Serum metabolomic markers for traumatic brain injury: a mouse model
- 579 Downloads
Traumatic brain injury (TBI) is physical injury to brain tissue that temporarily or permanently impairs brain function.
Evaluate the use of metabolomics for the development of biomarkers of TBI for the diagnosis and timing of injury onset.
A validated model of closed injury TBI was employed using 10 TBI mice and 8 sham operated controls. Quantitative LC–MS/MS metabolomic analysis was performed on the serum.
Thirty-six (24.0 %) of 150 metabolites were altered with TBI. Principal component analysis (PCA) and Partial least squares discriminant analysis (PLS-DA) analyses revealed clear segregation between TBI versus control sera. The combination of methionine sulfoxide and the lipid PC aa C34:4 accurately diagnosed TBI, AUC (95 % CI) 0.85 (0.644–1.0). A combination of metabolite markers were highly accurate in distinguishing early (4 h post TBI) from late (24 h) TBI: AUC (95 % CI) 1.0 (1.0–1.0). Spermidine, which is known to have an antioxidant effect and which is known to be metabolically disrupted in TBI, was the most discriminating biomarker based on the variable importance ranking in projection (VIP) plot. Several important metabolic pathways were found to be disrupted including: pathways for arginine, proline, glutathione, cysteine, and sphingolipid metabolism.
Using serum metabolomic analysis we were able to identify novel putative serum biomarkers of TBI. They were accurate for detecting and determining the timing of TBI. In addition, pathway analysis provided important insights into the biochemical mechanisms of brain injury. Potential clinical implications for diagnosis, timing, and monitoring brain injury are discussed.
KeywordsTraumatic brain injury Metabolomics Serum Biomarkers Mouse model
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Institutional Animal Care and Use Committee of the University of Colorado (IACUG), protocol number B-79612(01)1E.
- Altura, B. M., Gebrewold, A., Zheng, T., & Altura, B. T. (2002). Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: insight into mechanisms and possible relation to brain injury and stroke. Brain Research Bulletin, 58, 271–278.CrossRefPubMedGoogle Scholar
- Bahado-Singh, R. O., Graham, S. F., Beauchamp, K., Beauchamp, T. C., Han, B., Stahel, P. F., et al. (2016). Identification of candidate biomarkers of brain damage in a mouse model of closed head injury: a metabolomic pilot study. Metabolomics, 12, 1–13. doi: 10.1007/s11306-016-0957-1.CrossRefGoogle Scholar
- Faul, M., Xu, L., Wald M. M. (2006). Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006. Atlanta, GA: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control Google Scholar
- Graham, S. F., Chevallier, O. P., Roberts, D., Holscher, C., Elliott, C. T., & Green, B. D. (2013a). Investigation of the human brain metabolome to identify potential markers for early diagnosis and therapeutic targets of Alzheimer’s disease. Analytical Chemistry, 85, 1803–1811. doi: 10.1021/ac303163f.CrossRefPubMedGoogle Scholar
- Langlois, J. A., W. Rutland-Brown, K. E. Thomas (2004). Traumatic Brain Injury in the United States: Emergency Department visits, hospitalizations, and deaths. Atlanta, Ga: Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Injury Prevention and Control,Google Scholar
- Mondello, S., & Hayes, R. L. (2015). Biomarkers. In G. Jordan & M. S. Andres (Eds.), Handbook of clinical neurology (pp. 245–265). Amsterdam: Elsevier.Google Scholar
- Park, Y. M., Han, S. H., Seo, S. K., Park, K. A., Lee, W. T., & Lee, J. E. (2015). Restorative benefits of transplanting human mesenchymal stromal cells overexpressing arginine decarboxylase genes after spinal cord injury. Cytotherapy, 17, 25–37. doi: 10.1016/j.jcyt.2014.08.006.CrossRefPubMedGoogle Scholar
- Reed, T. T., Owen, J., Pierce, W. M., Sebastian, A., Sullivan, P. G., & Butterfield, D. A. (2009). Proteomic identification of nitrated brain proteins in traumatic brain-injured rats treated postinjury with gamma-glutamylcysteine ethyl ester: insights into the role of elevation of glutathione as a potential therapeutic strategy for traumatic brain injury. Journal of Neuroscience Research, 87, 408–417. doi: 10.1002/jnr.21872.CrossRefPubMedGoogle Scholar
- Zaloshnja, E., Miller, T., Langlois, J. A., & Selassie, A. W. (2008). Prevalence of long-term disability from traumatic brain injury in the civilian population of the United States, 2005. The Journal of head trauma rehabilitation, 23, 394–400. doi: 10.1097/01.HTR.0000341435.52004.ac.CrossRefPubMedGoogle Scholar