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Metabolomics

, 12:100 | Cite as

Serum metabolomic markers for traumatic brain injury: a mouse model

  • Ray O. Bahado-Singh
  • Stewart F. Graham
  • BeomSoo Han
  • Onur Turkoglu
  • James Ziadeh
  • Rupasri Mandal
  • Anil Er
  • David S. Wishart
  • Philip L. Stahel
Original Article

Abstract

Introduction

Traumatic brain injury (TBI) is physical injury to brain tissue that temporarily or permanently impairs brain function.

Objectives

Evaluate the use of metabolomics for the development of biomarkers of TBI for the diagnosis and timing of injury onset.

Methods

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.

Results

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.

Conclusion

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.

Keywords

Traumatic brain injury Metabolomics Serum Biomarkers Mouse model 

Notes

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This study was approved by the Institutional Animal Care and Use Committee of the University of Colorado (IACUG), protocol number B-79612(01)1E.

Supplementary material

11306_2016_1044_MOESM1_ESM.pdf (77 kb)
Supplementary Fig. 1. (a) 2D Principal Component analysis (PCA): TBI versus sham operated control mice (serum); (b) 3D Principal Component analysis (PCA): TBI versus sham operated control mice (serum)
11306_2016_1044_MOESM2_ESM.pdf (153 kb)
Supplementary Fig. 2 Partial Least Square Discriminant analysis (PLS-DA) – TBI versus sham operated control mice (serum); (b) Predicted result using cross-validation dataset
11306_2016_1044_MOESM3_ESM.pdf (18 kb)
Supplementary Fig. 3 ROC curve for distinguishing early from late TBI (diagnosis of timing of TBI): serum data. AUC: 1.0 (CI: 1.0–1.0), six metabolites were used in the PLS-DA model to include: methionine sulfoxide, C3, SM C18:0, SM C18:1, methionine and proline
11306_2016_1044_MOESM4_ESM.pdf (180 kb)
Supplementary Table 1 Metabolite concentrations changes over time in serum

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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ray O. Bahado-Singh
    • 1
  • Stewart F. Graham
    • 2
  • BeomSoo Han
    • 3
  • Onur Turkoglu
    • 2
  • James Ziadeh
    • 4
  • Rupasri Mandal
    • 3
  • Anil Er
    • 5
  • David S. Wishart
    • 3
  • Philip L. Stahel
    • 6
    • 7
  1. 1.Department of Obstetrics and GynecologyOakland University William Beaumont School of MedicineRoyal OakUSA
  2. 2.Department of Obstetrics and GynecologyBeaumont HealthRoyal OakUSA
  3. 3.Department of Biological and Computing SciencesUniversity of AlbertaEdmontonCanada
  4. 4.Department of Emergency MedicineOakland University William Beaumont School of MedicineRoyal OakUSA
  5. 5.Department of Pediatric Emergency Medicine, School of MedicineDokuz Eylul UniversityBalcovaTurkey
  6. 6.Department of Neurosurgery, Denver Health Medical Center, School of MedicineUniversity of ColoradoDenverUSA
  7. 7.Department of Orthopedics, Denver Health Medical Center School of MedicineUniversity of ColoradoDenverUSA

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