SV2A PET in Spinal Cord Injury Imaging

摘要 创伤性脊髓损伤(SCI)包括严重的神经损害事件，可导致长期的运动和 感觉缺陷，以及认知和情感功能障碍。计算机断层扫描(CT)和磁学 磁共振成像(MRI)是临床上常用的脊髓损伤治疗方法。然而，这两种方法 提供脊髓损伤进展和恢复的生理学信息。我们建议通过申请来填补这一空白 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定量成像 突触密度和神经可塑性随病程的变化而变化。定量SV2APET成像具有 被用来揭示包括阿尔茨海默氏症在内的各种神经精神障碍的突触密度变化 疾病、帕金森氏症、抑郁症、癫痫、精神分裂症和中风。我们的试点PET成像研究 使用最新开发的SV2APET显像剂表明，SV2APET可用于定量 啮齿动物、猴子和人类脊髓中的突触密度。我们的先导性SV2APET啮齿动物成像研究 中度胸廓损伤后10天应用SV2A型正电子发射计算机断层扫描检测微小突触丢失的可行性 挫伤伤。根据这些初步结果和文献证据，我们假设改变了SV2A 水平是脊髓损伤神经可塑性的生物标志物，SV2APET有助于脊髓损伤的诊断和预后 并在临床试验中评价其治疗效果。我们建议通过以下方式检验这些假设 目的：1)检测脊髓损伤动物模型中突触标志物的表达水平和动态变化 随着时间的推移，使用分子生物学和体外定量成像方法；2)验证SV2APET成像 在脊髓损伤啮齿动物模型中通过小动物PET、体外和体外测试及行为学测试来应用 SV2A型正电子发射计算机断层扫描在客观评价抗Nogo抗体治疗效果中的应用 临床翻译和验证的关键一步，我们将选择最有前途的脊髓SV2APET示踪剂 以非人灵长类动物为动物模型进行成像。该项目的成功完成将产生一个敏感的， 可靠的、定量的成像方法可用于脊髓损伤患者的诊断和预后 也是探索脊髓损伤动物模型和患者神经可塑性的研究工具。它还将 考虑到对脊髓损伤进展和恢复的客观和纵向跟踪。

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.