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成像数据均显示，在阿尔茨海默病（AD）的轻度认知障碍（MCI）阶段发现海马结构（HIP）和新皮质异常。非常需要对进展敏感并且对AD病理学特异的改进的生物标志物。目前还没有已知的机制解释疾病进展。我们的建议是使用一种新的MRI HIP成像方案和测试的CSF生物标志物，以便：a）改善认知下降的预测，B）开发进展敏感的标志物，和c）测试AD进行性脑病理学的血管机制。我们开发了一种MRI-动脉自旋标记（ASL）方法，用于无伪影测量HIP中的脑血流量（CBF），并测试对二氧化碳的血管反应性（VR-CO2）。目的1是评估MCI患者中，CBF和VR-CO 2作为认知功能下降的预测因子。先前的工作表明，在MCI阶段检测AD相关变化时，功能成像方式优于结构成像方式上级。我们的计划是检验这样一个假设，即HIP和皮质CBF和VR-CO 2的无伪影MRI测量在评估与AD相关的认知下降的未来风险中是有用的，并且灌注成像优于传统的容积方法上级。由于流量和体积变化都不是AD特异性的，因此次要目标是检查两种AD病理学特异性生物标志物的额外贡献：升高的CSF过度磷酸化tau（P-tau 231）和降低的CSF淀粉样蛋白β 1-42（A242）。目的2是测试AD进展的候选机制。升高的血浆A240水平和血管内A240沉积都降低了转基因小鼠的HIP-CBF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降低相关。我们提出了一个纵向研究社区居住的老年人检查假设，区域减少HIP VR-CO2预测组织体积损失和认知能力下降。我们计划对115名MCI（65-80岁）和30名人口统计学匹配的正常对照者每隔18个月进行三次临床检查。主要结局是认知能力下降，次要结局是临床下降至AD。将检验五个研究假设。目的1：H1）基线区域CBF和VR可用于组分类和结局预测，并有助于体积测量。H2）HIP CBF和VR增加CSF P-tau 231和A242对预后的预测。H3）在识别患有进行性认知障碍的患者时，AD易受伤害区域的纵向CBF减少优于体积减少上级。目标二：H4）在基线和纵向，HIP VR-CO2与血浆A240水平负相关;和H5）VR-CO2降低的脑区域将显示进行性CBF和体积减少。本研究所需的所有临床、实验室和成像部分均采用质量控制标准化。有充足的受试者数量和足够的统计功效进行假设检验。 公共卫生相关性：AD的预防需要对进行性临床前AD敏感的生物测量，是病理特异性的，并且基于相关的生物机制。我们提出了一种新的MRI技术来检查：（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体积和AD有效CSF生物标志物的预测;以及c）CBF对CO2激发的反应降低是否：1）与血浆A240水平升高相关，2）预测进行性组织体积和认知功能丧失。

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.