Background: Grey matter (GM) damage provides the best correlate of the variable accumulation of physical and cognitive deficits and one of the main substrates of disability progression in multiple sclerosis (MS). New advanced imaging techniques have allowed a more accurate estimation of the load of GM demyelination and brain atrophy, suggesting that increased levels of GM pathology play a critical role in more rapid progressive outcome. Meningeal B-cell infiltrates have been proposed as the main source of the intrathecal inflammatory/cytotoxic milieu in the cerebrospinal fluid (CSF) that may mediate and exacerbate the gradient of tissue injury in the adjacent GM. Objectives: Identifying specific biomarkers and imaging tools to predict and monitor GM pathology and its association with MS progression. Methods: A new approach, combining advanced MRI imaging of GM damage with an extensive protein analysis of patient’s CSF, was performed on 70 MS patients and 12 controls. Analysis of molecular expression in paired meningeal and CSF samples from 20 post-mortem SPMS cases and 10 control cases was also performed in order to verify whether inflammatory mediators expressed by the meningeal infiltrates are released into the CSF. Results: A pronounced pro-inflammatory CSF profile, including over-expression of CXCL13, CXCL12, CCL19, CCL21, IL6, IL10, APRIL, BAFF, TNF, TNFR1, LIGHT, IFN-γ, GM-CSF and MMP2, suggesting lymphoid-neogenesis, B-cell and plasmablast/plasma cell involvement, in addition to a TNF-mediated inflammatory response, was found to be strictly associated with increased GM pathology and disease progression in MS patients. A pattern of increased regulatory molecules, including IFNα, IFNβ, IFNλ, CCL22 and CCL25, was associated with a lower level of GM pathology. In keeping with this, increased expression of CXCL13, CXCL9, TNF, IFNγ, LTα, LTβ, IL10, IL16, IL12p40 was detected in the meninges and CSF samples of post-mortem SPMS cases with higher level of meningeal inflammation and GM demyelination. Conclusion: The pro-inflammatory CSF profile of patients with high levels of GM damage suggests that meningeal B-cell infiltrates may represent the main source of inflammatory/cytotoxic molecules that are released into the CSF to cause cortical tissue injury in progressive MS. Such CSF profile significantly differs from that of patients with low level of GM damage, thus confirming that this may represent a useful approach for patient stratification at disease onset. (Study supported by the PMSA grant PA0124)
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