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Mass Spectrometry-Based Approaches for Clinical Biomarker Discovery in Traumatic Brain Injury

  • Critical Care Neurology (H Hinson, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of Review

Precision treatments to address the multifaceted pathophysiology of traumatic brain injury (TBI) are desperately needed, which has led to the intense study of fluid-based protein biomarkers in TBI. Mass Spectrometry (MS) is increasingly being applied to biomarker discovery and quantification in neurological disease to explore the proteome, allowing for more flexibility in biomarker discovery than commonly encountered antibody-based assays. In this narrative review, we will provide specific examples of how MS technology has advanced translational research in traumatic brain injury (TBI) focusing on clinical studies, and looking ahead to promising emerging applications of MS to the field of Neurocritical Care.

Recent Findings

Proteomic biomarker discovery using MS technology in human subjects has included the full range of injury severity in TBI, though critically ill patients can offer more options to biofluids given the need for invasive monitoring. Blood, urine, cerebrospinal fluid, brain specimens, and cerebral extracellular fluid have all been sources for analysis. Emerging evidence suggests there are distinct proteomic profiles in radiographic TBI subtypes, and that biomarkers may be used to distinguish patients sustaining TBI from healthy controls. Metabolomics may offer a window into the perturbations of ongoing cerebral insults in critically ill patients after severe TBI.

Summary

Emerging MS technologies may offer biomarker discovery and validation opportunities not afforded by conventional means due to its ability to handle the complexities associated with the proteome. While MS techniques are relatively early in development in the neurosciences space, the potential applications to TBI and neurocritical care are likely to accelerate in the coming decade.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Multiple Cause of Death Data on CDC WONDER [Internet]. [cited 2022 May 28]. Available from: https://wonder.cdc.gov/mcd.html

  2. •• Wilde EA, Wanner I-B, Kenney K, Gill J, Stone JR, Disner S, et al. A framework to advance biomarker development in the diagnosis, outcome prediction, and treatment of traumatic brain injury. J Neurotrauma. 2022;39:436–57. Excellent overview of the concept of biomarkers and their utility in traumatic brain injury.

    Article  Google Scholar 

  3. Dadas A, Washington J, Diaz-Arrastia R, Janigro D. Biomarkers in traumatic brain injury (TBI): a review. NDT. 2018;14:2989–3000.

    Article  CAS  Google Scholar 

  4. Edalatfar M, Piri SM, Mehrabinejad M-M, Mousavi M-S, Meknatkhah S, Fattahi M-R, et al. Biofluid biomarkers in traumatic brain injury: a systematic scoping review. Neurocrit Care. 2021;35:559–72.

    Article  CAS  Google Scholar 

  5. • Bazarian JJ, Biberthaler P, Welch RD, Lewis LM, Barzo P, Bogner-Flatz V, et al. Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study. Lancet Neurol. 2018;17:782–9. The study served as the basis for the first FDA-approved blood-based biomarker study in traumatic brain injury.

    Article  CAS  Google Scholar 

  6. Gan ZS, Stein SC, Swanson R, Guan S, Garcia L, Mehta D, et al. Blood biomarkers for traumatic brain injury: a quantitative assessment of diagnostic and prognostic accuracy. Front Neurol. 2019;10:446.

    Article  Google Scholar 

  7. •• Mondello S, Sorinola A, Czeiter E, Vámos Z, Amrein K, Synnot A, et al. Blood-based protein biomarkers for the management of traumatic brain injuries in adults presenting to emergency departments with mild brain injury: a living systematic review and meta-analysis. J Neurotrauma. 2021;38:1086–106. Comprehensive review of blood-based biomarkers in traumatic brain injury.

    Article  Google Scholar 

  8. Mondello S, Muller U, Jeromin A, Streeter J, Hayes RL, Wang KKW. Blood-based diagnostics of traumatic brain injuries. Expert Rev Mol Diagn. 2011;11:65–78.

    Article  Google Scholar 

  9. Kingsmore SF. Multiplexed protein measurement: technologies and applications of protein and antibody arrays. Nat Rev Drug Discov. 2006;5:310–21.

    Article  CAS  Google Scholar 

  10. Snapkov I, Chernigovskaya M, Sinitcyn P, Quý KL, Nyman TA, Greiff V. Progress and challenges in mass spectrometry-based analysis of antibody repertoires. Trends in Biotechnology Elsevier. 2022;40:463–81.

    Article  CAS  Google Scholar 

  11. • Graves PR, Haystead TAJ. Molecular biologist’s guide to proteomics. Microbiol Mol Biol Rev. 2002;66:39–63; table of contents. A nice overview of proteomics for those outside the field.

  12. Brown TA. Genomes [Internet]. 2nd ed. Oxford: Wiley-Liss; 2002 [cited 2022 Apr 13]. Available from: http://www.ncbi.nlm.nih.gov/books/NBK21128/

  13. Banerjee S. Empowering clinical diagnostics with mass spectrometry. ACS Omega. 2020;5:2041–8.

    Article  CAS  Google Scholar 

  14. Mass Spectrometry: Basics [Internet]. [cited 2022 Apr 13]. Available from: https://masspec.scripps.edu/learn/ms/

  15. Korecka M, Shaw LM. Mass spectrometry-based methods for robust measurement of Alzheimer’s disease biomarkers in biological fluids. J Neurochem. 2021;159:211–33.

    Article  CAS  Google Scholar 

  16. Pasinetti GM, Ungar LH, Lange DJ, Yemul S, Deng H, Yuan X, et al. Identification of potential CSF biomarkers in ALS. Neurology. Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology; 2006;66:1218–22.

  17. Bharucha T, Gangadharan B, Kumar A, de Lamballerie X, Newton PN, Winterberg M, et al. Mass spectrometry-based proteomic techniques to identify cerebrospinal fluid biomarkers for diagnosing suspected central nervous system infections. A systematic review Journal of Infection. 2019;79:407–18.

    Google Scholar 

  18. Karpievitch YV, Polpitiya AD, Anderson GA, Smith RD, Dabney AR. Liquid chromatography mass spectrometry-based proteomics: Biological and technological aspects. Ann Appl Stat [Internet]. 2010 [cited 2022 Apr 18];4. Available from: https://projecteuclid.org/journals/annals-of-appliedstatistics/volume-4/issue-4/Liquid-chromatography-mass-spectrometry-based-proteomics--Biologicaland-technological/10.1214/10-AOAS341.full

  19. McDonald WH, Yates JR. Shotgun proteomics and biomarker discovery. Dis Markers. 2002;18:99–105.

    Article  CAS  Google Scholar 

  20. Singh SA, Aikawa M. Unbiased and targeted mass spectrometry for the HDL proteome. Curr Opin Lipidol. 2017;28:68–77.

    Article  CAS  Google Scholar 

  21. Catherman AD, Skinner OS, Kelleher NL. Top Down proteomics: facts and perspectives. Biochem Biophys Res Commun. 2014;445:683–93.

    Article  CAS  Google Scholar 

  22. Kochanek AR, Kline AE, Gao W-M, Chadha M, Lai Y, Clark RSB, et al. Gel-based hippocampal proteomic analysis 2 weeks following traumatic brain injury to immature rats using controlled cortical impact. Dev Neurosci. 2006;28:410–9.

    Article  CAS  Google Scholar 

  23. Haskins WE, Kobeissy FH, Wolper RA, Ottens AK, Kitlen JW, McClung SH, et al. Rapid discovery of putative protein biomarkers of traumatic brain injury by SDS-PAGE-capillary liquid chromatography-tandem mass spectrometry. J Neurotrauma. 2005;22:629–44.

    Article  Google Scholar 

  24. Kobeissy FH, Ottens AK, Zhang Z, Liu MC, Denslow ND, Dave JR, et al. Novel differential neuroproteomics analysis of traumatic brain injury in rats. Mol Cell Proteomics. 2006;5:1887–98.

    Article  CAS  Google Scholar 

  25. Hogan SR, Phan JH, Alvarado-Velez M, Wang MD, Bellamkonda RV, Fernández FM, et al. Discovery of lipidome alterations following traumatic brain injury via high-resolution metabolomics. J Proteome Res. 2018;17:2131–43.

    Article  CAS  Google Scholar 

  26. • Ottens AK, Stafflinger JE, Griffin HE, Kunz RD, Cifu DX, Niemeier JP. Post-acute brain injury urinary signature: a new resource for molecular diagnostics. J Neurotrauma. 2014;31:782–8. An innovative mass spectrometry approach examining the urinary proteome in TBI patients, leading to the development of sub profiles that correlated with magnitude of injury and functional outcomes.

    Article  Google Scholar 

  27. Millioni R, Tolin S, Puricelli L, Sbrignadello S, Fadini GP, Tessari P, et al. High abundance proteins depletion vs low abundance proteins enrichment: comparison of methods to reduce the plasma proteome complexity. Ho PL, editor. PLoS One. 2011;6:e19603.

  28. Patel PD, Stafflinger JE, Marwitz JH, Niemeier JP, Ottens AK. Secreted peptides for diagnostic trajectory assessments in brain injury rehabilitation. Neurorehabil Neural Repair. 2021;35:169–84.

    Article  Google Scholar 

  29. • Abu Hamdeh S, Shevchenko G, Mi J, Musunuri S, Bergquist J, Marklund N. Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue. Sci Rep. 2018;8:6807. This study compares biopsies of normal cortex to severe TBI cortex and contrasts the proteomes of cortical samples using label-free, mass spectroscopy.

    Article  Google Scholar 

  30. Ziebell JM, Morganti-Kossmann MC. Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury. Neurotherapeutics. 2010;7:22–30.

    Article  CAS  Google Scholar 

  31. Haqqani AS, Hutchison JS, Ward R, Stanimirovic DB. Biomarkers and diagnosis; protein biomarkers in serum of pediatric patients with severe traumatic brain injury identified by ICAT-LC-MS/MS. J Neurotrauma. 2007;24:54–74.

    Article  Google Scholar 

  32. Gao W, Lu C, Kochanek PM, Berger RP. Serum amyloid A is increased in children with abusive head trauma: a gel-based proteomic analysis. Pediatr Res. 2014;76:280–6.

    Article  CAS  Google Scholar 

  33. Carabias CS, Castaño-León AM, Blanca Navarro B, Panero I, Eiriz C, Gómez PA, et al. Serum amyloid A1 as a potential intracranial and extracranial clinical severity biomarker in traumatic brain injury. J Intensive Care Med. 2020;35:1180–95.

    Article  Google Scholar 

  34. Picotti P, Aebersold R. Selected reaction monitoring-based proteomics: workflows, potential, pitfalls and future directions. Nat Methods. 2012;9:555–66.

    Article  CAS  Google Scholar 

  35. Orwoll ES, Wiedrick J, Jacobs J, Baker ES, Piehowski P, Petyuk V, et al. High-throughput serum proteomics for the identification of protein biomarkers of mortality in older men. Aging Cell. 2018;17.

  36. Shi T, Fillmore TL, Gao Y, Zhao R, He J, Schepmoes AA, et al. Long-gradient separations coupled with selected reaction monitoring for highly sensitive, large scale targeted protein quantification in a single analysis. Anal Chem. 2013;85:9196–203.

    Article  CAS  Google Scholar 

  37. Nie S, Shi T, Fillmore TL, Schepmoes AA, Brewer H, Gao Y, et al. Deep-dive targeted quantification for ultrasensitive analysis of proteins in nondepleted human blood plasma/serum and tissues. Anal Chem. 2017;89:9139–46.

    Article  CAS  Google Scholar 

  38. Hinson HE, Jacobs J, McWeeney S, Wachana A, Shi T, Martin K, et al. Antibody-free mass spectrometry identification of vascular integrity markers in major trauma. Neurotrauma Rep. 2021;2:322–9.

    Article  CAS  Google Scholar 

  39. Whitehouse DP, Monteiro M, Czeiter E, Vyvere TV, Valerio F, Ye Z, et al. Relationship of admission blood proteomic biomarkers levels to lesion type and lesion burden in traumatic brain injury: a CENTER-TBI study. eBioMedicine. 2022;75:103777.

  40. Funk RS, Singh RK, Becker ML. Metabolomic profiling to identify molecular biomarkers of cellular response to methotrexate in vitro. Clin Transl Sci. 2020;13:137–46.

    Article  CAS  Google Scholar 

  41. Fiandaca MS, Mapstone M, Mahmoodi A, Gross T, Macciardi F, Cheema AK, et al. Plasma metabolomic biomarkers accurately classify acute mild traumatic brain injury from controls. Miller MW, editor. PLoS One. 2018;13:e0195318.

  42. Fiandaca M, Gross T, Johnson T, Hu M, Evetts S, Wade-Martins R, et al. Potential metabolomic linkage in blood between Parkinson’s disease and traumatic brain injury. Metabolites. 2018;8:50.

    Article  Google Scholar 

  43. Orešič M, Posti JP, Kamstrup-Nielsen MH, Takala RSK, Lingsma HF, Mattila I, et al. Human serum metabolites associate with severity and patient outcomes in traumatic brain injury. EBioMedicine. 2016;12:118–26.

    Article  Google Scholar 

  44. • Wolahan SM, Lebby E, Mao HC, McArthur D, Real C, Vespa P, et al. Novel metabolomic comparison of arterial and jugular venous blood in severe adult traumatic brain injury patients and the impact of pentobarbital infusion. J Neurotrauma. 2019;36:212–21. Metabolomic study that compared simultaneously collected arterial and jugular venous metabolites using mass spectroscopy in acute TBI subjects vs age match controls and discovered unique metabolomic profiles in TBI patients and between the two blood sources.

    Article  Google Scholar 

  45. Thomas I, Dickens AM, Posti JP, Czeiter E, Duberg D, Sinioja T, et al. Serum metabolome associated with severity of acute traumatic brain injury. Nat Commun. 2022;13:2545.

    Article  CAS  Google Scholar 

  46. Loo O, R R. Top-down, bottom-up, and side-to-side proteomics with virtual 2-D gels. 2004 [cited 2022 Feb 7]; Available from: https://escholarship.org/uc/item/2hj540sc

  47. Datta S, Malhotra L, Dickerson R, Chaffee S, Sen CK, Roy S. Laser capture microdissection: big data from small samples. Histol Histopathol. 2015;30:1255–69.

    CAS  Google Scholar 

  48. Wulf M, Barkovits-Boeddinghaus K, Sommer P, Schork K, Eisenacher M, Riederer P, et al. Laser microdissection-based protocol for the LC-MS/MS analysis of the proteomic profile of neuromelanin granules. J Vis Exp. 2021;

  49. •• Perkel J. Proteomics at the single cell level. Nature. 2021;597:580–3. The emerging field of single-cell proteomics is reviewed here.

    Article  CAS  Google Scholar 

  50. Woo J, Williams SM, Markillie LM, Feng S, Tsai C-F, Aguilera-Vazquez V, et al. High-throughput and high-efficiency sample preparation for single-cell proteomics using a nested nanowell chip. Nat Commun. 2021;12:6246.

    Article  CAS  Google Scholar 

  51. Hollerbach AL, Conant CR, Nagy G, Ibrahim YM. Implementation of ion mobility spectrometry-based separations in structures for lossless ion manipulations (SLIM). Methods Mol Biol. 2022;2394:453–69.

    Article  Google Scholar 

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Acknowledgements

The authors wish to thank Dr. Shraddha Mainali for reviewing their paper. Work was performed in the Environmental Molecular Sciences Laboratory, a US Department of Energy Office of Biological and Environmental Research national scientific user facility located at Pacific Northwest National Laboratory in Richland, Washington. Pacific Northwest National Laboratory is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05-76RLO 1830.

Funding

Research reported in this publication was supported by the National Institute Of Neurological Disorders And Stroke of the National Institutes of Health under Award Number K23NS110828. Portions of this research were also supported by NIH NIGMS GM103493.

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Authors and Affiliations

  1. Department of Neurology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, CR-127, Portland, OR, 97239, USA

    Matthew Creech DO, MPH, Lindsey Carvalho MD & H. E. Hinson MD, MCR

  2. Biological Sciences Division, Pacific Northwest National Laboratories, Richland, WA, USA

    Heather McCoy MD & Jon Jacobs PhD

  3. Department of Emergency Medicine, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, CR-127, Portland, OR, 97239, USA

    H. E. Hinson MD, MCR

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  1. Matthew Creech DO, MPH
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Correspondence to H. E. Hinson MD, MCR.

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Creech, M., Carvalho, L., McCoy, H. et al. Mass Spectrometry-Based Approaches for Clinical Biomarker Discovery in Traumatic Brain Injury. Curr Treat Options Neurol 24, 605–618 (2022). https://doi.org/10.1007/s11940-022-00742-3

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