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: 9980756
• 负责人: Abhijit J Chaudhari
• 金额: $ 15.7万
• 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 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980756
• 关键词: Address; Affect; Age; Age-Months; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Alzheimer’s disease biomarker; American; Amyloid deposition; Animals; Astrocytes; Atlases; Biological Markers; Brain; 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; 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.

抽象的 阿尔茨海默氏病（AD）影响约570万美国人，预计将达到1400万 2050年。尽管进行了数十年的研究，但AD的主动性和进展仍然很差 理解齿，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 功能障碍正在评估是评估AD风险的潜在生物标志物；但是，大多数研究 日期在横截面或端点上放松，离体分析。我们假设体内成像 突触密度的测量方法将对组织学测量进行仔细的验证，将是预测的 在检测淀粉样蛋白沉积和神经原纤维缠结之前的AD病理生物标志物在体内 成像。检验该假设的积极结果将使处于危险中的个体识别 以及在大量神经元丧失之前采用治疗策略来阻止疾病进展 发生。我们的研究将在呈现关键的新型转基因大鼠模型中利用PET和MR成像 人类AD中重要性的病理特征。我们的第一个特定目标将建立空间相关性 在体内成像措施（突触密度，淀粉样蛋白沉积和通过PET和结构性的Tauopathy）之间 通过TG344-AD转基因大鼠模型与先天年龄的TG344-AD转基因大鼠模型中通过MRI）和并发组织病理学的措施 匹配的野生型动物。我们的第二个特定目标将绘制突触密度的时空模式， TGF344-AD大鼠中的体内PET和MRI和年龄 - 匹配的对照动物。使用Radiotracers 18F-UCB-H，18F-Florbetapir和18F-T807的PET作为代理 突触密度，淀粉样蛋白β沉积和TAU积累的度量和结构MRI的衡量标准 基于T2加权扫描，将在呈现突触和ad-的时间过程中进行 相关病理。每次动物子集中的大脑将分析的组织病理学标记 神经元丧失和变性，以提供与体内成像相关的基础真相测量值 措施。这项研究不会留下潜力：（i）强有力地验证体内成像的突触度量 功能障碍是AD的早期生物标志物，针对其他成像措施和组织病理学，这是一个 迈向基于证据的临床翻译的必要步骤； （ii）提供初步数据以支持未来 关于突触功能障碍与其他区域和临时关系的机械假设 与广告相关的病理，其最终目标是提高我们对AD风险的理解； （iii） 了解不同的体内成像和组织病理学测量的一致性和不一致， 总而言之，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，以评估突触丧失在AD中的作用和 监测处理以保持突触密度和功能。