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

目前，临床前TBI研究和TBI动物模型中的实验性治疗剂的测试 模型中，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、旋转棒）。虽然这些 衡量标准显然是有用的--它们缺乏告知潜在的不同 与人类TBI相关的病理生理机制。这些因素可能导致了 新的TBI疗法缺乏从动物模型有效性到临床的转化成功 试验功效与神经创伤转化结果项目的愿景一致 (TOP-NT）（UG 3/UH 3）RFA，在这里，我们精心组建了一个多学科团队，并建议 评价两种互补的基于病理机制的TBI结果测量-（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。这些评估是选择 因为它们都是高度定量的，并且可以容易地过渡到临床TBI研究， 未来的治疗试验我们的中心假设如下：在临床前多部位 多TBI动物模型设置、基于生物流体的生物标志物和基于定量MRI的神经成像 生物标志物评估可以发展成有用的转化结果测量， 解决了一系列临床TBI病理机制亚表型，包括轴突损伤， 挫伤/组织坏死、突触连续性丧失、白色损伤、微血管 损伤/脑出血和神经炎症。我们还制定了“临床创伤性脑损伤 翻译咨询”小组，以帮助我们将我们的发现转化为临床研究。

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.