Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Clinical Chemistry and Laboratory Medicine (CCLM)

Published in Association with the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM)

Editor-in-Chief: Plebani, Mario

Ed. by Gillery, Philippe / Greaves, Ronda / Lackner, Karl J. / Lippi, Giuseppe / Melichar, Bohuslav / Payne, Deborah A. / Schlattmann, Peter


IMPACT FACTOR 2018: 3.638

CiteScore 2018: 2.44

SCImago Journal Rank (SJR) 2018: 1.191
Source Normalized Impact per Paper (SNIP) 2018: 1.205

Online
ISSN
1437-4331
See all formats and pricing
More options …
Volume 57, Issue 10

Issues

Dynamics of extracellular matrix proteins in cerebrospinal fluid and serum and their relation to clinical outcome in human traumatic brain injury

Karolina Minta
  • Corresponding author
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Nicholas C. Cullen
  • Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Faiez Al Nimer / Eric P. Thelin
  • Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • Department of Clinical Neurosciences, Division of Neurosurgery, University of Cambridge, Cambridge, UK
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Fredrik Piehl / Marcus Clarin
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Mats Tullberg
  • Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Anna Jeppsson
  • Department of Clinical Neuroscience, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Erik Portelius
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Henrik Zetterberg
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Department of Neurodegenerative Disease, UCL Institute of Neurology, London, UK
  • UK Dementia Research Institute at UCL, London, UK
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Kaj Blennow
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ulf Andreasson
  • Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
  • Clinical Neurochemistry Laboratory, Sahlgrenska University Hospital, Mölndal, Sweden
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2019-04-15 | DOI: https://doi.org/10.1515/cclm-2019-0034

Abstract

Background

Brevican, neurocan, tenascin-C and tenascin-R are extracellular matrix proteins present in brain that show increased expression in experimental animal models of brain injury. However, little is known about the dynamics of these proteins in human body fluids, such as cerebrospinal fluid (CSF) and serum, after traumatic brain injury (TBI). The aims of this study were to investigate if matrix proteins in CSF and serum are associated with functional outcome following traumatic brain injury, if their concentrations change over time and to compare their levels between brain injured patients to controls.

Methods

In total, 42 traumatic brain injury patients, nine healthy controls and a contrast group consisting of 38 idiopathic normal pressure hydrocephalus patients were included. Enzyme-linked immunosorbent assays (ELISAs) were used to measure the concentrations of proteins.

Results

Increased concentrations of brevican, tenascin-C and tenascin-R in CSF correlated with unfavourable outcome, with stronger outcome prediction ability compared to other biomarkers of brain tissue injury. CSF brevican, tenascin-R and serum neurocan gradually decreased with time (p = 0.04, p = 0.008, p = 0.005, respectively), while serum tenascin-C (p = 0.01) increased. CSF concentrations of brevican, neurocan and tenascin-R (only in time point 3) after TBI were lower than in the idiopathic normal pressure hydrocephalus group (p < 0.0001, p < 0.0001, and p = 0.0008, respectively). In serum, tenascin-C concentration was higher and neurocan lower compared to healthy controls (p = 0.02 and p = 0.0009).

Conclusions

These findings indicate that levels of extracellular matrix proteins are associated with clinical outcome following TBI and may act as markers for different pathophysiology than currently used protein biomarkers.

This article offers supplementary material which is provided at the end of the article.

Keywords: brevican; neurocan; tenascin-C; tenascin-R; traumatic brain injury

References

  • 1.

    Hyder AA, Wunderlich CA, Puvanachandra P, Gururaj G, Kobusingye OC. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation 2007;22:341–53.PubMedGoogle Scholar

  • 2.

    Zetterberg H, Smith DH, Blennow K. Biomarkers of mild traumatic brain injury in cerebrospinal fluid and blood. Nat Rev Neurol 2013;9:201–10.Web of SciencePubMedCrossrefGoogle Scholar

  • 3.

    Li X, Li TQ, Andreasen N, Wiberg MK, Westman E, Wahlund LO. The association between biomarkers in cerebrospinal fluid and structural changes in the brain in patients with Alzheimer’s disease. J Intern Med 2014;275:418–27.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 4.

    Neselius S, Brisby H, Theodorsson A, Blennow K, Zetterberg H, Marcusson J. CSF-biomarkers in Olympic boxing: diagnosis and effects of repetitive head trauma. PLoS One 2012;7:e33606.Web of ScienceCrossrefPubMedGoogle Scholar

  • 5.

    Zetterberg H, Hietala MA, Jonsson M, Andreasen N, Styrud E, Karlsson I, et al. Neurochemical aftermath of amateur boxing. Arch Neurol 2006;63:1277–80.CrossrefPubMedGoogle Scholar

  • 6.

    Shahim P, Gren M, Liman V, Andreasson U, Norgren N, Tegner Y, et al. Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Sci Rep 2016;6:36791.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 7.

    Ost M, Nylen K, Csajbok L, Ohrfelt AO, Tullberg M, Wikkelso C, et al. Initial CSF total tau correlates with 1-year outcome in patients with traumatic brain injury. Neurology 2006;67:1600–4.CrossrefPubMedGoogle Scholar

  • 8.

    Zemlan FP, Jauch EC, Mulchahey JJ, Gabbita SP, Rosenberg WS, Speciale SG, et al. C-tau biomarker of neuronal damage in severe brain injured patients: association with elevated intracranial pressure and clinical outcome. Brain Res 2002;947:131–9.CrossrefPubMedGoogle Scholar

  • 9.

    Franz G, Beer R, Kampfl A, Engelhardt K, Schmutzhard E, Ulmer H, et al. Amyloid beta 1-42 and tau in cerebrospinal fluid after severe traumatic brain injury. Neurology 2003;60:1457–61.PubMedCrossrefGoogle Scholar

  • 10.

    Goyal A, Failla MD, Niyonkuru C, Amin K, Fabio A, Berger RP, et al. S100b as a prognostic biomarker in outcome prediction for patients with severe traumatic brain injury. J Neurotrauma 2013;30:946–57.CrossrefPubMedGoogle Scholar

  • 11.

    Berger RP, Pierce MC, Wisniewski SR, Adelson PD, Clark RS, Ruppel RA, et al. Neuron-specific enolase and S100B in cerebrospinal fluid after severe traumatic brain injury in infants and children. Pediatrics 2002;109:E31.CrossrefPubMedGoogle Scholar

  • 12.

    Czeiter E, Mondello S, Kovacs N, Sandor J, Gabrielli A, Schmid K, et al. Brain injury biomarkers may improve the predictive power of the IMPACT outcome calculator. J Neurotrauma 2012;29:1770–8.Web of ScienceCrossrefPubMedGoogle Scholar

  • 13.

    Kirino T, Brightman MW, Oertel WH, Schmechel DE, Marangos PJ. Neuron-specific enolase as an index of neuronal regeneration and reinnervation. J Neurosci 1983;3:915–23.CrossrefPubMedGoogle Scholar

  • 14.

    Huang XJ, Glushakova O, Mondello S, Van K, Hayes RL, Lyeth BG. Acute temporal profiles of serum levels of UCH-L1 and GFAP and relationships to neuronal and astroglial pathology following traumatic brain injury in rats. J Neurotrauma 2015;32:1179–89.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 15.

    Raponi E, Agenes F, Delphin C, Assard N, Baudier J, Legraverend C, et al. S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia 2007;55:165–77.CrossrefWeb of ScienceGoogle Scholar

  • 16.

    Lista S, Faltraco F, Prvulovic D, Hampel H. Blood and plasma-based proteomic biomarker research in Alzheimer’s disease. Prog Neurobiol 2013;101–102:1–17.Web of SciencePubMedGoogle Scholar

  • 17.

    Vos PE, Jacobs B, Andriessen TM, Lamers KJ, Borm GF, Beems T, et al. GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology 2010;75:1786–93.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 18.

    Thelin EP, Jeppsson E, Frostell A, Svensson M, Mondello S, Bellander BM, et al. Utility of neuron-specific enolase in traumatic brain injury; relations to S100B levels, outcome, and extracranial injury severity. Crit Care 2016;20:285.Web of ScienceCrossrefPubMedGoogle Scholar

  • 19.

    Al Nimer F, Thelin E, Nystrom H, Dring AM, Svenningsson A, Piehl F, et al. Comparative assessment of the prognostic value of biomarkers in traumatic brain injury reveals an independent role for serum levels of neurofilament light. PLoS One 2015;10:e0132177.CrossrefWeb of SciencePubMedGoogle Scholar

  • 20.

    Zetterberg H, Blennow K. Fluid biomarkers for mild traumatic brain injury and related conditions. Nat Rev Neurol 2016;12:563–74.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 21.

    Teasdale G, Jennett B. Assessment of coma and impaired consciousness. A practical scale. Lancet 1974;2:81–4.PubMedGoogle Scholar

  • 22.

    Olsson B, Zetterberg H, Hampel H, Blennow K. Biomarker-based dissection of neurodegenerative diseases. Prog Neurobiol 2011;95:520–34.PubMedWeb of ScienceCrossrefGoogle Scholar

  • 23.

    World Health Organization. WHO International Programme on Chemical Safety Biomarkers in Risk Assessment: Validity and Validation 2001. Available at: http://www.inchem.org/documents/ehc/ehc/ehc222.htm. Accessed: 26 Oct 2018.

  • 24.

    Thelin EP, Johannesson L, Nelson D, Bellander BM. S100B is an important outcome predictor in traumatic brain injury. J Neurotrauma 2013;30:519–28.Web of ScienceCrossrefPubMedGoogle Scholar

  • 25.

    Carulli D, Rhodes KE, Brown DJ, Bonnert TP, Pollack SJ, Oliver K, et al. Composition of perineuronal nets in the adult rat cerebellum and the cellular origin of their components. J Comp Neurol 2006;494:559–77.PubMedCrossrefGoogle Scholar

  • 26.

    Zhang Y, Anderson PN, Campbell G, Mohajeri H, Schachner M, Lieberman AR. Tenascin-C expression by neurons and glial cells in the rat spinal cord: changes during postnatal development and after dorsal root or sciatic nerve injury. J Neurocytol 1995;24:585–601.CrossrefPubMedGoogle Scholar

  • 27.

    Siebert JR, Conta Steencken A, Osterhout DJ. Chondroitin sulfate proteoglycans in the nervous system: inhibitors to repair. Biomed Res Int 2014;2014:845323.PubMedWeb of ScienceGoogle Scholar

  • 28.

    Grumet M, Friedlander DR, Sakurai T. Functions of brain chondroitin sulfate proteoglycans during developments: interactions with adhesion molecules. Perspect Dev Neurobiol 1996;3:319–30.PubMedGoogle Scholar

  • 29.

    Cui H, Freeman C, Jacobson GA, Small DH. Proteoglycans in the central nervous system: role in development, neural repair, and Alzheimer’s disease. IUBMB Life 2013;65:108–20.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 30.

    Fournier AE, Strittmatter SM. Repulsive factors and axon regeneration in the CNS. Curr Opin Neurobiol 2001;11:89–94.PubMedCrossrefGoogle Scholar

  • 31.

    Camand E, Morel MP, Faissner A, Sotelo C, Dusart I. Long-term changes in the molecular composition of the glial scar and progressive increase of serotoninergic fibre sprouting after hemisection of the mouse spinal cord. Eur J Neurosci 2004;20:1161–76.CrossrefPubMedGoogle Scholar

  • 32.

    Schafer R, Dehn D, Burbach GJ, Deller T. Differential regulation of chondroitin sulfate proteoglycan mRNAs in the denervated rat fascia dentata after unilateral entorhinal cortex lesion. Neurosci Lett 2008;439:61–5.Web of SciencePubMedCrossrefGoogle Scholar

  • 33.

    Beggah AT, Dours-Zimmermann MT, Barras FM, Brosius A, Zimmermann DR, Zurn AD. Lesion-induced differential expression and cell association of Neurocan, Brevican, Versican V1 and V2 in the mouse dorsal root entry zone. Neuroscience 2005;133:749–62.CrossrefPubMedGoogle Scholar

  • 34.

    Becker T, Anliker B, Becker CG, Taylor J, Schachner M, Meyer RL, et al. Tenascin-R inhibits regrowth of optic fibers in vitro and persists in the optic nerve of mice after injury. Glia 2000;29:330–46.CrossrefPubMedGoogle Scholar

  • 35.

    Jones LL, Margolis RU, Tuszynski MH. The chondroitin sulfate proteoglycans neurocan, brevican, phosphacan, and versican are differentially regulated following spinal cord injury. Exp Neurol 2003;182:399–411.CrossrefPubMedGoogle Scholar

  • 36.

    Tang X, Davies JE, Davies SJ. Changes in distribution, cell associations, and protein expression levels of NG2, neurocan, phosphacan, brevican, versican V2, and tenascin-C during acute to chronic maturation of spinal cord scar tissue. J Neurosci Res 2003;71:427–44.CrossrefPubMedGoogle Scholar

  • 37.

    Asher RA, Morgenstern DA, Fidler PS, Adcock KH, Oohira A, Braistead JE, et al. Neurocan is upregulated in injured brain and in cytokine-treated astrocytes. J Neurosci 2000;20:2427–38.CrossrefPubMedGoogle Scholar

  • 38.

    Zhao YY, Lou L, Yang KC, Wang HB, Xu Y, Lu G, et al. Correlation of tenascin-C concentrations in serum with outcome of traumatic brain injury in humans. Clin Chim Acta 2017;472:46–50.CrossrefWeb of SciencePubMedGoogle Scholar

  • 39.

    Suzuki H, Kanamaru K, Shiba M, Fujimoto M, Kawakita F, Imanaka-Yoshida K, et al. Tenascin-C is a possible mediator between initial brain injury and vasospasm-related and -unrelated delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. Acta Neurochir Suppl 2015;120:117–21.PubMedGoogle Scholar

  • 40.

    Olsson M, Arlig J, Hedner J, Blennow K, Zetterberg H. Sleep deprivation and CSF biomarkers for Alzheimer disease. Sleep 2018;41.PubMedGoogle Scholar

  • 41.

    Yamaguchi Y. Brevican: a major proteoglycan in adult brain. Perspect Dev Neurobiol 1996;3:307–17.Google Scholar

  • 42.

    Kurazono S, Okamoto M, Sakiyama J, Mori S, Nakata Y, Fukuoka J, et al. Expression of brain specific chondroitin sulfate proteoglycans, neurocan and phosphacan, in the developing and adult hippocampus of Ihara’s epileptic rats. Brain Res 2001;898:36–48.PubMedCrossrefGoogle Scholar

  • 43.

    Probstmeier R, Braunewell K, Pesheva P. Involvement of chondroitin sulfates on brain-derived tenascin-R in carbohydrate-dependent interactions with fibronectin and tenascin-C. Brain Res 2000;863:42–51.PubMedCrossrefGoogle Scholar

  • 44.

    Fluck M, Tunc-Civelek V, Chiquet M. Rapid and reciprocal regulation of tenascin-C and tenascin-Y expression by loading of skeletal muscle. J Cell Sci 2000;113(Pt 20):3583–91.PubMedGoogle Scholar

  • 45.

    von Holst A, Egbers U, Prochiantz A, Faissner A. Neural stem/progenitor cells express 20 tenascin C isoforms that are differentially regulated by Pax6. J Biol Chem 2007;282:9172–81.PubMedCrossrefWeb of ScienceGoogle Scholar

  • 46.

    Sommer JB, Gaul C, Heckmann J, Neundorfer B, Erbguth FJ. Does lumbar cerebrospinal fluid reflect ventricular cerebrospinal fluid? A prospective study in patients with external ventricular drainage. Eur Neurol 2002;47:224–32.PubMedCrossrefGoogle Scholar

  • 47.

    Ulfig N, Bohl J, Neudorfer F, Rezaie P. Brain macrophages and microglia in human fetal hydrocephalus. Brain Dev 2004;26:307–15.CrossrefPubMedGoogle Scholar

About the article

Received: 2018-10-26

Accepted: 2019-02-24

Published Online: 2019-04-15

Published in Print: 2019-09-25


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: The study was supported by grants from the Swedish Research Council, the European Research Council, Swedish State Support for Clinical Research, the Knut and Alice Wallenberg Foundation, the Edit Jacobson Foundation and the Torsten Söderberg Foundation and Stiftelsen för Gamla Tjänarinnor. EPT is funded by grants from the Swedish Society for Medical Research.

Employment or leadership: In case of non-competing interests, unrelated to this work, KB has served as a consultant or at advisory boards for Alzheon, CogRx, Biogen, Novartis, and Roche Diagnostics, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Venture-based platform company at the University of Gothenburg. HZ has served on scientific advisory boards for Roche Diagnostics, Samumed, CogRx and Wave and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg.

Honorarium: None declared.

Competing interests: The authors report no competing financial interests. The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Clinical Chemistry and Laboratory Medicine (CCLM), Volume 57, Issue 10, Pages 1565–1573, ISSN (Online) 1437-4331, ISSN (Print) 1434-6621, DOI: https://doi.org/10.1515/cclm-2019-0034.

Export Citation

©2019 Walter de Gruyter GmbH, Berlin/Boston.Get Permission

Supplementary Article Materials

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Giulia Musso and Mario Plebani
Clinical Chemistry and Laboratory Medicine (CCLM), 2019, Volume 57, Number 10, Page 1433

Comments (0)

Please log in or register to comment.
Log in