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Degree of Meningeal Inflammation and Cortical Pathology May be a Useful Tool to Stratify Early Progressive MS Patients (ACTRIMS 2016)
The degree of meningeal inflammation and cortical pathology may be useful tools to stratify patients with early progressive MS according to a presentation at Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2016, held February 18-20 in New Orleans.
Cortical lesion load is associated with disease progression in MS. “The changing course of MS is a matter of gray matter,” stated Dr. Robert Magliozzi, MD, from the University of Verona, Italy, and Imperial College London, United Kingdom. As MS progresses, the immune system becomes compartmentalized. Compartmentalized meningeal inflammation is associated with increased cortical demyelination and a more severe disease outcome. Meningeal inflammation is associated with increased expression of inflammatory genes in the meninges and protein in the CSF in neuropathology specimens.
The researchers looked at gene and protein expression profiles in cerebrospinal fluid (CSF) and the association with cortical damage as visualized by MRI and neuropathology in patients with rapidly progressing MS. They also further stratified patients with and without a high degree of meningeal inflammation.
There was a significant increase in lymphoid stimulating chemokines (CXCL13, CXCL10, and CXCL9) and pro-inflammatory cytokines (CXCL20, CCL22, IL22, IL2) in the post-mortem CSF of patients with a high degree of meningeal inflammation. In contrast, there was a significant increase in gene expression of regulatory molecules (IL17a and IL9) in patients with a lower degree of meningeal inflammation. The researchers summarized that MS patients with a high degree of meningeal inflammation also had a high intrathecal pro-inflammatory profile, including several molecules linked to B-cell activity.
The group also combined advanced MRI techniques (3D double inversion recovery MRI profiling) of gray matter damage with protein analysis in 36 patients with MS and 12 control patients with non-inflammatory neurologic diseases. When the MS patients were stratified by lesion load, the CSF inflammatory profile was different between the groups of patients. Those patients with a lower cortical lesion load had significant increases in anti-inflammatory molecules in CSF; specifically, the anti-viral immune response (IFNα, IFNβ, and IFNλ) and Th2 regulatory cytokines (CCL22 and CCL25). This suggests that the “anti-inflammatory and regulatory intrathecal inflammatory profile is associated with lower cortical lesion load,” stated Dr. Magliozzi.
In patients with a higher cortical lesion load, significant increases in the levels of inflammatory molecules were observed, specifically lymphoid chemokines (CXCL13, CXCL12, CCL19, CCL21), plasmablast differentiation (IL-6, IL-10, TNF), and pro-inflammatory mediators (IFNγ, GM-CSF, Pentraxin II, and MMP2). She summarized that this suggests that the intrathecal inflammatory profile linked to B-cell activation and lymphoid neogenesis as well as a pro-inflammatory profile was associated with higher cortical lesion load.
In conclusion, Dr. Magliozzi stated that meningeal infiltrates may represent the main source of intrathecal inflammatory activity mediating the gradient of cortical tissue injury in progressive MS. Molecular CSF and cortical MRI profiling of MS patients may provide a useful tool for stratifying patients by disease prognosis.
Howell OW, Reeves CA, Nicholas R, Carassiti D, Radotra B, Gentleman SM, Serafini B, Aloisi F, Roncaroli F, Magliozzi R, Reynolds R. Meningeal inflammation is widespread and linked to cortical pathology in multiple sclerosis. Brain. 2011 Sep;134(Pt 9):2755-71.