Multiple Sclerosis Severity Score Research Articles

Polymorphisms in the Dopaminergic Receptor D3 Gene Correlate with Disease Progression Rate in Relapsing-Remitting Multiple Sclerosis Patients.

Multiple sclerosis (MS) is a common chronic autoimmune disease of the central nervous system. In MS, disability progresses unpredictably. Dopamine (DA) is a modulator of immune functions, and compelling evidence supports its involvement in both pathogenesis and treatment of MS. Although single nucleotide polymorphisms (SNPs) in dopaminergic receptor (DR) genes have been extensively studied, their role in MS progression remains unexplored. Therefore, the aim of this explorative study is to investigate the potential association between functional SNPs in DR genes and MS progression. Caucasian patients with relapsing-remitting (RR) MS were enrolled, and disease progression assessed by the Multiple Sclerosis Severity Score (MSSS). Out of the 59 RRMS patients enrolled, those with the G/G genotype for rs6280 and rs1800828 SNPs in DRD3 showed significantly higher MSSSs compared to those with ancestral and heterozygous genotypes. If confirmed in a larger prospective study, the reported findings could contribute to a better understanding of MS pathophysiological mechanisms, opening the way for the identification of marker(s) for assessing MS progression as well as novel therapeutic strategies. A personalized approach to MS management has the potential to improve the overall well-being of MS patients and alleviate the burden on their caregivers.

GR.2 Obesity and multiple sclerosis severity: a Mendelian randomization study

Background: Obesity is increasingly implicated in the development of multiple sclerosis (MS), but its effect on disease disability is less well-established. This study aims to investigate the association between obesity and MS severity utilizing Mendelian Randomization (MR). Methods: Employing a two-sample MR setting, we examined the effects of various obesity measures and adiposity distribution metrics on MS severity. Genetic proxies for body mass index (BMI) were selected from a study of 806,834 participants, with MS severity determined from a genetic study of age-related MS severity scores in 12,584 individuals with MS. Results: The main analysis reveals an association between elevated BMI and increased MS severity (P = 0.03). This is supported by a significant effect of whole body fat (P = 0.04), aligning with the hypothesis that obesity exacerbates MS disability. Sensitivity analyses suggest minimal heterogeneity and bias, indicating a potential causal effect. Conclusions: Our findings suggest that obesity adversely influences long-term disability outcomes in MS. The convergence of this genetic evidence with some of the prior observational studies strengthens the argument for a causal relationship between obesity and MS severity. These insights highlight obesity as a potentially modifiable risk factor in managing MS, underscoring the importance of weight management in MS treatment strategies.

Interaction between miR-142-3p and BDNF Val/Met Polymorphism Regulates Multiple Sclerosis Severity.

MiR-142-3p has recently emerged as key factor in tailoring personalized treatments for multiple sclerosis (MS), a chronic autoimmune demyelinating disease of the central nervous system (CNS) with heterogeneous pathophysiology and an unpredictable course. With its involvement in a detrimental regulatory axis with interleukin-1beta (IL1β), miR-142-3p orchestrates excitotoxic synaptic alterations that significantly impact both MS progression and therapeutic outcomes. In this study, we investigated for the first time the influence of individual genetic variability on the miR-142-3p excitotoxic effect in MS. We specifically focused on the single-nucleotide polymorphism Val66Met (rs6265) of the brain-derived neurotrophic factor (BDNF) gene, known for its crucial role in CNS functioning. We assessed the levels of miR-142-3p and IL1β in cerebrospinal fluid (CSF) obtained from a cohort of 114 patients with MS upon diagnosis. By stratifying patients according to their genetic background, statistical correlations with clinical parameters were performed. Notably, in Met-carrier patients, we observed a decoupling of miR-142-3p levels from IL1β levels in the CSF, as well as from of disease severity (Expanded Disability Status Score, EDSS; Multiple Sclerosis Severity Score, MSSS; Age-Related Multiple Sclerosis Severity Score, ARMSS) and progression (Progression Index, PI). Our discovery of the interference between BDNF Val66Met polymorphism and the synaptotoxic IL1β-miR-142-3p axis, therefore hampering miR-142-3p action on MS course, provides valuable insights for further development of personalized medicine in the field.

Gas6/TAM system as potential biomarker for multiple sclerosis prognosis.

The protein growth arrest-specific 6 (Gas6) and its tyrosine kinase receptors Tyro-3, Axl, and Mer (TAM) are ubiquitous proteins involved in regulating inflammation and apoptotic body clearance. Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous system leading to progressive and irreversible disability if not diagnosed and treated promptly. Gas6 and TAM receptors have been associated with neuronal remyelination and stimulation of oligodendrocyte survival. However, few data are available regarding clinical correlation in MS patients. We aimed to evaluate soluble levels of these molecules in the cerebrospinal fluid (CSF) and serum at MS diagnosis and correlate them with short-term disease severity. In a prospective cohort study, we enrolled 64 patients with a diagnosis of clinical isolated syndrome (CIS), radiological isolated syndrome (RIS) and relapsing-remitting (RR) MS according to the McDonald 2017 Criteria. Before any treatment initiation, we sampled the serum and CSF, and collected clinical data: disease course, presence of gadolinium-enhancing lesions, and expanded disability status score (EDSS). At the last clinical follow-up, we assessed EDSS and calculated MS severity score (MSSS) and age-related MS severity (ARMSS). Gas6 and TAM receptors were determined using an ELISA kit (R&D Systems) and compared to neurofilament (NFLs) levels evaluated with SimplePlex™ fluorescence-based immunoassay. At diagnosis, serum sAxl was higher in patients receiving none or low-efficacy disease-modifying treatments (DMTs) versus patients with high-efficacy DMTs (p = 0.04). Higher CSF Gas6 and serum sAXL were associated with an EDSS<3 at diagnosis (p = 0.04; p = 0.037). Serum Gas6 correlates to a lower MSSS (r2 = -0.32, p = 0.01). Serum and CSF NFLs were confirmed as disability biomarkers in our cohort according to EDSS (p = 0.005; p = 0.002) and MSSS (r2= 0.27, p = 0.03; r2 = 0.39, p = 0.001). Results were corroborated using multivariate analysis. Our data suggest a protective role of Gas6 and its receptors in patients with MS and suitable severity disease biomarkers.

Familial vs sporadic multiple sclerosis in the Israeli population: Differences in ethnicity distribution and disease progression, with anticipation in successive generations

BackgroundMultiple Sclerosis (MS) may cluster in families, an entity known as familial MS (FMS), possibly due to aggregation of genetic and environmental factors. Though previous studies have characterized FMS in different populations, no study to the best of our knowledge has yet characterized FMS in the unique Israeli population, which is comprised of relatively endogamous ethnicities. Our goal in this study was to compare demographic and clinical characteristics between FMS and sporadic MS (SMS), and to search for intra-familial patterns. MethodsIn a retrospective study of 101 FMS patients and 508 SMS patients, ethnicity and sex distribution was assessed. Clinical aspects were compared between 172 paired FMS and SMS patients, matched for sex, age and ethnicity, and between generations of the FMS cohort. ResultsFemales comprised 75.3 % of FMS and 67.5 % of SMS patients (p = 0.1). Ethnic distribution was significantly different between FMS and SMS (p = 0.014), with the former comprising a higher proportion of Christian-Arabs (15.4% vs. 5.1 %, p = 0.004) and lower proportion of Jews (60% vs. 74.2 %, p = 0.016). Age at disease onset or diagnosis, frequency of positive Oligoclonal bands and comorbidity of other autoimmune/inflammatory disease or chronic diseases was comparable between FMS and SMS, yet motor symptoms at onset were more prevalent in FMS (34% vs. 20 %, p = 0.02). Annualized relapse rates throughout 10 years from onset were comparable. Among FMS, mean Expanded-Disability-Status-Scale (EDSS) and slope of deterioration in EDSS over 20 years from diagnosis were higher (p = 0.0004 and p = 0.023, respectively), time to EDSS ≥ 3 was shorter (7.1 vs. 12.1 years, HR 1.6, p = 0.036) and MS-Severity-Score (MSSS) was higher (3.84 vs. 2.95, p = 0.04), compared to SMS. Following adjustment for smoking, which tended to be higher among FMS patients (P = 0.06), mean EDSS and slope of deterioration in EDSS over 20 years remained significantly higher (p = 0.0006 and p = 0.025, respectively) in FMS, time to EDSS ≥ 3 tended to be higher (HR 1.5, p = 0.06), while MSSS was comparable. An inter-generational analysis of the total FMS cohort, as well as an intra-familial analysis, both adjusted for year of diagnosis, revealed significantly earlier age of onset (p < 0.0001 and p < 0.0001) and diagnosis (p = 0.001 and p < 0.0001) in the younger compared to the older generations, respectively. ConclusionIn this Israeli cohort, the proportions of specific ethnicities differ between FMS and SMS, indicating that FMS has a population-specific prevalence pattern, and that further investigation for susceptibility genes is warranted. Disease progression is faster in FMS patients and anticipation is observed in families with multiple cases of MS. Closer surveillance and application of a pro-active induction or early highly-effective therapeutic strategy for FMS patients should be considered, to reduce high disease activity and fast disability progression.

Prevalence and disease disability in immigrants with multiple sclerosis in Malmö, southern Sweden

BackgroundMultiple sclerosis (MS) is the most common chronic demyelinating disease of the central nervous system and the major non-traumatic cause of permanent disability in young adults. Several migration studies have been performed over the years suggesting a pattern of higher disease disability in certain ethnic groups. To our knowledge, differences in disease progression in immigrants have not been studied in Sweden before. Thus, the aims of our study were to estimate the prevalence of multiple sclerosis among first-generation immigrants in the City of Malmö and to compare differences in disease severity with the native population. MethodsAll persons with multiple sclerosis living in Malmö on prevalence day 31 Dec 2010 were included. Cases were classified according to the country of birth into Scandinavians, Western and non-Western. ResultsThe crude prevalence was 100/100,000 (95% CI, 80–124) among first-generation immigrants, 154/100,000 (95% CI, 137–173) among individuals with Scandinavian background, 123/100,000 (95% CI, 94–162) in the Western group and 76/100,000 (95% CI, 53–108) in the non-Western group. The mean Multiple Sclerosis Severity Score (MSSS) value among Scandinavians was 4.2 (SD 3.5), whereas the figures in the immigrant group were 4.6 (SD 3.3) and 5.2 (SD 3.7) among Westerns respectively non-Westerns, which differences were not statistically significant. When adjusting for gender, age at onset and initial disease course, the mean MSSS difference between the non-Western and the Scandinavian individuals was 1.7 (95% CI 0.18–3.3, p = 0.030). There were no differences on time to diagnosis or the time from diagnosis to treatment initiation between the three groups. ConclusionsWe found a lower prevalence among Western and non-Western first-generation immigrants compared to the Scandinavian population and a more severe disease in non-Western immigrants than in Scandinavians.

Lower Multiple Sclerosis Severity Score Is Associated with Higher Adherence to Mediterranean Diet in Subjects with Multiple Sclerosis from Northwestern Italy.

The Mediterranean Diet (MD) is described in the literature as a beneficial dietary pattern for neurodegenerative diseases such as Multiple Sclerosis (MS). The objective of this study was to evaluate the dietary habits in people with MS (pwMS) and to test whether adherence to the MD could have an impact on the severity of the disease measured as the MS severity score (MSSS). Adherence to the MD was assessed in 31 PwMS using the Mediterranean Diet Adherence Screener (MEDAS), the Pyramid-based Mediterranean Diet Score (PyrMDS) index, and the Italian Mediterranean Index (IMI), and their eating habits were recorded in a food diary for a one-year follow-up. When data obtained from dietary analysis were compared to the MSSS, results showed that pwMS with lower MSSS adhere more to the MD than the other pwMS groups according to the MEDAS index. Furthermore, a high consumption of fiber in the MS mild severity class was observed. Further studies are needed to clarify which of the nutritional components of the MD may impact the course of MS and if the sensitization of pwMS to MD adherence can be a strategy for mitigating the disease.

Serum neurofilament level as a biomarker in multiple sclerosis

Background &amp; Objective: Currently, MS disease activity and neurodegeneration are assessed mainly through clinical evaluation and magnetic resonance imaging. These measures lack sensitivity and specificity, leading to a constant search for a new biomarker. Several markers have been studied, and the most promising to date is the neurofilament. Our objective was to examine the relationship between serum neurofilament levels and multiple sclerosis parameters. Methods: Fifty-six adults who fulfilled the McDonald’s criteria 2017 for the diagnosis of MS, and forty-four healthy controls were enrolled in this study. Serum samples were collected to assess neurofilament light and heavy chain (NfL &amp; NfH) levels using the ELISA method, the results were compared for MS patients and controls; and were also correlated to the type of MS, disease duration, EDSS (expanded disability status scale), MSSS (MS severity score) and disease activity. Results: The mean serum NfL and NfH levels for cases were 133.3 pg/ml and 3654.5 pg/ml respectively, which are significantly higher than that for controls (NfL = 80 pg/ml; and NfH = 408.8 pg/ml; p-value &lt; 0.001). There were no significant correlations between serum neurofilament levels and EDSS, MSSS, disease activity, type, and duration. Conclusions: In our study, we could not find a significant role for the ELISA neurofilament serum level as a biomarker for MS disease activity and severity.

Complement Activation Is Associated With Disease Severity in Multiple Sclerosis.

Histopathologic studies have identified immunoglobulin (Ig) deposition and complement activation as contributors of CNS tissue damage in multiple sclerosis (MS). Intrathecal IgM synthesis is associated with higher MS disease activity and severity, and IgM is the strongest complement-activating immunoglobulin. In this study, we investigated whether complement components (CCs) and complement activation products (CAPs) are increased in persons with MS, especially in those with an intrathecal IgM synthesis, and whether they are associated with disease severity and progression. CC and CAP levels were quantified in plasma and CSF of 112 patients with clinically isolated syndrome (CIS), 127 patients with MS (90 relapsing-remitting, 14 primary progressive, and 23 secondary progressive), 31 inflammatory neurologic disease, and 44 symptomatic controls from the Basel CSF databank study. Patients with CIS/MS were followed in the Swiss MS cohort study (median 6.3 years). Levels of CC/CAP between diagnosis groups were compared; in CIS/MS, associations of CC/CAP levels with intrathecal Ig synthesis, baseline Expanded Disability Status Scale (EDSS) scores, MS Severity Score (MSSS), and neurofilament light chain (NfL) levels were investigated by linear regression, adjusted for age, sex, and albumin quotient. CSF (but not plasma) levels of C3a, C4a, Ba, and Bb were increased in patients with CIS/MS, being most pronounced in those with an additional intrathecal IgM production. In CIS, doubling of C3a and C4a in CSF was associated with 0.31 (CI 0.06-0.56; p = 0.016) and 0.32 (0.02-0.62; p = 0.041) increased EDSS scores at lumbar puncture. Similarly, doubling of C3a and Ba in CIS/MS was associated with 0.61 (0.19-1.03; p < 0.01) and 0.74 (0.18-1.31; p = 0.016) increased future MSSS. In CIS/MS, CSF levels of C3a, C4a, Ba, and Bb were associated with increased CSF NfL levels, e.g., doubling of C3a was associated with an increase of 58% (Est. 1.58; CI 1.37-1.81; p < 0.0001). CNS-compartmentalized activation of the classical and alternative pathways of complement is increased in CIS/MS and associated with the presence of an intrathecal IgM production. Increased complement activation within the CSF correlates with EDSS, future MSSS, and NfL levels, supporting the concept that complement activation contributes to MS pathology and disease progression. Complement inhibition should be explored as therapeutic target to attenuate disease severity and progression in MS.

Low-contrast visual acuity test is associated with central inflammation and predicts disability development in newly diagnosed multiple sclerosis patients.

The visual system is a prominent site of damage in MS since the earliest phases of the disease. Altered low-contrast visual acuity (LCVA) test has been associated with visual impairment and retinal degeneration, predicting medium- and long-term disability. However, it is unclear whether LCVA may also represent a reliable measure of neuroinflammation and a predictor of disease evolution in the very early stages of MS. We explored in a group of 76 consecutive newly diagnosed relapsing-remitting MS (RR-MS) patients without visual impairment or altered visual evoked potentials, the association between LCVA scores at 2.5% and 1.25% and clinical characteristics, including prospective disability evaluated after 1- and 2 years of follow-up. Associations between LCVA and the CSF levels of IL-10 at diagnosis were also analyzed. A negative correlation was found between LCVA at 2.5% and Expanded Disability Status Scale (EDSS) evaluated at first (Spearman's Rho = -0.349, p = 0.005, n = 62) and second year (Spearman's Rho = -0.418, p < 0.001, n = 62) of follow-up, and negative correlations were found with Multiple Sclerosis Severity Score (MSSS) at first (Spearman's Rho = -0.359, p = 0.004, n = 62) and second year (Spearman's Rho = -0.472, p < 0.001, n = 62). All the data were confirmed by a mixed effect model, considering other clinical variables. A positive correlation was found between the CSF concentrations of IL-10 and LCVA at 2.5% (Spearman's Rho = 0.272, p = 0.020, n = 76), and 1.25% (Spearman's Rho, = 0.276, p = 0.018, n = 76), also evidenced in a linear regression. In MS patients at diagnosis, altered LCVA may be associated with CSF inflammation and represent a useful parameter to identify patients with worse disease course.

Oral Contraceptives Interact with Adiposity-Associated Markers in Patients with Multiple Sclerosis.

Growing evidence suggests the involvement of adipose tissue in modulating the clinical course of relapsing-remitting multiple sclerosis (RRMS). This study aimed to investigate whether the intake of combined oral contraceptives (COCs) affects body weight and leptin and adiponectin (APN) blood levels in these patients. Clinical data from 62 women (M = 33.23 year) were recorded prior to the initiation of disease-modifying therapy. Patients who were taking COCs at the time of experiencing the first symptoms of disease (COC user) were compared with those who never used these formulations or stopped taking them before disease onset (COC non-user). Bivariate Pearson's correlations and hierarchical multiple linear regressions analysis were conducted. Normalized APN levels were lower in the COC-using patients (p = 0.013). Negative correlations between waist circumference and normalized APN (p = 0.001) were observed only in the COC non-user patients. A longer duration of COC intake was associated with increased body mass index and waist circumference (p = 0.003). Normalized APN predicted the MS Severity Score (MSSS) (p = 0.020), but this correlation was lost in the COC user patients. After adjusting for confounders, only age (p = 0.027) and, later, disease onset (p = 0.014) were correlated with the MSSS. Larger and prospective studies are needed to investigate the interactions of sex steroids with adipose metabolism in modulating disease progression.

Association between active and passive smoking and the clinical course of multiple sclerosis and neuromyelitis optica spectrum disorder

&lt;i&gt;Objective&lt;/i&gt;: Active and passive smoking are common environmental risk factors, but there is no definite conclusion about their effects on relapse and disability progression in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). &lt;i&gt;Methods&lt;/i&gt;: This was a retrospective cohort study. Patients were included from four centers. Demographic and clinical data were extracted from the clinical database, while data involving environmental exposures during daily life, relapse, and disability progression were obtained through telephone follow-up interviews. Determinants of relapse were assessed by Cox proportional models, and disability progression was assessed by linear regression. Kaplan‒Meier survival was used to estimate relapse within five years after the first attack. &lt;i&gt;Results&lt;/i&gt;: A total of 130 MS patients and 318 NMOSD patients were included in this study, and females accounted for 60% and 79.6%, respectively. MS patients with an active smoking history had a higher risk of relapse, for which the association became borderline significant after accounting for covariates (aHR=1.52, 95% CI=1.00, 2.31; &lt;i&gt;p&lt;/i&gt;=0.052). The relapse risk between ever-smokers who smoked more than 10 cigarettes per day and smokers who smoked less than 10 cigarettes per day was not significantly different (aHR=0.96, 95% CI=0.63, 1.47; &lt;i&gt;p&lt;/i&gt;=0.859). However, exposure to passive smoking was associated with a reduced risk of MS relapse (aHR=0.75, 95% CI=0.56, 1.00; &lt;i&gt;p&lt;/i&gt;=0.044) compared with never-exposed patients. No associations were observed between active smoking/passive smoking and the risk of NMOSD relapse, but patients with a history of smoking were associated with a lower annual progression rate by Expanded Disability Status Scale (EDSS) (aβ=−0.20, 95% CI=−0.38, −0.01; &lt;i&gt;p&lt;/i&gt;=0.036) and Multiple Sclerosis Severity Score (MSSS) (aβ=−0.23, 95% CI=−0.44, −0.03; &lt;i&gt;p&lt;/i&gt;=0.028). &lt;i&gt;Conclusion&lt;/i&gt;: Our research shows that active smoking increases the relapse risk of MS and has a negative impact on disability progression; thus, smoking cessation should be encouraged.

A multiscale assessment of bowel impairment in an Italian multiple sclerosis cohort

Bowel dysfunctions (BD) in multiple sclerosis (MS) are under reported despite their clinical relevance. Scales usually applied do not thoroughly assess constipation and fecal incontinence. Instead, a proper qualitative and quantitative description of these symptoms might have relevant clinical and scientific consequences. The aim of this project is to study the prevalence of BD in a cohort of persons with MS (pwMS). Four-hundred and forty-seven pwMS (330 relapsing–remitting MS-RRMS and 117 progressive MS-PMS) were recruited. Three different questionnaires were administered: the neurogenic bowel dysfunction score (NBDS), the Wexner constipation scale (WexCon) and the Wexner incontinence scale (WexInc). All the scales were divided in subscores according to symptom severity. The prevalence of BD, considered as NBDS > 0, was 53.7%. Mean scores in pwMS group were as follows: NBDS 2.6 (SD 3.5), WexInc 1.1 (SD 2.4), WexCon 4.4 (SD 5.9). NBDS, WexCon and WexInc were significantly higher in PMS vs RRMS (p < 0.001), and significantly associated with disease duration, EDSS, multiple sclerosis severity score (p < 0.001), as well as with each other (p < 0.001). Our study confirms the presence of bowel dysfunctions in a large group of pwMS with a wide range of disability and their association with progressive disease phenotype and clinical disability.

Relevance of Multiple Sclerosis Severity Genotype in Predicting Disease Course: A Real-World Cohort.

Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329A ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management. We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes. We were unable to detect any association between rs10191329A and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329A . However, we were able to replicate the association of two suggestive SNVs (rs7289446G and rs868824C ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset. Identification of rs10191329A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.

Seasonality and clinical characteristics of MS in an equatorial country

BackgroundMonth and season of birth have been associated with risk of multiple sclerosis (MS), but there is relatively little evidence regarding their influence on the timing and severity of disease at onset. ObjectiveTo assess whether month and season of birth influence the age and phenotype at onset of MS as well as its severity in a cohort of Colombian patients. MethodsThis study is an analysis on MS cases only, drawn from a previously published case-control study. MS cases confirmed with current diagnostic criteria cared for at least once in our center were included. We assessed the influence of the month and season of birth in the age at MS onset, MS severity score, and age-related MS severity score using multiple and pairwise comparisons. Age at onset was also studied using Kaplan–Meier survival estimates compared with the log-rank test. The likelihood of progressive MS onset was evaluated with OR estimated from logistic regression models adjusted for age at onset and sex. Results668 MS cases were included. No significant differences were found in the age at MS onset according to month of birth or season of birth. Neither month of birth nor season of birth conferred significant differences in MS severity score or age-related MS severity score. No significant association was found between month (ORs ranging from 0.62 to 3.11, none significant) or season of birth (OR 0.91; 95 %CI: 0.46–1.84) with primary progressive MS. ConclusionThe month or season of birth do not appear to influence the age onset and phenotype of MS in our country.

"No association between disease modifying treatment and fatigue in multiple sclerosis".

Fatigue affects 60-90% of people with multiple sclerosis (MS). It reduces quality of life and the ability to work. The cause of fatigue in MS remains unknown. Several disease-modifying treatments (DMTs) slow the disease process in relapsing MS by suppressing neuroinflammation. We aimed to investigate if treatment with a DMT is associated with lower rates of fatigue. In this cross-sectional study of the MS population in three counties in Norway, we used the Fatigue Scale for Motor and Cognitive Functions (FSMC) and the Hospital Anxiety and Depression Scale (HADS) to assess patient-reported fatigue, anxiety and depression. Clinical data were retrieved from the electronic patient record system. We categorized DMTs as high-efficacy therapy or moderate-efficacy therapy. High-efficacy drugs included fingolimod, natalizumab, ocrelizumab, rituximab, alemtuzumab, daclizumab, and autologous hematopoietic stem cell transplantation. Moderate-efficacy drugs included interferons, glatiramer acetate, dimethyl fumarate, and teriflunomide. We included persons with relapsing MS only. Of 1142 patients, 80% had fatigue. Fifty-six percent of the patients were on DMTs (25% on moderate-efficacy treatment and 30% on high-efficacy treatment), 18% had discontinued treatment and 26% had never received any DMT. Sex, level of disability as measured by the Multiple Sclerosis Severity Score, anxiety and depression were independently associated with fatigue. Moderate-efficacy treatment was associated with less fatigue, but not after adjustment for other variables. There was no association between high-efficacy treatment and fatigue. We found no independent relationship between the use of disease-modifying treatment and fatigue in MS.

Proteomics reveal biomarkers for diagnosis, disease activity and long-term disability outcomes in multiple sclerosis

Sensitive and reliable protein biomarkers are needed to predict disease trajectory and personalize treatment strategies for multiple sclerosis (MS). Here, we use the highly sensitive proximity-extension assay combined with next-generation sequencing (Olink Explore) to quantify 1463 proteins in cerebrospinal fluid (CSF) and plasma from 143 people with early-stage MS and 43 healthy controls. With longitudinally followed discovery and replication cohorts, we identify CSF proteins that consistently predicted both short- and long-term disease progression. Lower levels of neurofilament light chain (NfL) in CSF is superior in predicting the absence of disease activity two years after sampling (replication AUC = 0.77) compared to all other tested proteins. Importantly, we also identify a combination of 11 CSF proteins (CXCL13, LTA, FCN2, ICAM3, LY9, SLAMF7, TYMP, CHI3L1, FYB1, TNFRSF1B and NfL) that predict the severity of disability worsening according to the normalized age-related MS severity score (replication AUC = 0.90). The identification of these proteins may help elucidate pathogenetic processes and might aid decisions on treatment strategies for persons with MS.

Analysis of Cdx2 VDR gene polymorphism rs11568820 in association with multiple sclerosis in Slovaks

ABSTRACT Vitamin D deficiency is involved in the pathogenesis of multiple sclerosis (MS), a severe autoimmune demyelinating disease of the central nervous system. The gene polymorphism Cdx-2 (rs11568820, G/A) seriously influences the trancriptional activity of the vitamin D receptor (VDR) that binds the vitamin D responsive elements of target genes including HLA-DRB1*15. The aim of the present study in Slovaks was to analyse the association of Cdx-2 variants with the risk of MS and disability progression, and to assess the DRB1*15:01 allele as a possible confounding factor. In total, 493 MS patients and 417 healthy controls were involved in this study. The genotyping of Cdx-2 was performed using restriction analysis; DRB1*15:01 positivity was determined by a high-resolution melting analysis of its surrogate marker rs3135388 (G/A). Our results did not prove any allelic association between Cdx-2 and a risk of MS (minor allele A − 0.181 in patients vs. 0.161 in controls, OR = 1.15, .95 CI = 0.90–1.47, p = 0.289). The logistic regression analysis, adjusted for sex and age, showed no differences in Cdx-2 genotype counts when using an additive, dominant or recessive genetic model (p = 0.351, 0.150, 0.240 respectively). The Cdx-2 variants were also not associated with disease disability progression, evaluated using the Multiple Sclerosis Severity Score. The HLA-DRB1*15:01 allele was found to strongly increase the risk of MS in our study (0.300 in patients vs. 0.101 in controls, OR = 3.83, .95 CI = 2.94–4.99, p = 1.016 × 10−26, dominant genetic model OR = 4.62, .95 CI = 3.40–6.26, p = 9.1 × 10−23). In summary, we found the Cdx-2 as a single genetic marker not to be associated with MS development or progression in Slovaks, independently of HLA-DRB1*15:01 status.

Longitudinal associations between quality of diet and disability over 7.5 years in an international sample of people with multiple sclerosis.

Modifiable lifestyle factors, including diet, have been implicated in multiple sclerosis (MS) progression, but prospective evidence is limited. The aim of this study was to examine prospective relationships between quality of diet and subsequent disability over 7.5 years in an international cohort of people living with MS (pwMS). Data from 602 participants in the HOLISM (Health Outcomes and Lifestyle In a Sample of people with Multiple sclerosis) study were analysed. Quality of diet was assessed using the modified Diet Habits Questionnaire (DHQ). Disability was assessed using the Patient-determined MS Severity Score (P-MSSS). Characteristics of disability were assessed by log-binomial, log-multinomial and linear regression, adjusted for demographic and clinical covariates, as appropriate. Higher baseline total DHQ scores (>80-89, >89%) were associated with lower risks of increased P-MSSS at 7.5 years (adjusted risk ratio [aRR] 0.46, 95% confidence interval [CI] 0.23, 0.91 and aRR 0.48, 95% CI 0.26, 0.89, respectively), and with less P-MSSS accrual (aβ = -0.38, 95% CI -0.78, 0.01 and aβ = -0.44, 95% CI -0.81, -0.06). Of the DHQ domains, fat subscore was most strongly associated with subsequent disability. Participants with reducing baseline-to-2.5- years total DHQ scores had greater risk of increased P-MSSS at 7.5 years (aRR 2.77, 95% CI 1.18, 6.53) and higher P-MSSS accrual (aβ = 0.30, 95% CI 0.01, 0.60). Participants reporting baseline meat and dairy consumption had greater risk of increased P-MSSS at 7.5 years (aRR 2.06, 95% CI 1.23, 3.45 and aRR 2.02, 95% CI 1.25, 3.25) and higher P-MSSS accrual (aβ = 0.28, 95% CI 0.02, 0.54 and aβ = 0.43, 95% CI 0.16, 0.69, respectively). However, reported meat consumption was confounded by quality of diet. Changes in meat or dairy consumption from baseline were inconsistently associated with subsequent disability. We show for the first time robust long-term associations between quality of diet and subsequent disability progression in pwMS. Subject to replication, dietary modification may represent a point of intervention for reducing disability in pwMS.

ADAR Expression and Single Nucleotide Variants in Multiple Sclerosis Patients Affect the Response to Interferon Beta Therapy.

Interferon (IFN)-β is the first-line disease management choice in multiple sclerosis (MS) with profound effects; however, in up to 50% of patients, clinical response does not occur. Ascertaining the responding state, need a long-term clinical follow-up, and this may lead to delay in use of other effective medications. IFN-induced cascade and its regulation is considered to play a major role in MS. Adenosine deaminase, RNA-specific (ADAR) dysregulation is important to IFN signaling pathway as an activity suppressor. Hence, we investigated the expression of ADAR and its single nucleotide variants of rs2229857 association with response to IFN-β in relapsing-remitting MS patients. mRNA levels and genotyping of rs2229857 in 167 MS patients were investigated via SYBR Green real-time (RT)-quantitative polymerase chain reaction and high-resolution melting RT PCR, respectively. The allele-A in rs2229857 and higher expression of ADAR were associated with poor response to IFN-β. Two response groups were significantly different in terms of annualized relapse rate, first symptoms, first extended disability status scale (EDSS), current EDSS, and the MS severity score. According to this study's findings, assessment of transcript levels and also variants in ADAR may be useful in identifying patients' response to IFN-β before starting treatment. Further investigations are needed to determine the potency of ADAR to be a predictive biomarker in drug responsiveness.