SV2A PET in Spinal Cord Injury Imaging

SV2A PET 在脊髓损伤成像中的应用

• 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
• 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' 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

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 感觉缺陷以及认知和情感功能障碍。计算机断层扫描（CT）和磁性 共振成像（MRI）通常用于SCI的临床管理。但是，这两种方法 提供SCI进展和恢复的物理信息。我们建议通过申请来填补这一空白 使用我们新开发的突触囊泡糖蛋白2A（SV2A）radiotracer进行定量PET成像 突触密度在疾病过程中变化和神经可塑性。定量SV2A PET成像具有 我们被用来揭示各种神经精神疾病的突触密度变化，包括阿尔茨海默氏症 疾病，帕金森氏病，抑郁症，癫痫，精神分裂症和中风。我们的飞行员宠物成像研究 使用最近开发的SV2A PET成像剂，表明SV2A PET可用于量化 啮齿动物，猴子和人类的脊髓中的突触密度。我们的飞行员SV2A PET啮齿动物成像研究 证明使用SV2A PET在中度胸腔后10天检测细微的合成损失的可行性 挫伤伤害。基于这些初步结果和文献证据，我们假设改变了SV2A 水平是SCI和SV2A PET中神经可塑性的生物标志物，可用于促进诊断和预后 SCI并评估临床试验中的治疗作用。我们建议通过 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力学 随着时间的流逝，使用分子生物学和定量体外成像方法； 2）验证SV2A PET成像 在SCI啮齿动物模型中，通过小动物宠物，离体和体外测定和行为测试，并进行应用 SV2A PET成像在对抗Nogo抗体治疗的治疗作用的客观评估中； 3） 临床翻译和验证的关键步骤，我们将选择最有前途的SV2A PET示踪剂 使用非人类灵长类动物作为动物模型进行成像。成功完成该项目将产生敏感的 可靠的定量成像方法准备在SCI患者中进行测试作为诊断和预后 模态以及一种研究工具，用于探测SCI动物模型和患者的神经可塑性。它也会 允许对SCI进展和恢复的客观和纵向跟踪。