否预测认知诊断和/或 进展对于多巴胺能替代状态是不变的。最后，我们将研究皮质的轮廓， 与认知障碍不同病理生理机制的生物标志物相关的系统变化 在警局我们的初步研究表明，综合性和区域性的系统破坏措施增加， 与CSF中α-突触核蛋白或Aβ42浓度的（病理性）降低成比例。我们将复制这个 发现在一个单独的小组PD参与者，并继续分析是否综合和区域措施， 系统破坏介导皮质病理学和认知的CSF生物标志物之间的关系。在 通过本中心其他项目的二次分析，我们将把这种新方法扩展到其他项目。 疾病机制的标志物：SAI（胆碱能张力的测量，项目3）和定量分子标记物 病理学，项目1。在这个项目中获得的新知识将是精准医学的基础， 帕金森病认知障碍的不同分子驱动因素。

PROJECT 2 (GRABOWSKI): ABSTRACT MR-based systems imaging of PD-related cognitive impairment and inherited variants in APOE or GBA. Emerging evidence indicates that variability in cognitive impairment in Parkinson Disease (PD) in part reflects fundamental biological heterogeneity. We hypothesize that the difference is mediated by differential compromise of intrinsic cortical systems, and that functional connectivity fMRI will demonstrate specific systems-level alternations in neurophysiologic relationships that vary depending upon the specific molecular driver of disease. The findings that APOE ε4 and GBA variants are robust genetic predictors of dementia in PD, and that they may modify the profile of the cognitive impairment, justify a focus on these genetically- defined groups. We will apply novel dynamic and established functional connectivity fMRI methods in APOE ε4 and GBA variant carriers, and healthy comparison subjects. These analyses will be conducted in the practical dopaminergic OFF state. We expect that APOE ε4 disproportionately affects memory-related systems including the parietal and temporal components of the default mode network, while GBA variants accelerate pathological effects on dopaminergic targets in the mesial frontal wall and the basal ganglia, and their functionally integrated lateral frontoparietal networks. Using the same genetically-defined participants, we will test the hypothesis that dynamic functional connectivity and network kernel analyses, approaches we have developed for both resting and task state fMRI, can sensitively predict the development and progression of cognitive impairment in PD. These analyses will be conducted with fMRI data taken ON dopaminergic medication. We will also evaluate whether functional connectivity predicting cognitive diagnosis and/or progression are invariant to dopaminergic replacement status. Finally we will investigate profiles of cortical systems change associated with biomarkers of different pathophysiologic mechanisms of cognitive impairment in PD. Our preliminary studies establish that omnibus and regional measures of system disruption increase in proportion to the (pathologic) reduction of α-synuclein or Aβ42 concentration in CSF. We will replicate this finding in a separate group of PD participants and go on to analyze whether omnibus and regional measures of system disruption mediate the relationship between CSF biomarkers of cortical pathology and cognition. In secondary analyses informed by the other Projects in this Center, we will extend this novel approach to other markers of disease mechanisms: SAI (a measure of cholinergic tone, Project 3) and quantitative molecular pathology, Project 1. The new knowledge gained in this Project will be foundational to precision medicine for different molecular drivers of cognitive impairment in PD.