Moderator Of 1 Session
Author Of 9 Presentations
LB1209 - A tablet-based videogame for capturing slowing processing speed in multiple sclerosis patients: a pilot study (ID 2064)
Abstract
Background
Slowing information processing speed (IPS) is a biomarker of neuronal damage in patients with MS (pwMS). Computerized tools allow testing different cognitive load conditions that might reveal initial IPS inefficiencies before the appearance of formal cognitive impairment (CI) as assessed with paper-and-pencil neuropsychological tests.
Objectives
To further explore the feasibility of computerizes tools, we developed a tablet-based videogame for quickly and efficiently measuring IPS in pwMS without formal CI with the aim to assess its specificity and sensitivity in testing IPS in different cognitive load conditions in pwMS as compared to healthy controls (HC).
Methods
Forty-five pwMS (age:36.8±9.3; edu:13.9±3.1; F=33) without CI and 20 matched HC (age:34.4±12.3; edu:17.5±2.5; F=7) underwent 3 videogame levels of increasing cognitive load. Reaction times (RTs) and accuracy were recorded and subjected to mixed-repeated ANOVAs. PwMS also underwent neuropsychological tests of IPS, attention, executive functioning (EF), and memory; correlation analyses between RTs of each level and the neuropsychological tests were performed.
Results
Significant differences between pwMS and HC were found as a function of increasing cognitive load conditions, on both RTs (p<.001) and accuracy (p<.001), with pwMS being on average significantly slower (p=.003) and less accurate (p=.004) than HC. Significant correlations between RTs of each level and composite score of IPS-attention (level 1: p=.006; level 2: p=.009; level 3: p=.002) and EF (level 1: p=.03; level 2: p=.002; level 3: p=.002), but not memory (all ps>.12), were found.
Conclusions
Measuring IPS efficiency in pwMS with computerized tools (i.e., videogame) could be useful in both screening and monitoring disease progression and response to therapies within a telemedicine perspective. The inverse relationship between increasing cognitive load and slowing IPS efficiency might be related either to over-recruitment or dysfunction of neural networks (i.e., neural plasticity) which may induce cognitive inefficiency even before the appearance of formal CI.
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.
P0085 - Harmonization of real-world studies in multiple sclerosis: retrospective analysis from the RIReMS group (ID 687)
Abstract
Background
Worldwide multiple sclerosis (MS) centers have coordinated their efforts to use data acquired in clinical practice for real-world observational studies.
Objectives
In this retrospective study, we aim to harmonize outcome measures, and to evaluate their heterogeneity within the Rising Italian Researchers in MS (RIReMS) study group.
Methods
RIReMS members filled in a structured questionnaire evaluating the use of different outcome measures in clinical practice. Thereafter, thirty-four already-published papers from RIReMS centers were used for heterogeneity analyses, using the DerSimonian and Laird random-effects method to compute the between-study variance (τ2).
Results
Based on questionnaire results, we defined basic modules for diagnosis and follow-up, consisting of outcome measures recorded by all participating centers at the time of diagnosis, and, then, at least annually; we also defined more detailed/optional modules, with outcome measures recorded less frequently and/or in the presence of specific clinical indications. Looking at heterogeneity, we found 5-year variance in age at onset (ES=27.34; 95%CI=26.18, 28.49; p<0.01; τ2=4.76), and 7% in female percent (ES=66.42; 95%CI=63.08, 69.76; p<0.01; τ2=7.15). EDSS variance was 0.2 in studies including patients with average age <36.1 years (ES=1.96; 95%CI=1.69, 2.24; p<0.01; τ2=0.19), or from 36.8 to 41.1 years (ES=2.70; 95%CI=2.39, 3.01; p<0.01; τ2=0.18), but increased to 3 in studies including patients aged >41.4 years (ES=4.37; 95%CI=3.40, 5.35; p<0.01; τ2=2.96). The lowest variance of relapse rate was found in studies with follow-up duration ≤2 years (ES=9.07; 95%CI=5.21, 12.93; p=0.02; τ2=5.53), whilst the lowest variance in EDSS progression was found in studies with follow-up duration >2 years (ES=5.41; 95%CI=3.22, 7.60; p=0.02; τ2=1.00).
Conclusions
We suggest common sets of biomarkers to be acquired in clinical practice, that can be used for research purposes. Also, we provide researchers with specific indications for improving inclusion criteria and data analysis, ultimately allowing data harmonization and high-quality collaborative studies.
P0625 - Quantitative Susceptibility Mapping in the cortical ribbon of MS patients and its dependence on cortical thinning. (ID 1142)
Abstract
Background
Neuropathological examinations of multiple sclerosis (MS) brains indicate sub-pial cortical grey matter (GM) demyelination and damage occurring according to a “surface-in” gradient related to elevated levels of inflammation compartmentalized in sub-arachnoid spaces and meninges. Quantitative susceptibility mapping (QSM) is an MRI technique sensitive to changes in iron or myelin.
Objectives
To test the ability of QSM to detect and localize alterations in cortical iron/myelin content in MS and to investigate possible QSM alterations possibly caused by cortical thinning.
Methods
A group of 105 RR-MS patients (40.7±10.2 y mean±std; m:f 13:92; EDSS median 2 (0 - 6)) and 21 matched healthy controls (HC; 39.5±10.5 y; m:f 8:13) were examined by using 3T MRI 3D-EPI (0.5x0.5x0.5mm), 3D T1w (1x1x1mm) and a 3D FLAIR sequence (1x1x1mm). QSM was computed using a total generalized variation algorithm. T1 lesion filled images were analyzed with Freesurfer to reconstruct WM/GM and pial surfaces. QSM was sampled across the entire cortex with steps of 25% of cortical volume (0%: WM/GM, 100%: pial surface) and projected to the 32k vertices Conte-69 template. Group-wise QSM differences were performed by a permutation-based ANOVA test employing threshold-free cluster enhancement to correct for multiple comparisons (p<0.05 FWE corrected). A vertex-wise cortical thickness (CTh) regressor was used to investigate the impact of cortical thinning on QSM alterations.
Results
Significant differences in QSM showing higher susceptibility in RR-MS than HC were present in majority in cerebral sulci (21, 55 and 55% at 25, 50 and 75%) compared to gyri (9, 37, 38% at 25, 50 and 75%) and in the outer portion of the cortex compared to the inner cortex. The percentage of vertices significantly altered was higher in the outer layer (75%) respect to the inner ones (25%) in several regions, including portions of temporal and parietal lobes, precuneus and para- and post-central sulcus. The use of the CTh regressor, showed significant alterations in the same regions, and revealed further alterations of the cingulate cortex.
Conclusions
Surface analysis of QSM exhibits the presence of increase susceptibility in the cortex of MS patients compared to HC: the alterations are more extended in the outer layers of the cortical ribbon than the inner ones, supporting the hypothesis of a “surface-in” gradient of iron/myelin alterations in the cortex of MS patients. Moreover, these differences were not entirely explained by the presence of cortical thinning.
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.
P0957 - Does peripheral immune profile reflect intrathecal inflammation in multiple sclerosis patients at time of diagnosis? (ID 1728)
Abstract
Background
Intrathecal inflammation, possibly compartmentalized in meninges, perivascular cuffs and cerebrospinal fluid (CSF), represents one of the main features of Multiple Sclerosis (MS). Recent studies have shown that a specific panel of CSF molecules present at diagnosis may be able to stratify naïve MS patients in two subgroups according to the high (SMhigh) or low (MSlow) level of CSF inflammation and cortical damage and to predict their disease outcome.
Objectives
Verify whether the inflammatory CSF intrathecal profile may correlate with the protein and cell inflammatory profile of the paired blood at diagnosis.
Methods
Immunoassay protein analysis of 79 inflammatory molecules was evaluated in paired CSF and serum obtained at diagnosis by 71 patients with MS and 36 subjects with other neurodegenerative diseases. Each patient was annually subjected to detailed clinical/radiological examination by 3 T-MRI. By using flow-cytometry we also analysed the specific blood immunophenotypes in paired CSF and blood samples of a subgroup of 15 MS patients.
Results
We found significant (p<0,01) correlations between number of spinal lesions both at diagnosis (T0) and after 2 years and the expressions of CXCL16, (r=0.54), CXCL5, (r=0.46), sTNFR1, (r= 0.39), TWEAK (r=0.43) and finally IL12p70 (r=0.39), as well as with number of blood total CD19+ B cells (r= -0.93; p<0.05) in MS patients but not in controls. However, no correlation between the protein inflammatory profile of paired CSF/serum samples has been revealed, with the only exception of interleukin 10 (IL-10), which was found elevated in both CSF (p<0.01) and serum (p<0.05) of MShigh compared to MSlow patients. Significant correlation was measured between IL-10 serum levels and the number of B cells in the blood (r=0.67; p<0.01), in particular with a subset of switched memory CD19+CD27+IgD- B cells and in particular in the MShigh group. In addition, positive correlation (p<0.05) was found between blood exhausted CD19+CD27-IgD- B cells and number white matter lesions at diagnosis (r=0,55), volume of white matter lesions (r=0.69), global cortical thickness (r=0.71), number of cortical lesions (r=0.79), volume of cortical lesions (r=0.80) and global cortical thickness (r=0.82). On the contrary, the percentage of some memory CD19+CD27-IgG+B cells correlates (p<0.05) with the cortical thickness (r=0.70) and age at diagnosis (r= -0.67). When we analysed possible correlation between blood and CSF immunophenotypes at diagnosis, we found significant correlation (r=0.74; p<0.05) between blood naïve B cells (CD19+CD27-IgD+) and CSF memory CD19+CD27-IgG+B cells.
Conclusions
Serum inflammatory profile at diagnosis only partially reflects intrathecal CSF inflammation. Only IL-10 appeared to represent a useful link between CSF and serum inflammation at diagnosis and may help to identify a subgroup pf MS patients with high involvement of B lymphocytes in early MS pathogenesis.
P0969 - Imbalance of TNF and TNF receptors in the cerebrospinal fluid of naïve multiple sclerosis patients (ID 1602)
Abstract
Background
Background: An imbalance in TNF signaling in the inflammatory milieu generated in the cortical subarachnoid space of the multiple sclerosis (MS) brain is thought to lead to increased cortical pathology.
Objectives
Objectives: To investigate the changes in TNF and its soluble receptors in CSF at the early stages of MS and how they associate with clinical outcome.
Methods
Methods: Protein levels of TNF, sTNFR1 and sTNFR2 were assayed in CSF collected from 122 naïve MS patients and 34 subjects with other neurological conditions at diagnosis. Potential correlations with other molecules of TNF family and other cytokines/chemokines were evaluated by using BioPlex System immunoassay and Ingenuity pathway analysis. TNF and TNFRs levels in CSF were correlated with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T2).
Results
Results: Significant increased levels of TNF (fold change:7.739; p<0.001), sTNFR1 (fold change:1.693; p<0.001) and sTNFR2 (fold change:2.189; p<0.001) were detected in CSF of MS patients compared to the control group at T0, and were found especially high in patients with enhanced CSF inflammation. Increased TNF levels in CSF were significantly (p<0.01) associated with increased EDSS change (r=0.43), relapses (r=0.48) and new white matter lesions (r=0.49) at T2. Elevated CSF levels of sTNFR1 were associated with higher cortical lesion volume (r=0.41) at T0, as well as with new cortical lesions (r=0.56) and signs of disease activity (r= 0.61) at T2, whilst no correlation could be found between sTNFR2 levels inCSF and clinical or MRI features. By performing combined correlation and pathway analysis, CSF TNF signalling (encompassing elevated levels of BAFF, IFN-G, IL-1beta, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) was found predominantly related to interplay between innate and adaptive immune cell. CSF sTNFR1 pathway (encompassing high levels of CXCL13, TWEAK, LIGHT, IL35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to dendritic cell maturation and acute immune response pathway. Finally, CSF sTNFR2 pathway (encompassing high CSF levels of IFN-B, IFN-L2, sIL-6Ra) was linked to Th cell differentiation and regulatory cytokine pathway.
Conclusions
Conclusions: CSF dysregulation of TNF and TNFRs pathways can be early identified in MS patients at time of diagnosis and associates with a specific clinical/MRI profile. This, in turn, could have a key role in predicting the disease outcome.