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).

FIG. 1.

(A) Ubiquitin C-terminal hydrolase L1 (UCH-L1) levels as a function of injury severity. Mean UCH-L1 levels differ between moderate to severe TBI (GCS 3–12) and mild TBI (mTBI) (GCS 13–15) and also differ between complicated mTBI (GCS 13–15 with abnormal cranial CT) and uncomplicated mTBI. (***p<0.0001; **p=0.012) (B) Receiver-operator characteristics (ROC) curve for distinguishing CT positive from CT negative patients. UCH-L1 levels are modestly predictive of cranial CT abnormalities for mTBI patients (area under the curve [AUC] 0.713), data shown) or for all patients (AUC=0.667, data not shown).

FIG. 2.

Relationship of ubiquitin C-terminal hydrolase (L1UCH-L1) levels with outcome. Outcome was assessed using the Glasgow Outcome Scale–Extended (GOS-E) at 3 months after injury. (A) Patients who recovered fully tended to have lower UCH-L1 levels that those who did not (p=0.07). (B) Patients who had poor outcomes (GOS-E≤4) had higher UCH-L1 levels. (C, D) UCH-L1 levels were poorly predictive of a complete recovery (area under the curve [AUC]=0.586), but reasonably predictive of poor outcome (GOS-E≤4) (AUC=0.803).

FIG. 3.

Relationship between serum ubiquitin C-terminal hydrolase (UCH-L1) and glial fibrillary acidic protein (GFAP) levels. Serum levels of the two biomarkers were weakly correlated (R=0.364, 95% CI 0.233–0.482, p<0.0001). Using log transformation to spread out data points at the low end of the distribution, it was apparent that most patients with elevated UCH-L1 levels also had elevated GFAP levels, whereas many patients with elevated GFAP levels had normal UCH-L1 levels.

FIG. 4.

Receiver-operator characteristics (ROC) curves for ubiquitin C-terminal hydrolase (UCH-L1), glial fibrillary acidic protein (GFAP), and both biomarkers in combination for discriminating between traumatic brain injury (TBI) patients and healthy controls.