Intense Inflammation and Nerve Damage in Early Multiple Sclerosis Subsides at Older Age: A Reflection by Cerebrospinal Fluid Biomarkers
Open Access
- 7 May 2013
- journal article
- research article
- Published by Public Library of Science (PLoS) in PLOS ONE
- Vol. 8 (5), e63172
- https://doi.org/10.1371/journal.pone.0063172
Abstract
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.Keywords
This publication has 60 references indexed in Scilit:
- Cerebrospinal Fluid IL-12p40, CXCL13 and IL-8 as a Combinatorial Biomarker of Active Intrathecal InflammationPLOS ONE, 2012
- Validation of new biomarkers in systemic autoimmune diseasesNature Reviews Rheumatology, 2011
- Axonal damage in relapsing multiple sclerosis is markedly reduced by natalizumabAnnals of Neurology, 2010
- The Chemokine CXCL13 Is a Prognostic Marker in Clinically Isolated Syndrome (CIS)PLOS ONE, 2010
- The relation between inflammation and neurodegeneration in multiple sclerosis brainsBrain, 2009
- Analysis of cerebrospinal fluid and cerebrospinal fluid cells from patients with multiple sclerosis for detection of JC virus DNAMultiple Sclerosis Journal, 2009
- Osteopontin: Role in immune regulation and stress responsesCytokine & Growth Factor Reviews, 2008
- Multiple sclerosisThe Lancet, 2008
- Cerebrospinal Fluid B Cells Correlate with Early Brain Inflammation in Multiple SclerosisPLOS ONE, 2008
- Three or more routes for leukocyte migration into the central nervous systemNature Reviews Immunology, 2003