Ubiquitin C-terminal hydrolase is a novel biomarker in humans for severe traumatic brain injury

Abstract

Objective: Ubiquitin C-terminal hydrolase (UCH-L1), also called neuronal-specific protein gene product (PGP 9.3), is highly abundant in neurons. To assess the reliability of UCH-L1 as a potential biomarker for traumatic brain injury (TBI) this study compared cerebrospinal fluid (CSF) levels of UCH-L1 from adult patients with severe TBI to uninjured controls; and examined the relationship between levels with severity of injury, complications and functional outcome.

Design: This study was designed as prospective case control study.

Patients: This study enrolled 66 patients, 41 with severe TBI, defined by a Glasgow coma scale (GCS) score of < or =8, who underwent intraventricular intracranial pressure monitoring and 25 controls without TBI requiring CSF drainage for other medical reasons.

Setting: : Two hospital system level I trauma centers.

Measurements and main results: Ventricular CSF was sampled from each patient at 6, 12, 24, 48, 72, 96, 120, 144, and 168 hrs following TBI and analyzed for UCH-L1. Injury severity was assessed by the GCS score, Marshall Classification on computed tomography and a complicated postinjury course. Mortality was assessed at 6 wks and long-term outcome was assessed using the Glasgow outcome score 6 months after injury. TBI patients had significantly elevated CSF levels of UCH-L1 at each time point after injury compared to uninjured controls. Overall mean levels of UCH-L1 in TBI patients was 44.2 ng/mL (+/-7.9) compared with 2.7 ng/mL (+/-0.7) in controls (p <.001). There were significantly higher levels of UCH-L1 in patients with a lower GCS score at 24 hrs, in those with postinjury complications, in those with 6-wk mortality, and in those with a poor 6-month dichotomized Glasgow outcome score.

Conclusions: These data suggest that this novel biomarker has the potential to determine injury severity in TBI patients. Further studies are needed to validate these findings in a larger sample.

Figure 1

Comparison of cerebrospinal fluid levels of ubiquitin C-terminal hydrolase (UCH-L1) in patients with traumatic brain injury (TBI) vs. control at all time points. Levels of UCH-L1 were predominantly elevated in the first 24 hrs after injury compared with control patients for each time point (n = 9, 10, 20, 26, 35, 32, 15, 22, 12, 18, respectively) (*p ≤ .05 compared with control). Values represent means (ng/mL ± SEM).

Figure 2

Comparison of levels of ubiquitin C-terminal hydrolase (UCH-L1) in patients with a Glasgow Coma Scale (GCS) score 3–5 and GCS score 6 – 8 in the first 24 hrs after injury: Mean levels of UCH-L1 (ng/mL ± SEM). Mean 12- and 24-hr levels of UCH-L1 in cerebrospinal fluid are significantly elevated in patients with GCS 3–5 (n = 5, 8) compared with those with a GCS 6 – 8 (n = 20, 21) at day 1 after injury.

Figure 3

Overall mean levels of ubiquitin C-terminal hydrolase (UCH-L1) and the Marshall classification on admission computed tomography (CT) scan. There were no significant differences in levels of UCH-L1 between the Marshall classes (n = 1, 15, 4, 14, 2, respectively). There were no patients in the class IV group. The overall mean level of UCH-L1 in the evacuated mass lesion (V-EM) group vs. the nonevacuated mass lesion (VI-NEM) group was 28.3 (±6.1) and 113.6 (±104.8), respectively (p = .43).

Figure 4

Comparison of levels of ubiquitin C-terminal hydrolase (UCH-L1) measured at all time points after injury in patients with and without a complicated postinjury course. In patients with a complicated postinjury course, levels of UCH-L1 were significantly elevated at 24, 48, and 72 hrs after injury (p = .033, p = .004 and p = .045, respectively) compared with those without a complicated course. The number of patients without a complicated postinjury course at each time point was n = 0, 8, 7, 7, 5, 3, 2, 2, and those with a complicated course n = 2, 8, 11, 14, 12, 9, 10, 9, respectively.

Figure 5

Comparison of levels of ubiquitin C-terminal hydrolase (UCH-L1) in cerebrospinal fluid 24 hrs after injury in patients with who survived to 6 wks vs. nonsurvivors. Patients who did not survive for 6 wks had significantly higher values (mean ± SEM) of UCH-L1 in cerebrospinal fluid at 24 hrs after injury when compared with patients who survived (p = .010) (n = 6, 23, respectively).

Figure 6

Comparison of levels of ubiquitin C-terminal hydrolase (UCH-L1) in cerebrospinal fluid at 96, 120, and 168 hrs after injury in patients with poor outcome vs. good outcome at 6 months. Patients with poor outcome had significantly higher values (mean ± SEM) of UCH-L1 at 96 and 168 hrs after injury when compared with patients with good outcome (p = .05 and p = .032, respectively). UCH-L1 levels drawn at 120 hrs showed a similar trend, but values were not statistically significant (p = .08). The number of patients with good outcome at the respective time points was n = 3, 3, 3 and those with a poor outcome n = 7, 15, 9. GOS, Glasgow Outcome Scale.