MRI Progression Markers of Cognitive Decline in the Elderly

描述(申请人提供)：神经病理学和我们的成像数据都表明，在阿尔茨海默病(AD)的轻度认知障碍(MCI)阶段，发现海马体结构(HIP)和新皮质异常。迫切需要改进的生物标志物，这些标志物对进展敏感，对AD病理具有特异性。目前还没有已知的解释疾病进展的机制。我们的建议是使用一种新的MRI髋关节成像方案和测试脑脊液生物标记物，以：a)改善认知功能下降的预测，b)开发进展敏感的标记物，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，可以无伪影地测量髋部脑血流量(CBF)，并测试血管对二氧化碳的反应性(VR-CO2)。目的1是评价在MCI患者中，CBF和VR-CO2作为认知功能减退的预测指标。先前的工作表明，在MCI阶段，功能成像模式在检测AD相关变化方面优于结构性。我们的计划是验证这样一种假设，即髋部和皮质CBF的无伪影MRI测量和VR-CO2有助于评估与AD相关的认知功能下降的未来风险，并且灌注成像优于传统的体积测量方法。因为血流和体积的改变都不是AD特有的，次要目标是研究两个AD病理特异性生物标志物的附加作用：升高的脑脊液过度磷酸化tau(P-tau231)和降低的脑脊液淀粉样β1-42(A242)。目标2是测试AD进展的候选机制。血浆A240水平升高和血管内A240沉积都降低了转基因小鼠的髋部CBF和VR-CO2，从而导致实质损伤(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，且血浆A240水平升高与髋关节VR-CO2降低之间存在关联。我们建议对社区居住的老年人进行一项纵向研究，以检验这样一种假设，即区域性减少的髋关节VR-CO2预测组织体积减少和认知能力下降。我们的计划是每隔18个月对115名MCI(65-80岁)和30名人口统计学上匹配的正常对照进行三次临床检查。主要结果是认知能力下降，次要结果是阿尔茨海默病的临床下降。五个研究假设将被检验。目的：1)基线局部CBF和VR可用于分组和预后预测，并有助于容量测量。(2)髋部CBF和VR升高脑脊液P-tau231和A242对预后的预测作用。H3)阿尔茨海默病易感区域的纵向脑血流量减少在识别进行性认知障碍患者方面优于体积减少。目的2)H4)在基线和纵向上，髋部VR-CO2与血浆A240水平呈负相关；H5)VR-CO2降低的脑区将出现进行性脑血流和体积减少。这项研究所需的所有临床、实验室和成像组件都通过质量控制进行了标准化。有足够数量的受试者和足够的统计能力进行假设检验。 公共卫生相关性：预防阿尔茨海默病需要对进行性临床前阿尔茨海默病敏感的生物学措施，具有病理学特异性，并基于相关的生物学机制。我们提出了一种新的MRI技术来检验：(A)脑血流量(CBF)的纵向测量是否有助于预测MCI的认知功能下降；(B)CBF是否改善了对MRI容量和AD有效的脑脊液生物标志物的预测；以及c)CBF对二氧化碳挑战的反应是否降低：1)与血浆A240水平升高有关；2)预测进行性组织体积和认知能力丧失。

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.