Developing novel cognitive and neuroimaging markers of early Alzheimers disease pathologies

项目摘要 这项研究的目的是开发新的认知和神经成像标记物，以检测微妙的 与β-淀粉样蛋白（Aβ）沉积和tau蛋白神经递质相关的认知和神经变化 神经纤维缠结（NFT），阿尔茨海默病（AD）的病理标志，在临床上完整的老年人。最近 体内正电子发射断层扫描（PET）的进展显著提高了我们对 在大约20-50%的认知正常老年人中存在Aβ斑块， 作为临床前AD。区分健康的老年人与处于AD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措施是敏感的， 在临床前AD阶段检测Aβ斑块存在的特异性方法在很大程度上缺乏。此外，委员会认为， 这些个体中NFT病理的共同存在使得难以将AD病理与特定的 认知功能确定脑老化和AD病理学如何影响认知和潜在的神经系统功能 系统将提供更复杂的行为表型和神经标记，具有临床实用性， 早期诊断和治疗监测，否则可能无法发现与传统的 神经心理学测试我们将招募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 假设认知正常老年人的Aβ沉积和NFT将不同地影响一组认知功能， 额顶叶和内侧颞叶功能负担过重的任务。目标2将测试 Aβ沉积和NFT不同地影响大脑激活和连接模式， 在认知任务中使用额顶叶和内侧的梯度程度的结构和功能MRI 颞叶功能目的3：比较Aβ沉积效应的敏感性和特异性 认知成分任务和传统神经心理学评估之间的认知NFT。一 这些目标的成功完成将阐明AD病理学和认知功能之间的机制联系。 在疾病的早期阶段的后果，并有助于新的行为和神经影像学标志物 早期AD开发的认知任务组合有潜力被开发为筛选测试的 以非侵入性、更容易获得和更经济实惠的方式， 完整的老年人

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.