title: Relationship between cerebrospinal fluid biomarkers for inflammation, demyelination and neurodegeneration in acute optic neuritis.
abstract: BACKGROUND
  Various inflammatory biomarkers show prognostic potential for multiple sclerosis (MS)-risk after clinically isolated syndromes. However, biomarkers are often examined singly and their interrelation and precise aspects of their associated pathological processes remain unclear. Clarification of these relationships could aid the appropriate implementation of prognostic biomarkers in clinical practice.
  
  
  OBJECTIVE
  To investigate the interrelation between biomarkers of inflammation, demyelination and neurodegeneration in acute optic neuritis and to assess their association to measures of MS risk.
  
  
  METHODS
  A prospective study at a tertiary referral centre from June 2011 to December 2012 of 56 patients with optic neuritis as a first demyelinating symptom and 27 healthy volunteers. Lumbar puncture was performed within 28 (median 16) days of onset. CSF levels of CXCL13, matrix metalloproteinase (MMP)-9, CXCL10, CCL-2, osteopontin and chitinase-3-like-1, myelin basic protein (MBP) and neurofilament light-chain (NF-L) were determined. MS-risk outcome measures were dissemination in space (DIS) of white matter lesions on cerebral MRI, CSF oligoclonal bands and elevated IgG-index.
  
  
  RESULTS
  IN THE INTERRELATION ANALYSIS THE BIOMARKERS SHOWED CLOSE CORRELATIONS WITHIN TWO DISTINCT GROUPS: Biomarkers of leukocyte infiltration (CXCL13, MMP-9 and CXCL10) were strongly associated (p<0.0001 for all). Osteopontin and chitinase-3-like-1 were also tightly associated (p<0.0001) and correlated strongly to tissue damage markers (NF-L and MBP). The biomarkers of leukocyte infiltration all associated strongly with MS-risk parameters, whereas CHI3L1 and MBP correlated with MRI DIS, but not with CSF MS-risk parameters and osteopontin and NF-L did not correlate with any MS-risk parameters.
  
  
  CONCLUSIONS
  OUR FINDINGS SUGGEST TWO DISTINCT INFLAMMATORY PROCESSES: one of leukocyte infiltration, represented by CXCL13, CXCL10 and MMP-9, strongly associated with and potentially predicting MS-risk; the other represented by osteopontin and CHI3L1, suggesting tissue damage-related inflammation, potentially predicting residual disabilities after attack and perhaps cumulative damage over time. These hypotheses should be further addressed in follow-up studies.
authors.affiliation: MS Clinic, Department of Neurology, Copenhagen University Hospital Glostrup, Glostrup, Denmark.
authors.forename: Signe
authors.initials: S
authors.lastname: Modvig
authors.forename: Matilda
authors.initials: M
authors.lastname: Degn
authors.forename: Henrik
authors.initials: H
authors.lastname: Horwitz
authors.forename: Stig P
authors.initials: SP
authors.lastname: Cramer
authors.forename: Henrik B W
authors.initials: HB
authors.lastname: Larsson
authors.forename: Benedikte
authors.initials: B
authors.lastname: Wanscher
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
authors.forename: Jette L
authors.initials: JL
authors.lastname: Frederiksen
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D003711:Demyelinating Diseases / Q000134:cerebrospinal fluid* / Q000150:complications; D005260:Female; D006801:Humans; D007249:Inflammation / Q000134:cerebrospinal fluid* / Q000150:complications; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid* / Q000150:complications / Q000453:epidemiology; D019636:Neurodegenerative Diseases / Q000134:cerebrospinal fluid* / Q000150:complications; D009902:Optic Neuritis / Q000134:cerebrospinal fluid* / Q000150:complications; D011446:Prospective Studies; D012307:Risk Factors
chemical_list: D015415:Biomarkers