NIBA-TBI: Neuro-Imaging and biofluid-based Biomarker Assessments as translational pathophysiological outcome measures in TBI

项目摘要-摘要 目前，脑外伤的临床前研究和动物实验治疗试验 脑外伤模型的模型，最常用的结局终点是病变 体积/大小、神经细胞保存和行为功能结果测量 (如Morris水迷宫、Rotarod)。虽然这些措施显然是有用的，但它们 缺乏了解潜在的不同病理生理机制的能力 与人类脑损伤相关。这些因素可能是导致缺乏翻译的原因之一 脑外伤新疗法从动物模型疗效到临床试验疗效的成功。 与神经创伤的转化性结果项目的愿景一致(上- NT)(UG3/UH3)RFA，在这里我们精心组建了一个多学科团队，并 建议评估两种互补的基于病理机制的脑外伤预后 措施-(I)生物流体生物标志物评估，和(Ii)MRI-神经成像生物标志物 评估。之所以选择这些评估，是因为它们都是高度量化的 并且可以很容易地过渡到临床脑损伤研究和未来的治疗试验。我们的 中心假设如下：在临床前多部位多创伤性脑损伤动物模型设置中， 基于生物流体的生物标志物和基于MRI的定量神经影像生物标志物 评估可以发展为有用的转换结果衡量标准，有助于 介绍包括轴突在内的一系列临床脑损伤病理机制亚型 损伤，挫伤/组织坏死，突触连续性丧失，脑白质损伤， 微血管损伤/脑出血和神经炎症。我们也已经把 共同组成“临床TBI翻译咨询”小组，协助我们翻译我们的 将研究结果转化为临床研究。

PROJECT SUMMARY- ABSTRACT Currently, preclinical TBI research and testing of experimental therapeutic in animal models of TBI models, the most commonly used outcome endpoints are lesion volume/size, neuronal cell preservation and behavioral functional outcome measures (such as Morris water maze, rotarod). While these measures are clearly useful – they lack the ability to inform on the underlying distinct pathophysiological mechanisms relevant in human TBI. These factors might have contributed to the lack of translational success for new TBI therapeutics from animal models efficacy to clinical trial efficacy. Consistent with the vision of the Translational Outcomes Project in Neurotrauma (TOP- NT) (UG3/UH3) RFA, here we carefully assembled a multidisciplinary team and proposed to evaluate two complementary pathological mechanism-based TBI outcome measures – (i) biofluid biomarker assessment, and (ii) MRI-neuroimaging biomarker assessment. These assessments are chosen because they are both highly quantitative and can readily transition into clinical TBI studies and future therapeutic trials. Our central hypothesis is as follows: In preclinical multi-site multi-TBI animal model setting, biofluid-based biomarker and quantitative MRI-based neuroimaging biomarker assessment can be developed into useful translational outcome measures that can help address a range of clinical TBI pathological mechanistic subphenotypes including axonal injury, contusion/tissue necrosis, loss of synaptic continuity, white matter injury, microvascular injury/brain hemorrhage and neuroinflammation. We have also put together a “Clinical TBI Translational Advisory” panel to assist us with translating our findings into clinical studies.