Search Results (4,067)

(1) Background: Physical fatigue, either in short anaerobic exercises or in aerobic ones, affects locomotion patterns. Those effects, if consistently observed, may function as fatigue proxies. The present study focuses on the regularity of the pseudo-periodic acceleration patterns measured by a wearable sensor. Studies during laboratory anaerobic tasks on healthy subjects and on persons with multiple sclerosis during 6 min walking tests demonstrated that regularity decreases with fatigue. This study’s objective is to verify if the gait regularity during an unsupervised endurance aerobic walking task progressively decreases in healthy subjects. (2) Methods: Ten healthy male adults, not competitive recreational athletes, equipped with an accelerometer, participated in a non-competitive 100 km walk in about 24 h. (3) Results: Eight participants took from about 22 to 25 h to complete the task. Two did not finish. The trend of locomotion regularity (on average −6.3%, p < 0.001, effect size 1.41) was negative for all the participants. The gait speed decrease, in all the participants, explained less than 20% of the regularity decrease. Other outcome indices, such as that related to cadence, did not provide unique trends. (4) Conclusions: Regularity decrease is associated with fatigue in submaximal locomotor efforts; due to the experimental group limitations in size and composition, further studies should extend regularity assessments to women, and to persons with neuromuscular disabilities or attending walking rehabilitation. Full article

The GGGGCC hexanucleotide repeat expansion (HRE) in C9ORF72 was recognized as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Repeat-associated non-AUG (RAN) translation of the expanded repeat generated dipeptide repeat proteins (DPRs), which disrupted multiple cellular processes and contributed to neurodegeneration. Emerging evidence indicated that disease pathogenesis involved both gain-of-function (GOF) and loss-of-function (LOF) mechanisms. DPR-mediated GOF toxicity induced ribosomal dysfunction, nucleolar stress, proteostatic impairment, and neuronal injury, whereas C9ORF72 LOF disrupted lysosomal and autophagic pathways in microglia, impairing the immune homeostasis. Neuronal injury further promoted the release of damage-associated signals that triggered secondary microglial activations and chronic neuroinflammations. This review summarized current knowledge of DPR biology, microglial dysfunction, and their contributions to disease progression in C9ORF72-associated ALS/FTD. Therapeutic strategies targeting repeated RNA, DPR productions, proteostasis, autophagy, and neuroinflammatory pathways were also discussed. In addition, the potentials of fluid biomarkers, including cerebrospinal fluid poly (GP) and blood neurofilament light chain (NfL), for diagnosis, disease monitoring, and therapeutic assessment were shown. Together, these findings provided important insights into disease mechanisms and potential avenues for improved clinical management. Full article

Multiple sclerosis (MS) is a neuro-inflammatory disease characterized by demyelination in the central nervous system (CNS). Although a substantial endogenous capacity for remyelination has been demonstrated, this process is frequently incomplete and exhibits marked intra- and inter-individual heterogeneity. Several factors influence the extent of spontaneous myelin regeneration, including age, sex, disease course, and lesion localization. Oligodendrocytes (OL), derived from oligodendrocyte progenitor cells (OPCs), are the principal myelinating cells of the CNS. The regenerative cascade involves several key stages, including OPC activation, recruitment, differentiation into oligodendrocytes (OL), and myelin deposition. This process is orchestrated in a spatiotemporal manner by a complex interplay of intracellular signaling pathways, genetic determinants, and dynamic microenvironmental cues, which together balance inhibitory and pro-remyelinating influences. Several lines of evidence indicate that chronically demyelinated axons are vulnerable to degeneration, whereas successful remyelination may confer neuroprotection. These observations underscore remyelination as a promising neuroprotective therapeutic target for preventing or slowing disability progression in MS, a condition in which gradual neuroaxonal degeneration is believed to underlie irreversible disability progression. In this review, we aim to bridge the gap between fundamental biological mechanisms of remyelination and their clinical relevance. We examine recent advances in in vivo techniques for assessing remyelination and discuss how these measures correlate with clinical and disability outcomes. In addition, we review recent clinical trials of remyelination-promoting therapies and analyze the challenges that have limited their advancement beyond phase II. Overall, we seek to provide a comprehensive overview of the remyelination process from bench to bedside, highlighting both the obstacles and the therapeutic potential of remyelination strategies in MS. Full article

Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by demyelination, neuroinflammation, and progressive neurodegeneration. While there is a small component of genetic susceptibility to MS risk, environmental factors, including infectious exposures, are gaining increased recognition as playing a critical role in MS initiation and progression. Viral infections, especially by Epstein–Barr virus (EBV), have emerged as strong candidates and triggers of MS symptoms, through antibody-mediated molecular mimicry and B-cell dysregulation. In contrast, parasitic infections, including helminths and select protozoa, appear to exert neuroprotective effects by skewing immune responses toward regulation and tolerance. In this review, we examine antibody-driven mechanisms by which viral pathogens promote autoimmunity in MS and contrast these with parasite-induced immunoregulatory pathways that suppress pathogenic inflammation. We further discuss diagnostic and therapeutic implications, highlighting how insights from infectious immunology may inform novel strategies for MS treatment. Full article

Background: Falls and fall-related injuries are common in older adults and are frequently accompanied by fear of falling (FoF), which may lead to activity avoidance and functional decline. Because many interventions target falls or FoF in isolation, we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) to identify, describe, and evaluate interventions reporting both falls and FoF outcomes in older adults. Methods: This systematic review and meta-analysis were registered in PROSPERO (CRD420251113137) and conducted in accordance with PRISMA guidelines. PubMed, Embase, and Web of Science were searched from inception to 4 November 2025. Eligible studies were English-language RCTs that included adults aged ≥60 years, evaluated nonpharmacological interventions, and reported both FoF and falls. Methodological quality was assessed using the PEDro scale. Random-effects meta-analyses were performed for FoF (Hedges g), and Bayesian random-effects binomial meta-analyses were conducted for falls. Results: Ten RCTs published between 1998 and 2018 (sample sizes per trial: n = 27–540) were included. Interventions included cognitive–behavioral therapy-based programs, Tai Chi, physiotherapist-led strength and balance training, computerized visual feedback, and video-guided home exercise. PEDro scores ranged from 6 to 9 (mean, 7.7). Pooled analyses showed no significant effect on FoF at the end of intervention (g = −0.20, 95% CI −1.45 to 1.05; p = 0.68; high heterogeneity) or at follow-up (g = −0.14, 95% CI −0.60 to 0.33; p = 0.50). For falls, postintervention evidence favored the null (BF₁₀ = 0.16; pooled estimate −0.01, 95% credible interval [CrI] −0.30 to 0.14). Follow-up results were inconclusive (BF₁₀ = 2.07; pooled CrI −0.56 to 0.00), with substantial uncertainty. Conclusions: Across RCTs that measured both outcomes, interventions did not consistently improve both FoF and falls outcomes. These findings may suggest a partial dissociation between psychological and physical fall-related outcomes, highlighting the need for integrated, adequately powered trials that utilize standardized measures and longer follow-up periods. Full article

B-cell-depleting therapies have revolutionized multiple sclerosis (MS) treatment, yet relapses persist in some patients—suggesting additional pathogenic drivers beyond peripheral B cells. Tertiary lymphoid structures (TLS) are extensively documented in progressive MS at autopsy, but whether their formation begins during the relapsing-remitting phase and how they evolve during the transition to progression remain undefined. Here, using the relapsing-remitting PLP_139–151-induced EAE model, we uncover that TLS-like structures form in the subventricular zone during relapse, once established, persist through remission as niches containing both B cells and persistently activated microglia. Neither B-cell depletion alone nor BTK inhibition alone fully prevents relapse. Strikingly, early combined B-cell depletion and BTK inhibition virtually abolishes TLS-like structure formation and may effectively prevent complete disease relapse in this model. By contrast, late initiation of the same combination fails to resolve existing TLS-like structures or prevent relapse, although it attenuates disease severity. These data indicate that established TLS-like structures may represent treatment-resistant compartments, and that both B cells and microglia may be crucial during early formation for sustaining their disease relapse-driving activity. Our study confirms that TLS-like structures may be a key factor driving the compartmentalization of central nervous system inflammation, points to a potentially narrow therapeutic window for intervention, and proposes that early combined B-cell depletion and BTK inhibition may represent a promising strategy worthy of further investigation. Full article

Background and Clinical Significance: Tumefactive Multiple Sclerosis (TMS) represents a rare and diagnostically challenging form of demyelinating disease characterized by large space-occupying lesions that can closely mimic intracranial neoplasms, abscesses, and other inflammatory or vascular conditions. Case Presentation: The case highlights the overlapping radiologic features that frequently lead to diagnostic uncertainty and underscores the importance of careful interpretation of multimodal imaging and ancillary studies. Overall a comprehensive multidisciplinary evaluation is essential to reduce the risk of misdiagnosis and avoid unnecessary invasive interventions. Conclusions: This review summarizes current evidence regarding the diagnostic approach, imaging characteristics, and therapeutic strategies for tumefactive demyelinating lesions. Additionally, we present a clinical case that illustrates the diagnostic complexity of this entity, in which neuroimaging findings and cerebrospinal fluid analysis supported a demyelinating rather than neoplastic process. Full article

Background: Multiple sclerosis (MS) is a condition that requires long-term, multidisciplinary management. The growing digital transformation in healthcare has highlighted the central role of nurses in supporting key aspects such as patient self-management, continuity of (at home) care, and patient empowerment. However, evidence on nurse-led digital interventions in MS remains fragmented. Objective: To map the available literature on nurse-led digital interventions in MS, focusing on the role of nurses, clinical outcomes, and research gaps. Methods: The review was conducted using the methodological framework of the Joanna Briggs Institute (JBI) and the PRISMA-ScR checklist. A systematic search was performed in PubMed, Scopus, Web of Science, and CINAHL. Studies were included if they described digital or telehealth interventions led or coordinated by nurses in patients with MS. Results: A total of 12 studies published between 2015 and 2025 met the inclusion criteria. Four main thematic areas were identified: (1) telenursing and empowerment-based interventions; (2) mobile and web-based patient self-management programs; (3) digital systems for monitoring and integrated care pathways; and (4) digital interventions targeting symptom management and psychosocial outcomes. Across the studies, nurse-led digital interventions were associated with improvements in self-management, treatment adherence, self-efficacy, and health-promoting behaviors. Positive effects were also reported on clinical outcomes such as fatigue, sleep quality, and balance, as well as on psychosocial variables including quality of life, coping strategies, and emotional well-being. Furthermore, the identified systems, in general, contributed to enhanced continuity of care, patient engagement, and organizational efficiency. Conclusions: Nurse-led digital interventions represent a promising approach in the management of patients with multiple sclerosis, supporting both clinical and psychosocial outcomes while enhancing continuity of care. However, the current evidence base remains limited by small sample sizes, heterogeneity of interventions, and short follow-up periods. Future research should prioritize multicenter randomized studies with larger samples and long-term follow-up to strengthen the evidence. Additionally, the integration of digital interventions into routine clinical practice, along with targeted training for nurses, is essential to ensure sustainability, accessibility, and equitable implementation. Further studies should also explore cost-effectiveness and the impact on caregivers and long-term quality of life. Full article

Background: Over the years, it has become increasingly clear that neurological conditions, such as multiple sclerosis (MS), commonly exhibit other health problems. Therefore, this is the first study aimed at investigating the prevalence of and factors associated with three binary outcomes: depression, anxiety, and an overactive bladder (OAB) among MS patients in the Qassim region, Saudi Arabia. Methods: This cross-sectional study was conducted in the neurological department of King Fahad Specialist Hospital in the Qassim region, Saudi Arabia, from January to December 2024. Data on age, sex, marital status, occupation, body mass index (BMI), MS duration, comorbidities, anxiety, depression, and OAB symptoms (frequency, nocturia, urgency, and urge incontinence) were obtained. Results: Of the 262 MS patients in this study, 184 (70.2%) were females, and 78 (29.8%) were males. The median values [IQR] of age and MS duration were 34 [26–40] and 5 [2–9] years, respectively. The prevalence of depression, anxiety, and OAB were 53.4%, 43.9%, and 50%, respectively. Nocturia was the most frequent urinary symptom, and urge incontinence was significantly higher among females. Multiple logistic regression analyses were conducted to assess factors associated with three binary outcomes: depression, anxiety, and OAB. For depression, being single and anxiety were associated with increased risk. Regarding anxiety, being a student was related to decreased risk, while being female and having depression were associated with increased risk. For OAB, only anxiety was associated with increased risk. Conclusions: Approximately one in two MS patients experience either depression or OAB, while anxiety was reported by fewer than half of the patients. This high prevalence of the three outcomes has critical implications for healthcare policy and resource allocation. Thus, screening, early diagnosis, and intervention, as well as integrated care, should be prioritized by healthcare institutions and practitioners to address these conditions and improve MS patients’ quality of life. Full article

Background/Objectives: Multiple sclerosis (MS) is most frequently diagnosed in young adults of reproductive age. Although current evidence indicates that MS itself does not usually preclude pregnancy or parenthood, patients may still have insufficient knowledge in this area. The aim of this study was to assess knowledge about the relationship of MS and pregnancy, childbirth, breastfeeding, fertility, and parenthood among women and men with MS. Methods: This single-center questionnaire-based study included 194 patients with MS: 144 women and 50 men. Participants completed a 12-item paper-and-pen questionnaire assessing general patient-level knowledge. Results were analyzed according to sex and age group: ≤35 years and >35 years. The mean number of correct answers and the proportion of participants reaching the predefined threshold of ≥50% correct answers were calculated. Results: Participants aged ≤ 35 years achieved a higher mean number of correct answers than those aged > 35 years: 5.0 versus 3.2, respectively. This difference was also observed among women: 5.9 versus 3.3 correct answers. Among men, no age-related difference was observed: 2.7 versus 2.8 correct answers. The predefined threshold of ≥50% correct answers was reached by 38.5% of participants aged ≤ 35 years and 27.9% of those aged > 35 years. Women had higher percentages of correct answers than men for all questionnaire items. Conclusions: Knowledge about MS, pregnancy, childbirth, breastfeeding, fertility, and parenthood was limited in this cohort. Women and younger adults achieved higher knowledge. Education should be proactive, repeated during routine MS care, and addressed to both women and men with MS. Full article

Background and Objectives: Non-invasive biomarkers reflecting neurodegeneration are increasingly important in multiple sclerosis (MS). Optical coherence tomography (OCT) provides quantitative measures of retinal structure, most commonly peripapillary retinal nerve fiber layer (pRNFL) thickness. However, the potential clinical relevance of optic nerve head morphology, including cup-to-disc ratio (CDR), remains insufficiently explored. We investigated associations between OCT-derived parameters, subjective visual vertical (SVV), and disability in MS. Materials and Methods: In this retrospective study, 100 patients with MS were included. OCT parameters (pRNFL thickness and area-based CDR) were analyzed at baseline and follow-up. Clinical disability was assessed using the Expanded Disability Status Scale (EDSS). Detailed optic neuritis history was not consistently available in the retrospective clinical records and therefore could not be systematically accounted for in the analyses. SVV was evaluated in 37 patients using a virtual reality–based protocol. Associations were assessed using Spearman correlation and linear regression analyses. Multivariable regression models were adjusted for age, sex, and follow-up duration. Results: pRNFL thickness was not associated with baseline EDSS (rho = −0.06, p = 0.55) or annualized EDSS change. Baseline CDR correlated with both baseline EDSS (rho = 0.30, p = 0.0065) and follow-up EDSS (rho = 0.46, p < 0.0001). In univariable regression analysis, baseline CDR was associated with follow-up EDSS (B = 3.33, R² = 0.23, p < 0.0001), remaining significant after adjustment for age, sex, and follow-up duration (B = 2.59, 95% CI 1.26–3.92, p = 0.0002). No significant associations were observed between OCT parameters and SVV measures. Conclusions: Higher CDR values, but not pRNFL thickness, were associated with disability measures in this exploratory MS cohort. However, these findings should be interpreted cautiously because optic neuritis history could not be systematically accounted for and physiological optic disc variability may substantially influence CDR measurements. Full article

Multiple sclerosis (MS) is a heterogeneous autoimmune disorder of the central nervous system of polygenic nature. Uncovering the genetic predictors of MS phenotype can help to explain the nature of the disease’s clinical heterogeneity, and contribute to the development of novel tools for precise disease prognosis. We conducted a retrospective genetic association study of 35 polymorphic variants in immune-related genes with MS severity assessed using the Multiple Sclerosis Severity Score (MSSS) in a sample of 548 Russian relapsing-onset MS patients who have not previously received immunomodulatory therapy. Variants in the CXCR5, EOMES, TNFRSF1A, IRF8, PVT1, CCR5, HLA-DRB1, IL6, TCF7, and CD40 genes were identified as MSSS-associated in at least two of the three models analyzed (MSSS > 3.5 versus ≤3.5; MSSS > 5.0 versus <2.5; MSSS as a continuous variable). Among them, variants in CCR5, HLA-DRB1 and IL6 genes were associated with MSSS only in women, while variants in the TCF7 and CD40 genes only in men. The variant in CXCR5 was MSSS-associated both in the total sample and in subgroups of female and male MS patients. Thus, we demonstrate that several GWAS-identified MS risk genes, along with other immunological loci, act as modifiers of the MS phenotype. Full article

Neuroinflammation plays a central role in the onset and progression of neurodegenerative disorders. Several disease-modifying therapies have been developed to target neuroinflammatory pathways in specific disorders. However, their ability to stop disease progression or restore neuronal and mitochondrial homeostasis remains limited. This is still a major unmet clinical need. In this context, mesenchymal stromal cell (MSC)-derived Extracellular Vesicles (EVs) have emerged as a promising cell-free therapeutic strategy due to their ability to modulate immune responses and promote neuroprotection through the delivery of bioactive cargo. Recent evidence has identified a distinct subset of EVs, known as mitochondrial EVs (mito-EVs), which carry mitochondrial DNA, proteins, and functional components. These vesicles may uniquely influence cellular bioenergetics, redox balance, and neuroinflammatory signaling, offering additional therapeutic potential compared to conventional MSC-EVs. This review summarizes the role of MSC-derived EVs in neuroinflammatory disorders, with a particular focus on mito-EVs. It also discusses preconditioning strategies to enhance EV efficacy, including hypoxic, inflammatory, pharmacological priming and genetic engineering approaches. Finally, we critically evaluate current preclinical evidence regarding the treatment of major neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Multiple Sclerosis, and Amyotrophic Lateral Sclerosis, as well as Traumatic Injury, highlighting the key challenges for clinical translation. Full article

Neuroinflammation in multiple sclerosis (MS) is driven by the infiltration of myelin-reactive T cells into the central nervous system (CNS). Interferon-β (IFN-β) is one of the earliest disease-modifying treatments (DMTs) approved for MS and remains widely used in special populations (pregnant and elderly patients) owing to its favorable safety profile. However, the exact mechanism of action of this drug and reliable biomarkers of treatment response remain unclear. Transcriptomic profiling and data integration approaches offer powerful tools for investigating complex patterns of regulation and molecular mechanisms underlying therapeutic efficacy. In this study, we performed an integrative analysis of openly available transcriptomic datasets to characterize IFN-β-induced gene expression changes in MS patients. By combining data from large independent cohorts, we identified a 43-gene transcriptional signature consistently associated with IFN-β treatment across disease stages, including progressive MS. To explore the relevance of this signature, we cross-referenced the 43-gene signature with publicly available expression quantitative trait loci (eQTL) datasets to determine whether these genes could be influenced by known MS-associated risk variants highlighting Interferon-Induced Transmembrane Protein 3 (IFITM3) as a candidate molecular mediator of MS. This integrative approach provides new insights into IFN-β-driven immune modulation and supports the development of therapeutic strategies for MS. Full article

Background: Multiple sclerosis (MS), an autoimmune disease, involves peripheral immune activation followed by CNS inflammation in a compartmentalized manner. Although high-efficacy disease-modifying therapies (HE-DMTs) have been effective in suppressing relapses in MS patients, they fail to effectively target chronic microglial activation and smoldering lesions in MS patients. Bruton’s tyrosine kinase inhibitors (BTKis), which are orally active and capable of crossing the blood–brain barrier, have been found to be effective in modulating B cells and CNS-resident myeloid cells. Objective: The objective was to assess the efficacy and safety of Bruton’s tyrosine kinase inhibitors in patients with relapsing, secondary, and primary progressive MS. Methods: We performed a systematic review and meta-analysis according to the Cochrane and PRISMA guidelines (PROSPERO registration number: 1323474). We included randomized controlled trials (RCTs) that assessed fenebrutinib, evobrutinib, or tolebrutinib in adult MS patient populations. The main outcome measures were annualized relapse rate, MRI lesion activity, disability progression (EDSS), and hepatotoxicity. The quality of the included trials was assessed for bias by the RoB2 tool. Results: Six RCTs with 3616 participants were included. BTK inhibitors significantly reduced ARR compared with control therapy (pooled RR 0.24; 95% CI 0.15–0.39). MRI activity was reduced (mean difference −1.45 new/enlarging T2 lesions; 95% CI −2.08 to −0.82). Disability progression was unchanged in short-term relapsing MS trials. Serious hepatotoxicity was reported in 11.0% of BTKi-treated patients compared with 13.7% of control patients (pooled RR 0.80; 95% CI 0.66–0.96). However, increased transaminase elevations were reported in placebo-controlled trials, which indicates that hepatotoxicity remains a clinically relevant safety concern for the class. Conclusions: BTK inhibitors reduce inflammatory disease activity in relapsing MS and have emerging efficacy in progressive MS phenotypes; however, continued monitoring for hepatotoxicity is warranted. Optimization of CNS penetrance and pharmacologic selectivity may influence long-term clinical positioning. Full article