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

每年，至少有140万人患有TBI，超过110万人接受治疗并从急诊科（艾德）出院。大约有125，000名TBI患者，通常是那些受伤更严重的患者，由于大脑损伤而导致永久性残疾。另一方面，轻度TBI（占所有TBI的至少75%）导致更微妙的功能和认知缺陷，这些缺陷在急性环境中通常未被发现。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，可能数周或数月无法恢复工作。据估计，仅轻度TBI每年就花费美国超过170亿美元的长期护理和生产力损失。 缺乏诊断TBI的客观标准是开发治疗和改善临床结果的重大障碍。有头部损伤史的患者通常在艾德接受使用计算机断层扫描（CT）的筛查性脑部扫描，尽管检测轻度损伤的灵敏度较低。该项目的目的是生成自然病史数据，用于基于队列的比较，以作为未来假设驱动方案的基础，并通过描述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）的临床和生理学理解。特别是，正在研究使用MRI来识别生物标志物，诊断急性TBI和预测结果。 这是一项在已知和疑似非穿透性急性创伤性脑损伤受试者中进行的前瞻性研究，这些受试者入组了两项IRB批准的方案之一。使用放射学、血液学、临床和功能/认知结果测量，在参与医院的急诊科或创伤服务中对具有近期头部损伤史的受试者在其住院期间和出院后进行研究。除了到我们当地医院接受急诊治疗的患者外，还可以选择从当地医院以外招募受试者，将其带到NIH临床中心进行更全面的评估和转诊到其他研究。 根据结果将受试者分层到队列中进行比较。该设计有意扩大范围，以允许获取用于开发未来假设驱动方案的初始数据。根据本方案进行的研究不干扰标准治疗，受试者不接受实验性治疗作为研究的一部分。如果受试者在知情同意书上批准了这一选择，则在本研究中收集的数据将与其他研究者共享，而不使用个人标识符。到目前为止，近2000名有近期头部损伤病史的成人受试者（伴或疑似非穿透性急性TBI）已入选两个方案之一。从NIH和非NIH医院之间的合作项目中招募了具有不同程度TBI严重程度的受试者。大约80%的受试者被归类为轻度TBI、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NIH临床中心接受极高场（7 T）成像，使用正电子发射断层扫描（PET）成像，有些人在合作项目下接受了长达5年的随访。 该项目是美国国立卫生研究院统一服务大学-神经科学和再生医学中心（CNRM）的一部分，并通过CNRM急性研究核心支持。2019年，停止了对核心的支持，停止了招募，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。 在过去一年，我们集中注意以下方面： 创伤性微出血： 我们以前已经证明了小出血性病变的流行和持续性：创伤性微出血或TMB。在我们研究的轻度TBI患者中，高达20%的患者发现了它们，并且根据我们的病理学工作提示微血管损伤。它们预示着更糟糕的结果。我们最近完成了一项研究，证明了TMB和细胞毒性水肿（本质上是小的卒中样病变）之间的相关性。与其他基线因素无关，急性MRI上观察到的细胞毒性水肿证据可预测30-90天时的持续性功能缺损。 创伤性脑膜强化： 我们对大约650名患者的最大研究已经完成，手稿正在准备中。2例TBI患者中约1例有脑膜损伤。我们在MRI上检测到的损伤的严重程度预测了30天时脑膜的持续增强，表明修复失败，如在小鼠模型中所见（Dorian McGavern，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TBI生物标志物表征（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TBI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.