title: Multiple sclerosis normal-appearing white matter: pathology-imaging correlations.
abstract: OBJECTIVE
  The study was undertaken to determine the pathologic basis of subtle abnormalities in magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI) parameters observed in normal-appearing white matter (NAWM) in multiple sclerosis brains.
  
  
  METHODS
  Brain tissues were obtained through a rapid postmortem protocol that included in situ magnetic resonance imaging (MRI). Four types of MRI-defined regions of interest (ROIs) were analyzed: (1) regions that were abnormal on all images (T2T1MTR lesions); (2) NAWM regions with slightly abnormal MTR located close to white matter lesions (sa-WM Close); (3) NAWM regions with slightly abnormal MTR located far from lesions (sa-WM Far); and (4) NAWM regions with normal MTR (NAWM). Immunohistochemical analysis for each ROI comprised immunostaining for myelin, axonal markers, activated microglia/macrophages, astrocytes, plasma proteins, and blood vessels.
  
  
  RESULTS
  Forty-eight ROIs from 4 secondary progressive MS brains were analyzed. sa-WM Close ROIs were associated with significantly more axonal swellings. There were more enlarged major histocompatibility complex II(+) microglia and macrophages detected in sa-WM Far, sa-WM Close, and T2T1MTR lesions than in NAWM. Across all ROIs, MTR and DTI measures were moderately correlated with myelin density, axonal area, and axonal counts. Excluding T2T1MTR lesions from analysis revealed that MTR and DTI measures in nonlesional white matter (WM) were correlated with activated microglia, but not with axonal or myelin integrity.
  
  
  CONCLUSIONS
  The pathologic substrates for MRI abnormalities in NAWM vary based on distance from focal WM lesions. Close to WM lesions, axonal pathology and microglial activation may explain subtle MRI changes. Distant from lesions, microglial activation associated with proximity to cortical lesions might underlie MRI abnormalities.
authors.affiliation: Neuroinflammation Research Center and Department of Neurosciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Natalia M
authors.initials: NM
authors.lastname: Moll
authors.forename: Anna M
authors.initials: AM
authors.lastname: Rietsch
authors.forename: Smitha
authors.initials: S
authors.lastname: Thomas
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Ransohoff
authors.forename: Jar-Chi
authors.initials: JC
authors.lastname: Lee
authors.forename: Robert
authors.initials: R
authors.lastname: Fox
authors.forename: Ansi
authors.initials: A
authors.lastname: Chang
authors.forename: Richard M
authors.initials: RM
authors.lastname: Ransohoff
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fisher
mesh_terms: D000328:Adult; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D001798:Blood Proteins / Q000378:metabolism; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000473:pathology*; D056324:Diffusion Tensor Imaging; D005260:Female; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D017628:Microglia / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D009413:Nerve Fibers, Myelinated / Q000473:pathology*; D011180:Postmortem Changes
chemical_list: D015415:Biomarkers; D001798:Blood Proteins