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The formation of inflammatory demyelinated lesions in cerebral white matter
Author(s) -
Maggi Pietro,
Macri Sheila M. Cummings,
Gaitán María I.,
Leibovitch Emily,
Wholer Jillian E.,
Knight Heather L.,
Ellis Mary,
Wu Tianxia,
Silva Afonso C.,
Massacesi Luca,
Jacobson Steven,
Westmoreland Susan,
Reich Daniel S.
Publication year - 2014
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.24242
Subject(s) - pathology , multiple sclerosis , medicine , microglia , marmoset , magnetic resonance imaging , vascular permeability , lesion , white matter , perivascular space , encephalomyelitis , experimental autoimmune encephalomyelitis , inflammation , immunology , biology , radiology , paleontology
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). Interpretation 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. Ann Neurol 2014;76:594–608