Association of Blood-Based Biomarkers and 6-Month Patient-Reported Outcomes in Patients With Mild TBI: A CENTER-TBI Analysis

Abstract

Background and objectives: There is seemingly contradictory evidence concerning relationships between day-of-injury biomarkers and outcomes after mild traumatic brain injury (mTBI). To address this issue, we examined the association between a panel of biomarkers and multidimensional TBI outcomes.

Methods: Participants with mTBI (Glasgow coma scores [GCSs] 13-15) were selected from Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury, a European observational study recruiting patients with TBI with indication for brain CT and presentation within 24 hours. Exclusion criteria for this secondary analysis were age younger than 16 years, incomplete biomarker panel, death, or no recorded outcomes. Participants were separated into 2 groups, CT-negative and CT-positive. Multivariable binary logistic regression was used to assess the relation between the log biomarker level (glial fibrillary acidic protein [GFAP], neurofilament light [NfL], neuron-specific enolase [NSE], S100 calcium-binding protein B [S100B], tau, ubiquitin C-terminal hydrolase L1 [UCH-L1]) and dichotomized 6-month outcomes (functional outcomes [GOSE score <8], health-related quality of life [HRQoL; Quality of Life after Brain Injury-Overall Scale (QOLIBRI-OS) score <52, Short-Form 12-Item Survey version 2 Mental Component Summary (SF12v2 MCS) score <40, Short-Form 12-Item Survey version 2 Physical Component Summary (SF12v2 PCS) score <40], persistent postconcussion symptoms [Rivermead Post-Concussion Symptoms Questionnaire score ≥16], anxiety disorder [Generalized Anxiety Disorder-7 (GAD-7) score ≥8], depression [Patient Health Questionnaire-9 (PHQ-9) score ≥10], and post-traumatic stress disorder [PTSD Checklist for DSM-5 (PCL-5) score ≥33]).

Results: A total of 1,589 participants (865 CT-negative, 724 CT-positive) were included (77% GCS 15, median age 52 years, 66% male). Higher biomarker levels were associated with a GOSE score <8: CT-negative: S100B (odds ratio [OR] 1.78, 95% CI 1.43-2.23) and UCH-L1 (OR 1.16, 95% CI 1.01-1.33); CT-positive: GFAP (OR 1.22, 95% CI 1.11-1.36), NfL (OR 1.30, 95% CI 1.11-1.52), S100B (OR 1.51, 95% CI 1.23-1.86), tau (OR 1.36, 95% CI 1.17-1.59), and UCH-L1 (OR 1.34, 95% CI 1.17-1.53). In CT-positive participants, positive association was seen between NfL (OR 1.3, 95% CI 1.06-1.60) and UCH-L1 (OR 1.28, 95% CI 1.07-1.54) with QOLIBRI-OS; S100B (OR 1.32, 95% CI 1.02-1.70) with SF12v2 PCS; and NSE (OR 1.52, 95% CI 1.06-2.18) and UCH-L1 (OR 1.21, 95% CI 1.01-1.46) with the GAD-7. However, in CT-negative participants only, negative associations were seen between GFAP and impairment on the QOLIBRI-OS (OR 0.76, 95% CI 0.66-0.88), SF12v2 MCS (OR 0.71, 95% CI 0.61-0.82), SF12v2 PCS (OR 0.79, 95% CI 0.68-0.91), GAD-7 (OR 0.80, 0.68-0.95), PHQ-9 (OR 0.80, 95% CI 0.68-0.93), and PCL-5 (OR 0.80, 95% CI 0.66-0.97).

Discussion: Participants with higher biomarker levels had greater odds of impaired functional recovery. However, in CT-negative participants, higher GFAP concentrations were associated with better HRQoL and less impaired mental health. Further exploration is required of the patient phenotypes that may explain the relationships observed in this analysis.

Figure 1. Flowchart of the Derived Sample

CENTER-TBI = Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury; GCS = Glasgow coma score.

Figure 2. Distribution of Biomarker Concentration Between Participants With CT-Negative and CT-Positive Mild TBI

Log10 of day-of-injury biomarker concentration in participants with mild TBI divided by presence of acute CT abnormality. Significance derived from the Wilcoxon test with adjustment for multiple comparisons with the Benjamini-Hochberg method. ***p ≤ 0.001, **p < 0.01, *p < 0.05 (Table 1 for details). GFAP = glial fibrillary acidic protein; NfL = neurofilament light; NSE = neuron-specific enolase; S100B = S100 calcium-binding protein B; TBI = traumatic brain injury; UCHL1 = ubiquitin C-terminal hydrolase L1.

Figure 3. PCA Loading Plot of Binary Outcome Variables in the (A) Participants With CT-Negative Mild TBI With a Complete Outcome Profile (n = 569) and (B) Participants With CT-Positive Mild TBI With a Complete Outcome Profile (n = 523)

GAD-7 = Generalized Anxiety Disorder-7; GOSE = Glasgow Outcome Scale Extended; PCL-5 = PTSD Checklist for DSM-5; PHQ-9 = Patient Health Questionnaire-9; QOLIBRI-OS = Quality of Life after Brain Injury-Overall Scale; RPQ = Rivermead Post-Concussion Symptoms Questionnaire; SF12v2 MCS = Short-Form 12-Item Survey version 2 Mental Component Summary; SF12v2 PCS = Short-Form 12-Item Survey version 2 Physical Component Summary; TBI = traumatic brain injury.

Figure 4. Adjusted Odds Ratios and 95% CIs of Log Biomarkers to Dichotomized Patient Outcomes in the (A) CT-Negative mTBI Cohort and (B) CT-Positive mTBI Cohort

Odds ratios adjusted using binary logistic regression for age, sex, extracranial injury, and time to biomarker sampling. ***p ≤ 0.001, **p < 0.01, *p < 0.05 (eTable 15 for details). Panel A showing the results for the C-negative participants and panel B showing the results for the CT-positive participants. GAD-7 = Generalized Anxiety Disorder-7; GFAP = glial fibrillary acidic protein; GOSE = Glasgow Outcome Scale Extended; mTBI = mild traumatic brain injury; NfL = neurofilament light; NSE = neuron-specific enolase; PCL-5 = PTSD Checklist for DSM-5; PHQ-9 = Patient Health Questionnaire-9; QOLIBRI-OS = Quality of Life after Brain Injury-Overall Scale; RPQ = Rivermead Post-Concussion Symptoms Questionnaire; S100B = S100 calcium-binding protein B; SF12v2 MCS = Short-Form 12-Item Survey version 2 Mental Component Summary; SF12v2 PCS = Short-Form 12-Item Survey version 2 Physical Component Summary; UCH-L1 = ubiquitin C-terminal hydrolase L1.