Contributions
Abstract: 112
Type: Oral
Abstract Category: Clinical aspects of MS - Clinical assessment tools
Introduction: Advanced imaging techniques and post-mortem tissue studies have demonstrated that cerebral grey matter (GM) damage is one of the main pathological substrates of the variable accumulation of physical and cognitive deficits in multiple sclerosis (MS) since early disease stages. Meningeal immune infiltrates are proposed as the main source of the intrathecal inflammation that mediates/exacerbates a gradient of GM injury.
Aims: By combining neuropathology, advanced MRI imaging of GM damage and patient CSF protein analysis, we aim to understand whether inflammatory mediators expressed by the meningeal infiltrates are released into the CSF to mediate damage of the adjacent GM and to develop prognostic biomarkers thereof.
Methods: Analysis of cytokine/chemokine gene expression in meningeal and CSF samples from 20 post-mortem SPMS cases and 10 control cases was performed. At the same time, we combined advanced Double Inversion Recovery (DIR) 3T MRI profiling with protein CSF analysis of the presence/levels of 68 inflammatory mediators in two independent cohorts of MS patients (35 subjects/each), at disease diagnosis, and 15 controls.
Results: Increased expression of CXCL13, CXCL9, TNF, IFN- γ, LT-α, LT-β, IL10, IL16, IL12p40 was detected in the meninges and CSF samples of post-mortem SPMS cases with increased levels of meningeal inflammation and GM demyelination. In keeping with this, increased expression of CXCL13, CXCL12, IL6, IL10, APRIL, BAFF, TNF, LIGHT, IFN-γ, pentraxin-3, sCD163 and MMP2, as well as neurofilament light-chains, in CSF from the first cohort of MS patients was associated with higher GM lesion load. On the contrary, a pattern of increased regulatory molecules, such as type I IFNs, CCL22 and CCL25, was found in the CSF of MS patients with lower GM lesion load. Confirmation of the significant correlation between increased expression of these molecules and the GM lesion load was obtained in the second independent “validation” MS cohort.
Conclusions: Meningeal immune activity plays a key role in creating specific intrathecal inflammatory profiles associated with different degrees of GM damage in both progressive and early MS. In particular, molecules related to B-cell immunity, lymphoid inflammation and pro-inflammatory activation appear associated with high levels of GM damage, while mediators linked to regulatory and innate immunity correlate with lower GM pathology involvement.
Disclosure: M. Calabrese: Advisory Board membership: Bayer-Shering, Genzyme, Biogen Idec
Payment for development of educational presentations including service on speakers bureaus: Biogen-Elan, Genzyme, TEVA, Bayer-Schering;
Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA
Abstract: 112
Type: Oral
Abstract Category: Clinical aspects of MS - Clinical assessment tools
Introduction: Advanced imaging techniques and post-mortem tissue studies have demonstrated that cerebral grey matter (GM) damage is one of the main pathological substrates of the variable accumulation of physical and cognitive deficits in multiple sclerosis (MS) since early disease stages. Meningeal immune infiltrates are proposed as the main source of the intrathecal inflammation that mediates/exacerbates a gradient of GM injury.
Aims: By combining neuropathology, advanced MRI imaging of GM damage and patient CSF protein analysis, we aim to understand whether inflammatory mediators expressed by the meningeal infiltrates are released into the CSF to mediate damage of the adjacent GM and to develop prognostic biomarkers thereof.
Methods: Analysis of cytokine/chemokine gene expression in meningeal and CSF samples from 20 post-mortem SPMS cases and 10 control cases was performed. At the same time, we combined advanced Double Inversion Recovery (DIR) 3T MRI profiling with protein CSF analysis of the presence/levels of 68 inflammatory mediators in two independent cohorts of MS patients (35 subjects/each), at disease diagnosis, and 15 controls.
Results: Increased expression of CXCL13, CXCL9, TNF, IFN- γ, LT-α, LT-β, IL10, IL16, IL12p40 was detected in the meninges and CSF samples of post-mortem SPMS cases with increased levels of meningeal inflammation and GM demyelination. In keeping with this, increased expression of CXCL13, CXCL12, IL6, IL10, APRIL, BAFF, TNF, LIGHT, IFN-γ, pentraxin-3, sCD163 and MMP2, as well as neurofilament light-chains, in CSF from the first cohort of MS patients was associated with higher GM lesion load. On the contrary, a pattern of increased regulatory molecules, such as type I IFNs, CCL22 and CCL25, was found in the CSF of MS patients with lower GM lesion load. Confirmation of the significant correlation between increased expression of these molecules and the GM lesion load was obtained in the second independent “validation” MS cohort.
Conclusions: Meningeal immune activity plays a key role in creating specific intrathecal inflammatory profiles associated with different degrees of GM damage in both progressive and early MS. In particular, molecules related to B-cell immunity, lymphoid inflammation and pro-inflammatory activation appear associated with high levels of GM damage, while mediators linked to regulatory and innate immunity correlate with lower GM pathology involvement.
Disclosure: M. Calabrese: Advisory Board membership: Bayer-Shering, Genzyme, Biogen Idec
Payment for development of educational presentations including service on speakers bureaus: Biogen-Elan, Genzyme, TEVA, Bayer-Schering;
Travel/accommodation expenses covered or reimbursed: Novartis Pharma, Genzyme, Biogen idec, Merck Serono, Bayer-Schering, TEVA