Imaging biomarkers of early synaptic changes in a preclinical model of Alzheimer’s disease

摘要 阿尔茨海默病(AD)影响着大约570万美国人，预计到2019年这一数字将达到1400万。 2050年。尽管经过了几十年的研究，但AD的启动和进展仍然很差 了解，我们目前缺乏可靠的生物标记物来纵向监测疾病的进展。突触 功能障碍正被评估为评估AD风险的潜在早期生物标志物；然而，大多数研究 数据依赖于横断面或终点的体外分析。我们假设活体成像 突触密度的测量将与组织学测量进行仔细的验证，这将是具有预测性的 体内检测淀粉样蛋白沉积和神经原纤维缠结前AD病理的生物标志物 成像。检验这一假设的积极结果将使识别高危个体成为可能 以及在实质性神经元丧失之前阻止疾病进展的治疗策略的应用 发生。我们的研究将在一种新的转基因大鼠模型中利用PET和MR成像，该模型提供了关键 人类阿尔茨海默病的重要病理特征。我们的第一个具体目标是建立空间相关性 在活体成像指标(突触密度、淀粉样蛋白沉积和通过PET和结构成像的肌张力病)之间 在Tg344-AD转基因大鼠模型中，Tg344-AD转基因大鼠模型与同源年龄- 与野生动物相匹配。我们的第二个具体目标是绘制突触密度的时空模式， 用体内PET和MRI研究TgF344-AD大鼠和AGE-AD大鼠的淀粉样蛋白沉积、节段性病变和神经变性 配对的对照动物。放射性示踪剂18F-UCB-H、18F-florbetapir和18F-T807在PET中的应用 分别测量突触密度、淀粉样β蛋白沉积和tau堆积，以及结构磁共振， 基于T2加权扫描，将在突触和AD的呈现的时间过程中执行 相关病理学。将在每个时间段分析来自一组动物的大脑的组织病理学标志物 神经元丢失和变性提供与活体成像相关的地面真实测量 措施。这项研究将释放出这样的可能性：(I)有力地验证突触的体内成像测量 功能障碍是AD的早期生物标志物，与其他成像方法和组织病理学对照，这是一种 向循证临床翻译迈出必要的一步；(2)提供初步数据以支持未来 关于突触功能障碍和其他疾病之间区域和时间关系的机械论假说 与AD相关的病理学，最终目的是改善我们对AD风险的理解；以及(Iii) 了解不同的活体成像和组织病理学方法之间的一致性和不一致性， 这将对治疗设计和测试产生影响。总而言之，该项目将提供关键 翻译元素，将为未来的人类研究提供信息，评估突触丢失在AD和 监测治疗以保护突触的密度和功能。

Abstract Alzheimer’s disease (AD) affects an estimated 5.7 million Americans, a number expected to reach 14 million by 2050. Despite several decades of research, the initiation and progression of AD continues to be poorly understood, and we currently lack reliable biomarkers to longitudinally monitor disease progression. Synaptic dysfunction is being evaluated as a potential early biomarker for evaluating AD risk; however, most studies to date have relied on cross-sectional or endpoint, ex vivo analyses. We hypothesize that in vivo imaging measures of synapse density, which will be carefully validated against histologic measures, will be predictive biomarkers of AD pathology that precede detection of amyloid deposition and neurofibrillary tangles by in vivo imaging. A positive outcome from testing this hypothesis would enable the identification of at-risk individuals and the application of therapeutic strategies to arrest disease progression before substantial neuronal loss occurs. Our studies will utilize PET and MR imaging in a novel transgenic rat model that presents key pathologic features of significance in human AD. Our first specific aim will establish the spatial correlation between in vivo imaging measures (synapse density, amyloid deposition and tauopathy via PET and structural measures via MRI) and concurrent histopathology in the Tg344-AD transgenic rat model versus congenic age- matched wildtype animals. Our second specific aim will map the spatiotemporal patterns of synapse density, amyloid deposition, tauopathy and neurodegeneration via in vivo PET and MRI in TgF344-AD rats and age- matched control animals. PET using the radiotracers 18F-UCB-H, 18F-florbetapir and 18F-T807, as proxy measures of synapse density, amyloid-beta deposition and tau accumulation, respectively, and structural MRI, based on T2-weighted scanning, will be performed over the time course of presentation of synaptic and AD- related pathology. Brains from a subset of animals at each time will be analyzed for histopathologic markers of neuronal loss and degeneration to provide ground-truth measures for correlating with the in vivo imaging measures. This study will unleash the potential to: (i) robustly validate in vivo imaging measures of synapse dysfunction as early biomarkers of AD against other imaging measures and histopathology, which is a necessary step towards their evidence-based clinical translation; (ii) provide preliminary data to support future mechanistic hypotheses about the regional and temporal relationships between synapse dysfunction and other AD-associated pathologies, with the ultimate goal of improving our understanding of AD risk; and (iii) understand concordance and discordance between the different in vivo imaging and histopathology measures, which will have implications for therapy design and testing. In summary, this project will provide key translational elements that will inform future human studies assessing the role of synapse loss in AD and for monitoring treatments to preserve synapse density and function.