Assessment of Blood Biomarker Profile After Acute Concussion During Combative Training Among US Military Cadets: A Prospective Study From the NCAA and US Department of Defense CARE Consortium.

Importance: Validation of protein biomarkers for concussion diagnosis and management in military combative training is important, as these injuries occur outside of traditional health care settings and are generally difficult to diagnose. Objective: To investigate acute blood protein levels in military cadets after combative training-associated concussions. Design, Setting, and Participants: This multicenter prospective case-control study was part of a larger cohort study conducted by the National Collegiate Athletic Association and the US Department of Defense Concussion Assessment Research and Education (CARE) Consortium from February 20, 2015, to May 31, 2018. The study was performed among cadets from 2 CARE Consortium Advanced Research Core sites: the US Military Academy at West Point and the US Air Force Academy. Cadets who incurred concussions during combative training (concussion group) were compared with cadets who participated in the same combative training exercises but did not incur concussions (contact-control group). Clinical measures and blood sample collection occurred at baseline, the acute postinjury point (<6 hours), the 24- to 48-hour postinjury point, the asymptomatic postinjury point (defined as the point at which the cadet reported being asymptomatic and began the return-to-activity protocol), and 7 days after return to activity. Biomarker levels and estimated mean differences in biomarker levels were natural log (ln) transformed to decrease the skewness of their distributions. Data were collected from August 1, 2016, to May 31, 2018, and analyses were conducted from March 1, 2019, to January 14, 2020. Exposure: Concussion incurred during combative training. Main Outcomes and Measures: Proteins examined included glial fibrillary acidic protein, ubiquitin C-terminal hydrolase-L1, neurofilament light chain, and tau. Quantification was conducted using a multiplex assay (Simoa; Quanterix Corp). Clinical measures included the Sport Concussion Assessment Tool-Third Edition symptom severity evaluation, the Standardized Assessment of Concussion, the Balance Error Scoring System, and the 18-item Brief Symptom Inventory. Results: Among 103 military service academy cadets, 67 cadets incurred concussions during combative training, and 36 matched cadets who engaged in the same training exercises did not incur concussions. The mean (SD) age of cadets in the concussion group was 18.6 (1.3) years, and 40 cadets (59.7%) were male. The mean (SD) age of matched cadets in the contact-control group was 19.5 (1.3) years, and 25 cadets (69.4%) were male. Compared with cadets in the contact-control group, those in the concussion group had significant increases in glial fibrillary acidic protein (mean difference in ln values, 0.34; 95% CI, 0.18-0.50; P < .001) and ubiquitin C-terminal hydrolase-L1 (mean difference in ln values, 0.97; 95% CI, 0.44-1.50; P < .001) levels at the acute postinjury point. The glial fibrillary acidic protein level remained high in the concussion group compared with the contact-control group at the 24- to 48-hour postinjury point (mean difference in ln values, 0.22; 95% CI, 0.06-0.38; P = .007) and the asymptomatic postinjury point (mean difference in ln values, 0.21; 95% CI, 0.05-0.36; P = .01). The area under the curve for all biomarkers combined, which was used to differentiate cadets in the concussion and contact-control groups, was 0.80 (95% CI, 0.68-0.93; P < .001) at the acute postinjury point. Conclusions and Relevance: This study's findings indicate that blood biomarkers have potential for use as research tools to better understand the pathobiological changes associated with concussion and to assist with injury identification and recovery from combative training-associated concussions among military service academy cadets. These results extend the previous findings of studies of collegiate athletes with sport-associated concussions.

Blood biomarkers for assessment of mild traumatic brain injury and chronic traumatic encephalopathy.

Mild traumatic brain injuries (mTBI) are prevalent and can result in significant debilitation. Current diagnostic methods have implicit limitations, with clinical assessment tools reliant on subjective self-reported symptoms or non-specific clinical observations, and commonly available imaging techniques lacking sufficient sensitivity to detect mTBI. A blood biomarker would provide a readily accessible detector of mTBI to meet the current measurement gap. Suitable options would provide objective and quantifiable information in diagnosing mTBI, in monitoring recovery, and in establishing a prognosis of resultant neurodegenerative disease, such as chronic traumatic encephalopathy (CTE). A biomarker would also assist in progressing research, providing suitable endpoints for testing therapeutic modalities and for further exploring mTBI pathophysiology. This review highlights the most promising blood-based protein candidates that are expressed in the central nervous system (CNS) and released into systemic circulation following mTBI. To date, neurofilament light (NF-L) may be the most suitable candidate for assessing neuronal damage, and glial fibrillary acidic protein (GFAP) for assessing astrocyte activation, although further work is required. Ultimately, the heterogeneity of cells in the brain and each marker's limitations may require a combination of biomarkers, and recent developments in microRNA (miRNA) markers of mTBI show promise and warrant further exploration.

Cost-Effectiveness of Biomarker Screening for Traumatic Brain Injury.

Intracranial hemorrhage after traumatic brain injury (TBI) can be life threatening and requires prompt diagnosis. Computed tomography (CT) scans are a rapid and accurate way to evaluate for hemorrhage. In patients with mild and moderate TBI, however, in whom the incidence of intracranial pathology is low, scanning every patient with CT can be costly. The Food and Drug Administration recently approved a novel biomarker screen, the Banyan Trauma Indicator (BTI), to help streamline the decision for CT scanning in mild to moderate TBI. The BTI screen diagnoses intracranial lesions with a sensitivity and specificity of 97.5% and 99.6%, respectively. We performed cost analyses of the BTI screen to determine the threshold of cost-effectiveness, compared with application of clinical decision rules or routine CT scans, for cases of mild or moderate TBI. With a 0.104 probability of an intracranial lesion in mild TBI, the biomarker screen is cost-effective if the cost is $308.96 or below per test. In moderate TBI, because of the greater prevalence of intracranial lesions at 0.663, there is a lower need for screening, and BTI becomes cost-effective up to $73.41 per test.

Ubiquitin C-Terminal Hydrolase 1 and Phosphorylated Axonal Neurofilament Heavy Chain in Infants Undergoing Cardiac Surgery: Preliminary Assessment as Potential Biomarkers of Brain Injury.

BACKGROUND: There are no reliable markers to assess brain injury in neonates following cardiac surgery. We examine ubiquitin C-terminal hydrolase 1 (UCHL1) and phosphorylated axonal neurofilament heavy chain (pNF-H), neuronal-specific biomarkers released following axonal and cortical injury, in neonates undergoing cardiac surgery involving cardiopulmonary bypass (CPB) and deep hypothermic circulatory arrest (DHCA). METHODS: Twenty-six patients younger than three months were prospectively enrolled (CPB only, n = 12 and DHCA, n = 14). Healthy newborns (n = 22) served as the control. Blood samples were collected preoperatively and postoperatively upon intensive care unit admission (hour 0) and subsequently at 12, 24, 36, and 48 hours. Serum was tested for UCHL1 and pNF-H using enzyme-linked immunosorbent assay. Concomitant arterial blood gas, lactate, and cerebral near-infrared spectroscopy (NIRS) monitoring were performed. RESULTS: Ubiquitin C-terminal hydrolase 1 showed a significant rise at 0 hours in the DHCA group compared to baseline (74.9 ± 13.7 pg/mL vs 33.9 ± 37.3 pg/mL, P < .0001). Levels returned to baseline at 12 hours. There was an early rise in UCHL1 at 0 hours in the CPB group, P = .09. Phosphorylated axonal neurofilament heavy chain was decreased at 0 hours in both the CPB and DHCA groups compared to baseline, P = .06. There was no difference between control and baseline levels of UCHL1 ( P = .9) or pNF-H ( P = .77). Decreased NIRS was observed in the DHCA group at 0 hours (57.3 ± 10.5) versus baseline (64.2 ± 12.3), but not significant ( P = .21). There was no correlation between biomarkers and NIRS at 0 hours. CONCLUSION: A rapid rise in UCHL1 levels was observed in the DHCA group, suggesting that it may be a marker for acute brain injury. Follow-up with neurodevelopmental studies is ongoing.

Prospective Assessment of Acute Blood Markers of Brain Injury in Sport-Related Concussion.

There is a pressing need to identify objective biomarkers for the assessment of sport-related concussion (SRC) to reduce the reliance on clinical judgment for the management of these injuries. The goal of the current study was to prospectively establish the acute effects of SRC on serum levels of S100 calcium-binding protein beta (S100B), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1). Collegiate and high school football players were enrolled and provided blood at pre-season. Injured athletes participated in follow-up visits at ∼6 and 24-48 h following documented SRC (n = 32). Uninjured football players participated in similar follow-up visits and served as controls (n = 29). The median time between injury and blood collection was 2 h (6 h visit) and 22.5 h (24-48 h visit) in concussed athletes. Concussed athletes had significantly elevated UCH-L1 levels at the 6 h visit relative to pre-season levels (Z = 2.22, p = 0.03) and levels in control athletes (Z = 3.02, p = 0.003). Concussed athletes also had elevated S100B at 6 h relative to pre-season (Z = 2.07, p = 0.04) and controls (Z = 2.75, p = 0.006). Both markers showed fair discrimination between concussed and control athletes (UCH-L1 area under receiver operating characteristic curve [AUC] [95% CI] = 0.74 [0.61-0.88], S100B AUC = 0.72 [0.58-0.87]). Percent-change of UCH-L1 and S100B at 6 h relative to pre-season also showed fair discrimination (AUC = 0.79 [0.66-0.92] and AUC = 0.77 [0.64-0.90]). GFAP levels did not differ between groups or in concussed athletes relative to pre-season. This study provides prospective evidence of significant increases in serum levels of UCH-L1 and S100B during the early acute period following SRC, and lays the foundation for future studies examining the clinical potential for blood-based biomarkers in the early detection of concussion.

Assessment of Serum UCH-L1 and GFAP in Acute Stroke Patients.

A rapid and reliable diagnostic test to distinguish ischemic from hemorrhagic stroke in patients presenting with stroke-like symptoms is essential to optimize management and triage for thrombolytic therapy. The present study measured serum concentrations of ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary astrocytic protein (GFAP) in acute stroke patients and healthy controls and investigated their relation to stroke severity and patient characteristics. We also assessed the diagnostic performance of these markers for the differentiation of intracerebral hemorrhage (ICH) from ischemic stroke (IS). Both UCH-L1 and GFAP concentrations were significantly greater in ICH patients than in controls (p < 0.0001). However, exclusively GFAP differed in ICH compared with IS (p < 0.0001). GFAP yielded an AUC of 0.86 for differentiating between ICH and IS within 4.5hrs of symptom onset with a sensitivity of 61% and a specificity of 96% using a cut-off of 0.34ng/ml. Higher GFAP levels were associated with stroke severity and history of prior stroke. Our results demonstrate that blood UCH-L1 and GFAP are increased early after stroke and distinct biomarker-specific release profiles are associated with stroke characteristics and type. We also confirmed the potential of GFAP as a tool for early rule-in of ICH, while UCH-L1 was not clinically useful.