Eval, Pathogenesis, Outcome of Subjects with or Suspected Traumatic Brain Injury

每年，至少有140万人患有脑损伤，其中超过110万人接受治疗并从急诊科出院。大约125,000名脑损伤患者，通常是那些伤势较重的患者，由于大脑损伤而经历永久性残疾。另一方面，轻度脑损伤至少占所有脑损伤的75%，导致更微妙的功能和认知障碍，在急性情况下往往没有被发现。这些患者的生活质量可能会发生剧烈变化，难以恢复日常活动，可能在数周或数月内无法重返工作岗位。据估计，仅轻微的创伤就使美国每年在长期护理和生产力损失方面损失超过170亿美元。 缺乏诊断颅脑损伤的客观标准是开发治疗方法和改善临床结果的重大障碍。有头部损伤病史的患者经常在急诊室接受使用计算机断层扫描(CT)的筛查脑扫描，尽管对检测轻微损伤的敏感性较低。该项目的目标是为基于队列的比较生成自然历史数据，作为未来假设驱动的方案的基础，并通过描述创伤性脑损伤的表现以及放射学、血液学、临床变量和标准功能/认知结果测量之间的关系，促进对创伤性脑损伤(TBI)的临床和生理理解。特别是，MRI用于识别生物标记物、诊断急性脑外伤和预测预后的研究正在进行中。 这是一项前瞻性研究，研究对象为已知和疑似非穿透性急性脑损伤的受试者，这些受试者参加了IRB批准的两种方案之一。对最近有头部损伤病史的参加医院急诊科或创伤服务的受试者在住院期间和出院后使用放射学、血液学、临床和功能/认知结果测量进行研究。除了到我们当地医院接受急性护理的患者外，还可以选择从当地医院以外的地方招募受试者，将其带到NIH临床中心进行更全面的评估和转介到其他研究。 受试者根据研究结果被分成不同的队列进行比较。该设计有意扩大范围，以允许为未来假说驱动的方案的开发获取初始数据。根据该方案进行的研究不会干扰护理标准，作为研究研究的一部分，受试者不会接受实验性治疗。根据这项研究收集的数据在没有个人识别符的情况下与其他研究人员共享，如果受试者在知情同意下批准这一选项。到目前为止，近2000名有近期颅脑损伤病史或怀疑为非穿透性急性颅脑损伤的成年受试者参加了两种方案中的一种。具有不同程度脑外伤严重程度的受试者是从国立卫生研究院和非国立卫生研究院医院之间的合作项目中招募的。大约80%的受试者被归类为轻度颅脑损伤、脑震荡或无损伤，大约一半的受试者直接从急诊科出院。受试者可以选择来到NIH临床中心接受非常高场(7T)的成像，并使用正电子发射断层扫描(PET)进行成像，其中一些受试者已经根据一个合作项目进行了长达5年的跟踪调查。 该项目是NIH制服服务大学神经科学和再生医学中心(CNRM)的一部分，并通过CNRM急性研究核心提供支持。2019年，停止了对核心的支持，停止了注册，并清理和锁定了数据。作为NINDS工作的一部分，并通过与CNRM的持续合作，继续分析和发布数据。 一年来，我们重点抓好了以下几个方面的工作： 创伤性微出血： 我们以前已经证明了小出血性病变的流行率和持久性：创伤性微出血或TMB。在我们研究过的轻度脑外伤患者中，有高达20%的患者发现了它们，根据我们的病理学工作，它们提示有微血管损伤。他们预测会出现更糟糕的结果。我们最近完成了一项研究，证明了TMBS与细胞毒性水肿区的相关性，细胞毒性水肿区本质上是小的、卒中样的病变。与其他基线因素无关，急性MRI上所见的细胞毒性水肿的证据预示着30-90天的持续性缺陷。 外伤性脑膜强化： 我们对大约650名患者进行的最大规模的研究已经完成，手稿正在准备中。近1/2的脑外伤患者脑膜受损。我们在MRI上检测到的损伤的严重程度预示着30天后脑膜的持续强化，这表明修复失败，就像在小鼠模型中看到的那样(多里安·麦加弗恩，PI)。 协作科学： 作为国防部CNRM的一部分，我们继续通过直接合作提供数据。今年的合作项目包括基于血液的生物标记物表征脑损伤(Jessica Gill，PI)、局灶性皮质萎缩和全身性脑萎缩(John Butman，PI)，以及开始与宾夕法尼亚大学医院的同事合作研究脑损伤的流行病学。

Each year, at least 1.4 million people sustain TBI, with over 1.1 million treated and released from the emergency department (ED). Approximately 125,000 patients with TBI, typically those more severely injured, experience permanent disability as a result of damage to the brain. On the other hand, mild TBI, accounting for at least 75% of all TBI, results in more subtle functional and cognitive deficits that often go undetected in the acute setting. These patients can experience drastic changes in their quality of life, have difficulties returning to daily activities and may be unable to return to work for weeks or months. It is estimated that mild TBI alone costs the United States in excess of $17 billon per year in long-term care and lost productivity. Lack of objective criteria for diagnosing TBI presents a significant impediment to developing therapies and improving clinical outcomes . Patients with a history of head injury often receive a screening brain scan using computed tomography (CT) in the ED despite a low sensitivity for detecting mild injury. The objective of this project is to generate natural history data for cohort-based comparisons to serve as the basis for future hypothesis-driven protocols and to contribute to the clinical and physiological understanding of traumatic brain injury (TBI) through the description of manifestations of the injury and the relationship among radiological, hematological, clinical variables and standard functional/cognitive outcome measures. In particular, the use of MRI to identify biomarkers, diagnose acute TBI, and predict outcome is being study. This is a prospective study of subjects with known and suspected non-penetrating acute traumatic brain injury who are enrolled in one of two IRB approved protocols. Subjects presenting to the emergency department or trauma service at participating hospitals with a history of recent head injury are studied during the course of their hospital stay and after discharge using radiological, hematological, clinical and functional/cognitive outcome measures. In addition to patients presenting to our local hospitals for acute care, there is an option to recruit subjects from beyond the local hospitals to be brought to the NIH Clinical Center for a more comprehensive battery of assessments and referral to other studies. Subjects are stratified according to findings into cohorts for comparison. The design is intentionally broad in scope to allow acquisition of initial data for the development of future hypothesis-driven protocols. Research performed under this protocol does not interfere with standard of care and subjects are not treated with experimental therapies as part of the research study. Data collected under this research study is shared without personal identifiers with other researchers if subjects approve this option on the informed consent. To date, nearly 2000 adult subjects with history of recent head injury with or suspected non-penetrating acute TBI have been enrolled in one of two protocols. Subjects having varying degrees of TBI severity have been recruited from the collaborative programs between NIH and non-NIH hospitals. Approximately 80% of subjects are classified as mild TBI, concussion, or no injury, with approximately one half of subjects enrolled being discharged directly from the emergency department. Subjects were offered the option of coming to the NIH Clinical Center to be imaged at very high fields (7T), imaged with positron emission tomography (PET), and some have been followed for up to 5 years under a collaborative project. The project was part of the NIH Uniform Services University - Center for Neuroscience and Regenerative Medicine (CNRM) and supported through the CNRM Acute Studies core. In 2019, support for the core was discontinued, enrollment was halted, and data was cleaned and locked. Work continues to analyze and publish data as part of the NINDS effort and through continued collaboration with CNRM. During the past year, we have focused on the following areas: Traumatic microbleeds: We have previously demonstrated the prevalence and persistence of small hemorrhagic lesions: traumatic microbleeds or TMB. They are found in up to 20% of patients with mild TBI we have studied and are suggestive of microvascular injury based on our pathology work. They are predictive of worse outcome. We have recently finished a study demonstrating the association between TMBs and areas of cytotoxic edema, essentially small, stroke-like appearing lesions. Independent of other baseline factors, evidence of cytotoxic edema seen on acute MRI is predictive of persistent deficits at 30-90 days. Traumatic meningeal enhancement: Our largest study of approximately 650 patients is complete and the manuscript in preparation. The meninges are injured in nearly 1 of 2 patients with TBI. The severity of the injury we detect on MRI is predictive of persistent enhancement of the meninges at 30 days, suggesting failure to repair as was seen in the mouse model (Dorian McGavern, PI). Collaborative science: As part of the Department of Defense CNRM, we continue to make data available through direct collaboration. This year collaborative projects have included blood-based biomarker characterization of TBI (Jessica Gill, PI), focal cortical atrophy and generalized brain atrophy (John Butman, PI), and the start of a collaboration with colleagues at the Hospital of the University of Pennsylvania on the epidemiology of TBI.