Circulating Brain-Derived Neurotrophic Factor Has Diagnostic and Prognostic Value in Traumatic Brain Injury

Abstract

Brain-derived neurotrophic factor (BDNF) is important for neuronal survival and regeneration. We investigated the diagnostic and prognostic values of serum BDNF in traumatic brain injury (TBI). We examined serum BDNF in two independent cohorts of TBI cases presenting to the emergency departments (EDs) of the Johns Hopkins Hospital (JHH; n = 76) and San Francisco General Hospital (SFGH, n = 80), and a control group of JHH ED patients without TBI (n = 150). Findings were subsequently validated in the prospective, multi-center Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study (n = 159). We investigated the association between BDNF, glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) and recovery from TBI at 6 months in the TRACK-TBI Pilot cohort. Incomplete recovery was defined as having either post-concussive syndrome or a Glasgow Outcome Scale Extended score <8 at 6 months. Median day-of-injury BDNF concentrations (ng/mL) were lower among TBI cases (JHH TBI, 17.5 and SFGH TBI, 13.8) than in JHH controls (60.3; p = 0.0001). Among TRACK-TBI Pilot subjects, median BDNF concentrations (ng/mL) were higher in mild (8.3) than in moderate (4.3) or severe TBI (4.0; p = 0.004. In the TRACK-TBI cohort, the 75 (71.4%) subjects with very low BDNF values (i.e., <the 1st percentile for non-TBI controls, <14.2 ng/mL) had higher odds of incomplete recovery than those who did not have very low values (odds ratio, 4.0; 95% confidence interval [CI]: 1.5-11.0). The area under the receiver operator curve for discriminating complete and incomplete recovery was 0.65 (95% CI: 0.52-0.78) for BDNF, 0.61 (95% CI: 0.49-0.73) for GFAP, and 0.55 (95% CI: 0.43-0.66) for UCH-L1. The addition of GFAP/UCH-L1 to BDNF did not improve outcome prediction significantly. Day-of-injury serum BDNF is associated with TBI diagnosis and also provides 6-month prognostic information regarding recovery from TBI. Thus, day-of-injury BDNF values may aid in TBI risk stratification.

Keywords: biomarkers; brain-derived neurotrophic factor; glial fibrillary acidic protein; traumatic brain injury; ubiquitin C-terminal hydrolase-L1.

Figures

FIG. 1.

Distribution of brain-derived neurotrophic factor (BDNF) in traumatic brain injury (TBI) and non-TBI cohorts. Graphical distribution of individual BDNF values and the corresponding box plots for Johns Hopkins Hospital (JHH) non-TBI control subjects, JHH TBI cases, San Francisco General Hospital (SFGH) TBI cases and Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot cases.

FIG. 2.

Receiver operator curve for distinguishing between traumatic brain injury (TBI) cases and controls with brain-derived neurotrophic factor (BDNF). The receiver operator curve for discriminating between Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot cases and Johns Hopkins Hospital (JHH) controls using BDNF values. The table reports the diagnostic accuracy of using a cut-off value of 14.2 ng/mL for distinguishing between TBI cases and controls.

FIG. 3.

Association between biomarkers examined and traumatic brain injury (TBI) severity. Presented are the graphical distribution of individual brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) values in Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot and the corresponding boxplots according to TBI severity, classified as mild, moderate, or severe; and the presence or absence of traumatic intracranial abnormality on head computed tomography (CT) scan: (A) depicts BDNF versus TBI severity classified as mild moderate or severe; (B) depicts BDNF versus TBI severity classified by CT scan; (C) depicts GFAP versus TBI severity classified as mild, moderate, or severe; (D) depicts GFAP versus TBI severity classified by head CT scan; (E) depicts UCH-L1 versus TBI severity classified as mild, moderate or severe; (F) depicts UCH-L1 versus TBI severity classified by head CT scan. Individual values that were extreme outliers are excluded from the graphical presentation.

FIG. 4.

Association between brain-derived neurotrophic factor (BDNF) and time from injury to blood sampling. This is a scatter plot of the association between day-of-injury BDNF values and time between injury and blood draw (in hours). The line represents the best fitting linear regression line that summarizes this association.

FIG. 5.

Association between brain-derived neurotrophic factor (BDNF) and age. This is a scatter plot of the association between day-of-injury BDNF values and age (in years). The line represents the best fitting linear regression line that summarizes this association.