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 At 7 tesla 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, though 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.

Neurite dispersion: a new marker of multiple sclerosis spinal cord pathology?

“…In vivo mapping of myelin density15 and g‐ratio16; iron deposition17; sodium concentration18; inflammation and axonal injury19 are examples of quantitative MRI techniques being developed to detect early multiple sclerosis pathology. Similar quantitative MRI metrics require extensive validation, in order to confirm their specificity and relevance to clinical outcomes 20, 21, 22…”

Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis

“…BBB breakdown is a contributing factor to the pathogenesis of both MS and EAE (2)(3)(4). Structural and functional BBB degradation precedes lesion development in both MS and EAE (5)(6)(7)(8)(9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7,11) and coincides with early infiltration of neutrophils before the onset of EAE (12).…”

“…Structural and functional BBB degradation precedes lesion development in both MS and EAE (5)(6)(7)(8)(9), and focal BBB abnormalities correlate with clinical exacerbations in the relapsing-remitting form of MS (10). Moreover, BBB leakage precedes the entry of T cells and monocytes into the brain parenchyma (7,11) and coincides with early infiltration of neutrophils before the onset of EAE (12). Although the severity of barrier leakage decreases over time for most relapsing-remitting MS lesions, as assessed by gadoliniumenhancing magnetic resonance imaging (7,(13)(14)(15), whether BBB recovery is an active process and, if so, which pathways mediate its repair, remain unclear.…”

Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common marmoset

“…This issue can be overcome with animal models which enable a direct comparison of MR images acquired in vivo with histopathology performed post mortem. Another advantage of animal models is the possibility to obtain pre-morbid MR images and to follow the development of brain lesions from the time of their first appearance until the termination of the experiment Maggi et al, 2014a). Similarly to human studies, conventional and non-conventional MRI techniques can be applied to these animals, thus allowing to better understand the biological correlates of the MRI findings, as well as validating novel more specific MRI markers of the different damages (such as demyelination, axonal pathology, iron deposition) occurring in brain lesions.…”