Abstract
Background
Traumatic brain injury (TBI) is a major public health concern worldwide, contributing to high rates of injury-related death and disability. Severe traumatic brain injury (sTBI), although it accounts for only 10% of all TBI cases, results in a mortality rate of 30–40% and a significant burden of disability in those that survive. This study explored the potential of metabolomics in the diagnosis of sTBI and explored the potential of metabolomics to examine probable primary and secondary brain injury in sTBI.
Methods
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 1 and 4 post-injury. In addition, we used advanced analytical methods to discover metabo-patterns associated with sTBI diagnosis and those related to probable primary and secondary brain injury.
Results
Our results 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 1 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 4. 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.
Conclusion
The results demonstrate that serum metabolomics has diagnostic potential for sTBI and may reflect molecular mechanisms of primary and secondary brain injuries when comparing metabolite profiles between day 1 and day 4 post-injury. These early changes in serum metabolites may provide insight into molecular pathways or mechanisms of primary injury and ongoing secondary injuries, revealing potential therapeutic targets for sTBI. This work also highlights the need for further research and validation of sTBI metabolite biomarkers in a larger cohort.
Key Points
- Significance of sTBI: Severe traumatic brain injury accounts for only 10% of all TBIs but results in high mortality (30–40%) and significant disability, necessitating advanced diagnostic tools to manage and predict outcomes effectively.
- Primary and Secondary Injuries: Primary brain injury results from immediate trauma, while secondary injuries evolve over time due to mechanisms such as inflammation, oxidative stress, and excitotoxicity, highlighting the need for dynamic diagnostic markers.
- Metabolomic Analysis: Advanced techniques, including 1H-NMR and DI/LC-MS/MS, identified 188 metabolites with distinct changes on days 1 and 4 post-injury, reflecting biochemical disruptions linked to energy metabolism, neurotransmitter activity, and lipid pathways.
- Metabolic Profiles: On day 1, energy-related metabolites like glucose, lactate, and pyruvate were elevated, while day 4 showed increases in neurotransmitter metabolites such as glutamate and phenylalanine, indicating a shift from primary to secondary injury mechanisms.
- Diagnostic Potential: Metabolomic profiling demonstrated high sensitivity and specificity in distinguishing sTBI from orthopedic injury (OI) controls, with predictive models achieving >99% accuracy on day 4.
- Injury Severity Correlation: Metabolite changes were significantly associated with Glasgow Coma Scale (GCS) scores, offering potential biomarkers for assessing injury severity and guiding clinical decision-making.
- Polytrauma Insights: Metabolomic profiles of patients with isolated brain injuries were similar to those with polytrauma, suggesting that identified metabolic changes are predominantly driven by brain injury.
- Pathophysiological Insights: Increased acylcarnitines and lysophosphatidylcholines (LysoPCs) on day 4 suggest mitochondrial dysfunction and neural cell degradation, implicating these pathways in secondary brain injury.
- Biomarker Applications: The study underscores the potential of combining metabolomics with existing biomarkers, such as GFAP and UCH-L1, to enhance diagnostic accuracy and develop personalized therapeutic strategies for sTBI.
- Future Research Needs: Larger studies integrating metabolomics with neuroimaging and clinical data are needed to validate findings, refine biomarker utility, and explore novel therapeutic targets for improving sTBI outcomes.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.
