Establishing the In Vivo Threshold for Amyloid Deposition in Normal Aging

描述（由申请人提供）：这是R01 AG033042的首次再提交。本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）淀粉样蛋白显像剂。我们之前的PiB PET研究开发了有效的简单的体内方法，为在世界各地的中心（包括参与的ADNI站点）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保留和死后淀粉样蛋白沉积相关的区域匹配比较，但不再包括MR图像采集（扩散张量成像被删除）。淀粉样蛋白沉积可以在阿尔茨海默病（AD）最早的临床症状出现之前就开始了。PiB PET显示淀粉样蛋白沉积最早开始于大脑的额叶和后扣带/楔前叶区，在多达25-30%的认知正常的老年人中。提出的R01的主要目的是使用PiB PET成像来建立体内阈值，可用于区分有淀粉样斑块沉积（PiB+）和没有（PiB）的认知正常受试者。R01的目标将在5年内与正在进行的PiB PET正常衰老研究（R37 AG025516“正常衰老中的淀粉样蛋白病理和认知”，PI: Klunk）同时进行。R01研究的目标超出了R37的范围，但将利用纵向数据收集作为R37拨款的一部分。本R01不收集任何成像数据。我们的第一个目标是建立PiB+和PiB-状态的定义标准，这些标准与体内PiB保留的相关性和死前接受PiB PET的受试者的死后AB沉积的区域匹配相关性相一致。第二个目标将完善PiB标准，并建立与纵向多模态神经成像结果（即ad相关成像异常的存在/不存在）一致的标准的置信区间。最后的目标是利用Aims 1和2的结果，建立一个体内淀粉样蛋白沉积的自然史的工作模型，该模型可以解释早期淀粉样蛋白沉积的空间和时间方面。R37成像在基线和随访间隔24或30个月进行，受试者年龄为65-84岁。这些假设将使用统计分类和建模方法以及神经病理学评估来解决。这项研究的重要意义在于将开发的工具，使我们机构和全世界的临床研究人员能够通过更好地了解症状前成像异常的含义，提高对早期ad相关大脑变化的检测。准确定义无淀粉样蛋白个体的淀粉样蛋白携带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R01研究将使用PIB PET成像来确定正常衰老中淀粉样蛋白沉积的体内检测阈值。这项研究将提供工具，使我们机构和全世界的临床研究人员能够通过更好地了解症状前成像异常的含义，提高对早期ad相关大脑变化的检测。

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.