Acute Biomarkers of Traumatic Brain Injury: Relationship between Plasma Levels of Ubiquitin C-Terminal Hydrolase-L1 and Glial Fibrillary Acidic Protein

Abstract

Biomarkers are important for accurate diagnosis of complex disorders such as traumatic brain injury (TBI). For a complex and multifaceted condition such as TBI, it is likely that a single biomarker will not reflect the full spectrum of the response of brain tissue to injury. Ubiquitin C-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) are among of the most widely studied biomarkers for TBI. Because UCH-L1 and GFAP measure distinct molecular events, we hypothesized that analysis of both biomarkers would be superior to analysis of each alone for the diagnosis and prognosis of TBI. Serum levels of UCH-L1 and GFAP were measured in a cohort of 206 patients with TBI enrolled in a multicenter observational study (Transforming Research and Clinical Knowledge in Traumatic Brain Injury [TRACK-TBI]). Levels of the two biomarkers were weakly correlated to each other (r = 0.364). Each biomarker in isolation had good sensitivity and sensitivity for discriminating between TBI patients and healthy controls (area under the curve [AUC] 0.87 and 0.91 for UCH-L1 and GFAP, respectively). When biomarkers were combined, superior sensitivity and specificity for diagnosing TBI was obtained (AUC 0.94). Both biomarkers discriminated between TBI patients with intracranial lesions on CT scan and those without such lesions, but GFAP measures were significantly more sensitive and specific (AUC 0.88 vs. 0.71 for UCH-L1). For association with outcome 3 months after injury, neither biomarker had adequate sensitivity and specificity (AUC 0.65-0.74, for GFAP, and 0.59-0.80 for UCH-L1, depending upon Glasgow Outcome Scale Extended [GOS-E] threshold used). Our results support a role for multiple biomarker measurements in TBI research. (ClinicalTrials.gov Identifier NCT01565551)

Plasma Anti-Glial Fibrillary Acidic Protein Autoantibody Levels during the Acute and Chronic Phases of Traumatic Brain Injury: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot Study

“…26,39 While the number of plasma samples is still relatively small within the cohort, the TRACK-TBI pilot dataset was selected for this study because it is well-characterized with 13 published articles regarding various components of these TBI patients across the full range of TBI severity-including proteomic and genetic biomarkers, neuroimaging, and outcome data. 31,36,37,[40][41][42][43] Based on the 217 subjects with available biosamples from this cohort, we identified that anti-GFAP autoantibody levels were elevated in acute plasma samples from brain injury subjects who had a self-reported history of previous TBI with or without LOC when compared with patients with acute TBI without self-reported previous TBI (Fig. 1).…”

“…1,36,37 Of 586 subjects with acute TBI from the TRACK-TBI pilot, we identified 196 with available acute plasma samples (collected within 24 h of injury) for this autoantibody study. Study patients covered the range of initial GCS of 3-15, which are reported with age, sex, and admission head CT distributions in Table 1.…”

Increases of Plasma Levels of Glial Fibrillary Acidic Protein, Tau, and Amyloid β up to 90 Days after Traumatic Brain Injury

“…Glial fibrillary acid protein (GFAP), 10,11 microtubule-associated protein tau, [12][13][14] and amyloid b peptide (particularly the 1-42 fragment, Ab42) 12 have been proposed as promising diagnostic and prognostic biomarkers in TBI. GFAP is a structural protein expressed almost exclusively in astrocytes and released upon disintegration of the cytoskeleton.…”

“…15 GFAP has been widely studied in TBI, and elevated levels in plasma show promise as a diagnostic and prognostic biomarker. 10,11 In moderate and severe TBI, GFAP levels are elevated in cerebrospinal fluid (CSF) and serum, particularly in patients who experienced an unfavorable outcome. 16 In addition, GFAP had excellent sensitivity to discriminate TBI patients from controls (with area under curve [AUC] 0.87) in the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) study in which 85% of the patient cohort had mild TBI.…”

Biomarkers of injury to neural tissue in veterinary medicine

“…Recently, UCH-L1 has been reported to be a useful TBI biomarker in humans (72). Another study found that measuring serum UCHL-1 and GFAP levels improves the sensitivity and specificity of the diagnosis of TBI, since these biomarkers reflect different injury mechanisms (16). The same authors also found that UCHL-1 was poorly predictive of patient recovery and was better at predicting poor outcome.…”