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Multiple sclerosis (MS), a debilitating autoimmune disorder targeting the central nervous system (CNS), is marked by relentless demyelination and inflammation. Clinically, it presents in three distinct forms: relapsing–remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). While disease-modifying therapies (DMTs) offer some relief to people with RRMS, treatment options for progressive MS (pMS) remain frustratingly inadequate. This gap highlights an urgent need for advanced disease modeling techniques to unravel the intricate pathology of pMS. Human induced pluripotent stem cell (iPSC) technologies and brain organoids are emerging as promising tools for disease modeling in both 2D and 3D in vitro environments. These innovative approaches enable the study of disease mechanisms that closely mimic human pathophysiology and offer new platforms for screening therapeutic compounds, surpassing the limitations of traditional animal models. However, deploying brain organoids in disease modeling presents challenges, especially in the context of non-monogenic disorders. This review delves into cutting-edge brain organoid techniques that hold the potential to revolutionize our understanding of pMS, offering a pathway to disentangle its underlying mechanisms and drive transformative discoveries. [ABSTRACT FROM AUTHOR]

Background and Purpose: The aim was to determine the value of autologous haematopoietic stem cell transplantation (aHSCT) as a therapeutic intervention for progressive multiple sclerosis (PMS) based on a systematic review of the current literature. Methods: All studies from the databases PubMed and Google Scholar published in English before February 2024 which provided individual data for PMS patients were systematically reviewed. PICO was defined as population (P), primary progressive MS and secondary progressive MS patients; intervention (I), treatment with aHSCT; comparison (C), none, disease‐modifying therapy treated/relapsing–remitting MS cohorts if available; outcome (O), transplant‐related mortality, progression‐free survival (PFS) and no evidence of disease activity. Results: A total of 15 studies met the criteria including 665 patients with PMS (74 primary progressive MS, 591 secondary progressive MS) and 801 patients with relapsing–remitting MS as controls. PFS data were available for 647 patients. PMS patients showed more severe disability at baseline than relapsing–remitting MS patients. The average transplant‐related mortality for PMS in 10 studies was 1.9%, with 10 deaths in 528 patients. PFS ranged from 0% to 78% in PMS groups 5 years after treatment initiation, demonstrating a high variability. No evidence of disease activity scores at 5 years ranged from 0% to 75%. Conclusion: Based on the available data, aHSCT does not halt progression in people with PMS. However, there appears to be evidence of improved outcome in selected patients. Due to the heterogeneity of the available data, more comprehensive clinical trials assessing the efficacy of aHSCT across different patient groups are urgently needed to reduce variability and improve patient stratification. [ABSTRACT FROM AUTHOR]

Background: Alemtuzumab is administered intravenously (IV) for relapsing-remitting multiple sclerosis (RRMS), with limited studies of subcutaneous (SC) treatment. Objectives: We sought to evaluate the pharmacodynamics (PD), pharmacokinetics (PK), and safety profile of SC-administered alemtuzumab in people with progressive multiple sclerosis (PMS). Design: SCALA was a phase I, open-label, randomized, parallel-group study with two 12-month periods and a safety monitoring phase to 60 months. Methods: Of 29 screened participants, 24 were enrolled and randomized 2:1 to two 12 mg/day alemtuzumab treatments (60 and 36 mg total; SC:IV). Key inclusion criteria: ⩾18 years with a PMS diagnosis. Key exclusion criteria included RRMS diagnosis and prior treatment with anti-CD52 antibodies. Primary endpoint: CD3+ lymphocyte count. Secondary endpoints: PD and PK parameters. Results: Demographics were broadly similar for participants in the SC (16) and IV (8) arms; more participants with primary PMS received SC (44%) versus IV (25%) treatment. After the first course, the mean CD3+ cell count/µL was reduced at month 1 in both arms (SC: baseline (BL) 1326 to 48 vs IV: BL 1155 to 84). Lymphocyte counts partially repopulated by month 12, with mean CD3+ cell counts/µL of SC 599 versus IV 528. The mean lymphocyte counts/µL decreased again after the second course at month 13 in both arms (SC: 90 vs IV: 129), with partial repopulation by month 24. Alemtuzumab serum concentrations were lower following SC administration relative to IV, with 32% bioavailability. There were no adverse events leading to permanent treatment discontinuation or death. Conclusion: In SCALA, there were similar patterns of lymphocyte depletion and repopulation for participants receiving SC or IV alemtuzumab. In both arms, alemtuzumab had a manageable safety profile, with no emerging safety concerns. The general stabilization of neurological outcomes observed over 60 months underscores the potential long-term benefits of alemtuzumab treatment. Trial registration: Clinicaltrials.gov identifier: NCT02583594. [ABSTRACT FROM AUTHOR]

• Meningeal-based myeloid cell infiltrates mediate neurotoxicity in a chronic multiple sclerosis model. • Targeting compartmentalized neuroinflammation effectively chronic-progressive experimental autoimmune encephalomyelitis. • Selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury. Demyelination and axonal injury in chronic-progressive Multiple Sclerosis (MS) are presumed to be driven by a neurotoxic bystander effect of meningeal-based myeloid infiltrates. There is an unmet clinical need to attenuate disease progression in such forms of CNS-compartmentalized MS. The failure of systemic immune suppressive treatments has highlighted the need for neuroprotective and repair-inducing strategies. Here, we examined whether direct targeting of CNS myeloid cells and modulating their toxicity may prevent irreversible tissue injury in chronic immune-mediated demyelinating disease. To that end, we utilized the experimental autoimmune encephalomyelitis (EAE) model in Biozzi mice, a clinically relevant MS model. We continuously delivered intracerebroventricularly (ICV) a retinoic acid receptor alpha agonist (RARα), as a potent regulator of myeloid cells, in the chronic phase of EAE. We assessed disease severity and performed pathological evaluations, functional analyses of immune cells, and single-cell RNA sequencing on isolated spinal CD11b+ cells. Although initiating treatment in the chronic phase of the disease, the RARα agonist successfully improved clinical outcomes and prevented axonal loss. ICV RARα agonist treatment inhibited pro-inflammatory pathways and shifted CNS myeloid cells toward neuroprotective phenotypes without affecting peripheral infiltrating myeloid cell phenotypes, or peripheral immunity. The treatment regulated cell-death pathways across multiple myeloid cell populations and suppressed apoptosis, resulting in paradoxically marked increased neuroinflammatory infiltrates, consisting mainly of microglia and CNS / border-associated macrophages. This work establishes the notion of bystander neurotoxicity by CNS immune infiltrates in chronic demyelinating disease. Furthermore, it shows that targeting compartmentalized neuroinflammation by selective regulation of CNS myeloid cell toxicity and survival reduces irreversible tissue injury, and may serve as a novel disease-modifying approach. [ABSTRACT FROM AUTHOR]

It remains elusive whether lesions and inflammation in the sub/juxtacortical white matter reflect cortical and/or meningeal pathologies. Elucidating this could have implications for MRI monitoring as sub/juxtacortical lesions are detectable by routine MRI, while cortical lesions and meningeal inflammation are not. By large‐area microscopy, we quantified total and mixed active plaque loads along with densities and sizes of perivascular mononuclear infiltrates (infiltrates) in the sub/juxtacortical white matter ≤2 mm from the cortex, intra‐cortically and in the meninges. Data were related to ante‐mortem clinical parameters in a false discovery rate‐corrected analysis. We compared 12 patients with primary progressive multiple sclerosis (PPMS) and 15 with secondary progressive MS to 22 controls. Fifteen patients and 11 controls contributed with hemispheric sections. Sections were stained with haematoxylin–eosin, for myelin and for microglia/macrophages. B cells and T cells were confirmed in a subset. Immunoglobulin G depositions in selected cortical plaques resembled depositions described before in “slowly expanding” plaques in the white matter. We quantified plaque activity by measuring microglia‐dominated and macrophage‐dominated areas. Sub/juxtacortical plaques (load and activity) reflected plaque activity in the cerebral cortex. Plaque activity and infiltrates were more pronounced in the sub/juxtacortical white matter than in the cerebral cortex while conversely, the total plaque load was highest in the cortex. Infiltrates correlated trans‐cortically and sub/juxtacortical plaque activity reflected cortical and meningeal infiltrates. Sub/juxtacortical infiltrate sizes correlated with shorter survival after progression onset. Two patients with PPMS and putatively fatal brain stem lesions argue against incidental findings. Trans‐cortical inflammatory flares and plaque activity may be pathogenic in progressive MS. We suggest emphasis on sub/juxtacortical MRI lesions as plausible surrogates for cortical and meningeal pathologies and, when present, as indicators for cognitive testing. [ABSTRACT FROM AUTHOR]

Progressive multiple sclerosis (PMS) is an immune-initiated neurodegenerative condition that lacks effective therapies. Although peripheral immune infiltration is a hallmark of relapsing-remitting MS (RRMS), PMS is associated with chronic, tissue-restricted inflammation and disease-associated reactive glial states. The effector functions of disease-associated microglia, astrocytes, and oligodendrocyte lineage cells are beginning to be defined, and recent studies have made significant progress in uncovering their pathologic implications. In this review, we discuss the immune-glia interactions that underlie demyelination, failed remyelination, and neurodegeneration with a focus on PMS. We highlight the common and divergent immune mechanisms by which glial cells acquire disease-associated phenotypes. Finally, we discuss recent advances that have revealed promising novel therapeutic targets for the treatment of PMS and other neurodegenerative diseases. Progressive multiple sclerosis (PMS) is a neurodegenerative condition with chronic inflammation and glial cell pathology. In this review, Garton et al. discuss immune-glia interactions in PMS, highlighting potential therapeutic targets for PMS and other neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Background: Many individuals with progressive multiple sclerosis (PMS) are challenged by reduced manual dexterity and limited rehabilitation options. Transcranial direct current stimulation (tDCS) during motor training can improve rehabilitation outcomes. We developed a protocol for remotely supervising tDCS to deliver sessions of stimulation paired with training at home. Objective: This study evaluated the effectiveness of at-home tDCS paired with manual dexterity training for individuals with PMS. Methods: Sixty-five right-hand dominant participants with PMS and hand impairment were randomized to receive either active or sham M1-SO tDCS paired with manual dexterity training over 4 weeks. Clinical outcomes were measured by the changes in Nine-Hole Peg Test (9-HPT) and Dellon-Modified-Moberg-Pick-Up Test (DMMPUT). Results: The intervention had high rates of adherence and completion (98% of participants completed at least 18 of 20 sessions). The active tDCS group demonstrated significant improvement for the left hand compared with baseline in 9-HPT (−5.85 ± 6.19 vs −4.23 ± 4.34, p = 0.049) and DMMPUT (−10.62 ± 8.46 vs −8.97 ± 6.18, p = 0.049). The active tDCS group reported improvements in multiple sclerosis (MS)-related quality of life (mean increase: 5.93 ± 13.04 vs −0.05 ± −8.27; p = 0.04). Conclusion: At-home tDCS paired with manual dexterity training is effective for individuals with PMS, with M1-SO tDCS enhancing training outcomes and offering a promising intervention for improving and preserving hand dexterity. [ABSTRACT FROM AUTHOR]

Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8+ T cell memory population expressing the invariant Va7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP-or SP-MS), ALS and age-and sex-matched healthy controls revealed specific loss of circulating CD8+ MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS), a debilitating autoimmune disorder targeting the central nervous system (CNS), is marked by relentless demyelination and inflammation. Clinically, it presents in three distinct forms: relapsing–remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS). While disease-modifying therapies (DMTs) offer some relief to people with RRMS, treatment options for progressive MS (pMS) remain frustratingly inadequate. This gap highlights an urgent need for advanced disease modeling techniques to unravel the intricate pathology of pMS. Human induced pluripotent stem cell (iPSC) technologies and brain organoids are emerging as promising tools for disease modeling in both 2D and 3D in vitro environments. These innovative approaches enable the study of disease mechanisms that closely mimic human pathophysiology and offer new platforms for screening therapeutic compounds, surpassing the limitations of traditional animal models. However, deploying brain organoids in disease modeling presents challenges, especially in the context of non-monogenic disorders. This review delves into cutting-edge brain organoid techniques that hold the potential to revolutionize our understanding of pMS, offering a pathway to disentangle its underlying mechanisms and drive transformative discoveries.

Background: Mesenchymal stem cell-neural progenitors (MSC-NPs) are a bone marrow mesenchymal stem cell (MSC)-derived ex vivo manipulated cell product with therapeutic potential in multiple sclerosis (MS). The objective of this study was to determine efficacy of intrathecal (IT) MSC-NP treatment in patients with progressive MS. Methods: The study is a phase II randomized, double-blind, placebo-controlled clinical trial with a compassionate crossover design conducted at a single site. Subjects were stratified according to baseline Expanded Disability Status Scale (EDSS) (3.0-6.5) and disease subtype (secondary or primary progressive MS) and randomized into either treatment or placebo group to receive six IT injections of autologous MSC-NPs or saline every two months. The primary outcome was EDSS Plus, defined by improvement in EDSS, timed 25-foot walk (T25FW) or nine-hole peg test. Secondary outcomes included the individual components of EDSS Plus, the six-minute walk test (6MWT), urodynamics testing, and brain atrophy measurement. Results: Subjects were randomized into MSC-NP (n = 27) or saline (n = 27) groups. There was no difference in EDSS Plus improvement between the MSC-NP (33%) and saline (37%) groups. Exploratory subgroup analysis demonstrated that in subjects who require assistance for ambulation (EDSS 6.0-6.5) there was a significantly higher percentage of improvement in T25FW and 6MWT in the MSC-NP group (3.7% ± 23.1% and − 9.2% ± 18.2%) compared to the saline group (-54.4% ± 70.5% and − 32.1% ± 30.0%), (p = 0.030 and p = 0.036, respectively). IT-MSC-NP treatment was also associated with improved bladder function and reduced rate of grey matter atrophy on brain MRI. Biomarker analysis demonstrated increased MMP9 and decreased CCL2 levels in the cerebrospinal fluid following treatment. Conclusion: Results from exploratory outcomes suggest that IT-MSC-NP treatment may be associated with a therapeutic response in a subgroup of MS patients. Trial Registration: ClinicalTrials.gov NCT03355365, registered November 14, 2017, https://clinicaltrials.gov/study/NCT03355365?term=NCT03355365&rank=1. [ABSTRACT FROM AUTHOR]

Introduction. The Symbol Digit Modalities Test (SDMT) is a highly sensitive neuropsychological tool used for the assessment of information processing speed (IPS) in various neurological disorders. State of the art. In this review, we have focused on the current knowledge regarding the use of SDMT selectively in the evaluation of progressive multiple sclerosis (PMS) patients. A literature review was performed regarding the application of SDMT in PMS, with a focus on the primary progressive and secondary progressive subtypes. Relationships of diverse disease-associated factors with SDMT have been described, including disease course, imaging findings, molecular biomarkers, treatment and others. Clinical implications. SDMT is a very useful and easily applicable instrument in the diagnostic armamentarium of neurologists and neuropsychologists. It is especially valuable in the evaluation of PMS patients, in whom the prevalence of IPS deficits is higher than in relapsing-remitting multiple sclerosis subjects or in healthy individuals. Future directions. An emphasis should be laid on larger study groups and differentiating between individual PMS subtypes and their separate analysis in the context of cognitive assessment. [ABSTRACT FROM AUTHOR]

Introduction: Despite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive multiple sclerosis (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers of disability progression that are insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing of metformin for treatment of PMS. The objective of this clinical trial is to evaluate whether metformin, as addon treatment, is superior to placebo in delaying disease progression in patients with non-active PMS. Methods and analysis: MACSiMiSE-BRAIN is a multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled clinical trial, conducted at five sites in Belgium. Enrollment of 120 patients with non-active PMS is planned. Each participant will undergo a screening visit with assessment of baseline magnetic resonance imaging (MRI), clinical tests, questionnaires, and a safety laboratory assessment. Following randomization, participants will be assigned to either the treatment (metformin) or placebo group. Subsequently, they will undergo a 96-week follow-up period. The primary outcome is change in walking speed, as measured by the Timed 25-Foot Walk Test, from baseline to 96 weeks. Secondary outcome measures include change in neurological disability (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) and hand function (9-Hole Peg test). Annual brain MRI will be performed to assess evolution in brain volumetry and diffusion metrics. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score will be additionally evaluated as an exploratory outcome. Other exploratory outcomes will consist of paramagnetic rim lesions, the 2-minute walking test and health economic analyses as well as both patient- and caregiver-reported outcomes like the EQ-5D-5L, the Multiple Sclerosis Impact Scale and the Caregiver Strain Index. Ethics and dissemination: Clinical trial authorization from regulatory agencies [Ethical Committee and Federal Agency for Medicines and Health Products (FAMHP)] was obtained after submission to the centralized European Clinical Trial Information System. The results of this clinical trial will be disseminated at scientific conferences, in peer-reviewed publications, to patient associations and the general public. [ABSTRACT FROM AUTHOR]

BACKGROUND: The relationship between dietary modification and Multiple Sclerosis (MS)-related disability has been emphasized in several researches. AIMS: To determine whether a co-administration of anti-inflammatory-antioxidant rich diet and synbiotics might improve clinical manifestations in progressive MS patients. METHODS: The study involved 70 patients with progressive MS (primary-progressive, secondary-progressive, and progressive-relapsing) who were randomized to receive either intervention (synbiotics capsule plus an anti-inflammatory-antioxidant-rich diet) or placebo. Quality of Life (QOL), Expanded Disability Status Scale (EDSS), and depression-anxiety scores were evaluated before and after the follow-up. Analysis of covariance was performed for final analysis (SPSS v.14). RESULTS: Significant reductions were seen in EDSS (2.6±1.1 to 2.4±1.0, P < 0.001), State Anxiety Inventory (53.7±10.3 to 47.8±10.6, P < 0.001), and QOL scores after four months of intervention. No significant difference was seen across the depression severity (Δ for intervention = –2.2±5.5 vs. Δ for control = –0.6±5.7; P = 0.264). CONCLUSION: This study demonstrates that a combination of synbiotics and diet could be a promising strategy to improve severity and clinical manifestations of progressive MS. [ABSTRACT FROM AUTHOR]

Background: Ibudilast has shown beneficial effects on several imaging outcomes in progressive multiple sclerosis (MS). Slowly enlarging lesions are a proposed imaging biomarker of compartmentalized inflammation within chronic active lesions. Objective: To assess the treatment effect of ibudilast on slowly enlarging lesion volumes over 96 weeks from a phase II clinical trial of ibudilast (Secondary and Primary Progressive Ibudilast NeuroNEXT Trial in Multiple Sclerosis [SPRINT-MS]). Methods: In total, 255 participants with progressive MS from 28 sites were randomized to oral ibudilast or placebo. Participants with at least four analyzable magnetic resonance imaging (MRI) were included. Slowly enlarging lesions were quantified using Jacobian determinant maps. A linear model was used to assess the effect of ibudilast. Magnetization transfer ratio within slowly enlarging lesions was assessed to determine the effect of ibudilast on tissue integrity. Results: In total, 195 participants were included in this analysis. Ibudilast significantly decreased slowly enlarging lesion volume (23%, p = 0.003). Ibudilast also reduced magnetization transfer ratio change in slowly enlarging lesions: 0.22%/year, p = 0.04. Conclusion: Ibudilast showed a significant effect on baseline volume of lesions that were slowly enlarging and magnetization transfer ratio in slowly enlarging lesions. The results support the use of slowly enlarging lesions for assessment of compartmentalized inflammation represented by chronic active lesions and provide further support for the neuroprotective effects of ibudilast in progressive MS. [ABSTRACT FROM AUTHOR]

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing–remitting MS (RRMS), PMS has been poorly investigated in this context. Male (n = 50) and female (n = 46) Dark Agouti rats received either VD (400 IU per week; VD+) or standard rodent food without extra VD (VD−) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems. [ABSTRACT FROM AUTHOR]

Neurological disorders, including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS), may be associated with alterations in blood cell composition and phenotype. Here, we focused our attention on circulating mucosal-associated invariant T (MAIT) cells, a CD8+ T cell memory population expressing the invariant Vα7.2 region in the T cell receptor and high surface levels of the CD161 marker. Transcriptomics data relative to peripheral blood mononuclear cells (PBMC) highlighted downregulation of CD161 and other MAIT-associated markers in progressive MS and not relapsing remitting (RR)-MS when gene expressions relative to each disease course were compared to those from healthy controls. Multiparametric flow cytometry of freshly isolated PBMC samples from untreated RR-MS, primary or secondary progressive MS (PP- or SP-MS), ALS and age- and sex-matched healthy controls revealed specific loss of circulating CD8+ MAIT cells in PP-MS and no other MS courses or another neurological disorder such as ALS. Overall, these observations point to the existence of immunological changes in blood specific for the primary progressive course of MS that may support clinical definition of disease.

Objective. To study possible clinical markers associated with the unfavorable course of multiple sclerosis and its transition to a progressive subtype. Materials and methods. This prospective study included healthy volunteers and patients with relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS). For a comprehensive clinical evaluation, the participants completed the Timed 25-Foot Walk Test (T25-FW), Nine-Hole Peg Test (9-HPT), Symbol Digit Modalities Test (SDMT), Fatigue test, and MSProDiscuss questionnaires. Then we compared the results between the groups. Results. We found significant differences between the groups in regard to most of the tests. Furthermore, we proposed a composite clinical score (CCS) based on T25-FW, SDMT, and 9-HPT results (for both hands). Discussion. Our CCS can be a useful clinical tool to determine the most likely course of multiple sclerosis at a certain timepoint.

IntroductionDespite advances in immunomodulatory treatments of multiple sclerosis (MS), patients with non-active progressive multiple sclerosis (PMS) continue to face a significant unmet need. Demyelination, smoldering inflammation and neurodegeneration are important drivers of disability progression that are insufficiently targeted by current treatment approaches. Promising preclinical data support repurposing of metformin for treatment of PMS. The objective of this clinical trial is to evaluate whether metformin, as add-on treatment, is superior to placebo in delaying disease progression in patients with non-active PMS.Methods and analysisMACSiMiSE-BRAIN is a multi-center two-arm, 1:1 randomized, triple-blind, placebo-controlled clinical trial, conducted at five sites in Belgium. Enrollment of 120 patients with non-active PMS is planned. Each participant will undergo a screening visit with assessment of baseline magnetic resonance imaging (MRI), clinical tests, questionnaires, and a safety laboratory assessment. Following randomization, participants will be assigned to either the treatment (metformin) or placebo group. Subsequently, they will undergo a 96-week follow-up period. The primary outcome is change in walking speed, as measured by the Timed 25-Foot Walk Test, from baseline to 96 weeks. Secondary outcome measures include change in neurological disability (Expanded Disability Status Score), information processing speed (Symbol Digit Modalities Test) and hand function (9-Hole Peg test). Annual brain MRI will be performed to assess evolution in brain volumetry and diffusion metrics. As patients may not progress in all domains, a composite outcome, the Overall Disability Response Score will be additionally evaluated as an exploratory outcome. Other exploratory outcomes will consist of paramagnetic rim lesions, the 2-minute walking test and health economic analyses as well as both patient- and caregiver-reported outcomes like the EQ-5D-5L, the Multiple Sclerosis Impact Scale and the Caregiver Strain Index.Ethics and disseminationClinical trial authorization from regulatory agencies [Ethical Committee and Federal Agency for Medicines and Health Products (FAMHP)] was obtained after submission to the centralized European Clinical Trial Information System. The results of this clinical trial will be disseminated at scientific conferences, in peer-reviewed publications, to patient associations and the general public.Trial registrationClinicalTrials.gov Identifier: NCT05893225, EUCT number: 2023-503190-38-00.

Background: Macrophage migration inhibitory factor (MIF) is a cytokine linked to multiple sclerosis (MS) progression that is thought to be inhibited by ibudilast. SPRINT-MS was a phase 2 placebo-controlled trial of ibudilast in progressive multiple sclerosis (PMS). Objective: To determine whether baseline MIF levels predict imaging outcomes and assess the effects of ibudilast on serum and cerebrospinal fluid (CSF) MIF levels in people with PMS treated with ibudilast. Methods: Participants in the SPRINT-MS trial were treated with either ibudilast or placebo and underwent brain magnetic resonance imaging (MRI) every 24 weeks over a duration of 96 weeks. MIF was measured in serum and CSF. Results: MIF levels were compared with imaging outcomes in 223 participants from the SPRINT-MS study. In the primary progressive multiple sclerosis (PPMS) cohort, males had higher serum (p < 0.001) and CSF (p = 0.01) MIF levels, as compared with females. Higher baseline serum MIF levels in PPMS were associated with faster brain atrophy (beta = −0.113%, 95% confidence interval (CI): −0.204% to −0.021%; p = 0.016). These findings were not observed in secondary progressive multiple sclerosis (SPMS). Ibudilast did not affect either serum or CSF MIF levels. Conclusions: Serum MIF levels were associated with male sex and predicted brain atrophy in PPMS, but not SPMS. Ibudilast did not demonstrate an effect on MIF levels, as compared with placebo, although we cannot exclude a functional effect. [ABSTRACT FROM AUTHOR]

• Gasdermin D (GSDMD) activation occurs in oligodendrocytes and CNS macrophages. • GDSMD and Ninjurin 1 are induced in neuroinflammatory demyelination. • GSDMD genetic deletion reduces neuroinflammatory demyelination and axonal injury. • GSDMD activation represents a potential therapeutic target for progressive MS. Neuroinflammation coupled with demyelination and neuro-axonal damage in the central nervous system (CNS) contribute to disease advancement in progressive multiple sclerosis (P-MS). Inflammasome activation accompanied by proteolytic cleavage of gasdermin D (GSDMD) results in cellular hyperactivation and lytic death. Using multiple experimental platforms, we investigated the actions of GSDMD within the CNS and its contributions to P-MS. Brain tissues from persons with P-MS showed significantly increased expression of GSDMD, NINJ1, IL-1β, and −18 within chronic active demyelinating lesions compared to MS normal appearing white matter and nonMS (control) white matter. Conditioned media (CM) from stimulated GSDMD+/+ human macrophages caused significantly greater cytotoxicity of oligodendroglial and neuronal cells, compared to CM from GSDMD-/- macrophages. Oligodendrocytes and CNS macrophages displayed increased Gsdmd immunoreactivity in the central corpus callosum (CCC) of cuprizone (CPZ)-exposed Gsdmd+/+ mice, associated with greater demyelination and reduced oligodendrocyte precursor cell proliferation, compared to CPZ-exposed Gsdmd-/- animals. CPZ-exposed Gsdmd+/+ mice exhibited significantly increased G-ratios and reduced axonal densities in the CCC compared to CPZ-exposed Gsdmd-/- mice. Proteomic analyses revealed increased brain complement C1q proteins and hexokinases in CPZ-exposed Gsdmd-/- animals. [18F]FDG PET imaging showed increased glucose metabolism in the hippocampus and whole brain with intact neurobehavioral performance in Gsdmd-/- animals after CPZ exposure. GSDMD activation in CNS macrophages and oligodendrocytes contributes to inflammatory demyelination and neuroaxonal injury, offering mechanistic and potential therapeutic insights into P-MS pathogenesis. [ABSTRACT FROM AUTHOR]

Recent terminological and conceptual refinements in the description of progression in multiple sclerosis (MS) help to distinguish between pathogenetic factors that have to be addressed with different therapeutic approaches. Inflammation and neurodegeneration occur in all disease stages of MS. Generalized CNS disease in MS is the foundation of progression independent of relapse activity (PIRA). Enhanced exposition of neurons to detrimental factors, their increased vulnerability, and a permanent loss of protective barriers and buffer mechanisms promote neurodegeneration in MS. Astrocytes and microglia are drivers of self-perpetuating neurodegeneration in MS. Future therapies of progressive MS should aim to combine anti-inflammatory and neuroprotective therapeutic strategies. A major therapeutic goal in the treatment of multiple sclerosis (MS) is to prevent the accumulation of disability over an often decades-long disease course. Disability progression can result from acute relapses as well as from CNS intrinsic parenchymal disintegration without de novo CNS lesion formation. Research focus has shifted to progression not associated with acute inflammation, as it is not sufficiently controlled by currently available treatments. This review outlines how recent advances in the understanding of the pathogenesis of progressive MS have been facilitated by the development of more precise, less static pathogenetic concepts of progressive MS, as well as by new techniques for the analysis of region-specific proteomic and transcriptomic signatures in the human CNS. We highlight key drivers of MS disease progression and potential targets in its treatment. [ABSTRACT FROM AUTHOR]

Background: Leptomeningeal enhancement (LME) has been described as a biomarker of meningeal inflammation in multiple sclerosis (MS). Objective: The aim of this study was to (1) assess if LME is predictive of disability worsening in progressive MS (pMS) patients and (2) investigate the pathological substrates of LME in an independent post-mortem MS series. Methods: In total, 115 pMS patients were imaged yearly with 1.5T MRI, using post-contrast CUBE 3D FLAIR for LME detection. Endpoint: to identify the baseline variables predictive of confirmed disability worsening (CDW) at 24 months follow-up. Post-mortem, inflammation, and structural changes of the leptomeninges were assessed in 12 MS/8 control brains. Results: LME (27% of patients at baseline) was associated with higher EDSS and lower brain volume (nBV). LME was unchanged in most patients over follow-up. LME at baseline MRI was independently associated with higher risk of 24 months CDW (HR 3.05, 95% CI 1.36–6.84, p = 0.007) in a Cox regression, including age, nBV, T2 lesion volume, high-efficacy treatments, and MRI disease activity. Post-mortem, focal structural changes (fibrosis) of the leptomeninges were observed in MS, usually associated with inflammation (Kendall's Tau 0.315, p < 0.0001). Conclusions: LME is frequently detected in pMS patients using 1.5T MRI and is independently predictive of disability progression. LME could result from both focal leptomeningeal post-inflammatory fibrosis and inflammation. [ABSTRACT FROM AUTHOR]

Current evidence has demonstrated that patients with Multiple Sclerosis (MS) have dysbiotic gut microbiomes, and anti-inflammatory nutritional interventions can normalize this status. Therefore, we aimed to investigate the effects of dietary intervention in patients with progressive forms of MS. Seventy patients with three forms of progressive MS (primary-progressive, secondary-progressive, and progressive-relapsing) were randomly assigned into intervention (daily synbiotics capsule plus anti-inflammatory-antioxidant rich diet) or control (placebo capsule plus dietary recommendations) groups for four months. Faecal calprotectin level, Impact of Vision Impairment (IVI), Gastrointestinal Symptom Rating Scale (GSRS), and anthropometric measurements were evaluated at baseline and trial cessation. Analysis of covariance was conducted and adjusted for age, gender, education level, family history & duration of MS, type of progressive MS, type of main drug, and physical activity. Sixty-nine participants were included in the final analysis (n of intervention = 34; n of control = 35). Synbiotics and dietary intervention significantly reduced Faecal calprotectin level after six months (110.5 ± 75.9–44.7 ± 49.3 ɥg/g, P < 0.001), and mean changes were statistically significant in comparison with control group. However, intervention did not elicit any change in the anthropometric measurements. Synbiotics supplementation and adherence to an anti-inflammatory-antioxidant-rich diet reduced intestinal inflammation and improved clinical manifestations in progressive forms of MS. Trial registration: Iranian Registry of Clinical Trials identifier: IRCT20141108019853N7.. [ABSTRACT FROM AUTHOR]

BackgroundIn multiple sclerosis, impact of treatment on disability progression can be confounded if treatment also reduces relapses.ObjectiveTo distinguish siponimod's direct effects on disability progression from those on relapses in the EXPAND phase 3 trial.MethodsThree estimands, one based on principal stratum and two on hypothetical scenarios (no relapses, or equal relapses in both treatment arms), were defined to determine the extent to which siponimod's effects on 3- and 6-month confirmed disability progression were independent of on-study relapses.ResultsPrincipal stratum analysis estimated that siponimod reduced the risk of 3- and 6-month confirmed disability progression by 14%-20% and 29%-33%, respectively, compared with placebo in non-relapsing patients. In the hypothetical scenarios, risk reductions independent of relapses were 14%-18% and 23% for 3- and 6-month confirmed disability progression, respectively.ConclusionBy controlling the confounding impact of on-study relapses on confirmed disability progression, these statistical approaches provide a methodological framework to assess treatment effects on disability progression in relapsing and non-relapsing patients. The analyses support that siponimod may be useful for treating secondary progressive multiple sclerosis in patients with or without relapses.

Background and Objectives: The current clinical course descriptors of multiple sclerosis (MS) include a combination of clinical and magnetic resonance imaging (MRI) features. Recently there has been a growing call to base these descriptors more firmly on biological mechanisms. We investigated the implications of proposing a new mechanism-driven framework for describing MS. Methods: In a web-based survey, multiple stakeholders rated the need to change current MS clinical course descriptors, the definitions of disease course and their value in clinical practice and related topics. Results: We received 502 responses across 49 countries. In all, 77% of the survey respondents supported changing the current MS clinical course descriptors. They preferred a framework that informs treatment decisions, aids the design and conduct of clinical trials, allows patients to understand their disease, and links disease mechanisms and clinical expression of disease. Clinical validation before dissemination and ease of communication to patients were rated as the most important aspects to consider when developing any new framework for describing MS. Conclusion: A majority of MS stakeholders agreed that the current MS clinical course descriptors need to change. Any change process will need to engage a wide range of affected stakeholders and be guided by foundational principles. [ABSTRACT FROM AUTHOR]

Background: Thalamic volume (TV) is a sensitive biomarker of disease burden of injury in multiple sclerosis (MS) and appears to reflect overall lesion loads. Ibudilast showed significant treatment effect on brain atrophy and magnetization transfer ratio (MTR) of normal-appearing brain tissue but not in new/enlarging T2 lesion in the SPRINT-MS randomized clinical trial. Objective: To evaluate the effect of ibudilast on thalamic tissue integrity and volume in the SPRINT-MS. Methods: A total of 255 participants with progressive MS were randomized to oral ibudilast or placebo, and thalamic MTR and normalized TV over 96 weeks were quantified. Mixed-effect modeling assessed treatment effects on the thalamic MTR and TV, separately. Similarly, the measures were compared between the participants with confirmed disability progression (CDP). Results: Ibudilast's treatment effect was observed compared to placebo for thalamic MTR (p = 0.03) but not for TV (p = 0.68) while TV correlated with T2 lesion volume (p < 0.001). CDP associated with thalamic MTR (p = 0.04) but not with TV (p = 0.7). Conclusion: Ibudilast showed an effect on thalamic MTR, which was associated with CDP, suggesting a clinically relevant effect on thalamic tissue integrity. However, the treatment effect was not observed in TV, suggesting that thalamic atrophy is more closely associated with global inflammatory activity than local tissue integrity. ClinicalTrials.gov: NCT01982942 [ABSTRACT FROM AUTHOR]

Background and purpose: There is increasing evidence that cardiovascular risk (CVR) contributes to disability progression in multiple sclerosis (MS). CVR is particularly prevalent in secondary progressive MS (SPMS) and can be quantified through validated composite CVR scores. The aim was to examine the cross‐sectional relationships between excess modifiable CVR, whole and regional brain atrophy on magnetic resonance imaging, and disability in patients with SPMS. Methods: Participants had SPMS, and data were collected at enrolment into the MS‐STAT2 trial. Composite CVR scores were calculated using the QRISK3 software. Prematurely achieved CVR due to modifiable risk factors was expressed as QRISK3 premature CVR, derived through reference to the normative QRISK3 dataset and expressed in years. Associations were determined with multiple linear regressions. Results: For the 218 participants, mean age was 54 years and median Expanded Disability Status Scale was 6.0. Each additional year of prematurely achieved CVR was associated with a 2.7 mL (beta coefficient; 95% confidence interval 0.8–4.7; p = 0.006) smaller normalized whole brain volume. The strongest relationship was seen for the cortical grey matter (beta coefficient 1.6 mL per year; 95% confidence interval 0.5–2.7; p = 0.003), and associations were also found with poorer verbal working memory performance. Body mass index demonstrated the strongest relationships with normalized brain volumes, whilst serum lipid ratios demonstrated strong relationships with verbal and visuospatial working memory performance. Conclusions: Prematurely achieved CVR is associated with lower normalized brain volumes in SPMS. Future longitudinal analyses of this clinical trial dataset will be important to determine whether CVR predicts future disease worsening. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system (CNS), characterized by demyelination and neurodegeneration. Oligodendrocytes play a vital role in maintaining the integrity of myelin, the protective sheath around nerve fibres essential for efficient signal transmission. However, in MS, oligodendrocytes become dysfunctional, leading to myelin damage and axonal degeneration. Emerging evidence suggests that metabolic changes, including mitochondrial dysfunction and alterations in glucose and lipid metabolism, contribute significantly to the pathogenesis of MS. Mitochondrial dysfunction is observed in both immune cells and oligodendrocytes within the CNS of MS patients. Impaired mitochondrial function leads to energy deficits, affecting crucial processes such as impulse transmission and axonal transport, ultimately contributing to neurodegeneration. Moreover, mitochondrial dysfunction is linked to the generation of reactive oxygen species (ROS), exacerbating myelin damage and inflammation. Altered glucose metabolism affects the energy supply required for oligodendrocyte function and myelin synthesis. Dysregulated lipid metabolism results in changes to the composition of myelin, affecting its stability and integrity. Importantly, low levels of polyunsaturated fatty acids in MS are associated with upregulated lipid metabolism and enhanced glucose catabolism. Understanding the intricate relationship between these mechanisms is crucial for developing targeted therapies to preserve myelin and promote neurological recovery in individuals with MS. Addressing these metabolic aspects may offer new insights into potential therapeutic strategies to halt disease progression and improve the quality of life for MS patients. [ABSTRACT FROM AUTHOR]

Vitamin D (VD) is the most discussed antioxidant supplement for multiple sclerosis (MS) patients and many studies suggest correlations between a low VD serum level and onset and progression of the disease. While many studies in animals as well as clinical studies focused on the role of VD in the relapsing-remitting MS, knowledge is rather sparse for the progressive phase of the disease and the development of cortical pathology. In this study, we used our established rat model of cortical inflammatory demyelination, resembling features seen in late progressive MS, to address the question about whether VD could have positive effects on reducing cortical pathology, oxidative stress, and neurofilament light chain (NfL) serum levels. For this purpose, we used male Dark Agouti (DA) rats, with one group being supplemented with VD (400 IE per week; VD+) from the weaning on at age three weeks; the other group received standard rodent food. The rat brains were assessed using immunohistochemical markers against demyelination, microglial activation, apoptosis, neurons, neurofilament, and reactive astrocytes. To evaluate the effect of VD on oxidative stress and the antioxidant capacity, we used two different oxidized lipid markers (anti- Cu++ and HOCl oxidized LDL antibodies) along with colorimetric methods for protective polyphenols (PP) and total antioxidative capacity (TAC). NfL serum levels of VD+ and VD− animals were analyzed by fourth generation single-molecule array (SIMOA) analysis. We found significant differences between the VD+ and VD− animals both in histopathology as well as in all serum markers. Myelin loss and microglial activation is lower in VD+ animals and the number of apoptotic cells is significantly reduced with a higher neuronal survival. VD+ animals show significantly lower NfL serum levels, a higher TAC, and more PP. Additionally, there is a significant reduction of oxidized lipid markers in animals under VD supplementation. Our data thus show a positive effect of VD on cellular features of cortical pathology in our animal model, presumably due to protection against reactive oxygen species. In this study, VD enhanced remyelination and prevented neuroaxonal and oxidative damage, such as demyelination and neurodegeneration. However, more studies on VD dose relations are required to establish an optimal response while avoiding overdosing. [ABSTRACT FROM AUTHOR]

Background and objectives: In progressive multiple sclerosis (MS) patients, CNS inflammation trapped behind a closed blood brain barrier drives continuous neuroaxonal degeneration, thus leading to deterioration of neurological function. Therapeutics in progressive MS are limited. High-dose intravenous glucocorticosteroids (HDCS) can cross the blood-brain barrier and may reduce inflammation within the CNS. However, the treatment efficacy of HDCS in progressive MS remains controversial. Serum neurofilament light chains (sNfL) are an established biomarker of neuroaxonal degeneration and are used to monitor treatment responses. We aimed to investigate whether repeated cycles of intravenous HDCS reduce the level of sNfL in progressive MS patients. Methods: We performed a monocentric observational study of 25 patients recruited during ongoing clinical routine care who were treated with repeated cycles of intravenous HDCS as long-term therapy for their progressive MS. sNfL were measured in 103 repeated blood samples (median time interval from baseline 28 weeks, range 2-55 weeks) with the Single Molecular Array (SiMoA) technology. The Expanded Disability Status Score (EDSS) was documented at baseline and follow-up. Results: The median age of patients was 55 years (range 46-77 years) with a median disease duration of 26 years (range 11-42 years). sNfL baseline levels at study inclusion were significantly higher in progressive MS patients compared to age-matched healthy controls (median 16.7 pg/ml vs 11.5 pg/ml, p=0.002). sNfL levels showed a positive correlation with patient age (r=0.2, p=0.003). The majority of patients (72%, 16/23) showed reduced sNfL levels ≥20 weeks after HDCS compared to baseline (median 13.3 pg/ml, p=0.03). sNfL levels correlated negatively with the time interval from baseline HDCS therapy (r=-0.2, p=0.03). This association was also evident after correction for treatment with disease-modifying drugs (adjusted R2=0.10, p=0.001). The EDSS remained stable (median 6.5) within a median treatment duration of 26 weeks (range 13-51 weeks). Conclusion: Although larger studies are needed to confirm our findings, we were able to demonstrate that HDCS treatment reduces sNfL levels and therefore may slow down neuroaxonal damage in a subgroup of patients with progressive MS. Moreover, a stable EDSS was observed during therapy. Findings suggest that HDCS may be beneficial for the treatment of progressive MS.

Multiple sclerosis (MS) can progress with neurodegeneration as a consequence of chronic inflammatory mechanisms that drive neural cell loss and/or neuroaxonal dystrophy in the central nervous system. Immune-mediated mechanisms can accumulate myelin debris in the disease extracellular milieu during chronicactive demyelination that can limit neurorepair/plasticity and experimental evidence suggests that potentiated removal of myelin debris can promote neurorepair in models of MS. The myelin-associated inhibitory factors (MAIFs) are integral contributors to neurodegenerative processes in models of trauma and experimental MS-like disease that can be targeted to promote neurorepair. This review highlights the molecular and cellular mechanisms that drive neurodegeneration as a consequence of chronic-active inflammation and outlines plausible therapeutic approaches to antagonize the MAIFs during the evolution of neuroinflammatory lesions. Moreover, investigative lines for translation of targeted therapies against these myelin inhibitors are defined with an emphasis on the chief MAIF, Nogo-A, that may demonstrate clinical efficacy of neurorepair during progressive MS. [ABSTRACT FROM AUTHOR]

Introduction: Rituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS. Patients and methods: Observational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS. Results: A total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5-27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy). Conclusion: Rituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment. [ABSTRACT FROM AUTHOR]

BACKGROUND:Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS). OBJECTIVE:To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations. METHODS:We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients. RESULTS:Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p

Multiple sclerosis (MS) can progress with neurodegeneration as a consequence of chronic inflammatory mechanisms that drive neural cell loss and/or neuroaxonal dystrophy in the central nervous system. Immune-mediated mechanisms can accumulate myelin debris in the disease extracellular milieu during chronic-active demyelination that can limit neurorepair/plasticity and experimental evidence suggests that potentiated removal of myelin debris can promote neurorepair in models of MS. The myelin-associated inhibitory factors (MAIFs) are integral contributors to neurodegenerative processes in models of trauma and experimental MS-like disease that can be targeted to promote neurorepair. This review highlights the molecular and cellular mechanisms that drive neurodegeneration as a consequence of chronic-active inflammation and outlines plausible therapeutic approaches to antagonize the MAIFs during the evolution of neuroinflammatory lesions. Moreover, investigative lines for translation of targeted therapies against these myelin inhibitors are defined with an emphasis on the chief MAIF, Nogo-A, that may demonstrate clinical efficacy of neurorepair during progressive MS.

BackgroundCognitive dysfunction and brain atrophy are both common in progressive multiple sclerosis (MS) but are seldom examined comprehensively in clinical trials. Antioxidant treatment may affect the neurodegeneration characteristic of progressive MS and slow its symptomatic and radiographic correlates.ObjectivesThis study aims to evaluate cross-sectional associations between cognitive battery components of the Brief International Cognitive Assessment for Multiple Sclerosis with whole and segmented brain volumes and to determine if associations differ between secondary progressive (SPMS) and primary progressive (PPMS) MS subtypes.DesignThe study was based on a baseline analysis from a multi-site randomized controlled trial of the antioxidant lipoic acid in veterans and other people with progressive MS (NCT03161028).MethodsCognitive batteries were conducted by trained research personnel. MRIs were processed at a central processing site for maximum harmonization. Semi-partial Pearson's adjustments evaluated associations between cognitive tests and MRI volumes. Regression analyses evaluated differences in association patterns between SPMS and PPMS cohorts.ResultsOf the 114 participants, 70% had SPMS. Veterans with MS made up 26% (n = 30) of the total sample and 73% had SPMS. Participants had a mean age of 59.2 and sd 8.5 years, and 54% of them were women, had a disease duration of 22.4 (sd 11.3) years, and had a median Expanded Disability Status Scale of 6.0 (with an interquartile range of 4.0–6.0, moderate disability). The Symbol Digit Modalities Test (processing speed) correlated with whole brain volume (R = 0.29, p = 0.01) and total white matter volume (R = 0.33, p < 0.01). Both the California Verbal Learning Test (verbal memory) and Brief Visuospatial Memory Test-Revised (visual memory) correlated with mean cortical thickness (R = 0.27, p = 0.02 and R = 0.35, p < 0.01, respectively). Correlation patterns were similar in subgroup analyses.ConclusionBrain volumes showed differing patterns of correlation across cognitive tasks in progressive MS. Similar results between SPMS and PPMS cohorts suggest combining progressive MS subtypes in studies involving cognition and brain atrophy in these populations. Longitudinal assessment will determine the therapeutic effects of lipoic acid on cognitive tasks, brain atrophy, and their associations.

In addition to disease-associated microglia (DAM), microglia with MHC-II and/or IFN-I signatures may form additional pathogenic subsets that are relevant to neurodegeneration. However, the significance of such MHC-II and IFN-I signatures remains elusive. We demonstrate here that these microglial subsets play intrinsic roles in orchestrating neurotoxic properties of neurotoxic Eomes+ Th cells under the neurodegeneration-associated phase of experimental autoimmune encephalomyelitis (EAE) that corresponds to progressive multiple sclerosis (MS). Microglia acquire IFN-signature after sensing ectopically expressed long interspersed nuclear element-1 (L1) gene. Furthermore, ORF1, an L1-encoded protein aberrantly expressed in the diseased central nervous system (CNS), stimulated Eomes+ Th cells after Trem2-dependent ingestion and presentation in MHC-II context by microglia. Interestingly, administration of an L1 inhibitor significantly ameliorated neurodegenerative symptoms of EAE concomitant with reduced accumulation of Eomes+ Th cells in the CNS. Collectively, our data highlight a critical contribution of new microglia subsets as a neuroinflammatory hub in immune-mediated neurodegeneration. [ABSTRACT FROM AUTHOR]

Background: Glatiramer acetate (GA) is a well-established treatment option for patients with clinically isolated syndrome and relapsing–remitting multiple sclerosis (MS) with few side effects. The double transgenic mouse model spontaneous opticospinal encephalomyelitis (OSE), based on recombinant myelin oligodendrocyte glycoprotein35-55 reactive T and B cells, mimicks features of chronic inflammation and degeneration in MS and related disorders. Here, we investigated the effects of prophylactic GA treatment on the clinical course, histological alterations and peripheral immune cells in OSE. Objective: To investigate the effects of prophylactic glatiramer acetate (GA) treatment in a mouse model of spontaneous opticospinal encephalomyelitis (OSE). Methods: OSE mice with a postnatal age of 21 to 28 days without signs of encephalomyelitis were treated once daily either with 150 µg GA or vehicle intraperitoneally (i. p.). The animals were scored daily regarding clinical signs and weight. The animals were sacrificed after 30 days of treatment or after having reached a score of 7.0 due to animal care guidelines. We performed immunohistochemistry of spinal cord sections and flow cytometry analysis of immune cells. Results: Preventive treatment with 150 µg GA i. p. once daily significantly reduced clinical disease progression with a mean score of 3.9 ± 1.0 compared to 6.2 ± 0.7 in control animals (p < 0.01) after 30 d in accordance with positive effects on weight (p < 0.001). The immunohistochemistry showed that general inflammation, demyelination or CD11c+ dendritic cell infiltration did not differ. There was, however, a modest reduction of the Iba1+ area (p < 0.05) and F4/80+ area upon GA treatment (p < 0.05). The immune cell composition of secondary lymphoid organs showed a trend towards an upregulation of regulatory T cells, which lacked significance. Conclusions: Preventive treatment with GA reduces disease progression in OSE in line with modest effects on microglia/macrophages. Due to the lack of established prophylactic treatment options for chronic autoimmune diseases with a high risk of disability, our study could provide valuable indications for translational medicine. [ABSTRACT FROM AUTHOR]

IntroductionRituximab (RTX) is considered a potential therapeutic option for relapsing-remitting (RRMS) and progressive forms (PMS) of multiple sclerosis (MS). The main objective of this work was to investigate the effectiveness and safety of rituximab in MS.Patients and methodsObservational multicenter study of clinical and radiological effectiveness and safety of rituximab in RRMS and PMS.ResultsA total of 479 rituximab-treated patients were included in 12 Spanish centers, 188 RRMS (39.3%) and 291 (60.7%) PMS. Despite standard treatment, the annualized relapse rate (ARR) the year before RTX was 0.63 (SD: 0.8) and 156 patients (41%) had at least one gadolinium-enhanced lesion (GEL) on baseline MRI. Mean EDSS had increased from 4.3 (SD: 1.9) to 4.8 (SD: 1.7) and almost half of the patients (41%) had worsened at least one point. After a median follow-up of 14.2 months (IQR: 6.5–27.2), ARR decreased by 85.7% (p < 0.001) and GEL by 82.9%, from 0.41 to 0.07 (p < 0.001). A significant decrease in EDSS to 4.7 (p = 0.046) was observed after 1 year of treatment and this variable remained stable during the second year of therapy. There was no evidence of disease activity in 68% of patients. Infusion-related symptoms were the most frequent side effect (19.6%) and most were mild. Relevant infections were reported only in 18 patients (including one case of probable progressive multifocal leukoencephalopathy).ConclusionRituximab could be an effective and safe treatment in RRMS, including aggressive forms of the disease. Some selected PMS patients could also benefit from this treatment.

While conventional magnetic resonance imaging (MRI) is central to the evaluation of patients with multiple sclerosis, its role in detecting the pathophysiology underlying neurodegeneration is more limited. One of the common outcome measures for progressive multiple sclerosis trials, atrophy on brain MRI, is non-specific and reflects end-stage changes after considerable neurodegeneration has occurred. Identifying biomarkers that identify processes underlying neurodegeneration before it is irreversible and that reflect relevant neurodegenerative pathophysiology is an area of significant need. Accumulating evidence suggests that oxidative stress plays a major role in the pathogenesis of multiple neurodegenerative diseases, including multiple sclerosis. Imaging markers related to inflammation, myelination, and neuronal integrity have been areas of advancement in recent years but oxidative stress has remained an area of unrealized potential. In this article we will begin by reviewing the role of oxidative stress in the pathogenesis of multiple sclerosis. Chronic inflammation appears to be directly related to the increased production of reactive oxygen species and the effects of subsequent oxidative stress appear to be amplified by aging and accumulating disease. We will then discuss techniques in development used in the assessment of MS as well as other models of neurodegenerative disease in which oxidative stress is implicated. Multiple blood and CSF markers of oxidative stress have been evaluated in subjects with MS, but non-invasive imaging offers major upside in that it provides real-time assessment within the brain. [ABSTRACT FROM AUTHOR]

Background: Autologous mesenchymal stem cell neurotrophic factor–secreting cells (NurOwn®) have the potential to modify underlying disease mechanisms in progressive multiple sclerosis (PMS). Objective: This open-label phase II study was conducted to evaluate safety/efficacy of three intrathecal cell treatments. Methods: Eighteen participants with non-relapsing PMS were treated. The primary endpoint was safety. Secondary endpoints included: cerebrospinal fluid (CSF) biomarkers; timed 25-foot walk speed, nine-hole peg test (9-HPT), low-contrast letter acuity, symbol digit modalities test, and 12-item multiple sclerosis (MS) walking scale. Seventeen participants received all treatments. Results: No deaths/adverse events related to worsening of MS, clinical/magnetic resonance imaging (MRI) evidence of disease activation, and clinically significant changes in safety lab results were reported. Two participants developed symptoms of low back and leg pain, consistent with a diagnosis of arachnoiditis, occurring in one of three intrathecal treatments in both participants. Nineteen percent of treated participants achieved pre-specified ⩾ 25% improvements in timed 25-foot walk speed/nine-HPT at 28 weeks compared to baseline, along with consistent efficacy signals for pre-specified response criteria across other secondary efficacy outcomes. CSF neuroprotective factors increased, and inflammatory biomarkers decreased after treatment, consistent with the proposed mechanism of action. Conclusion: Based on these encouraging preliminary findings, further confirmation in a randomized study is warranted. [ABSTRACT FROM AUTHOR]

Background: Progressive motor impairment anatomically associated with a "critical" lesion has been described in primary demyelinating disease. Most "critical" lesions occur within the spinal cord. Objective: To describe the clinical and radiological features of "critical" lesions of the cervicomedullary junction (CMJ). Methods: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. Results: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0–8.5) at last follow-up. No "critical" CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. Conclusion: CMJ "critical" lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease. [ABSTRACT FROM AUTHOR]

Background: Neurofilament light (NfL) levels reflect inflammatory disease activity in multiple sclerosis (MS), but it is less clear if NfL also can serve as a biomarker for MS progression in treated patients without relapses and focal lesion accrual. In addition, it has not been well established if clinically effective treatment re‐establishes an age and sex pattern for cerebrospinal fluid NfL (cNfL) as seen in controls, and to what degree levels are affected by disability level and magnetic resonance imaging (MRI) atrophy metrics. Methods: We included subjects for whom cNfL levels had been determined as per clinical routine or in clinical research, classified as healthy controls (HCs, n = 89), MS‐free disease controls (DCs, n = 251), untreated MS patients (uMS; n = 296), relapse‐free treated MS patients (tMS; n = 78), and ProTEct‐MS clinical trial participants (pMS; n = 41). Results: Using linear regression, we found a positive association between cNfL and age, as well as lower concentrations among women, in all groups, except for uMS patients. In contrast, disability level in the entire MS cohort, or T1 and T2 lesion volumes, brain parenchymal fraction, thalamic fraction, and cortical thickness in the pMS trial cohort, did not correlate with cNfL concentrations. Furthermore, the cNfL levels in tMS and pMS groups did not differ. Conclusions: In participants with MS lacking signs of inflammatory disease activity, disease modulatory therapy reinstates an age and sex cNfL pattern similar to that of control subjects. No significant association was found between cNfL levels and clinical worsening, disability level, or MRI metrics. [ABSTRACT FROM AUTHOR]

Increasing self-efficacy to exercise and minimizing disease-related barriers has been shown to improve physical activity levels and quality of life (QOL) in persons with multiple sclerosis (MS). Currently, little research has examined exercise self-efficacy in persons with more advanced MS. Purpose: Explore the effects of a self-efficacy plus exercise intervention on physical activity endurance and level, QOL, and fatigue in an individual with advanced MS and low self-efficacy. The participant was a 60-year-old, severely disabled female with secondary progressive MS and an Expanded Disability Status Score (EDSS) of 8. The 8-week intervention consisted of weekly discussions and MS-related education; four one-on-one sessions with a MS "mentor;" daily journal to record sleep quality, fatigue level, and physical activity. Outcomes included a modified 5-meter walk test (5MWT), MS Impact Scale (MSIS-29), Exercise Self-Efficacy Scale (EX-ES), Modified Fatigue Impact Scale (MFIS), MS Self-Efficacy Scale (MS-SES), Patient Health Questionnaire-9 (PHQ-9), and daily physical activity monitoring. Outcomes were assessed at baseline (week 0), post-intervention (week 8), and 8 weeks post intervention (week 16). The participant continued her regular exercise routine independently throughout the study period. There were notable improvements in EX-ES, MFIS, PHQ-9, MSIS-29 psychological subscale, sleep quality, and morning fatigue ratings post intervention, some of which were retained at follow up. The findings illustrate that an 8-week self-efficacy intervention increased exercise self-efficacy, QOL, and reduced perceived fatigue in a severely disabled individual with progressive MS. Future research should examine self-efficacy interventions in a larger sample size of persons with progressive MS. [ABSTRACT FROM AUTHOR]

Objective: An earlier follow-up study from the CogEx rehabilitation trial showed little change in symptoms of depression, anxiety and psychological distress during the first COVID-19 lockdown compared to pre-pandemic measurements. Here, we provide a second follow-up set of behavioral data on the CogEx sample. Methods: This was an ancillary, longitudinal follow-up study in CogEx, a randomized controlled trial of exercise and cognitive rehabilitation in people with progressive MS involving 11 centres in North America and Europe. Only individuals impaired on the Symbol Digit Modalities Test (SDMT) were included. Participants repeated the COVID Impact survey administered approximately a year later and completed self-report measures of depression, anxiety and MS symptoms that had been obtained at the trial baseline and during the first COVID Impact survey. Participants who completed the second COVID Impact follow-up were included. To identify predictors of the participants' ratings of their mental and physical well-being, step-wise linear regression was conducted. Results: Of the 131 participants who completed the first COVID impact survey, 74 participants completed the second follow-up survey (mean age 52 (SD = 6.4) years, 62.2% female, mean disease duration 16.4 (SD = 9.0) years, median EDSS 6.0). Pandemic restrictions prevented data collection from sites in Denmark and England (n = 57). The average time between measurements was 11.4 (SD = 5.56) months. There were no significant differences in age, sex, EDSS, disease course and duration between those who participated in the current follow-up study (n = 74) and the group that could not (n = 57). One participant had COVID in the time between assessments. Participants now took a more negative view of their mental/psychological well-being (p = 0.0001), physical well-being (p = 0.0009) and disease course (p = 0.005) compared to their last assessment. Depression scores increased on the HADS-depression scale (p = 0.01) and now exceeded the clinically significant threshold of ≥ 8.0 for the first time. Anxiety scores on the HADS remained unchanged. Poorer mental well-being was predicted by HADS depression scores (p = 0.012) and a secondary-progressive disease course (p = 0.0004). Conclusions: A longer follow-up period revealed the later onset of clinically significant depressive symptoms on the HADS and a decline in self-perceptions of mental and physical well-being associated with the COVID-19 pandemic relative to the first follow-up data point. Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated. [ABSTRACT FROM AUTHOR]

Ocrelizumab and siponimod are the two on‐label drugs used for progressive forms of multiple sclerosis (PMS). However, many patients with PMS do not have access to these high‐efficacy disease‐modifying drugs (DMDs). Off‐label prescription of other high‐efficacy DMDs (fingolimod, rituximab and natalizumab) may be a strategy to improve access to immunotherapy for these patients. We aim to compare on‐label and off‐label high‐efficacy drugs for their effect on disability progression in PMS. In December 2021, we searched MEDLINE (PubMed), Embase, Cochrane Central and Scopus databases for randomized clinical trials involving patients with PMS. High‐efficacy drugs were considered as intervention and placebos as comparison. The outcome contemplated was risk of Expanded Disability Severity Scale (EDSS) progression at 2 years. A network meta‐analysis was performed to compare the relative risk of EDSS progression at 2 years compared with placebo in on‐label and off‐label drugs. We included five studies with 4526 patients. The median EDSS progression at 2 years in patients that received any immunotherapy was 30%, compared with 35% in placebo groups. Overall, the risk of bias of individual studies was low. Network analysis revealed overlapping confidence intervals in off‐label drugs (CI95% 0.51–2.16) versus ocrelizumab (reference) and off‐label drugs (CI 95% 0.53–1.96) versus siponimod (reference), suggesting similar efficacy. The same result was found even after excluding studies with the risk of publication bias. Off‐label high efficacy immunotherapy in PMS has biological plausibility and presented similar effectiveness to on‐label DMDs in this network meta‐analysis. The use of fingolimod, rituximab or natalizumab may be a strategy that reduces costs and improves access to immunotherapy for patients with PMS. [ABSTRACT FROM AUTHOR]

Purpose of Review: Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) with a chronic and often progressive disease course. The current disease-modifying treatments (DMTs) limit disease progression primarily by dampening immune cell activity in the peripheral blood or hindering their migration from the periphery into the CNS. New therapies are needed to target CNS immunopathology, which is a key driver of disability progression in MS. This article reviews Bruton's Tyrosine Kinase Inhibitors (BTKIs), a new class of experimental therapy that is being intensely evaluated in MS. We focus on the potential peripheral and central mechanisms of action of BTKIs and their use in recent clinical trials in MS. Recent Findings: There is evidence that some BTKIs cross the blood–brain barrier and may be superior to currently available DMTs at dampening the chronic neuroinflammatory processes compartmentalized within the CNS that contribute to progressive worsening in people withMS (pwMS). Recently, evobrutinib and tolebrutinib have shown efficacy in phase II clinical trials, and there are numerous ongoing phase III clinical trials of various BTKIs in relapsing and progressive forms of MS. Results from these clinical trials will be essential to understand the efficacy and safety of BTKIs across the spectrum of MS and keydifferences between specific BTKIs when treating pwMS. Summary: Inhibition of BTK has emerged as an attractive strategy to target cells of the adaptive and innate immune system outside and within the CNS. BTKIs carry great therapeutic potential across the MS spectrum, where key pathobiology aspects seem confined to the CNS compartment. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) with a profound neurodegenerative component early in the disease pathogenesis. Age is a factor with a well-described effect on the primary disease phenotype, namely, the relapsing-remitting vs. the primary progressive disease. Moreover, aging is a prominent factor contributing to the transition from relapsing-remitting MS (RRMS) to secondary progressive disease. However, sex also seems to, at least in part, dictate disease phenotype and evolution, as evidenced in humans and in animal models of the disease. Sex-specific gene expression profiles have recently elucidated an association with differential immunological signatures in the context of experimental disease. This review aims to summarize current knowledge stemming from experimental autoimmune encephalomyelitis (EAE) models regarding the effects of sex, either independently or as a factor combined with aging, on disease phenotype, with relevance to the immune system and the CNS.