Multiple Sclerosis Phenotypes Research Articles

T1-Based Synthetic Magnetic Resonance Contrasts Improve Multiple Sclerosis and Focal Epilepsy Imaging at 7 T.

Ultra-high field magnetic resonance imaging (MRI) (≥7 T) is a unique opportunity to improve the clinical diagnosis of brain pathologies, such as multiple sclerosis or focal epilepsy. However, several shortcomings of 7 T MRI, such as radiofrequency field inhomogeneities, could degrade image quality and hinder radiological interpretation. To address these challenges, an original synthetic MRI method based on T1 mapping achieved with the magnetization-prepared 2 rapid acquisition gradient echo (MP2RAGE) sequence was developed. The radiological quality of on-demand T1-based contrasts generated by this technique was evaluated in multiple sclerosis and focal epilepsy imaging at 7 T. This retrospective study was carried out from October 2017 to September 2019 and included 21 patients with different phenotypes of multiple sclerosis and 35 patients with focal epilepsy who underwent MRI brain examinations using a whole-body investigative 7 T magnetic resonance system. The quality of 2 proposed synthetic contrast images were assessed and compared with conventional images acquired at 7 T using the MP2RAGE sequence by 4 radiologists, evaluating 3 qualitative criteria: signal homogeneity, contrast intensity, and lesion visualization. Statistical analyses were performed on reported quality scores using Wilcoxon rank tests and further multiple comparisons tests. Intraobserver and interobserver reliabilities were calculated as well. Radiological quality scores were reported higher for synthetic images when compared with original images, regardless of contrast, pathologies, or raters considered, with significant differences found for all 3 criteria (P < 0.0001, Wilcoxon rank test). None of the 4 radiologists ever rated a synthetic image "markedly worse" than an original image. Synthetic images were rated slightly less satisfying for only 3 epileptic patients, without precluding lesion identification. T1-based synthetic MRI with the MP2RAGE sequence provided on-demand contrasts and high-quality images to the radiologist, facilitating lesion visualization in multiple sclerosis and focal epilepsy, while reducing the magnetic resonance examination total duration by removing an additional sequence.

Alexithymia in multiple sclerosis: Clinical and radiological correlations.

Alexithymia, meaning no words for emotions is a common problem that could affect up to 53% of patients in multiple sclerosis (MS). To determine the frequency of alexithymia in MS and investigate MS-related abnormalities in structural magnetic resonance imaging (MRI) and their associations with fatigue and cognitive functions. Ninety-five patients at all stages of the disease were examined: 21 with clinically isolated syndromes (CIS), 30 with relapsing-remitting MS (RRMS), 21 with primary (PP) and 23 with secondary progressive MS (SPMS). Alexithymia was measured with the Toronto alexithymia scale (TAS-20) and correlated to cognitive functions, depression, and fatigue. Voxel-based morphometry MRI was analyzed to determine lesion load, cerebral and regional atrophy. Fifty-seven of patients had alexithymia with no significant difference between the clinical phenotypes. Alexithymic patients differed from non-alexithymic patients on fatigue, depression and information processing speed. Compared to non-alexithymic patients, alexithymic patients had decreased volumes of cerebral and cerebellar white matter and there was a significant relationship between alexithymia and decreased brainstem, thalamic and corpus callosum volume. Regardless of the phenotype of MS, alexithymia is associated with atrophy of cerebral and cerebellar white matter, brainstem, corpus callosum, and thalami.

Serum ROCK2, miR-300 and miR-450b-5p levels in two different clinical phenotypes of multiple sclerosis: Relation to patient disability and disease progression

Relapsing remitting multiple sclerosis (RRMS) is the most prevalent MS subtype. Years after disease onset, most of RRMS patients show transition into secondary progressive form (SPMS). Currently, no biomarkers are available for tracking disease progression. Here, we observed marked elevation of Rho-associated protein kinase 2 (ROCK2) along with significant downregulation of miRNAs 300 and 450b-5p expressions in the serum of 39 RRMS and 35 SPMS Egyptian patients compared to healthy controls. More pronounced alterations were found in SPMS versus RRMS patients. Our findings also suggest relations between elevated ROCK2 and reduced expression of both miRNAs with the degree of disability and disease progression. Notably, these biomarkers effectively discriminated RRMS from SPMS patients with miR-450b-5p showing the highest prognostic power.

Longitudinal cortical thinning progression differs across multiple sclerosis phenotypes and is clinically relevant: A multicentre study

Background: Longitudinal evolution of cortical thickness (CTh) in different MS phenotypes has been rarely studied. Aim: To investigate the regional pattern and 1-year progression of cortical thinning in relapsing-remitting (RR) and progressive (P) MS. Methods: 3T high-resolution T1-weighted magnetic resonance imaging (MRI) was obtained from 86 patients (75 RRMS, 11 PMS) and 34 healthy controls (HC) at three European sites at baseline and 1-year follow-up. Using FreeSurfer, baseline CTh between-group differences, longitudinal CTh changes and their correlations with clinical and MRI variables were assessed. Results: Baseline frontal, parietal and sensorimotor atrophy was found in MS versus HC. Such pattern was driven by RRMS, while PMS showed additional parietal, insular and sensorimotor cortical atrophy versus RRMS. At 1-year versus baseline, additional frontal and temporal cortical thinning was detected in RRMS patients, while a widespread CTh reduction was found in PMS patients (significant at time-by-group interaction vs RRMS). In MS, baseline fronto-parietal atrophy correlated with more severe disability and higher lesion volume. Baseline inferior parietal CTh decrease and 1-year temporal cortical thinning correlated with more severe disability. Conclusion: Parieto-temporal baseline CTh abnormalities and thinning pattern over time characterized the main MS clinical phenotypes and were associated with 1-year disability worsening.

Thalamic atrophy correlates with dysfunctional impulsivity in multiple sclerosis

BackgroundRecent studies highlight the central role of thalamic atrophy in Multiple Sclerosis (MS) related disorders. Behavioural aspects of (MS) are rarely explored but their investigation is of high interest. Dickman's Impulsiveness Inventory (DII) allows distinguishing functional impulsivity (FI) which is the ability to react fast and properly when necessary, from dysfunctional impulsivity (DI) which is a behavioural symptom corresponding to the tendency to miss forethought before acting. ObjectiveThis paper aims to explore whether MS patients show significantly high and pathological DI, and to evaluate the impulsivity frequency in the different forms of MS including at the early stage of the Clinically Isolated Syndrome. Furthermore, this study focused on the factors that may induce abnormal impulsivity, and the link between thalamic atrophy and dysfunctional impulsivity in patients with MS. Methods95 patients with demyelinating diseases including 21 Clinically Isolated Syndrome (CIS), 30 Relapsing-Remitting MS (RRMS), 23 Secondary Progressive MS (SPMS) and 21 Primary Progressive MS (PPMS) were prospectively recruited, and covered by extensive cognitive evaluation including the BCCogSEP (French version of the Brief Repeatable Battery for Neurological disease), the CSCT (Computerized Speed Cognitive Test) for processing speed of information (PSI), the DII to measure FI and DI, the Fast BDI to evaluate depression, and the EMIF-SEP scale to study physical, cognitive and social fatigues. 3D T2-FLAIR and 3D T1-weighted MRI were analyzed using automatic segmentation tools to quantify the T2 lesion load and to measure the whole and regional brain atrophy. Results7% showed a pathologically high DI. The level of DI tended to differ significantly depending on the MS phenotype. There was no significant difference between RRMS, SPMS and PPMS, but RRMS showed significantly higher DI than CIS patients. Cognitive fatigue (r:-0.27, p<.01), depression (r:-0.21, p=.04) but mainly PSI (r:.33, p<.001) showed a significant correlation with DI. Among the brain regions of interest, the strongest significant correlation with DI was with thalamic atrophy (r:.33, p<.001). ConclusionSome MS patients show a pathologically high DI, mainly RRMS compared to CIS. Previous study highlighted impulsive traits in MS patients only in relation with the presence of depression. The present study demonstrates that depression tends to correlate with DI, but that cognitive fatigue, and mainly slowing of PSI, which is the most early and severe cognitive impairment in MS, have a stronger impact on the rise of pathological impulsive behaviour. DI in MS is linked to frontal regions but even more strongly to thalamus atrophy. This is in line with the hypothesis of a disconnection syndrome in MS that causes cognitive impairment to trigger and could have the same impact on behaviour. Hence, impulsive behaviour should be evaluated and taken into account in the care of patients with MS.

IL-6 in the Cerebrospinal Fluid Signals Disease Activity in Multiple Sclerosis.

Specific proinflammatory and anti-inflammatory molecules could represent useful cerebrospinal fluid (CSF) biomarkers to predict the clinical course of multiple sclerosis (MS). The proinflammatory molecule interleukin (IL)-6 has been investigated in the pathophysiology of MS and has been associated in previous smaller studies to increased disability and disease activity. Here, we wanted to further address IL-6 as a possible CSF biomarker of MS by investigating its detectability in a large cohort of 534 MS patients and in 103 individuals with other non-inflammatory neurological diseases. In these newly diagnosed patients, we also explored correlations between IL-6 detectability, MS phenotypes, and disease characteristics. We found that IL-6 was more frequently detectable in the CSF of MS patients compared with their control counterparts as significant differences emerged between patients with Clinically isolated syndrome (CIS), Relapsing–remitting (RR), and secondary progressive and primary progressive MS compared to non-inflammatory controls. IL-6 was equally present in the CSF of all MS phenotypes. In RR MS patients, IL-6 detectability was found to signal clinically and/or radiologically defined disease activity, among all other clinical characteristics. Our results add further evidence that CSF proinflammatory cytokines could be useful for the identification of those MS patients who are prone to increased disease activity. In particular, IL-6 could represent an interesting prognostic biomarker of MS, as also demonstrated in other diseases where CSF IL-6 was found to identify patients with worse disease severity.

Multiple sclerosis in a multi-ethnic population from Northern California: a retrospective analysis, 2010\u20132016

BackgroundResearch is needed to examine differences in multiple sclerosis (MS) prevalence by race-ethnicity. The goal of this study was to quantify MS prevalence in a health care system in Northern California and examine differences in prevalence and phenotype by race-ethnicity.MethodsWe conducted a retrospective, observational cohort study of adults (2010–2016). MS prevalence estimates were standardised to distributions of gender and race-ethnicity for the underlying geographic region and stratified by gender and race-ethnicity with age adjustment. We performed a chart review of a racial-ethnic stratified sample of patients to examine disease phenotypes.Results1,058,102 patients were identified, of which 3286 had MS. The overall direct-standardised prevalence was 288.0 cases per 100,000 population (95% confidence interval: 276.3–299.8). Age-adjusted prevalence ranged from 677.0 per 100,000 among non-Hispanic black women to 49.7 per 100,000 among non-Hispanic Asian men. Non-Hispanic blacks compared with other groups more often had primary-progressive (10.0% vs. 0.0–4.0%) or progressive-relapsing MS (6.0% vs. 0.0–2.0%).ConclusionsIn this Northern Californian Cohort, between 2010 and 2016 the direct-standardised MS prevalence was estimated at 288.0 per 100,000 population, and increased over time. Non-Hispanic blacks, especially women, were disproportionately affected and had less common, earlier progressive MS phenotypes.

Prevalence of GLA gene mutations and polymorphisms in patients with multiple sclerosis: A cross-sectional study

PurposeFabry Disease (FD) has been frequently proposed as possible underestimated differential diagnosis of Multiple Sclerosis (MS), but no study has been performed to test prevalence of GLA gene mutations in a population fulfilling diagnostic criteria of MS. Aim of this study is to determine the prevalence of GLA gene mutations in a large and representative population diagnosed with MS, simultaneously providing a critical revision of current literature reports of coexistence or misdiagnosis between these two conditions. MethodsIn this mono-centric cross-sectional study, 927 patients fulfilling McDonald diagnostic criteria and encompassing all MS phenotypes were enrolled. Patients underwent evaluation of α-GalA activity and genotyping. Both genetic variants annotated as pathogenic and GVUS were considered. Estimated alleles frequencies were then compared to the ones reported in the gnomAD database. ResultsGLA gene variants were found in seven individuals. Five patients carried variants previously described having controversial impact on FD phenotype, and the analysis of exome database revealed that they are not rare among healthy individuals. One patient showed a new variant never described before, and another one carried a late-onset FD cardiac variant. ConclusionsThe overall prevalence of GLA gene variants in MS patients is comparable to the one estimated in healthy population. This result is further supported by critical revision of current literature evidences of misdiagnosis between MS and FD, arguing in favour of independence between these disorders.

Identification of a predominant cognitive phenotype in patients with multiple sclerosis.

Cognitive impairment occurs frequently in multiple sclerosis (MS). However, the prevalence and clinical characteristics of cognitive MS phenotype are not well established. The aim of the study was to characterize the clinical course and neurocognitive impairment of patients with MS meeting an Expanded Disability Status Scale (EDSS)-defined cognitive phenotype. A total of 2302 patients from the Comprehensive Longitudinal Investigation of Multiple Sclerosis at Brigham and Women's Hospital (CLIMB) study were studied. Predominant cognitive MS phenotype was defined as EDSS Cerebral Functional System (FS) subscore ≥3 and remaining EDSS FS subscores ≤2 on at least one clinical visit. Demographic/clinical characteristics, phenotype stability and neurocognitive domain impairment of these subjects were assessed. A total of 60 of 2302 (2.6%) patients (age 52.8±10.8years, 68% female, 82% relapsing MS) met criteria for phenotype designation. A total of 29 of 60 (48%) were designated within 10years of their presenting MS symptom. The mean cohort annualized relapse rate was 0.38 and EDSS score at last clinical assessment was 3.2±1.3. Cognitive phenotype status was poorly sustained, with only 27% of subjects maintaining Cerebral FS score ≥2 throughout all follow-up. However, predominant cognitive phenotype subjects with clinical neuropsychiatric testing [n=39/60 (65%)] frequently had cognitive impairment (1.5 SD below mean) in ≥1 domain [n=30/39 (77%) of subjects] affecting memory, attention/executive function and processing speed. A total of 11 of 39 (28%) patients had severe-range cognitive impairment (3.0 SD below mean). Cognitive phenotype designation was associated with low rate of employment at last clinical assessment. Predominant cognitive MS phenotype is rare, although an EDSS-based definition identifies patients with multidomain cognitive impairment and may serve as a practical screen for identification of patients who might warrant close monitoring of neurocognitive status.

Association of Multiple Sclerosis Phenotypes with Single Nucleotide Polymorphisms of IL7R, LAG3, and CD40 Genes in a Jordanian Population: A Genotype-Phenotype Study.

It is thought that genetic variations play a vital role in the Multiple Sclerosis (MS) etiology. However, the role of genetic factors that influence the clinical features of MS remains unclear. We investigated the correlation between 21 single nucleotide polymorphisms within three genes (IL7R, LAG3, and CD40) and MS clinical characteristics in the Jordanian population. Blood samples and clinical phenotypic data were collected from 218 Arab Jordanian MS patients, vitamin D was measured, genomic DNA was extracted, and genotyping of the candidate genes’ polymorphisms were analyzed using the Sequenom MassARRAY® system. The association of these single nucleotide polymorphisms (SNPs) with MS was performed using a Chi-square, Fisher exact test, and one-way ANOVA. We found a significant association between vitamin D deficiency and three SNPs of the IL7R gene, namely rs987107 (P-value = 0.047), rs3194051 (P-value = 0.03), and rs1494571 (P-value = 0.036), in addition to two SNPs of CD40, namely rs1883832 and rs6074022 (P-value = 0.049 for both). rs3194051 of the IL7R gene (P-value = 0.003) and rs1922452 of the LAG3 gene (P-value = 0.028) were strongly associated with comorbidity. The number of relapses before drug onset was found to be correlated with IL7R SNPs rs969128 (P-value = 0.04) and rs1494555 (P-value = 0.027), whereas the expanded disability status scale (EDSS) was associated with rs1494555 polymorphism of IL7R gene (P-value = 0.026). Current findings indicate important correlations between certain SNPs and the risk of various phenotypes of multiple sclerosis in the Jordanian community. Therefore, this will not only contribute to the understanding of MS, but will also assist with the development of personalized treatment procedures.

Volume loss in the deep gray matter and thalamic subnuclei: a longitudinal study on disability progression in multiple sclerosis.

Volume loss in the deep gray matter (DGM) has been reported in patients with multiple sclerosis (MS) already at early stages of the disease and is thought to progress throughout the disease course. To investigate the impact and predictive value of volume loss in DGM and thalamic subnuclei on disability worsening in patients MS over a 6-year follow-up period. Hundred and seventy-nine patients with RRMS (132 women; median Expanded Disability Status Scale, EDSS: 2.5) and 50 with SPMS (27 women; median EDSS: 4.5) were included in the study. Patients underwent annual EDSS assessments and annual MRI at 1.5T. DGM/thalamic subnuclei volumes were identified on high-resolution T1-weighted. A hierarchical linear mixed model for each anatomical DGM area and each thalamic subnucleus was performed to investigate the associations with disability scores. Cox regression was used to estimate the predictive properties of volume loss in DGM and thalamic subnuclei on disease worsening. In the whole sample and in RRMS, volumes of the thalamus and the striatum were associated with the EDSS; however, only thalamic volume loss was associated with EDSS change at follow-up. Regarding thalamic subnuclei, volume loss in the anterior nucleus, the pulvinar and the ventral anterior nucleus was associated with EDSS change in the whole cohort. A trend was observed for the ventral lateral nucleus. Volume loss in the anterior and ventral anterior nuclei was associated with EDSS change over time in patients with RRMS. Moreover, MS phenotype and annual rates of volume loss in the thalamus and ventral lateral nucleus were predictive of disability worsening. These results highlight the relevance of volume loss in the thalamus as a key metric for predicting disability worsening as assessed by EDSS (in RRMS). Moreover, the volume loss in specific nuclei such as the ventral lateral nucleus seems to play a role in disability worsening.

Video-oculography in multiple sclerosis: Links between oculomotor disorders and brain magnetic resonance imaging (MRI)

BackgroundEye movement abnormalities (EMA) are common in multiple sclerosis (MS). However, type and severity according to the MS stage are poorly known, especially in Radiologically Isolated Syndrome (RIS) and in Clinically Isolated Syndrome (CIS). Although MRI has been included in the MS diagnostic criteria, there may be clinical-radiological dissociation. ObjectiveTo analyze by video-oculography (VOG) prevalence of EMA in different MS phenotypes and study correlations with brain and cervical cord MRI T2 lesions location. Methods76 participants were prospectively recruited (12 RIS, 10 CIS, 11 relapsing-remitting-MS, 10 secondary progressive-MS, 10 primary progressive MS and 23 gender and age-matched healthy controls). We analyzed fixations, anti-saccades, horizontal and vertical reflex saccades and smooth pursuit. ResultsEMA were frequent and of gradual severity from RIS to progressive forms. Internuclear ophthalmoplegia (INO) and centripetal hypermetria were strong arguments for the diagnosis of a demyelinating disorder versus a control population. Some EMA were linked to infratentorial T2 lesion location, but others like INO were not. ConclusionThis study confirm that EMA are common in all MS phenotypes, even at the earliest stages. VOG can be useful to detect demyelinating process at preclinical stage by highlighting subclinical EMA even in absence of characteristic lesions visible on MRI.

Epidemiology and phenotypes of multiple sclerosis in the Middle East North Africa (MENA) region.

The Middle East North Africa (MENA) region falls in the low-to-moderate multiple sclerosis (MS) prevalence zone, with prevalence rates slightly lower than Southern Europe but much higher than sub-Saharan Africa. However, there is clearly a trend toward increased MS prevalence over the last few decades, consistent with the globally rising prevalence of the disease. We analyzed all data collected from the MENACTRIMS (Middle East North Africa Committee for Treatment and Research in Multiple Sclerosis) registry by the end of December 2018. A total of 6885 patients were eligible for the study. Overall, the clinical phenotype of MS in the MENA region was not different from the Western phenotype except for earlier age at onset and a more aggressive clinical course leading to earlier disability.

Prospects for Treatment of Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is a disease related to anti-aquaporin-4 antibody. Since NMOSD was once considered a phenotype of multiple sclerosis, no approved drugs are available for its treatment. In Japan, the current standard treatment for preventing relapses in patients with NMOSD is low-dose prednisolone and/or oral immuno-suppressants. There is a critical unmet need for non-steroid treatments for patients with NMOSD. Four monoclonal antibodies have completed their clinical trials in Japan and are pending approval. In this review, we summarize the results of each of these clinical trials.

Duration of natalizumab therapy and reasons for discontinuation in a multiple sclerosis population.

ObjectiveTo determine multiple sclerosis patient characteristics that predict a shorter duration of natalizumab treatment.MethodsThe Tysabri Outreach: Unified Commitment to Health database was reviewed to identify patients treated with natalizumab at our centers. Cox proportional hazards models were used to evaluate patient characteristics associated with shorter treatment durations on natalizumab. Associations were also assessed with respect to specific reasons for stopping natalizumab.ResultsWe identified 554 patients who began and stopped natalizumab treatment during the observation period. The average disease duration at natalizumab initiation was 7.6 years, and the average number of infusions was 30. The multivariable Cox proportional hazards model identified greater age (P = 0.035), longer disease duration (P < 0.001), progressive relapsing multiple sclerosis phenotype (P = 0.003), current smoking (P = 0.031), and greater depression (P = 0.026) as significant predictors for natalizumab discontinuation. Greater disability levels (P = 0.022) and gadolinium-enhancing lesions on baseline magnetic resonance imaging (P < 0.001) were significantly associated with longer natalizumab treatment. Individuals with progressive relapsing multiple sclerosis had a 14-fold increased hazard of discontinuing natalizumab due to inflammatory events (P < 0.001) than those with relapsing–remitting multiple sclerosis. Smokers had an 80% increased hazard of discontinuation due to intolerance (P = 0.008).ConclusionsOur results suggest that smoking, depression, and a progressive relapsing multiple sclerosis phenotype are associated with shorter natalizumab treatment durations.

Diffusion tensor imaging tractography reveals altered fornix in all diagnostic subtypes of multiple sclerosis.

IntroductionDiffusion tensor imaging (DTI) has shown abnormalities of the fornix and other limbic white matter tracts in multiple sclerosis (MS), mainly focusing on relapsing‐remitting MS.MethodsThe goal here was to evaluate the fornix, cingulum, and uncinate fasciculus with DTI tractography at 1.7 mm isotropic resolution in three MS subgroups (11 relapsing‐remitting (RRMS), nine secondary progressive (SPMS), eight primary progressive (PPMS)) versus 11 controls, and assess correlations with cognitive and clinical scores.ResultsThe MS group overall showed extensive diffusion abnormalities of the fornix with less volume, lower fractional anisotropy (FA), and higher mean and radial diffusivities, which were similarly affected in all three MS subgroups. The uncinate fasciculus had lower FA only in the secondary progressive subgroup, and the cingulum had no DTI differences in any MS subgroup. The FA and/or volumes of these tracts correlated negatively with larger total lesion volume. The only DTI‐cognitive correlation was lower right cingulum FA and greater depression over the entire MS cohort.ConclusionsDiffusion tractography identified abnormalities in the fornix that appears to be affected early and consistently across all three primary MS phenotypes of RRMS, SPMS, and PPMS regardless of Expanded Disability Status Scale, time since diagnosis, or cognitive scores.

Impact of multiple sclerosis phenotypes on burden of disease in Finland

Aims: The aim of this study was to quantify how multiple sclerosis (MS) phenotypes differ from each other in respect of costs and quality-of-life.Materials and methods: The study is based on survey data from Finnish patients with MS (n = 553). The information contained disease type, disease severity according to self-reported Expanded Disease Severity Scale (EDSS), healthcare resource use, and medication use. In addition, information related to employment and early retirement was collected. EQ-5D-VAS and Multiple Sclerosis Impact Scale-29 (MSIS-29) instruments were used to collect quality-of-life data, and Fatigue Severity Scale (FSS) instrument for evaluating fatigue. Patients were stratified based on their disease type (relapsing-remitting MS (RRMS), secondary progressive MS (SPMS), primary progressive MS (PPMS)) and disease severity. The data were primarily analyzed using summary statistics.Results: SPMS had the highest annual total cost (71,177€) followed by PPMS (51,082€) and RRMS (36,492€). Early retirement covered the greatest share of costs in RRMS (39%) and SPMS (43%). In PPMS, early retirement and professional care were the two most equally important cost drivers, contributing together 56% of the total costs. Direct healthcare costs were responsible for 33%, 19%, and 18% of total costs in RRMS, SPMS, and PPMS. The mean EDSS in RRMS, SPMS, and PPMS were 2.5, 5.5, and 5.9, respectively. Differences in the quality-of-life were observed with both disease specific (MSIS-29) and generic (EQ-5D-VAS) instruments. The mean utility value from EQ-5D among patients with RRMS, SPMS, and PPMS was 0.76, 0.52, and 0.49, respectively. In addition, patients with SPMS and PPMS were more likely to report fatigue than patients with RRMS.Conclusions: MS phenotype has an impact on costs and quality-of-life of the patients. Early retirement seems to be one of the most important contributors to MS-related costs.

Morphological MRI phenotypes of multiple sclerosis differ in resting-state brain function

We aimed to assess differences in resting-state functional connectivity (FC) between distinct morphological MRI-phenotypes in multiple sclerosis (MS). Out of 180 MS patients, we identified those with high T2-hyperintense lesion load (T2-LL) and high normalized brain volume (NBV; a predominately white matter damage group, WMD; N = 37) and patients with low T2-LL and low NBV (N = 37; a predominately grey matter damage group; GMD). Independent component analysis of resting-state fMRI was used to test for differences in the sensorimotor network (SMN) between MS MRI-phenotypes and compared to 37 age-matched healthy controls (HC). The two MS groups did not differ regarding EDSS scores, disease duration and distribution of clinical phenotypes. WMD compared to GMD patients showed increased FC in all sub-units of the SMN (sex- and age-corrected). WMD patients had increased FC compared to HC and GMD patients in the central SMN (leg area). Only in the WMD group, higher EDSS scores and T2-LL correlated with decreased connectivity in SMN sub-units. MS patients with distinct morphological MRI-phenotypes also differ in brain function. The amount of focal white matter pathology but not global brain atrophy affects connectivity in the central SMN (leg area) of the SMN, consistent with the notion of a disconnection syndrome.

B cell function impacts the efficacy of IFN-β therapy in EAE

Recent studies identified that interferon beta (IFN-β) treatment skews B-cells towards a regulatory phenotype in multiple sclerosis. To assess B cell involvement during IFN-β therapy, we compared IFN-β treatment in a B cell-independent model and a B cell-dependent model of experimental autoimmune encephalomyelitis (EAE). We show that in B cell-independent EAE, IFN-β ameliorates neuroinflammation. Conversely, in B cell-dependent EAE, IFN-β has no effect on disease. Effective IFN-β therapy in B cell-independent EAE was associated with reduced inflammatory T cells in the CNS and skewed splenic B cells towards an immature population and away from a germinal center population. These immune cell populations were unchanged in B cell-dependent EAE. Finally, we found that IFN-β increased marginal zone B cells in both EAE models. These findings indicate that B cell function impacts IFN-β efficacy during neuroinflammation.

Genetic Alterations in Patients with Two Clinical Phenotypes of Multiple Sclerosis.

The etiology of multiple sclerosis (MS) is still not known, but the interaction of genetic, immunological, and environmental factors seem to be involved. This study aimed to investigate genetic alterations and the vitamin D status in patients with relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS). A total of 53 patients (29 RRMS; 24 SPMS) and 25 healthy subjects were recruited to evaluate the micronucleated cell (MNC) frequency and nuclear abnormalities in the buccal mucosa, gene expression profiling in mononuclear cells, and plasmatic vitamin D concentration in the blood. Results showed a higher frequency of cells with karyorrhexis (SPMS) and lower frequencies of nuclear pyknosis (RRMS and SPMS) and karyolysis (SPMS) in patients with MS. Significant increase in the frequency of MNC was detected in the buccal mucosa of RRMS and SPMS patients. HIF1A, IL13, IL18, MYC, and TNF were differentially expressed in MS patients, and APP was overexpressed in cells of RRMS compared to SPMS patients. No relationship was observed between vitamin D level and the differentially expressed genes. In conclusion, the cytogenetic alterations in the buccal mucosa can be important indicators of genetic instability and degenerative processes in patients with MS. Furthermore, our data introduced novel biomarkers associated with the molecular pathogenesis of MS.