Establishing the In Vivo Threshold for Amyloid Deposition in Normal Aging

这是R01 AG033042的首次重新提交。该项目着眼于匹兹堡的进一步发展。 化合物B(或PIB)作为正电子发射断层扫描(PET)淀粉样蛋白显像剂。我们之前的PIB PET的努力导致了有效的、简单的活体方法的开发，为 在世界各地的中心(包括参与ADNI的站点)使用PIB PET。修订后的应用程序现在 包括体内PIB滞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(取消了扩散张量成像)。 淀粉样蛋白沉积可以早在阿尔茨海默病(AD)的最早临床症状之前就开始了。 PIB PET已表明淀粉样蛋白沉积最早开始于额叶和后扣带/楔前叶。 在认知正常的老年人中，多达25%-30%的人有大脑区域。建议的主要目标是 R01是使用PIB PET成像来建立体内阈值，可以用来区分 有淀粉样斑块沉积(PIB+)和没有淀粉样斑块沉积(PIB)的认知正常受试者。这个 R01 AIMS将在5年内与正在进行的奖励PIB PET正常老化相结合 研究(R37 AG025516“正常衰老中的淀粉样病理学和认知”，PI：KUNOK)。该计划的目标是 R01研究超出了R37的范围，但将利用收集的纵向数据作为R37的一部分 格兰特。不会收集任何成像数据作为R01的一部分。 我们的第一个目标是为认知正常的人建立定义PIB+和PIB-状态的标准 与体内PIB滞留和区域匹配后PIB的相关性一致的老年对照 对死前接受PIB PET检查的受试者确定A？沉积的尸检相关性。这个 第二个目标将细化PIB标准，并建立关于符合以下条件的标准的可信区间 与纵向多模式神经成像结果一致(即存在/不存在AD相关 成像异常)。最终目标是开发体内淀粉样蛋白自然历史的工作模型。 解释早期淀粉样蛋白沉积的空间和时间方面的沉积，使用以下结果 目标1和目标2。R37成像在基线和24或30个月的随访间隔中进行， 受试者年龄65-84岁。这些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。 拟议的研究的意义在于将开发的工具能够使临床 我们机构和世界各地的研究人员致力于提高对早期AD相关脑的检测 通过更好地了解症状前影像异常的含义而发生变化。 准确定义非淀粉样蛋白携带者的淀粉样蛋白对于早期鉴定至关重要。 那些可能从抗淀粉样蛋白治疗中受益最多的人。

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.