Characterization of leptomeningeal inflammation in rodent experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis

Exp Neurol. 2019 Apr;314:82-90. doi: 10.1016/j.expneurol.2019.01.013. Epub 2019 Jan 23.

Abstract

Background: Leptomeningeal inflammation, as evidenced by leptomeningeal contrast enhancement (LMCE), is associated to cortical pathology in multiple sclerosis. The temporal pattern of LMCE in experimental autoimmune encephalomyelitis (EAE) myelin oligodendrocyte glycoprotein (MOG) is unknown.

Objective: To investigate LMCE using serial MRI in the EAE model of MS, and its association with clinical disease progression. To characterize the relationship between LMCE and underlying histological correlates.

Design: Thirteen C57BL/6J mice, MOG-immunized (35-55 amino acid) and 8 saline injected animals were assessed at pre-induction and at 3, 6, 10, 20, 27, 32, 45 and 63 days post induction (dPI). LMCE scan was obtained using FLAIR-RARE sequence after post-contrast gadolinium administration on 9.4 T scanner. Brain cryo-sections were assessed for measuring cellular density of Iba1 positive macrophage/microglia at 10 dPI and 32 dPI, and for the presence of T, B and macrophage cells in the meningeal layer at 10 dPI and 63 dPI.

Results: All EAE-MOG animals showed presence of LMCE and none of the control mice. The peak signal intensity of LMCE was evidenced at 10dPI in the meninges and decreased through 10-63 dPI. The peak of LMCE was associated with a weight loss starting at 1 week PI and with clinical symptoms starting at 2 weeks PI. Histological analysis of the brain tissue showed a higher density of Iba1 positive microglial cells in the EAE-MOG animals, corresponding to the areas of LMCE. Meninges of EAE mice showed higher density of Iba1 stained macrophage cells relative to saline animals. EAE animals also showed the presence of T and B cells in the meninges which were absent in the saline animals.

Conclusions: LMCE peak intensity in the meninges corresponds to the acute inflammatory phase of EAE-MOG disease progression, and is associated with clinical symptoms and higher inflammatory cell density.

Keywords: EAE; Inflammation; Leptomeningeal enhancement; MRI; Multiple sclerosis.

MeSH terms

  • Animals
  • B-Lymphocytes / pathology
  • Calcium-Binding Proteins / biosynthesis
  • Calcium-Binding Proteins / genetics
  • Cerebral Cortex / pathology
  • Encephalomyelitis, Autoimmune, Experimental / diagnostic imaging
  • Encephalomyelitis, Autoimmune, Experimental / pathology*
  • Female
  • Inflammation / pathology
  • Macrophages / metabolism
  • Macrophages / pathology
  • Magnetic Resonance Imaging
  • Meninges / pathology*
  • Mice
  • Mice, Inbred C57BL
  • Microfilament Proteins / biosynthesis
  • Microfilament Proteins / genetics
  • Microglia / metabolism
  • Microglia / pathology
  • Multiple Sclerosis / diagnostic imaging
  • Multiple Sclerosis / pathology*
  • Myelin-Oligodendrocyte Glycoprotein / biosynthesis
  • Myelin-Oligodendrocyte Glycoprotein / genetics
  • T-Lymphocytes / pathology
  • Weight Loss

Substances

  • Aif1 protein, mouse
  • Calcium-Binding Proteins
  • Microfilament Proteins
  • Mog protein, mouse
  • Myelin-Oligodendrocyte Glycoprotein