GFAP-BDP as an acute diagnostic marker in traumatic brain injury: results from the prospective transforming research and clinical knowledge in traumatic brain injury study

Abstract

Reliable diagnosis of traumatic brain injury (TBI) is a major public health need. Glial fibrillary acidic protein (GFAP) is expressed in the central nervous system, and breakdown products (GFAP-BDP) are released following parenchymal brain injury. Here, we evaluate the diagnostic accuracy of elevated levels of plasma GFAP-BDP in TBI. Participants were identified as part of the prospective Transforming Research And Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Study. Acute plasma samples (<24 h post-injury) were collected from patients presenting with brain injury who had CT imaging. The ability of GFAP-BDP level to discriminate patients with demonstrable traumatic lesions on CT, and with failure to return to pre-injury baseline at 6 months, was evaluated by the area under the receiver operating characteristic curve (AUC). Of the 215 patients included for analysis, 83% had mild, 4% had moderate, and 13% had severe TBI; 54% had acute traumatic lesions on CT. The ability of GFAP-BDP level to discriminate patients with traumatic lesions on CT as evaluated by AUC was 0.88 (95% confidence interval [CI], 0.84-0.93). The optimal cutoff of 0.68 ng/mL for plasma GFAP-BDP level was associated with a 21.61 odds ratio for traumatic findings on head CT. Discriminatory ability of unfavorable 6 month outcome was lower, AUC 0.65 (95% CI, 0.55-0.74), with a 2.07 odds ratio. GFAP-BDP levels reliably distinguish the presence and severity of CT scan findings in TBI patients. Although these findings confirm and extend prior studies, a larger prospective trial is still needed to validate the use of GFAP-BDP as a routine diagnostic biomarker for patient care and clinical research. The term "mild" continues to be a misnomer for this patient population, and underscores the need for evolving classification strategies for TBI targeted therapy. (ClinicalTrials.gov number NCT01565551; NIH Grant 1RC2 NS069409).

FIG. 1.

Violin and box plot of glial fibrillary acidic protein and breakdown products (GFAP-BDP) levels in traumatic brain injury (TBI) subjects with negative head CT for intracranial lesions versus subjects with evidence of pathoanatomic features. Box plots are shown in black with density distribution of GFAP-BDP values in gray. Patients negative for intracranial lesions on CT (CT-, n=106) had a mean plasma GFAP-BDP level of 0.26 ng/mL (SD 0.41 ng/mL), whereas patients positive for any intracranial lesion types (CT+, n=109) had a mean plasma GFAP-BDP level of 2.88 ng/mL (SD 3.74 ng/mL).

FIG. 2.

Mean plasma glial fibrillary acidic protein and breakdown products (GFAP-BDP) levels (ng/mL) for increasing numbers of lesions seen on admission head CT after acute TBI. Lesion types include epidural hematoma (EDH), acute subdural hemorrhage (ASDH), traumatic subarachnoid hemorrhage (tSAH), contusion, and intraventricular hemorrhage (IVH). Patients with no intracranial lesion (number of lesions=None) had statistically significant lower mean GFAP-BDP levels than those with one, two, and three or more lesion types (p<0.0001). Patients with one lesion type also had statistically significant lower mean GFAP-BDP levels than those with three or more lesion types (p<0.0001).

FIG. 3.

Receiver operating-characteristic curve for diagnosing traumatic brain injury (TBI) subjects with pathologic CT features. The area under the curve (AUC) demonstrates that glial fibrillary acidic protein and breakdown products (GFAP-BDP) levels are able to discriminate between subjects with and without radiographic evidence of TBI, AUC 0.88 (95% CI, 0.84–0.93).

FIG. 4.

Box plots displaying the concentration distribution of glial fibrillary acidic protein and breakdown products (GFAP-BDP) for each level of traumatic brain injury (TBI) severity, mild (Glasgow Coma Scale [GCS] score 13–15), moderate (GCS 9–12) and severe (GCS 3–8). Median (lower quartile, upper quartile) plasma GFAP-BDP concentration is 0.263 (0.025, 1.033) for mild TBI, 1.831 (0.772, 3.483) for moderate TBI, and 3.596 (1.09, 7.272) for severe TBI.

FIG. 5.

Mean levels (+/− SD) of plasma glial fibrillary acidic protein and breakdown products (GFAP-BDP) concentration across 6 month Glasgow Outcome Scale-Extended (GOS-E) scores. Higher GFAP-BDP levels are associated with greater detraction from full global recovery. The mean GFAP-BDP difference trends toward significance (p=0.067, ANOVA), especially between traumatic brain injury (TBI) patients with GOS-E=8 versus those with GOS-E=5 and 6 (p=0.055, ANOVA) at 6 months post-injury.

FIG. 6.

Receiver operating-characteristic curve for predicting global recovery of traumatic brain injury (TBI) subjects at 6 months post-injury using the eight point Glasgow Outcome Scale – Extended (GOS-E). A GOS-E score of 8 signifies full recovery to baseline function, whereas a score ≤7 signifies deficits in recovery. GOS-E of ≤4 signifies an unfavorable functional recovery. The area under the curve (AUC) in the left panel demonstrates that glial fibrillary acidic protein and breakdown products (GFAP-BDP) are able to adequately discriminate between subjects of favorable versus unfavorable functional recovery, area under the curve (AUC) 0.74 (95% CI, 0.61–0.87). Right panel demonstrates that GFAP-BDP are able to somewhat discriminate between subjects who have made a full versus a partial recovery, AUC 0.65 (95% CI, 0.55–0.74).