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

阿尔茨海默病临床前模型中早期突触变化的成像生物标志物

基本信息

批准号：
9807999
负责人：
Abhijit J Chaudhari
金额：
$ 27.48万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2021-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9807999
关键词：
Address Affect Age Age-Months Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease risk Alzheimer’s disease biomarker American Amyloid deposition Animals Astrocytes Atlases Biological Markers Brain Brain Diseases Characteristics Clinical Clinical Trials Control Animal Data Dementia Detection Disease Disease Management Disease Progression Dose Early Diagnosis Elements Functional disorder Future Gliosis Goals Gold Hippocampus (Brain)Histologic Histology Histopathology Human Image Impaired cognition In Vitro Individual Inflammation MRI Scans Magnetic Resonance Imaging Maps Measurement Measures Methods Microglia Modeling Monitor Motivation Neocortex Nerve Degeneration Neurofibrillary Tangles Neurologic Neurons Onset of illness Outcome Pathologic Pathology Patients Pattern Positron-Emission Tomography Pre-Clinical Model Process Proxy Rattus Research Research Design Risk Role Scanning Senile Plaques Sensitivity and Specificity Signal Transduction Structure Synapses Tauopathies Testing Therapeutic Time Transgenic Organisms abeta accumulation abeta deposition age related base cerebral amyloidosis cerebral atrophy clinical translation congenic density design early detection biomarkers evidence base image registration imaging biomarker improved in vivo in vivo imaging insight neuron loss novel novel therapeutic intervention novel therapeutics predictive marker preservation radiotracer response risk variant societal costs spatiotemporal statistics tau Proteins tau aggregation therapy design tool

项目摘要

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.

抽象的据估计，阿尔茨海默病 (AD) 影响着 570 万美国人，预计到 2020 年这一数字将达到 1400 万 2050. 尽管进行了数十年的研究，AD 的发生和进展仍然很差理解，但我们目前缺乏可靠的生物标志物来纵向监测疾病进展。功能障碍正在被评估为评估 AD 风险的潜在早期生物标志物；然而，大多数研究都认为数据依赖于横截面或终点、离体分析，我们追求的是体内成像。突触密度的测量将根据组织学测量进行仔细验证，将具有预测性 AD 病理学的生物标志物，先于体内检测淀粉样蛋白沉积和神经原纤维缠结测试这一假设的积极结果将有助于识别高危个体。以及应用治疗策略在严重神经功能丧失之前阻止疾病进展我们的研究将在新型转基因大鼠模型中利用 PET 和 MR 成像，这提供了关键。我们的第一个具体目标是建立空间相关性。体内成像测量（突触密度、淀粉样蛋白沉积和 tau 蛋白病，通过 PET 和结构通过 MRI 测量）和 Tg344-AD 转基因大鼠模型与同源年龄的同时组织病理学我们的第二个具体目标是绘制突触密度的时空模式，通过体内 PET 和 MRI 观察 TgF344-AD 大鼠和年龄组中的淀粉样蛋白沉积、tau 蛋白病和神经退行性变使用放射性示踪剂 18F-UCB-H、18F-florbetapir 和 18F-T807 作为代理进行 PET 匹配。分别测量突触密度、β-淀粉样蛋白沉积和 tau 蛋白积累，以及结构 MRI，基于 T2 加权扫描，将在突触和 AD 呈现的时间过程中进行每次都会对一部分动物的大脑进行组织病理学标记物分析。神经元损失和变性提供与体内成像相关的真实测量这项研究将释放以下潜力：(i) 强有力地验证突触的体内成像测量。功能障碍作为 AD 早期生物标志物与其他影像学测量和组织病理学的比较，这是一个 (ii) 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的区域和时间关系的机制假设 AD 相关病理，最终目标是提高我们对 AD 风险的了解；以及 (iii) 不同体内成像和组织病理学测量之间的一致性和不一致，这将对治疗设计和测试产生影响总之，该项目将提供关键。转化元素将为未来的人类研究提供信息，评估突触损失在 AD 中的作用以及治疗监测以保持突触密度和功能。