Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, t-Tau, or p-Tau, published in PubMed/EMBASE up to April 10th, 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g., ICP monitoring), thus we focused on blood biomarkers' temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Out of the 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19, and p-Tau in seven. Data in rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham) with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers' trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.

中文翻译：

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利用基于血液的生物标志物使临床前模型与人类创伤性脑损伤保持一致。


啮齿动物模型是研究创伤性脑损伤 （TBI） 的病理生理学和为这种毁灭性神经系统疾病开发新的治疗干预措施的重要研究工具。然而，将药物从动物试验转化为 TBI 人类治疗的失败率为 100%。虽然对此有几种可能的解释，但之前的临床试验依赖于临床前研究的外推来考虑关键设计考虑因素，包括药物剂量优化、受伤后药物治疗的开始和持续时间。将临床相关的生物标志物纳入临床前研究可能提供一个机会，将临床前模型校准为人类相同（或类似）的测量值，与人类 TBI 生物力学和病理生理学相关联，并指导治疗决策。为了支持这一转化目标，我们对啮齿动物的临床前 TBI 研究进行了系统的文献综述，这些研究测量了临床使用的 GFAP、UCH-L1、NfL、t-Tau 或 p-Tau 的血液水平，发表在 PubMed/EMBASE 上，截至 2024 年 4 月 10 日。尽管许多因素会影响临床 TBI 结果，但其中许多因素无法在啮齿动物研究（例如 ICP 监测）中常规评估，因此我们专注于血液生物标志物的时间轨迹，并在最新的临床 TBI 生物标志物数据的背景下讨论我们的发现。在 805 项原始临床前研究中，74 项符合纳入标准，在 CAMARADES 检查表上的中位质量评分为 5 分（第 25-75 个百分位数：4-7）。43 项研究测量了 GFAP，21 项研究测量了 UCH-L1,20 项研究测量了 NfL，19 项研究测量了 t-Tau，7 项研究测量了 p-Tau。啮齿动物模型中的数据表明，所有生物标志物都表现出具有不同时间特征的损伤严重程度依赖性升高。 GFAP 和 UCH-L1 在 TBI 后第一天达到峰值（中度至重度 TBI 与假手术相比分别增加 30 倍和 4 倍），在挫伤 TBI 模型中观察到最高水平。NfL 在几天内达到峰值 （增加 18 倍），并在受伤后 6 个月内保持升高。在临床前模型中评估神经保护疗法的研究中，GFAP 和 NfL 分别在 64.7% 和 60% 的研究中显示出药效学反应。然而，GFAP 在损伤后的迅速下降可能限制了其在了解实验性 TBI 后超急性期之后对新疗法反应的效用。此外，与人类一样，亚急性 NfL 水平决定了 TBI 后的慢性白质丢失。t-Tau 和 p-Tau 水平在 TBI 后数周内升高（分别高达 6 倍和 16 倍）;然而，它们与潜在神经退行性变的关系尚未得到解决。需要进一步研究 TBI 后亚急性和慢性期的生物标志物水平，以充分了解支撑血液生物标志物轨迹的病理机制，并选择最合适的实验模型，以最佳方式将临床前机制研究与人类临床观察联系起来。这种新方法可以加速神经保护治疗从实验室实验到现实世界临床实践的转化。