MRI Progression Markers of Cognitive Decline in the Elderly

描述（由申请人提供）：神经病理学和我们的影像学数据显示，在阿尔茨海默病（AD）轻度认知障碍（MCI）阶段发现海马形成（HIP）和新皮质异常。迫切需要改进对进展敏感和对阿尔茨海默病病理特异性的生物标志物。目前还没有关于疾病进展的已知机制。我们的建议是使用一种新的MRI HIP成像方案和测试脑脊液生物标志物，以便：a)提高对认知能力下降的预测，b)开发进展敏感标志物，以及c)测试AD进行性脑病理的血管机制。我们开发了一种mri动脉自旋标记（ASL）方法，以提供髋关节脑血流量（CBF）的无伪影测量，并测试血管对二氧化碳的反应性（VR-CO2）。目的1是评估MCI患者，CBF和VR-CO2作为认知能力下降的预测指标。先前的研究表明，在MCI阶段，功能成像方式在检测AD相关变化方面优于结构成像方式。我们的计划是验证无伪影MRI测量髋关节和皮质CBF以及VR-CO2在评估AD相关认知能力下降的未来风险方面有用的假设，并且灌注成像优于传统的容积法。由于流量和体积变化都不是AD特异性的，因此第二个目标是检查两种AD病理特异性生物标志物的额外贡献：脑脊液过度磷酸化tau蛋白（P-tau231）升高和脑脊液淀粉样蛋白β 1-42 （A242）降低。目的2是测试AD进展的候选机制。在转基因小鼠中，血浆A240水平升高和血管内A240沉积降低了髋-脑血流和VR-CO2，导致实质损伤（体积损失）和炎症。我们的初步数据显示MCI患者血浆A240水平升高，血浆A240水平升高与HIP VR-CO2降低之间存在关联。我们提出了一项对社区居住老年人的纵向研究，以检验区域性降低HIP VR-CO2预测组织体积损失和认知能力下降的假设。我们的计划是每隔18个月对115名轻度认知障碍患者（65-80岁）和30名人口统计学匹配的正常对照进行3次临床检查。主要结果是认知能力下降，次要结果是AD的临床下降。五个研究假设将被检验。目的1:H1)基线区域CBF和VR对分组分类和结果预测有用，并有助于体积测量。H2) HIP CBF和VR增加CSF P-tau231和A242对预后的预测作用。H3)在识别进行性认知障碍患者时，AD易感区域的纵向CBF减少优于体积减少。目标2:H4)在基线和纵向上，HIP VR-CO2与血浆A240水平呈负相关；和H5) VR-CO2减少的脑区将显示进行性脑血流和体积减少。本研究所需的所有临床、实验室和成像组件均通过质量控制标准化。有足够数量的可用对象和足够的统计能力进行假设检验。

DESCRIPTION (provided by applicant): Both the neuropathology and our imaging data show that hippocampal formation (HIP) and neocortical abnormalities are found in the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). Much needed are improved biological markers that sensitive to progression and specific for AD pathology. Currently there are no known mechanisms accounting for disease progression. Our proposal is to use a novel MRI HIP imaging protocol and tested CSF biomarkers in order to: a) improve the prediction of cognitive decline, b) develop progression sensitive markers, and c) test a vascular mechanism for the progressive brain pathology of AD. We developed an MRI-Arterial Spin Labeling (ASL) method to give artifact free measures of cerebral blood flow (CBF) in the HIP and test the vasoreactivity to carbon dioxide (VR-CO2). Aim 1 is to evaluate among MCI patients, CBF and VR-CO2 as predictors of cognitive decline. Prior work shows that functional imaging modalities are superior to structural in the detection of AD related changes at the MCI stage. Our plan is to test the hypothesis that artifact free MRI measurement of HIP and cortical CBF and VR-CO2 are useful in assessing the future risk for cognitive decline related to AD, and perfusion imaging is superior to conventional volumetric methods. Because neither flow nor volume changes are specific for AD, a secondary goal is to examine the added contribution of two AD pathology-specific biomarkers: elevated CSF hyperphosphorylated tau (P-tau231) and decreased CSF amyloid beta 1-42 (A242). Aim 2 is to test a candidate mechanism for AD progression. Both elevated plasma A240 levels and intravascular A240 deposits reduce HIP-CBF and VR-CO2 in transgenic mice with resultant parenchymal damage (volume loss) and inflammation. Our preliminary data show elevated plasma A240 levels in MCI, and an association between elevated plasma A240 levels and reduced HIP VR-CO2. We propose a longitudinal study of community residing elders to examine the hypothesis that regionally reduced HIP VR-CO2 predicts tissue volume loss and cognitive decline. Our plan is to conduct three clinical exams at 18-month intervals on 115 MCI (65-80 yrs) and 30 demographically matched normal controls. The primary outcome is decreased cognitive performance and the secondary outcome is clinical decline to AD. Five study hypotheses will be tested. Aim 1: H1) Baseline regional CBF and VR are useful for group classification and outcome prediction and contribute to volume measurement. H2) HIP CBF and VR increment CSF P-tau231 and A242 in the prediction of outcome. H3) Longitudinal CBF reductions in AD vulnerable regions are superior to volume reductions in identifying patients with progressive cognitive impairments. Aim 2: H4) At baseline and longitudinally, HIP VR-CO2 is inversely related to the plasma A240 level; and H5) Brain regions with reduced VR-CO2 will show progressive CBF and volume reductions. All the required clinical, laboratory, and imaging components for this study are standardized with quality controls. There are ample numbers of subjects available and adequate statistical power for hypothesis testing. PUBLIC HEALTH RELEVANCE: The prevention of AD requires biological measurements that are sensitive to progressive preclinical AD, are pathology specific, and based on relevant biological mechanisms. We propose a new MRI technique to examine whether: (a) longitudinal measurement of cerebral blood flow (CBF) is useful in predicting cognitive decline in MCI; b) whether CBF improves the prediction over MRI volume and AD-valid CSF biomarkers; and c) whether a reduced CBF response to CO2 challenge is: 1) associated with elevated plasma A240 levels and 2) predicts progressive tissue volume and cognitive losses.