PET Imaging of Macrophages and Amyloid in AD

描述（由申请人提供）：神经病理学上，阿尔茨海默病（AD）是由淀粉样蛋白（Abeta）和活化的小胶质细胞组成的缠结和斑块的存在所定义的。在活着的受试者中识别AD病理是一个重要的目标，因为它可以使早期诊断和症状前病理的识别得到改进。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手段。我们的研究小组开发了一种新的淀粉样蛋白成像正电子发射断层扫描（PET）放射性示踪剂，称为“匹兹堡化合物- b”（PIB），该示踪剂可将AD与对照组区分开来，并具有与死后斑块分布一致的区域分布。此外，我们使用放射性标记的PK11195外周苯二氮卓类受体配体，允许PET评估小胶质细胞激活。本R21将探讨淀粉样蛋白沉积和小胶质细胞激活在阿尔茨海默病不同阶段之间的关系。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。所有受试者将由匹兹堡大学阿尔茨海默病研究中心（ADRC）进行临床评估和诊断，并通过ADRC进行神经心理学电池进一步评估。所有受试者将通过PIB和PK11195 PET扫描进行横断面研究。此外，将进行体积核磁共振成像，以便我们可以直接比较这些当前的神经成像标准。定量PIB和PK11195 PET数据将与神经心理学测量进行比较，以探索区域淀粉样蛋白负荷、激活的小胶质细胞与功能特异性认知测试（如额叶或视觉空间任务）表现之间可能的相关性。我们假设认知障碍更严重的受试者会表现出更大的PIB保留和更大的淀粉样蛋白负担，并且会表现出更大的PK11195保留，这与增加的小胶质细胞激活一致。描述淀粉样蛋白沉积和小胶质细胞活化之间的关系将有助于确定小胶质细胞活化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，有助于识别活化的小胶质细胞在消除淀粉样蛋白中的作用。

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.