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

项目摘要/摘要：创伤性脑损伤是导致死亡率和致残率的主要原因之一。 影响人类，也是公认的晚年神经退行性疾病的危险因素。不存在 神经创伤领域中经过验证的生物标记物是该领域药物开发的障碍，作为一种 结果：目前还没有限制脑外伤负担的疾病修正疗法。TBI是一种复杂的 疾病进程，需要确定和测量伤害的亚型，以便提高精确度 以特定的病理生物学过程为靶点的医学途径 治疗。创伤性轴索损伤(TAI)是颅脑损伤的常见病理后果，是部分 伤害造成的最严重的致残后果，包括认知和情感问题。最近在以下方面的突破 临床前模型表明，新的治疗干预措施在提高受伤人员的韧性方面是有效的。 轴突与改善实验性脑外伤后的神经学预后。将这些有希望的疗法转化为 成功的临床试验将需要能够测量单个患者TAI的预后生物标记物，所以他们 可用于轴突保护治疗的早期研究，以及药效学生物标记物 才能衡量这类治疗的生物疗效。目前，TAI最好的生物标志物是分数 用扩散张量成像(DTI)测量白质束的各向异性(FA)和平均扩散系数(MD) 核磁共振检查。这项技术虽然健壮，但不太适合动态纵向评估，并测量 轴突变性的最终结果，而不是神经退化过程的早期步骤。最近， 检测外周血中轴突蛋白的能力使快速评估TAI成为可能， 廉价的，纵向的。最有希望作为轴突标志物的轴突蛋白 变性是神经细丝轻链(NF-L)。我们推测，核因子-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核因子-L的参考区间 标准协会(CLSI)指南，使用商业上可用的分析方法(Quanterix，LLC，LLC，Lexington，MA)。 具体目标2.我们将检测多中心登记参与者现有血清样本中的核因子-L 观察性研究(Track-TBI)，在伤后2周和6个月进行核磁共振检查。两国关系 核因子-L升高与TAI(2周扫描时测量FA)和轴突的神经影像测量之间的关系 将对变性(损伤后6个月的白质体积)进行评估。 具体目标3.我们将把部分Track-TBI参与者的随访期从1年延长到5年 损伤后数年，评估持续性的核因子-L升高与神经退行性变的关系。这个 这些受试者的现有临床、影像和生物标记物数据将被用来识别风险因素，共同 长期脑外伤相关变性的发病率和预后生物标志物。

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.