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

• 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
• 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' s Disease; Alzheimer' s disease model; Alzheimer' 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

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.

摘要 阿尔茨海默氏病（AD）影响着大约570万美国人，预计到2020年将达到1400万。 2050.尽管有几十年的研究，但AD的发生和进展仍然很差， 我们目前缺乏可靠的生物标志物来纵向监测疾病进展。突触 功能障碍被评估为评估AD风险的潜在早期生物标志物;然而，大多数研究 数据依赖于横截面或终点，离体分析。我们假设体内成像 突触密度的测量，将仔细验证组织学测量，将是预测 AD病理学生物标志物先于淀粉样蛋白沉积和神经纤维缠结的体内检测 显像测试这一假设的积极结果将使识别处于风险中的个人成为可能。 以及在大量神经元损失之前阻止疾病进展的治疗策略的应用 发生。我们的研究将利用PET和MR成像在一个新的转基因大鼠模型，提出了关键的 在人类AD中具有重要意义的病理学特征。我们的第一个具体目标是建立空间相关性 在体内成像测量（突触密度、淀粉样蛋白沉积和通过PET的tau蛋白病和结构蛋白病）之间， 通过MRI测量）和Tg 344-AD转基因大鼠模型中的并行组织病理学对比同源年龄- 匹配野生型动物。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在TgF 344-AD大鼠和年龄- 匹配的对照动物。使用放射性示踪剂18F-UCB-H、18F-florbetapir和18F-T807作为替代物的PET 分别测量突触密度、β淀粉样蛋白沉积和tau积聚，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。 相关病理学将分析每次动物亚组的脑组织病理学标志物， 神经元损失和变性，以提供与体内成像相关的地面实况测量 措施这项研究将释放潜力：（i）强大地验证突触的体内成像测量 功能障碍作为AD的早期生物标志物对其他成像措施和组织病理学，这是一个 （二）提供初步数据，以支持未来的研究; 关于突触功能障碍和其他神经元之间的区域和时间关系的机械假说， AD相关病理，最终目标是提高我们对AD风险的理解;以及（iii） 了解不同体内成像和组织病理学测量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。总之，该项目将提供关键 翻译元件，将为未来的人类研究提供信息，评估突触丢失在AD中的作用， 监测治疗以保持突触密度和功能。