Quantifying synaptic density loss in a monkey model of early Alzheimer's Disease

量化早期阿尔茨海默病猴子模型中的突触密度损失

基本信息

批准号：
9809280
负责人：
Abhijit J Chaudhari
金额：
$ 30.88万
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/9809280
关键词：
AD pathology Address Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid deposition Animals Atlases Attenuated Autopsy Behavioral Biological Markers Biological Models Blood - brain barrier anatomy Brain Brain Pathology Brain region Cerebrum Clinical Research Control Animal DNA Sequence Alteration Data Development Diagnosis Diagnostic Disease Progression Dose Early Diagnosis Elements Follow-Up Studies Functional disorder Future Goals Gold Health Histologic Human Imaging Techniques Impaired cognition Infusion procedures Intervention Studies Investigation Longitudinal Studies MRI Scans Macaca mulatta Magnetic Resonance Imaging Maps Measurement Measures Metabolic Metabolic dysfunction Methods Microscopic Modeling Molecular Monkeys Neurons Nuclear Pathogenesis Pathologic Pathology Patients Pattern Peptides Phase Positron-Emission Tomography Process Research Research Design Rodent Role Sample Size Scanning Signal Transduction Spatial Distribution Structure Synapses Testing Therapeutic Tissues Treatment Effectiveness Validation abeta oligomer base brain tissue cerebral atrophy cost density design disabling disease fluorodeoxyglucose fluorodeoxyglucose positron emission tomography follow-up glucose metabolism imaging modality improved in vivo in vivo imaging indexing interest lateral ventricle multimodality neuropathology nonhuman primate novel preclinical study predictive marker radiotracer response serial imaging sex spatiotemporal tau aggregation therapeutic evaluation therapy design treatment strategy

AD pathology Address Age Alzheimer&apos s Disease Alzheimer&apos s disease risk Amyloid beta-Protein Amyloid deposition Animals Atlases Attenuated Autopsy Behavioral Biological Markers Biological Models Blood - brain barrier anatomy Brain Brain Pathology Brain region Cerebrum Clinical Research Control Animal DNA Sequence Alteration Data Development Diagnosis Diagnostic Disease Progression Dose Early Diagnosis Elements Follow-Up Studies Functional disorder Future Goals Gold Health Histologic Human Imaging Techniques Impaired cognition Infusion procedures Intervention Studies Investigation Longitudinal Studies MRI Scans Macaca mulatta Magnetic Resonance Imaging Maps Measurement Measures Metabolic Metabolic dysfunction Methods Microscopic Modeling Molecular Monkeys Neurons Nuclear Pathogenesis Pathologic Pathology Patients Pattern Peptides Phase Positron-Emission Tomography Process Research Research Design Rodent Role Sample Size Scanning Signal Transduction Spatial Distribution Structure Synapses Testing Therapeutic Tissues Treatment Effectiveness Validation abeta oligomer base brain tissue cerebral atrophy cost density design disabling disease fluorodeoxyglucose fluorodeoxyglucose positron emission tomography follow-up glucose metabolism imaging modality improved in vivo in vivo imaging indexing interest lateral ventricle multimodality neuropathology nonhuman primate novel preclinical study predictive marker radiotracer response serial imaging sex spatiotemporal tau aggregation therapeutic evaluation therapy design treatment strategy

展开

项目摘要

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.

项目摘要/摘要阿尔茨海默氏病（AD）是一种极为普遍且严重致残的疾病。尽管几十年在研究中，AD发病机理的理解仍然很差，我们目前缺乏可靠的生物标志物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，开发增强的生物标志物，以早期和客观地跟踪诊断性广告病理学。为此最后，该建议将利用我们对AD早期“突触阶段”的高度翻译的猴子模型评估体内成像措施的优点（从PET进行突触密度（使用11C-UCB-J）和葡萄糖代谢（使用18F-FDG），结构MRI）反对验尸，最先进的显微镜和在纵向研究设计中，脑组织的组织学分析。我们的假设是宠物测量值量化突触损失和代谢功能障碍的替代物将充当早期，独立的预测升高AD风险和认知功能障碍的生物标志物。我们的第一个具体目标将建立我们的体内成像措施用猴子中AD相关病理的验尸组织标记模型与年龄和性别匹配的对照动物。我们的第二个特定目标将绘制时空我们的猴子模型与对照动物中PET合成损失与脑葡萄糖代谢的模式在12周内。两个目标的完成都将提供新颖的数据，以提高我们对 AD开发中的突触神经病理学。因此，该提案对PAR-18-760的反应很高。积极的发现将证实最近研究突触功能障碍的作用的人类研究增加广告风险的主要因素。在相关模型系统中对体内成像策略的验证将为（i）优化未来早期广告疗法的治疗窗口，以便他们的效率可以最大化；（ii）测试与突触丧失的作用/阻塞相关的机械假设；（iii）总而言之，这个项目有提供关键转化元素的潜力，可以为人类研究提供评估的体内标记突触功能障碍。