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

PLoS One. 2013 May 7;8(5):e63172. doi: 10.1371/journal.pone.0063172. Print 2013.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Biomarkers

Grant support

AS has received travel support and/or lecture honoraria from BiogenIdec, MerckSerono, Genzyme/SanofiAventis, and Baxter, and he has received unconditional research grants from BayerScheringPharma and BiogenIdec. TO has received personal compensation for consultancy or lecture fees from BiogenIdec, MerckSerono, SanofiAventis, BayerSchering and Novartis. BiogenIdec Sweden AB provided an unrestricted grant for this study. LB has recieved teaching and consultation fees from BiogenIdec, SanofiAventis, Novartis, Genzyme and Amirall. MK, AD, JG, AW, FA, RH, MA and FP have no conflicts to declare. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials.