Clinical Validation of Serum Neurofilament Light as a Biomarker of Traumatic Axonal Injury

创伤性脑损伤（TBI）是导致死亡和发病的主要原因之一 影响人类，并且是晚年神经退行性疾病的公认风险因素。没有 在神经创伤领域中验证的生物标志物是这一领域药物开发的障碍， 因此，目前没有限制TBI负担的疾病修饰疗法。TBI是一种复杂的 疾病过程，并且需要识别和测量损伤的亚型，以发展精确性 医学方法，其中特定的病理生物学过程是通过机械上适当的 治疗创伤性轴索损伤（TAI）是TBI的常见病理后果，并且是一些创伤性脑损伤的基础。 最致残的伤害后果，包括认知和情感问题。最近的突破， 临床前模型表明，新的治疗干预措施在促进受伤者的恢复力方面是有效的。 轴突和改善实验性TBI后的神经学结果。将这些有前途的疗法转化为 成功的临床试验需要能够测量个体患者TAI的预后生物标志物， 可以选择用于轴突保护疗法的早期研究，以及药效学生物标志物 来衡量这些治疗的生物学效果。目前，TAI的最佳生物标志物是分数 使用扩散张量成像（DTI）测量的白色物质束的各向异性（FA）和平均扩散率（MD） 核磁共振这种技术虽然稳健，但不太适合动态纵向评估， 这是轴突变性的最终结果，而不是神经变性过程的早期步骤。近日 测定外周血中轴突蛋白的能力使得快速评估TAI成为可能， 便宜地，纵向地。轴突蛋白最有希望作为轴突标记物， 变性是神经丝轻链（NF-L）。我们假设NF-L是TAI的预后生物标志物。 我们的项目有三个具体目标： 具体目标1.我们将根据临床实验室确定NF-L的参考区间（RI） 标准协会（CLSI）指南，使用市售检测试剂盒（Quanterix，LLC，列克星敦，MA）。 具体目标2。我们将测量来自多中心参与者的现有血清样本中的NF-L， 观察性研究（TRACK-TBI），他们在受伤后2周和6个月也进行了MRI检查。的关系 NF-L升高与TAI神经影像学指标（2周扫描时FA的DTI指标）和轴突 将评估变性（损伤后6个月时的白色物质体积）。 具体目标3。我们将TRACK-TBI参与者的随访期从1年延长至5年 年后受伤，以评估持续性NF-L升高和神经退行性变之间的关系。的 将利用这些受试者的现有临床、成像和生物标志物数据来识别风险因素， 发病率和长期TBI相关变性的预后生物标志物。

Project Summary/Abstract: Traumatic brain injury (TBI) is one the leading causes of mortality and morbidity affecting humanity, and a recognized risk factor for late-life neurodegenerative disorders. The absence of validated biomarkers in the neurotrauma field is a barrier to drug development in this area, and as a consequence there are currently no disease-modifying therapies that limit the burden of TBI. TBI is a complex disease process, and there is a need to identify and measure subtypes of injury, in order to develop precision medicine approaches where specific pathobiological processes are targeted by mechanistically appropriate therapies. Traumatic axonal injury (TAI) is a common pathologic consequence of TBI, and underlies some of the most disabling consequences of injury, including cognitive and affective problems. Recent breakthroughs in pre-clinical models indicate that novel therapeutic interventions are effective in promoting resilience of injured axons and improving neurologic outcome after experimental TBI. Translation of such promising therapies into successful clinical trials will require prognostic biomarkers that can measure TAI in individual patients, so they can be selected for early phase studies of axono-protective therapies, as well pharmacodynamic biomarkers than can measure the biologic efficacy of such treatments. Currently, the best biomarker for TAI is fractional anisotropy (FA) and mean diffusivity (MD) of white matter tracts, measured using diffusion tensor imaging (DTI) MRI. This technique, while robust, is poorly suited for dynamic longitudinal assessments, and measures the end-result of axonal degeneration, rather than an early step in the neurodegenerative process. Recently, the ability to assay axonal proteins in peripheral blood has made it potentially feasible to assess of TAI rapidly, inexpensively, and longitudinally. The axonal protein that holds the most promise as a marker of axonal degeneration is neurofilament light chain (NF-L). We hypothesize that NF-L is a prognostic biomarker of TAI. Our project has 3 specific aims: Specific aim 1. We will determine reference intervals (RIs) for NF-L according to Clinical Laboratory Standards Institute (CLSI) guidelines, using commercially available assays (Quanterix, LLC, Lexington, MA). Specific aim 2. We will measure NF-L in existing serum samples from participants enrolled in a multi-center observational study (TRACK-TBI) who also have MRIs at 2 weeks and 6 months after injury. The relationship between NF-L elevations and neuroimaging measures of TAI (DTI measure of FA at the 2-week scan) and axonal degeneration (white matter volume at 6 months after injury) will be assessed. Specific aim 3. We will extend the follow-up period of a subset of TRACK-TBI participants from 1 year to 5 years after injury, to assess the relationship between persistent NF-L elevations and neurodegeneration. The existing clinical, imaging, and biomarker data in these subjects will be leveraged to identify risk factors, co- morbidities, and prognostic biomarkers of long-term TBI-associated degeneration.