Relapsing-remitting Multiple Sclerosis Research Articles

Human B-cells can form Hetero-aggregates with Blood Platelets: A Novel Insight into Adaptive Immunity Regulation in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by inflammation and neurodegeneration. Our original study analyzes the interactions between blood platelets and leukocytes in MS, focused on their potential role in modulating immune responses. We demonstrated, for the first time, a significant increase in leukocyte migration towards platelets, indicating their higher chemotactic capabilities in MS. This novel finding is supported by microscopic imaging of platelet-leukocyte hetero-aggregates (PLAs). Our study included platelet activation status and platelet-lymphocyte cross-talk analysis distinguishing lymphocytic subpopulation in patients with relapsing-remitting (RRMS) and secondary progressive MS (SPMS) compared to healthy controls (HC). Flow cytometry method revealed an elevated expression of platelet activation typical markers i.e. PAC-1 and CD62P in both phenotypes of MS, especially in RRMS, and higher GPVI level in SPMS. Detailed immunophenotyping and confocal imaging showed an increased pool of platelet-lymphocyte aggregates (PLAs-Ly), particularly involving B-cells over T-cells across both MS phenotypes. The study also explored the involvement of the CD40-CD40L pathway, discovering significant correlations between platelet CD40L expression and lymphocytic antigen CD40, especially on B-cells in SPMS. This novel finding may indicate the special significance of platelet-B-cell cross-talk in progressive disease phenotype. Our research identified potential platelet-leukocyte interaction pathways that may influence the lymphocyte-mediated immune response in MS, highlighting the unexplored formation of platelet-B cell hetero-aggregates (PLAs-LyB).

Restless legs syndrome in multiple sclerosis: uncovering prevalence and clinical aspects.

The aim of the study is to determine the prevalence of restless legs syndrome (RLS) in patients with relapsing-remitting multiple sclerosis (RRMS) and explore its associations with sleep quality, comorbidities and quality of life. RLS and RRMS diagnosis were made using the latest criteria the International Classification of Sleep Disorders-3 (ICSD-3) criteria and 2017 McDonald criteria. A total of 210 individuals, including 105 patients diagnosed with RRMS and 105 healthy volunteers were included into the study. Data of demographical and disease characteristics and RLS properties were collected. Several scales to assess anxiety, depression, fatigue, sleep quality and quality of life scales were used. RLS prevalence was found in 21.9% of RRMS patients and 12.4%of healthy volunteers. RRMS patients with RLS exhibit significantly higher anxiety and depression scores in sleep quality, fatigue and quality of life compared to the patients without RLS. This study highlights a higher prevalence of RLS in patients with RRMS compared to healthy individuals. RRMS patients with RLS exhibited distinct characteristics, including lower sleep quality and higher quality of life scores while RLS was nod significantly associated with demographic or clinical variables. Recognizing RLS in patients with RRMS is important for the treatment and improving their overall well-being.

Dimethyl Fumarate Reduces Methylglyoxal-derived Carbonyl Stress Through Nrf2/GSH Activation in SH-SY5Y Cells.

Carbonyl stress refers to the excessive accumulation of advanced glycation end products (AGEs) in mammalian tissues. This phenomenon plays a significant role in the pathogenesis of various diseases, including diabetes, chronic renal failure, arteriosclerosis, and central nervous system (CNS) disorders. We have previously demonstrated that an increase in glutathione concentration, dependent on the nuclear factor erythroid 2-related factor 2 (Nrf2) system, provides a potent cytoprotective effect against Methylglyoxal (MGO)-induced carbonyl stress. Meanwhile, dimethyl fumarate (DMF), known for its Nrf2-activating effects, was recently approved as a treatment for multiple sclerosis (MS), a neurodegenerative disease. DMF is a first line therapy for relapsing-remitting MS and may also be effective for other neurodegenerative conditions. However, the detailed mechanisms by which DMF mitigates neurodegenerative pathologies remain unclear. This study investigates the impact of DMF on anticarbonyl activity and its underlying mechanism focusing on the accumulation of carbonyl protein in the cell. MGO, a glucose metabolite, was used to induce carbonylation in the neuronal cell line. MGO is a typical carbonyl compound that readily reacts with arginine and lysine residues to form AGE-modified proteins. Methylglyoxal-derived hydroimidazolone 1 (MG-H1) often forms uncharged, hydrophobic residues on the protein surface, which can affect protein distribution and lead to misfolding. Our findings indicate that DMF increases levels of glutathione (GSH), glutamate cysteine ligase modifier subunit (GCLM), and nuclear Nrf2 in SH-SY5Y cells. Importantly, DMF pretreatment significantly reduced the accumulation of MG-H1-modified proteins. Furthermore, this effect of DMF was diminished when Nrf2 expression was suppressed and when GCL, a rate-limiting enzyme in GSH synthesis, was inhibited. Thus, the increase in GSH levels, leading to the activation of the Nrf2 pathway, a key factor in DMF's ability to suppress the accumulation of MG-H1-modified proteins. This study is the first to demonstrate that DMF possesses strong anticarbonyl stress activity in neuronal cells. Therefore, future research may extend the application of DMF to other CNS diseases associated with carbonyl stress, such as Alzheimer's and Parkinson's disease.

Vitamin D receptor gene polymorphisms in patients with relapsing multiple sclerosis.

The relationship between the vitamin D receptor (VDR) gene and many pathogenic pathways in relapsing-remitting multiple sclerosis (RRMS) remains unclear. Given the significance of the topic, we conducted this study to explore the correlation between vitamin D receptor gene polymorphisms and clinical and inflammatory factors in patients suffering from relapsing-remitting multiple sclerosis. The current research is a case/control study conducted based on the Helsinki Ethical Principles. RRMS disease was confirmed based on history, clinical symptoms, radiological signs and neurologist diagnosis. The research population consisted of healthy people and patients with RRMS who were referred to Hazrat Rasool Akram Hospital between 2021 and 2023. For each person participating in the study (RRMS patient and healthy), five milliliters of peripheral blood containing the anticoagulant EDTA was collected. Polymerase chain reaction was performed using two specific and appropriate oligonucleotide primers. The restriction fragment length polymorphism technique was used, one of the standard methods for identifying polymorphisms. Statistical analysis was performed using SPSS software version 23. The odds ratio and 95% confidence limits were calculated. The SNP Analyzer software was used to analyze the allele frequency of each polymorphism in healthy and RRMS individuals and compare the values. Prism version 5 software was used to draw diagrams. In the present study, a statistically significant difference was observed between the percentage of FokI genotypes in RRMS patients and healthy individuals. FokI polymorphism showed a significantly increased risk with an odds ratio of 7.28 in patients with the FF genotype compared to healthy individuals. ApaI, TaqI, and BsmI were not significantly different between the two groups. Based on the findings of the present study, FokI polymorphism showed a significant risk increase in RRMS patients with FF genotype compared to healthy individuals.

Real-World Safety and Effectiveness of Dimethyl Fumarate in Patients with MS: Results from the ESTEEM Phase4 and PROCLAIM Phase3 Studies with a Focus on Older Patients.

Real-world studies in the USA report that 41-56% of patients with multiple sclerosis (MS) are ≥ 50years old, yet data on their response to disease-modifying therapies (DMTs) is limited. Dimethyl fumarate (DMF) is an oral DMT approved for treating relapsing MS. This analysis evaluated the safety, efficacy, and immunophenotype changes of DMF in patients ≥ 50years compared with patients < 50years. ESTEEM, a 5-year, real-world, observational phase4 study, assessed the safety and effectiveness of DMF, including treatment-emergent serious adverse events (SAEs) and adverse events (AEs) leading to treatment discontinuation. Absolute lymphocyte counts (ALCs) were recorded from a subset of patients. The PROCLAIM study, a phase3b interventional study, reported safety outcomes and lymphocyte subset changes in patients with relapsing-remitting MS (RRMS) treated with DMF. The study evaluated safety outcomes by analyzing the incidence of SAEs and detailed changes in CD4+ and CD8+ Tcell compartments over 96weeks of DMF treatment. ESTEEM included 4020 patients aged < 50years and 1069 aged ≥ 50years. AEs leading to discontinuation were reported by 19.6% patients < 50years and 29.6% of patients ≥ 50years, with gastrointestinal disorders being the most common. SAEs were reported by 5.2% of patients < 50years and 8.9% those ≥ 50years. In PROCLAIM, SAEs were reported in 13% of patients < 50years and 10% of those ≥ 50years. Median ALC decreased by 35% in patients < 50years and 50% in those ≥ 50years in ESTEEM, with similar patterns observed in PROCLAIM. ESTEEM found no unexpected safety signals in older patients and annualized relapse rates (ARRs) were significantly reduced in both age groups. Both studies indicated that DMF is efficacious and has a favorable safety profile in patients with RRMS aged ≥ 50years. ESTEEM (NCT02047097), PROCLAIM (NCT02525874).

Ocrelizumab-associated cryptogenic organizing pneumonia in multiple sclerosis: Two case reports and comprehensive literature review.

Cryptogenic organizing pneumonia (COP) is an interstitial lung disease, with causes including anti-CD20 antibodies. Ocrelizumab is a humanized monoclonal antibody against CD20 approved for use in relapsing-remitting or primary progressive multiple sclerosis (MS), with no conclusive data regarding pulmonary toxicity. We describe two cases of COP associated with ocrelizumab use in multiple sclerosis patients. We suggest considering COP whenever respiratory symptoms arise in MS patients receiving ocrelizumab therapy. COP diagnosis requires clinical and radiological exclusion of alternative diagnoses such as opportunistic infections, autoimmunity, drugs, and neoplasms. Appropriate steroid therapy has an excellent clinical response rate.

Effects of resveratrol supplementation on inflammatory markers, fatigue scale, fasting blood sugar and lipid profile in relapsing-remitting multiple sclerosis patients: a double-blind, randomized placebo-controlled trial

ABSTRACT Objectives: Resveratrol, a polyphenol found in grapes, has been studied extensively for its potential benefits on metabolic markers and inflammation. While promising results have been observed in animal studies and some human trials, the overall evidence is mixed. Moreover, elevated inflammatory markers have been closely linked to more severe symptoms of Multiple Sclerosis (MS). Therefore, strategies to reduce systemic inflammation could potentially improve outcomes for MS patients. So we aimed to examine the effectiveness of resveratrol supplementation on inflammatory markers in patients with Multiple sclerosis (MS), in a randomized placebo-controlled double-blinded parallel clinical trial. Methods: A total of 55 subjects with MS were enrolled in this study and randomly assigned to the two groups who were supplemented with resveratrol at a dose of 500 mg/day or received placebo capsules for 8 weeks. Tumor necrosis factor-alpha (TNF-α), Malondialdehyde (MDA), fasting blood sugar (FBS), triglycerides, total cholesterol, low-density lipoprotein – cholesterol (LDL-C), high-density lipoprotein – cholesterol (HDL-C), and the degree of fatigue were measured at baseline and after the intervention. Results: Resveratrol treatment significantly decreased TNF-α (P < 0.001), and MDA (P < 0.001) compared to the placebo. The respective increase and decrease in FBS and HDL levels were seen in both groups, while the change in participants receiving resveratrol was significantly less pronounced. Changes in the levels of TG and fatigue scale remained unchanged. Conclusion: This study showed that resveratrol supplementation exerted anti-inflammatory and anti-oxidant effects in patients with MS. Trial registration: Iranian Registry of Clinical Trials identifier: IRCT20230315057731N1.

Epstein-Barr nuclear antigen 1 antibody-based indices are increased in patients with multiple sclerosis

BackgroundMultiple sclerosis (MS) is a chronic central nervous system (CNS) disease, which is diagnosed by a combination of clinical symptoms and magnetic resonance imaging and measurement of an increased intrathecal antibody synthesis. Genetic as well as environmental factors influence onset of the disease, where especially Epstein-Barr virus (EBV) infection is directly involved in MS development. In this open retrospective study, we aimed to elaborate whether various serum and cerebrospinal fluid (CSF)-based EBV antibody indices may aid in the diagnosis of MS. MethodsEpstein-Barr nuclear antigen (EBNA)1 IgG concentrations in serum and CSF of relapsing-remitting (RR)MS patients (n=61) (M:F 28:33, average 40 years), optic neuritis patients (n=26) (M:F 9:17, average 47 years) and healthy controls (HCs) (n=15) (M:F 8:7, average 43 years) were determined by enzyme-linked immunosorbent assay. The obtained EBNA1 IgG levels were compared to factors such as total IgG, albumin concentrations, specific antibody index, and various serum- and CSF-based indices. ResultsSignificantly elevated EBNA1 IgG levels were detected in serum and CSF of RRMS patients compared to HCs. CSF EBNA1 IgG and indices based on specific CSF EBNA1 IgG associated with CSF albumin or serum EBNA1 IgG associated with total serum IgG obtained the highest sensitivities and complemented the IgG index and oligoclonal bands. ConclusionThese findings indicate that aforementioned indices may supplement existing indices and aid in the diagnosis of MS.

Expression of STAT- and T-cell-related genes in women with first-line treatment of relapsing-remitting multiple sclerosis.

Relapsing-remitting multiple sclerosis is associated with changes in Jak/STAT pathways in immune cells, but the influence of disease-modifying drugs on these pathways is poorly understood. The aim of this study was to evaluate the impact of first-line disease-modifying drugs used in treatment of RRMS on expression of the STAT pathway and T-cell-related genes in the blood and on serum concentrations of sgp130 and TGF-β1 in women, as well as on the level of phosphorylated STAT3 and STAT5 proteins in T cells of untreated patients and heathy controls. Expression of STAT1, STAT3, STAT5A, STAT5B, SOCS1, SOCS3, FOXP3, IKZF2, RORC and ICOS genes in the blood of untreated RRMS patients, in the blood of patients treated with interferon-β, glatiramer acetate, dimethyl fumarate or teriflunomide and in the blood of healthy controls was evaluated using droplet digital PCR. Serum concentrations of sgp130 and TGF-β1 were evaluated by ELISA. Phosphorylated STAT3 and STAT5 protein levels in T cells were evaluated by flow cytometry. STAT3 gene expression was significantly higher in untreated patients than in healthy control, but the level of phosphorylated STAT3 in T cells was significantly lower. Patients treated with interferon-β or dimethyl fumarate had significantly lower STAT3 gene expression. Patients treated with teriflunomide had higher STAT1 gene expression, than untreated patients. Patients treated with dimethyl fumarate also had significantly lower RORC gene expression than untreated patients. The study shows the impact of drugs used in first-line treatment of relapsing-remitting multiple sclerosis on expression of STAT and T-cell-related genes.

Validation of a Set of Clinical Criteria for the Diagnosis of Secondary Progressive Multiple Sclerosis.

Background/Objectives: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by progressive impairment of neuronal transmission due to focal demyelination. The most common form is RRMS (relapsing-remitting multiple sclerosis), which, under the influence of certain factors, can progress to SPMS (secondary progressive multiple sclerosis). Our study aimed to validate the criteria proposed by a working group of the Romanian Society of Neurology versus the criteria proposed by a group of experts from Spain, Karolinska, and Croatia concerning the progression from RRMS to SPMS. Methods: This was done by gathering epidemiological data (age, gender) and by applying clinical tests such as the 9HPT (9-hole peg test), 25FWT (25-foot walk test), and EDSS (expanded disability status scale) tests and the SDMT test (symbol digit modalities test). The present research is a cohort study that included a number of 120 patients diagnosed with MS according to the McDonald Diagnostic Criteria 2017. The study was carried out between January 2023 and April 2024, including patients hospitalized in the Neurology Clinic of the Clinical Rehabilitation Hospital from Iasi, Romania. The data were collected at baseline (T0) and at a 12-month interval (T1). Results: The statistical analysis was conducted using Kaiser-Meyer-Olkin analysis, which indicated a value of 0.683, thus validating the clinical tests used. The correlation matrix and the linear regression for all the tests showed highly significant statistical results. Furthermore, the ROC curve analysis of the criteria suggested by the working group of the Romanian Society of Neurology demonstrated that the EDSS, 9HPT, and 25FWT are highly sensitive in diagnosing SPMS, an opinion that is shared with the Spanish experts, but not with the Karolinska expert panel. Using the criteria given by the Croatian expert group in the ROC curve analysis showed that only the EDSS was strongly significant for the progression to the SPMS phase. Conclusions: In conclusion, all clinical methods used demonstrated that they are valid and can contribute to identifying patients with an increased risk of progression. The model proposed by the Romanian Society of Neurology working group is similar to other countries' expert opinions and can be used to detect the risk of disease progression and establish a more tailored therapeutic management of SPMS.

Biomarkers of response to ocrelizumab in relapsing-remitting multiple sclerosis.

To ascertain the changes of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) values in relapsing-remitting multiple sclerosis (RRMS) patients treated with ocrelizumab and their association with treatment response. Multicenter prospective study including 115 RRMS patients initiating ocrelizumab treatment between February 2020 and March 2022 followed during a year. Serum samples were collected at baseline and every 3 months to measure sNfL and sGFAP levels using single-molecule array (SIMOA) technology. Based on age and body mass index, sNfL values were standardized using z-score. NEDA (non-evidence of disease activity)-3 status was defined for patients free of disease activity after a year of follow-up. Inflammation (INFL) was considered when new relapses occurred during follow-up or new MRI lesions were found at 1-year exploration. PIRA (progression independent of relapse activity) was defined as disability progression occurring in the absence of relapses or new MRI activity. After a year on ocrelizumab, 85 patients (73.9%) achieved NEDA-3. Thirty patients did not achieve NEDA: 20 (17.4%) because of INFL and 10 (8.7%) because of PIRA. Of INFL patients, 6 (30.0%) had relapses, and 17 (85.0%) had at least one new MRI lesion at the 12-month examination. At baseline, INFL patients had higher sNfL (p = 0.0003) and sGFAP (p = 0.03) than the NEDA-3 group. PIRA patients mostly exhibited low sNfL and heterogeneous sGFAP levels. After a year, NEDA-3 and INFL patients showed similar decreases in sNfL (p < 0.0001) and sGFAP (p < 0.0001 for NEDA-3 and p = 0.001 for INFL ones). However, the decrease occurred earlier in NEDA-3 patients. Accordingly, sNfL > 1.5 z-score 3 months after ocrelizumab initiation indicated a higher risk of inflammation (OR = 13.6; p < 0.0001). Decrease in sGFAP values occurred later in both groups, with significant reductions observed at 12 months for INFL and 6 and 12 months for NEDA-3. No significant changes in sNfL or sGFAP were observed in PIRA patients. Ocrelizumab induced normalization of sNfL and sGFAP in the majority of NEDA-3 and inflammatory patients but did not cause changes in the PIRA group. Our data suggest that normalization of sNfL and sGFAP is associated with the lack of inflammatory-associated disease progression but it may not affect non-inflammatory PIRA.

TEC-ADHERE: Real-World Persistence and Adherence on Dimethyl Fumarate in Patients with Relapsing-Remitting Multiple Sclerosis in the French OroSEP Patient-Support Program.

Treatment persistence and adherence are essential for achieving therapeutic goals in patients with multiple sclerosis (MS). OroSEP is an independent patient-support program (PSP) in France for patients with relapsing-remitting MS (RRMS) receiving oral disease-modifying therapies. TEC-ADHERE (NCT04221191; 08/19/2019-09/15/2022) was a prospective, non-interventional, phase4 study to assess the effect of OroSEP on persistence and adherence to dimethyl fumarate (DMF; Tecfidera™) in patients with RRMS. Outcomes were compared for patients in OroSEP versus non-OroSEP patients who received their neurologists' standard of care (SoC). Patients initiated DMF at month0 (M0); follow-up visits occurred at M3 and M6. Primary outcome was persistence at M6. Secondary outcomes included persistence at M1 and M3, adherence at M6 (Girerd questionnaire), anxiety (Generalized Anxiety Disorder Assessment), patient satisfaction at M6 (Treatment Satisfaction Questionnaire for Medication), patient and neurologist satisfaction with OroSEP participation, and adverse events (AEs). Per-protocol population included 341 patients (OroSEP, n = 135; SoC, n = 206). Persistence was similar for OroSEP vs SoC (M6, 75.9% vs 76.6%; M1, 96.0% vs 92.4%; M3, 85.5% vs 89.0%). At M6, mean adherence was higher for OroSEP (5.4) vs SoC (4.7; p < 0.0001), and good adherence (Girerd score = 6) was achieved by more OroSEP patients (55.7%) than SoC patients (29.6%; p < 0.01). Mean anxiety scores were lower in the OroSEP group than in the SoC group at baseline (7.1 vs 8.8; p = 0.02) and M6 (3.4 vs 6.1; p < 0.001). Mean satisfaction scores at M6 were higher for OroSEP (77.4) vs SoC (64.2; p < 0.01). Most neurologists (n = 11/14) agreed that OroSEP helped improve adherence. Treatment-related AEs occurred in 62 (36.3%) OroSEP patients and 76 (42.9%) SoC patients; most common were flushing, diarrhea, hot flush, and abdominal pain. These outcomes support the value of PSPs in encouraging adherence, alleviating anxiety, improving patient satisfaction, and supporting patients to be more independent in managing MS. ClinicalTrials.gov identifier, NCT04221191.

Relevance of optic nerve B-mode sonography in multiple sclerosis diagnosis and follow-up

BackgroundAmong young people, multiple sclerosis (MS) accounts for the majority of non-traumatic neurological impairments. Almost all MS patients develop optic neuritis as the illness progresses. In MS, the optic nerve (ON) is vulnerable to demyelinating injury and is considered “eloquent” in comparison with the brain. Thus, it serves as a clinical model for MS. Since the eye is a suitable target for ultrasonography due to its high-water content, non-invasive trans-orbital sonography (TOS) can determine the optic nerve sheath diameter (ONSD). This research aimed to determine the effectiveness of ON ultrasonography as a simple, low-cost method for diagnosing and following up MS patients, facilitating their treatment plan. It correlates the findings of ONSD using TOS and visual-evoked potential (VEP), the number of magnetic resonance imaging (MRI) black holes, and other clinically significant parameters in 30 relapsing–remitting MS (RRMS) patients versus 30 controls.ResultsWe examined a total of 120 eyes. The ONSD values at 3 mm, 5 mm, and myelination index were significantly lower in the patients (4.7 ± 0.3, 5.5 ± 0.3, and 0.86 ± 0.03, respectively) versus the controls (5.6 ± 0.3, 6.2 ± 0.4, and 0.90 ± 0.03, respectively) (p < 0.001 in each). The mean P 100 latency was significantly delayed in the patients (125.5 ± 6.1 ms) than the controls (100.2 ± 3.3 ms), (p < 0.001). The mean VEP amplitude was significantly lower in the patients (4.9 ± 0.7 μV) than the controls (6.8 ± 0.8 μV) (p < 0.001). There was a highly significant positive correlation between the ONSD and P 100 amplitude, and highly significant negative correlations between the ONSD and disease duration, number of optic neuritis attacks, EDSS, MRI black holes number, and P 100 latency.ConclusionsTrans-orbital sonography is a practical and easily accessible approach for assessing ON atrophy in MS. It can measure axonal loss and brain atrophy indirectly and is a reliable paraclinical diagnostic tool, suggesting that ONSD could be a biomarker of disease activity.

Changes in the sensory regions of the brain in patients with multiple sclerosis after complex neurorehabilitation according to resting functional magnetic resonance imaging

BACKGROUND: Multiple sclerosis is the one of leading causes of non-traumatic disability in young adult patients. An in-depth understanding of the processes of neuroplasticity underlying rehabilitation measures will ensure full and effective recovery of patients with this disease. AIM: To evaluate changes in the brain connectome in patients with multiple sclerosis in response to complex rehabilitation. MATERIALS AND METHODS: A prospective cohort study included 20 patients with relapsing-remitting multiple sclerosis (EDSS 1.5–6.5) in remission. All patients underwent comprehensive inpatient neurorehabilitation in a volume corresponding to individual rehabilitation needs for 5 weeks. To assess changes in the connectome, resting-state functional magnetic resonance imaging (rs-fMRI) was performed at three points: before the start of rehabilitation, immediately after its completion, and one month after discharge from the hospital. Statistical analysis is carried out using the CONN 7 (based on MathLab). Clinical neurological examination included examination using functional tests, passing questionnaires, and determining scores on the EDSS scale before and after rehabilitation. RESULTS: A total of 20 patients were examined, 13 of them at three control points. According to rs-fMRI data, clusters of decreased connectivity were identified between the left parahippocampal gyrus and the lateral cortex of the right occipital lobe, and between the right parahippocampal gyrus and the precuneus (p-FWE, p-FDR of cluster size and mass 0.05). Clusters of increased connectivity were determined between the left inferior temporal gyrus and the lateral occipital cortex of the left hemisphere, between the left middle temporal gyrus and the right frontal field, between the pole of the left temporal lobe and the lateral cortex of the left hemisphere (p-FWE, p-FDR of cluster size and mass 0.05). Other clusters of sufficient size demonstrated borderline statistical significance (individual adjusted p values for cluster size and mass exceeded 0.05). CONCLUSION: The identified changes indicate a functional reorganization of brain structures responsible for the perception of complex visual information, the functioning of executive control systems, as well as the implementation of memory and sequential action planning.

Features of the vaginal microbiota in women with relapsing-remitting multiple sclerosis

Introduction. Multiple sclerosis (MS) is a chronic disease of the central nervous system predominantly affecting women of reproductive age. It is known that there is a high incidence of low urinary tract infections in MS. However, information about microbiology of the genital tract in women with MS is extremely limited.Aim. To study the qualitative and quantitative composition of the vaginal microflora in patients with MS.Materials and methods. 19 patients with relapsing-remitting MS of the main group and 19 healthy women of the control group, the qualitative and quantitative composition of the microflora in the vaginal secretion was determined using the polymerase chain reaction method in real time (a set of reagents was used to study the biocenosis of the urogenital tract in women, Femoflor 16, DNA-Technology, Moscow), a gynecological smear from the vagina was performed. The neurological status was assessed using the EDSS scale and The questionnaire on pelvic organ function. The following statistical indicators were determined: frequency, spread, average and χ² test.Results. A status of normocenosis was observed in the majority of women with MS (14 subjects, 73.7%), Lactobacillus bacteria were found in 16 subjects (84.2%), and an increased number of facultative anaerobes was identified in 7 subjects (37.4%), there were no significant differences with the comparator group. Bacteriological examination findings from vaginal smears did not show any signs of inflammation in either group. A high incidence of vaginal infections in anamnesis was reported in women with neurogenic lower urinary tract dysfunction (16 subjects, 84.2%).Conclusion. Data on the state of the vaginal biocenosis of women with MS has been presented for the first time. It was found the preservation of normocenosis with a tendency to shift the balance towards dysbiotic processes in the vagina.

Investigating the Effect of COVID-19 Vaccination on the Course of Disease and Recurrence of Attacks in Patients with Multiple Sclerosis

Background: The COVID-19 pandemic, with its high mortality rate, has underscored the urgent need for the rapid production of vaccines. This has prompted research into the effects of vaccines on specific populations, including patients with immune diseases such as multiple sclerosis (MS). Objectives: This study aimed to examine the impacts of COVID vaccination on individuals with MS. Methods: A retrospective cohort study was conducted involving 302 patients with relapsing-remitting MS who had received the coronavirus vaccine. These patients were referred to the MS clinic of two referral hospitals affiliated with Tehran University of Medical Sciences. The data collection instrument used was a checklist that included demographic information and disease-related details, such as the duration of the disease, underlying conditions, type and timing of vaccine administration, and the occurrence of attacks before and after the vaccination rounds. Results: During the first and second rounds of vaccination, the majority of patients (90.7% and 87.1%, respectively) received the Sinopharm vaccine. In the third round, approximately one-third (32.8%) did not receive the vaccine, and in the fourth round, the majority of individuals (85.8%) also did not receive it. However, most vaccinated individuals had received the Sinopharm vaccine. Among the sample, 34 individuals (11.3%) were newly diagnosed with MS after receiving the vaccine. Additionally, 41.7% of individuals experienced an attack within three months after receiving one of the vaccine doses. Conclusions: Vaccinations during the COVID era have significantly contributed to saving lives and preventing death. However, they have also had consequences that need careful examination and consideration in future vaccine production and epidemic management. The results obtained from this study can be associated with the vaccine, but given the retrospective nature of the study, further research on the long-term effects of the vaccine is needed to generalize the findings.

Assessment of the concomitant action of XBD173 and interferon β in a mouse model of multiple sclerosis using infrared marker bands

Disease modifying therapies including interferon-β (IFNβ) effectively counteract the inflammatory component in relapsing-remitting multiple sclerosis (RRMS) but this action, generally associated with severe side effects, does not prevent axonal/neuronal damages. Hence, axonal neuroprotection, which is pivotal for MS effective treatment, remains a difficult clinical challenge. Growing evidence suggested as promising candidate for neuroprotection, Emapunil (AC-5216) or XBD173, a ligand of the mitochondrial translocator protein highly expressed in glial cells and neurons. Indeed, elegant studies previously showed that low and well tolerated doses of XBD173 efficiently improved clinical symptoms and neuropathological markers in MS mice. Here we combined clinical scoring in vivo with Fourier transform infrared spectroscopy of sera samples to investigate the hypothesis that the concomitant treatment of RRMS mice with low doses of IFNβ and XBD173 may increase their beneficial effects against MS symptoms and additionally decrease IFNβ-induced side effects. Our results show a significant alteration of the composition of serum protein and lipids in the spectra of the sera of RRMS mice. While the signature of proteins remains altered upon treatment, the signature of lipids is recovered comparatively well with 20 kIU IFNβ and upon concomitant treatment with a low dose of XBD173 (10 mg/kg) and IFNβ (10 kIU), but not with 10 kIU of IFNβ alone. The concomitant therapy with XBD173 (10 mg/kg) and IFNβ (10 kIU), devoid of side effects, exhibited at least equal or even better efficacy than IFNβ (20 kIU) treatment against RRMS symptoms.

Assessing and tailoring predictive equations of VO2max for women with multiple sclerosis with mild to moderate disability

BackgroundEstablished equations to predict peak oxygen uptake (VO2max) in healthy subjects are not directly applicable to patient populations, including people with multiple sclerosis (PwMS). PwMS, who commonly exhibit impaired cardiorespiratory and neuromuscular function, often require tailored predictive models. This study aimed at (1) testing the validity, reliability, and accuracy of four widely used formulae, developed in healthy populations, to estimate VO2max in mildly to moderately disabled women with MS, and (2) develop adjusted formulae tailored on MS features. MethodsFifty-one mildly to moderately disabled women (mean age 46, median EDSS 3.5) with relapsing-remitting multiple sclerosis (RRMS) underwent incremental cardiopulmonary exercise testing (CPET) using cycle ergometry. Gas exchanges were analyzed by open-circuit spirometry. Four commonly employed predictive equations (ACSM, Storer's, Uth's, and Myers’) were tested for reliability and accuracy against measured VO2max. Regressions were performed to identify significant VO2max predictors and to introduce adjustments to develop gender-specific equations aimed at estimating cardiorespiratory fitness with varying degrees of exercise involvement. ResultsACSM and Storer's equations underestimated VO2max (-6.09 %, Z = -3.22, p = 0.001; and -21.74 %, Z = -5.02, p < 0.001, respectively) whereas Uth's and Myers’ equations overestimated it (+20.19 %, Z = -5.92, p < 0.001; and +19.31 %, Z = -6.19, p < 0.001, respectively). Regressions for adjusted equations revealed work rate/bodyweight (WR/BW) (β = 0.867, p < 0.001) for ACSM adjusted; age (β = -0.275, p = 0.004), BW (β = -0.658, p < 0.001) and peak Watts (β = 0.485, p < 0.001) for Storer's adjusted; heart rate ratio (β = 0.512, p < 0.001) for Uth's adjusted, and age (β = -0.492, p < 0.001), BW (β = -0.483, p < 0.001) and EDSS (β = -0.211, p = 0.046) for Myers’ adjusted as predictors of VO2max. ConclusionsVO2max can be validly estimated in women with MS using established formulae, provided that specific adjustments are introduced to account for their signature functional impairments. The models proposed in this study enable reliable assessment of cardiorespiratory fitness with protocols at different levels of exercise involvement, making them practical for clinical and everyday use. This approach supports a translationally driven bench-to-bedside perspective, allowing for patient VO2max assessment in virtually all settings.

Fear of Relapse Scale: Spanish version and psychometric characteristics in a sample of patients with Relapsing-Remitting multiple sclerosis

IntroductionRelapses are a hallmark of multiple sclerosis, being a characteristic feature of relapsing-remitting multiple sclerosis (RRMS). The occurrence of a relapse constitutes a source of significant discomfort that impacts all domains of daily life of patients with multiple sclerosis (PwMS). In this study we first explored the psychometric properties of the Spanish version of the Fear of Relapse Scale (FoR) in a sample of patients with RRMS. Besides, we explored the relationship between the Fear of Relapse Scale with fatigue and cognitive perceived deficits in our PwMS sample. MethodsAn online cross-sectional survey was conducted on 173 MS patients from 12 Spanish-speaking countries (Argentina, Mexico, Uruguay, Dominican Republic, Spain, Cuba, Colombia, Guatemala, Chile, Paraguay, Peru, and El Salvador). Confirmatory factor analysis (CFA) was performed to assess the factor structure of the scale. Multiple linear regression was used to evaluate the effects of health self-perception, fatigue, and perceived cognitive deficits over fear of relapse. ResultsThe three-factor model in the CFA yielded a good model fit (χ2/df = 2.25, P < .001, RMSEA = .078, CFI = .91). McDonalds’ Omega of the FoR (Spanish version) was .91. There was a statistically significant inverse correlation between FoR and health self-perception, and a positive correlation between FoR, fatigue, and perceived cognitive deficits. Finally, level of fatigue was a predictor of fear of relapse. ConclusionsThe Spanish version of the Fear of Relapse Scale is a valid and reliable instrument to explore the experience of fear of relapse in patients with RRMS.

Multi-Omic characterization of the effects of Ocrelizumab in patients with relapsing-remitting multiple sclerosis

The study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF). This was followed by an upregulation of a number of signaling and metabolic pathways at 12 months. Patients with higher baseline brain MRI lesion load demonstrated both higher levels of cytotoxic and structural proteins in plasma at baseline and more pronounced biomarker change trajectories over time. Digital cytometry identified a putative increase in myeloid cells and a pro-inflammatory subset of T-cells. Therapeutic effects of ocrelizumab extend beyond CD20-mediated B-cell lysis and implicate metabolic reprogramming, juxtaposing the early normalization of immune activation, cytokine signaling and metabolite and lipid turnover in periphery with changes in the dynamics of immune cell activation or composition. We identify BAFF increase following CD20 depletion as a tentative compensatory mechanism that contributes to the reconstitution of targeted B-cells, necessitating further research.