Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study

John K Yue; Firas H Kobeissy; Sonia Jain; Xiaoying Sun; Ryan R L Phelps; Frederick K Korley; Raquel C Gardner; Adam R Ferguson; J Russell Huie; Andrea L C Schneider; Zhihui Yang; Haiyan Xu; Cillian E Lynch; Hansen Deng; Miri Rabinowitz; Mary J Vassar; Sabrina R Taylor; Pratik Mukherjee; Esther L Yuh; Amy J Markowitz; Ava M Puccio; David O Okonkwo; Ramon Diaz-Arrastia; Geoffrey T Manley; Kevin K W Wang

doi:10.1089/neur.2022.0060

Neuroinflammatory Biomarkers for Traumatic Brain Injury Diagnosis and Prognosis: A TRACK-TBI Pilot Study

Neurotrauma Rep. 2023 Mar 24;4(1):171-183. doi: 10.1089/neur.2022.0060. eCollection 2023.

Authors

John K Yue^{1

2}, Firas H Kobeissy^{3

4

5}, Sonia Jain⁶, Xiaoying Sun⁶, Ryan R L Phelps^{1

2}, Frederick K Korley⁷, Raquel C Gardner⁸, Adam R Ferguson^{1

2}, J Russell Huie^{1

2}, Andrea L C Schneider^{9

10}, Zhihui Yang^{3

4}, Haiyan Xu^{3

4}, Cillian E Lynch⁹, Hansen Deng¹¹, Miri Rabinowitz¹¹, Mary J Vassar^{1

2}, Sabrina R Taylor^{1

2}, Pratik Mukherjee^{2

12}, Esther L Yuh^{2

12}, Amy J Markowitz^{1

2}, Ava M Puccio¹¹, David O Okonkwo¹¹, Ramon Diaz-Arrastia⁹, Geoffrey T Manley^{1

2}, Kevin K W Wang^{3

4

5}

Affiliations

¹ Department of Neurosurgery, University of California, San Francisco, San Francisco, California, USA.
² Brain and Spinal Injury Center, Zuckerberg San Francisco General Hospital, San Francisco, California, USA.
³ Departments of Emergency Medicine, Psychiatry, Neuroscience, and Chemistry, University of Florida, Gainesville, Florida, USA.
⁴ McKnight Brain Institute, University of Florida, Gainesville, Florida, USA.
⁵ Center for Neurotrauma, Multiomics and Biomarkers, Morehouse School of Medicine, Atlanta, Georgia, USA.
⁶ Division of Biostatistics and Bioinformatics, Departments of Family Medicine and Public Health, University of California, San Diego, San Diego, California, USA.
⁷ Department of Emergency Medicine, University of Michigan, Ann Arbor, Michigan, USA.
⁸ Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
⁹ Department of Neurology, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹⁰ Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
¹¹ Department of Neurosurgery, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
¹² Department of Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, California, USA.

Abstract

The relationship between systemic inflammation and secondary injury in traumatic brain injury (TBI) is complex. We investigated associations between inflammatory markers and clinical confirmation of TBI diagnosis and prognosis. The prospective TRACK-TBI Pilot (Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot) study enrolled TBI patients triaged to head computed tomography (CT) and received blood draw within 24 h of injury. Healthy controls (HCs) and orthopedic controls (OCs) were included. Thirty-one inflammatory markers were analyzed from plasma. Area under the receiver operating characteristic curve (AUC) was used to evaluate discriminatory ability. AUC >0.7 was considered acceptable. Criteria included: TBI diagnosis (vs. OC/HC); moderate/severe vs. mild TBI (Glasgow Coma Scale; GCS); radiographic TBI (CT positive vs. CT negative); 3- and 6-month Glasgow Outcome Scale-Extended (GOSE) dichotomized to death/greater relative disability versus less relative disability (GOSE 1-4/5-8); and incomplete versus full recovery (GOSE <8/ = 8). One-hundred sixty TBI subjects, 28 OCs, and 18 HCs were included. Markers discriminating TBI/OC: HMGB-1 (AUC = 0.835), IL-1b (0.795), IL-16 (0.784), IL-7 (0.742), and TARC (0.731). Markers discriminating GCS 3-12/13-15: IL-6 (AUC = 0.747), CRP (0.726), IL-15 (0.720), and SAA (0.716). Markers discriminating CT positive/CT negative: SAA (AUC = 0.767), IL-6 (0.757), CRP (0.733), and IL-15 (0.724). At 3 months, IL-15 (AUC = 0.738) and IL-2 (0.705) discriminated GOSE 5-8/1-4. At 6 months, IL-15 discriminated GOSE 1-4/5-8 (AUC = 0.704) and GOSE <8/ = 8 (0.711); SAA discriminated GOSE 1-4/5-8 (0.704). We identified a profile of acute circulating inflammatory proteins with potential relevance for TBI diagnosis, severity differentiation, and prognosis. IL-15 and serum amyloid A are priority markers with acceptable discrimination across multiple diagnostic and outcome categories. Validation in larger prospective cohorts is needed. ClinicalTrials.gov Registration: NCT01565551.

Keywords: acute phase reactant; alarmin; cytokine; neuroinflammation; prognosis; traumatic brain injury.

Associated data

ClinicalTrials.gov/NCT01565551