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

• 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
• 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' s Disease; Alzheimer' 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

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.

项目总结/文摘