MRI Progression Markers of Cognitive Decline in the Elderly

老年人认知能力下降的 MRI 进展标志物

基本信息

批准号：
8142126
负责人：
HENRY RUSINEK
金额：
$ 61.11万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8142126
关键词：
Accounting Alzheimer disease detection Alzheimer disease prevention Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Animal Experiments Atrophic Biological Biological Markers Biological Markers Blood Vessels Brain Brain Injuries Brain Pathology Brain region Carbon Dioxide Cerebrospinal Fluid Cerebrovascular Circulation Classification Clinical Cognitive Communities Control Groups Data Deposition Detection Diagnosis Disease Progression Elderly Evaluation Functional Imaging Future Goals Hippocampal Formation Hippocampus (Brain)Human Image Impaired cognition Inflammation Laboratories Longitudinal Studies Magnetic Resonance Imaging Measurement Measures Methods Modality Modeling Morphologic artifacts Mus Neuropsychological Tests Outcome Pathology Patients Performance Perfusion Physiological Plasma Procedures Protocols documentation Quality Control Resolution Rest Risk Sampling Specificity Spin Labels Staging Stimulus Tauopathies Techniques Testing Threonine Time Tissues Transgenic Mice Transgenic Organisms Vasoconstrictor Agents Work amyloid pathology base cognitive change cognitive function cohort experience hyperphosphorylated tau imaging modality improved in vivo innovation longitudinal design mild neurocognitive impairment neocortical neuropathology neuropsychological novel pre-clinical primary outcome progression marker public health relevance response secondary outcome

项目摘要

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.

描述（由申请人提供）：神经病理学和我们的影像数据均表明，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。非常需要改进的生物标志物，这些标志物对进展敏感并且对 AD 病理具有特异性。目前尚无已知的疾病进展机制。我们的建议是使用一种新型 MRI HIP 成像方案并测试 CSF 生物标志物，以便：a) 改善认知能力下降的预测，b) 开发进展敏感标志物，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，可对 HIP 中的脑血流量 (CBF) 进行无伪影测量，并测试二氧化碳 (VR-CO2) 的血管反应性。目标 1 是在 MCI 患者中评估 CBF 和 VR-CO2 作为认知能力下降的预测因素。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。我们的计划是检验这样的假设：HIP、皮质 CBF 和 VR-CO2 的无伪影 MRI 测量有助于评估与 AD 相关的认知能力下降的未来风险，并且灌注成像优于传统的体积方法。由于流量和体积变化都不是 AD 所特有的，因此次要目标是检查两种 AD 病理学特异性生物标志物的附加贡献：脑脊液过度磷酸化 tau (P-tau231) 升高和脑脊液淀粉样蛋白 β 1-42 (A242) 降低。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 沉积物都会降低转基因小鼠的 HIP-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，并且血浆 A240 水平升高与 HIP VR-CO2 降低之间存在关联。我们提出了一项针对社区老年人的纵向研究，以检验区域性 HIP VR-CO2 减少可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 MCI（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 的临床衰退。将测试五项研究假设。目标 1：H1) 基线区域 CBF 和 VR 对于群体分类和结果预测很有用，并有助于体积测量。 H2) HIP CBF 和 VR 在结果预测中增加 CSF P-tau231 和 A242。 H3) 在识别患有进行性认知障碍的患者方面，AD 易受影响区域的纵向 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； H5) VR-CO2 减少的大脑区域将显示出渐进的 CBF 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进行标准化。有足够数量的可用受试者和足够的统计能力来进行假设检验。公共卫生相关性：AD 的预防需要对进行性临床前 AD 敏感、具有病理学特异性并基于相关生物学机制的生物学测量。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 的认知能力下降； b) CBF 是否改善了对 MRI 体积和 AD 有效 CSF 生物标志物的预测； c) CBF 对 CO2 挑战的反应减少是否：1) 与血浆 A240 水平升高相关，2) 预测进行性组织体积和认知丧失。