Chronic immunosuppression across 12 months and high ability of acute and subacute CNS-injury biomarker concentrations to identify individuals with complicated mTBI on acute CT and MRI

Abstract

Background: Identifying individuals with intracranial injuries following mild traumatic brain injury (mTBI), i.e. complicated mTBI cases, is important for follow-up and prognostication. The main aims of our study were (1) to assess the temporal evolution of blood biomarkers of CNS injury and inflammation in individuals with complicated mTBI determined on computer tomography (CT) and magnetic resonance imaging (MRI); (2) to assess the corresponding discriminability of both single- and multi-biomarker panels, from acute to chronic phases after injury.

Methods: Patients with mTBI (n = 207), defined as Glasgow Coma Scale score between 13 and 15, loss of consciousness < 30 min and post-traumatic amnesia < 24 h, were included. Complicated mTBI - i.e., presence of any traumatic intracranial injury on neuroimaging - was present in 8% (n = 16) on CT (CT+) and 12% (n = 25) on MRI (MRI+). Blood biomarkers were sampled at four timepoints following injury: admission (within 72 h), 2 weeks (± 3 days), 3 months (± 2 weeks) and 12 months (± 1 month). CNS biomarkers included were glial fibrillary acidic protein (GFAP), neurofilament light (NFL) and tau, along with 12 inflammation markers.

Results: The most discriminative single biomarkers of traumatic intracranial injury were GFAP at admission (CT+: AUC = 0.78; MRI+: AUC = 0.82), and NFL at 2 weeks (CT+: AUC = 0.81; MRI+: AUC = 0.89) and 3 months (MRI+: AUC = 0.86). MIP-1β and IP-10 concentrations were significantly lower across follow-up period in individuals who were CT+ and MRI+. Eotaxin and IL-9 were significantly lower in individuals who were MRI+ only. FGF-basic concentrations increased over time in MRI- individuals and were significantly higher than MRI+ individuals at 3 and 12 months. Multi-biomarker panels improved discriminability over single biomarkers at all timepoints (AUCs > 0.85 for admission and 2-week models classifying CT+ and AUC ≈ 0.90 for admission, 2-week and 3-month models classifying MRI+).

Conclusions: The CNS biomarkers GFAP and NFL were useful single diagnostic biomarkers of complicated mTBI, especially in acute and subacute phases after mTBI. Several inflammation markers were suppressed in patients with complicated versus uncomplicated mTBI and remained so even after 12 months. Multi-biomarker panels improved diagnostic accuracy at all timepoints, though at acute and 2-week timepoints, the single biomarkers GFAP and NFL, respectively, displayed similar accuracy compared to multi-biomarker panels.

Keywords: Concussion; Cytokines; Growth factors; Mixed-mechanism mild TBI; Neuroimaging; Prediction; Predictive modeling.

Fig. 1

Flow chart depicting enrolment and follow-up of patients with mTBI from admission to 12 months. mTBI, mild traumatic brain injury

Fig. 2

Biomarker concentrations over time in CT + and CT- patients with mTBI. Biomarker concentrations are presented as box plots with median as the midline, box borders representing the 25th and 75th percentile and whiskers calculated as the 25th and 75th percentile + 1.5 * interquartile range. Points above and below the whiskers represent outliers. Individual data points are presented within the boxplots. ** = p < 0.01; *** = p < 0.001. GFAP = Glial Fibrillary Acidic Protein; NFL = Neurofilament Light; Tau; IFNγ = Interferon Gamma; IL-8 = Interleukin-8; Eotaxin; MIP-1β = Macrophage Inflammatory Protein-1β; MCP-1 = Monocyte Chemoattractant Protein-1; IP-10 = IFNγ-induced Protein-10; IL-17A = Interleukin-17A; IL-9 = Interleukin-9; TNF = Tumor Necrotic Factor; FGF-basic = Basic Fibroblast Growth Factor; PDGF = Platelet-derived Growth Factor IL-1ra = Interleukin-1ra

Fig. 3

Biomarker concentrations over time in MRI + and MRI- patients with mTBI. Biomarker concentrations are presented as box plots with median as the midline, box borders representing the 25th and 75th percentile and whiskers calculated as the 25th and 75th percentile + 1.5 * interquartile range. Points above and below the whiskers represent outliers. Individual data points are presented within the boxplots. ** = p < 0.01; *** = p < 0.001. GFAP = Glial Fibrillary Acidic Protein; NFL = Neurofilament Light; Tau; IFNγ = Interferon Gamma; IL-8 = Interleukin-8; Eotaxin; MIP-1β = Macrophage Inflammatory Protein-1β; MCP-1 = Monocyte Chemoattractant Protein-1; IP-10 = IFNγ-induced Protein-10; IL-17A = Interleukin-17A; IL-9 = Interleukin-9; TNF = Tumor Necrotic Factor; FGF-basic = Basic Fibroblast Growth Factor; PDGF = Platelet-derived Growth Factor IL-1ra = Interleukin-1ra

Fig. 4

ROC curves indicating diagnostic accuracy for the algorithmically selected biomarker combinations discriminating CT + and MRI + patients. ROC curves are based on the optimal combination of biomarkers for predicting CT + and MRI + patients at each timepoint. AUC values for each timepoint are indicated in the plot. Biomarkers included for findings on CT: Admission: GFAp, NFL, MIP-1β, IP-10, eotaxin, IL-ra; 2 weeks: GFAp, NFL, MIP-1β, IP-10, eotaxin, IL-ra 3 months: NFL, MIP-1β, IP-10. 12 months: MIP-1β, IP-10. Biomarkers included for findings on MRI: Admission: GFAp, NFL, MIP-1β, IP-10, eotaxin; 2 weeks: GFAp, NFL, MIP-1β, IP-10, eotaxin 3 months: NFL, MIP-1β, IP-10. 12 months: MIP-1β, IL-9. ROC, Receiver Operating Characteristic; AUC, Area Under the Curve; GFAP = Glial fibrillary acidic protein; NFL = Neurofilament light; IFNγ = Interferon Gamma; IL = Interleukin; MIP = Macrophage Inflammatory Protein; MCP = Monocyte Chemoattractant Protein; IP = IFNγ-induced Protein; TNF = Tumor Necrotic Factor; FGF-basic = Basic Fibroblast Growth Factor; PDGF = Platelet-derived Growth Factor