Dissecting Temporal Profiles of Neuronal and Axonal Damage After Mild Traumatic Brain Injury

Biomarkers are molecules that can be measured in accessible biological fluids that reflect physiological, pharmacological, or disease processes and can suggest the etiology of, susceptibility to, activity levels of, or progress of a disease. Biomarkers have historically been critical to patient progress in a broad range of clinical conditions. Diagnostic and therapeutic advances in fields as disparate as cardiology and oncology have relied on the ability to measure biomarkers that are reliable indicators of the underlying pathology. The absence of validated biomarkers in the neurotrauma field is a major factor limiting our understanding of the natural history and the long-term effects of traumatic brain injury (TBI), as well as a barrier to drug development in this area. According to the US Food and Drug Administration,1,2 biomarkers fall into the following 4 categories, which are not mutually exclusive: diagnostic, prognostic, predictive, and pharmacodynamic. Diagnostic biomarkers measure disease characteristics that categorize a person by the presence or absence of a specific physiological or pathophysiological state. Prognostic biomarkers are baseline measurements that categorize patients by degree of risk for disease progression and inform about the natural history of the disorder. Predictive biomarkers are baseline characteristics that categorize patients by their likelihood of response to a particular treatment. Finally, pharmacodynamic biomarkers are dynamic measurements that show that biological response has occurred in a patient after a therapeutic intervention. Biomarkers are particularly important for progress in the managementof concussionandmildTBI (mTBI).MildTBI can beachallenge todiagnosebecause thesymptomsareoftenprotean and overlap with other conditions that frequently confound the clinical picture, such as intoxication, delirium, and functional disorders like posttraumatic stress disorder. Mild TBI is defined as a traumatically induced physiological disruptionof brain function resulting from theheadbeing struck or striking an object or the brain undergoing an acceleration or deceleration movement, as manifested by at least 1 of the following: (1) anyperiodof lossof consciousnessup to30minutes; (2)posttraumaticamnesianotexceeding24hours; (3) any periodof confusionor disorientation; (4) transient neurological abnormalities, including focal signs, seizures, and intracranial lesions not requiring surgery; and (5) a score of 13 to 15 on the Glasgow Coma Scale.3 Reliance on recall of the event and subjective report of loss of consciousness, posttraumatic amnesia, and symptoms affects the diagnostic accuracy of mTBI and introduces selection bias,4,5 particularly in cases of unwitnessed traumaorwhen the reportingof symptoms is influenced bypotential secondary gain, such as desire to return to play in athletes or involvement in accident-related litigation.Therefore,while there remainsaneed forprognostic, predictive, andpharmacodynamic biomarkers formTBI, diagnosis remains a common challenge in emergency departments, aswell as at the sitesofunintentional injuries, sportingevents, and military combat zones. In this issue of JAMA Neurology, Papa et al6 report a substantial step toward validation and ultimate clinical usefulness of 2 candidate diagnostic biomarkers of mTBI. The investigators examined the diagnostic accuracy of 2 blood biomarkers (glial fibrillary acidic protein [GFAP] and ubiquitin C-terminal hydrolase L1 [UCH-L1]) separately and in combination in cohorts with mild and moderate TBI within 7 days of the injury with respect to diagnostic precision of TBI, presence of traumatic intracranial lesions detected by computed tomography (CT), and need for neurosurgical interventions. While there has been much work recently investigating TBI biomarkers, GFAP and UCH-L1 are among the most widely studied molecules. The ultimate importance of this single-center prospective study addressing the role of these well-studied blood biomarkers of TBI relates to the following reasons. First, this work is based on a thoughtful study design that included multiple blood sampling (starting from 4 hours up to 180 hours after TBI, with up to 19 time points in total), allowing the authors to carefully track temporal profiles of biomarkers of the TBI population at a level I trauma center. Second, the results and conclusions of this study are derived from the large numbers of patients enrolled and the many blood samples collected (1831 samples from 584 patients), allowing careful examination of temporal profiles of these biomarkers in different subgroups of the TBI cohort (such as mTBI with vs without loss of consciousness and subgroups of patients with TBI requiring surgical intervention vs conservative treatment only). This feature of the data collection allowed the authors to adjust the data for multiple moderators (including age, sex, and Glasgow Coma Scale score), which is the noteworthy advantage of this study. Third, this study is unique in using as controls patients who had experienced orthopedic or other non– central nervous system injuries (with similar mechanisms as for the TBI cohort but with normal mental status and no evidence of TBI). Fourth, the data are collected by meticulous and rigorous methodological assessments of patients with mTBI, ensuring eligibility of the patients by initial screening of emergency department physicians, followed by secondary assessment of the study team, thus confirming the accuracy of classification of the enrolled patients. GFAP is a structural protein expressed almost exclusively in astrocytes and released on disintegration of the cytoskeleton.7 It has been widely studied in TBI, and elevated levels inplasmashowpromiseasadiagnostic andprognostic biomarker.8,9 Inmoderate and severe TBI, GFAP levels are elevated in cerebrospinal fluid and serum, particularly in patients who experienced unfavorable outcome.10 In addiRelated article page 551 Opinion Editorial