Developing novel cognitive and neuroimaging markers of early Alzheimers disease pathologies

项目总结 这项拟议的研究的目标是开发新的认知和神经成像标记物来检测细微的 与β-淀粉样蛋白(Aβ)沉积和tau蛋白神经原纤维相关的认知和神经改变 缠绕(NFT)，阿尔茨海默病(AD)的病理特征，在临床正常的老年人中。近期 体内正电子发射断层扫描(PET)的进展极大地提高了我们对 现在被认为是认知正常的老年人中大约20%-50%存在β斑块 临床前阿尔茨海默病。区分健康的老年人和处于阿尔茨海默病临床前阶段的老年人， 然而，仍然具有挑战性，部分原因是行为和神经测量是敏感的和 在临床前AD阶段，特异性检测A-β斑块的存在很大程度上缺乏。此外， 在这些个体中，NFT病理的共同存在使得很难将AD病理与特定的 认知功能。确定大脑老化和AD病理如何影响认知和潜在的神经 系统将提供更复杂的行为表型和神经标记物，具有临床实用价值 早期诊断和治疗监测，否则可能无法发现传统的 神经心理测试。我们将招募50名健康的年轻人和125名认知正常的老年人 接受认知实验、神经成像和神经心理学评估。目标1将测试 认知正常老年人的β沉积和NFT将不同地影响一组认知的假说 不成比例地对额顶和内侧颞叶功能征税的组成部分任务。AIM 2将测试 Aβ沉积和NFT对大脑激活和连接模式的不同影响 在使用额顶和内侧梯度的认知任务中的结构和功能磁共振 颞叶功能。目标3将比较在检测β沉积效果方面的敏感性和特异性 认知成分任务与传统的神经心理学评估之间的认知NFT。一个 这些目标的成功完成将阐明AD病理和认知之间的机制联系 疾病早期的后果，并有助于新的行为和神经成像标记物 公元早期。开发的认知任务组有可能被开发为一种筛查测试 以非侵入性、更易获得且更经济实惠的方式为临床提供AD病理 完好无损的老年人。

PROJECT SUMMARY The goal of the proposed study is to develop novel cognitive and neuroimaging markers to detect subtle cognitive and neural changes in association with beta-amyloid (Aβ) deposition and tau-protein neurofibrillary tangles (NFT), pathological hallmarks of Alzheimer's disease (AD), among clinically intact older adults. Recent advances in in vivo positron emission tomography (PET) have significantly increased our awareness of the presence of Aβ plaques in approximately 20-50% of cognitively normal older adults who are now considered as preclinical AD. Differentiating healthy older adults from those who are in the preclinical stage of AD, however, remains to be challenging, in part because behavioral and neural measures that are sensitive and specific to detect the presence of Aβ plaques in the stage of preclinical AD are largely lacking. Furthermore, the co-presence of NFT pathology in these individuals makes it difficult to link AD pathologies to specific cognitive function. Identifying how brain aging and AD pathology affect cognition and the underlying neural systems would offer more sophisticated behavioral phenotypes and neural markers with clinical utility in aiding early diagnosis and treatment monitoring that otherwise may remain undetected with traditional neuropsychological tests. We will recruit 50 healthy young adults and 125 cognitively normal elderly who will undergo cognitive experimental, neuroimaging, and neuropsychological assessments. Aim 1 will test the hypothesis that Aβ deposition and NFTs in cognitively normal elderly will differentially impact a set of cognitive component tasks that disproportionately tax frontoparietal and medial temporal lobe functions. Aim 2 will test that Aβ deposition and NFTs differentially affect brain activation and connectivity patterns measured by structural and functional MRI during cognitive tasks that use a gradient degree of frontoparietal and medial temporal lobe function. Aim 3 will compare the sensitivity and specificity in detecting the effect of Aβ deposition and NFTs on cognition between cognitive component tasks and traditional neuropsychological assessments. A successful completion of the aims will elucidate the mechanistic link between AD pathologies and cognitive consequences in the early stage of the disease and contribute to novel behavioral and neuroimaging markers of early AD. The developed cognitive task battery has a potential to be developed as a screening test for the presence of AD pathologies in a non-invasive, more accessible, and more affordable manner for clinically intact older adults.