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: 7110136
• 负责人: Clayton A. Wiley
• 金额: $ 14.86万
• 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 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110136
• 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（由申请人提供）：从神经病理学上讲，阿尔茨海默氏病（AD）是由由淀粉样蛋白（ABETA）蛋白和活化小胶质细胞组成的缠结和斑块定义的。鉴定生物中的AD病理学是一个重要目标，因为它可以允许早期诊断和鉴定症状前病理学的鉴定。此外，新的抗淀粉样蛋白疗法的最佳发展将需要一种监测脑淀粉样蛋白负荷及其主动去除的方法。我们的小组开发了一种新型的淀粉样成像正电子发射断层扫描（PET）radiotracer，称为“匹兹堡化合物-B”（PIB），该（PIB）将AD与对照对象区分开，并且具有与斑块术后分布相一致的区域分布。此外，我们使用了放射性标记的PK11195外围苯二氮卓受体配体，可允许对小胶质细胞激活的PET评估。该R21将检查阿尔茨海默氏病不同阶段的淀粉样沉积与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个较小的认知受损，5名轻度和5例中度AD患者。所有受试者将由匹兹堡大学阿尔茨海默氏病研究中心（ADRC）对临床评估和诊断，并通过ADRC通过神经心理学电池进行了进一步评估。所有受试者将通过PIB和PK11195 PET扫描对所有受试者进行研究。此外，将进行体积MRI，因此我们可以直接比较这些当前的神经影像学标准。将定量的PIB和PK11195 PET数据与神经心理学指标进行比较，以探索区域淀粉样蛋白负荷，激活的小胶质细胞和功能特定功能特异性认知测试（例如额叶或视觉疗法任务）之间可能的相关性。我们假设患有更严重认知障碍的受试者将显示出更大的PIB保留率一致且淀粉样蛋白负担更大，并且将显示出更大的PK11195保留率与小胶质细胞激活一致。淀粉样蛋白沉积与小胶质细胞激活之间关系的描述将有助于定义小胶质细胞活化在淀粉样蛋白沉积的发病机理中的作用以及免疫疗法的发展，有助于识别活化的小胶质细胞在消除淀粉样蛋白方面的作用。