Translational Outcomes Project in Neurotrauma (TOP-NT) Pre-Clinical Consortium Study: A Synopsis

神经创伤转化结果项目（TOP-NT）临床前联盟研究概述

Traumatic brain injury (TBI) has long been a leading cause of death and disability, yet research has failed to successfully translate findings from the pre-clinical, animal setting into the clinic. One factor that contributes significantly to this struggle is the heterogeneity observed in the clinical setting where patients present with injuries of varying types, severities, and comorbidities. Modeling this highly varied population in the laboratory remains challenging. Given feasibility constraints, individual laboratories often focus on single injury types and are limited to an abridged set of outcome measures. Furthermore, laboratories tend to use different injury or outcome methodologies from one another, making it difficult to compare studies and identify which pre-clinical findings may be best suited for clinical translation. The NINDS-funded Translational Outcomes Project in Neurotrauma (TOP-NT) is a multi-site consortium designed to address the reproducibility, rigor, and transparency of pre-clinical development and validation of clinically relevant biomarkers for TBI. The current overview article provides a detailed description of the infrastructure and strategic approach undertaken by the consortium. We outline the TOP-NT strategy to address three goals: (1) selection and cross-center validation of biomarker tools, (2) development and population of a data infrastructure to allow for the sharing and reuse of pre-clinical, animal research following findable, accessible, interoperable, and reusable data guidelines, and (3) demonstration of feasibility, reproducibility, and transparency in conducting a multi-center, pre-clinical research trial for TBI biomarker development. The synthesized scientific analysis and results of the TOP-NT efforts will be the topic of future articles.

创伤性脑损伤（TBI）长期以来一直是导致死亡和残疾的主要原因，然而相关研究未能成功将临床前动物实验的发现转化到临床应用中。造成这一困境的一个重要因素是临床场景中观察到的异质性 —— 患者的损伤类型、严重程度和合并症各不相同。在实验室中对这种高度多样化的人群进行建模仍然具有挑战性。受可行性限制，单个实验室通常专注于单一损伤类型，并且只能采用有限的一组结局指标。此外，不同实验室往往使用不同的损伤模型或结局评估方法，这使得研究之间难以比较，也难以确定哪些临床前发现最适合转化到临床。由美国国立神经疾病和卒中研究所（NINDS）资助的神经创伤转化结果项目（TOP-NT）是一个多中心联盟，旨在解决 TBI 临床相关生物标志物的临床前开发和验证过程中的可重复性、严谨性和透明度问题。本综述文章详细描述了该联盟所采用的基础设施和战略方法。我们概述了 TOP-NT 为实现三个目标所采取的策略：（1）生物标志物工具的筛选和跨中心验证；（2）开发和构建数据基础设施，以遵循可查找、可访问、可互操作和可重用的数据准则，实现临床前动物研究数据的共享和复用；（3）证明在 TBI 生物标志物开发中开展多中心临床前研究试验的可行性、可重复性和透明度。TOP-NT 工作的综合科学分析和结果将成为未来文章的主题。

[REF: Radabaugh HL, Harris NG, Wanner IB, et al. Translational Outcomes Project in Neurotrauma (TOP-NT) Pre-Clinical Consortium Study: A Synopsis. J Neurotrauma. 2025;42(9-10):898-912. doi:10.1089/neu.2023.0654 PMID: 39841551]

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Prospective Harmonization, Common Data Elements, and Sharing Strategies for Multicenter Pre-Clinical Traumatic Brain Injury Research in the Translational Outcomes Project in Neurotrauma Consortium

神经创伤联盟转化结果项目中多中心临床前创伤性脑损伤研究的前瞻性协调、通用数据要素及共享策略

Effective team science requires procedural harmonization for rigor and reproducibility. Multicenter studies across experimental modalities (domains) can help accelerate translation. The Translational Outcomes Project in NeuroTrauma (TOP-NT) is a pre-clinical traumatic brain injury (TBI) consortium charged with establishing and validating noninvasive TBI assessment tools through team science. Here, we present practical approaches for harmonization of TBI research across five centers providing needed vocabulary and structure to achieve centralized data organization and use. We report data curation steps suited for data storage using the Open Data Commons for TBI as a centralized data repository, allowing unbiased cross-site analysis. This approach leads to introducing a higher level, syndromic understanding of TBI signatures. TOP-NT authors outline a semantic and structural framework suggesting strategies for robust pre-clinical research in multicenter trials to improve translatability for TBI assessments.

高效的团队需要流程协调以确保严谨性和可重复性。跨实验模式（领域）的多中心研究有助于加速转化进程。神经创伤转化结果项目（TOP-NT）是一个临床前创伤性脑损伤（TBI）联盟，其使命是通过团队建立并验证无创性 TBI 评估工具。在此，我们提出了适用于五个中心的 TBI 研究协调实用方法，提供了实现数据集中组织与应用所需的术语体系和结构框架。我们报告了适合数据存储的管理步骤，采用 TBI 开放数据共享平台作为集中式数据存储库，支持无偏倚的跨站点分析。这种方法推动了对 TBI 特征更高级别、综合征层面的理解。TOP-NT 作者概述了语义和结构框架，为多中心试验中可靠的临床前研究提出策略，以提升 TBI 评估的转化适用性。

[REF: Wanner IB, McCabe JT, Huie JR, et al. Prospective Harmonization, Common Data Elements, and Sharing Strategies for Multicenter Pre-Clinical Traumatic Brain Injury Research in the Translational Outcomes Project in Neurotrauma Consortium. J Neurotrauma. 2025;42(9-10):877-897. doi:10.1089/neu.2023.0653 PMID: 39831841]

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Molecular Pathway Changes Associated with Different Post-Conditioning Exercise Interventions After Experimental TBI

实验性创伤性脑损伤后不同运动干预相关的分子通路变化

Traumatic brain injury (TBI) causes complex, time-dependent molecular and cellular responses, which include adaptive changes that promote repair and recovery, as well as maladaptive processes such as chronic inflammation that contribute to chronic neurodegeneration and neurological dysfunction. Hormesis is a well-established biological phenomenon in which exposure to low-dose toxins or stressors results in protective responses to subsequent higher-level stressors or insults. Hormetic stimuli show a characteristic U-shaped or inverted J-shaped dose–response curve, as well as being time and exposure-frequency dependent, similar to pre-conditioning and post-conditioning actions. Voluntary exercise interventions, before or after injury, appear to follow these general hormetic principles. But the molecular alterations associated with exercise interventions or more general hormetic responses have received only limited attention. In this study, we used a well-characterized mouse TBI model to assess the effects of different post-conditioning exercise-intervention paradigms on diverse molecular pathways, including neuroinflammation regulators, and post-traumatic neurological deficits. Overall, our study delineates regional and interventional parameters, as well as related molecular pathway changes, associated with post-conditioning exercise treatment, which may help inform future translational interventional strategies.

创伤性脑损伤（TBI）会引发复杂的、具有时间依赖性的分子和细胞反应，其中既包括促进修复与恢复的适应性变化，也包括如慢性炎症等导致慢性神经退行性变和神经功能障碍的适应性不良过程。 hormesis（ hormesis 效应，即毒物兴奋效应）是一种已被充分证实的生物学现象，指暴露于低剂量毒素或应激源可使机体对后续更高水平的应激源或损伤产生保护反应。hormetic 刺激呈现典型的 U 形或倒 J 形剂量 - 反应曲线，且具有时间和暴露频率依赖性，这与预处理和后处理作用相似。损伤前后的自愿运动干预似乎遵循这些普遍的 hormesis 原则。然而，与运动干预或更普遍的 hormesis 反应相关的分子改变仅受到有限关注。在本研究中，我们使用一种特征明确的小鼠 TBI 模型，评估不同运动干预模式对多种分子通路（包括神经炎症调节因子）及创伤后神经功能缺损的影响。总体而言，本研究描绘了与后处理运动治疗相关的区域和干预参数，以及相关的分子通路变化，这可能有助于为未来的转化干预策略提供依据。

[REF: Barrett JP, Aubrecht TG, Smith A, et al. Molecular Pathway Changes Associated with Different Post-Conditioning Exercise Interventions After Experimental TBI. J Neurotrauma. 2025;42(9-10):851-876. doi:10.1089/neu.2024.0120 PMID: 39078326]

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Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior

重复性轻度创伤性脑损伤对促肾上腺皮质激素释放因子调节外侧缰核兴奋性及动机行为的影响

Mild traumatic brain injury (mTBI) is a significant health burden due to mTBI-related chronic debilitating cognitive and psychiatric morbidities. Recent evidence from our laboratory suggests a possible dysregulation within reward/motivational circuit function at the level of a subcortical structure, the lateral habenula (LHb), where we demonstrated a causal role for hyperactive LHb in mTBI-induced motivational deficits in self-care grooming behavior in young adult male mice when exposed to mTBI during late adolescence (at ∼8 weeks old). In this study, we extended this observation by further characterizing neurobehavioral effects of this repetitive closed head injury model of mTBI in both young adult male and female mice on LHb excitability, corticotropin releasing factor (CRF) modulation of LHb activity, and behavioral responses of motivation to self-care behavior and approach versus avoidance behavior in the presence of a social- or threat-related stimulus. Overall, our study provides further translational validity for the use of this pre-clinical model of mTBI for investigation of mTBI-related reward circuit dysfunction and mood/motivation-related behavioral deficits in both sexes while uncovering a few sexually dimorphic neurobehavioral effects of this model that may differentially affect young males and females when exposed to this type of mTBI during late adolescence.

轻度创伤性脑损伤（mTBI）因其相关的慢性衰弱性认知和精神疾病，已成为重大的健康负担。我们实验室的最新证据表明，在皮层下结构外侧缰核（LHb）水平，奖赏 / 动机环路功能可能存在失调。我们已证实，对于青春期后期（约 8 周龄）暴露于 mTBI 的年轻成年雄性小鼠，LHb 过度活跃在 mTBI 诱导的自我梳理行为动机缺陷中起因果作用。在本研究中，我们扩展了这一观察，进一步探讨重复性闭合性头部损伤 mTBI 模型对年轻成年雄性和雌性小鼠的神经行为影响，包括 LHb 兴奋性、促肾上腺皮质激素释放因子（CRF）对 LHb 活动的调节，以及在社交或威胁相关刺激存在时，自我护理行为动机和趋近 - 回避行为的行为反应。总体而言，我们的研究为该 mTBI 临床前模型的应用提供了进一步的转化有效性，可用于研究 mTBI 相关的奖赏环路功能障碍及雌雄两性的情绪 / 动机相关行为缺陷，同时揭示了该模型的一些性别二态性神经行为效应 —— 当青春期后期暴露于此类 mTBI 时，这些效应可能对年轻雄性和雌性产生不同影响。

[REF: Flerlage WJ, Simmons SC, Thomas EH, et al. Effects of Repetitive Mild Traumatic Brain Injury on Corticotropin-Releasing Factor Modulation of Lateral Habenula Excitability and Motivated Behavior. J Neurotrauma. 2025;42(9-10):832-850. doi:10.1089/neu.2024.0184 PMID: 38943284]

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Attenuation of Blood–Brain Barrier Disruption in Traumatic Brain Injury via Inhibition of NKCC1 Cotransporter: Insights into the NF-κB/NLRP3 Signaling Pathway

通过抑制 NKCC1 协同转运蛋白减轻创伤性脑损伤中的血脑屏障破坏：NF-κB/NLRP3 信号通路的研究启示

Following traumatic brain injury (TBI), inhibition of the Na+-K+-Cl− cotransporter1 (NKCC1) has been observed to alleviate damage to the blood–brain barrier (BBB). However, the underlying mechanism for this effect remains unclear. This study aimed to investigate the mechanisms by which inhibiting the NKCC1 attenuates disruption of BBB integrity in TBI. The findings demonstrate that the suppression of the NKCC1 cotransporter protein alleviates BBB disruption through the NF-κB/NLRP3 signaling pathway following TBI.

创伤性脑损伤（TBI）后，抑制 Na+-K+-Cl−协同转运蛋白 1（NKCC1）已被观察到可减轻血脑屏障（BBB）损伤。然而，这种效应的潜在机制仍不明确。本研究旨在探究抑制 NKCC1 减轻 TBI 中 BBB 完整性破坏的机制。研究结果表明，抑制 NKCC1 协同转运蛋白可通过 TBI 后的 NF-κB/NLRP3 信号通路减轻 BBB 破坏。

[REF: Zhang Z, Wang H, Tao B, et al. Attenuation of Blood-Brain Barrier Disruption in Traumatic Brain Injury via Inhibition of NKCC1 Cotransporter: Insights into the NF-κB/NLRP3 Signaling Pathway. J Neurotrauma. 2025;42(9-10):814-831. doi:10.1089/neu.2023.0580 PMID: 39879999]

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Validation of the GCS−Pupil Scale in Traumatic Brain Injury: Incremental Prognostic Value of Pupillary Reactivity with GCS in the Prospective Observational Cohorts CENTER-TBI and TRACK-TBI

创伤性脑损伤中 GCS - 瞳孔量表的验证：在前瞻性观察队列 CENTER-TBI 和 TRACK-TBI 中，瞳孔反应性联合 GCS 的增量预后价值

The goal of this study is to compare the incremental prognostic value of pupillary reactivity captured as part of the Glasgow Coma Scale–Pupils (GCS–P) score or added as separate variable to the GCS+P, in traumatic brain injury (TBI). GCS–P showed a stronger association with 6-month outcome after TBI than GCS alone and provides a single integrated score. However, this comes at a loss of clinical and prognostic information compared with GCS+P. For prognostic models, inclusion of GCS and pupillary reactivity as separate factors may be preferable to using a GCS–P summary score.

本研究旨在比较作为格拉斯哥昏迷量表 - 瞳孔（GCS-P）评分一部分的瞳孔反应性，或作为独立变量添加到 GCS+P 中时，在创伤性脑损伤（TBI）中的增量预后价值。结果显示，与单独使用 GCS 相比，GCS-P 与 TBI 后 6 个月的预后具有更强的关联性，并能提供单一综合评分。然而，与 GCS+P 相比，这会导致临床和预后信息的丢失。对于预后模型而言，将 GCS 和瞳孔反应性作为独立因素纳入，可能比使用 GCS-P 综合评分更为可取。

[REF: Vreeburg RJG, van Leeuwen FD, Manley GT, et al. Validation of the GCS-Pupil Scale in Traumatic Brain Injury: Incremental Prognostic Value of Pupillary Reactivity with GCS in the Prospective Observational Cohorts CENTER-TBI and TRACK-TBI. J Neurotrauma. 2025;42(9-10):798-813. doi:10.1089/neu.2024.0458 PMID: 39686742]

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Blood-Based Protein Biomarkers in the Chronic Phase of Traumatic Brain Injury: A Systematic Review

创伤性脑损伤慢性期血液蛋白生物标志物的系统综述

There has been limited exploration of blood-based biomarkers in the chronic period following traumatic brain injury (TBI). Our objective was to conduct a systematic review of studies examining blood-based protein biomarkers with at least one sample collected 12 months post-TBI in adults (≥16 years). Findings for NfL were inconclusive. Longitudinal data were mostly available for acute samples followed until 12 months post-injury, with limited evaluation of changes beyond 12 months. Associations of some blood-based biomarkers with cognitive, sleep, and functional outcomes were reported. The overall strength of the evidence in this review was limited by the risk of bias and small sample sizes. Replication is required within prospective longitudinal studies that move beyond 12 months post-injury. Novel efforts should be guided by promising neurodegenerative-disease markers and use panels to model polypathology.

在创伤性脑损伤（TBI）慢性期，基于血液的生物标志物研究仍较为有限。我们的目标是对相关研究进行系统综述，探讨那些在成年患者（≥16 岁）TBI 后至少 12 个月采集至少一份样本的血液蛋白生物标志物。关于神经丝轻链蛋白（NfL）的研究结果尚无定论。纵向数据大多来自急性样本的追踪，直至伤后 12 个月，而对 12 个月后的变化评估有限。部分研究报道了血液生物标志物与认知、睡眠及功能预后的关联。本综述的整体证据强度受限于偏倚风险和小样本量。未来需要在伤后 12 个月以上的前瞻性纵向研究中重复验证这些发现。新的研究工作应借鉴有前景的神经退行性疾病标志物，并采用多标志物组合来模拟多重病理机制。

[REF: Hicks AJ, Carrington H, Bura L, et al. Blood-Based Protein Biomarkers in the Chronic Phase of Traumatic Brain Injury: A Systematic Review. J Neurotrauma. 2025;42(9-10):759-797. doi:10.1089/neu.2024.0294 PMID: 40176450]

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