Impact of Amyloid and Tau on the Aging Brain: The Harvard Aging Brain Study

 描述(申请人提供)：哈佛大学老龄化脑研究(HABS)项目于五年多前启动，旨在阐明淀粉样蛋白β(Aβ)在临床正常(CN)老年人中积累的生物学和临床意义。在目前的筹资周期中，我们取得了很大成就，包括成功地招募了300多名老年人(60岁至90岁)，他们的族裔和社会经济地位各不相同。我们发表了70多篇论文，并为国际指南和预防试验设计做出了贡献。我们发现了一致的证据，在近三分之一的老年CN中，Aβ升高，在PIB-PET成像中可以检测到，也显示了突触功能受损和神经变性的证据，以及微小但可检测到的认知变化。然而，到目前为止，我们的发现支持了这样的假设，即Aβ的积累是必要的，但不足以预测即将发生的认知损害。因此，我们必须找到更多的标记物来准确预测阿尔茨海默病(AD)的认知衰退。长期以来，神经病理学研究表明，AD的另一个标志性病理--神经纤维缠结(NFTs)和其他tau聚集体(简称Tau)--与突触和神经元丢失以及AD的认知症状有更强的相关性。最近PET成像的显著进步使我们能够在活体内成像Tau病理。我们使用18F-T807的初步Tau PET数据表明，这项新技术将证明这项新技术在我们阐明Aβ、Tau和认知功能下降之间的联系方面具有极其重要的价值。我们的初步T807数据证实了先前的尸检报告，即MTLTau积聚在60岁后非常常见，但无论是否有Aβ，这种病理如何有助于“年龄相关的”记忆变化仍是未知的。根据我们的初步工作，我们假设β加速了Tau在MTL内外的扩散，扰乱了分布式脑网络的功能，启动了神经退行性变，导致认知能力下降。为了进一步调查这一点，我们建议 4个综合项目，由4个核心支持。项目1：研究正电子发射计算机断层扫描β和牛磺酸测量与葡萄糖代谢、突触功能障碍和皮质变薄的关系。项目2：研究T807的神经病理相关性，以及与Tau相关的神经元、神经胶质细胞和突触的变化，这些变化来自与赤潮病种群相似的队列中的大脑标本。项目3：实施先进的磁共振成像技术，在个体受试者水平上检测固有大脑网络中与Aβ和Tau相关的改变。项目4：检测认知功能的早期改变 通过新颖的ipad测验和任务功能磁共振成像，考察A-β和Tau在预测纵向认知衰退中的交互作用。此次PPG更新将利用一群杰出的多学科研究人员、获得尖端成像和实验室技术，以及具有极好特征的队列，以及纵向多模式成像和敏感的认知评估，以确定最能预测临床前AD发展轨迹上的复原力与进展的因素。

 DESCRIPTION (provided by applicant): The Harvard Aging Brain Study (HABS) PPG was launched just over five years ago with the goal of elucidating the biological and clinical significance of amyloid β-protein (Aβ) accumulation in clinically normal (CN) older humans. We have accomplished a great deal over the current funding cycle, including the successful recruitment of more than 300 older individuals (ages 60-90) who are diverse in ethnicity and socioeconomic status. We have published over 70 manuscripts, and contributed to international guidelines and prevention trial design. We have found consistent evidence that the nearly 1/3 of older CN with elevated Aβ, detectable on PiB-PET imaging, also demonstrate evidence of impaired synaptic function and neurodegeneration, as well as subtle but detectable changes in cognition. However, our findings thus far support the hypothesis that Aβ accumulation is necessary but not sufficient to predict imminent cognitive impairment. Thus it is imperative that we find additional markers to accurately predict cognitive decline along the Alzheimer's disease (AD) trajectory. Neuropathologic studies have long suggested that the other hallmark pathology of AD - neurofibrillary tangles (NFTs) and other tau aggregates (referred to as Tau) - correlate more strongly with synaptic and neuronal loss, and the cognitive symptoms of AD. Remarkable recent advances in PET imaging now allow us to image Tau pathology in vivo. Our preliminary Tau PET data using 18F-T807 suggest this new technology will prove extremely valuable in our quest to elucidate the link between Aβ, Tau, and cognitive decline. Our preliminary T807 data confirm previous autopsy reports that MTL Tau accumulation is very common after age 60, but it remains unknown how this pathology contributes to "age-related" memory change, with or without Aβ. Based on our preliminary work, we postulate that Aβ accelerates the spread of Tau both within and beyond the MTL, disrupting function and initiating neurodegeneration in distributed brain networks, resulting in cognitive decline. To investigate this further, we propose 4 integrated Projects, supported by 4 Cores. Project 1: Investigate the relationship of PET Aβ and Tau measures to glucose metabolism, synaptic dysfunction, and cortical thinning. Project 2: Investigate the neuropathologic correlates of T807, and neuronal, glial and synaptic alterations associated with Tau in brain specimens from cohorts similar to the HABS population. Project 3: Implement advanced MRI techniques to detect Aβ- and Tau-related alterations in intrinsic brain networks at the individual subject level. Project 4: Detect early alterations in cognitive function through novel iPad tests and task-fMRI, and investigate the interactions between Aβ and Tau in the prediction of longitudinal cognitive decline. This PPG renewal will leverage an outstanding group of multidisciplinary investigators, access to cutting-edge imaging and laboratory technology, and an extremely well-characterized cohort with longitudinal multi-modality imaging and sensitive cognitive assessments to determine the factors that best predict resilience vs. progression along the trajectory of preclinical AD.