Understanding the dynamic interactions between tau pathology and microgliamediated inflammation in Alzheimer's Disease

项目摘要/摘要 阿尔茨海默病的病因、发病机制、进展及其与病理的关系 对临床表现，尚不完全了解。新出现的研究表明炎症和小胶质细胞 激活是阿尔茨海默病发生和发展的重要因素。牛磺酸和牛磺酸之间的联系 小胶质细胞尤其重要，因为tau与阿尔茨海默病关系最为密切。传统上被接受的 这种相互作用的顺序是错误折叠的促炎tau导致小胶质细胞激活， 导致树突修剪，最终导致神经细胞死亡。然而，最近出现的是小胶质细胞 激活本身可以导致tau聚集和随后的传播。因此，这些因素之间的因果关系 相互作用是有争议的，并且需要在活体内对人类进行非常需要的阐明。这项提案的目标是 是为了了解tau、神经变性、小胶质细胞和 全身性炎症在人类阿尔茨海默病病因和进展中的作用。这项建议涉及一系列 将首次揭示这些关系的原则性统计和基于数学模型的测试 时间，直接在病人身上。这项建议涉及对100个AD频谱的新的前瞻性纵向研究 使用新一代TSPO配体对激活的小胶质细胞进行脑MRI和PET成像的患者 使用一种相对新颖的配体MK6240进行DPA-713和tau-PET成像。相同的成像协议 (MRI、DPA-713和MK6240PET)将在18个月和36个月的随访时间点重复。所有受试者都将 用氟倍他滨PET测量基线时的淀粉样神经性斑块密度。接下来，这项提案涉及 通过数学模型开发和测试小胶质细胞炎症-tau相互作用模型 用DPA-PET测定AD患者的局部小胶质细胞介导的神经炎症是否更高 谱系患者或认知正常的老年人；以及区域小胶质细胞激活是否可预测 直接来自tau和/或淀粉样蛋白。最后，这项拟议的研究包括测试tau的网络传播模型 和小胶质细胞。越来越多的动物数据暗示了tau通过大脑的跨神经元传递机制 网络。利用疾病传播的网络扩散模型，这项提议将进一步调查 在人类中，小胶质细胞直接参与tau的进展。由于tau和小胶质细胞提供了关于 不断演变的病理学，这一提议将决定是否将测量两者的成像研究结合起来 生物标记物将导致对AD进展的独特的强大和预测的测试。考虑到快速发展的 了解小胶质细胞和全身性炎症在痴呆中的作用，目前的建议是及时的， 这是推进人类痴呆症研究的热门和必要的。如果成功，它将给出第一个经过验证的 AD病理和神经炎症因果相互作用的时空模型，催化 预测和靶向抗炎治疗的未来进展。

Project Summary/Abstract The etiology, mechanism and progression of Alzheimer’s Disease (AD), and the relationship of AD pathology to clinical manifestations, are not fully understood. Emerging studies suggest that inflammation and microglial activation is an important contributor to AD pathogenesis and progression. The association between tau and microglia is especially critical, since tau is most closely associated with AD. The conventionally accepted sequence of this interaction is that misfolded tau, which is pro-inflammatory, causes microglial activation, leading to dendritic pruning and eventually neuronal cell death. However, it is recently emerging that microglial activation can itself cause tau aggregation and subsequent propagation. Therefore the causality of these interactions is controversial, and requires much needed elucidation in humans in vivo. The goal of this proposal is to understand the interaction and causal sequencing between tau, neurodegeneration, microglia and systemic inflammation in governing the etiology and progression of human AD. This proposal involves a series of principled statistical and mathematical model-based tests that will uncover these relationships, for the first time, directly in patients. This proposal involves a new prospective longitudinal study of 100 AD spectrum patients acquiring brain MRI and PET imaging of activated microglia using a new generation TSPO ligand called DPA-713 and tau-PET imaging using a relatively novel ligand, MK6240. The same imaging protocol (MRI, DPA-713 and MK6240 PET) will be repeated at 18- and 36-month follow up time points. All subjects will have amyloid neuritic plaque density measured at baseline using florbetaben PET. Next this proposal involves developing and testing a model of microglial inflammation-tau interaction via mathematical models to determine whether regional microglia-mediated neuroinflammation measured by DPA-PET is higher in AD spectrum patients or in cognitively normal older adults; and whether regional microglial activation is predictable directly from tau and/or amyloid. Finally, this proposed research includes testing a network spread model of tau and microglia. Mounting animal data implicate a trans-neuronal transmission mechanism of tau through brain networks. Using a network diffusion model of disease spread, this proposal will further investigate the role of microglia in tau progression directly in humans. Since tau and microglia provide complementary signal about evolving pathology, this proposal will determine whether combining imaging studies that measure both biomarkers will result in a uniquely powerful and predictive test of AD progression. Given the rapidly evolving understanding of the role of microglia and systemic inflammation in dementias, the current proposal is timely, topical and necessary for advancing human dementia research. If successful, it will give the first validated spatiotemporal model of the causal interactions between pathology and neuroinflammation in AD, catalyzing future advances in prognostication and targeted anti-inflammatory therapies.