Establishing the In Vivo Threshold for Amyloid Deposition in Normal Aging

描述（由申请人提供）：这是R 01 AG 033042的首次重新提交。该项目的重点是进一步开发匹兹堡化合物-B（或PiB）作为正电子发射断层扫描（PET）淀粉样蛋白成像剂。我们之前的PiB PET工作开发了有效的简单体内方法，为在全球中心（包括参与的ADNI中心）使用PiB PET提供了坚实的基础。修订后的应用程序现在包括体内PiB保留和淀粉样蛋白沉积的死后相关性的区域匹配比较，但不再包括MR图像采集（删除了扩散张量成像）。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已经表明淀粉样蛋白沉积最早开始于大脑的前部和后部扣带/楔前叶区域，在多达25-30%的认知正常的老年人中。R 01的主要目的是使用PiB PET成像来建立体内阈值，该阈值可用于区分有淀粉样斑块沉积（PiB+）和无淀粉样斑块沉积（PiB）的认知正常受试者。R 01目标将在5年内与正在进行的Merit奖PiB PET正常老化研究（R37 AG 025516“正常老化中的淀粉样蛋白病理学和认知“，PI：Klunk）一起解决。R 01研究的目的超出了R37的范围，但将利用作为R37赠款的一部分收集的纵向数据。将不收集成像数据作为本R 01的一部分。我们的第一个目标是建立标准的定义PiB+和PiB-状态的认知功能未受损的老年对照组，在体内的PiB保留和区域匹配的尸检相关性的AB沉积确定谁接受了PiB PET受试者死亡前的相关性一致。第二个目标将细化PiB标准，并建立与纵向多模态神经成像结果一致的标准的置信区间（即，存在/不存在AD相关成像异常）。最终的目标是开发一个工作模型的自然历史的体内淀粉样蛋白沉积，占空间和时间方面的早期淀粉样蛋白沉积，使用的结果，目标1和2。对于65-84岁的受试者，在基线和24或30个月的随访间隔时进行R37成像。将使用统计分类和建模方法以及神经病理学评价来解决这些假设。拟议研究的意义在于将开发的工具，使我们机构和世界各地的临床研究人员能够通过更好地了解症状前成像异常的影响来改善最早AD相关脑变化的检测。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那些可能从抗淀粉样蛋白治疗中获益最多的人至关重要。公共卫生相关性：拟议的R 01研究将使用PIB PET成像来定义正常老化中淀粉样蛋白沉积的体内检测阈值。这项研究将提供工具，使我们机构和世界各地的临床研究人员能够通过更好地了解症状前成像异常的影响来改善早期AD相关脑变化的检测。

DESCRIPTION (provided by applicant): 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 AB 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. PUBLIC HEALTH RELEVANCE: The proposed R01 research will use PIB PET imaging to define the in vivo detection threshold for amyloid deposition in normal aging. This research will provide tools that will enable clinical researchers at our institution and throughout the world to improve the detection of early AD-related brain changes through better understanding of the implications of presymptomatic imaging abnormalities.