Prognostic value of single-subject grey matter networks in early multiple sclerosis.

The identification of prognostic markers in early multiple sclerosis (MS) is challenging and requires reliable measures that robustly predict future disease trajectories. Ideally, such measures should make inferences at the individual level to inform clinical decisions. This study investigated the prognostic value of longitudinal structural networks to predict 5-year Expanded Disability Status Scale (EDSS) progression in patients with relapsing-remitting MS (RRMS). We hypothesized that network measures, derived from MRI, outperform conventional MRI measurements at identifying patients at risk of developing disability progression. This longitudinal, multicentre study within the Magnetic Resonance Imaging in MS (MAGNIMS) network included 406 patients with RRMS (mean age = 35.7 ± 9.1 years) followed up for 5 years (mean follow-up = 5.0 ± 0.6 years). EDSS was determined to track disability accumulation. A group of 153 healthy subjects (mean age = 35.0 ± 10.1 years) with longitudinal MRI served as controls. All subjects underwent MRI at baseline and again 1 year after baseline. Grey matter atrophy over 1 year and white matter lesion load were determined. A single-subject brain network was reconstructed from T1-weighted scans based on grey matter atrophy measures derived from a statistical parameter mapping-based segmentation pipeline. Key topological measures, including network degree, global efficiency and transitivity, were calculated at single-subject level to quantify network properties related to EDSS progression. Areas under receiver operator characteristic (ROC) curves were constructed for grey matter atrophy and white matter lesion load, and the network measures and comparisons between ROC curves were conducted. The applied network analyses differentiated patients with RRMS who experience EDSS progression over 5 years through lower values for network degree [H(2) = 30.0, P < 0.001] and global efficiency [H(2) = 31.3, P < 0.001] from healthy controls but also from patients without progression. For transitivity, the comparisons showed no difference between the groups [H(2) = 1.5, P = 0.474]. Most notably, changes in network degree and global efficiency were detected independent of disease activity in the first year. The described network reorganization in patients experiencing EDSS progression was evident in the absence of grey matter atrophy. Network degree and global efficiency measurements demonstrated superiority of network measures in the ROC analyses over grey matter atrophy and white matter lesion load in predicting EDSS worsening (all P-values < 0.05). Our findings provide evidence that grey matter network reorganization over 1 year discloses relevant information about subsequent clinical worsening in RRMS. Early grey matter restructuring towards lower network efficiency predicts disability accumulation and outperforms conventional MRI predictors.

A wearable device perspective on the standard definitions of disability progression in multiple sclerosis.

INTRODUCTION: Multiple sclerosis (MS) is a leading cause of disability among young adults, but standard clinical scales may not accurately detect subtle changes in disability occurring between visits. This study aims to explore whether wearable device data provides more granular and objective measures of disability progression in MS. METHODS: Remote Assessment of Disease and Relapse in Central Nervous System Disorders (RADAR-CNS) is a longitudinal multicenter observational study in which 400 MS patients have been recruited since June 2018 and prospectively followed up for 24 months. Monitoring of patients included standard clinical visits with assessment of disability through use of the Expanded Disability Status Scale (EDSS), 6-minute walking test (6MWT) and timed 25-foot walk (T25FW), as well as remote monitoring through the use of a Fitbit. RESULTS: Among the 306 patients who completed the study (mean age, 45.6 years; females 67%), confirmed disability progression defined by the EDSS was observed in 74 patients, who had approximately 1392 fewer daily steps than patients without disability progression. However, the decrease in the number of steps experienced over time by patients with EDSS progression and stable patients was not significantly different. Similar results were obtained with disability progression defined by the 6MWT and the T25FW. CONCLUSION: The use of continuous activity monitoring holds great promise as a sensitive and ecologically valid measure of disability progression in MS.

Nitric oxide involvement in the disability and active disease of multiple sclerosis: Systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic and immune-mediated disease of unknown etiology and leading to a physical and cognitive disability. Different studies suggest that nitrosative stress may play a pivotal role in the pathogenesis and disability in MS. Besides, reports evaluated NO and their metabolites, expressed by nitrite and nitrate (NOx) levels of MS patients compared with other pathologies, but did not evaluate disability and relapse/remission phases. OBJECTIVE: Thus, this study aimed to conduct a systematic review and meta-analysis of NOx levels in MS patients in relapse/remission phases and its involvement in patient disability. METHODS: The protocol was registered in PROSPERO (CRD42022327161). We used GRADE to estimate the articles' quality and evaluated the publication bias using Egger's and Begg's tests. RESULTS: Here, through a search in the Pubmed, Scopus, and EMBASE databases, 5.276 studies were found, and after the selection process, 20 studies were included in this systematic review and meta-analysis. The studies included data from 1.474 MS patients and 1.717 healthy controls, 1.010 RRMS and 221 primary progressive MS (PPMS). CONCLUSION: NOx levels are increased in relapsing-remitting MS (RRMS) patients in the relapse phase. Also, NOx levels were increased in MS patients with higher disability. However, further studies are still needed to control lifestyle habits, pain, and MS treatment effects in biased NOx levels.

T1 hypointense brain lesions in NMOSD and its relevance with disability: a single institution cross-sectional study.

BACKGROUND: T1 hypointense lesions are considered a surrogate marker of tissue destruction. Although there is a shortage of evidence about T1 hypointense brain lesions, black holes, in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD), the clinical significance of these lesions is not well determined. OBJECTIVES: The impact of T1 hypointense brain lesions on the clinical status and the disability level of patients with NMOSD was sought in this study. METHODS: A total of 83 patients with the final diagnosis of NMOSD were recruited. Aquaporin-4 measures were collected. The expanded disability status scale (EDSS) and MRI studies were also extracted. T1 hypointense and T2/FLAIR hyperintense lesions were investigated. The correlation of MRI findings, AQP-4, and EDSS was assessed. RESULTS: T1 hypointense brain lesions were detected in 22 patients. Mean ± SD EDSS was 3.7 ± 1.5 and significantly higher in patients with brain T1 hypointense lesions than those without them (p-value = 0.01). Noticeably, patients with more than four T1 hypointense lesions had EDSS scores ≥ 4. The presence of T2/FLAIR hyperintense brain lesions correlated with EDSS (3.6 ± 1.6 vs 2.3 ± 1.7; p-value = 0.01). EDSS was similar between those with and without positive AQP-4 (2.7 ± 1.6 vs. 3.2 ± 1.7; p-value = 0.17). Also, positive AQP-4 was not more prevalent in patients with T1 hypointense brain lesions than those without them (50.9 vs 45.4%; p-value = 0.8). CONCLUSION: We demonstrated that the presence of the brain T1-hypointense lesions corresponds to a higher disability level in NMOSD.

The relationship between dietary profile and adherence to the Mediterranean diet with EDSS and quality of life in multiple sclerosis patients: a retrospective cross-sectional study.

BACKGROUND: Multiple sclerosis (MS), one of the main neurological causes of disability seen at young ages, affects the quality of life of patients. Studies on which dietary pattern or consumption of food groups may have an impact on quality of life for MS patients are insufficient. The study was conducted to determine the relationship between adherence to Mediterranean diet and consumption levels of food groups on quality of life in multiple sclerosis patients. METHODS: This study was conducted with 95 patients, 76 females and 19 males, aged 18-65 years, who had been diagnosed with MS for at least 2 years and did not have any other chronic disease. Food Frequency Questionnaire, Mediterranean Diet Adherence Screener (MEDAS), Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Quality of Life-54 Instrument (MS-QoL-54) used as tools. Data were analyzed by SPSS 25.0. RESULTS: Adherence to the Mediterranean diet was associated with EDSS and physical and mental quality of life parameters (CPH and CMH), independent of progression. It was associated with EDSS and CMH in progressive MS. A statistically significant negative weak correlation was found between daily milk and oilseed consumption and EDSS. Daily fruit consumption was associated with CMH, and vegetable consumption was associated with both CPH and CMH. CONCLUSIONS: The Mediterranean diet may be an effective nutritional model in MS patients and may be related to the disability level and quality of life of the patients. Some food groups can be associated with the quality of life and disability level of MS patients.

Clinical characteristics and dynamics of disability progression in a cohort of patients with multiple sclerosis in Latvians.

There is wide variation in the time from the onset to secondary progressive multiple sclerosis (MS) and some controversy regarding the clinical characteristics of the courses (phenotypes) of MS. The present study aimed to characterize demographic and clinical factors that potentially influence long-term disability progression in the cohort of Latvian MS patients. A descriptive longitudinal incidence study was conducted using a cohort of 288 MS patients beginning in 2011 (disease duration from 1 to 51 years). Socio-demographic and clinical information from the first visit to 15/20 years was analysed in groups stratified by gender and visits at five-time points (the first visit; after a year or 2; after 5 ± 1 year; after 10 ± 2 years; after 15-20 years). Our study was dominated by patients from urban areas and non-smokers. The female/male ratio was 2.4:1; the distribution of clinical courses at the first visit was consistent with most European studies. The most common symptom at presentation in our study was optic manifestations, followed by sensory disturbances and motor deficits. In the Latvian study, gender was not a significant influencing factor on the rate of disease progression; however, patient age was statistically significantly associated with EDSS (Expanded Disability Status Scale) value at the first visit. Early clinical features of MS are important in predicting the disability accumulation of patients. Despite the small differences regarding the first MS symptoms, the disability outcomes in the cohort of Latvian patients are similar to other regions of the world.

The Faces of "Too Late"-A Surprisingly Progressive Cohort of "Stable" Relapsing Remitting Multiple Sclerosis Patients.

Background and Objectives: Although available therapies have changed the natural evolution of multiple sclerosis (MS), in time some patients assume a progressive course and no longer respond to treatment. There is no definitive clinical or laboratory parameter to certify MS progression from relapsing remitting MS (RRMS) to secondary progressive MS (SPMS) in early phases of transition. Our study aims to evaluate the value of clinical parameters and serum neurofilament light chain levels (sNfLs) as early warning signs of conversion to SPMS. Materials and Methods: The Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test (9HPT), 25-foot walk test (25FWT) and Symbol Digit Modalities Test (SDMT) were evaluated at 12 months apart in a cohort of 83 RRMS treated patients. sNfLs were evaluated at the second time point. Results: sNfLs correlate with EDSS and SDMT, with EDSS change and disease duration. Clinical parameters correlate among themselves and perform well in supporting the diagnosis of SPMS in logistic regression and ROC curves analysis. Eighty percent of the RRMS patients in our study (of which 65% are treated with high-efficacy disease-modifying drugs) showed some type of progression independent of relapses (PIRA) after 12 months, with one in five patients experiencing isolated cognitive worsening and almost two-thirds some type of motor worsening. We found no differences in terms of progression between patients treated with platform drugs versus high-efficacy drugs. Conclusions: An elevated level of progression independent of relapses (PIRA) was found in our cohort, with high-efficacy drugs providing no supplementary protection. As sNfL levels were correlated with the progression of EDSS (the main clinical progression marker), they may be considered potential prognostic markers, but further studies are necessary to precisely define their role in this direction. The lack of early sensitive markers for risk of progression may contribute to therapeutic delay and failure.

Predicting clinical progression and cognitive decline in patients with relapsing-remitting multiple sclerosis: a 6-year follow-up study.

INTRODUCTION: Cognitive impairment occurs from the earliest stages of multiple sclerosis (MS) and progresses over time. The introduction of disease modifying therapies (DMTs) has changed the prognosis for MS patients, offering a potential opportunity for improvement in the cognitive arena as well. MATERIAL AND METHODS: 41 patients with relapsing-remitting multiple sclerosis (MS) were recruited to the study. Thirty patients were available for final follow-up and were included in the analysis. Baseline (BL) brain MRI including volumetry and neuropsychological tests were performed. Blood samples were collected at BL and follow-up (FU) and were tested for: vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM1), soluble platelet-endothelial CAM-1 (sPECAM1), and soluble intercellular CAM-1 (sICAM-1). Patients were invited for a final neuropsychological follow-up after a median of 6 years. Disease activity (relapses, EDSS increase, new/active brain lesions on MRI) was analysed between BL and FU. RESULTS: The study group deteriorated in the Rey-Osterrieth Complex Figure (ROCF) test (p = 0.001), but improved significantly in three other tests, i.e. semantic fluency test (p = 0.013), California Verbal Learning Test (CVLT, p = 0.016), and Word Comprehension Test (WCT, p < 0.001). EDSS increase correlated negatively with semantic fluency and WCT scores (r = -0.579, p = 0.001 and r = -0.391, p = 0.033, respectively). Improvements in semantic fluency test and WCT correlated positively with baseline deep grey matter, grey matter, and cortical volumes (p < 0.05, r > 0). Higher EDSS on FU correlated significantly negatively with baseline left and right pallidum, right caudate, right putamen, right accumbens, and cortical volume (p < 0.05, r < 0). No significant relationship was found between the number of relapses and EDSS on FU or neuropsychological deteriorations. Improvements in WCT and CVLT correlated positively with baseline sPECAM1 and sVCAM1 results, respectively (r > 0, p < 0.05). Deterioration in ROCF test correlated significantly with higher levels of baseline VEGF and sVCAM1 (p < 0.05). CONCLUSIONS: Brain volume is an important predictor of future EDSS and cognitive functions outcome. MS patients have a potential for improving in neuropsychological tests over time. It remains to be established whether this is related to successful disease modification with immunotherapy. Baseline volumetric measures are stronger predictors of cognitive performance than relapse activity, which yet again highlights the importance of atrophy in MS prognosis.

Early miR-320b and miR-25-3p miRNA levels correlate with multiple sclerosis severity at 10 years: a cohort study.

BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating autoimmune disorder which may cause long-term disability. MicroRNA (miRNA) are stable, non-coding molecules that have been identified in our Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB)-cohort, as well as other international cohorts, as potential disease biomarkers in MS. However, few studies have evaluated the association of miRNA expression early in the MS disease course with long-term outcomes. Therefore, we aimed to evaluate the potential role of three candidate serum miRNAs previously correlated with MS disability in patients with MS, miR-320b, miR-25-3p and miRNA 486-5p, as early biomarkers of MS disability at 10-year follow-up. MAIN BODY: We included 144 patients with serum obtained within three years of MS onset. miRNA expression was measured by RNA extraction followed by RT-PCR. Demographic, clinical, brain MRI and other biomarkers were collected. The primary outcome was the association between early miRNA expression and retaining benign MS, defined as EDSS ≤ 2 at 10-year follow-up. Among the 144 patients, 104 were benign and 40 were not benign at 10-year follow-up. 89 (62%) were women, with mean age at onset 37.7 (SD: 9.6) years. Patients who retained benign MS had lower values of miR-25-3p (p = 0.047) and higher miR-320b (p = 0.025) values. Development of SPMS was associated with higher miR-320b (p = 0.002) levels. Brain parenchymal fraction at year 10 was negatively correlated with miR-25-3p (p = 0.0004) and positively correlated with miR-320b (p = 0.006). No association was found between miR-486-5p and any outcome, and 10-year T2-lesion volume was not associated with any miRNA. CONCLUSIONS: Our results show that miR-320b and miR-25-3p expression are early biomarkers associated with MS severity and brain atrophy. This study provides class III evidence of that miR-320b and miR-25-3p are associated with long-term MS disability which may be a potential tool to risk-stratify patients with MS for early treatment decisions.

miRNA 548a-3p as biomarker of NEDA-3 at 2 years in multiple sclerosis patients treated with fingolimod.

BACKGROUND: Multiple sclerosis (MS) is a disabling autoimmune demyelinating disorder affecting young people and causing significant disability. In the last decade, different microRNA (miRNA) expression patterns have been associated to several treatment response therapies such as interferon and glatiramer acetate. Nowadays, there is increasing interest in the potential role of miRNA as treatment response biomarkers to the most recent oral and intravenous treatments. In this study, we aimed to evaluate serum miRNAs as biomarkers of No Evidence of Disease Activity (NEDA-3) at 2 years in patients with relapsing remitting MS (RRMS) treated with fingolimod. MAIN BODY: A Discovery cohort of 31 RRMS patients treated with fingolimod were identified from the CLIMB study and classified as No Evidence of Disease Activity (NEDA-3) or Evidence of Disease Activity (EDA-3) after 2 years on treatment. Levels of miRNA expression were measured at 6 months using human serum miRNA panels and compared in EDA-3 and NEDA-3 groups using the Wilcoxon rank sum test. A set of differentially expressed miRNA was further validated in an independent cohort of 22 fingolimod-treated patients. We found that 548a-3p serum levels were higher levels in fingolimod-treated patients classified as NEDA-3, compared to the EDA-3 group in both the Discovery (n = 31; p = 0.04) and Validation (n = 22; p = 0.03) cohorts 6 months after treatment initiation; miR-548a-3p provided an AUC of 0.882 discriminating patients with NEDA-3 at 2 years in the Validation cohort. CONCLUSION: Our results show differences in miR-548a-3p expression at 6 months after fingolimod start in patients with MS with NEDA-3 at 2 years. These results provide class III evidence of the use of miR-548a-3p as biomarker of NEDA-3 in patients with fingolimod.

Neurocognitive impairment in multiple sclerosis and its association with thiol-disulfide homeostasis and ischemia-modified albumin.

This study aimed to assess the possible association between cognitive impairment and two important biochemical biomarkers of oxidative stress, thiol-disulfide homeostasis (TDH), and ischemia-modified albumin (IMA) in patients with multiple sclerosis (MS). This study included 85 patients with MS (38 treatment-naïve relapsing-remitting MS (RRMS), 31 RRMS on fingolimod therapy, and 16 secondary progressive MS (SPMS)) and 33 healthy controls. Cognitive evaluation was carried out by applying the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) test battery and the scores were adjusted for age and years of education. Plasma TDH was assessed using an automated method and plasma IMA levels were determined using the cobalt-albumin binding assay. Plasma native thiol and total thiol levels were significantly decreased in patients with SPMS when compared with the naïve patients and healthy controls. Cognitive impairment was detected in 47.4% of naïve patients, 64.5% of patients on fingolimod therapy, and 80% of patients with SPMS. Naïve patients or patients on fingolimod therapy who were cognitively impaired had significantly decreased levels of native thiol and total thiol compared to the cognitively normal patients. Logistic regression analysis revealed total thiol and native thiol to be significantly associated with cognitive impairment in naïve patients and patients on fingolimod therapy. Significant correlations were determined between BICAMS scores, TDH, IMA, clinical indices of disease severity (EDSS and MSSS), and magnetic resonance imaging parameters. This study has shown for the first time that plasma TDH parameters are associated with cognitive impairment in MS.

Optical coherence tomography versus other biomarkers: Associations with physical and cognitive disability in multiple sclerosis.

BACKGROUND: Optical coherence tomography (OCT) is a biomarker of neuroaxonal loss in multiple sclerosis (MS). OBJECTIVE: The objective was to assess the relative role of OCT, next to magnetic resonance imaging (MRI) and serum markers of disability in MS. METHODS: A total of 100 patients and 52 controls underwent OCT to determine peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell-inner plexiform layers (GCIPL). Serum neurofilament light chain (sNfL), total lesion volume (TLV), and brain parenchymal fraction (BPF) were also assessed. The associations of OCT with disability were examined in linear regression models with correction for age, vision, and education. RESULTS: In patients, pRNFL was associated with the Symbol Digit Modalities Test (SDMT; p = 0.030). In the multivariate analysis including sNfL and MRI measures, pRNFL (ß = 0.19, p = 0.044) and TLV (ß = -0.24, p = 0.023) were the only markers associated with the SDMT. pRNFL (p < 0.001) and GCIPL (p < 0.001) showed associations with the Expanded Disability Status Scale (EDSS). In the multivariate analysis, GCIPL showed the strongest association with the EDSS (ß = -0.32, p < 0.001) followed by sNfL (ß = 0.18, p = 0.024). CONCLUSION: The associations of OCT measures with cognitive and physical disability were independent of serum and brain MRI markers of neuroaxonal loss. OCT can be an important tool for stratification in MS, while longitudinal studies using combinations of biomarkers are warranted.

Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis.

BACKGROUND: The circulating metabolome is altered in multiple sclerosis (MS), but its prognostic capabilities have not been extensively explored. Lipid metabolites might be of particular interest due to their multiple roles in the brain, as they can serve as structural components, energy sources, and bioactive molecules. Gaining a deeper understanding of the disease may be possible by examining the lipid metabolism in the periphery, which serves as the primary source of lipids for the brain. OBJECTIVE: To determine if altered serum lipid metabolites are associated with the risk of relapse and disability in children with MS. METHODS: We collected serum samples from 61 participants with pediatric-onset MS within 4 years of disease onset. Prospective longitudinal relapse data and cross-sectional disability measures (Expanded Disability Status Scale [EDSS]) were collected. Serum metabolomics was performed using untargeted liquid chromatography and mass spectrometry. Individual lipid metabolites were clustered into pre-defined pathways. The associations between clusters of metabolites and relapse rate and EDSS score were estimated utilizing negative binomial and linear regression models, respectively. RESULTS: We found that serum acylcarnitines (relapse rate: normalized enrichment score [NES] = 2.1, q = 1.03E-04; EDSS: NES = 1.7, q = 0.02) and poly-unsaturated fatty acids (relapse rate: NES = 1.6, q = 0.047; EDSS: NES = 1.9, q = 0.005) were associated with higher relapse rates and EDSS, while serum phosphatidylethanolamines (relapse rate: NES = -2.3, q = 0.002; EDSS: NES = -2.1, q = 0.004), plasmalogens (relapse rate: NES = -2.5, q = 5.81E-04; EDSS: NES = -2.1, q = 0.004), and primary bile acid metabolites (relapse rate: NES = -2.0, q = 0.02; EDSS: NES = -1.9, q = 0.02) were associated with lower relapse rates and lower EDSS. CONCLUSION: This study supports the role of some lipid metabolites in pediatric MS relapses and disability.

A pro-inflammatory diet in people with multiple sclerosis is associated with an increased rate of relapse and increased FLAIR lesion volume on MRI in early multiple sclerosis: A prospective cohort study.

BACKGROUND: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. OBJECTIVE: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. METHODS: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. RESULTS: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = -1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (ß = 0.38, 95% CI = 0.04, 0.72, p = 0.03). CONCLUSION: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS.

Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.

BACKGROUND AND PURPOSE: This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). METHODS: We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. RESULTS: Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. CONCLUSIONS: DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.

Stability of sensor-based gait parameters reassessed after a period of one year in people with multiple sclerosis.

BACKGROUND: Currently, there are several studies showing that wearable inertial sensors are highly sensitive in the detection of gait disturbances in people with multiple sclerosis (PwMS), showing excellent reliability within one or 7-14 days. However, it is not known how stable these gait parameters remain over a longer period of time. This is surprising, because many treatments last longer than two weeks. Thus, the purpose of the current study was to examine gait parameters obtained by means of wearable inertial sensors during a 6-min walk and to reassess these parameters after a period of one year. METHODS: Fifty PwMS (without a relapse or a recent change in the Expanded Disability Status Scale (EDSS) or treatment) and 20 healthy participants were examined at two assessment points (interval between assessments: 14.4 ± 6.6 months). At each assessment point, all participants had to complete a 6-min walking test, an observer-rater test (Berg Balance Scale, BBS) and a Timed-up and Go Test (TUG). To measure mean gait parameters (i.e. walking speed, stride length, stride time, the duration of the stance and swing phase and minimum toe-to-floor distance), as well as the intraindividual standard deviation of each mean gait parameter, wearable inertial sensors were utilized. RESULTS: We found that even after one year all mean gait parameters showed excellent Intraclass Correlation Coefficients (ICC between 0.75 and 0.95) in PwMS. Looking at MS subgroups, the ICCs were slightly higher in MS subgroup 2 (EDSS 2.0-5.0) than those in MS subgroup 1 (EDSS 0.0-1.5) and healthy controls. Compared to the mean gait parameters, parameters of gait variability showed only good-to-fair ICC values in PwMS. Concerning BBS and TUG, the ICC values after one year were close to the ICC values of the measured mean gait parameters. CONCLUSIONS: Due to the excellent stability of mean gait parameters after one year, these sensor-based gait parameters can be identified as clinically relevant markers to evaluate treatment effects over a longer (several months) period of time in MS.

Chitinase-3-like 1-protein in CSF: a novel biomarker for progression in patients with multiple sclerosis.

BACKGROUND: Chitinase -3-like 1-protein (CHI3L1) is a glycoside secreted by monocytes, microglia, and activated astrocytes. Its distribution in inflammatory lesions denotes its role in astrocytic response to modulate CNS inflammation. In multiple sclerosis (MS), CHI3L1 levels have been found to be influenced by disease severity, activity, and progression. We aimed to measure CSF level of CHI3L1 in patients with MS and correlate its level with disability measures for a possible role as a biomarker for disease progression. METHODS: Fifty-two MS patients (30 relapsing-remitting MS and 22 progressive MS) and thirty-five age and sex-matched healthy controls were included. They all underwent full clinical assessment (including disability and cognitive scales), radiological assessment, and CSF level of CHI3L1. RESULTS: Patients with MS had higher CSF level of CHI3L1 than controls. Patients with progressive forms had higher levels than relapsing forms. There were positive correlations between disease duration, number of attacks, total EDSS, and CSF level of CHI3L1. Patients who had higher level of CSF CHI3L1 showed worse performance in MMSE and BICAMS and more lesions in T2 MRI brain. A cut off value of 154 ng/mL was found between patients with RRMS and PMS patients. CONCLUSION: CHI3L1 can be considered as a biomarker of disease progression. CHI3L1 level increases in progressive MS more than RRMS. Also, high CSF level of CHI3L1 was associated with more disability including motor, cognitive, and radiological aspects.

Eye-tracking control of an adjustable electric bed: construction and validation by immobile patients with multiple sclerosis.

BACKGROUND: In severe conditions of limited motor abilities, frequent position changes for work or passive and active rest are essential bedside activities to prevent further health complications. We aimed to develop a system using eye movements for bed positioning and to verify its functionality in a control group and a group of patients with significant motor limitation caused by multiple sclerosis. METHODS: The eye-tracking system utilized an innovative digital-to-analog converter module to control the positioning bed via a novel graphical user interface. We verified the ergonomics and usability of the system by performing a fixed sequence of positioning tasks, in which the leg and head support was repeatedly raised and then lowered. Fifteen women and eleven men aged 42.7 ± 15.9 years in the control group and nine women and eight men aged 60.3 ± 9.14 years in the patient group participated in the experiment. The degree of disability, according to the Expanded Disability Status Scale (EDSS), ranged from 7 to 9.5 points in the patients. We assessed the speed and efficiency of the bed control and the improvement during testing. In a questionnaire, we evaluated satisfaction with the system. RESULTS: The control group mastered the task in 40.2 s (median) with an interquartile interval from 34.5 to 45.5 s, and patients mastered the task in in 56.5 (median) with an interquartile interval from 46.5 to 64.9 s. The efficiency of solving the task (100% corresponds to an optimal performance) was 86.3 (81.6; 91.0) % for the control group and 72.1 (63.0; 75.2) % for the patient group. Throughout testing, the patients learned to communicate with the system, and their efficiency and task time improved. A correlation analysis showed a negative relationship (rho = - 0.587) between efficiency improvement and the degree of impairment (EDSS). In the control group, the learning was not significant. On the questionnaire survey, sixteen patients reported gaining confidence in bed control. Seven patients preferred the offered form of bed control, and in six cases, they would choose another form of interface. CONCLUSIONS: The proposed system and communication through eye movements are reliable for positioning the bed in people affected by advanced multiple sclerosis. Seven of 17 patients indicated that they would choose this system for bed control and wished to extend it for another application.

Multiple Sclerosis-Associated Gut Microbiome in the Israeli Diverse Populations: Associations with Ethnicity, Gender, Disability Status, Vitamin D Levels, and Mediterranean Diet.

Microbiome dysbiosis is increasingly being recognized as implicated in immune-mediated disorders including multiple sclerosis (MS). The microbiome is modulated by genetic and environmental factors including lifestyle, diet, and drug intake. This study aimed to characterize the MS-associated gut microbiome in the Israeli populations and to identify associations with demographic, dietary, and clinical features. The microbiota from 57 treatment-naive patients with MS (PwMS) and 43 age- and gender-matched healthy controls (HCs) was sequenced and abundance compared. Associations between differential microbes with demographic or clinical characteristics, as well as diet and nutrient intake, were assessed. While there was no difference in α- or ß-diversity of the microbiome, we identified 40 microbes from different taxonomic levels that differ in abundance between PwMS and HCs, including Barnesiella, Collinsella, Egerthella, Mitsuokella, Olsenella Romboutsia, and Succinivibrio, all enhanced in PwMS, while several members of Lacnospira were reduced. Additional MS-differential microbes specific to ethnicity were identified. Several MS-specific microbial patterns were associated with gender, vitamin D level, Mediterranean diet, nutrient intake, or disability status. Thus, PwMS have altered microbiota composition, with distinctive patterns related to geographic locations and population. Microbiome dysbiosis seem to be implicated in disease progression, gender-related differences, and vitamin D-mediated immunological effects recognized in MS. Dietary interventions may be beneficial in restoring a "healthy microbiota" as part of applying comprehensive personalized therapeutic strategies for PwMS.

Functional Disability and Brain MRI Volumetry Results among Multiple Sclerosis Patients during 5-Year Follow-Up.

Background and Objectives: We aimed to determine the link between brain volumetry results and functional disability calculated using the Expanded Disability Status Scale (EDSS) among multiple sclerosis (MS) patients in relation to the provided treatment (disease-modifying therapies (DMTs)) during a 5-year follow-up period. Materials and Methods: A retrospective cohort study was performed enrolling 66 consecutive patients with a confirmed diagnosis of MS, predominantly females (62% (n = 41)). Relapsing-remitting (RR) MS was noted in 92% (n = 61) of patients, with the rest being patients with secondary progressive (SP) MS. The mean age was 43.3 years (SD 8.3 years). All patients were evaluated clinically using the EDSS and "FreeSurfer© 7.2.0" radiologically during a 5-year follow-up. Results: A significant increase in patient functional disability was noted, calculated using the EDSS during a 5-year follow-up. The baseline EDSS ranged between 1 and 6 with a median of 1.5 (IQR 1.5-2.0), and after 5 years, the EDSS was between 1 and 7, with a median EDSS of 3.0 (IQR 2.4-3.6). Compared with RRMS patients, SPMS patients demonstrated a significant increase in EDSS score during a 5-year period, with a median EDSS of 2.5 in RRMS patients (IQR 2.0-3.3) and 7.0 (IQR 5.0-7.0) among SPMS patients. Significantly lower brain volumetry results in different brain areas were found, including cortical, total grey and white matter, p < 0.05. Statistically significant differences were observed between baseline volumetry results of the hippocampus and the middle anterior part of the corpus callosum and their volumetry results after 5 years, p < 0.001. In this study population, the thalamus did not demonstrate significant changes in volumetry results during follow-up, p > 0.05. The provided treatment (DMTs) did not demonstrate a significant impact on the brain MRI volumetry results during a 5-year follow-up, p > 0.05. Conclusions: Brain MRI volumetry seriously impacts the early detection of brain atrophic changes. In this study, significant relationship between brain magnetic resonance volumetry results and disability progression among MS patients with no important impact of the provided treatment was described. Brain MRI volumetry may aid in the identification of early disease progression among MS patients, as well as enrich the clinical evaluation of MS patients in clinical patient care.