Establishing the In Vivo Threshold for Amyloid Deposition in Normal Aging

描述(申请人提供)：这是R01 AG033042的第一次重新提交。该项目致力于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的努力导致了有效、简单的活体方法的开发，为PIB PET在世界各地的中心(包括参与ADNI的地点)的使用提供了坚实的基础。修订后的应用现在包括体内PIB滞留和死后淀粉样蛋白沉积相关性的区域匹配比较，但不再包括MR图像采集(扩散张量成像被移除)。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研究表明，淀粉样蛋白沉积最早开始于大脑的额叶和后扣带/楔前叶区域，在认知正常的老年人中，这一比例高达25%-30%。建议的R01的主要目标是使用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+)和没有淀粉样斑块沉积(PIB)的认知正常受试者。R01的AIMS将在5年内与正在进行的荣誉奖PIB PET正常老化研究(R37 AG025516“正常老化中的淀粉样病理学和认知”，PI：KUNK)一起解决。R01研究的目的超出了R37的范围，但将利用作为R37拨款一部分收集的纵向数据。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在认知正常的老年人对照组中建立定义PIB+和PIB-状态的标准，这些标准与在生前接受PIB PET检查的受试者体内PIB保留和死后AB沉积的区域匹配相关性一致。第二个目标将完善PIB标准，并建立与纵向多模式神经成像结果(即是否存在AD相关成像异常)一致的标准的可信区间。最终目标是利用AIMS 1和AIMS 2的结果，开发一个体内淀粉样蛋白沉积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。R37成像在基线上进行，每隔24个月或30个月随访一次，受试者年龄在65岁至84岁之间。这些假说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含义来改进对与AD相关的早期脑变化的检测。准确定义非淀粉样蛋白携带者的淀粉样蛋白对于早期识别那些可能从抗淀粉样蛋白治疗中受益最大的人至关重要。公共卫生相关性：拟议的R01研究将使用PIB PET成像来定义正常衰老时淀粉样蛋白沉积的活体检测阈值。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含义，改进与AD相关的早期脑变化的检测。

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.