Imaging Amyloid Pathology and its Functional Sequelae

描述(申请人提供)：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十多年就开始，体内淀粉样蛋白成像可能会使临床前诊断和更准确地识别非常早期或不典型的病例。匹兹堡化合物B(PIB)是正电子发射断层扫描(PET)淀粉样蛋白显像剂(由我们小组成员开发)，它的开发为在体评估人类淀粉样蛋白沉积引入了新的可能性。R21研究的主要目标是开发和评估一种多模式功能成像方法，对淀粉样蛋白沉积(PIB保留)和神经心理学任务诱导的脑激活结果进行体素水平整合，以产生对无症状和临床前受试者状态的更全面和更敏感的评估。初步数据表明，最早的PIB保留在额叶和后扣带/楔前叶区域，这些区域的PIB保留与认知转移和延迟单词回忆任务的表现有关。在认知控制任务和陈述性记忆任务的执行过程中，将使用功能磁共振成像(FMRI)对40名受试者进行研究。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受试者都将被研究。多变量统计分析将在体素的基础上进行，以将PIB保留与区域fMRI任务激活和感兴趣脑区(功能连接)之间的信号协变联系起来。预计将确定一个多变量结果，该结果是受试者状态的综合指数，比单独的地区性PIB PET测量、功能磁共振结果或认知测试结果更敏感和更具信息量。只有功能磁共振研究将作为R21研究的一部分进行，因为PIB PET数据将作为正在进行的纵向研究的一部分在相同的受试者中获得(R37 AG025516和P01 AG025204)。这种综合的多模式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性后遗症，以改进对无症状和早期AD病理的识别，更好地识别那些可以从介入治疗中受益的个人，促进对自然疾病进展的了解，并提高诊断的准确性。这项拟议的研究将独一无二地为淀粉样蛋白沉积和与淀粉样蛋白病理相关的脑功能障碍的综合神经成像测量提供支持。这种综合成像方法的意义在于，它可以在任何时间点应用，以更好地识别哪些人可以从介入治疗中受益，促进对自然疾病进展的了解，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，并有助于了解进行性淀粉样蛋白沉积对认知表现和大脑功能回路的影响。

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.