title: Normal-appearing white matter changes vary with distance to lesions in multiple sclerosis.
abstract: OBJECTIVE
  Multiple sclerosis (MS) disease processes in normal-appearing white matter (NAWM) may be different close to MR-visible lesions than farther from these lesions. We aimed to investigate the relationship of NAWM changes to the distance to the lesions.
  
  
  METHODS
  We measured B(1)-corrected T1 and magnetization transfer ratio (MTR) maps in 63 patients with MS (11 primary progressive, 34 relapsing-remitting, 18 secondary progressive). We used histogram analyses to assess the global properties of lesions, of 4 consecutive 1-mm pixel layers of NAWM around the lesions, and of distant NAWM located at least 4-mm from lesions in all directions. In 22 healthy controls, we measured white matter MTR and T1 histograms. Histogram parameters were statistically analyzed by using a linear mixed model.
  
  
  RESULTS
  The first and second NAWM pixel layers around the lesions had a significantly lower MTR histogram peak position than distant NAWM, whereas T1 histogram peak position was similar between all types of NAWM. Furthermore, MTR histograms of distant NAWM were statistically indistinguishable from those of control white matter, whereas T1 histograms of distant NAWM had significantly decreased peak height for relapsing-remitting MS and secondary progressive MS and significantly increased peak position for secondary progressive MS.
  
  
  CONCLUSIONS
  Our results may suggest that axonal damage and demyelination in NAWM mainly arise as a secondary result of visible lesions, with the largest effect close to these lesions. NAWM disease farther from the lesions may be mainly characterized by subtle blood-brain barrier damage, with leakage of fibrinogen into the parenchyma and microplaque formation, processes that are detected with T1 but not with MTR.
authors.affiliation: Department of Radiology, MR Center for MS Research, VU University Medical Center, Amsterdam, the Netherlands. h.vrenken@vumc.nl
authors.forename: H
authors.initials: H
authors.lastname: Vrenken
authors.forename: J J G
authors.initials: JJ
authors.lastname: Geurts
authors.forename: D L
authors.initials: DL
authors.lastname: Knol
authors.forename: C H
authors.initials: CH
authors.lastname: Polman
authors.forename: J A
authors.initials: JA
authors.lastname: Castelijns
authors.forename: P J W
authors.initials: PJ
authors.lastname: Pouwels
authors.forename: F
authors.initials: F
authors.lastname: Barkhof
mesh_terms: D000328:Adult; D016880:Anisotropy; D001921:Brain / Q000473:pathology; D005260:Female; D006801:Humans; D007089:Image Enhancement; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D008432:Mathematical Computing; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000175:diagnosis*; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000175:diagnosis*; D009413:Nerve Fibers, Myelinated / Q000473:pathology*