Establishing the In Vivo Threshold for Amyloid Deposition in Normal Aging

这是R01 AG033042的首次重新提交。该项目的重点是进一步发展匹兹堡 化合物-B（或PiB）作为正电子发射断层摄影术（PET）淀粉样蛋白成像剂。我们以前的PiB PET的努力导致了有效的简单体内方法的发展，为研究提供了坚实的基础。 在全球各中心（包括参与的ADNI研究中心）使用PiB PET。现在修改后的应用程序 包括体内PiB保留和死后淀粉样蛋白相关性的区域匹配比较， 但不再包括MR图像采集（删除弥散张量成像）。 淀粉样蛋白沉积可以在阿尔茨海默病（AD）的最早临床症状之前开始。 PiB PET显示淀粉样蛋白沉积最早开始于额叶和后扣带回/楔前叶， 在认知正常的老年人中，多达25 - 30%的人在大脑中的某些区域。建议的主要目标 R01将使用PiB PET成像来建立可用于区分 具有淀粉样蛋白斑块沉积（PiB+）的认知正常受试者和没有淀粉样蛋白斑块沉积（PiB）的受试者。的 R01目标将在5年内与正在进行的Merit奖PiB PET正常老化一起解决 研究（R37 AG025516 "正常衰老中的淀粉样蛋白病理学和认知"，PI：Klunk）。的目标 R01研究超出了R37的范围，但将利用作为R37的一部分收集的纵向数据 格兰特.将不收集成像数据作为本R01的一部分。 我们的第一个目标是建立标准的定义PiB+和PiB-状态的认知未受损 老年对照组与体内PiB保留和区域匹配的后 在死亡前接受PiB PET的受试者中确定的A ²沉积的死亡相关性。的 第二个目标是完善PiB标准，并建立有关标准的置信区间， 与纵向多模态神经成像结果一致（即，存在/不存在AD相关 成像异常）。最终的目标是建立一个体内淀粉样蛋白自然史的工作模型 沉积，解释了早期淀粉样蛋白沉积的空间和时间方面，使用的结果， 目标1和2。R37成像发生在基线和24或30个月的随访间隔， 受试者年龄为65 - 84岁。假设将使用统计分类和建模来解决 方法和神经病理学评价。 拟议研究的意义在于将开发的工具，使临床 我们机构和世界各地的研究人员，以提高最早的AD相关的大脑检测 通过更好地理解症状前成像异常的影响来改变。 从无淀粉样蛋白的个体中准确定义淀粉样蛋白携带者对于早期识别至关重要 最能从抗淀粉样蛋白治疗中获益的人群。

This is the first resubmission of R01 AG033042. This project focuses on further development of Pittsburgh Compound-B (or PiB) as a positron emission tomography (PET) amyloid imaging agent. Our previous PiB PET efforts resulted in the development of valid simple in vivo methods that provided a solid basis for the use of PiB PET at centers world-wide (including participating ADNI sites). The revised application now includes region-matched comparisons of in vivo PiB retention and post-mortem correlates of amyloid deposition but no longer includes MR image acquisition (diffusion tensor imaging was removed). Amyloid deposition can begin well before the earliest clinical symptoms of Alzheimer's disease (AD). PiB PET has indicated that amyloid deposition begins earliest in frontal and posterior cingulate/precuneus areas of brain, in as many as 25-30% of cognitively normal elders. The primary objective of the proposed R01 is to use PiB PET imaging to establish in vivo thresholds that can be used to distinguish between cognitively normal subjects who have amyloid plaque deposition (PiB+) and those that do not (PiB). The R01 aims will be addressed over 5 years in tandem with an ongoing Merit award PiB PET normal aging study (R37 AG025516 "Amyloid Pathology and Cognition in Normal Aging ", PI: Klunk). The aims of the R01 research are beyond the scope of the R37 but will utilize longitudinal data collected as part of the R37 grant. No imaging data will be collected as part of this R01. Our first aim is to establish criteria for the definition of PiB+ and PiB- status in cognitively unimpaired elderly controls that are consistent with correlations of in vivo PiB retention and region-matched post- mortem correlates of A¿ deposition determined for subjects who underwent PiB PET prior to death. The second aim will refine the PiB criteria and establish confidence intervals about the criteria that are consistent with longitudinal multi-modality neuroimaging results (i.e., presence/absence of AD-related imaging abnormalities). The final aim is to develop a working model of the natural history of in vivo amyloid deposition that accounts for spatial and temporal aspects of early amyloid deposition, using the results of Aims 1 and 2. The R37 imaging occurs at baseline and at follow-up intervals of 24 or 30 months, for subjects 65-84 years of age. The hypotheses will be addressed using statistical classification and modeling methods and neuropathological evaluations. The significance of the proposed research lies in the tools that will be developed to enable clinical researchers at our institution and throughout the world to improve the detection of earliest AD-related brain changes through better understanding of the implications of presymptomatic imaging abnormalities. Accurate definition of amyloid-bearing from amyloid-free individuals will be critical for the early identification of those who may benefit most from anti-amyloid therapy.