Quantifying synaptic density loss in a monkey model of early Alzheimer's Disease

项目概要/摘要 阿尔茨海默病（Alzheimer's disease，AD）是一种非常普遍和严重致残的疾病。尽管几十年来 研究表明，AD的发病机制仍然知之甚少，我们目前缺乏可靠的生物标志物， 时空跟踪和预测疾病进展。我们的总体目标是应对这些挑战， 开发用于早期诊断AD病理学和客观跟踪治疗的增强型生物标志物。与 最后，这项提议将利用我们的AD早期“突触期”的高度翻译猴模型， 评估体内成像测量的优点（来自突触密度的PET（使用11 C-UCB-J）和葡萄糖 代谢（使用18F-FDG），结构MRI）对死后，最先进的显微镜和 脑组织的组织学分析，在纵向研究设计中。我们的假设是PET测量， 替代量化突触损失和代谢功能障碍，将作为早期，独立的预测， AD风险升高和认知功能障碍的生物标志物。我们的第一个具体目标将建立以下相关性： 我们的体内成像测量与我们的猴子AD相关病理的死后组织标志物 模型与年龄和性别匹配的对照动物。我们的第二个目标是绘制 我们的猴模型与对照动物中PET突触丢失与脑葡萄糖代谢的模式 在12周内。这两个目标的完成将提供新的数据，以提高我们对 AD发展中的突触神经病理学因此，本提案对PAR-18-760具有高度响应性。 积极的发现将证实最近的人类研究，调查突触功能障碍的作用， AD风险增加的主要因素。在相关模型系统中验证体内成像策略将 有助于（i）优化未来早期AD治疗的治疗窗口， （ii）测试与突触丧失的作用/阻断相关的机制假设;（iii） 快速评估新的治疗策略及其剂量反应关系。总而言之，该项目具有 提供关键翻译元件的潜力，将为人类研究提供信息， 突触功能障碍

Project Summary/Abstract Alzheimer’s disease (AD) is an extremely prevalent and severely disabling disease. Despite several decades of research, AD pathogenesis continues to be poorly understood, and we currently lack reliable biomarkers to spatiotemporally track and predict disease progression. Our overall goal is to address these challenges and develop enhanced biomarkers for diagnosing AD-pathology early and objectively tracking treatments. To that end, this proposal will utilize our highly translational monkey model of the early “synaptic phase” of AD to assess the merits of in vivo imaging measures (from PET for synaptic density (using 11C-UCB-J) and glucose metabolism (using 18F-FDG), with structural MRI) against postmortem, state-of-the-art microscopic and histologic analysis of brain tissue, in a longitudinal study design. Our hypothesis is that PET measures, as surrogates for quantifying synaptic loss and metabolic dysfunction, will serve as early, independent predictive biomarkers for elevated AD risk and cognitive dysfunction. Our first specific aim will establish the correlation of our in vivo imaging measures with postmortem tissue markers of AD-associated pathologies in our monkey model versus age- and sex-matched control animals. Our second specific aim will map the spatiotemporal patterns of PET synaptic loss versus cerebral glucose metabolism in our monkey model versus control animals over a 12-week period. Completion of both aims will provide novel data to improve our understanding of synaptic neuropathology in AD development. Therefore, this proposal is highly responsive to the PAR-18-760. Positive findings would corroborate recent human studies investigating the role of synaptic dysfunction as a major factor for increased AD risk. Validation of in vivo imaging strategies in a relevant model system will contribute towards (i) optimizing the therapeutic window for future early AD treatments so that their efficacy can be maximized; (ii) testing mechanistic hypotheses associated with the role/blockage of synapse loss; (iii) rapidly evaluating new treatment strategies and their dose-response relationships. In summary, this project has the potential to provide key translational elements that will inform human studies evaluating in vivo markers of synaptic dysfunction.