The oral-gut-brain axis is a path connecting the gastrointestinal tract and the central nervous system (CNS). The gut microbiota influences the immune system, metabolism, and nerve cells through the production of neurotransmitters and microbial metabolites that can cross the blood-brain barrier (BBB). The interplay between neuroinflammation and altered oral and gut microbiota is a bidirectional complex path modulated by inflammatory mediators. Recent studies suggest a potential role for Toll-like receptor (TLR) signaling pathways in the induction of neuroinflammation via the oral-gut-brain axis. As neuroinflammation is one of the key elements in the pathophysiology of neurodegenerative and neuropsychiatric disorders, this review was conducted to reflect on the pathophysiological pathways and clinical evidence on the role of TLR and inflammasome signaling pathways via oral-gut-brain axis in neurodegenerative diseases such as cognitive impairment, Alzheimer's disease, Multiple sclerosis, Parkinson's disease, Huntington's disease, and Amyotrophic lateral sclerosis, and psychiatric disorders such as major depressive disorder, anxiety disorders, schizophrenia, bipolar disorders, and Autism spectrum disorders. Because the contributing factors have not been fully understood yet, further studies could help provide novel therapeutic opportunities.

Multiple sclerosis (MS) is a chronic, inflammatory disorder of the central nervous system (CNS) characterized by overlapping relapsing and progressive pathologies. Although they exist along a continuum, pathology in relapsing MS (RMS) is primarily driven by the peripheral adaptive immune system, while progressive MS (PMS) pathology is underpinned by innate immune activity and other pathologic processes compartmentalized within the CNS. While currently approved therapies are highly effective in targeting aspects underpinning relapsing pathology, they have limited efficacy in PMS due to either inability to cross the blood brain barrier (BBB) or inability to modulate pathologies driving PMS. Bruton's tyrosine kinase (BTK) inhibitors are an emerging class of oral agents that represent a novel approach to MS treatment. These agents target BTK, an enzyme which plays a pivotal role in both adaptive and innate immune signaling. As small molecules, some BTK inhibitors can cross the BBB at biologically relevant concentrations. Therefore, BTK inhibitors may potentially modulate both relapsing and progressive MS pathology. Data from Phase 2 and Phase 3 trials have been promising in this regard. The unique pharmacological profile of each BTK inhibitor may underpin observed differences in efficacy and safety outcomes to date. In particular, tolebrutinib has demonstrated efficacy against disability progression in non-relapsing secondary progressive MS, while fenebrutinib has recently shown promise in both relapsing and primary progressive MS. However, adverse events include elevated liver enzymes, which can reach life-threatening levels. This review highlights the role of BTK in immune signaling and the rationale for BTK inhibition in MS, discusses the evolution of BTK inhibitors for MS and other indications, summarizes findings from Phase 2 and Phase 3 trials in RMS and PMS, and explores practical questions around the potential use of BTK inhibitors in real-world practice.

Bruton's tyrosine kinase inhibitors: a new class of multiple sclerosis therapeutics.

Assessing nonlinear gait characteristics in multiple sclerosis: Insights from a systematic review.

Smokers with multiple sclerosis (MS) experience worse disease, yet underlying mechanisms remain unknown. Smoking disrupts bile acid and tryptophan metabolism in non-MS populations; both pathways involve host-microbiome co-metabolism and have been linked to MS. Determine whether smoking perturbs these metabolic pathways in MS and whether such alterations statistically mediate smoking's effect on MS severity. We analyzed serum bile acid, tryptophan, and tobacco-related metabolites across four independent MS cohorts (N = 266) using discovery-replication analyses. Mixed-effects regression assessed replicating associations with current smoking and nicotine exposure. Mediation analyses tested if replicating metabolites were potential mediators between smoking and MS severity. Hypothesis-generating metagenomic analyses explored smoking-associated gut-microbial shifts and metabolite correlations. Current smokers and nicotine-exposed MS subjects had reductions in bile acids and tryptophan metabolites, notably indolepropionate, a neuroprotective, anti-inflammatory gut-microbial metabolite. Lower indolepropionate statistically mediated ~20% of smoking's adverse effect on MS severity. Metagenomic analyses identified potential smoking-enriched MS-linked taxa, and that indolepropionate broadly co-occurs with microbial networks (e.g. Lachnoclostridium appeared inversely associated with indolepropionate in smokers with MS). Tobacco exposure disrupts host-microbiome tryptophan and bile acid metabolism in persons with multiple sclerosis, with indolepropionate depletion partially mediating disease severity, highlighting a potential mechanistic pathway warranting further investigation in MS smokers.

Autonomic dysfunction is common in multiple sclerosis (MS), and autonomic symptoms are independent contributors to MS fatigue. Aerobic training (AT) has been shown to reduce fatigue severity and to promote functional network reorganization in MS. We explored resting-state (RS) functional connectivity (FC) of the central autonomic network (CAN) in MS, its relationship with fatigue severity, and its modifications after AT vs non-AT. Seventy-five patients with MS (38 with relapsing-remitting [RR] and 37 with progressive [P]) underwent 3T RS functional MRI at baseline and at the end of AT (24 training sessions, 2-3 times per week for 2-3 months) or non-AT of equivalent duration. Sixty-seven matched healthy controls (HCs) served as a reference for baseline RS FC. At both visits, all patients were assessed using the Modified Fatigue Impact Scale (MFIS). Seed-based RS FC used core CAN modulatory regions: left/right ventromedial prefrontal cortex (vmPFC), mid-cingulate cortex (MCC), amygdala, hypothalamus, and anterior and posterior insula. Compared with HCs, patients with MS showed increased baseline RS FC of the right amygdala, anterior insula, and vmPFC with superior frontal gyri, precentral gyri and right precuneus. Considering disease phenotype, we found a divergent behavior of baseline RS FC in the interaction analysis (p < 0.05, corrected), with patients with RRMS showing predominantly increased RS FC of the amygdala, anterior insula, and MCC with supplementary motor areas (SMAs) and deep gray matter, whereas patients with PMS showed widespread baseline RS FC decrease, particularly involving posterior insula connections with the cerebellum and parietal regions, and MCC connections with frontotemporal areas. In patients with RRMS, increased baseline CAN RS FC inversely correlated with fatigue severity (r = range -0.33/-0.54, p range = 0.046/0.001), while no significant correlations were found in patients with PMS. In patients who underwent AT, decreased hypothalamic network RS FC at follow-up vs baseline was observed (p < 0.001, significant time-by-treatment interaction vs non-AT), with more prominent changes in patients with RRMS compared with patients with PMS. No correlations were found between longitudinal RS FC modifications and concomitant fatigue changes. CAN dysregulation is present in MS, with distinct RS FC abnormalities characterizing patients with RRMS and PMS and correlating with fatigue severity. AT modulates CAN RS FC, particularly in patients with RRMS.

Areas of improvement for high-quality multiple sclerosis care: Insights from interviews with people with multiple sclerosis, providers, and clinical educators.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory demyelinating disorder that overlaps clinically with multiple sclerosis (MS) but immunopathologically distinct. Although often considered an acute inflammatory disease, recurrent attacks in MOGAD can lead to demyelination, axonal injury, and secondary neurodegeneration. Reliable biomarkers associated with relapse risk and disease subphenotypes, including optic neuritis, remain limited. Here, we aimed to define molecular and cellular signatures that distinguish MOGAD from MS as a prototypical neuroinflammatory disease and from Alzheimer disease (AD) as a proxy of neurodegeneration and to identify candidate immune-proteomic features associated with relapse frequency and clinical phenotype in MOGAD. CSF, serum, and whole-blood samples from patients with MOGAD (n = 67), MS (n = 49), and AD (n = 36) were profiled using NULISAseq™ CSF proteomics, Olink Explore 3072 CSF and serum proteomics, and high-dimensional mass cytometry for immune cell characterization. In MOGAD, longitudinal clinical data, including total attack counts from the earliest documented attack through follow-up, were integrated with immune and proteomic profiles to assess associations with disease course and clinical phenotype. CSF and blood proteomic profiling revealed distinct inflammatory and cardiometabolic proteomic profiles in MOGAD, differentiating it from both MS and AD. Compared with MS, MOGAD showed relative reductions in lymphocyte populations with regulatory phenotypes. Within MOGAD, relapsing disease was associated with reduced frequencies of CD8+CCR7+CD31+CTLA4+ T cells and concurrent expansion of double-negative γδ T-cell subsets. IL-13 correlated positively with relapse frequency and inversely with circulating regulatory T cells, whereas IL-32 and CASP4 showed opposite associations, correlating negatively with relapse count and positively with Treg frequency. IL-13 was also inversely associated with CD31-expressing CD8+ T cells. Phenotype-stratified analyses suggested that these immune-proteomic relationships differed according to clinical presentation, including optic neuritis vs nonoptic neuritis phenotypes. This integrative immune-proteomic analysis identifies cellular and molecular features associated with relapsing vs monophasic MOGAD, suggesting a model of impaired peripheral immune regulation in relapsing disease. While exploratory, these findings generate a concrete hypothesis for future longitudinal and functional studies aimed at refining biomarker-based monitoring and informing individualized therapeutic strategies in MOGAD.

Incidence of multiple sclerosis in Switzerland - results from the Swiss multiple sclerosis registry.

Pediatric-onset multiple sclerosis is associated with high inflammatory activity early in the disease course, yet sensitive biomarkers of early disease pathology are limited. Hyper-reflective foci on optical coherence tomography have been proposed as markers of inflammation in adult multiple sclerosis, but their relevance in pediatric populations remains unclear. We aimed to identify and quantify retinal layer-specific hyper-reflective foci burden in children with pediatric-onset multiple sclerosis and evaluate associations with MRI markers of disease severity. In this cross-sectional study, 53 children with pediatric-onset multiple sclerosis and 36 age- and sex-matched healthy controls underwent spectral-domain optical coherence tomography and MRI, including three-dimensional T1-weighted and fluid-attenuated inversion recovery sequences, near disease onset. Patients with a history of optic neuritis were excluded. Hyper-reflective foci were quantified within the ganglion cell-inner plexiform layer and inner nuclear layer as counts and as a normalized hyper-reflective foci index (count divided by retinal layer volume). Brain MRIs underwent parcellation and multiple sclerosis lesion segmentation. Generalized estimating equation models accounted for inter-eye correlation and adjusted for demographic and retinal structural covariates. Linear regression assessed associations between hyper-reflective foci burden and magnetic resonance imaging measures, including thalamic volume, cortical volume, and white matter lesion volume. Hyper-reflective foci counts and indexes were significantly increased in pediatric-onset multiple sclerosis compared with controls across both retinal layers. Higher ganglion cell-inner plexiform layer hyper-reflective foci index correlated with greater white matter lesion volume (r = 0.38, P = 0.006) and lower thalamic volume (r = -0.35, P = 0.012), but not cortical volume. In adjusted models, multiple sclerosis was independently associated with higher ganglion cell-inner plexiform and inner nuclear layer hyper-reflective foci counts and indexes (both P < 0.001). Inner nuclear layer hyper-reflective foci were negatively associated with macular retinal nerve fiber layer thickness and volume (β = -0.18, P < 0.01; β = -0.006, P < 0.01). Higher ganglion cell-inner plexiform layer hyper-reflective foci index remained associated with lower thalamic volume (β = -0.321, P = 0.024), greater lesion volume (β = 5.253, P = 0.011), and lower cortical volume (β = -6.403, P = 0.016). Children with multiple sclerosis demonstrate increased retinal hyper-reflective foci burden early in disease, in the absence of optic neuritis. The observed relationships between ganglion cell-inner plexiform layer hyper-reflective foci burden, thalamic and cortical atrophy, and white matter lesion volume suggest that hyper-reflective foci capture aspects of both inflammatory and neurodegenerative disease activity. Hyper-reflective foci represent a promising non-invasive biomarker of disease severity in pediatric-onset multiple sclerosis.

Mechanistic insights into Nicotine-derived nitrosamine ketone (NNK) in multiple sclerosis via integrated systems analyses.

Signaling pathways driving multiple sclerosis: From mechanisms to natural‑product interventions.

Word finding difficulties in multiple sclerosis and its relation to cognitive impairment, fatigue and depression.

Multimodal benefits of VR-based treadmill training in multiple sclerosis: A systematic review.

Optical coherence tomography measurements between multiple sclerosis and neuromyelitis optica spectrum disorder: A systematic review and meta-analysis.

Longitudinal changes in serum protein levels are associated with disability progression in multiple sclerosis.

Distribution of IL-33 genetic variants and circulating IL-33 levels in patients with multiple sclerosis: associations with clinical parameters in a Lithuanian population study.

The effects of hybrid assistive limb (HAL) application on locomotor function and balance parameters in individuals with multiple sclerosis.

Chronic lesion tissue expansion (CLTE) reflects slow, concentric growth of established multiple sclerosis (MS) lesions and is linked to central brain atrophy and disability progression. Whether existing MS disease-modifying therapies (DMTs) differentially influence this aspect of progressive MS biology remains unclear. To compare the effect of current DMTs on CLTE in a multicentre, real-world MS cohort. We conducted a retrospective, observational study using linked clinical data from MSBase and the MSBase Imaging Repository. Data from patients aged ⩾18 years with ⩾3 longitudinal MRI scans, and 7 therapies with ⩾100 stable treatment epochs were included. Therapy effects on CLTE, new T2 lesions, and brain atrophy were assessed using epoch-based covariate-adjusted generalised estimating equation models, with fingolimod as a comparator. The cohort included 564 patients contributing 1648 stable treatment epochs. After adjustment for demographic, clinical, and imaging covariates, B-cell depleting therapy was the only DMT associated with significantly lower CLTE (β = -4.03, p = 0.017) relative to fingolimod. CLTE was independently associated with age, baseline lesion volume, and centre effects. B-cell depletion is associated with reduced CLTE, a promising biomarker of progressive MS biology.

Spatial and temporal trends of multiple sclerosis mortality in Spain, 1992-2022.