Circulating extracellular vesicle-associated microRNAs (EV-miRNAs) are emerging as promising peripheral biomarkers in multiple sclerosis (MS). This prospective, observational pilot study was conceived as a hypothesis-generating investigation to characterize the expression profile of four candidate EV-miRNAs (miR-223-5p, miR-155-5p, miR-30a-5p, and miR-146a-5p) within an EV-enriched plasma fraction. The cohort comprised 16 patients with secondary progressive MS (SPMS) undergoing siponimod therapy, 13 age- and sex-matched healthy controls (HCs), and 7 patients with relapsing-remitting MS (RRMS) included as an exploratory comparator. Quantification was performed by quantitative real-time PCR employing the ΔΔC_t methodology, with miR-16-5p as the endogenous normalizer. Analyses were conducted cross-sectionally and longitudinally, the latter within a paired subgroup of 11 SPMS patients evaluated at baseline and after twelve months of uninterrupted treatment. Cross-sectional comparisons demonstrated a significant downregulation of EV-miR-223-5p in SPMS patients relative to HCs (fold-change [FC] = 0.26; FDR q = 0.026), whereas EV-miR-155-5p was significantly reduced in both the SPMS (FC = 0.35; FDR q = 0.033) and RRMS (FC = 0.28; FDR q = 0.046) cohorts compared with HCs. No significant intergroup differences were observed for EV-miR-30a-5p or EV-miR-146a-5p. Longitudinal assessment revealed no significant modulation of any target EV-miRNA following one year of siponimod therapy. These preliminary observations should be interpreted with caution, given the exploratory nature and modest cohort size. Importantly, the isolation of total plasma EVs does not permit resolution of the specific cellular provenance of the observed signals, nor does it capture their downstream functional consequences. Nevertheless, the selective downregulation of EV-miR-223-5p and EV-miR-155-5p may tentatively suggest candidate molecular signatures warranting further interrogation. Adequately powered studies incorporating cell-specific EV sorting and paired cerebrospinal fluid sampling will be required to substantiate these signals and clarify their potential utility in monitoring disease progression and therapeutic response in progressive MS.

Background: Environmental factors are known to influence the clinical presentation of patients with multiple sclerosis. This study aims to compare the demographic and clinical characteristics of multiple sclerosis patients treated at two diverse geographical settings. Methods: A cross-sectional, observational cohort study was conducted in two MS centers: the Danish Multiple Sclerosis Center (DMSC) in Copenhagen, Denmark and the Regional MS Center in Târgu Mureș, Romania. We compared patients’ demographic and clinical characteristics between MS centers, including sex distribution, current age, MS onset age, latest EDSS scores, symptomatology at disease onset, MS phenotype and type of ongoing DMT. Results: In both cohorts, sex distribution was similar, with females constituting 69.2% in DMSC, and 65.7% in Târgu Mureș. Pyramidal symptoms at MS onset were predominant among Targu Mures patients (32.7%), while sensory symptoms were more frequent among DMSC patients (33%). Progressive forms of MS were more prevalent in Târgu Mureș (22.6%) compared to DMSC (9.9%). High-efficacy DMTs were on use by 58.3% patients in DMSC and only by 29.4% patients in Târgu Mureș, who were mostly on low-efficacy DMTs (54.4% vs. 12.4% in DMSC). Conclusions: The study highlights both shared and distinct characteristics of MS patients treated in these two centers. These findings underscore the importance of regional considerations in the management and treatment of MS.

Although microRNAs (miRNAs) are an active area of research in multiple sclerosis (MS) and have been proposed as potential biomarkers of treatment response, the evidence remains difficult to interpret. This systematic review examines the relationship between miRNA expression and response to disease-modifying therapies (DMTs) in adults with MS. The PubMed/MEDLINE and Web of Science databases were systematically searched from inception to 11 February 2026. Fifteen studies that compared miRNA expression between responders and non-responders or assessed changes in miRNA expression after DMT initiation were synthesized narratively by treatment group and outcome, in accordance with the 2020 PRISMA guidelines. After considering study design, treatment response definitions, and miRNA analytical methods, miR-548a-3p in fingolimod-treated patients and miR-223-3p, miR-23a/b-3p, and miR-27a/b-3p in dimethyl fumarate (DMF)-treated patients appeared the most promising miRNAs investigated; however, each was assessed in a single study and has not yet been validated in independent external cohorts. However, they were notable because they had been evaluated in clinically relevant settings: miR-548a-3p in relation to no evidence of disease activity-3 and receiver operating characteristic-based discrimination, and the DMF-associated miRNAs through baseline expression levels and early fold-change analyses. Although miR-23a-3p, miR-26a-5p, miR-146a-5p, miR-155, miR-34a-5p, miR-223-3p, miR-660-5p, and miR-326 had been reported in more than one study, most were investigated in different DMT or outcome contexts. Therefore, the existing literature correlating miRNA expression levels with treatment response provides valuable but limited and heterogeneous evidence. Thus, miRNAs should currently be considered exploratory biomarkers and require further independent validation before their use in clinical practice.

Multiple sclerosis (MS) is an incurable disease of the central nervous system that affects young adults and determines significant disability. The past decade has seen a change in the treatment options, moving toward disease-modifying therapies. cladribine (Cladribine) tablets are the only short-course oral immune reconstitution therapy approved for highly active relapsing MS (RMS). Romanian authorities approved the full reimbursement in July 2021. MATERIALS AND METHODS:We conducted a multicenter, observational, post-marketing, real-world cohort study in Romania that included all patients with MS (PwMS) who completed at least one cycle of CLD with at least three months of follow-up as of September 2024. Demographic variables and MS clinical characteristics regarding each patient were recorded. No Evidence of Disease Activity (NEDA-3) was assessed at one and two years after CLD initiation. The primary outcome was the proportion and characteristics of PwMS achieving NEDA-3 at 12 and 24 months after CLD initiation and the identification of predictors of failure in achieving NEDA-3. RESULTS:A total of 348 PwMS cases were included, of which CLD was the first DMT option in 129 (37.1%). At one year, 76.74% of the patients with complete available data fulfilled all criteria, achieving NEDA-3 status, with similar proportions between previously DMT-treated PwMS and naïve PwMS. In the univariate analysis, the onset of long-tract involvement, as compared to infratentorial (OR = 6.32, p = 0.01), and the number of Gd-enhancing lesions (OR = 1.12, p = 0.02), were significantly associated with increased odds of not achieving NEDA-3 at one year. In the multivariate model, long tracts (OR = 10.28, p = 0.006), higher baseline EDSS (OR = 1.39, p = 0.01), and longer disease duration (OR = 0.92, p = 0.04) were independent predictors. CONCLUSIONS:The initiation of CLD treatment was associated with achieving NEDA-3 at one year in >70% of cases. CLD demonstrated an improvement in MS control, irrespective of the patients' demographics, RMS history, or prior DMT exposure. CLD treatment has a favorable safety profile and a high level of patient adherence.

Multiple sclerosis (MS) is a chronic, immune-mediated disease that affects young adults, leading to neurological disability. Regardless of the studies and the research involved in developing an efficient disease-modifying therapy (DMT), relapsing-remitting multiple sclerosis (RRMS) will transition to a progressive multiple sclerosis phenotype. The moment of transition from RRMS to secondary progressive multiple sclerosis (SPMS) is difficult to predict, and the diagnosis is based on the accumulation of disabilities in the evolution of the disease. Research on microRNAs’ (miRNAs) role in MS began in the early 2000s, with miR-155 frequently cited for its link to blood–brain barrier dysfunction and neurodegeneration, making it an early transition biomarker from RRMS to SPMS. The purpose of this review is to reveal the importance of finding a biomarker from the molecular field that will be able to identify the transition phase so patients can receive high-efficacy treatments and to cease the clinical progression.

Background and Objectives: Traditionally regarded as a purely motor disorder, amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the degeneration of upper and lower motor neurons. However, it is increasingly recognized as a condition with a broader clinical spectrum, encompassing a variety of non-motor symptoms (NMS) that significantly impact patients’ quality of life and may influence disease progression and prognosis. Materials and Methods: The study included 44 patients diagnosed with probable or definite ALS and 35 healthy controls (HC). Functional neurological status, non-motor manifestations, and cognitive and affective domains were evaluated using the revised ALS Functional Rating Scale (ALSFRS-R), the Non-Motor Symptoms Questionnaire (NMSQuest), the Frontal Assessment Battery (FAB), and the Beck Depression Inventory (BDI), respectively. Results: A majority of ALS patients exhibited non-motor symptoms (NMS). Significant associations were identified between specific NMS domains and ALSFRS-R subdomains: sleep disturbances were associated with lower fine motor, respiratory, and total scores; digestive symptoms with lower bulbar, respiratory, and total scores; cardiovascular symptoms with lower total scores; urinary symptoms with higher bulbar subscores and a significantly slower progression rate (ΔPR); and sensory symptoms with higher gross motor subscores. BDI scores were negatively correlated with respiratory and bulbar functions, whereas FAB scores showed positive correlations with both bulbar and total ALSFRS-R scores. Conclusions: Non-motor symptoms are highly prevalent in this ALS cohort. These symptoms do not consistently correlate with greater motor impairment, as urinary and somatosensory involvement may occur independently of functional decline. Cognitive, affective, and behavioral alterations co-exist with motor symptoms and are associated with poorer overall functional performance.

Background: Short-chain fatty acids (SCFAs) and medium-chain fatty acids (MCFAs) are human metabolites which are involved in various biochemical processes and can offer valuable insights and information on various pathological and metabolic issues of patients. Accurate, precise, high-performance bioanalytical methods are important tools in both research and diagnostics of many pathologies, with LC-MS being the most frequently used methodology in modern metabolomics studies. Methods: The current paper describes a complete LC-MS/MS methodology for the accurate quantification of total plasmatic SCFA concentrations in humans using high-resolution QTOF mass spectrometric detection, including sample cleanup, preparation, and derivatization. Results and Conclusions: The method was validated with regard to all relevant parameters (selectivity, sensitivity, accuracy, precision, linearity, recovery, carryover, and reproducibility of sample preparation) according to the current applicable guidelines and tested in an in vivo study to quantify peripheral SCFAs in human patients as biomarkers for gut-brain axis disruption.

Background: Left undiagnosed and untreated, the association between multiple sclerosis and mental health difficulties significantly increases the multimorbidity risk in these patients. Hence, the purpose of this systematic review and meta-analysis was to estimate the prevalence of neuroticism, depression, and anxiety in MS and to explore the cumulative impact of these psychological factors on the disease expression. Methods: A literature search was conducted on PubMed, Web of Science, Scopus, and Google Scholar databases, according to the PRISMA guidelines. Also, the potential risk of bias was assessed using the AXIS tool. Result: After a rigorous full-text examination, among the 756 identified studies, 22 investigations were considered for the systematic review, and 10 studies were selected for the meta-analysis. The prevalence of neuroticism in the studied population was 24.06% (95% CI: 16.79–33.34), of depression 20.77% (95% CI: 7.67–33.88), while the presence of anxiety was found in 23.94% (95% CI: 6.21–40.36). Conclusions: The main finding of this research confirms that psychiatric disorders often co-occur with MS, impacting the clinical symptoms and life quality of patients living with this illness. For a better understanding of the interaction between personality, depression, anxiety, and the disease symptoms, future research should consider conducting comparisons on more homogenous studies.

Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative central nervous system (CNS) disorder, characterized by focal inflammation, demyelination, irreversible axonal loss and neurodegeneration. The proposed mechanism involves auto-reactive T lymphocytes crossing the blood–brain barrier (BBB), contributing to inflammation and demyelination. Pro-inflammatory Th1 and Th17 lymphocytes are pivotal in MS pathogenesis, highlighting an imbalanced interaction with regulatory T cells. Dysbiosis in the gut microbiota, characterized by microbial imbalance is implicated in systemic inflammation, yet its exact role in MS remains elusive. Short-chain fatty acids (SCFAs), including valerate, butyrate, propionate, and acetate, produced through dietary fiber fermentation by the gut microbiota, modulate inflammation and immune responses. Particularly, butyrate and propionate exhibit pronounced anti-inflammatory effects in both the gut and CNS. These SCFAs influence regulatory T lymphocyte expression and BBB permeability. This review discusses the potential therapeutic implications of SCFA in MS, highlighting their ability to modulate the gut–brain axis and restore immune balance.

Background: Multiple sclerosis (MS) is a neurodegenerative immunological disease causing significant impairment in all life areas. Therefore, personality changes are observed and associated with higher prevalence of depression and anxiety disorders. Considering this relationship, we hypothesized that clinical symptoms and personality disorders are more prevalent in MS and that dysfunctional psychological mechanisms mediate the path from personality disorders to clinical symptoms. Methods: The study sample consisted of 43 patients with MS (age M = 41.9, SD = 11.5) and 31 controls (age M = 39.8, SD = 10.3). Measures of personality, anxiety, depression, fatigue, health status, and dysfunctional psychological mechanisms were conducted. Results: The prevalence of clinical symptoms was increased in MS patients as compared to controls. Also, dependent and schizoid personality traits (PTs) were observed in the patient sample. Negative automatic thoughts (NATs) were found to mediate the association between dependent PT and clinical symptoms. Along with schizoid PT, all dysfunctional psychological mechanisms impacted clinical symptoms. Discussion: The results of our research are in line with previous studies showing that anxiety, depression, and dysfunctional personality traits are more prevalent in MS as compared to controls. Conclusions: PTs and dysfunctional psychological mechanisms predicted depression, anxiety, fatigue, and health status in MS patients. Cognition acts as a strong mediator between PTs and psychopathology in MS. Hence, integrative personalized psychological treatment is recommended to improve the quality of care in MS.

Background: Multiple sclerosis (MS) is one of the most debilitating neurodegenerative diseases in youth, significantly affecting all life domains. Therefore, a strong association between MS, depression and anxiety symptoms has been established. The objective of the present interventional one-group pretest–posttest study is to assess the feasibility of an online single-session intervention (SSI) based on a cognitive behavioral therapy protocol targeting depressive and anxiety symptoms, psychological mechanisms, fatigue and overall health status. Methods: In this pilot study, 31 patients with MS (Mage = 42 years, SD = 12.2) received the online CBT SSI. The impact of the intervention was assessed using validated instruments two weeks after the intervention and after a two-month follow-up period. Results: Statistically significant effects were observed for the reduction of depression, with B = −7.58, 95% CI (−12.84, −2.31) and p < 0.01, and anxiety, with B = −15.17, 95% CI (−18.31, −12.02) and p < 0.001, at post-test and follow-up screening. Additionally, positive outcomes were seen for irrational beliefs at post-test, with B = −25.86, 95% CI (−46.10, −5.61), along with negative automatic thoughts, with B = −4.47, 95% CI (−10.65, 1.71), which were preserved at follow-up. Despite the health status also improving, no significant changes were observed for dysfunctional attitudes and fatigue. Conclusions: This research proves that the online CBT SSI was efficient for decreasing mild to moderate symptoms of depression and anxiety and reducing the intensity of dysfunctional psychological mechanisms in our sample.

Introduction: Alterations in intestinal permeability and microbiota dysregulation have been linked to the development of multiple sclerosis (MS). Short-chain fatty acids (SCFA) and medium-chain fatty acids (MCFA) are products of gut bacteria fermentation which are involved in immune regulation processes. In MS, SCFA have important immunomodulatory properties both in the periphery and the central compartment. Interferon (3 (IFN(3) was the first disease-modifying therapy approved for the treatment of MS and its effects on the gut microbiota are not fully elucidated. Patients and Methods: We performed a prospective observational study aimed to assess peripheral levels of SCFA and MCFA in 23 newly diagnosed, treatment-na & iuml;ve MS patients (nMS) before and after one year of IFN(3 treatment and 23 healthy controls (HC). We investigated their associations with inflammation, interleukin-10 (IL-10), and blood-brain barrier permeability, matrix metalloproteiResults: No significant differences in SCFA/MCFA levels were observed between baseline and after IFN(3 treatment. Caproic acid levels were significantly higher in nMS compared to HC (1.64 vs 1.27 mu M, p=0.005). The butyric acid/caproic acid ratio was higher in HC compared to nMS (5.47 vs 2.55, p=0.005). Correlation analysis revealed associations between SCFA/MCFA levels and inflammatory biomarkers. Conclusion: nMS have a higher gut-inflammatory activity as seen by the caproic acid ratio as opposed to HC. In this cohort, IFN(3 does not appear to modify the peripheral SCFA/MCFA levels after one year of treatment. The quantifications of peripheral SCFA/ MCFA may prove to be a useful biomarker for gut-brain axis disruption in MS patients.

Background Multiple sclerosis (MS) is a debilitating neurological disease characterized by inflammation, demyelination, and neurodegeneration in the central nervous system. Despite extensive research, the pathology of MS remains incompletely understood. Ocrelizumab (OCRE), a monoclonal antibody targeting CD20-positive B cells, has shown efficacy in relapsing (RR) and primary progressive (PP) MS. Neurofilaments (Nf) are emerging biomarkers of neuroaxonal injury, reflecting disease activity and treatment response in MS. This study aimed to assess the impact of OCRE on serum Nf levels (NfLs) in RRMS and PPMS patients and explore factors influencing treatment response.Methods A prospective study included 23 RRMS and PPMS patients initiating OCRE and 23 healthy controls. Serum NfLs were quantified using ELISA. Statistical analyses evaluated changes in NfLs and factors influencing treatment response.Results MS patients exhibited significantly higher NfLs than controls. OCRE treatment led to a significant reduction in NfLs after one cycle. Age and gender influenced treatment response, with older patients and females experiencing greater NfL reduction. Disability level and disease duration did not significantly affect NfLs reduction. Both RRMS and PPMS patients showed decreased NfLs levels with OCRE treatment.Conclusions In conclusion, OCRE demonstrated efficacy in reducing NfLs levels in RRMS and PPMS patients after one cycle, with potential age and gender-related variations in treatment response. Larger longitudinal studies are needed to further elucidate OCRE's mechanisms and implications for personalized MS treatment.

Background: A limited subgroup of multiple sclerosis (MS) patients present with a longterm disease evolution characterized by a limited disease progression, known as benign MS (BMS). Chitinase 3-like-1 (CHI3L1) levels are sensitive to inflammatory processes and may play a role in the pathogenesis of MS. In this observational, cross-sectional study, we aimed to evaluate the implications of serum CHI3L1 and inflammatory cytokines in BMS patients treated with interferon β-1b for over a decade. Methods: We collected serum samples from 17 BMS patients and 17 healthy controls (HC) to measure serum CHI3L1 levels and a Th17 panel of inflammatory cytokines. Serum levels of CHI3L1 were analysed using the sandwich ELISA method and the Th17 panel was assessed using the multiplex XMap technology on a Flexmap 3D Analyzer. Results: Serum CHI3L1 levels did not differ significantly from HC. We identified a positive correlation between CHI3L1 levels and relapses during treatment. Conclusions: Our findings suggest that there are no differences in serum CHI3L1 levels between BMS patients and HC. However, serum CHI3L1 levels are sensitive to clinical inflammatory activity and may be associated with relapses in BMS patients.

Background: Multiple sclerosis (MS) is a prevalent chronic inflammatory and neurodegenerative disease of the central nervous system. The main evolving forms, relapsing–remitting MS (RRMS) and secondary progressive MS (SPMS), lack clear delineation. Methods: We conducted an observational study on 523 Caucasian RRMS patients receiving first-line disease-modifying therapies (DMTs), analyzing demographic, clinical, and geographical data. Results: RRMS patients experienced a statistically significant reduction in relapse rates post-DMT initiation. Significant differences in time to reach an Expanded Disability Status Score (EDSS) of 3.0 and 6.0 were observed based on demographics and onset topography. Kaplan–Meier analysis revealed that the onset with optic or supratentorial symptoms is linked to a longer time until EDSS = 3.0 is reached. Urban origin correlated with a prolonged time until EDSS = 3.0. Gender and environment showed no significant associations with the hazard of reaching an EDSS = 6.0. Cox regression analysis revealed no significant impact of relapses on the time to reach EDSS scores of 3.0 and 6.0 in our study cohort. Conclusions: Multivariate analysis identified several predictive factors for disability progression, including environment, age at onset, and disability level at DMT initiation.

Fatigue is the most common and disabling symptom in patients with multiple sclerosis (PwMS), representing one of the main determinants of reduced quality of life among PwMS due to its interference with social activities and work capacity. This study aimed to identify the sociodemographic determinants of fatigue in a cohort of 150 PwMS and 100 healthy controls (HCs). Fatigue was assessed using one of the most suitable and appropriate tools for measuring the degree of fatigue: the Modified Fatigue Impact Scale (MFIS). By comparing the median scores for the MFIS, we observed that the PwMS group had significantly higher MFIS scores than the HCs (p = 0.0001). In PwMS, MFIS scores correlated positively with age, total number of relapses, total disease duration, disability status, and Beck Depression Inventory-II score and negatively with cognitive performance. Patients with relapsing-remitting MS had significantly lower fatigue levels than those with secondary progressive MS (p = 0.0010). Fatigue levels were significantly lower among male than female PwMS (p = 0.0120). Other determinant factors of fatigue in our study proved to be the marital and occupational status, as well as the presence of children, but in a linear multivariate regressions analysis with MFIS score as the dependent variable, the fatigue levels were influenced only by sex, occupational status, marital status, children status, and BDI-II test results. Considering the significant impact of fatigue on the quality of life of PwMS, clinicians must diagnose fatigue as early as possible, identify its modifiable determinants, and manage it effectively to increase their quality of life.

Despite extensive research into the pathophysiology of multiple sclerosis (MS) and recent developments in potent disease-modifying therapies (DMTs), two-thirds of relapsing-remitting MS patients transition to progressive MS (PMS). The main pathogenic mechanism in PMS is represented not by inflammation but by neurodegeneration, which leads to irreversible neurological disability. For this reason, this transition represents a critical factor for the long-term prognosis. Currently, the diagnosis of PMS can only be established retrospectively based on the progressive worsening of the disability over a period of at least 6 months. In some cases, the diagnosis of PMS is delayed for up to 3 years. With the approval of highly effective DMTs, some with proven effects on neurodegeneration, there is an urgent need for reliable biomarkers to identify this transition phase early and to select patients at a high risk of conversion to PMS. The purpose of this review is to discuss the progress made in the last decade in an attempt to find such a biomarker in the molecular field (serum and cerebrospinal fluid) between the magnetic resonance imaging parameters and optical coherence tomography measures.

Stroke prevention, a significant public-health concern, begins with recognizing and addressing risk factors. Interventions targeted at modifiable risk factors can effectively prevent ischemic stroke, while Omega-3 fatty acids have been shown to improve stroke outcomes. Our study aimed to investigate the relationship between ischemic-stroke risk factors and fatty acids using a prospective observational study with 274 patients. We collected clinical data on risk factors and measured fatty-acid levels using high-performance liquid chromatography coupled with mass spectrometry. We found that several risk factors, including age, sex, smoking, atrial fibrillation, dyslipidemia, and previous stroke history, had a direct relationship with fatty acids. Of these, smoking had the most significant impact, negatively impacting levels of docosahexaenoic and eicosapentaenoic acid. Conversely, dyslipidemia and atrial fibrillation positively correlated with fatty acids, particularly in female patients and those with recurrent strokes. Age was found to directly correlate with other risk factors and variations in fatty-acid ratios. The stroke rate was higher in males than females before the age of 70, but this trend reversed. Our findings suggest that better management of risk factors, particularly modifiable lifestyle factors, could improve fatty-acid profiles and the balance of Omega-3 and Omega-6 in patients with ischemic stroke.

Stroke is the primary cause of disability in the adult population. Hypertension represents the leading risk factor being present in almost half the patients. The renin-angiotensin system is involved in the physiopathology of stroke and has an essential impact on hypertension as a risk factor. This article targeted the role of the renin-angiotensin system in stroke neuroprotection by reviewing the current literature available. The mechanism of action of the renin-angiotensin system was observed through the effects on AT1, AT2, and Mas receptors. The neuroprotective properties ascertained by angiotensin in stroke seem to be independent of the blood pressure reduction mechanism, and include neuroregeneration, angiogenesis, and increased neuronal resistance to hypoxia. The future relationship of stroke and the renin-angiotensin system is full of possibilities, as new agonist molecules emerge as potential candidates to restrict the impairment caused by stroke.