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（AD）是一种极其普遍且严重致残的疾病。尽管几十年 随着研究的深入，AD 发病机制仍然知之甚少，而且我们目前缺乏可靠的生物标志物来 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并 开发增强的生物标志物，用于早期诊断 AD 病理并客观跟踪治疗。对此 最后，该提案将利用我们的 AD 早期“突触阶段”的高度转化猴子模型来 评估体内成像测量（通过 PET 获取突触密度（使用 11C-UCB-J）和葡萄糖）的优点 代谢（使用 18F-FDG），结构 MRI）针对尸检，最先进的显微镜和 在纵向研究设计中对脑组织进行组织学分析。我们的假设是 PET 测量为 量化突触损失和代谢功能障碍的替代物将作为早期、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是建立以下相关性： 我们利用猴子的死后 AD 相关病理组织标志物进行体内成像测量 模型与年龄和性别匹配的对照动物。我们的第二个具体目标是绘制时空地图 我们的猴子模型与对照动物的 PET 突触损失与脑葡萄糖代谢的模式 超过 12 周的时间。这两个目标的完成将为我们提供新的数据来加深我们的理解 AD 发展中的突触神经病理学。因此，该提案对 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，该研究调查了突触功能障碍作为 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，使其疗效能够 最大化； (ii) 测试与突触损失的作用/阻碍相关的机制假设； (三) 快速评估新的治疗策略及其剂量反应关系。综上所述，本项目有 提供关键翻译元素的潜力将为评估体内标记物的人类研究提供信息 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.