Multiple Sclerosis Severity Research Articles

Resilience, Mental Health, Sleep, and Smoking Mediate Pathways Between Lifetime Stressors and Multiple Sclerosis Severity

Introduction: Lifetime stressors (e.g., poverty, violence, discrimination) have been linked to features of multiple sclerosis (MS); yet mechanistic pathways and relationships with cumulative disease severity remain nebulous. Further, protective factors like resilience, that may attenuate the effects of stressors on outcomes, are seldom evaluated. Aim: To deconstruct pathways between lifetime stressors and cumulative severity on MS outcomes, accounting for resilience. Methods: Adults with MS (N = 924) participated in an online survey through the National MS Society listserv. Structural equation modeling was used to examine the direct and indirect effects of lifetime stressors (count/severity) on MS severity (self-reported disability, relapse burden, fatigue, pain intensity, and interference) via resilience, mental health (anxiety and depression), sleep disturbance, and smoking. Results: The final analytic model had an excellent fit (GFI = 0.998). Lifetime stressors had a direct relationship with MS severity (β = 0.27, p < 0.001). Resilience, mental health, sleep disturbance, and smoking significantly mediated the relationship between lifetime stressors and MS severity. The total effect of the mediation was significant (β = 0.45). Conclusions: This work provides foundational evidence to inform the conceptualization of pathways by which stress could influence MS disease burden. Resilience may attenuate the effects of stressors, while poor mental health, smoking, and sleep disturbances may exacerbate their impact. Parallel with usual care, these mediators could be targets for early multimodal therapies to improve the disease course.

Effect of Diet and Dietary Patterns on the Progression of Multiple Sclerosis: A Review

The link between diet and the progression of Multiple Sclerosis (MS) is a topic of growing interest and investigation within the medical community. This review explored the mechanisms through which dietary interventions can impact the course of MS and shape the clinical outcomes and quality of life of individuals with the disease. By synthesizing current knowledge from clinical studies and observational research, the review aimed to provide insights into the role of diet in managing MS. A comprehensive literature search was conducted, focusing on the effect of diet and dietary patterns on the progression of MS. Key findings indicated that individuals with higher diet quality exhibit reduced disability levels and lower symptom severity, emphasizing the importance of maintaining a healthy diet and adopting a holistic, healthy lifestyle in managing MS. The review also delved into the potential impact of macronutrients, vitamins, and minerals on the progression of MS, highlighting the importance of adequate nutrient intake for optimal health outcomes. Additionally, the study explored the association between dietary intake variations and the severity of MS, suggesting that further investigation is needed to understand the potential implications of nutrient deficiencies in MS patients. Overall, the review serves as a valuable resource for healthcare professionals and individuals living with MS, providing evidence-based dietary approaches that may help optimize health outcomes and mitigate the burden of the disease. It also calls for future research directions in the critical area of dietary management of MS to enhance our understanding and improve patient care.

Obesity and Multiple Sclerosis Severity: A Mendelian Randomization Study.

Obesity is implicated in the development of multiple sclerosis (MS), but its effect on disability is less well-established. This study examined the effects of various obesity measures on MS severity in 12,584 MS cases, using Mendelian randomization to mitigate confounding. Results showed a significant association between higher genetically-determined body mass index (N = 806,834) and increased MS severity (P = 0.02). This finding was supported by additional measures of general obesity but not adiposity distribution. The convergence of this genetic evidence with prior observational studies strengthens the association between obesity and adverse long-term disability in MS, suggesting weight management as a potential therapeutic strategy. ANN NEUROL 2024.

A mendelian randomization analysis of the associations between haptoglobin and multiple sclerosis.

Observational studies have suggested an association between plasma haptoglobin and multiple sclerosis (MS). Haptoglobin plays an important role in the pathogenesis of MS. However, whether it has a causal effect on MS remains unknown. We here used a two-sample bidirectional Mendelian randomization (MR) method to investigate the causality between haptoglobin and MS. Genetic variants associated with plasma haptoglobin from two independent genome wide association studies (GWASs) (used as the discovery and replication datasets, respectively) were applied as the exposure. Their causal effects on summary statistics of GWASs of MS and disease severity were evaluated using the inverse-variance weighted (IVW) approach as the main analysis component. We found in both discovery and replication dataset that plasma haptoglobin was causally positively associated with the risk of MS (discovery: OR: 1.063, 95% CI: 1.022-1.106, P = 0.002; replication: OR: 1.041, 95% CI: 1.005-1.078, P = 0.026), but it was not associated with MS severity (discovery: OR: 1.017, 95% CI: 0.993-1.042, P = 0.168; replication: OR: 1.011, 95% CI: 0.987-1.036, P = 0.373). Besides, we did not detect any significant results in the reverse causation analysis. Our study provides evidence for the causal effects of plasma haptoglobin on the risk of MS.

The relationship between ethnicity and multiple sclerosis characteristics in the United Kingdom: A UK MS Register study.

Previous studies have suggested differences in multiple sclerosis (MS) severity according to ethnicity. Data were obtained from the UK MS Register, a prospective longitudinal cohort study of persons with MS. We examined the association between self-reported ethnic background and age at onset, symptom of onset and a variety of participant-reported severity measures. We used adjusted multivariable linear regression models to explore the association between ethnicity and impact of MS, and Cox proportional hazards models to assess disability progression. We analysed data from 17,314 people with MS, including participants from self-reported Black (n = 157) or South Asian (n = 230) ethnic backgrounds. Age at MS onset and diagnosis was lower in those of South Asian (median 30.0) and Black (median 33.0) ethnicity compared with White ethnicity (median 35.0). In participants with online MS severity measures available, we found no statistically significant evidence for an association between ethnic background and physical disability in MS in both cross-sectional and longitudinal analyses. We found no association between ethnic background and MS severity in a large, diverse UK cohort. These findings suggest that other factors, such as socioeconomic status and structural inequalities, may explain previous findings.

Assessment of the Multiple Sclerosis Severity Score and the Age-Related Multiple Sclerosis Severity Score as health indicators in a population-based cohort.

People with multiple sclerosis (MS) present varying degrees of disability throughout their disease course. The Multiple Sclerosis Severity Score (MSSS) and the Age-Related Multiple Sclerosis Severity Score (ARMSSS) adjust the Expanded Disability Status Scale (EDSS) according to disease duration and age, respectively. These measures could be useful for quantifying MS severity and as health outcome indicators for benchmarking in population-based settings. The aim of this study was to describe the severity of MS in our health district using the MSSS and ARMSSS and to assess their consistency over time. This population-based study included patients from our health district who were diagnosed with MS according to the 2010 McDonald criteria, had a disease duration of at least one year and were followed up in our MS unit. Sex, age at onset, disease duration, clinical course, age and irreversible EDSS at the last follow-up visit were collected, and the MSSS and ARMSSS were calculated at two time points: 2017 and 2020. One hundred seventy-seven patients were included in 2017, and 208 in 2020. The prevalence of MS was 90 and 104 per 100,000 inhabitants, respectively. The median MSSS was 1.77 (IQR 0.76-4.28) in 2017 and 2.03 (IQR 0.82-4.36) in 2020. The median ARMSSS was 2.90 (IQR 1.47-5.72) in 2017 and 2.93 (IQR 1.51-5.56) in 2020. No significant differences were found. According to the MSSS and ARMSSS, the severity of MS in our area is mild, and these instruments are consistent. These measures could be reliable health outcome measures.

The effects of the MTHFR 677C>T (rs1801133) genetic variant on susceptibility and disability worsening in multiple sclerosis patients are mediated by homocysteine

BackgroundInteractions between genetic and environmental variables contribute to the autoimmune inflammatory process in multiple sclerosis (MS). Elevated homocysteine levels, and vitamin D, vitamin B12, and folate deficiencies are some of the environmental factors associated with the pathogenesis of MS. Considering that the relationship between MTHFR 677C>T (rs1801133) genetic variant, homocysteine, and folate in patients with MS remains unclear and that their role were not extensively explored in the clinical course of the disease, we investigated whether this variant and plasma homocysteine and folate levels are associated with MS susceptibility, disability, disability progression, and inflammatory biomarkers. MethodsThe case-control study included 163 patients with MS categorized using the Expanded Disability Status Scale (EDSS) as mild (EDSS<3) and moderate/high (EDSS≥3) disability, and 226 healthy controls (HC). Disability progression was evaluated using Multiple Sclerosis Severity Score (MSSS) and the MTHFR 677C>T variant was genotyped using real time polymerase chain reaction. The plasma levels of some inflammatory biomarkers were determined. Two new composed scores were proposed: the first, namely as inflammatory activity index (IAI), was entered as a latent vector extracted from the macrophage M1 + T helper (Th)1 + Th17 + Th2 + T regulatory (Treg) cytokines, + tumor necrosis factor (TNF)-α+ soluble TNF receptor (sTNFR)-1 + sTNFR2. The second score, namely MS-severity index was entered as a latent vector extracted from the EDSS + MSSS scores + MS diagnosis. ResultsPatients with MS showed higher homocysteine and folate than controls (p < 0.001); homocysteine, and the M1, Th1, Th17, and Th2 Treg cytokine values were different between the three study groups and increased from HC to MS patients with mild disability and to MS patients with moderate/high disability (p < 0.0001). The levels of TNF-α and their soluble receptors sTNFR1 and sTNFR2 were higher in MS patients with EDSS≥3 than in the two other groups (EDSS<3 and HC) (p < 0.001). There was no association between the MTHFR 677 C > T genotypes and MS susceptibility, disability and disability progression (p > 0.05). Moreover, 21.8 % of the disability variance was explained by age, IAI and C-reactive protein (CRP) (all positively associated); 10.9 % of the disability progression variance was predicted by IAI and CRP (both positively) and 25-hydroxyvitamin D (negatively), whereas 54.4 % of the severity index (MS-EDSS-MSSS) was explained by the regression on age, IAI, homocysteine, folate, and CRP (all positively), and adiponectin, body mass index, and 25-hydroxyvitamin D (all negatively), female sex, and the MTHFR 677 TT genotype. In patients and controls, 16.6 % of the variance in the homocysteine was explained by the MTHFR 677 TT genotype and age (both positively), folate (negatively) and male sex. ConclusionThe MTHFR 677C>T variant has an indirect effect on the increase in disability in patients with MS, which also depends on factors such as age, sex, ad folate status.

Multiple sclerosis treatment underutilization predicts high risk for obstructive sleep apnea in patients with multiple sclerosis

BackgroundObstructive sleep apnea (OSA) is more common in patients with multiple sclerosis (MS) than in the general population, which suggests MS may predispose patients to OSA. However, the relationships between MS treatment, disease activity, disease severity, fatigue, and OSA are unknown. ObjectivesTo evaluate the connections between OSA risk, MS fatigue, and MS severity, controlling for well-established risk factors for OSA in the general population. MethodsWe administered OSA and fatigue-related questionnaires to patients with MS and collected relevant demographic and clinical data. Then, we utilized multivariate logistic regression to examine relationships between OSA risk and MS disease severity. ResultsWe identified an inverse correlation between medication possession ratio (MPR) and high OSA risk. Statistical models also demonstrated a positive correlation between fatigue and nonwhite race with high OSA risk, controlling for male sex, younger age, and body mass index (BMI). ConclusionWe identified disease-modifying therapy (DMT) underutilization, fatigue, and nonwhite race as predictors of high OSA risk in patients with MS. These findings support aggressive treatment of MS to avoid risk of comorbid OSA and MS-induced fatigue.

Social determinants of health on attitudes toward childbearing among women with multiple sclerosis: A cross-sectional study.

Pregnancy and motherhood are very valuable but challenging for women with multiple sclerosis (MS). Given that there are limited studies in this field, this study aimed to determine the social determinants of health on attitudes toward childbearing among women with MS. We conducted a cross-sectional study on 206 women with MS in Alborz province, Iran, from February to June 2023 using convenience sampling. The data were collected using the questionnaire, and a linear regression analysis was applied. The mean age of the participants was 36.80±6.50 years. Participants' Attitudes toward Fertility and Childbearing (PAFC) had a positive significant association with social support (B=.10, SE=.04, p=.023) and a significant negative association with the total score of depression, anxiety, and stress scale (B=-.13, SE=.06, p=.047) and depression (B=-.40, SE=.18, p=.023). However, the association between anxiety (B=-.25, SE=.20, p=.211), stress (B=-.36, SE=.18, p=.050), MS severity (B=.04, SE=.30, p=.890), and socioeconomic status scale (SES) (B=-.08, SE=.32, p=.806) was nonsignificant with PAFC. Our results showed that factors, including social support and mental health especially depression, can affect PAFC in women with MS. Therefore, it is necessary to determine specific strategies for policymakers to help MS patients manage pregnancy and motherhood.

Neurofilaments light chains as a diagnostic and predictive biomarker for Tunisian Multiple Sclerosis patients

BackgroundMultiple Sclerosis (MS) course was shown to be more severe among North Africans compared to Caucasians. Validation of prognostic biomarkers of disease activity and severity is a priority in our practice. ObjectiveWe aimed to investigate the association between baseline cerebrospinal fluid (CSF) and serum NfL (sNFL) levels and disease activity and disability accrual in a cohort of Tunisian patients with MS. MethodsA cross-sectional study was conducted, in the department of Neurology of Razi Hospital, including patients diagnosed with MS. Patient's data were retrieved from our local MS database. Blood and CSF sampling were performed at the first visit. sNFL levels were measured using the Enzyme-Linked Immuno-Sorbent Assay (ELISA) sandwich technique. ResultsThree hundred MS patients were enrolled (sex-ratio= 3.05; mean age at MS onset=28.83 years+9.55, mean MS course = 10.21 years+8.96). MS phenotype was predominately relapsing (73%). CSF NfL levels were significantly correlated to the serum ones. NfL concentrations were significantly associated with MS activity (p = 0.012), disease progression (p = 0.001), and higher Multiple Sclerosis Severity Scores (MSSS) (p = 0.0017, r = 0.28). ConclusionsThese results support the value of NfL as a sensitive and clinically meaningful CSF and blood biomarker to evaluate MS activity and outcomes among Tunisian MS patients.

Ocrelizumab alters the circulating metabolome in people with relapsing-remitting multiple sclerosis.

Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. To assess changes in the circulating metabolome produced by ocrelizumab treatment in people with relapsing-remitting MS (RRMS). Thirty-one individuals with RRMS eligible for beginning treatment with ocrelizumab were recruited and followed with demographic, clinical, quality-of-life, and global metabolomics data collected at each visit. Modules of highly correlated metabolites were identified using the weighted correlation network analysis approach. Changes in each module's eigenmetabolite values and individual metabolites during the study were evaluated using linear mixed-effects models. Patients with a mean age of 40.8 (SD = 10.30) years, and median disease duration of 4.0 (IQR = 8.5) years, were monitored for a median of 3.36 (IQR = 1.43) years. Two out of twelve identified sets of metabolites were altered significantly. The first module mainly contained androgenic and pregnenolone steroids (p-value <0.001, coefficient: -0.10). The second module primarily consisted of several lysophospholipids, arachidonic acid, some endocannabinoids, and monohydroxy fatty acid metabolites (p-value = 0.016, coefficient: -0.12), which its reduction was significantly associated with improvement based on overall disability response score (OR 3.09e-01, 95% CI: 6.83e-02, 9.09e-01, p-value = 3.15E-02). In this longitudinal observational study, using a global untargeted metabolomics approach, we showed significant alteration in circulating metabolome in RRMS patients undergoing ocrelizumab treatment. In particular, we observed a significant reduction in metabolites involved in the lysophospholipid pathway, which was associated with patients' improvement.

Clinical characteristics and disease burden of African, Caribbean, and Black people with multiple sclerosis in Toronto, Canada

BackgroundDifferent racial and ethnic groups have demonstrated heterogeneity in the clinical course of multiple sclerosis(MS). ObjectiveWe aimed to evaluate disease characteristics in African, Caribbean, and Black people with MS(ACB-MS) followed at a single centre in Toronto, Canada. MethodsACB-MS were compared with age- and sex-matched people with MS (pwMS) of European descent(EUR-MS) identified through the clinic registry. Results344 PwMS were included(n = 172 ACB-MS, n = 172 EUR-MS; mean age 43 years, 68 % female). Baseline mean Expanded disability status scale (EDSS) scores (ACB-MS 2.3 ± 2.3 vs. EUR-MS 2.2 ± 2.0, p = 0.38) and subsequent clinical and radiological measures of disease activity were similar between groups, including annualized relapse rate (ARR)(ACB-MS 0.47 ± 0.47 vs. EUR-MS 0.41 ± 0.34, p = 0.2) and most recent EDSS (ACB-MS 2.7 ± 2.2 vs. EUR-MS 2.3 ± 2.1, p = 0.10). However, the proportion of MRI brain demonstrating new disease activity was higher(37% vs. 26 %, p < 0.05) and disability progression greater in ACB-MS vs. EUR-MS(43% vs. 33 %,p < 0.05) but measures of disease severity including MS Severity Score(3.17 vs. 2.58, p = 0.3) and Progression Index(PI) (0.27 vs. 0.30, p = 0.5) were comparable. Conclusion: Disability progression was seen more commonly in ACB-MS, though clinical disease activity and severity were generally comparable between ACB-MS and EUR-MS patients in Toronto, Canada. These findings partially differ from prior studies demonstrating more overtly aggressive MS disease courses in Black and African American PwMS, necessitating further studies to understand how structural determinants of health drive these disparities.

Investigating cortical hypoxia in multiple sclerosis via time-domain near-infrared spectroscopy.

Hypoperfusion and tissue hypoxia have been implicated as contributory mechanisms in the neuropathology of multiple sclerosis (MS). Our objective has been to study cortical oxygenation in vivo in patients with MS and age-matched controls. A custom, multiwavelength time-domain near-infrared spectroscopy system was developed for assessing tissue hypoxia from the prefrontal cortex. A cross-sectional case-control study was undertaken assessing patients with secondary progressive MS (SPMS) and age-matched controls. Co-registered magnetic resonance imaging was used to verify the location from which near-infrared spectroscopy data were obtained through Monte Carlo simulations of photon propagation. Additional clinical assessments of MS disease severity were carried out by trained neurologists. Linear mixed effect models were used to compare cortical oxygenation between cases and controls, and against measures of MS severity. Thirty-three patients with secondary progressive MS (median expanded disability status scale 6 [IQR: 5-6.5]; median age 53.0 [IQR: 49-58]) and 20 age-matched controls were recruited. Modeling of photon propagation confirmed spectroscopy data were obtained from the prefrontal cortex. Patients with SPMS had significantly lower cortical hemoglobin oxygenation compared with controls (-6.0% [95% CI: -10.0 to -1.9], P = 0.004). There were no significant associations between cortical oxygenation and MS severity. Using an advanced, multiwavelength time-domain near-infrared spectroscopy system, we demonstrate that patients with SPMS have lower cortical oxygenation compared with controls.

Identification of commensal gut microbiota signatures as predictors of clinical severity and disease progression in multiple sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system and a leading cause of neurological disability in young adults. Clinical presentation and disease course are highly heterogeneous. Typically, disease progression occurs over time and is characterized by the gradual accumulation of disability. The risk of developing MS is driven by complex interactions between genetic and environmental factors, including the gut microbiome. How the commensal gut microbiota impacts disease severity and progression over time remains unknown. In a longitudinal study, disability status and associated clinical features in 58 MS patients were tracked over 4.2 ± 0.98 years, and the baseline fecal gut microbiome was characterized via 16S amplicon sequencing. Progressor status, defined as patients with an increase in Expanded Disability Status Scale (EDSS), were correlated with features of the gut microbiome to determine candidate microbiota associated with risk of MS disease progression. We found no overt differences in microbial community diversity and overall structure between MS patients exhibiting disease progression and non-progressors. However, a total of 41 bacterial species were associated with worsening disease, including a marked depletion in Akkermansia, Lachnospiraceae, and Oscillospiraceae, with an expansion of Alloprevotella, Prevotella-9, and Rhodospirillales. Analysis of the metabolic potential of the inferred metagenome from taxa associated with progression revealed enrichment in oxidative stress-inducing aerobic respiration at the expense of microbial vitamin K2 production (linked to Akkermansia), and a depletion in SCFA metabolism (linked to Oscillospiraceae). Further, as a proof of principle, statistical modeling demonstrated that microbiota composition and clinical features were sufficient to predict disease progression. Additionally, we found that constipation, a frequent gastrointestinal comorbidity among MS patients, exhibited a divergent microbial signature compared with progressor status. These results demonstrate a proof of principle for the utility of the gut microbiome for predicting disease progression in MS in a small well-defined cohort. Further, analysis of the inferred metagenome suggested that oxidative stress, vitamin K2, and SCFAs are associated with progression, warranting future functional validation and mechanistic study.

Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis.

The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes. In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes. The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL. The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.

Serum NfL and GFAP are weak predictors of long-term multiple sclerosis prognosis: A 6-year follow-up

BackgroundSerum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) are promising biomarkers that might be associated with clinical and radiological markers of multiple sclerosis (MS) severity. However, it is not known whether they can accurately identify patients at risk of disability progression in the medium and long term. ObjectivesWe wanted to determine the association between sNfL and sGFAP, Expanded Disability Status Scale score changes, and conversion to secondary progressive MS (SPMS) in a cohort of 133 patients with relapsing remitting MS. MethodsBlood samples were collected at inclusion to measure SNfL and sGFAP by single molecule array and their prognostic value was assessed using a linear mixed model. ResultsIn this cohort, 37 patients (27.8 % of 133) experienced disability progression and 12 patients (9.0 %) converted to SPMS during the follow-up (mean follow-up duration: 6.4 years). Only sNfL (p = 0.03) was associated with conversion to SPMS, and neither SNfL nor sGFAP was associated with disability progression. ConclusionSerum NfL and GFAP do not seem to accurately predict MS outcome in the long term. More studies are needed to determine how serum biomarkers, associated with other clinical and MRI biomarkers, might be used to improve MS prognostication.

Peroxynitrite reduces Treg cell expansion and function by mediating IL-2R nitration and aggravates multiple sclerosis pathogenesis

T-helper 17 cells and regulatory T cells (Treg) are critical regulators in the pathogenesis of multiple sclerosis (MS) but the factors affecting Treg/Th17 balance remains largely unknown. Redox balance is crucial to maintaining immune homeostasis and reducing the severity of MS but the underlying mechanisms are unclear yet. Herein, we tested the hypothesis that peroxynitrite, a representative molecule of reactive nitrogen species (RNS), could inhibit peripheral Treg cells, disrupt Treg/Th17 balance and aggravate MS pathology by inducing nitration of interleukin-2 receptor (IL-2R) and down-regulating RAS/JNK-AP-1 signalling pathway. Experimental autoimmune encephalomyelitis (EAE) mouse model and serum samples of MS patients were used in the study. We found that the increases of 3-nitrotyrosine and IL-2R nitration in Treg cells were coincided with disease severity in the active EAE mice. Mechanistically, peroxynitrite-induced IL-2R nitration down-regulated RAS/JNK signalling pathway, subsequently impairing peripheral Treg expansion and function, increasing Teff infiltration into the central nerve system (CNS), aggravating demyelination and neurological deficits in the EAE mice. Those changes were abolished by peroxynitrite decomposition catalyst (PDC) treatment. Furthermore, transplantation of the PDC-treated-autologous Treg cells from donor EAE mice significantly decreased Th17 cells in both axillary lymph nodes and lumbar spinal cord, and ameliorated the neuropathology of the recipient EAE mice. Those results suggest that peroxynitrite could disrupt peripheral Treg/Th17 balance, and aggravate neuroinflammation and neurological deficit in active EAE/MS pathogenesis. The underlying mechanisms are related to induce the nitration of IL-2R and inhibit the RAS/JNK-AP-1 signalling pathway in Treg cells. The study highlights that targeting peroxynitrite-mediated peripheral IL-2R nitration in Treg cells could be a novel therapeutic strategy to restore Treg/Th17 balance and ameliorate MS/EAE pathogenesis. The study provides valuable insights into potential role of peripheral redox balance in maintaining CNS immune homeostasis.

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.

Consanguineous marriage among familial multiple sclerosis subjects: A national registry-based study

BackgroundThe rising prevalence of familial multiple sclerosis (MS) in Iran has spurred interest in the potential impact of parental consanguinity on the risk of developing the disease. This study aims to aggregate current knowledge on parental consanguinity and its possible effect on MS risk, particularly among familial MS patients from various regions and ethnicities in Iran. The objective is to enhance the understanding of MS genetics and encourage further research in this field. Materials and methodsA cross-sectional study was conducted on clinically definite familial MS (FMS) patients registered in the nationwide MS registry of Iran (NMSRI). Data were extracted and supplemented with structured telephone follow-ups to gather detailed histories of MS in relatives and the familial relationships of the patients' parents. A family penetration score was proposed. Descriptive statistics and inferential statistical tests were used to analyze the data at a significance level of 0.05, adhering to ethical guidelines. ResultsOut of 19,911 individuals registered in the NMSRI, 2307 FMS patients across 13 provinces were included in the final analysis. Among these, 385 (19.3 %) reported parental consanguinity, with 283 (14.2 %) having parents who were cousins and 102 (5.1 %) having parents who were distant relatives. The data showed no significant association between parental kinship and variables such as MS phenotype, number of affected relatives with MS, hospitalization rates, and expanded disability status scale score. Similarly, MS severity did not differ based on parental consanguinity (P-value >0.05). While the rate of consanguineous marriage was higher among patients with an onset age less than 18 years, there was no statistically significant difference in disease onset age based on parental consanguinity status. ConclusionOur study highlights the complexity of factors influencing MS development, including genetic and environmental components. These results highlight the need for further research to achieve a more comprehensive understanding of MS etiology.

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.