Predicting recovery in patients with mild traumatic brain injury and a normal CT using serum biomarkers and diffusion tensor imaging (CENTER-TBI): an observational cohort study

Sophie Richter; Stefan Winzeck; Marta M Correia; Endre Czeiter; Daniel Whitehouse; Evgenios N Kornaropoulos; Guy B Williams; Jan Verheyden; Tilak Das; Olli Tenovuo; Jussi P Posti; Anne Vik; Kent Gøran Moen; Asta K Håberg; Kevin Wang; Andras Buki; Andrew Maas; Ewout Steyerberg; David K Menon; Virginia F J Newcombe; Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Magnetic Resonance Imaging (CENTER-TBI MRI) Substudy Participants and Investigators

doi:10.1016/j.eclinm.2024.102751

Predicting recovery in patients with mild traumatic brain injury and a normal CT using serum biomarkers and diffusion tensor imaging (CENTER-TBI): an observational cohort study

EClinicalMedicine. 2024 Aug 8:75:102751. doi: 10.1016/j.eclinm.2024.102751. eCollection 2024 Sep.

Authors

Sophie Richter¹, Stefan Winzeck¹, Marta M Correia², Endre Czeiter^{3

4

5}, Daniel Whitehouse¹, Evgenios N Kornaropoulos¹, Guy B Williams⁶, Jan Verheyden⁷, Tilak Das⁸, Olli Tenovuo⁹, Jussi P Posti^{9

10}, Anne Vik^{11

12}, Kent Gøran Moen^{12

13

14

15}, Asta K Håberg^{11

16}, Kevin Wang¹⁷, Andras Buki¹⁸, Andrew Maas^{19

20}, Ewout Steyerberg²¹, David K Menon¹, Virginia F J Newcombe¹; Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Magnetic Resonance Imaging (CENTER-TBI MRI) Substudy Participants and Investigators

Collaborators

Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury Magnetic Resonance Imaging (CENTER-TBI MRI) Substudy Participants and Investigators:
Krisztina Amrein, Nada Andelic, Lasse Andreassen, Audny Anke, Philippe Azouvi, Bo-Michael Bellander, Habib Benali, Andras Buki, Alessio Caccioppola, Emiliana Calappi, Marco Carbonara, Giuseppe Citerio, Hans Clusmann, Mark Coburn, Jonathan Coles, Marta Correia, Endre Czeiter, Véronique De Keyser, Vincent Degos, Bart Depreitere, Live Eikenes, Erzsébet Ezer, Kelly Foks, Shirin Frisvold, Damien Galanaud, Alexandre Ghuysen, Ben Glocker, Asta Haberg, Iain Haitsma, Eirik Helseth, Peter J Hutchinson, Evgenios Kornaropoulos, Noémi Kovács, Ana Kowark, Steven Laureys, Didier Ledoux, Hester Lingsma, Andrew Ir Maas, Geoffrey Manley, David K Menon, Tomas Menovsky, Benoit Misset, Visakh Muraleedharan, Ingeborg Nakken, Virginia Newcombe, Wibeke Nordhøy, József Nyirádi, Fabrizio Ortolano, Paul M Parizel, Vincent Perlbarg, Paolo Persona, Wilco Peul, Jussi P Posti, Louis Puybasset, Sophie Richter, Cecilie Roe, Olav Roise, Rolf Rossaint, Sandra Rossi, Daniel Rueckert, Ranjit D Singh, Toril Skandsen, Abayomi Sorinola, Emmanuel Stamatakis, Ewout W Steyerberg, Nino Stocchetti, Riikka Takala, Viktória Tamás, Olli Tenovuo, Zoltán Vámos, Gregory Van der Steen, Inge A van Erp, Wim Van Hecke, Thijs Vande Vyvere, Jan Verheyden, Anne Vik, Victor Volovici, Lars T Westlye, Daniel Whitehouse, Guy Williams, Stefan Winzeck, Peter Ylén, Tommaso Zoerle

Affiliations

¹ Department of Medicine, University of Cambridge, Cambridge, UK.
² MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
³ Neurotrauma Research Group, Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
⁴ Department of Neurosurgery, Medical School, University of Pécs, Pécs, Hungary.
⁵ HUN-REN-PTE Clinical Neuroscience MR Research Group, University of Pécs, Pécs, Hungary.
⁶ Wolfson Brain Imaging Centre, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
⁷ Research and Development, icometrix, Leuven, Belgium.
⁸ Department of Radiology, Addenbrooke's Hospital, Cambridge, UK.
⁹ Turku Brain Injury Center, Turku University Hospital & University of Turku, Turku, Finland.
¹⁰ Department of Neurourgery, Turku University Hospital & University of Turku, Turku, Finland.
¹¹ Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
¹² Department of Neurosurgery, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹³ Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway.
¹⁴ Department of Radiology and Nuclear Medicine, St.Olavs Hospital, Trondheim University Hospital, N-7006, Trondheim, Norway.
¹⁵ Department of Radiology, Vestre Viken Hospital Trust, Drammen Hospital, Drammen, Norway.
¹⁶ Center for Medical Equipment, Technology and Innovation, St. Olavs Hospital, Trondheim University Hospital, Trondheim, Norway.
¹⁷ Center for Neurotauma, MultiOmic & Biomarkers, Department of Neurobiology, Neuroscience Institute, Morehouse School of Medicine, Atlanta, USA.
¹⁸ Örebro University, School of Medical Sciences, Örebro, Sweden.
¹⁹ Department of Neurosurgery, Antwerp University Hospital, Edegem, Belgium.
²⁰ Department of Translational Neurosciences, Faculty of Medicine and Health Science, University of Antwerp, Edegem, Belgium.
²¹ Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, the Netherlands.

Abstract

Background: Even patients with normal computed tomography (CT) head imaging may experience persistent symptoms for months to years after mild traumatic brain injury (mTBI). There is currently no good way to predict recovery and triage patients who may benefit from early follow-up and targeted intervention. We aimed to assess if existing prognostic models can be improved by serum biomarkers or diffusion tensor imaging metrics (DTI) from MRI, and if serum biomarkers can identify patients for DTI.

Methods: We included 1025 patients aged >18 years with a Glasgow Coma Score >12 and normal CT from the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study which recruited between December 19,2014 and December 17, 2017 (NCT02210221). Biomarkers (GFAP, NFL, S100B) were obtained at a median of 8.8 h (Q1-Q3 4.2-16.7) and DTI at 13 days (3-19) after injury. DTI metrics were available in 153 patients for 48 white matter tracts (ICBM-DTI-81 atlas). Incomplete recovery at three months was defined as an extended Glasgow Outcome Scale score <8. Existing prognostic models were fitted with and without biomarkers, or with and without DTI, and internally validated using bootstrapping.

Findings: 385 (38%) patients had incomplete recovery. Adding biomarkers did not improve performance beyond the best existing clinical prognostic model [optimism-corrected AUC 0.69 (95% CI 0.65-0.72) and R² 17% (11-22)]. Adding DTI metrics significantly enhanced all models [best optimism-corrected AUC 0.82 (0.79-0.85) and R² 75% (39-100)]. The top three prognostic tracts were the left posterior thalamic radiation, left superior cerebellar peduncle and right uncinate fasciculus. Serum biomarkers could have avoided 1 in 5 DTI scans, with GFAP <12 h and NFL 12-24 h from injury performing best.

Interpretation: DTI substantially improved existing prognostic models for functional outcome in patients with mTBI and a normal CT, and biomarkers could help select patients for MRI. If validated, DTI could allow for targeted follow-up and enrichment of clinical trials of early interventions to improve outcome.

Funding: EU Seventh Framework Programme, Hannelore Kohl Stiftung, One Mind, Integra LifeSciences, NeuroTrauma Sciences.

Keywords: Biomarkers; Concussion; Imaging; Outcome; Prognostication; Traumatic brain injury.