Quantitative MRI‐pathology correlations of brain white matter lesions developing in a non‐human primate model of multiple sclerosis

Abstract

Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligodendrocyte glycoprotein in the common marmoset is a useful preclinical model of multiple sclerosis in which white matter lesions can be well visualized with MRI. In this study we characterized lesion progression with quantitative in vivo MRI (4.7 T ; T 1 relaxation time AE Gd-DTPA; T 2 relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T 1 and T 2 relaxation times; MTR) and histology. The histopathological characterization included axonal density measurements and the numeric quantification of infiltrated macrophages expressing markers for early active [luxol fast blue (LFB) or migration inhibition factor-related protein-14 positive] or late active/inactive [periodic acid Schiff (PAS) positive] demyelinating lesion. MRI experiments were done every two weeks until the monkeys were sacrificed with severe EAE-related motor deficits. Compared with the normal appearing white matter, lesions showed an initial increase in T 1 relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T 1 values, while T 2 initially increased and stabilized thereafter and MTR remained decreased. Gd-DTPA leakage was highly variable throughout the experiment. MRI characteristics of the cortex and (normal appearing) white matter did not change during the experiment. We observed that in vivo MTR values correlated positively with the number of early active (LFBþ) and negatively with late active (PASþ) macrophages. Ex vivo MTR and relaxation times correlated positively with the number of PAS-positive macrophages. None of the investigated MRI parameters correlated with axonal density.

Late B Cell Depletion with a Human Anti-Human CD20 IgG1κ Monoclonal Antibody Halts the Development of Experimental Autoimmune Encephalomyelitis in Marmosets

“…One cerebral hemisphere collected at necropsy was fixed in 4% buffered formalin and 2 wk later transferred into buffered saline containing sodium azide to allow stabilization of magnetic resonance (MR) relaxation time characteristics (31). High-contrast postmortem MR images were recorded on a 9.4 T horizontal bore nuclear magnetic resonance spectrometer (Varian ,Table I.…”

Magnetic resonance imaging of experimental autoimmune encephalomyelitis in the common marmoset

“…The same techniques can be applied to the marmoset EAE at various magnetic field strengths (1.5 T, 3 T and 7 T) (Jordan et al, 1999;Gaitan et al, 2013;Maggi et al, 2014a;Blezer et al, 2007;Helms et al, 2013). Similarly to MS, new WM lesions in the marmoset EAE appear hyperintense on T2w and PDw and hypointense on T1w sequences.…”

“…Some of these advanced techniques (such as magnetization transfer imaging and T1 relaxometry) have also been applied to the marmoset EAE (Maggi et al, 2014a;Blezer et al, 2007;Richards et al, 1995).…”

“…5]. In acute EAE lesions, a decrease in MTR has been associated with inflammation (Blezer et al, 2007;t Hart et al, 2004) most likely due to the increased water content from edema [ Fig. 5].…”

Modelling of Autoimmune Encephalomyelitis in a Non-Human Primate

“…This is especially the case for biological agents, which due to high species-specificity are inactive in lower species. A particularly attractive aspect of the marmoset model is the possibility to visualize the large-sized lesions in the brain with clinically relevant magnetic resonance techniques (Blezer et al 2007;'t Hart & van Kooyk 2004). This has enabled determination of the direct effect of new immunotherapies on lesions independent of the effects on neurological signs ('t Hart & Heije 2005).…”