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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]

Objective: Multiple sclerosis (MS) is a heterogenous, inflammatory disease of the central nervous system. Microbiota alterations in MS versus healthy controls (HC) are observed, but results are inconsistent. We studied diversity, enterotypes, and specific gut microbial taxa variation between MS and HC, and between MS subgroups. Methods: Amplicon sequencing of the 16S ribosomal RNA V4 region (Illumina MiSeq) was used to evaluate alpha and beta diversity, enterotypes, and relative taxa abundances on stool samples. MS subgroups were based on phenotype, disease course modifiers, and treatment status. Results were controlled for recently identified confounders of microbiota composition. Results: Ninety‐eight MS patients and 120 HC were included. Microbial richness was lower in interferon‐treated (RRMS_I, N = 24) and untreated relapsing–remitting MS during relapse (RRMS_R, N = 4) when compared to benign (BMS, N = 20; Z = −3.07, Pcorr = 0.032 and Z = −2.68, Pcorr = 0.055) and primary progressive MS (PPMS, N = 26; Z = −2.39, Pcorr = 0.062 and Z = −2.26, Pcorr = 0.071). HC (N = 120) and active untreated MS (RRMS_U, N = 24) showed intermediate microbial richness. Enterotypes were associated with clinical subgroups (N = 218, χ2 = 36.10, P = 0.002), with Bacteroides 2 enterotype being more prevalent in RRMS_I. Butyricicoccus abundance was lower in PPMS than in RRMS_U (Z = −3.00, Pcorr = 0.014) and BMS (Z = −2.56, Pcorr = 0.031), lower in RRMS_I than in BMS (Z = −2.50, Pcorr = 0.034) and RRMS_U (Z = −2.91, Pcorr = 0.013), and inversely correlated with self‐reported physical symptoms (rho = −0.400, Pcorr = 0.001) and disease severity (rho = −0.223, P = 0.027). Interpretation: These results emphasize the importance of phenotypic subcategorization in MS‐microbiome research, possibly explaining previous result heterogeneity, while showing the potential for specific microbiome‐based biomarkers for disease activity and severity. [ABSTRACT FROM AUTHOR]

Background/objectives: Fluoxetine and prucalopride might change phosphocreatine (PCr) levels via the cAMP-PKA pathway, an interesting target in the neurodegenerative mechanisms of MS.Methods: We conducted a two-center double-blind, placebo-controlled, randomized trial including 48 relapsing-remitting MS patients. Patients were randomized to receive placebo (n = 13), fluoxetine (n = 15), or prucalopride (n = 14) for 6 weeks. Proton (1H) and phosphorus (31P) magnetic resonance spectroscopy (MRS) as well as volumetric and perfusion MR imaging were performed at weeks 0, 2, and 6. Clinical and cognitive testing were evaluated at weeks 0 and 6.Results: No significant changes were observed for both 31P and 1H MRS indices. We found a significant effect on white matter volume and a trend towards an increase in grey matter and whole brain volume in the fluoxetine group at week 2; however, these effects were not sustained at week 6 for white matter and whole brain volume. Fluoxetine and prucalopride showed a positive effect on 9-HPT, depression, and fatigue scores.Conclusion: Both fluoxetine and prucalopride had a symptomatic effect on upper limb function, fatigue, and depression, but this should be interpreted with caution. No effect of treatment was found on 31P and 1H MRS parameters, suggesting that these molecules do not influence the PCr metabolism. [ABSTRACT FROM AUTHOR]

Cell-based therapies are gaining momentum as promising treatments for rare neurological autoimmune diseases, including neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. The development of targeted cell therapies is hampered by the lack of adequate animal models that mirror the human disease. Most cell-based treatments, including HSCT, CAR-T cell, tolerogenic dendritic cell and mesenchymal stem cell treatment have entered early stage clinical trials or have been used as rescue treatment in treatment-refractory cases. The development of antigen-specific cell-based immunotherapies for autoimmune diseases is slowed down by the rarity of the diseases, the lack of surrogate outcomes and biomarkers that are able to predict long-term outcomes and/or therapy effectiveness as well as challenges in the manufacturing of cellular products. These challenges are likely to be overcome by future research. [ABSTRACT FROM AUTHOR]

Background: When aiming to restore myelin tolerance using antigen-specific treatment approaches in MS, the wide variety of myelin-derived antigens towards which immune responses are targeted in multiple sclerosis (MS) patients needs to be taken into account. Uncertainty remains as to whether the myelin reactivity pattern of a specific MS patient can be predicted based upon the human leukocyte antigen (HLA) class II haplotype of the patient. Methods: In this study, we analyzed the reactivity towards myelin oligodendrocyte glycoprotein (MOG), myelin basic protein (MBP) and proteolipid protein (PLP) peptides using direct interferon (IFN)-γ enzyme-linked immune absorbent spot (ELISPOT). Next, the HLA class II haplotype profile was determined by next-generation sequencing. In doing so, we aimed to evaluate the possible association between the precursor frequency of myelin-reactive T cells and the HLA haplotype. Results: Reactivity towards any of the analyzed peptides could be demonstrated in 65.0% (13/20) of MS patients and in 60.0% (6/10) of healthy controls. At least one of the MS risk alleles HLA-DRB1*15:01, HLA-DQA1*01:02 and HLA-DQB1*06:02 was found in 70.0% (14/20) of patients and in 20.0% (2/10) of healthy controls. No difference in the presence of a myelin-specific response, nor in the frequency of myelin peptide-reactive precursor cells could be detected among carriers and non-carriers of these risk alleles. Conclusion: No association between HLA haplotype and myelin reactivity profile was present in our study population. This complicates the development of antigen-specific treatment approaches and implies the need for multi-epitope targeting in an HLA-unrestricted manner to fully address the wide variation in myelin responses and HLA profiles in a heterogeneous group of MS patients. [ABSTRACT FROM AUTHOR]

Little is known about the interplay between the autonomic nervous system and disease activity in multiple sclerosis (MS). We examined the relationship between heart rate variability (HRV), a reliable measure of vagal nerve function, and disease characteristics in a prospective MS cohort. Standard deviation of each normal-to-normal inter-beat interval (SDNN) and root mean square of successive differences (RMSSD), global indices of HRV, were measured in 114 MS patients, which included four predefined subgroups, and 30 age and sex-matched healthy controls (HC). We assessed group differences at baseline, HRV reproducibility at month 3, and used logistic regression modeling to relate baseline HRV with relapse occurrence. No significant HRV differences were found between MS and HC and between MS subgroups. In MS patients, both HRV indices correlated with age (r = −0.278, p = 0.018 and r = −0.319, p < 0.001, respectively) and with month 3 assessments (r = 0.695 and r = 0.760, p < 0.001). Higher SDNN and RMSSD at baseline were associated with self-reported relapses at month 3 (OR = 1.053, 95% CI (1.013–1.095), p = 0.009 and OR = 1.065, 95% CI (1.016–1.117), p = 0.009), and SDNN at baseline with relapses at month 12 (OR = 1.034, 95% CI (1.009–1.059), p = 0.008; ROC, AUC = 0.733, p = 0.002). There were no baseline HRV differences between MS and HC or between subgroups. Post-hoc analysis showed an association with an increased relapse risk. [ABSTRACT FROM AUTHOR]

'Mind–body' debates assume that better brain–body associations are healthy. This study examined whether degree of associations between a neurophysiological vagal nerve index and peripheral disease biomarkers predict prognosis in pancreatic cancer (PC) and multiple sclerosis (MS). Sample 1 included 272 patients with advanced PC. Sample 2 included 118 patients with MS. We measured the vagal nerve index heart rate variability (HRV) derived from electrocardiograms. We examined associations between HRV and patients' peripheral disease biomarkers: CA19-9 in PC and neurofilament light chain (NFL) in MS. Associations between HRV and each biomarker were examined separately in patients who survived or died (PC), and in those with and without relapse during 12 months (MS). In PC, HRV was significantly inversely related to the tumor marker CA19-9 in patients who later survived (r = −0.44, p < 0.05) but not in those who died (r = 0.10, NS). In MS, HRV was significantly and inversely related to NFL only in those who did not relapse (r = −0.25, p < 0.05), but not in those who relapsed (r = −0.05, NS). The degree of association between a neurophysiological vagal marker and peripheral disease biomarkers has prognostic value in two distinct diseases. [ABSTRACT FROM AUTHOR]