Exploring Severity of Traumatic Brain Injury with DI/LC-MS/MS

A recent study explored the potential of metabolomics in the diagnosis of severe traumatic brain injury (sTBI) and the examination of probable primary and secondary brain injury in sTBI. Serum samples from 59 adult patients with sTBI and 35 age- and sex-matched orthopedic injury controls were subjected to quantitative metabolomics, including proton nuclear magnetic resonance (¹H-NMR) and direct infusion/liquid chromatography-tandem mass spectrometry (DI/LC-MS/MS), to identify and quantify metabolites on days one and four post-injury. A paper based on this research was published in Critical Care (1).

A significant public health concern that affects millions of people globally, current estimates are that TBI causes one-third of global injury-related deaths and disability (2,3).

Despite sTBI accounting for only 10% of all TBI cases, it is still important because the global mortality rate associated with it is as high as 30–40% (4). TBI is an increasing silent epidemic necessitating heightened public awareness because of the frequency of brain injuries inflicted in road traffic accidents, falls in the elderly, and military operations (5). sTBI is associated with long periods of hospitalization, extensive complex care, extended rehabilitation, and a wide range of short- and long-term physical, cognitive, behavioral, and emotional disabilities (6).

The TBI pathophysiology of TBI is primarily divided into primary and secondary brain injury (7). Primary brain injury occurs because of an immediate insult to the brain due to traumatic forces such as hemorrhage, contusions, or diffuse axonal injury (DAI), while secondary brain injury occurs at any time after the primary injury as a result of many different pathological secondary mechanisms of injury, such as edema, hypoxia, cytotoxicity, and inflammation. (8). Timely and accurate diagnosis of sTBI is critical to begin the appropriate treatment and prevent further deterioration caused by secondary brain injury. This is an especially challenging task for clinicians due to the variability of brain injuries seen as well as the frequent presence of other associated serious injuries in patients requiring intensive care unit (ICU) care (9,1).

The resultsof the study showed different serum metabolic profiles between sTBI and orthopedic injury (OI) controls, with significant changes in measured metabolites on day 1 and day 4 post-brain injury. The number of altered metabolites and the extent of their change were more pronounced on day 4 as compared to day 1 post-injury, suggesting an evolution of mechanisms from primary to secondary brain injury. Data showed high sensitivity and specificity in separating sTBI from OI controls for diagnosis. Energy-related metabolites such as glucose, pyruvate, lactate, mannose, and polyamine metabolism metabolites (spermine and putrescine), as well as increased acylcarnitines and sphingomyelins, occurred mainly on day one post-injury. Metabolites of neurotransmission, catecholamine, and excitotoxicity mechanisms such as glutamate, phenylalanine, tyrosine, and branched-chain amino acids (BCAAs) increased to a greater degree on day four. Further, there was an association of multiple metabolites, including acylcarnitines (ACs), lysophosphatidylcholines (LysoPCs), glutamate, and phenylalanine, with injury severity at day 4, while lactate, glucose, and pyruvate correlated with injury severity on day 1 (1).

The researchers admit that their study has several limitations to consider, including a relatively small sample size, incomplete sample availability on days one and four post-injury, a male-skewed cohort, and a lack of ICU-based control groups to enhance the clinical applicability and interpretation of our findings, which may affect the generalizability of results. Importantly, in this study, the data on patients with brain injury alone are presented as well as data including those with brain injury plus other injuries (polytrauma) for comparison. This study showed the results are similar for these groups, but the numbers are small. Future research should consider examining metabolites beyond day 4 to better understand secondary brain injury dynamics, as changes in metabolites over time may offer more detailed information about brain injury (1).

3D illustration showing the nervous system, highlighting a brain injury with a glowing red area indicating pain or trauma. © WACHI - stock.adobe.com

References

1. Banoei, M. M.; Hutchison, J.; Panenka, W.; Wong, A.; Wishart, D. S.; Winston, B. W. ; Canadian Biobank and Database for Traumatic Brain Injury (CanTBI) study investigators; Canadian Critical Care Translational Biology Group (CCCTBG); Canadian Traumatic Brain Injury Research Consortium (CTRC). Metabolomic in Severe Traumatic Brain Injury: Exploring Primary, Secondary Injuries, Diagnosis, and Severity. Crit. Care 2025, 29 (1), 26. DOI: 10.1186/s13054-025-05258-1

2. Hyder, A. A.; Wunderlich, C. A.; Puvanachandra, P.; Gururaj, G.; Kobusingye, O. C. The Impact of Traumatic Brain Injuries: A Global Perspective. NeuroRehabilitation 2007, 22 (5), 341-353. DOI: 10.3233/NRE-2007-22502

3. Reis, C.; Wang, Y.; Akyol, O.; Ho, W. M.; Applegate, II, R.; Stier, G.; Martin, R.; Zhang, J. H.; What's New in Traumatic Brain Injury: Update on Tracking, Monitoring and Treatment. Int. J. Mol. Sci. 2015, 16 (6), 11903-11965. DOI: 10.1186/s13054-025-05258-1

4. Majdan, M.; Plancikova, D.; Brazinova, A.; Rusnak, M.; Nieboer, D.; Feigin, V, Maas A. Epidemiology of Traumatic Brain Injuries in Europe: A Cross-Sectional Analysis. Lancet Public Health 2016, 1 (2), e76-e83. DOI: 10.1016/S2468-2667(16)30017-2

5. Guingab-Cagmat JD, Cagmat EB, Hayes RL, Anagli J. Integration of proteomics, bioinformatics, and systems biology in traumatic brain injury biomarker discovery. Front Neurol. 2013 May 31;4:61. DOI: 10.3389/fneur.2013.00061

6. Green REA, Dabek MK, Changoor A, Rybkina J, Monette GA, Colella B. Moderate-Severe TBI as a Progressive Disorder: Patterns and Predictors of Cognitive Declines in the Chronic Stages of Injury. Neurorehabil. Neural Repair 2023, 37 (11-12), 799-809. DOI: 10.1177/15459683231212861

7. Pop, V.; Badaut, J. A Neurovascular Perspective for Long-Term Changes after Brain Trauma. Transl. Stroke Res. 2011, 2 (4), 533-545. DOI: 10.1007/s12975-011-0126-9

8. Thapa, K.; Khan, H.; Singh, T. G.; Kaur, A. Traumatic Brain Injury: Mechanistic Insight on Pathophysiology and Potential Therapeutic Targets. J. Mol Neurosci. 2021, 71 (9), 1725-1742. DOI: 10.1007/s12031-021-01841-7

9. Sandler, S. J.; Figaji, A. A.; Adelson, P. D. Clinical Applications of Biomarkers in Pediatric Traumatic Brain Injury. Child's Nervous System 2010, 26, 205-213. DOI: 10.1007/s00381-009-1009-1