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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：
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
项目类别：
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&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease model Alzheimer&apos s disease pathology Alzheimer&apos s disease patient Alzheimer&apos 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

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.

摘要