Antecedent Neuroimaging Biomarkers

阿尔茨海默型痴呆症(DAT)高危人群大脑早期结构和功能的变化尚不清楚。通常情况下，DAT的诊断是使用神经心理学表现测试和临床评估。我们团队和其他人之前的工作已经确定了DAT的临床前阶段，该阶段与一系列生物标记物的变化有关，包括脑脊液(CSF)Abeta42(AP42)水平下降，PET(使用匹兹堡B化合物(PIB)检测到脑内纤维淀粉样蛋白沉积增加)，以及加剧萎缩，尤其是在海马区。这些生物标志物与DAT的危险因素之间存在交互作用，如家族史和基因(即载脂蛋白E)。临床前事件的确切顺序及其对导致DAT的神经元功能障碍的影响尚不清楚。磁共振成像的最新进展可以在这方面提供独特的信息。其中，静息状态功能连接性磁共振成像(FcMRI)、扩散张量成像(DTI)和动脉自旋标记(ASL)灌注成像三种技术可以提供神经功能(FcMRI)、脑血流量(ASL)和白质完整性(DTI)的敏感指标。使用这些神经成像技术的重复纵向测量可能会增加与DAT相关的大脑功能最早变化相关的时间进程的新信息。本项目有三个目标：目标1：在横断面分析中使用fcMRI、ASL和DTI的神经元结构的变化将与年龄、APOE基因以及生化和行为生物标志物相关。目的2：受试者对重复的fcMRI、ASL和DTI进行纵向追踪，将提供神经成像生物标志物变化序列的时间概况。目的3：将fcMRI、静息脑血流量和DTI测量的径向弥散系数随时间的变化率与认知功能减退(临床核心)、PIB评估的皮质淀粉样蛋白负荷的变化(项目1)、脑脊液生物标记物的变化(项目2)和神经心理指标(项目3)相关联。

Early structural and functional changes in the brains of individuals at risk for developing dementia of the Alzheimer type (DAT) are not well understood. Typically a diagnosis of DAT is made using neuropsychological performance testing and clinical evaluation. Previous work by our group and others has identified a preclinical phase of DAT that is associated with a constellation of changes in biomarkers including decreased cerebral spinal fluid (CSF) Abeta42 (AP42) levels, increased fibrillar amyloid deposits in the brain as detected by PET (using Pittsburgh B compound (PIB)), and increased atrophy, particularly within the hippocampus. An interaction exists between these biomarkers and risk factors for DAT such as family history and genotype (ie., apolipoprotein E (APOE). The exact sequence of preclinical events, and their effects on neuronal dysfunction that leads to DAT, remain unclear. Recent advancements in MR imaging could provide unique information in this regard. Specifically three techniques- resting state functional connectivity MRI (fcMRI), diffusion tensor imaging (DTI), and arterial spin labeling (ASL) perfusion imaging, could provide sensitive measures of neuronal function (fcMRI), cerebral blood flow (ASL) and white matter integrity (DTI). Repeated longitudinal measures using these neuroimaging techniques could add new information concerning the temporal course associated with the very earliest changes in brain function associated with DAT. This project has 3 aims: Aim 1: Changes in neuronal structure using fcMRI, ASL and DTI in a cross-sectional analysis will be correlated with age, APOE genotype, and biochemical and behavioral biomarkers. Aim 2. Subjects followed longitudinally with repeat fcMRI, ASL, and DTI will provide a temporal profile of the sequence of changes in neuroimaging biomarkers. Aim 3: Associate the rates of change over time in fcMRI, resting cerebral blood flow, and radial diffusivity in DTI measures with cognitive decline (Clinical Core), changes in cortical amyloid load as assessed by PIB (Project 1), changes in CSF biomarkers (Project 2), and neuropsychological measures (Project 3).