PET Imaging of Macrophages and Amyloid in AD

AD 中巨噬细胞和淀粉样蛋白的 PET 成像

• 批准号: 6899036
• 负责人: Clayton A. Wiley
• 金额: $ 15.22万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6899036
• 关键词: Alzheimer' s disease; amyloid proteins; brain imaging /visualization /scanning; clinical research; human subject; macrophage; microglia; neuritic plaques; neurofibrillary tangles; neuropsychological tests; positron emission tomography; radiotracer

DESCRIPTION (provided by applicant): Neuropathologically, Alzheimer's disease (AD) is defined by the presence of tangles and plaques composed of the amyloid-beta (Abeta) protein and activated microglia. Identification of AD pathology in living subjects is an important goal because it could allow refinement of early diagnosis and identification of pre-symptomatic pathology. In addition, the optimal development of new anti-amyloid therapies will require a means to monitor brain amyloid load and its active removal. Our group has developed a novel amyloid-imaging positron emission tomography (PET) radiotracer termed "Pittsburgh compound-B" (PIB) that distinguish AD from control subjects and had a regional distribution consistent with that of the post-mortem distribution of plaques. Additionally we have used radiolabeled PK11195 a peripheral benzodiazepine receptor ligand that permits PET assessment of microglial activation. This R21 will examine the relationship between amyloid deposition and microglial activation in different stages of Alzheimer's Disease. We will recruit 5 control subjects, 5 minor cognitively impaired, 5 mild, and 5 moderate AD patients. All subjects will have been clinically evaluated and diagnosed by the University of Pittsburgh Alzheimer Disease Research Center (ADRC) and further evaluated with a neuropsychological battery through the ADRC. All subjects will be studied cross-sectionally with PIB and PK11195 PET scans. In addition, volumetric MRI will be performed so we can directly compare these current neuroimaging standards. The quantitative PIB and PK11195 PET data will be compared to neuropsychological measures to explore possible correlations between regional amyloid load, activated microglia and performance on function-specific cognitive testing (e.g. frontal or visuospatial tasks). We hypothesize that subjects with more severe cognitive impairment will show greater PIB retention consistent and greater amyloid burden and will show greater PK11195 retention consistent with increased microglial activation. Delineation of the relationship between amyloid deposition and microglial activation will help define the role of microglial activation in the pathogenesis of amyloid deposition and with development of immunotherapies, help discern the role of activated microglia in eliminating amyloid.

描述(申请人提供)：神经病理学上，阿尔茨海默病(AD)的定义是由淀粉样β蛋白(Abeta)和激活的小胶质细胞组成的缠结和斑块的存在。在活体受试者中识别AD病理是一个重要的目标，因为它可以改进早期诊断和识别症状前的病理。此外，新的抗淀粉样蛋白疗法的优化开发将需要一种监测大脑淀粉样蛋白负载及其主动清除的手段。我们团队开发了一种新型的淀粉样蛋白成像正电子发射断层扫描(PET)放射示踪剂，名为“匹兹堡化合物-B”(PIB)，可以区分AD和对照组，其区域分布与死后斑块的分布一致。此外，我们还使用了放射性标记的PK11195，这是一种外周的苯二氮卓类受体配体，允许PET评估小胶质细胞的激活。这份R21将研究阿尔茨海默病不同阶段淀粉样蛋白沉积和小胶质细胞激活之间的关系。我们将招募5名对照受试者，5名轻度认知障碍患者，5名轻度和5名中度AD患者。所有受试者都将接受匹兹堡大学阿尔茨海默病研究中心(ADRC)的临床评估和诊断，并通过ADRC通过神经心理学小组进一步评估。所有受试者将通过PIB和PK11195 PET扫描进行横断面研究。此外，还将进行体积磁共振成像，以便我们可以直接比较这些当前的神经成像标准。量化的PIB和PK11195 PET数据将与神经心理学指标进行比较，以探索区域淀粉样蛋白负荷、激活的小胶质细胞与特定功能认知测试(例如额叶或视觉空间任务)表现之间的可能相关性。我们假设，认知损害越严重的受试者将表现出更大的PIB保持一致性和更大的淀粉样蛋白负荷，并且将表现出更大的PK11195保持与小胶质细胞激活的增加一致。阐明淀粉样蛋白沉积和小胶质细胞激活之间的关系将有助于明确小胶质细胞激活在淀粉样蛋白沉积发病机制中的作用，并随着免疫疗法的发展，有助于识别激活的小胶质细胞在消除淀粉样蛋白中的作用。