title: The formation of inflammatory demyelinated lesions in cerebral white matter.
abstract: OBJECTIVE
  Vascular permeability and inflammatory demyelination are intimately linked in the brain, but what is their temporal relationship? We aimed to determine the radiological correlates of the earliest tissue changes accompanying demyelination in a primate model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE) in the common marmoset.
  
  
  METHODS
  By 7T magnetic resonance imaging (MRI), T1 maps, proton density, and T2-weighted images were acquired before and after EAE induction in 5 marmosets (every other week before lesions appeared, weekly thereafter). From scans before and after intravenous injection of contrast material, we measured the evolution of lesional blood-brain barrier (BBB) permeability, comparing in vivo MRI to postmortem tissue examination.
  
  
  RESULTS
  On average, BBB permeability increased 3.5-fold (p < 0.0001) over the 4 weeks prior to lesion appearance. Permeability gradually decreased after lesion appearance, with attendant changes in the distribution of inflammatory cells (predominantly macrophages and microglia) and demyelination. On tissue analysis, we also identified small perivascular foci of microglia and T cells without blood-derived macrophages or demyelination. These foci had no visible MRI correlates, although permeability within the foci, but not outside, increased in the weeks before the animals died (p < 0.0001).
  
  
  CONCLUSIONS
  This study provides compelling evidence that in marmoset EAE, which forms lesions strongly resembling those of MS, early changes in vascular permeability are associated with perivascular inflammatory cuffing and parenchymal microglial activation but precede the arrival of blood-derived monocytes that accompany demyelination. Prospective detection of transient permeability changes could afford an opportunity for early intervention to forestall tissue damage in newly forming lesions.
authors.affiliation: National Institute for Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA; Department of Neurosciences, Drug Research, and Child's Health, University of Florence, Florence, Italy.
authors.forename: Pietro
authors.initials: P
authors.lastname: Maggi
authors.forename: Sheila M Cummings
authors.initials: SM
authors.lastname: Macri
authors.forename: María I
authors.initials: MI
authors.lastname: Gaitán
authors.forename: Emily
authors.initials: E
authors.lastname: Leibovitch
authors.forename: Jillian E
authors.initials: JE
authors.lastname: Wholer
authors.forename: Heather L
authors.initials: HL
authors.lastname: Knight
authors.forename: Mary
authors.initials: M
authors.lastname: Ellis
authors.forename: Tianxia
authors.initials: T
authors.lastname: Wu
authors.forename: Afonso C
authors.initials: AC
authors.lastname: Silva
authors.forename: Luca
authors.initials: L
authors.lastname: Massacesi
authors.forename: Steven
authors.initials: S
authors.lastname: Jacobson
authors.forename: Susan
authors.initials: S
authors.lastname: Westmoreland
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Reich
mesh_terms: D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002144:Callithrix; D002540:Cerebral Cortex / Q000473:pathology*; D003287:Contrast Media; D004195:Disease Models, Animal; D004660:Encephalitis / Q000209:etiology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000150:complications* / Q000473:pathology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007091:Image Processing, Computer-Assisted; D039841:Leukocyte L1 Antigen Complex / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008840:Microfilament Proteins / Q000378:metabolism; D066127:White Matter / Q000378:metabolism / Q000473:pathology*
chemical_list: D003287:Contrast Media; D005904:Glial Fibrillary Acidic Protein; D039841:Leukocyte L1 Antigen Complex; D008840:Microfilament Proteins; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases
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