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

 描述（由申请人提供）：哈佛衰老脑研究（HABS）PPG于五年前启动，旨在阐明临床正常（CN）老年人中淀粉样β蛋白（Aβ）蓄积的生物学和临床意义。我们在当前的资助周期中取得了很大的成就，包括成功招募了300多名年龄在60-90岁之间的老年人，他们的种族和社会经济地位各不相同。我们已经发表了70多篇论文，并为国际指南和预防试验设计做出了贡献。我们发现一致的证据表明，近1/3的老年CN Aβ升高，在PiB-PET成像上可检测到，也证明了突触功能受损和神经退行性变的证据，以及认知的细微但可检测的变化。然而，到目前为止，我们的研究结果支持这一假设，即Aβ积累是必要的，但不足以预测即将发生的认知障碍。因此，我们必须找到额外的标记物，以准确地预测认知能力下降沿着阿尔茨海默病（AD）的轨迹。神经病理学研究长期以来表明，AD的另一标志性病理学-神经元缠结（NFT）和其他tau聚集体（称为Tau）-与突触和神经元损失以及AD的认知症状更强烈地相关。PET成像的显着最新进展现在允许我们在体内对Tau病理进行成像。我们使用18F-T807的初步Tau PET数据表明，这项新技术在我们寻求阐明Aβ、Tau和认知能力下降之间的联系方面将被证明是非常有价值的。我们的初步T807数据证实了先前的尸检报告，即MTL Tau积累在60岁后非常常见，但仍不清楚这种病理学如何导致“年龄相关”的记忆变化，有或没有Aβ。基于我们的初步工作，我们假设Aβ加速了Tau在MTL内外的扩散，破坏了分布式脑网络的功能并引发了神经退行性变，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PET Aβ和Tau指标与葡萄糖代谢、突触功能障碍和皮质变薄的关系。项目二：研究T807的神经病理学相关性，以及来自类似于HABS群体的队列的脑标本中与Tau相关的神经元、神经胶质和突触改变。项目3：实施先进的MRI技术，在个体受试者水平上检测内在脑网络中Aβ和Tau相关的改变。项目4：检测认知功能的早期改变 通过新的iPad测试和任务功能磁共振成像，并探讨Aβ和Tau在预测纵向认知衰退中的相互作用。PPG的更新将利用一组优秀的多学科研究者，获得尖端的成像和实验室技术，以及一个具有纵向多模态成像和敏感认知评估的非常良好特征的队列，以确定最能预测临床前AD的恢复力与进展的因素。

 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.