SV2A PET in Spinal Cord Injury Imaging

摘要 创伤性脊髓损伤（SCI）涉及严重的神经损伤事件，可导致长期的运动和神经功能障碍。 感官缺陷以及认知和情感功能障碍。计算机断层扫描（CT）和磁 核磁共振成像（MRI）通常用于SCI的临床治疗。然而，这两种方法 提供SCI进展和恢复的生理信息。我们建议填补这一空白， 使用我们新开发的突触囊泡糖蛋白2A（SV 2A）放射性示踪剂进行定量PET成像， 突触密度的变化和神经可塑性的疾病过程中。定量SV 2A PET成像具有 已经被用来揭示包括阿尔茨海默氏症在内的各种神经精神疾病的突触密度变化 疾病、帕金森病、抑郁症、癫痫、精神分裂症和中风。我们的试点PET成像研究 使用最近开发的SV 2A PET显像剂表明，SV 2A PET可用于定量 啮齿动物、猴子和人类脊髓中的突触密度。我们的SV 2A PET啮齿动物成像试验研究 证明了使用SV 2A PET检测中度胸后10天的细微突触丢失的可行性， 挫伤基于这些初步的结果和文献证据，我们假设SV 2A基因的改变可能是由于SV 2A基因的突变引起的。 SV 2A水平是SCI和SV 2A PET中神经可塑性的生物标志物，可用于辅助诊断和预后 并在临床试验中评估治疗效果。我们建议通过以下方法来检验这些假设： 目的：1）研究大鼠脊髓损伤模型中突触标记物的表达水平和动态变化 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SV 2A PET成像 通过小动物PET、离体和体外测定以及行为测试， SV 2A PET成像用于客观评价抗Nogo抗体治疗的疗效; 3）作为 临床转化和验证的关键步骤，我们将选择最有前途的SV 2A脊髓PET示踪剂 使用非人灵长类动物作为动物模型进行成像。这个项目的成功完成将产生一个敏感的， 一种可靠的定量成像方法，可用于SCI患者的诊断和预后 的形式，以及一个研究工具，探讨神经可塑性在SCI动物模型和患者。它还将 允许对SCI进展和恢复进行客观和纵向跟踪。

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.