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Objective: Multiple Sclerosis (MS) is an autoimmune disorder characterized by demyelination occurring within the white matter of the central nervous system. While its pathogenesis is intricately linked with the body's immune response, the precise underlying mechanisms remain elusive. This study aims to explore potential immune-related genes associated with MS and assess the causal relationship between these genes and the risk of developing MS. Methods: We retrieved expression datasets of peripheral blood mononuclear cells from MS patients from the Gene Expression Omnibus (GEO) database. Immune-related differentially expressed genes (IM-DEGs) were identified using the ImmPort database. GO and KEGG analyses were subsequently performed to elucidate the functions and pathways associated with the IM-DEGs. To visualize protein–protein interactions (PPIs), we used STRING, Cytoscape, and Cytohubba to construct networks of PPIs and hub genes. The diagnostic efficacy of hub genes was assessed using the nomogram model and ROC curve. The correlation of these hub genes was further validated in the mouse EAE model using quantitative PCR (qPCR). Finally, Mendelian randomization (MR) was performed to ascertain the causal impact of hub genes on MS. Results: Twenty-eight IM-DEGs were selected from the intersection of DEGs and immune genes. These genes are involved mainly in antigen receptor-mediated signaling pathways, B cell differentiation, B cell proliferation, and B cell receptor signaling pathways. Using Cytoscape software for analysis, the top 10 genes with the highest scores were identified as PTPRC, CD19, CXCL8, CD79A, IL7, CR2, CD22, BLNK, LCN2, and LTF. Five hub genes (PTPRC, CD19, CXCL8, CD79A, and IL7) are considered to have strong diagnostic potential. In the qPCR validation, the relative expression of these five genes showed significant differences between the control and EAE groups, indicating that these genes may play a potential role in the pathogenesis of MS. The MR results indicate that elevated levels of CD79A (OR = 1.106, 95% CI 1.002–1.222, p = 0.046) are causally positively associated with the risk of developing MS. Conclusion: This study integrated GEO data mining with MR to pinpoint pivotal immune genes linked to the onset of MS, thereby offering novel strategies for the treatment of MS. [ABSTRACT FROM AUTHOR]

Introduction: Reactivation of thymopoiesis in adult patients with autoimmune disorders treated with autologous haematopoietic stem cell transplantation (AHSCT) is supported by studies exploring immunoreconstitution. Radiological evidence of thymic hyperplasia after AHSCT was previously reported in patients with systemic sclerosis, but, to our knowledge, it has not been described in multiple sclerosis (MS), where premature thymic involution has been observed and immunosenescence might be accelerated by disease-modifying treatments (DMTs). Participants and methods: monocentric case series including MS patients who performed a chest CT scan for clinical purposes after having received AHSCT (BEAM/ATG regimen) for aggressive MS failing DMTs. Chest CT exams were reviewed by a thoracic radiologist: thymic hyperplasia was defined as a rounded mass in the thymic loggia with a density around 40 Hounsfield Units (HU) and thickness >1.3 cm. Results: Fifteen MS patients were included; the median time interval between AHSCT and chest CT scan was 2 (range 1-18) months. All the patients were free from new inflammatory events and DMTs over a median follow-up of 36 months (range 12-84) after AHSCT. Thymic hyperplasia was detected in 3/15 (20%) cases in an exam taken 1 to 3 months after AHSCT; all these patients were females, and aged 30 to 40 years. Lung infections and secondary autoimmunity were diagnosed in 5 and 1 cases, respectively, none of which showed thymic hyperplasia. No associations between thymic hyperplasia and clinical-demographic characteristics or post-AHSCT outcomes were observed. Conclusions: Thymic hyperplasia was detected in 20% of MS patients recently treated with AHSCT. These results are consistent with previous immunological studies showing that AHSCT promotes thymus reactivation in MS patients, further supporting de-novo thymopoiesis as a cornerstone of immune reconstitution after AHSCT in this population. [ABSTRACT FROM AUTHOR]

Human T cells expressing CD20 play an important role in the defense against virus and cancer and are central in the pathogenesis of both malignancies and various autoimmune disorders. Therapeutic modulation of CD20+ T cells and the CD20 expression level is therefore of significant interest. In rodents, CD20 on T cells is likely the product of an active transfer of CD20 from a donor B cell interacting with a recipient T cell in a process termed trogocytosis. Whether the same applies to human CD20+ T cells is highly debated. Investigating this dispute showed that human CD20− T cells could achieve CD20 along with a series of other B-cell markers from B cells through trogocytosis. However, none of these B-cell markers were co-expressed with CD20 on human CD20+ T cells in blood or inflamed CSF, implying that additional mechanisms may be involved in the development of human CD20+ T cells. In support of this, we identified true naïve CD20+ T cells, measured endogenous production of CD20, and observed that CD20 could be inherited to daughter cells, contradicting that all human CD20+ T cells are a product of trogocytosis. [ABSTRACT FROM AUTHOR]

Chronic pathological conditions often induce persistent systemic inflammation, contributing to neuroinflammatory diseases like Multiple Sclerosis (MS). MS is known for its autoimmune-mediated damage to myelin, axonal injury, and neuronal loss which drive disability accumulation and disease progression, often manifesting as cognitive impairments. Understanding the involvement of neural stem cells (NSCs) and neural progenitor cells (NPCs) in the remediation of MS through adult neurogenesis (ANG) and gliogenesis—the generation of new neurons and glial cells, respectively is of great importance. Hence, these phenomena, respectively, termed ANG and gliogenesis, involve significant structural and functional changes in neural networks. Thus, the proper integration of these newly generated cells into existing circuits is not only key to understanding the CNS's development but also its remodeling in adulthood and recovery from diseases such as MS. Understanding how MS influences the fate of NSCs/NPCs and their possible neuroprotective role, provides insights into potential therapeutic interventions to alleviate the impact of MS on cognitive function and disease progression. This review explores MS, its pathogenesis, clinical manifestations, and its association with ANG and gliogenesis. It highlights the impact of altered NSCs and NPCs' fate during MS and delves into the potential benefits of its modifications. It also evaluates treatment regimens that influence the fate of NSCS/NPCs to counteract the pathology subsequently. [ABSTRACT FROM AUTHOR]

Introduction: Increasing shortage of neurologists compounded by the global aging of the population have translated into suboptimal care of patients with chronic neurological diseases. While some patients might benefit from expanding telemedicine, monitoring neurological disability via telemedicine is challenging. Smartphone technologies represent an attractive tool for remote, self-administered neurological assessment. To address this need, we have developed a suite of smartphone tests, called neurological functional test suite (NeuFun-TS), designed to replicate traditional neurological examination. The aim of this study was to assess the ability of two NeuFun-TS tests—short walk and foot tapping—to quantify motor functions of lower extremities as assessed by a neurologist. Methods: A cohort of 108 multiple sclerosis (MS) patients received a full neurological examination, imaging of the brain, and completed the NeuFun-TS smartphone tests. The neurological exam was digitalized using the NeurEx™ platform, providing calculation of traditional disability scales, as well as quantification of lower extremities-specific disability. We assessed unilateral correlations of 28 digital biomarkers generated from the NeuFun-TS tests with disability and MRI outcomes and developed machine learning models that predict physical disability. Model performance was tested in an independent validation cohort. Results: NeuFun-TS-derived digital biomarkers correlated strongly with traditional outcomes related to gait and lower extremities functions (e.g., Spearman ρ > 0.8). As expected, the correlation with global disability outcomes was weaker, but still highly significant (e.g., ρ 0.46–0.65; p < 0.001 for EDSS). Digital biomarkers also correlated with semi-quantitative imaging outcomes capturing locations that can affect lower extremity functions (e.g., ρ ~ 0.4 for atrophy of medulla). Reliable digital outcomes with high test-retest values showed stronger correlation with disability outcomes. Combining strong, reliable digital features using machine learning resulted in models that outperformed predictive power of best individual digital biomarkers in an independent validation cohort. Discussion: NeuFun-TS tests provide reliable digital biomarkers of lower extremity motor functions. [ABSTRACT FROM AUTHOR]

Objective: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

Background: Pediatric-onset multiple sclerosis (POMS) patients often exhibit a wide range of cognitive deficits. Therefore, therapeutic approaches should aim not only to prevent cognitive decline but also to promote cognitive improvement. Objective: This study aimed to explore the effects of natalizumab (NTZ) on cognitive function, as measured by the Symbol Digit Modalities Test (SDMT), in both POMS and adult-onset multiple sclerosis (AOMS) patients. Method: A total of 63 patients (34 AOMS and 29 POMS) were enrolled in this retrospective, single-center study. Patients were clinically and radiologically assessed every 6 months, and they completed the SDMT at baseline and after at least 24 months of follow-up. SDMT values were reported as corrected values (cSDMT) and z-scores (zSDMT). Annualized cSDMT and zSDMT scores were calculated by dividing the change in scores by the length of the follow-up period (expressed in years). Results: Both POMS and AOMS groups showed improvement in annualized cSDMT and zSDMT scores, but the improvement was significantly greater in the POMS group compared to the AOMS group (+3.85 ± 4.32 vs. +1.76 ± 2.80, p = 0.010 for cSDMT; 0.41 ± 0.40 vs. 0.25 ± 0.34, p = 0.026 for zSDMT). After re-baselining at 6 months, 93% of POMS patients (27 patients) and 85.3% of AOMS patients (29 patients, p = 0.84) achieved NEDA-3 (no evidence of disease activity). The NEDA-3 status, along with clinical and demographic parameters at baseline, did not account for the observed SDMT improvement. Conclusion: The favorable clinical, radiological, and neuropsychological outcomes observed in this study support the use of natalizumab as a viable treatment option in POMS. [ABSTRACT FROM AUTHOR]

Background: Serum neurofilament light chain (sNfL) is a biomarker of neuroaxonal destruction that correlates with acute inflammation (AI) in multiple sclerosis (MS). However, in the treatment era, progression without AI is the main driver of long-term disability. sNfL may provide added value in detecting ongoing axonal damage and neurological worsening in patients without AI. We conducted a prospective three-year study on patients with a first MS relapse to evaluate the basal cut-off value predicting early increased disability unrelated to relapses. Methods: sNfL levels and AI presence were measured every 6 months during the first year and the Expanded Disability Status Scale (EDSS) was monitored until the third year. Baseline cohorts were stratified by sNfL levels, using a cut-off derived from patients without AI (absence of clinical relapses, new/enlarging T2 lesions, or gadolinium enhancement in magnetic resonance imaging) at year one. Results: Fifty-one patients were included. A sNfL cut-off of 11 pg/mL predicted sustained neurological worsening independent of AI. Patients exceeding this threshold exhibited features of highly active MS (higher proportion of AI, oligoclonal M bands and higher EDSS). Despite AI ablation, sNfL levels persisted elevated and were significantly associated with increased EDSS at baseline and year 3. Patients with low sNfL and concurrent AI (n = 8) experienced relapses in the optic nerve, brainstem, and spinal cord topographies. Conclusion: sNfL elevation may detect patients with increased disability even when AI is controlled. This may reveal mechanisms associated with early axonal degeneration and help identify patients at higher risk of progression. [ABSTRACT FROM AUTHOR]

Introduction: The presence of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is a pivotal diagnostic marker for multiple sclerosis (MS). These bands play a crucial role in the diagnosis and understanding of a wide array of immune diseases. In this study, we explore the relationship between the cognitive profile of autoimmune encephalitis (AIE) and the presence of OCBs in CSF, with a particular emphasis on NMDA receptor antibodies. Methods: We studied a cohort of 21 patients across five tertiary centers, segregated into two distinct categories. One group comprised individuals who tested positive only for autoimmune encephalitis antibodies indicative of encephalitis, while the other group included patients whose CSF was positive for both autoimmune encephalitis antibodies and OCBs. Our investigation focused primarily on cognitive functions and behavioral alterations, supplemented by auxiliary diagnostic assessments such as CSF cell count, magnetic resonance imaging (MRI), and electroencephalogram (EEG) results, evaluated for the two patient groups. To validate our findings, we employed statistical analyses such as Fisher’s exact test with Benjamini-Hochberg correction. Results: Our study included 21 patients, comprising 14 who were presented with only autoimmune encephalitis antibodies, and 7 who were dual-positive. Among these patients, we focused on those with NMDA receptor antibodies. Of these, five were dual positive, and nine were positive only for NMDA receptor antibodies. The dual-positive NMDA group, with an average age of 27 ± 16.47 years, exhibited significantly higher CSF cell counts (p=0.0487) and more pronounced language and attention deficits (p= 0.0264). MRI and EEG results did not differ significantly between the groups. Conclusions: Our results point to OCBs as an additional marker of disease severity in AIE, especially in NMDA receptor-antibody positive patients, possibly indicating a broader inflammatory process, as reflected in elevated CSF lymphocytes. Regular testing for OCBs in cases of suspected AIE may aid in disease prognosis and identification of patients more prone to language and attention disorders, improving diagnosis and targeting treatment for these cognitive aspects. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood–brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: Physical exercise (PE) improves symptoms and quality of life in people with multiple sclerosis (pwMS). However, incorporating PE into daily lives of pwMS pose difficulties. As an alternative to in-person PE, e-based PE has been proposed because of its advantages in terms of accessibility and convenience. Objective: To synthesize existing evidence on e-based PE at home in adults MS and discuss study designs, rehabilitation programs, intervention effects and possible knowledge gaps. Methods: In this scoping review, a systematic search in electronic databases including Embase, Medline, CINAHL and Cochrane Library was conducted following the PRISMA guidelines. Peer-reviewed articles in English on e-based PE interventional studies at home involving adult pwMS, published from 2008 until April 2023, were identified and exported to Covidence. Data from the included studies were extracted and synthesized. This scoping review identified different types of e-based PE interventions used in pwMS across different study designs, but when evaluating intervention effects, this review focused solely on randomized controlled trials (RCTs). Results: A total of 3,006 studies were retrieved and 179 studies were screened in full text, resulting in the inclusion of 54 studies with a total of 2,359 pwMS. Of those, 33 were RCTs and three were qualitative studies. The studies reported on various e-based interventions including video-based programs. telerehabilitation, and web-based programs. The interventions evaluated muscle strength, cardiorespiratory fitness, walking speed, endurance, balance, and fatigue, as well as symptoms of depression and cognitive dysfunction. E-based PE interventions at home in RCTs demonstrated improvement of depressive symptoms and anxiety, while inconsistent results were reported for fatigue, walking speed and balance. No significant benefits were observed regarding dexterity. Results were generally heterogeneous and were limited by small sample sizes. Several limitations were identified, such as lack of physical activity assessment prior to the intervention and poor reporting of duration, intensity, frequency and adherence to e-based PE interventions. Conclusion: E-based PE interventions in pwMS may improve MS-related symptoms, but the study quality is generally low, and findings are often inconsistent. Several important limitations of the existing literature have been identified in the present review, which can guide future research. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system CNS characterized by demyelination, inflammation, and neurodegenerative changes, making it the most common nontraumatic disabling neurological disease in young adults. While current pharmacological treatments primarily target immunomodulation or immunosuppression, exercise is gaining increasing attention from the scientific community as an adjunctive therapy. This review explores the potential biological mechanisms of exercise in animal models of MS, focusing on its effects on neuroprotection and inflammation. The review examines how exercise inhibits pro-inflammatory microglial reactivity, stabilizes the blood-brain barrier, and enhances neurotrophic factor expression in animal studies. Future research directions are proposed by summarizing the evidence and limitations of existing animal models of MS, emphasizing the need to further validate these mechanisms in humans to better integrate exercise into the comprehensive management of MS. Additionally, investigating exercise-induced biomarkers for MS symptom reduction may provide a scientific basis for new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Introduction: The presence of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) is a pivotal diagnostic marker for multiple sclerosis (MS). These bands play a crucial role in the diagnosis and understanding of a wide array of immune diseases. In this study, we explore the relationship between the cognitive profile of autoimmune encephalitis (AIE) and the presence of OCBs in CSF, with a particular emphasis on NMDA receptor antibodies. Methods: We studied a cohort of 21 patients across five tertiary centers, segregated into two distinct categories. One group comprised individuals who tested positive only for autoimmune encephalitis antibodies indicative of encephalitis, while the other group included patients whose CSF was positive for both autoimmune encephalitis antibodies and OCBs. Our investigation focused primarily on cognitive functions and behavioral alterations, supplemented by auxiliary diagnostic assessments such as CSF cell count, magnetic resonance imaging (MRI), and electroencephalogram (EEG) results, evaluated for the two patient groups. To validate our findings, we employed statistical analyses such as Fisher's exact test with Benjamini-Hochberg correction. Results: Our study included 21 patients, comprising 14 who were presented with only autoimmune encephalitis antibodies, and 7 who were dual-positive. Among these patients, we focused on those with NMDA receptor antibodies. Of these, five were dual positive, and nine were positive only for NMDA receptor antibodies. The dual-positive NMDA group, with an average age of 27 ± 16.47 years, exhibited significantly higher CSF cell counts (p=0.0487) and more pronounced language and attention deficits (p= 0.0264). MRI and EEG results did not differ significantly between the groups. Conclusions: Our results point to OCBs as an additional marker of disease severity in AIE, especially in NMDA receptor-antibody positive patients, possibly indicating a broader inflammatory process, as reflected in elevated CSF lymphocytes. Regular testing for OCBs in cases of suspected AIE may aid in disease prognosis and identification of patients more prone to language and attention disorders, improving diagnosis and targeting treatment for these cognitive aspects. [ABSTRACT FROM AUTHOR]

Computed tomography (CT) scans and magnetic resonance imaging (MRI) are commonly utilized to detect brain gliomas and central nervous system inflammation diseases. However, there are instances where depending solely on medical imaging for a precise diagnosis may result in unsuitable medications or treatments. Pathological analysis is regarded as the definitive method for diagnosing brain gliomas or central nervous system inflammation diseases. To achieve this, a craniotomy or stereotaxic biopsy is necessary to collect brain tissue, which can lead to complications such as cerebral hemorrhage, neurological deficits, cerebrospinal fluid leaks, and cerebral edema. Consequently, the advancement of non-invasive or minimally invasive diagnostic techniques is currently a high priority. This study included samples from four glioma patients and five patients with central nervous system inflammatory diseases, comprising both serum and paired cerebrospinal fluid (CSF). A total of 40 human cytokines were identified in these samples. We utilized a receiver operating characteristic (ROC) analysis to assess the sensitivity and specificity for distinguishing central nervous system inflammation diseases and gliomas. Additionally, we examined the correlation of these factors between serum and CSF in the patients. Ultimately, the identified factors were validated using serum from patients with clinically confirmed gliomas and central nervous system inflammation diseases followed by detection and statistical analysis through ELISA. The levels of serum factors IL-4, IFN-α, IFN-γ, IL-6, TNF-α, CCL4, CCL11, and VEGF were found to be significantly higher in gliomas compared with inflammatory diseases of the central nervous system (p < 0.05). Furthermore, a strong correlation was observed between the levels of CCL4 in serum and CSF, with a correlation coefficient of r = 0.92 (95% CI = 0.20-0.99, p = 0.027). We gathered more clinical samples to provide further validation of the abundance of CCL4 expression. A clinical study analyzing serum samples from 19 glioma patients and 22 patients with central nervous system inflammation diseases revealed that CCL4 levels were notably elevated in the inflammatory group compared with the glioma group (p < 0.001). These results suggest that assessing serum CCL4 levels may be useful in distinguishing those patients for clinical diagnostic purposes. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is an inflammatory chronic autoimmune and neurodegenerative disorder of the brain and spinal cord, resulting in loss of motor, sensorial, and cognitive function. Among the non-pharmacological interventions for several brain conditions, photobiomodulation (PBM) has gained attention in medical society for its neuroprotective effects. We systematically reviewed the effects of PBM on MS. Methods: We conducted a systematic search on the bibliographic databases (PubMed and ScienceDirect) with the keywords based on MeSH terms: PBM, low-level laser therapy, multiple sclerosis, autoimmune encephalomyelitis, demyelination, and progressive multiple sclerosis. Data search was limited from 2012 to July 2024. We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The initial systematic search identified 126 articles. Of these, 68 articles were removed by duplicity and 50 by screening. Thus, 8 studies satisfied the inclusion criteria. Results: The reviewed studies showed that PBM modulates brain markers linked to inflammation, oxidative stress, and apoptosis. Improvements in motor, sensorial, and cognitive functions in MS patients were also observed after PBM therapy. No study reported adverse effects of PBM. Conclusion: These findings suggest the potential of PBM as a promising nonpharmacological intervention for the management of MS, although further research is needed to standardize PBM protocols and assess its long-term effects. [ABSTRACT FROM AUTHOR]

Blood-brain barrier dysfunction might be driven by peripheral inflammation. TNFa inhibitors (TNF-αi) are occasionally associated with a wide spectrum of neurological immuno-mediated disorders. However, patients with systemic autoimmune disorders, including rheumatoid arthritis (RA), might be prone to develop further organ-specific, including central nervous system (CNS), autoimmunity. Here we report the case of a patient, affected by RA and treated with etanercept, who suddenly developed focal neurological symptoms. Cerebrospinal fluid, magnetic resonance imaging (MRI), and positron emission tomography (PET)/MRI findings are reported and support the diagnosis of TNF-αi-associated aseptic meningitis. [ABSTRACT FROM AUTHOR]

Background: Despite the evidence of beneficial effects of physical activity (PA), people with multiple sclerosis (pwMS) are less physically active than the general population. To increase PA in pwMS, we developed a structured individually tailored PA promotion program which is conducted within clinical practice in a university-based outpatient clinic since 2016. This study serves as retrospective quality control of this program. Objective: In a retrospective cohort study, we assessed the physical fitness of pwMS and the impact of the program on short- and long-term PA changes and behavioral determinants. Methods: The program consisted of four appointments each 2–4 weeks apart. Spiroergometric test results of female pwMS were compared to female non-MS controls who underwent a voluntary physical fitness analysis. The short version of the Freiburger questionnaire, self-developed questions and the modified Physical activity screening questionnaire (PASQ) were sent to all participants assessing the PA levels before the program, 3 months after the program (shortterm), and at the time of the survey (long-term). Additionally, established questionnaires assessed behavioral determinants before the program and longterm. Results: A total of 166 participants [mean age 38.32 (± 10.61 SD), mean EDSS 2.30 (±1.29 SD)] and mostly females (63.3%, n =  105) were included in the study and started the program. A total of 136 participants completed the program. Out of these 63.9% (n  =  87) answered the questionnaires in 12.38 (±11.34 SD) months after finishing the program. At baseline female pwMS (n  =  100) showed a lower physical fitness in comparison to non-MS controls (n  =  26) (maximal workload (Watts): 138.86  ±  37.85 vs. 191.73  ±  45.25, p  <  0.001; peak oxygen consumption (ml  min−1 kg−1 ): 26.40  ±  7.23 vs. 31.56  ±  10.10, p  =  0.020). pwMS were more regularly active in short- (62.1%) and long-term (55.2%) compared to baseline (24.2%, p  <  0.001). Among the activated participants, we observed improved internal motivation (p  =  0.002) and decreased perception of barriers (p  =  0.006) compared to baseline. Conclusion: PwMS showed a lower physical fitness in comparison to nonMS controls. An individually tailored PA promotion program might improve behavioral determinants and thereby increase short- and long-term PA levels of pwMS. [ABSTRACT FROM AUTHOR]

This review will briefly introduce microRNAs (miRNAs) and dissect their contribution to multiple sclerosis (MS) and its clinical outcomes. For this purpose, we provide a concise overview of the present knowledge of MS pathophysiology, biomarkers and treatment options, delving into the role of selectively expressed miRNAs in clinical forms of this disease, as measured in several biofluids such as serum, plasma or cerebrospinal fluid (CSF). Additionally, up-to-date information on current strategies applied to miRNA-based therapeutics will be provided, including miRNA restoration therapy (lentivirus expressing a specific type of miRNA and miRNA mimic) and miRNA inhibition therapy such as antisense oligonucleotides, small molecules inhibitors, locked nucleic acids (LNAs), anti-miRNAs, and antagomirs. Finally, it will highlight future directions and potential limitations associated with their application in MS therapy, emphasizing the need for improved delivery methods and validation of therapeutic efficacy. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS), a chronic autoimmune disorder marked by demyelination in the central nervous system, is exceptionally uncommon in China, and remains poorly understood in terms of its peripheral blood manifestations. Methods: We conducted a cohort study comprising 39 MS patients and 40 normal controls (NC). High-dimensional mass cytometry, protein arrays, and targeted metabolomics were utilized to profile immune subsets, proteins, and metabolites in blood. Differences in multi-omics signatures were scrutinized across varying MS subtypes. Results: Immune profiling demonstrated an elevation in various B cell subsets and monocytes, alongside a reduction in dendritic cells among MS patients. Proteomic data revealed a downregulation in neurotrophic and tissue repair proteins. Metabolomic assessment showed a noted decrease in antiinflammatory molecules and sphingolipids. Integrated analysis identified distinct molecular patterns distinguishing MS from controls. Additionally, multi-omics differences among different MS subtypes were uncovered. Notably, hippuric acid levels was consistently lower in MS subgroups with greater disease severity. Conclusion: This study represents the pioneering exploration of multi-omics in Chinese MS patients, presenting a comprehensive view of the peripheral blood changes in MS. Our study underscores the robust capability of multi-omics assessments in identifying peripheral blood biomarkers that delineate the varied clinical presentation, and facilitates future development of biomarkers and targeted therapeutic interventions in MS. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the safety of COVID-19 vaccines in patients with multiple sclerosis (MS) by assessing their impact on serum neurofilament light chain (sNfL) levels as a marker of neuroaxonal damage. Methods: Single-center observational longitudinal study including patients with MS who consecutively received their initial vaccination against SARS-CoV-2 at Hospital Universitario Ramo'n y Cajal, following the first national immunization program in Spain. Serum samples were collected at baseline and after receiving the second dose of the vaccine. sNfL levels were quantified using the single molecule array (SIMOA) technique. Adverse events, including clinical or radiological reactivation of the disease, were recorded. Results: Fifty-two patients were included (median age, 39.7 years [range, 22.5-63.3]; 71.2% female). After SARS-CoV-2 vaccination, no increased inflammatory activity, either determined by the presence of relapses and/or new MRI lesions and/or high sNfL levels, was detected. Accordingly, there was no difference between median sNfL levels before and after vaccination (5.39 vs. 5.76 pg/ml, p=0.6). Despite this, when looking at baseline patient characteristics before vaccination, younger age associated with disease activity after vaccination (OR 0.87, 95% CI: 0.77-0.98, p=0.022). Larger studies are needed to validate these results. Conclusion: COVID-19 vaccines did not cause reactivation of disease at a clinical, radiological or molecular level, thus suggesting that they are safe in MS patients. [ABSTRACT FROM AUTHOR]

Purpose: To explore ocular changes in patients with MS and NMOSD via SDOCT and PVEP analysis. Methods: From August 2020 to July 2021, 82 patients (164 eyes) diagnosed with MS, 59 patients (118 eyes) diagnosed with NMOSD and 50 healthy controls (100 eyes) were retrospectively selected. SD-OCT and PVEP were performed to compare retinal nerve fibre layer (RNFL) thickness around the optic disc, ganglion cell inner plexiform layer (GCIPL) thickness in the macula and P100 latency and amplitude between the disease groups and the control group. Results: In the NMOSD and MS groups, the thickness of the GCIPL quadrants in eyes with optic neuritis was thinner than that in eyes without optic neuritis, and the amplitude of the P100 wave decreased. In addition, in eyes with optic neuritis, patients with NMOSD have thinner RNFL thicknesses in the temporal and superior quadrants than patients with MS, and the thickness of the GCIPL is thinner in each region. In eyes without optic neuritis, patients with MS have thinner nasal RNFL than do those with NMOSD. Conclusion: SD-OCT and VEP may be useful for monitoring and distinguishing pathological changes in MS and NMOSD patients. [ABSTRACT FROM AUTHOR]

Introduction: Alemtuzumab is a highly effective pulsed immune reconstitution therapy for multiple sclerosis (MS). Aim: To evaluate serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) in patients with relapsing-remitting MS who have been treated with Alemtuzumab over the course of 2 years. Methods: This prospective study involved MS patients treated with Alemtuzumab at a referral MS center. Both sNfL and sGFAP were analyzed at baseline and then again at 6, 12, and 24 months post-treatment using the single molecule array (SiMoA) technique. We also recruited matched healthy controls (HCs) for comparison. Results: The study included 46 patients (with a median age of 34.2 [Interquartile range (IQR), 28.7–42.3] years, 27 of which were women [58%]) and 76 HCs. No differences in demographic characteristics were observed between patients and HC. The median disease duration was 6.22 (IQR, 1.56–10.13) years. The median annualized relapse rate before treatment was 2 (IQR, 1–3). At baseline, sNfL and sGFAP levels were higher in MS patients (median of 18.8 [IQR, 10.7–52.7] pg/ml and 158.9 [IQR, 126.9–255.5] pg/ml, respectively) when compared to HC (6.11 [IQR, 2.03–8.54] pg/ml and 91.0 [72.6–109] pg/ml, respectively) (p<0.001 for both comparisons). The data indicates that 80% of patients had high (≥10 pg/ml) sNfL values at baseline. We observed a significant decrease in sNfL levels at 6 (65%, p = 0.02), 12 (70.8%, p<0.001), and 24 (78.1%, p<0.001) months. sNfL reached similar levels to HC only after 24 months of Alemtuzumab treatment. During the follow-up period, no changes were identified in the sGFAP values. Conclusion: Alemtuzumab leads to the normalization of sNfL values in MS patients after 2 years of treatment, with no apparent effect on sGFAP values. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a devastating immune-mediated disorder of the central nervous system resulting in progressive disability accumulation. As there is no cure available yet for MS, the primary therapeutic objective is to reduce relapses and to slow down disability progression as early as possible during the disease to maintain and/or improve health-related quality of life. However, optimizing treatment for people with MS (pwMS) is complex and challenging due to the many factors involved and in particular, the high degree of clinical and subclinical heterogeneity in disease progression among pwMS. In this paper, we discuss these many different challenges complicating treatment optimization for pwMS as well as how a shift towards a more pro-active, data-driven and personalized medicine approach could potentially improve patient outcomes for pwMS. We describe how the ‘Clinical Impact through AI-assisted MS Care’ (CLAIMS) project serves as a recent example of how to realize such a shift towards personalized treatment optimization for pwMS through the development of a platform that offers a holistic view of all relevant patient data and biomarkers, and then using this data to enable AI-supported prognostic modelling. [ABSTRACT FROM AUTHOR]

Introduction: There are no reports in LATAM related to longitudinal humoral and cellular response to adenovirus based COVID-19 vaccines in people with Multiple Sclerosis (pwMS) under different disease modifying therapies (DMTs) and neutralization of the Omicron and Wuhan variants of SARS-COV-2. Methods: IgG anti- SARS-COV-2 spike titer were measured in a cohort of 101 pwMS under fingolimod, dimethyl fumarate, cladribine and antiCD20, as well as 28 healthy controls (HC) were measured 6 weeks after vaccination with 2nd dose (Sputnik V or AZD1222) and 3nd dose (homologous or heterologous schedule). Neutralizing capacity was against Omicron (BA.1) and Wuhan (D614G) variants and pseudotyped particles and Cellular response were analyzed.Results: Multivariate regression analysis showed anti-cd20 (β= -,349, 95% CI: -3655.6 - -369.01, p=0.017) and fingolimod (β=-,399, 95% CI: -3363.8 - -250.9, p=0.023) treatments as an independent factor associated with low antibody response (r² adjusted=0.157). After the 2nd dose we found a correlation between total and neutralizing titers against D614G (rho=0.6; p<0.001; slope 0.8, 95% CI:0.4-1.3), with no differences between DMTs. Neutralization capacity was lower for BA.1 (slope 0.3, 95%CI:0.1-0.4). After the 3rd dose, neutralization of BA.1 improved (slope: 0.9 95%CI:0.6-1.2), without differences between DMTs. A fraction of pwMS generated anti-Spike CD4+ and CD8+ T cell response. In contrast, pwMS under antiCD20 generated CD8+TNF+IL2+ response without differences with HC, even in the absence of humoral response. The 3rd dose significantly increased the neutralization against the Omicron, as observed in the immunocompetent population. Discussion: Findings regarding humoral and cellular response are consistent with previous reports [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is the most common non-traumatic disabling disease affecting young adults. A definitive curative treatment is currently unavailable. Many randomized controlled trials (RCTs) have reported the efficacy of Chinese herbal medicine (CHM) on MS. Because of the uncertain quality of these RCTs, the recommendations for routine use of CHM for MS remain inconclusive. The comprehensive evaluation of the quality of RCTs of CHM for MS is urgent. Methods: Nine databases, namely, PubMed, Embase, Web of Science, Cochrane Library, EBSCO, Sinomed, Wanfang Database, China National Knowledge Infrastructure, and VIP Database, were searched from inception to September 2023. RCTs comparing CHM with placebo or pharmacological interventions for MS were considered eligible. The Consolidated Standards of Reporting Trials (CONSORT) and its extension for CHM formulas (CONSORT-CHM Formulas) checklists were used to evaluate the reporting quality of RCTs. The risk of bias was assessed using the Cochrane Risk of Bias tool. The selection criteria of highfrequency herbs for MS were those with cumulative frequency over 50% among the top-ranked herbs. Results: A total of 25 RCTs were included. In the included RCTs, 33% of the CONSORT items and 21% of the CONSORT-CHM Formulas items were reported. Eligibility title, sample size calculation, allocation concealment, randomized implementation, and blinded description in CONSORT core items were reported by less than 5% of trials. For the CONSORT-CHM Formulas, the source and authentication method of each CHM ingredient was particularly poorly reported. Most studies classified the risk of bias as “unclear” due to insufficient information. The top five most frequently used herbs were, in order, Radix Rehmanniae Preparata, Radix Rehmanniae Recens, Herba Epimedii, Scorpio, and Poria. No serious adverse effect had been reported. Conclusions: The low reporting of CONSORT items and the unclear risk of bias indicate the inadequate quality of RCTs in terms of reporting completeness and result validity. The CONSORT-CHM Formulas appropriately consider the unique characteristics of CHM, including principles, formulas, and Chinese medicinal substances. To improve the quality of RCTs on CHM for MS, researchers should adhere more closely to CONSORT-CHM Formulas guidelines and ensure comprehensive disclosure of all study design elements. [ABSTRACT FROM AUTHOR]

Background: Telerehabilitation (TR) offers a valuable opportunity to improve access to care and has shown results comparable to onsite rehabilitation (SR) across different conditions. The present study aimed to explore the efficacy of TR and SR in improving clinically meaningful outcomes in people with multiple sclerosis (pwMS). Materials and methods: Subjects enrolled in the study were assigned to one of two treatment arms: a 6-week TR intervention or a 6-week onsite rehabilitation (SR) intervention. Pre-and post-intervention evaluation included assessment of global wellbeing using the Multiple Sclerosis Quality of Life-54 scale (QoL), fatigue using the Fatigue Severity Status scale (FSS), cognitive status using the Symbol Digit Modalities Test (SDMT), and balance dysfunction using the Berg Balance Scale (BBS). Group-level and single-subject improvements were considered as outcome measures, with QoL as the primary endpoint. To determine significant group changes over time for the entire pwMS cohort, a paired t-test was applied to the overall QoL score, focusing on both physical and mental composites. An independent sample t-test was used to assess differences in baseline and follow-up performance, as well as changes over time between the intervention groups (TR and SR). This same analysis was repeated for the other clinical domains (FSS, BBS, and SDMT). The minimal clinically important difference (MCID) according to treatment group (TR vs. SR) was explored using logistic regression. Additionally, a multiple linear regression model was applied to evaluate the impact of baseline clinical-demographic features on the observed post-intervention modifications. Results: A total of 51 subjects completed the study (37 women, mean age 46.3 ± 9.8, median Expanded Disability Status Scale 3.5, min. 2, max. 6.5). The entire sample benefited from the rehabilitation treatment, with significant improvements observed at both the group and individual levels across all measured domains for both intervention groups (TR vs. SR). Quality of life improved significantly (p = 0.005), as did fatigue and balance (both p < 0.001), and cognition (p = 0.003). Conclusions: Both SR and TR approaches effectively improved the perception of fatigue, cognitive performance, balance, and quality of life in a population of MS patients with moderate disability. [ABSTRACT FROM AUTHOR]

Proinflammatory cytokines are implicated in promoting neurodegeneration in multiple sclerosis (MS) by affecting excitatory and inhibitory transmission at central synapses. Conversely, the synaptic effects of anti-inflammatory molecules remain underexplored, despite their potential neuroprotective properties and their presence in the cerebrospinal fluid (CSF) of patients. In a study involving 184 newly diagnosed relapsing-remitting (RR)-MS patients, we investigated whether CSF levels of the anti-inflammatory interleukin (IL)-10 were linked to disease severity and neurodegeneration measures. Additionally, we examined IL-10 impact on synaptic transmission in striatal medium spiny neurons and its role in counteracting inflammatory synaptopathy induced by IL-1β in female C57BL/6 mice with experimental autoimmune encephalomyelitis (EAE). Our findings revealed a significant positive correlation between IL-10 CSF levels and changes in EDSS (Expanded Disability Status Scale) scores one year after MS diagnosis. Moreover, IL-10 levels in the CSF were positively correlated with volumes of specific subcortical brain structures, such as the nucleus caudate. In both MS patients' CSF and EAE mice striatum, IL-10 and IL-1β expressions were upregulated, suggesting possible antagonistic effects of these cytokines. Notably, IL-10 exhibited the ability to decrease glutamate transmission, increase GABA transmission in the striatum, and reverse IL-1β-induced abnormal synaptic transmission in EAE. In conclusion, our data suggest that IL-10 exerts direct neuroprotective effects in MS patients by modulating both excitatory and inhibitory transmission and attenuating IL-1β-induced inflammatory synaptopathy. These findings underscore the potential therapeutic significance of IL-10 in mitigating neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a frequently disabling neurological disorder characterized by symptoms, clinical signs and imaging abnormalities that typically fluctuate over time, affecting any level of the CNS. Prominent lymphocytic inflammation, many genetic susceptibility variants involving immune pathways, as well as potent responses of the neuroinflammatory component to immunomodulating drugs, have led to the natural conclusion that this disease is driven by a primary autoimmune process. In this Hypothesis and Theory article, we discuss emerging data that cast doubt on this assumption. After three decades of therapeutic experience, what has become clear is that potent immune modulators are highly effective at suppressing inflammatory relapses, yet exhibit very limited effects on the later progressive phase of MS. Moreover, neuropathological examination of MS tissue indicates that degeneration, CNS atrophy, and myelin loss are most prominent in the progressive stage, when lymphocytic inflammation paradoxically wanes. Finally, emerging clinical observations such as "progression independent of relapse activity" and "silent progression," now thought to take hold very early in the course, together argue that an underlying "cytodegenerative" process, likely targeting the myelinating unit, may in fact represent the most proximal step in a complex pathophysiological cascade exacerbated by an autoimmune inflammatory overlay. Parallels are drawn with more traditional neurodegenerative disorders, where a progressive proteopathy with prion-like propagation of toxic misfolded species is now known to play a key role. A potentially pivotal contribution of the Epstein-Barr virus and B cells in this process is also discussed. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is an inflammatory and degenerative disease of the central nervous system. More than 90,000 Canadians are affected; a cure is yet to be found. Available treatments to manage the disease course are only partially effective. For many years, persons with MS (PwMS) have used cannabis to relax, to reduce pain and spasticity, or to improve sleep and daily functioning, despite the lack of scientific evidence on the efficacy of specific cannabinoids [i.e., tetrahydrocannabinol (THC) and cannabidiol (CBD)] on these MS symptoms. The purpose of this clinical trial is to assess the effectiveness of different doses of these cannabinoids, alone or combined, on spasticity relief, compared to placebo. Moreover, we aim to determine which treatment is best effective to address other key MS conditions. Methods: A double-blinded, randomized, factorial, placebo-controlled trial will be performed. We intend to include up to 250 PwMS aged over 21 recruited from the Centre hospitalier de l’Université de Montréal MS Clinic. PwMS will be randomly assigned on a 1:1:1:1 ratio to one of the trial arms: THC alone, CBD alone, THC/CBD combination, or placebo, using stratified blocked randomization, with random blocks within each stratum. The primary outcome is a self-assessment of spasticity using the mean Numeric Rating Scale score over 7  days. The main outcome will be the difference in this score at 4  weeks compared to baseline. Secondary outcomes include assessments of spasticity as measured by a clinician, pain, fatigue, sleep, bowel, bladder, and sexual dysfunction, restless legs syndrome, mental health, quality of life, mobility, cognitive functioning, and adverse events. Treatment responders are eligible for a 12-week extension phase, using the same treatment allocation and assessments. Discussion: Previous clinical studies examined the efficacy of cannabis-based medicines in PwMS, mostly using products with 1:1 THC/CBD ratio. The major barrier to effectively use cannabis in real-world clinical settings is the lack of evidence on benefits of specific cannabinoids and information on possible related risks. The CANSEP study will contribute to overcome these limitations and identify the risks and benefits of cannabis-based treatments in PwMS. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) and Cerebral Small Vessel Disease (CSVD) exhibit some similarities in Magnetic resonance imaging (MRI), potentially leading to misdiagnosis and delaying effective treatment windows. It is unclear whether CSVD can be detected with Paramagnetic Rim Lesions (PRL), which is special in MS. Objective: We aimed to investigate whether PRL can serve as a neuroimaging marker for discriminating between MS and CSVD. Methods: In this retrospective study, 49 MS and 104 CSVD patients underwent 3.0 T Magnetic resonance imaging (MRI). Visual assessment of 37 MS patients and 89 CSVD patients with or without lacunes, cerebral microbleeds (CMBs), enlarged perivascular spaces (EPVS), white matter hyperintensity (WMH), central vein sign (CVS), and PRL. The distribution and number of PRL were then counted. Results: Our study found that PRL was detected in over half of the MS patients but was entirely absent in CSVD patients (78.38 vs. 0%, p < 0.0001), and PRL showed high specificity with good sensitivity in discriminating between MS and CSVD (sensitivity: 78.38%, specificity: 100%, AUC: 0.96). Conclusion: Paramagnetic Rim Lesions is a special imaging feature in MS, absent in CSVD. Detection of PRL can be very helpful in the clinical management of MS and CSVD. [ABSTRACT FROM AUTHOR]

Introduction: Vertigo, dizziness, gaze instability and disequilibrium are highly prevalent in people with MS (PwMS) and head movement induced dizziness is commonly reported. Vestibular physical therapy (VPT) is a specialised, noninvasive and effective therapy for these problems but usually involves travel for the person to a specialist center with both personal and carbon costs. The use of wearable sensors to track head movement and smartphone applications to deliver and track programs has potential to improve VPT in MS. Methods: This study investigated the usability and effects of a commercially available digital VPT system (wearable head sensor, smartphone app and clinician software) to deliver VPT to PwMS. A pre/post treatment design was employed and the primary outcome was the System Usability Scale (SUS). Other patient reported outcomes were the Service User Acceptability Questionnaire (SUTAQ), the Patient Enablement Instrument (PEI) and the Dizziness Handicap Inventory (DHI). Physical outcomes measurements included Mini-BESTest (MB), Modified Dynamic Gait Index (mDGI), Gait Speed (GS), Dynamic Visual Acuity (DVA) and head kinematics and symptoms during exercise. Results: Sixteen PwMS (14 female), mean age 44(±14) years were recruited to the study and twelve completed VPT. Mean adherence to exercise, measured digitally was 60% (±18.4). SUS scores were high at 81 (±14) and SUTAQ scores also demonstrated high levels of satisfaction and acceptability of the system. Statistically significant improvements in MB (mean change 2.25; p = 0.004), mDGI (median change 1.00; p = 0.008), DVA (median change -1.00; p = 0.004) were found. Head frequencies significantly improved with concurrent decreased intensity of dizziness during head movements (mean change across 4 gaze stabilization exercises was 23 beats per minute; p < 0.05). Non-significant improvements were seen in DHI (p = 0.07) and GS (p = 0.15). 64.5% of follow up visits were conducted remotely (video or phone), facilitated by the system. Discussion: This study had two main outcomes and benefits for PwMS. Firstly, we showed that the system used was both acceptable and could be used by PwMS. Secondly, we demonstrated an improvement in a range of dizziness, balance and gait metrics with remotely delivered care. This system has the potential to positively impact on MS physiotherapy service provision with the potential to deliver effective remote care. [ABSTRACT FROM AUTHOR]

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Comorbidities in patients with multiple sclerosis (MS) and antibody-mediated diseases of the central nervous system (CNS) including neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein (MOG)- antibody-associated disease (MOGAD) are common and may influence the course of their neurological disease. Comorbidity may contribute to neuronal injury and therefore limit recovery from attacks, accelerate disease progression, and increase disability. This study aims to explore the impact of comorbidity, particularly vascular comorbidity, and related risk factors on clinical and paraclinical parameters of MS, NMOSD and MOGAD. We propose COMMIT, a prospective multicenter study with longitudinal follow-up of patients with MS, NMOSD, and MOGAD, with or without comorbidities, as well as healthy subjects as controls. Subjects will be stratified by age, sex and ethnicity. In consecutive samples we will analyze levels of inflammation and neurodegeneration markers in both fluid and cellular compartments of the peripheral blood and cerebrospinal fluid (CSF) using multiple state-of-the-art technologies, including untargeted proteomics and targeted ultrasensitive ELISA assays and quantitative reverse transcription polymerase chain reaction (RT-qPCR) as well as high-dimensional single-cell technologies i.e., mass cytometry and single-cell RNA sequencing. Algorithm-based data analyses will be used to unravel the relationship between these markers, optical coherence tomography (OCT) and magnetic resonance imaging (MRI), and clinical outcomes including frequency and severity of relapses, long-term disability, and quality of life. The goal is to evaluate the impact of comorbidities on MS, NMOSD, and MOGAD which may lead to development of treatment approaches to improve outcomes of inflammatory demyelinating diseases of the CNS. [ABSTRACT FROM AUTHOR]

Background: Previous research suggested that quadripulse (QPS)-induced synaptic plasticity is associated with both cognitive and motor function in patients with multiple sclerosis (MS) and does not appear to be reduced compared to healthy controls (HCs). Objective: This study aimed to explore the relationship between the degree of QPS-induced plasticity and clinically significant decline in motor and cognitive functions over time. We hypothesized that MS patients experiencing functional decline would exhibit lower levels of baseline plasticity compared to those without decline. Methods: QPS-induced plasticity was evaluated in 80 MS patients (56 with relapsing-remitting MS and 24 with progressive MS), and 69 age-, sex-, and education-matched HCs. Cognitive and motor functions, as well as overall disability status were evaluated annually over a median follow-up period of 2 years. Clinically meaningful change thresholds were predefined for each outcome measure. Linear mixed-effects models, Cox proportional hazard models, logistic regression, and receiver-operating characteristic analysis were applied to analyse the relationship between baseline plasticity and clinical progression in the symbol digit modalities test, brief visuospatial memory test revised (BVMT-R), nine-hole peg test (NHPT), timed 25-foot walk test, and expanded disability status scale. Results: Overall, the patient cohort showed no clinically relevant change in any functional outcome over time. Variability in performance was observed across time points in both patients and HCs. MS patients who experienced clinically relevant decline in manual dexterity and/or visuospatial learning and memory had significantly lower levels of synaptic plasticity at baseline compared to those without such decline (NHPT: β = -0.25, p = 0.02; BVMT-R: β = -0.50, p = 0.005). Receiver-operating characteristic analysis underscored the predictive utility of baseline synaptic plasticity in discerning between patients experiencing functional decline and those maintaining stability only for visuospatial learning and memory (area under the curve = 0.85). Conclusion: Our study suggests that QPS-induced plasticity could be linked to clinically relevant functional decline in patients with MS. However, to solidify these findings, longer follow-up periods are warranted, especially in cohorts with higher prevalences of functional decline. Additionally, the variability in cognitive performance in both patients with MS and HCs underscores the importance of conducting further research on reliable change based on neuropsychological tests. [ABSTRACT FROM AUTHOR]

Significant advancements have been achieved in delineating the progress of the Global PROMS (PROMS) Initiative. The PROMS Initiative, a collaborative endeavor by the European Charcot Foundation and the Multiple Sclerosis International Federation, strives to amplify the influence of patient input on MS care and establish a cohesive perspective on Patient-Reported Outcomes (PROs) for diverse stakeholders. This initiative has established an expansive, participatory governance framework launching four dedicated working groups that have made substantive contributions to research, clinical management, eHealth, and healthcare system reform. The initiative prioritizes the global integration of patient (For the purposes of the Global PROMS Initiative, the term "patient" refers to the people with the disease (aka People with Multiple Sclerosis - pwMS): any individual with lived experience of the disease. People affected by the disease/Multiple Sclerosis: any individual or group that is affected by the disease: E.g., family members, caregivers will be also engaged as the other stakeholders in the initiative). insights into the management of MS care. It merges subjective PROs with objective clinical metrics, thereby addressing the complex variability of disease presentation and progression. Following the completion of its second phase, the initiative aims to help increasing the uptake of eHealth tools and passive PROs within research and clinical settings, affirming its unwavering dedication to the progressive refinement of MS care. Looking forward, the initiative is poised to continue enhancing global surveys, rethinking to the relevant statistical approaches in clinical trials, and cultivating a unified stance among 'industry', regulatory bodies and health policy making regarding the application of PROs in MS healthcare strategies. [ABSTRACT FROM AUTHOR]

Introduction: The influence of non-teaching staff on localizing Sustainable Development Goals (SDGs) within universities is underexplored despite its potential significance. This study examines the familiarization with SDGs at Great Zimbabwe University (GZU). Methods: The triangulation convergence model of the mixed methods research design was adopted as the strategy for inquiry. The study surveyed 70 randomly selected non-teaching staff from diverse departments and key informant interviews were done with purposively selected non-teaching staff. Secondary data sources were obtained from the information department and the university website for additional details on SDG localisation initiatives. Results: The results indicate that the non-teaching staff members at GZU exhibit a moderate familiarity with SDGs, scoring 42.14%. About 42.86% of the employees had engaged with SDGs documents. Interestingly, respondents perceived the institution as well-prepared for SDGs localization, scoring 62.17%. The overall SDGs localization score is 58.5%, with variations between specific SDGs. In particular, SDG 5 (Gender Equality) scores highest, while SDG 14 (Life below Water) is the least localized. The study identifies several obstacles that hinder non-teaching staff from actively contributing to SDG implementation, such as primarily financial constraints followed by lack of awareness, demotivated employees, insufficient training, and a scarcity of SDG materials. Structural challenges within the institution were also observed. Discussion: To facilitate the mainstreaming of SDGs issues among nonacademic staff activities and initiatives, the study underscores the need for management to play an enabling role and designate focal persons for SDGs to oversee projects' execution. Overall, this research sheds light on the current status of SDGs familiarization in higher learning institutions and offers insights for enhancing the involvement of non-teaching staff in achieving SDG targets. [ABSTRACT FROM AUTHOR]

Introduction: Disease modifying therapies (DMTs) used to treat multiple sclerosis (MS) can be associated to the occurrence of hematological disorders. This systematic review aims to provide an overview of these events occurring in reallife conditions, by describing case reports and series published in the literature. Methods: A literature search of all publications up to January 5th 2024 on the Medline and Embase databases was carried out. The results were presented both in the text and in tables. Results: Sixty-seven case reports/series were included in this review, of which more than half related to alemtuzumab, natalizumab and ocrelizumab. The publication date of included studies ranged from 2006 to 2024. The majority of case reports and series described the occurrence of late-onset hematological disorders (events that occurred more than 30 days after the first DMT administration), mainly represented by case of neutropenia, autoimmune hemolytic anemia and immune thrombocytopenia. All cases reported a favorable outcome, apart one case report that described a fatal case. Among included cases, 4 articles, all related to natalizumab, described the occurrence of myeloid disorders in 13 newborns from mother receiving the DMT. Discussion: Considering the limitations identified in the majority of included studies, further ad hoc studies are strongly needed to better evaluate the hematological disorders of DMTs. Meantime, the strict monitoring of treated patients for the occurrence of these toxicities should be highly recommended. [ABSTRACT FROM AUTHOR]

Background: Multiple Sclerosis (MS) is a common neurological disease among white populations of European origin. Frequencies among Latin Americans continue to be studied, however, epidemiologic, and clinical characterization studies lack from Central American and Caribbean countries. Ethnicity in these countries is uniformly similar with a prevalent Mestizo population. Methods and results: Data from January 2014 to December 2019 from Guatemala, El Salvador, Honduras, Nicaragua, Costa Rica, Panama, Dominican Republic, and Aruba on demographic, clinical, MRI and phenotypic traits were determined in coordinated studies: ENHANCE, a population-based, retrospective, observational study on incidence and clinical characteristics, and from the subgroup with MS national registries (Aruba, Dominican Republic, Honduras, and Panama), data on prevalence, phenotypes and demographics. Expanded Disability Status Scale (EDSS), and therapeutic schemes were included. ENHANCE data from 758 patients disclosed 79.8% of Mestizo ethnicity; 72.4% female; median age at onset 31.0 years and 33.2 at diagnosis. The highest incidence rate was from Aruba, 2.3–3.5 × 100,000 inhabitants, and the lowest, 0.07–0.15 × 100,000, from Honduras. Crude prevalence rates per 100,000 inhabitants fluctuated from 27.3 (Aruba) to 1.0 (Honduras). Relapsing MS accounted for 87.4% of cases; EDSS <3.0 determined in 66.6% (mean disease duration: 9.1 years, SD ± 5.0); CSF oligoclonal bands 85.7%, and 87% of subjects hydroxyvitamin D deficient. Common initial therapies were interferon and fingolimod. Switching from interferon to fingolimod was the most common escalation step. The COVID-19 pandemic affected follow-up aspects of these studies. Conclusion: This is the first study providing data on frequencies and clinical characteristics from 8 countries from the Central American and Caribbean region, addressing MS as an emergent epidemiologic disorder. More studies from these areas are encouraged. [ABSTRACT FROM AUTHOR]

Background: The primary treatment for acute relapses in multiple sclerosis (MS) is the intravenous administration of high-dose methylprednisolone (IVMP). However, the mechanisms through which corticosteroid treatment impacts acute neuroinflammation in people with MS (pwMS) remain not fully understood. In particular, the changes induced by glucocorticoids (GCs) on cells of the innate immune system and the differences between patients with distinct immunotherapies have received little attention to date. Methods: We conducted immunophenotyping using flow cytometry on peripheral blood mononuclear cells of pwMS who received IVMP treatment during a relapse. We compared the impact of an IVMP treatment on a broad variety of immune cell subsets within three groups: twelve patients who were treatment-naïve to disease modifying therapies (wDMT) to ten patients on platform therapies (PT) and eighteen patients on fingolimod therapy (FTY). Results: We observed pronounced interindividual short- and intermediate-term effects of IVMP on distinct immune cells subsets. In addition to the welldocumented decrease in T-helper cells (Th cells), we detected significant alterations after the first IVMP infusion within the innate immune response among neutrophil, eosinophil and basophil granulocytes, monocytes and plasmacytoid dendritic cells (pDCs). When comparing patients wDMT to the PT and FTY cohorts, we found that IVMP had a similar impact on innate immune cells across all treatment groups. However, we did not observe a significant further decline in T lymphocyte counts during IVMP in patients with pre-existing lymphopenia under FTY treatment. Although T cell apoptosis is considered the main mechanism of action of GCs, patients with FTY still reported symptom improvement following IVMP treatment. Conclusion: In addition to T cell suppression, our data suggests that further immunoregulatory mechanisms of GC, particularly on cells of the innate immune response, are of greater significance than previously understood. Due to the regulation of the adaptive immune cells by DMTs, the impact of GC on these cells varies depending on the underlying DMT. Additional studies involving larger cohorts and cerebrospinal fluid samples are necessary to gain a deeper understanding of the immune response to GC in pwMS with different DMTs during relapse to define and explain differences in clinical response profiles. [ABSTRACT FROM AUTHOR]

Background: Leptomeningeal enhancement (LME) is considered an MRI marker of leptomeningeal inflammation in inflammatory neurological disorders, including multiple sclerosis (MS). To our knowledge, no disease-modifying therapies (DMTs) have been demonstrated to affect LME number or morphology so far. Methods: Monocentric study investigating the frequency and number of LME in a cohort of people with (pw)MS who performed a 3 T brain MRI with a standardized protocol (including a post-contrast FLAIR sequence), and exploring the impact of autologous hematopoietic stem cell transplantation (AHSCT) on this marker. In a longitudinal pilot study, consecutive MRIs were also analyzed in a subgroup of pwMS, including patients evaluated both pre- and post-AHSCT. Results: Fifty-five pwMS were included: 24/55 (44%) had received AHSCT (AHSCT group) and 31 other treatments (CTRL group). At least one LME was identified in 19/55 (35%) cases (42 and 29% in the AHSCT and CTRL groups, respectively; p = 0.405). In the AHSCT group, LME number correlated with age at AHSCT (R = 0.50; p = 0.014), but not with age at post-treatment MRI. In the longitudinal pilot study (n = 8), one LME disappeared following AHSCT in 1/4 patients, whereas LME number was unchanged in the remaining four pwMS from the CTRL group. Discussion: These results suggest that AHSCT may affect development and persistence of LME, strengthening the indication for early use of effective therapies bioavailable within the central nervous system (CNS), and therefore potentially targeting compartmentalized inflammation. [ABSTRACT FROM AUTHOR]

Historically, the central nervous system (CNS) was regarded as 'immuneprivileged', possessing its own distinct immune cell population. This immune privilege was thought to be established by a tight blood-brain barrier (BBB) and blood-cerebrospinal-fluid barrier (BCSFB), which prevented the crossing of peripheral immune cells and their secreted factors into the CNS parenchyma. However, recent studies have revealed the presence of peripheral immune cells in proximity to various brain-border niches such as the choroid plexus, cranial bone marrow (CBM), meninges, and perivascular spaces. Furthermore, emerging evidence suggests that peripheral immune cells may be able to infiltrate the brain through these sites and play significant roles in driving neuronal cell death and pathology progression in neurodegenerative disease. Thus, in this review, we explore how the brain-border immune niches may contribute to the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). We then discuss several emerging options for harnessing the neuroimmune potential of these niches to improve the prognosis and treatment of these debilitative disorders using novel insights from recent studies. [ABSTRACT FROM AUTHOR]

Ultra-low field (ULF) magnetic resonance imaging (MRI) holds the potential to make MRI more accessible, given its cost-effectiveness, reduced power requirements, and portability. However, signal-to-noise ratio (SNR) drops with field strength, necessitating imaging with lower resolution and longer scan times. This study introduces a novel Fourier-based Super Resolution (FouSR) approach, designed to enhance the resolution of ULF MRI images with minimal increase in total scan time. FouSR combines spatial frequencies from two orthogonal ULF images of anisotropic resolution to create an isotropic T2-weighted fluidattenuated inversion recovery (FLAIR) image. We hypothesized that FouSR could effectively recover information from under-sampled slice directions, thereby improving the delineation of multiple sclerosis (MS) lesions and other significant anatomical features. Importantly, the FouSR algorithm can be implemented on the scanner with changes to the k-space trajectory. Paired ULF (Hyperfine SWOOP, 0.064 tesla) and high field (Siemens, Skyra, 3 Tesla) FLAIR scans were collected on the same day from a phantom and a cohort of 10 participants with MS or suspected MS (6 female; mean ± SD age: 44.1 ± 4.1). ULF scans were acquired along both coronal and axial planes, featuring an in-plane resolution of 1.7 mm × 1.7 mm with a slice thickness of 5 mm. FouSR was evaluated against registered ULF coronal and axial scans, their average (ULF average) and a gold standard SR (ANTs SR). FouSR exhibited higher SNR (47.96 ± 12.6) compared to ULF coronal (36.7 ± 12.2) and higher lesion conspicuity (0.12 ± 0.06) compared to ULF axial (0.13 ± 0.07) but did not exhibit any significant differences contrastto-noise-ratio (CNR) compared to other methods in patient scans. However, FouSR demonstrated superior image sharpness (0.025 ± 0.0040) compared to all other techniques (ULF coronal 0.021 ± 0.0037, q = 5.9, p-adj. = 0.011; ULF axial 0.018 ± 0.0026, q = 11.1, p-adj. = 0.0001; ULF average 0.019 ± 0.0034, q = 24.2, p-adj. < 0.0001) and higher lesion sharpness (-0.97 ± 0.31) when compared to the ULF average (-1.02 ± 0.37, t(543) = -10.174, p = <0.0001). Average blinded qualitative assessment by three experienced MS neurologists showed no significant difference in WML and sulci or gyri visualization between FouSR and other methods. FouSR can, in principle, be implemented on the scanner to produce clinically useful FLAIR images at higher resolution on the fly, providing a valuable tool for visualizing lesions and other anatomical structures in MS. [ABSTRACT FROM AUTHOR]

Disease-modifying therapies (DMTs) for multiple sclerosis (MS) reduce relapse frequency, magnetic resonance imaging (MRI) activity, and slow disability progression. Numerous DMTs are approved for relapsing forms of MS although real-world data on patient-reported outcomes (PROs) and quality of life (QoL) are needed to inform treatment choice. Immune reconstitution therapy with cladribine tablets is a highly effective treatment for relapsing MS (RMS). We present the protocol for an observational study to prospectively assess the effectiveness of cladribine tablets on clinical and MRI parameters as well as on PROs, including treatment satisfaction, QoL, sleep quality, self-perceived health, fatigue, and physical function. Enrolled patients at study sites in Italy will be adults with RMS (including relapsing-remitting and active secondary progressive MS) who are either treatment naïve or have received at least one firstline disease modifying DMT or no more than one second-line DMT. The primary objective will be change in global treatment satisfaction measured with the Treatment Satisfaction Questionnaire for Medication Version 1.4 approximately 24 months after initiating cladribine tablets in patients switching from previous DMTs. Secondary objectives will include global treatment satisfaction at earlier timepoints, will comprise treatment naïve patients, and will quantify treatment effectiveness and tolerability. We will also assess relapses, disability progression, MRI activity, and other PROs at approximately 12 and 24 months. The findings will provide insight from daily clinical practice into the patient's experience to complement data from controlled trials and inform treatment choice. EU PAS Registration Number EUPAS49334 filed 17/10/2022. [ABSTRACT FROM AUTHOR]

Background: While cerebral infarction in children is rare, its prognosis is poor, and this condition can seriously burden society and families. A correlation between patent foramen ovale (PFO) and ischemic stroke has not been found in pediatric patients. Case presentation: We report a 7-year-old boy who suffered from multiple cerebral infarctions. Subsequently, the patient was diagnosed with an abnormal shunt of PFO. He underwent PFO closure and was followed up for 1 year. The patient did not experience any further cerebral infarction. Conclusions: With this case report, we want to illustrate that although the incidence rate of ischemic cerebral infarction in adolescents is very low, we should not neglect the role of PFO. Therefore, after exclusion other causes of cerebral infarction, PFO should be considered in adolescent and adult stroke patients with adult closure criteria in the same way. [ABSTRACT FROM AUTHOR]

Background: Currently, an increasing body of research suggests that bloodbased long non-coding RNAs (lncRNAs) could serve as biomarkers for diagnosing multiple sclerosis (MS). This meta-analysis evaluates the diagnostic capabilities of selected lncRNAs in distinguishing individuals with MS from healthy controls and in differentiating between the relapsing and remitting phases of the disease. Methods: We conducted comprehensive searches across seven databases in both Chinese and English to identify relevant studies, applying stringent inclusion and exclusion criteria. The quality of the selected references was rigorously assessed using the QUADAS-2 tool. The analysis involved calculating summarized sensitivity (SSEN), specificity (SSPE), positive likelihood ratio (SPLR), negative likelihood ratio (SNLR), and diagnostic odds ratio (DOR) with 95% confidence intervals (CIs). Accuracy was assessed using summary receiver operating characteristic (SROC) curves. Results: Thirteen high-quality studies were selected for inclusion in the metaanalysis. Our meta-analysis assessed the combined diagnostic performance of lncRNAs in distinguishing MS patients from healthy controls. We found a SSEN of 0.81 (95% CI: 0.74-0.87), SSPE of 0.84 (95% CI: 0.78-0.89), SPLR of 5.14 (95% CI: 3.63-7.28), SNLR of 0.22 (95% CI: 0.16-0.31), and DOR of 23.17 (95% CI: 14.07-38.17), with an AUC of 0.90 (95% CI: 0.87-0.92). For differentiating between relapsing and remitting MS, the results showed a SSEN of 0.79 (95% CI: 0.71-0.85), SSPE of 0.76 (95% CI: 0.64-0.85), SPLR of 3.34 (95% CI: 2.09-5.33), SNLR of 0.28 (95% CI: 0.19-0.40), and DOR of 12.09 (95% CI: 5.70-25.68), with an AUC of 0.84 (95% CI: 0.81-0.87). Conclusion: This analysis underscores the significant role of lncRNAs as biomarkers in MS diagnosis and differentiation between its relapsing and remitting forms. [ABSTRACT FROM AUTHOR]

Background: Aging has always been considered as a risk factor for neurodegenerative diseases, but there are individual differences and its mechanism is not yet clear. Epigenetics may unveil the relationship between aging and neurodegenerative diseases. Methods: Our study employed a bidirectional two-sample Mendelian randomization (MR) design to assess the potential causal association between epigenetic aging and neurodegenerative diseases. We utilized publicly available summary datasets from several genome-wide association studies (GWAS). Our investigation focused on multiple measures of epigenetic age as potential exposures and outcomes, while the occurrence of neurodegenerative diseases served as potential exposures and outcomes. Sensitivity analyses confirmed the accuracy of the results. Results: The results show a significant decrease in risk of Parkinson's disease with GrimAge (OR = 0.8862, 95% CI 0.7914-0.9924, p = 0.03638). Additionally, we identified that HannumAge was linked to an increased risk of Multiple Sclerosis (OR = 1.0707, 95% CI 1.0056-1.1401, p = 0.03295). Furthermore, we also found that estimated plasminogen activator inhibitor-1(PAI-1) levels demonstrated an increased risk for Alzheimer's disease (OR = 1.0001, 95% CI 1.0000-1.0002, p = 0.04425). Beyond that, we did not observe any causal associations between epigenetic age and neurodegenerative diseases risk. Conclusion: The findings firstly provide evidence for causal association of epigenetic aging and neurodegenerative diseases. Exploring neurodegenerative diseases from an epigenetic perspective may contribute to diagnosis, prognosis, and treatment of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Multiple Sclerosis (MS) is an immune-mediated condition that persistently harms the central nervous system. While existing treatments can slow its course, a cure remains elusive. Stem cell therapy has gained attention as a promising approach, offering new perspectives with its regenerative and immunomodulatory properties. This article reviews the application of stem cells in MS, encompassing various stem cell types, therapeutic potential mechanisms, preclinical explorations, clinical research advancements, safety profiles of clinical applications, as well as limitations and challenges, aiming to provide new insights into the treatment research for MS. [ABSTRACT FROM AUTHOR]