Imaging Amyloid Pathology and its Functional Sequelae

描述（由申请人提供）：淀粉样蛋白沉积可在阿尔茨海默病（AD）最早临床症状出现前开始超过十年，体内淀粉样蛋白成像可用于临床前诊断和更精确地识别极早期或非典型病例。Pittsburgh Compound B（PI B）是一种正电子发射断层扫描（PET）淀粉样蛋白显像剂，（由我们小组的成员开发），R21研究的主要目的是开发和评估一种多模态功能成像方法，该方法可以对淀粉样蛋白沉积进行体素水平的整合（PIB保持）和神经心理学任务诱导的大脑激活结果，以产生对无症状和临床前受试者状态的更全面和灵敏的评估。初步数据表明，最早的PIB保留在额叶和后扣带/楔前叶地区和PIB保留在这些地区与认知转移和延迟单词回忆任务的性能。40名受试者将在认知控制任务和陈述性记忆任务的执行过程中使用功能性磁共振成像（fMRI）进行研究。将研究淀粉样蛋白阴性（PIB-）和淀粉样蛋白阳性（PIB+）对照和轻度认知障碍（MCI）受试者，以及PIB+轻度AD受试者。将在体素基础上进行多变量统计分析，以将PIB保留与区域fMRI任务激活和大脑感兴趣区域之间的信号协变（功能连接）联系起来。预计将确定多变量结局，这是受试者状态的综合指数，比个体区域PIB PET测量、fMRI结果或认知测试结果更敏感和信息量更大。作为R21研究的一部分，将仅进行fMRI研究，因为作为正在进行的纵向研究的一部分，将在相同受试者中获得PIB PET数据（R37 AG 025516和P01 AG 025204）。这种综合多模态成像方法的意义在于，它可以在任何时候应用于评估淀粉样蛋白沉积及其功能后遗症，以改善无症状和早期AD病理的识别，更好地识别那些可以从干预治疗中受益的个体，促进对自然疾病进展的理解，并提高诊断准确性。拟议的研究将独特地允许开发淀粉样蛋白沉积和与淀粉样蛋白病理学相关的脑功能障碍的综合神经成像测量。这种综合成像方法的意义在于，它可以在任何时间点应用，以更好地识别那些可以从干预治疗中受益的个体，促进对自然疾病进展的理解，并提高诊断准确性。这项研究有可能提供以前无法获得的信息，并促进了解进行性淀粉样蛋白沉积对认知能力和功能性脑回路的影响。

DESCRIPTION (provided by applicant): Amyloid deposition can begin over a decade before the earliest clinical symptoms of Alzheimer's disease (AD) and in vivo amyloid imaging may allow preclinical diagnosis and more precise identification of very early or atypical cases. The development of Pittsburgh Compound B (PIB), the positron emission tomography (PET) amyloid-imaging agent (developed by members of our group), has introduced new possibilities for in vivo assessment of amyloid deposition in man. The primary objective of the R21 research is to develop and evaluate a multimodality functional imaging methodology that performs voxel-level integration of amyloid deposition (PIB retention) and neuropsychological-task-induced brain activation results to yield more comprehensive and sensitive assessments of asymptomatic and pre-clinical subject status. Preliminary data indicate earliest PIB retention in frontal and posterior cingulate/precuneus areas and PIB retention in these areas was associated with performance on cognitive shifting and delayed word recall tasks. Forty subjects will be studied using functional magnetic resonance imaging (fMRI) during the performance of both a cognitive control task and a declarative memory task. Both amyloid negative (PIB-) and amyloid positive (PIB+) control and mild cognitive impairment (MCI) subjects will be studied, as well as PIB+ mild AD subjects. Multivariate statistical analyses will be performed on a voxel basis to relate PIB retention to both regional fMRI task activation and signal covariation among brain areas-of-interest (functional connectivity). It is expected that a multivariate outcome will be determined that is an integrative index of subject status that is more sensitive and informative than the individual regional PIB PET measures, fMRI results, or cognitive test results. Only fMRI studies will be performed as part of the R21 research, as PIB PET data will be available in the same subjects as part of ongoing longitudinal studies (R37 AG025516 and P01 AG025204). The significance of this integrative multimodality imaging approach is that it can be applied at any point to assess amyloid deposition and its functional sequelae for the improved identification of asymptomatic and early AD pathology, to better identify those individuals who could benefit from intervention therapies, facilitate understanding of natural disease progression, and improve diagnostic accuracy. The proposed research will uniquely allow for the development an integrated neuroimaging measure of amyloid deposition and the brain dysfunction related to the amyloid pathology. The significance of this integrative imaging approach is that it can be applied at any point in time to better identify those individuals who could benefit from intervention therapies, facilitate understanding of natural disease progression, and improve diagnostic accuracy. This research has the potential to provide information that has not previously been obtainable and facilitate understanding of the impact of progressive amyloid deposition on both cognitive performance and functional brain circuitry.