title: Association between change in normal appearing white matter metabolites and intrathecal inflammation in natalizumab-treated multiple sclerosis.
abstract: BACKGROUND
  Multiple sclerosis (MS) is associated not only with focal inflammatory lesions but also diffuse pathology in the central nervous system (CNS). Since there is no firm association between the amount of focal inflammatory lesions and disease severity, diffuse pathology in normal appearing white matter (NAWM) may be crucial for disease progression. Immunomodulating treatments for MS reduce the number of focal lesions, but possible effects on diffuse white matter pathology are less studied. Furthermore, it is not known whether intrathecal levels of inflammatory or neurodegenerative markers are associated with development of pathology in NAWM.
  
  
  METHODS
  Quantitative proton magnetic resonance spectroscopy ((1)H-MRS) was used to investigate NAWM in 27 patients with relapsing MS before and after one year of treatment with natalizumab as well as NAWM in 20 healthy controls at baseline. Changes in (1)H-MRS metabolite concentrations during treatment were also correlated with a panel of intrathecal markers of inflammation and neurodegeneration in 24 of these 27 patients.
  
  
  RESULTS
  The group levels of (1)H-MRS metabolite concentrations were unchanged pre- to posttreatment, but a pattern of high magnitude correlation coefficients (r = 0.43-0.67, p<0.0005-0.03) were found between changes in individual metabolite concentrations (total creatine and total choline) and levels of pro-inflammatory markers (IL-1β and CXCL8).
  
  
  CONCLUSIONS
  Despite a clinical improvement and a global decrease in levels of inflammatory markers in cerebrospinal fluid during treatment, high levels of pro-inflammatory CXCL8 and IL-1β were associated with an increase in (1)H-MRS metabolites indicative of continued gliosis development and membrane turnover in NAWM.
authors.affiliation: Neurology, Department of Clinical and Experimental Medicine, Division of Neuroscience, Faculty of Health Sciences, Linköping University, Linköping, Sweden. johan.mellergard@lio.se
authors.forename: Johan
authors.initials: J
authors.lastname: Mellergård
authors.forename: Anders
authors.initials: A
authors.lastname: Tisell
authors.forename: Olof
authors.initials: O
authors.lastname: Dahlqvist Leinhard
authors.forename: Ida
authors.initials: I
authors.lastname: Blystad
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Landtblom
authors.forename: Kaj
authors.initials: K
authors.lastname: Blennow
authors.forename: Bob
authors.initials: B
authors.lastname: Olsson
authors.forename: Charlotte
authors.initials: C
authors.lastname: Dahle
authors.forename: Jan
authors.initials: J
authors.lastname: Ernerudh
authors.forename: Peter
authors.initials: P
authors.lastname: Lundberg
authors.forename: Magnus
authors.initials: M
authors.lastname: Vrethem
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000069442:Natalizumab; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D053583:Interleukin-1beta; D016209:Interleukin-8; D000069442:Natalizumab; D003401:Creatine; D002794:Choline