Search Results (239)

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article

Background/Objectives: Pediatric acquired demyelinating syndromes (ADSs) encompass a heterogeneous group of disorders, including multiple sclerosis (MS), MOG antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), with distinct clinical trajectories and prognoses. While analyzed collectively at baseline to reflect real-world diagnostic uncertainty, outcome predictors were also examined according to final diagnosis. Identifying early predictors is crucial for optimizing long-term outcomes. Methods: We retrospectively analyzed 30 pediatric patients (mean onset age: 11.3 years) with ADSs. Clinical, radiological, CSF, antibody, and neurophysiological data were collected and analyzed alongside treatment strategies. Outcomes—EDSS scores, neuroradiological changes, and clinical status—were evaluated over a 3-year period. Results: Final diagnoses included MOGAD (36.6%), MS (33.3%), NMOSD (6.6%), ADEM (10%), and other ADSs (13.3%). At onset, ≥3 brain lesions were present in 76.7% of patients. Disease-modifying therapies (DMTs) were used in 37% and acute immunotherapy in 90%. EDSS progression was significantly associated with DMT use at multiple timepoints, with additional predictors including MRI lesion type, CSF findings, antibody status, and evoked potentials. At 3 years, neurocognitive function predicted clinical outcome. Conclusions: Early immunotherapy and baseline instrumental findings are key predictors of outcome in pediatric ADSs. MOGAD showed a more favorable course, while MS and NMOSD were associated with greater long-term disability. A comprehensive, early diagnostic approach is essential for improving prognosis. Full article

Background and Clinical Significance: Neuromyelitis optica (NMO) is a chronic demyelinating inflammatory disease of the central nervous system (CNS), mediated by autoantibodies against aquaporin-4 (AQ4) receptors. In the spectrum of NMO, other autoimmune diseases also coexist, though their association with systemic lupus erythematosus (SLE) is rare. Case Presentation: We present two cases of patients in their 70s who were diagnosed with NMO in the context of SLE. The first case concerns a 78-year-old woman with drug-induced SLE and thoracic myelitis who developed T4-level incomplete paraplegia over three weeks. The second case involves a 71-year-old woman with a history of SLE and myasthenia gravis, presenting with cervical myelitis with progressive worsening of walking and C4-level paraparesis over two months. In both cases, elevated serum anti-AQ4 titers were detected, establishing the diagnosis of NMO and differentiation from an atypical manifestation of SLE-related myelitis. High doses of intravenous corticosteroids with gradual tapering, along with cyclophosphamide, followed by rituximab, were administered in both patients. The first patient showed a poor response, while the second showed improvement. Conclusions: The coexistence of NMO with SLE is rare, but the occurrence of myelitis in patients with connective tissue diseases should raise the suspicion of NMO, especially in elderly women and several years after the diagnosis of SLE. Time to treatment is critical, as delays in treating NMO can result in cumulative and disabling damage. Full article

Pediatric-onset multiple sclerosis (POMS) is a rare yet increasingly recognized demyelinating disease of the central nervous system, characterized by a highly inflammatory disease course and an elevated relapse rate compared to adult-onset MS (AOMS). Given the unique immunopathogenesis of POMS, recent therapeutic strategies have shifted toward early initiation of high-efficacy disease-modifying therapies (DMTs) to minimize irreversible neurological damage. Among these, B-cell-targeting therapies, particularly anti-CD20 monoclonal antibodies, have shown efficacy in adult MS and are emerging as promising candidates for POMS treatment. The present review summarizes the current knowledge of the role of B-cells in POMS pathophysiology and evaluates the therapeutic potential of anti-CD-20 agents. It also highlights ongoing clinical trials and future perspectives, including novel B-cell-directed approaches such as anti-CD19 therapies, Bruton’s tyrosine kinase (BTK) inhibitors, and BAFF-targeting agents. Full article

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that leads to inflammation and demyelination, manifesting in either a relapsing–remitting or progressive form. As a multifactorial disease, MS involves both genetic and environmental factors, with a known significant contribution from human leukocyte antigen (HLA) genes, mainly represented by the HLA-DRB1 and HLA-DQB1 loci, which have been linked to either susceptibility or protection, but variably across populations and ethnic groups. We aimed to study the distribution and polymorphism of HLA-DRB1 and HLA-DQB1 alleles in a population with MS from the southern Moroccan region, in comparison with healthy controls. Materials and Methods: A cross-sectional study was conducted over a period of 2 years (2022–2024) in a MS cohort including 40 patients and 100 healthy controls. DRB1 and DQB1 HLA genotyping was performed using a high-resolution reverse sequence-specific oligonucleotide (SSO) method, based on the Luminex system (xMAP technology, One lambda^®). Data were analyzed using SPSS 26; differences in allele frequencies were evaluated by the Chi-square test and Fisher’s exact test. OR (95% CI) was calculated, and FDR corrections were applied for multiple testing. Results: Among the various HLA-DRB1 and DQB1 alleles studied, including those considered as predisposing to MS, the DQB1*02:01 and DRB1*15:01 alleles were more prevalent in MS patients, with 40% and 8.8% vs. 16% and 4.08% in controls respectively, although these differences were not statistically significant (p = 0.06 and p = 0.12). Likewise, the DRB1*15:01-DQB1*06:02 association was significantly more prevalent in the MS group (9%, p = 0.004). In contrast, the DRB1*07:01 allele, linked to protection against MS in many populations, was significantly predominant in controls (17%, p = 0.004). Similarly, the DRB1*07:01–DQB*02:01 combination was rather more frequent in controls (12%, p = 0.01). Confronted to MS clinical forms, we remarkably noted that the DRB1*13:03 allele was found only among relapsing–remitting MS (RRMS) patients (6%, p = 0.003), while DQB1*02:01 was significantly associated with RRMS (42.1%) and primary progressive MS (41%, p = 0.001), with an intermediate Expanded Disability Status Scale (EDSS) score, which may indicate a possible link with disease progression and severity. Conclusions: The results of our study highlighted particular HLA alleles, DRB1 and DQB1, alone or in combination, as potential immunogenic factors of susceptibility to MS in a population from southern Morocco, while other alleles seem rather to protect against the disease. This HLA polymorphism is also reflected in the clinical forms of the disease, showing a tendency toward severity for certain alleles. However, such preliminary results need to be consolidated and confirmed by studies carried out on a larger population sample, and compared with others on a national scale. Full article

The occurrence of demyelination in the central nervous system (CNS) causes neurodegenerative lesions. The occurrence and development of demyelination involve multiple pathological mechanisms, including the generation of reactive oxygen species (ROS) caused by mitochondrial dysfunction in microglia and subsequent neuroinflammation. Scutellarin is a natural flavonoid drug with significant neuroprotective effects, including antioxidant, anti-inflammatory, and anti-apoptotic properties, and is widely used in the treatment of neurological diseases. However, the protective effects and mechanisms of scutellarin on demyelination have not yet been elucidated. This study aims to investigate the neuroprotective effects of scutellarin on demyelination and its underlying molecular mechanisms. Our results showed that treatment with scutellarin significantly alleviated Cuprizone-induced myelin damage, neuronal apoptosis, and neurological deficits in mice. In in vitro experiments, scutellarin significantly reduced Cuprizone–copper-induced pro-inflammatory microglia formation and inhibited the secretion of TNF-α, thereby reducing myelin cell damage. Mechanism studies revealed that scutellarin inhibited the secretion of TNF-α by microglia and alleviated myelin cell damage by reducing the excessive production of mitochondrial reactive oxygen species (Mito-ROS), reactive oxygen species (ROS), and malondialdehyde (MDA) induced by Cuprizone–copper in microglia. Finally, scutellarin improved mitochondrial dysfunction in microglia and significantly alleviated myelin cell damage by inhibiting the expression of p38MAPK. In conclusion, our findings demonstrate that scutellarin exerts significant neuroprotective effects on Cuprizone-induced mice by improving mitochondrial dysfunction in microglia, thereby reducing inflammatory responses. This effect is closely associated with the inhibition of the p38MAPK pathway. Full article

Viral infections have been associated with multiple sclerosis (MS), an immune-mediated disease in the central nervous system (CNS). Since Theiler’s murine encephalomyelitis virus (TMEV) can induce MS-like demyelination, TMEV infection is the most widely used viral model for MS. Although the precise pathophysiology is unknown, altered fecal bacterial populations were associated with distinct immune gene expressions in the CNS. We aimed to determine the role of gut microbiota in TMEV infection by administering an antibiotic cocktail in drinking water before (prophylactic administration) or after (therapeutic administration) TMEV infection. The antibiotic administration reduced total eubacteria, including the phyla Bacillota and Bacteroidota, but increased the phylum Pseudomonadata in feces. Prophylactic administration did not alter TMEV-induced inflammatory demyelination clinically or histologically, without changes in anti-viral IgG1/IgG2c levels or lymphoproliferative responses; therapeutic administration temporarily suppressed the neurological signs. Although antibiotic treatment had minimal effects on TMEV infection, adding metronidazole and ampicillin in drinking water substantially reduced water intake in the antibiotic group of mice, resulting in significant body weight loss. Since dehydration and stress could affect immune responses and gut microbiota, caution should be exercised when planning or evaluating the oral antibiotic cocktail treatment in experimental animals. Full article

Demyelination in the central nervous system (CNS) disrupts neuronal communication and promotes neurodegeneration. Despite the widespread use of cuprizone-induced demyelination models to study myelin injury and repair, the mechanisms underlying oligodendrocyte apoptosis and regeneration are poorly understood. This study investigated the dynamic cellular and molecular changes that occur during demyelination and remyelination, with a focus on glial cell responses, blood-brain barrier (BBB) integrity, and neuroimmune interactions. C57BL/6J mice exposed to cuprizone exhibited weight loss, sensorimotor deficits, and cognitive decline, which were reversed during remyelination. Histological and immunofluorescence analyses revealed reduced myelin protein levels, including myelin basic protein (MBP) and myelin-associated glycoprotein (MAG), and decreased oligodendrocyte populations during demyelination, with recovery during repair. The BBB permeability increases during demyelination, is associated with the decreased expression of tight junction proteins (ZO-1, Occludin), and normalizes during remyelination. Single-cell RNA sequencing revealed dynamic shifts in glial cell populations and upregulated Psap-Gpr37l1 signaling. Neuroimmune activation and oxidative stress peak during demyelination, characterized by elevated ROS, MDA, and immune cell infiltration, followed by recovery. Transcriptomic profiling revealed key inflammatory pathways (JAK-STAT, NF-κB) and hub genes associated with demyelination and repair. These findings provide insights into myelin repair mechanisms and highlight potential therapeutic targets for treating demyelinating diseases. Full article

Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system. The pathogenesis of MS involves an immune-mediated attack on myelin and neurons, accompanied by blood–brain barrier dysfunction and chronic CNS inflammation. Central to MS pathology is dysregulation of the kynurenine pathway, which metabolises tryptophan into neuroactive compounds. Kynurenine pathway (KP) activation, driven by inflammatory cytokines, leads to the production of both neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., quinolinic acid, QUIN) metabolites. Imbalance between these metabolites, particularly increased QUIN production, exacerbates glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction, contributing to neuronal and oligodendrocyte damage. Mitochondrial dysfunction plays a critical role in the pathophysiology of MS, exacerbating neurodegeneration through impaired energy metabolism and oxidative stress. This review integrates the current understanding of KP dysregulation in multiple sclerosis across disease stages. In RRMS, heightened KP activity correlates with inflammation and neuroprotection attempts through increased KYNA production. In contrast, SPMS and PPMS are associated with a shift towards a more neurotoxic KP profile, marked by elevated QUIN levels and reduced KYNA, exacerbating neurodegeneration and disability progression. Understanding these mechanisms offers insights into potential biomarkers and therapeutic targets for MS, emphasising the need for strategies to rebalance KP metabolism and mitigate neurotoxicity in progressive disease stages. Full article

Moyamoya angiopathy (MMA) is a cerebrovascular disease determining chronic progressive steno-occlusion of the supraclinoid internal carotid arteries and their main branches. The pathogenesis of MMA remains largely unknown. Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system characterized by the progressive accumulation of focal demyelinating lesions, whose pathophysiology has been theorized but still incompletely understood. Beyond misdiagnoses due to mimicking features among the two disorders, MS coexisting with MMA have been previously, rarely, reported. Herein, we present two other cases of patients with MMA with a concomitant, previously missed, diagnosis of MS and discuss their overlapping features as a hint for a potentially shared pathophysiology. The finding of typical angiographic features enables MMA diagnosis, yet it does not allow us to rule out other potentially concomitant disorders affecting the CNS. The association may be easily missed if the clinical/neuroradiological picture is not carefully assessed. Cerebral spinal fluid analysis and spine neuroimaging should be suggested in all MMA patients with atypical MRI lesions. Full article

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but most have failed to meaningfully prevent disease progression. While classically understood as a T cell-mediated condition, the most effective DMTs in slowing progression also target B cells. Novel classes of MS therapies in development, including anti-CD40L monoclonal antibodies, CD19 chimeric antigen receptor (CAR) T cells, and Bruton’s tyrosine kinase (BTK) inhibitors show greater capacity to target and eliminate B cells in the brain/CNS, as well as impacting T-cell and innate immune compartments. These approaches may help tackle the disease at its immunopathological core, addressing both peripheral and central immune responses that drive MS progression. Another emerging therapeutic strategy is to use bispecific antibodies, which have the potential for dual-targeting various disease aspects such as immune activation and neurodegeneration. As such, the next generation of MS therapies may be the first to reduce both inflammatory demyelination and disease progression in a clinically meaningful way. Their ability to target specific immune cell populations while minimizing broad immune suppression could also lead to better safety profiles. Here, we explore the biological rationale, advantages, limitations, and clinical progress of these emerging immunotherapies for relapsing–remitting and progressive forms of MS. Full article

Multiple sclerosis (MS) is a well-known, chronic autoimmune disorder of the central nervous system (CNS) involving demyelination and neurodegeneration. Research previously conducted in the area of the gut microbiome has highlighted it as a critical contributor to MS pathogenesis. Changes in the commensal microbiota, or dysbiosis, have been shown to affect immune homeostasis, leading to elevated levels of pro-inflammatory cytokines and disruption of the gut–brain axis. In this review, we provide a comprehensive overview of interactions between the gut microbiota and MS, especially focusing on the immunomodulatory actions of microbiota, such as influencing T-cell balance and control of metabolites, e.g., short-chain fatty acids. Various microbial taxa (e.g., Prevotella and Faecalibacterium) were suggested to lay protective roles, whereas Akkermansia muciniphila was associated with disease aggravation. Interventions focusing on microbiota, including probiotics, prebiotics, fecal microbiota transplantation (FMT), and dietary therapies to normalize gut microbial homeostasis, suppress inflammation and are proven to improve clinical benefits in MS patients. Alterations in gut microbiota represent opportunities for identifying biomarkers for early diagnosis, disease progression and treatment response monitoring. Further studies need to be conducted to potentially address the interplay between genetic predispositions, environmental cues, and microbiota composition to get the precise mechanisms of the gut–brain axis in MS. In conclusion, the gut microbiota plays a central role in MS pathogenesis and offers potential for novel therapeutic approaches, providing a promising avenue for improving clinical outcomes in MS management. Full article

Neurofilament light chain (NfL), an abundant cytoskeletal protein in neurons, has emerged as a promising serum biomarker that indicates non-specific neuronal damage secondary to various neurologic diseases, including multiple sclerosis (MS). Emerging evidence suggests that serum NfL levels correlate with future disability, brain atrophy, predict new disease activity, and decrease in response to various disease-modifying therapies. As research continues to validate NfL’s potential role in clinical practice, the need for a practical model to conceptualize and visualize its relevance to MS pathology becomes evident—not only for healthcare providers but also for patients. To address this, we propose the Neurofoundational Model (NFM), which likens a neuron to a home, with various parts of the home representing distinct regions of the central nervous system (CNS). In this model, the home (neuron) experiences scenarios such as a fire, an earthquake, and a slow flood, representing distinct MS disease states. A fire illustrates an MS relapse with good recovery, where serum NfL levels rise during the relapse and subsequently return near baseline. An earthquake represents an MS relapse with poor recovery, where NfL levels increase and remain elevated above baseline. Finally, a slow flood depicts MS in progressive stages, characterized by sustained and gradually increasing serum NfL levels without abrupt clinical changes. This approach offers a clear and relatable visualization for clinicians and patients alike, illustrating the dynamics of serum NfL levels during CNS damage caused by demyelination. By integrating this model into clinical practice, we aim to enhance understanding and communication regarding the role of NfL in MS pathology and its potential utility as a biomarker. Full article

Failure in the proliferation, recruitment, mobilization, and/or differentiation of oligodendrocyte precursor cells (OPCs) impedes remyelination in central nervous system (CNS) demyelinating diseases. Our group has recently achieved the generation of functional oligodendroglia through direct lineage conversion by expressing Sox10, Olig2, and Zfp536 genes in adult rat adipose tissue-derived stromal cells. The present study aimed to determine whether various repurposed drugs or molecules could enhance the myelinating capacities of these induced OPCs (iOPCs). We report that kainate, benztropine, miconazole, clobetasol, and baclofen promote in vitro iOPCs migration, differentiation, and ensheathing abilities through mechanisms similar to those observed in rat neural stem cell-derived OPCs. This research supports the potential use of iOPCs as they provide an alternative and reliable cell source for testing the effects of in vitro promyelinating repurposed drugs and for assessing the molecular and cellular mechanisms involved in therapeutic strategies for demyelinating diseases. Full article

Background: Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS), characterized by inflammation, demyelination, and neurodegeneration, resulting in the disruption of axonal signal conduction. Optic neuritis (ON) occurs in over 70% of MS cases, highlighting the involvement of the optic nerve in the progression of the disease. Optic nerve atrophy secondary to the inflammatory episode can be observed during fundoscopy as pallor in the temporal quadrant or of the entire optic disc. Our study aims to evaluate the diagnostic capacity of fundus ophthalmoscopy when compared with the temporal thickness of the pRNFL (peripapillary retinal nerve fiber layer) measured using optical coherence tomography (OCT). Methods: We analyzed 88 eyes from 44 relapsing remitting MS patients using fundus photography (FP) and OCT optic disc measurements, correlating the temporal pallor of the optic disc seen in fundus photographs (FPs) with structural parameters obtained using OCT. Results: Our analysis revealed the significant capacity of optic disc pallor grading using FPs in MS patients in order to discriminate between normal and quadrants with pallor (p = 0.006) or strong pallor (p = 0.003) and between ones with light pallor and moderate pallor (p = 0.002) or strong pallor (p = 0.001), while being unable to clearly differentiate between normal quadrants and ones with light pallor (p = 0.608) or between pallor and strong pallor (p = 0.33). Conclusions: Fundoscopy and FP are useful screening tools in evaluating optic nerve atrophy in MS patients that could be used to assess neurodegeneration because of their universal availability. With the proposed inclusion of the optic disc as the fifth part of the CNS, the optic nerve will benefit from multiple exploratory techniques in order to increase the understanding of disease progression and patient quality of life. Full article