SV2A PET in Spinal Cord Injury Imaging

SV2A PET 在脊髓损伤成像中的应用

基本信息

批准号：
10443973
负责人：
Zhengxin Cai
金额：
$ 68.75万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443973
关键词：
Affinity Age Alzheimer&apos s Disease Animal Model Animals Antibody Therapy Behavioral Binding Binding Sites Biological Assay Biological Markers Brain Chest Clinic Clinical Clinical Management Clinical Trials Cognitive Contusions Diagnosis Disease Electron Microscopy Emission-Computed Tomography Emotional Epilepsy Evaluation Event Functional disorder Glycoproteins Histologic Histology Human Image Immunohistochemistry In Vitro Injury Intervention Lead Levetiracetam Ligands Literature Macaca mulatta Magnetic Resonance Imaging Measures Mental Depression Methods Modality Modeling Molecular Biology Monkeys Motor Neuronal Plasticity Outcome Parkinson Disease Patients Persons Physiological Positron-Emission Tomography Prognosis Rattus Recovery Research Rodent Rodent Model Scanning Schizophrenia Sensory Severities Severity of illness Signal Transduction Specificity Spinal Cord Spinal Cord Contusions Spinal cord injury Spinal cord injury patients Stroke Synapses Synaptic Vesicles Synaptophysin Testing Therapeutic Therapeutic Effect Tissues Tracer Translating Treatment outcome United States Validation Western Blotting X-Ray Computed Tomography base behavior test clinical translation cost density dosimetry drug testing efficacy evaluation experimental study gastrointestinal system imaging agent imaging approach imaging modality imaging study improved in vitro Assay in vivo evaluation injury recovery neuropsychiatric disorder non-invasive imaging nonhuman primate novel outcome prediction public health relevance quantitative imaging radiotracer receptor relating to nervous system respiratory routine imaging spinal cord imaging therapeutic evaluation time use tool treatment effect treatment response uptake urinary

项目摘要

ABSTRACT Traumatic spinal cord injuries (SCI) involve serious neural damage events that can lead to long-term motor and sensory deficits, as well as cognitive and emotional dysfunctions. Computed tomography (CT) and magnetic resonance imaging (MRI) are routinely used in the clinical management of SCI. However, neither method provides physiological information of SCI progression and recovery. We propose to fill this gap by applying quantitative PET imaging using our newly developed synaptic vesicle glycoprotein 2A (SV2A) radiotracer to track the synaptic density changes and neuroplasticity over the disease course. Quantitative SV2A PET imaging has been used to reveal the synaptic density changes in a variety of neuropsychiatric disorders, including Alzheimer’s disease, Parkinson’s disease, depression, epilepsy, schizophrenia, and stroke. Our pilot PET imaging studies using the recently developed SV2A PET imaging agents indicate that SV2A PET could be used to quantify synapse density in the spinal cord of rodents, monkeys, and human. Our pilot SV2A PET rodent imaging study proved the feasibility of using SV2A PET to detect subtle synaptic loss at 10 days post moderate thoracic contusion injury. Based on these preliminary results and literature evidence, we hypothesize that altered SV2A level is a biomarker for neuroplasticity in SCI and SV2A PET can be used to facilitate the diagnose and prognosis of SCI and to evaluate therapeutic effects in clinical trials. We propose to test the hypotheses through the following aims: 1) to determine the expression levels and dynamics of synaptic markers in rodent model of SCI over time, using molecular biology and quantitative in vitro imaging approach; 2) to validate SV2A PET imaging in the SCI rodent model through small animal PET, ex vivo and in vitro assays and behavioral tests and to apply SV2A PET imaging in the objective evaluation of therapeutic effects of an anti-Nogo antibody treatment; 3) as a key step for clinical translation and validation, we will select the most promising SV2A PET tracer for spinal cord imaging using nonhuman primate as the animal model. Successful completion of this project will yield a sensitive, reliable, and quantitative imaging method ready to be tested in SCI patients as a diagnosis and prognosis modality, as well as a research tool to probe the neuroplasticity in SCI animal models and patients. It will also allow for the objective and longitudinal tracking of SCI progression and recovery.

抽象的创伤性脊髓损伤 (SCI) 涉及严重的神经损伤事件，可能导致长期运动和运动障碍感觉缺陷以及认知和情绪功能障碍。磁共振成像 (MRI) 常用于 SCI 的临床治疗，但这两种方法都没有。提供 SCI 进展和恢复的生理信息，我们建议通过应用来填补这一空白。使用我们新开发的突触小泡糖蛋白 2A (SV2A) 放射性示踪剂进行 PET 成像进行定量追踪定量 SV2A PET 成像显示了疾病过程中突触密度的变化和神经可塑性。已被用于揭示各种神经精神疾病（包括阿尔茨海默病）的突触密度变化我们的试点 PET 成像研究。使用最近开发的 SV2A PET 显像剂表明 SV2A PET 可用于定量我们的试点 SV2A PET 啮齿动物成像研究。证明了使用 SV2A PET 检测中度胸椎术后 10 天细微突触损失的可行性根据这些初步结果和文献证据，我们认为 SV2A 发生了改变。水平是 SCI 神经可塑性的生物标志物，SV2A PET 可用于促进诊断和预后我们建议通过以下方法来检验这些假设：以下目的：1）确定SCI啮齿动物模型中突触标记的表达水平和动态随着时间的推移，使用分子生物学和定量体外成像方法；2) 验证 SV2A PET 成像；通过小动物 PET、离体和体外分析以及行为测试，在 SCI 啮齿动物模型中应用 SV2A PET 成像用于客观评价抗 Nogo 抗体治疗的疗效；3) 临床转化和验证的关键一步，我们将选择最有前途的脊髓SV2A PET示踪剂使用非人类灵长类动物作为动物模型的成像，该项目的成功完成将产生敏感的、可靠、定量的成像方法可用于 SCI 患者的诊断和预后测试模态，以及探索 SCI 动物模型和患者神经可塑性的研究工具。允许对 SCI 进展和恢复进行客观和纵向跟踪。