Author Of 4 Presentations
LB1210 - Cerebrospinal fluid inflammatory profile of cognitive dysfunction in newly diagnosed multiple sclerosis patients (ID 2066)
Abstract
Background
Increased cerebrospinal fluid (CSF) expression of proinflammatory cytokines (IFNG, TNF, IL2, and IL22) and molecules related to sustained B-cell activity and lymphoid-neogenesis (CXCL13, CXCL10, LTa, IL6, and IL10) was found associated to increase cortical grey matter (GM) pathology and more active and severe disease outcome either in naive MS patients or in post-mortem MS cases. Cognitive impairment (CI) is one of the main features of GM damage in MS and can be early observed in newly diagnosed MS patients.
Objectives
To investigate whether a potential link between CSF inflammatory profile and CI exists in newly diagnosed MS patients.
Methods
Sixty-nine, treatment-naïve MS patients (54 F, age=37.3±11.6 ys; education=14.4±3.5 years) underwent an extended battery of neuropsychological tests (median time between LP and neuropsychological assessment: 1 month) and the protein analysis of the levels of 57 inflammatory mediators by using customized immune-assay multiplex Bio-Plex X200. MS patients were classified into three groups (Cognitively Normal: CN; mild CI: mCI; severe CI: sCI) according to the number of neuropsychological tests below the cut-off (5th percentile).
Results
Increased CSF levels of CXCL13 were detected in sCI (mean=29.6pg/ml±SD=59.3) compared to both CN (5.5±9.6) and mCI (6.7±6.3) patients. Furthermore, in mCI compared to CN patients were found higher levels of CHI3L1 (mCI: 5431.7±31942.7; CN: 32743.6±18050.9), CX3CL1 (mCI: 550.7±402.2; CN: 311.7±146.1), IL8 (mCI: 116.5±128.6; CN: 43.1±30.5), CCL3 (mCI: 8.8±7.7; CN: 4.7±2.7), CCL19 (mCI: 164.5±117.0; CN: 83.8±93.4), sTNFr2 (mCI: 1017.9±761.3; CN: 550.1±366.6), and CCL8 (mCI: 590.4±1097.6; CN: 97.4±194.5). Finally, in sCI compared to CN patients were found higher levels of IL22 (sCI: 46.5±43.7; CN: 17.1±15.2), IL35 (sCI: 330.0±214.2; CN: 192.1±133.2), IL12 (sCI: 31.0±37.1; CN: 9.6±11.9), and LIGHT (sCI: 291.3±519.3; CN: 61.6±100.1). In particular, significant correlations were found between the cytokines-chemokines and tests of memory, attention/executive functions, and information processing speed. No significant difference in the CSF Nf-L level was found among the three groups (p=.96).
Conclusions
The presence of CI might be reflected by increased CSF levels of inflammatory mediators. In particular, we found a specific molecular pattern discriminating CN (innate immunity) from mCI and sCI (B-cell chemotaxis and activity). These results demonstrate, for the first time, that specific intrathecal inflammatory milieu might possibly contribute to the MS-related cognitive impairment since the early phases of MS disease.
LB1216 - Cortical and deep grey matter volume loss is specifically linked to cerebrospinal fluid inflammation in early multiple sclerosis. (ID 2081)
Abstract
Background
Several neuropathological and imaging studies demonstrated that cortical and deep grey matter damage follows a ‘surface in’ gradient, suggesting the possibility that soluble inflammatory factors released in the cerebrospinal fluid (CSF) might play a pathogenetic role.
Objectives
To verify whether soluble factors released from meningeal and CSF inflammation are considered the most probably triggers of superficial grey matter damage.
Methods
We evaluated the association, at diagnosis, between, among 110 relapsing remitting naïve MS patients, who underwent blinded clinical, CSF and 3T-MRI evaluations at time of diagnosis. The CSF protein levels of 32 inflammatory mediators were correlated, by using multivariate regression analysis, with the volume loss in hippocampus, insula, cerebellum and thalamus.
Results
Significant correlations were found between: hippocampus volume loss and the CSF protein levels of CXCL13 (β=-5.65x10-3;p<0.0001), CXCL10 (β=-1.46x10-4;p<0.05) and sCD163 (β=-3.20x10-6; p<0.0001); thalamic volume loss and the CSF protein levels of CXCL13 (β=-12.5;p<0.0001), sTNF-R1 (β=-6.00x10-2; p<0.05), sCD163 (β=-1.33x10-2; p<0.0001) and fibrinogen (β=-31.48; p<0.05); cerebellum volume loss and the CSF protein levels of sCD163 (β=-6.78x10-2; p<0.001) and chitinase-3-like1(β=-3.20x10-2;p<0.05); finally, insula volume loss and the CSF protein levels of CXCL13 (β=-5.92x10-3; p<0.001), CCL20 (β=-1.14x10-1; p<0.001) and osteopontin (β=1.71x10-6; p<0.05).
Conclusions
At time of diagnosis, elevated CSF levels of the mayor B-cell chemoattractant molecule CXCL13 is substantially linked to grey matter atrophy in all the deep and cortical grey matter examined areas. In addition, elevated levels of markers of glia activity, such as sCD163, osteopontin, chitinase-3-like1 and sTNFR1 have also a key role in grey matter volume loss. These data represent the first demonstration of a direct link between intrathecal CSF inflammatory myelin and the surface in grey matter damage since early disease stages.
P0056 - CSF inflammatory profile of primary progressive multiple sclerosis (ID 1657)
Abstract
Background
Background: So far, no specific biomarkers that help to stratify primary progressive multiple sclerosis (PPMS) from relapsing remitting multiple sclerosis (RRMS) patients are still unknown. In the diagnosis of PPMS, among with clinical and imaging assessment, the analysis of cerebrospinal fluid with regard to evidence of oligoclonal bands and/or elevated IgG index is helpful.
Objectives
Objectives: To evaluate the levels of 69 pro and anti-inflammatory cytokines and chemochines as well as Nf-L in the CSF of PPMS at the diagnosis.
Methods
Methods: Levels of 69 inflammatory mediators and of NF-L has been evaluated in the CSF obtained at the diagnosis from 16 patients with PPMS, 80 patients with RRMS and 12 patients with central nervous system non-inflammatory neurological disorders by mean of immune-assay multiplex techniques based on the Luminex technology and Human NF-light enzyme-linked immunosorbentassays. Clinical assessment including EDSS and white and grey matter (WM and GM) lesion volume and numbers were collected by using 3-T MRI analysis.
Results
Results: No significant differences were noticed in IgG index, CSF lymphocyte count, NF-L levels, WM and GM lesion volume and number were not significantly different between PPMS and RRMS. PPMS patients had higher EDSS when compared to RRMS group (median[IQR] 3 [3-4] vs 2[1-2.375]) and older age (mean54.5±9.6y vs 36.8 ± 11.9, p<0.001). Among selected molecules that appeared increased in both PPMS and RRMS groups respect to controls, a multivariate logistic regression analysis showed that at diagnosis altered levels of some B-cell related cytokines such as IL-10 (OR=0.28, CI95%[0.09-0.96]) and CXCL12 (OR=3.97, CI95%[1.34-11.7]) and the monocyte-related osteopontin (OR=2.24, CI95%[1.01-4.99]) were predictive for a primary progressive course of the disease instead of a relapsing one. Kegg pathway analysis confirmed that most of molecules characterizing PPMS CSF profile are involved in chronic immune inflammatory diseases.
Conclusions
Conclusions: At the diagnosis, CSF of PPMS patients appeared characterized by high levels of inflammatory mediators. A detailed CSF profiling obtained at the diagnosis could help to differentiate progressive forms of MS, providing new insights into its pathogenesis and useful tools in clinical practice.
P0950 - Cerebrospinal fluid IgM associates with specific inflammatory profile and disease features in early multiple sclerosis. (ID 1739)
Abstract
Background
Patients with multiple sclerosis (MS) displayed high levels of IgM, IgA and IgG in the cerebrospinal fluid (CSF). In particular, intrathecal immunoglobulin M (IgM) synthesis has been suggested as a prognostic marker of a more rapid and severe disease progression in MS.
Objectives
Investigate whether IgM production is associated with a specific CSF inflammatory profile in naïve MS patients at the time of diagnosis.
Methods
CSF protein levels of IgM, IgA, IgG and of 34 inflammatory mediators were analysed using Bio-Plex Multiplex immunoassay in 103 naïve relapsing-remitting MS patients (RRMS) and 36 patients with other neurological disorders.CSF IgM levels were also correlated with clinical and neuroradiological measures (advanced 3T-MRI parameters) at diagnosis and after 2 years of follow-up.
Results
A 45.6% increase in CSF IgM levels was found in MS patients compared to controls (p=0.013), while no significant differences in IgG (p=0.360) and IgA (p=0.700) levels between the two groups have been detected. CSF IgM levels correlated with higher paired CSF levels of CXCL13 (p=0.039), CCL21 (p=0.023), IL-10 (p=0.025), IL-12p70 (p=0.020), CX3CL1 (p=0.036) and CHI3L1 (p=0.048) and were associated with earlier age of patients at diagnosis (p=0.008), white matter lesions (WMLs) number (p=0.039) and disease activity (p=0.033) after 2 years of follow-up.
Conclusions
IgM are the most abundant immunoglobulins present at diagnosis in naïve RRMS patients compared to other neurological conditions at the time of diagnosis and their association with further molecules related to both B-cell immunity (IL-10) and recruitment (CXCL13 and CCL21) and to macrophage/microglia activity (IL-12p70, CX3CL1 and CHI3L1) suggestsa link between humoral and innate intrathecal immunity.