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Mild TBI Results in a Long-Term Decrease in Circulating Phospholipids in a Mouse Model of Injury

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An Author Correction to this article was published on 20 February 2020

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Abstract

Neurophysiological and neurological dysfunction is usually experienced for a short period of time in patients with mild traumatic brain injury (mTBI). However, around 15 % of patients exhibit symptoms months after TBI. Phospholipid (PL) changes have been observed in plasma from mTBI patients at chronic stages, suggesting a role in TBI pathology. We examined long-term plasma phospholipid profiles in a mouse model of mTBI to determine their translational value in reproducing PL changes observed in mTBI patients. Plasma samples were collected at an acute timepoint (24 h post-injury) and at several chronic stages (3, 6, 12 and 24 months post-injury) from injured mice and sham controls. Phospholipids were identified and quantified using liquid chromatography/mass spectrometry analysis. In accordance with human data, we observed significantly lower levels of several major PL classes in mTBI mice compared to controls at chronic timepoints. Saturated, monounsaturated and polyunsaturated fatty acids (PUFAs) were differently regulated over time. As PUFA levels were decreased at 3 months, we measured levels of malondialdehyde to assess lipid peroxidation, which we found to be elevated at this timepoint. Ether-containing PE species were elevated at 24 h post-injury and decreased relative to controls at chronic stages. Arachidonic acid and docosahexaenoic acid-containing species were significantly decreased within all PL classes at the chronic stages. Our findings are similar to changes in PL levels observed in human mTBI subjects. Chronic TBI biomarkers have received little attention, even though disabilities at this stage can be of major importance. Our study provides information on biochemical abnormalities that persist long after the initial injury; these abnormalities may provide useful insight into the continuing pathogenesis and serve as diagnostic biomarkers.

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Change history

  • 20 February 2020

    The original version of this article unfortunately contained a mistake. Gary S. Laco should not be listed as an author in the author group.

References

  • Abdullah, L. (2014). Lipidomic analyses identify injury-specific phospholipid changes 3 mo after traumatic brain injury. FASEB Journal, 28(12), 5311–5321. Available at http://www.fasebj.org/cgi/doi/10.1096/fj.14-258228.

  • Abdullah, L., et al. (2012). Lipidomic profiling of phosphocholine-containing brain lipids in mice with sensorimotor deficits and anxiety-like features after exposure to Gulf War agents. Neuromolecular Medicine, 14(4), 349–61. Available at http://www.ncbi.nlm.nih.gov/pubmed/22798222.

  • Abdullah, L., et al. (2014). Lipidomic analyses identify injury-specific phospholipid changes 3 mo after traumatic brain injury. FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology, 28(12), 5311–5321.

    Article  CAS  Google Scholar 

  • Bazinet, R. P., & Layé, S. (2014). Polyunsaturated fatty acids and their metabolites in brain function and disease. Nature Reviews. Neuroscience, 15(12), 771–785. Available at http://dx.doi.org/10.1038/nrn3820.

  • Begum, H., et al. (2016). Discovering and validating between-subject variations in plasma lipids in healthy subjects. Scientific Reports, 6, 19139. doi:10.1038/srep19139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Braverman, N. E., & Moser, A. B. (2012). Functions of plasmalogen lipids in health and disease. Biochimica et Biophysica Acta, 1822(9), 1442–1452. Available at http://www.sciencedirect.com/science/article/pii/S0925443912001160 Accessed 11 Dec 2015.

  • Brenner, L. A. (2011). Neuropsychological and neuroimaging findings in traumatic brain injury and post-traumatic stress disorder. Dialogues in Clinical Neuroscience, 13(3), 311–323.

    PubMed  PubMed Central  Google Scholar 

  • Chaurio, R. A., et al. (2009). Phospholipids: Key players in apoptosis and immune regulation. Molecules, 14(12), 4892–4914.

    Article  CAS  PubMed  Google Scholar 

  • Coronado, V., et al. (2009). Neurotrauma and critical care of the brain. In J. Jallo & C. M. Loftus (Eds.), Epidemiology. New York: Thieme.

    Google Scholar 

  • Crawford, F. et al. (2012). Identification of plasma biomarkers of TBI outcome using proteomic approaches in an APOE mouse model. Journal of Neurotrauma, 29(2), 246–260. Available at http://online.liebertpub.com/doi/abs/10.1089/neu.2011.1789.

  • Dalleau, S. et al. (2013). Cell death and diseases related to oxidative stress: 4-hydroxynonenal (HNE) in the balance. Cell Death and Differentiation, 20(12), pp.1615–30. Available at http://dx.doi.org/10.1038/cdd.2013.138. Accessed 12 Jan 2016.

  • Department of Defense. (2014). http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi.

  • Emmerich, T. et al. (2015). Plasma lipidomic profiling in a military population of mTBI and PTSD with APOE ε4 dependent effect. Journal of Neurotrauma. Available at http://www.ncbi.nlm.nih.gov/pubmed/26714394. Accessed 12 Jan 2016.

  • Faul, M., Xu, L., Wald, M. M., & Coronado, V. (2010). Traumatic brain injury in the United States: Emergency department visits, hospitalizations, and deaths. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control, 891–904. Available at http://www.ncbi.nlm.nih.gov/pubmed/23630120.

  • Fischer, H. (2015). A guide to U.S. military casualty statistics: Operation Freedom’s Sentinel, Operation Inherent Resolve, Operation New Dawn, Operation Iraqi Freedom, and Operation Enduring Freedom. DoD Numbers for Traumatic Brain Injury, 1–5. http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi. Available at http://dvbic.dcoe.mil/dod-worldwide-numbers-tbi.

  • Folch, J., Lees, M., & Sloane Stanley, G. H. (1957). A simple method for the isolation and purification of total lipides from animal tissues. The Journal of biological chemistry, 226(1), 497–509.

    CAS  PubMed  Google Scholar 

  • Fredman, G., & Serhan, C. N. (2011). Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. Biochemical Journal, 437(Pt 2), 185–197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Frisardi, V., et al. (2011). Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer’s disease pathology. Progress in Lipid Research, 50(4), 313–330.

    Article  CAS  PubMed  Google Scholar 

  • Hamilton, J. A., et al. (2007). Brain uptake and utilization of fatty acids, lipids and lipoproteins: application to neurological disorders. Journal of Molecular Neuroscience: MN, 33(1), 2–11.

    Article  CAS  PubMed  Google Scholar 

  • Jackson Laboratories. (2007). Physiological data summary—C57BL/6 J (000664), (000664). Available at https://www.jax.org/strain/000664.

  • Kay, A. D., et al. (2003). Remodeling of cerebrospinal fluid lipoprotein particles after human traumatic brain injury. Journal of Neurotrauma, 20(8), 717–723.

    Article  PubMed  Google Scholar 

  • Kay, T., Harrington, D. E., Adams, R., Anderson, T., & Berrol, S. (1993). Definition of mild traumatic brain injury. Journal of Head Trauma Rehabilitation, 8, 86–88.

    Article  Google Scholar 

  • Kim, S. et al. (2014). Aging-related changes in mouse serum glycerophospholipid profiles. Osong public health and research perspectives, 5(6), 345–50. Available at http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4281626&tool=pmcentrez&rendertype=abstract. Accessed 19 Jan 2016.

  • Kosicek, M., & Hecimovic, S. (2013). Phospholipids and Alzheimer’s disease: Alterations, mechanisms and potential biomarkers. International Journal of Molecular Sciences, 14(1), 1310–1322.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kövesdi, E., et al. (2010). Update on protein biomarkers in traumatic brain injury with emphasis on clinical use in adults and pediatrics. Acta Neurochirurgica, 152(1), 1–17.

    Article  PubMed  Google Scholar 

  • Lovell, M. R. et al. (2003). Recovery from mild concussion in high school athletes. J Neurosurgery Pediatrics, 98(2), 296–301. Available at http://www.ncbi.nlm.nih.gov/pubmed/12593614.

  • McCrea, M. et al. (2013). Incidence, clinical course, and predictors of prolonged recovery time following sport-related concussion in high school and college athletes. Journal of the International Neuropsychological Society: INS, 19(1), 22–33. Available at http://www.ncbi.nlm.nih.gov/pubmed/23058235. Accessed 14 April 2016.

  • Mondello, S., et al. (2011). Blood-based diagnostics of traumatic brain injuries. Expert Review of Molecular Diagnostics, 11(1), 65–78.

    Article  PubMed  PubMed Central  Google Scholar 

  • Mouzon, B. et al. (2012). Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes. Journal of Neurotrauma, 29(18), 2761–2773. Available at http://online.liebertpub.com/doi/abs/10.1089/neu.2012.2498.

  • Mouzon, B. C. et al. (2014). Chronic neuropathological and neurobehavioral changes in a repetitive mild traumatic brain injury model. Annals of Neurology, 75(2), 241–254. Available at http://doi.wiley.com/10.1002/ana.24064.

  • Norman, A., et al. (2011). Competitive dopamine receptor antagonists increase the equiactive cocaine concentration during self-administration. Synapse (New York, N. Y.), 65(5), 404–411.

    Article  CAS  Google Scholar 

  • Ovsepian, L. M. et al. (2012). Age-dependent changes in phospholipid content and neutral lipid contents in aging. Advances in Gerontoloy, 25(2), 250–254. Available at http://www.ncbi.nlm.nih.gov/pubmed/23130515.

  • Papa, L., et al. (2012). Elevated levels of serum glial fibrillary acidic protein breakdown products in mild and moderate traumatic brain injury are associated with intracranial lesions and neurosurgical intervention. Annals of Emergency Medicine, 59(6), 471–483.

    Article  PubMed  Google Scholar 

  • Papa, L., et al. (2016). Time course and diagnostic accuracy of glial and neuronal blood biomarkers GFAP and UCH-L1 in a large cohort of trauma patients with and without mild traumatic brain injury. JAMA Neurology, 73(5), 551–560.

  • Pasvogel, A. E., Miketova, P., & Moore, I. M. (2010). Differences in CSF phospholipid concentration by traumatic brain injury outcome. Biological Research for Nursing, 11(4), 325–331.

    Article  CAS  PubMed  Google Scholar 

  • Polozova, A., & Salem, N. (2007). Role of liver and plasma lipoproteins in selective transport of n-3 fatty acids to tissues: a comparative study of 14C-DHA and 3H-oleic acid tracers. Journal of Molecular Neuroscience: MN, 33(1), 56–66.

    Article  CAS  PubMed  Google Scholar 

  • Purdon, A. D. et al. (2002). Energy consumption by phospholipid metabolism in mammalian brain. Neurochemical Research, 27(12), 1641–7. Available at http://www.ncbi.nlm.nih.gov/pubmed/12515317. Accessed 4 April 2016.

  • Raabe, A., et al. (1998). Jugular venous and arterial concentrations of serum S-100B protein in patients with severe head injury: A pilot study. Journal of Neurology, Neurosurgery and Psychiatry, 65(6), 930–932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Renò, F., et al. (1998). Phospholipid rearrangement of apoptotic membrane does not depend on nuclear activity. Histochemistry and Cell Biology, 110(5), 467–476.

    Article  PubMed  Google Scholar 

  • Røe, C. et al. (2009). Post-concussion symptoms after mild traumatic brain injury: influence of demographic factors and injury severity in a 1-year cohort study. Disability and rehabilitation, 31(15), 1235–1243. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19116810. Accessed 18 Jan 2016.

  • Romner, B., et al. (2000). Traumatic brain damage: serum S-100 protein measurements related to neuroradiological findings. Journal of Neurotrauma, 17(8), 641–647.

    Article  CAS  PubMed  Google Scholar 

  • Serhan, C. N., Yacoubian, S., & Yang, R. (2008). Anti-inflammatory and proresolving lipid mediators. Annual Review of Pathology, 3, 279–312.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spector, A. A. (2001). Plasma free fatty acid and lipoproteins as sources of polyunsaturated fatty acid for the brain. Journal of Molecular Neuroscience: MN, 16(2-3), 159–165. (discussion 215–221).

    Article  CAS  PubMed  Google Scholar 

  • Vance, D., & Vance, J. (2008). Biochemistry of lipids, lipoproteins and membranes. Elsevier, Amsterdam. Available at http://store.elsevier.com/Biochemistry-of-Lipids-Lipoproteins-and-Membranes/J_E_-Vance/isbn-9780444511386/.

  • Vincent, A. S., Roebuck-Spencer, T. M., & Cernich, A. (2014). Cognitive changes and dementia risk after traumatic brain injury: Implications for aging military personnel. Alzheimer’s and Dementia, 10(3 SUPPL.), S174–S187. Available at http://dx.doi.org/10.1016/j.jalz.2014.04.006.

  • Williams, W. H., Potter, S., & Ryland, H. (2010). Mild traumatic brain injury and postconcussion syndrome: A neuropsychological perspective. Journal of neurology, neurosurgery, and psychiatry, 81(10), 1116–1122. Available at http://www.ncbi.nlm.nih.gov/pubmed/20802217. Accessed 1 Jan 2016.

  • Xiong, Y., Mahmood, A., & Chopp, M. (2013). Animal models of traumatic brain injury. Nature Reviews Neuroscience, 14(2), 128–142.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang, S. et al. (2012). Arachidonic acid: a bridge between traumatic brain injury and fracture healing. Journal of Neurotrauma, 29(17), 2696–705. Available at http://www.ncbi.nlm.nih.gov/pubmed/22867040. Accessed 25 January 2016.

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Acknowledgments

This research was funded by Department of Defense Awards (W81XWH-10-1-0759 and W81XWH-13-1-0253) and VA Research Award (RX-16-007) to VA Research Career scientist Dr. Fiona Crawford and by the Roskamp Foundation. The contents do not represent the views of the Department of Veterans Affairs, or the US Government.

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Correspondence to Tanja Emmerich.

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Emmerich, T., Abdullah, L., Ojo, J. et al. Mild TBI Results in a Long-Term Decrease in Circulating Phospholipids in a Mouse Model of Injury. Neuromol Med 19, 122–135 (2017). https://doi.org/10.1007/s12017-016-8436-4

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