PET Imaging of Macrophages and Amyloid in AD

描述（由申请人提供）：在神经病理学上，阿尔茨海默病（AD）定义为存在由淀粉样β（Abeta）蛋白和活化的小胶质细胞组成的缠结和斑块。在活体受试者中识别AD病理是一个重要的目标，因为它可以允许细化早期诊断和识别症状前病理。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清除的方法。我们的小组已经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），区分AD从对照组，并有一个区域分布一致的斑块的死后分布。此外，我们还使用了放射性标记的PK 11195，这是一种外周苯二氮卓类受体配体，可以对小胶质细胞活化进行PET评估。这个R21将检查淀粉样蛋白沉积和小胶质细胞激活在阿尔茨海默病的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、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）进行临床评价和诊断，并通过ADRC使用神经心理成套测试进一步评价。所有受试者将接受PIB和PK 11195 PET扫描的横断面研究。此外，将进行容积MRI，以便我们可以直接比较这些当前的神经影像学标准。将定量PIB和PK 11195 PET数据与神经心理学测量进行比较，以探索局部淀粉样蛋白负荷、激活的小胶质细胞和功能特异性认知测试（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，认知障碍越严重的受试者将显示出更大的PIB保留一致性和更大的淀粉样蛋白负荷，并将显示出更大的PK 11195保留一致性增加的小胶质细胞活化。阐明淀粉样蛋白沉积与小胶质细胞活化之间的关系将有助于明确小胶质细胞活化在淀粉样蛋白沉积发病机制中的作用，随着免疫治疗的发展，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.