Intense inflammation and nerve damage in early multiple sclerosis subsides at older age: a reflection by cerebrospinal fluid biomarkers.

Publisher: Public Library of Science Country of Publication: United States NLM ID: 101285081 Publication Model: Electronic-Print Cited Medium: Internet ISSN: 1932-6203 (Electronic) Linking ISSN: 19326203 NLM ISO Abbreviation: PLoS One Subsets: MEDLINE

Original Publication: San Francisco, CA : Public Library of Science

Biomarkers/*cerebrospinal fluid ; Central Nervous System/*pathology ; Inflammation/*cerebrospinal fluid ; Multiple Sclerosis/*cerebrospinal fluid; Aged ; Case-Control Studies ; Demography ; Humans ; Inflammation/pathology ; Least-Squares Analysis ; Models, Biological ; Multiple Sclerosis, Relapsing-Remitting/cerebrospinal fluid ; Principal Component Analysis

Inflammatory mediators have crucial roles in leukocyte recruitment and subsequent central nervous system (CNS) neuroinflammation. The extent of neuronal injury and axonal loss are associated with the degree of CNS inflammation and determine physical disability in multiple sclerosis (MS). The aim of this study was to explore possible associations between a panel of selected cerebrospinal fluid biomarkers and robust clinical and demographic parameters in a large cohort of patients with MS and controls (n = 1066) using data-driven multivariate analysis. Levels of matrix metalloproteinase 9 (MMP9), chemokine (C-X-C motif) ligand 13 (CXCL13), osteopontin (OPN) and neurofilament-light chain (NFL) were measured by ELISA in 548 subjects comprising different MS subtypes (relapsing-remitting, secondary progressive and primary progressive), clinically isolated syndrome and persons with other neurological diseases with or without signs of inflammation/infection. Principal component analyses and orthogonal partial least squares methods were used for unsupervised and supervised interrogation of the data. Models were validated using data from a further 518 subjects in which one or more of the four selected markers were measured. There was a significant association between increased patient age and lower levels of CXCL13, MMP9 and NFL. CXCL13 levels correlated well with MMP9 in the younger age groups, but less so in older patients, and after approximately 54 years of age the levels of CXCL13 and MMP9 were consistently low. CXCL13 and MMP9 levels also correlated well with both NFL and OPN in younger patients. We demonstrate a strong effect of age on both inflammatory and neurodegenerative biomarkers in a large cohort of MS patients. The findings support an early use of adequate immunomodulatory disease modifying drugs, especially in younger patients, and may provide a biological explanation for the relative inefficacy of such treatments in older patients at later disease stages.

J Neuroimmunol. 1992 Nov;41(1):29-34. (PMID: 1334098)
J Neuroimmunol. 2003 Mar;136(1-2):112-8. (PMID: 12620649)
Mult Scler. 2013 Feb;19(2):188-98. (PMID: 22736750)
Ann Neurol. 2001 Jul;50(1):121-7. (PMID: 11456302)
QJM. 2002 Jan;95(1):3-13. (PMID: 11834767)
J Neurol Neurosurg Psychiatry. 2008 Dec;79(12):1368-74. (PMID: 18535026)
Brain Pathol. 1999 Oct;9(4):651-6. (PMID: 10517504)
Lancet. 2002 Apr 6;359(9313):1221-31. (PMID: 11955556)
J Neurol. 2006 Jun;253(6):720-3. (PMID: 16502213)
Brain. 1997 Mar;120 ( Pt 3):393-9. (PMID: 9126051)
Brain. 2006 Mar;129(Pt 3):606-16. (PMID: 16415308)
CNS Neurol Disord Drug Targets. 2012 Aug;11(5):506-17. (PMID: 22583433)
Mult Scler. 2009 Jan;15(1):28-35. (PMID: 18805840)
J Neurol Neurosurg Psychiatry. 1998 Mar;64(3):402-4. (PMID: 9527161)
Neurology. 2004 Nov 23;63(10):1788-95. (PMID: 15557491)
Neurology. 2006 Jan 24;66(2):172-7. (PMID: 16434648)
Lancet. 2008 Oct 25;372(9648):1502-17. (PMID: 18970977)
Mult Scler. 2011 Mar;17(3):335-43. (PMID: 21135023)
Brain. 1999 Oct;122 ( Pt 10):1941-50. (PMID: 10506095)
Arch Neurol. 2001 Jan;58(1):65-70. (PMID: 11176938)
Science. 2001 Nov 23;294(5547):1731-5. (PMID: 11721059)
J Neurol Sci. 2008 Nov 15;274(1-2):42-4. (PMID: 18715571)
Ann Neurol. 2011 Jan;69(1):83-9. (PMID: 21280078)
Immunol Rev. 2005 Jun;205:207-19. (PMID: 15882355)
NeuroRehabilitation. 2009;25(4):271-8. (PMID: 20037220)
PLoS One. 2012;7(11):e48370. (PMID: 23226202)
PLoS One. 2010 Aug 05;5(8):e11986. (PMID: 20700489)
Nat Rev Rheumatol. 2011 Nov 01;7(12):708-17. (PMID: 22045310)
PLoS One. 2008 Jul 02;3(7):e2559. (PMID: 18596942)
Brain. 2009 May;132(Pt 5):1175-89. (PMID: 19339255)
Eur J Neurol. 2009 Apr;16(4):528-36. (PMID: 19220425)
Mol Diagn Ther. 2009;13(4):225-44. (PMID: 19712003)
Brain Res Bull. 2003 Aug 15;61(3):347-55. (PMID: 12909304)
J Neuroimmunol. 2002 Jan;122(1-2):125-31. (PMID: 11777551)
Int Rev Cytol. 1991;124:187-215. (PMID: 2001916)
Neurology. 2009 Dec 8;73(23):2003-10. (PMID: 19996075)
Neurology. 2004 Nov 9;63(9):1586-90. (PMID: 15534240)
Ann Neurol. 1995 Nov;38(5):788-96. (PMID: 7486871)
Brain. 1998 Dec;121 ( Pt 12):2327-34. (PMID: 9874483)
Vaccine. 2000 Feb 25;18(16):1717-20. (PMID: 10689155)
Mult Scler. 2013 Jun;19(7):877-84. (PMID: 23178691)
Annu Rev Neurosci. 2008;31:247-69. (PMID: 18558855)
Neurology. 2013 Jan 1;80(1):47-54. (PMID: 23267030)
J Neurol Sci. 2007 Apr 15;255(1-2):35-41. (PMID: 17331540)
Cytokine Growth Factor Rev. 2008 Oct-Dec;19(5-6):333-45. (PMID: 18952487)
Brain. 2006 Jan;129(Pt 1):200-11. (PMID: 16280350)
Mult Scler. 2011 Jan;17(1):32-42. (PMID: 20921238)
Mult Scler. 2010 Mar;16(3):287-92. (PMID: 20086018)
J Clin Immunol. 2006 Jul;26(4):299-307. (PMID: 16652230)
Neurology. 1999 Jul 13;53(1):20-5. (PMID: 10408531)
Nat Rev Immunol. 2003 Jul;3(7):569-81. (PMID: 12876559)
Brain. 2006 Mar;129(Pt 3):595-605. (PMID: 16415309)
Ann Neurol. 2007 Jan;61(1):14-24. (PMID: 17262850)
Ann Neurol. 2009 Oct;66(4):460-71. (PMID: 19847908)
J Neurol Sci. 2005 Dec 15;239(1):95-9. (PMID: 16209877)
Ann Neurol. 2002 Apr;51(4):475-80. (PMID: 11921053)

0 (Biomarkers)

Date Created: 20130514 Date Completed: 20131217 Latest Revision: 20240319

20240319

PMC3646751

10.1371/journal.pone.0063172

23667585