title: Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque.
abstract: OBJECTIVE
  An extensive analysis of white matter plaques in a large sample of multiple sclerosis (MS) autopsies provides insights into the dynamic nature of MS pathology.
  
  
  METHODS
  One hundred twenty MS cases (1,220 tissue blocks) were included. Plaque types were classified according to demyelinating activity based on stringent criteria. Early active, late active, smoldering, inactive, and shadow plaques were distinguished. A total of 2,476 MS white matter plaques were identified. Plaque type distribution was analyzed in relation to clinical data.
  
  
  RESULTS
  Active plaques were most often found in early disease, whereas at later stages, smoldering, inactive, and shadow plaques predominated. The presence of early active plaques rapidly declined with disease duration. Plaque type distribution differed significantly by clinical course. The majority of plaques in acute monophasic and relapsing-remitting MS (RRMS) were active. Among secondary progressive MS (SPMS) cases with attacks, all plaque types could be distinguished including active plaques, in contrast to SPMS without attacks, in which inactive plaques predominated. Smoldering plaques were frequently and almost exclusively found in progressive MS. At 47 years of age, an equilibrium was observed between active and inactive plaques, whereas smoldering plaques began to peak. Men displayed a higher proportion of smoldering plaques.
  
  
  CONCLUSIONS
  Disease duration, clinical course, age, and gender contribute to the dynamic nature of white matter MS pathology. Active MS plaques predominate in acute and early RRMS and are the likely substrate of clinical attacks. Progressive MS transitions to an accumulation of smoldering plaques characterized by microglial activation and slow expansion of pre-existing plaques. Whether current MS therapeutics impact this pathological driver of disease progression remains uncertain.
authors.affiliation: Department of Neurosurgery, Medical University Vienna, Vienna, Austria.
authors.forename: Josa M
authors.initials: JM
authors.lastname: Frischer
authors.affiliation: Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Weigand
authors.affiliation: Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Yong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Nilufer
authors.initials: N
authors.lastname: Kale
authors.affiliation: Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN.|Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN.
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Parisi
authors.affiliation: Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Istvan
authors.initials: I
authors.lastname: Pirko
authors.affiliation: Department of Health Sciences Research, College of Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Jay
authors.initials: J
authors.lastname: Mandrekar
authors.affiliation: Department of Neurology, Copenhagen University Hospital, Bispebjerg, Denmark.|Department of Pathology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
authors.forename: Stephan
authors.initials: S
authors.lastname: Bramow
authors.affiliation: Department of Neuropathology, University of Göttingen, Göttingen, Germany.
authors.forename: Imke
authors.initials: I
authors.lastname: Metz
authors.affiliation: Department of Neuropathology, University of Göttingen, Göttingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Brück
authors.affiliation: Department of Neuroimmunology, Center for Brain Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Hans
authors.initials: H
authors.lastname: Lassmann
authors.affiliation: Department of Neurology, College of Medicine, Mayo Clinic, Rochester, MN.
authors.forename: Claudia F
authors.initials: CF
authors.lastname: Lucchinetti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000473:pathology; D001344:Autopsy; D003711:Demyelinating Diseases / Q000473:pathology; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D017628:Microglia / Q000473:pathology; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000473:pathology*; D020528:Multiple Sclerosis, Chronic Progressive / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000473:pathology; D012727:Sex Characteristics; D066127:White Matter / Q000473:pathology*; D055815:Young Adult