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Autoimmune demyelinating diseases—including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease, acute disseminated encephalomyelitis, and glial fibrillary acidic protein (GFAP)-associated meningoencephalomyelitis—are a heterogeneous group of diseases even though their common pathology is characterized by neuroinflammation, loss of myelin, and reactive astrogliosis. The lack of safe pharmacological therapies has purported the notion that cell-based treatments could be introduced to cure these patients. Among stem cells, mesenchymal stem cells (MSCs), obtained from various sources, are considered to be the ones with more interesting features in the context of demyelinating disorders, given that their secretome is fully equipped with an array of anti-inflammatory and neuroprotective molecules, such as mRNAs, miRNAs, lipids, and proteins with multiple functions. In this review, we discuss the potential of cell-free therapeutics utilizing MSC secretome-derived extracellular vesicles—and in particular exosomes—in the treatment of autoimmune demyelinating diseases, and provide an outlook for studies of their future applications.

Multiple sclerosis (MS) has traditionally been conceptualized through an event-based framework in which relapses, lesion accumulation, and disability progression evolve along a linear temporal axis. However, converging pathological, imaging, biomarker, and clinical trial evidence indicates that inflammatory activity, chronic lesion expansion, axonal degeneration, and network reorganization unfold with partially independent temporal dynamics. The 2024 revisions of the McDonald criteria formally incorporate markers of immune persistence and chronic inflammatory organization. Dissemination in space (DIS) remains the diagnostic entry point with a relaxation for the need of dissemination in time (DIT) yet prognosis cannot be reduced to event frequency alone. Disability accumulation reflects the interaction between Relapse-associated worsening (RAW) and progression independent of relapse activity (PIRA), revealing a decomposable hazard structure that challenges relapse-centered modeling. Traditional endpoints such as annualized relapse rate (ARR) and confirmed disability progression (CDP) capture partial projections of a higher-dimensional disease process. MS should therefore be understood not as an event-driven disorder but as a dynamically evolving system. Biological onset occurs before clinical presentation, diagnosis occurs at a threshold; progression unfolds as a trajectory through a multidimensional state space (MSS). Recognizing this distinction has direct implications for prognostic inference, trial design, biomarker integration, and state-dependent therapeutic modeling.

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.

BackgroundThree decades have passed since the initial approval of disease-modifying therapies (DMTs). Ongoing discussion is focused on fundamental aspects of the disease, highlighting a growing division between successes in managing relapsing multiple sclerosis (MS) and the persistent challenges posed by disease progression.MethodsA cohort study on prospectively acquired data from the Italian MS register. The primary outcome was to describe the MS disease course from onset to secondary progression (SP) defined according to a data-driven algorithm over 30 years follow-up and according to five different eras of disease onset.ResultsA total cohort of 9958 patients was analysed; 1364 converted to SP after a mean of 8.5 (SD 5.5) years. A higher rate of patients converting to SP had never been exposed to DMTs (135, 9.9% vs 424, 5.2%) than non-converting ones. The treatment coverage was also lower in patients converting to SP than non-converting ones 58.4 (SD 31.5) vs 73.6 (SD 27.6).The SP incidence rate was 1.26 (95% CI 1.19 to 1.32) overall. The rates showed a downward trend among the different eras: from 1st era 1.98 (95% CI 1.73 to 2.27) to 5th era 1.15 (95% CI 0.97 to 1.35).In the multivariable Cox model, 10% increase of treatment coverage was associated to 19% lower risk to convert to SP (10%, HR 0.89, 95% CI 0.87 to 0.90).ConclusionsThis 30-year analysis suggests that SP conversion rates have decreased over time, partially explained by improvements in therapeutic coverage. Future research should adopt a multifaceted approach to develop more comprehensive models of disease progression.

Background Multiple sclerosis (MS) involves a complex interplay between immune-mediated inflammation and neurodegeneration. Recent advances in biomarker research have provided new insights into the molecular underpinnings of MS, including ferritin, neurogranin, Triggering Receptor Expressed on Myeloid cells 2 (TREM2), and neurofilaments light chain. Objectives This pilot study aims to investigate the levels of these biomarkers in the cerebrospinal fluid (CSF) of MS patients and explore their associations with clinical, cognitive, and optical coherence tomography (OCT) parameters. Methods This cross-sectional pilot study included 26 patients with relapsing MS (RMS) and 13 symptomatic controls (SCs). Clinical, cognitive, and OCT assessments were performed, and CSF samples were analyzed for ferritin, neurogranin, TREM2, and neurofilaments. Results Neurogranin levels were significantly higher in RMS patients compared to SCs ( p  = 0.04), and the receiver-operating characteristic (ROC) analysis indicated that neurogranin could be considered a disease biomarker (AUC = 0.733, p  = 0.01). Ferritin and neurogranin showed a strong positive correlation ( r  = 0.690, p  < 0.01), and both were inversely correlated with retinal ganglion cell layer (GCL) thickness. TREM2 was positively associated with baseline Expanded Disability Status Scale score. Conclusion This pilot study suggests that neurogranin may be a potential biomarker at the time of MS diagnosis, and the interplay between ferritin, neurogranin, and TREM2 highlights the complex relationship between inflammation, oxidative stress, and neuronal damage in MS. The inverse association of ferritin and neurogranin with GCL thickness warrants further investigation into the role of iron metabolism and synaptic damage in the early stages of the disease.

Background: No consensus exists on the possibility to stop disease modifying therapies (DMTs) in Secondary Progressive Multiple Sclerosis (SPMS). Methods: The primary outcome was the time to reach 24-weeks confirmed Expanded Disability Status Scale (EDSS) 7.0. We enrolled all patients with a confirmed diagnosis of non-active SPMS (here, absence of clinical or radiological activity for at least 24 months before the conversion) between 1 January 2010 and 31 December 2015, at MS centers of Catania and Foggia, Italy. Patients were divided into two groups, according to the shared decision to stop DMTs (group A) or to maintain/switch to licensed interferon beta 1b for SPMS (group B). A Cox model adjusted with an inverse probability weighted propensity score (IPTW-PS) was employed. Results: A cohort of 311 patients was enrolled, 165 were in group A and 146 were in group B. Patients in the two groups were similar for baseline characteristics. The IPTW-PS adjusted Cox model for the event time to 24-weeks confirmed EDSS 7.0 did not show differences between the two groups (ExpB 0.96, CI 0.739–1.271, p = 0.819). Conclusions: In a real-world setting, in patients with non-active SPMS, the maintaining or switching to the licensed interferon beta 1b did not reduce the risk of reaching confirmed EDSS 7.0.

Several studies explored the effects of acetyl-L-carnitine (ALC) in dementia, suggesting a role in slowing down cognitive decline. Nevertheless, in 2003 a systematic review concluded there was insufficient evidence to recommend a clinical use, although a meta-analysis in the same year showed a significant advantage for ALC for clinical scales and psychometric tests. Since then, other studies have been published; however, a critical review is still lacking. We provide an update of the studies on ALC in primary and secondary dementia, highlighting the current limitations and translational implications. Overall, the role of ALC in dementia is still under debate. The underlying mechanisms may include restoring of cell membranes and synaptic functioning, enhancing cholinergic activity, promoting mitochondrial energy metabolism, protecting against toxins, and exerting neurotrophic effects. The effects of ALC on the gut–liver–brain axis seem to identify the category of patients in which the new insights contribute most to the mechanisms of action of ALC, likely being the liver metabolism and the improvement of hepatic detoxifying mechanisms the primary targets. In this framework, our research group has dealt with this topic, focusing on the ALC-related cross-talk mechanisms. Further studies with homogeneous sample and longitudinal assessment are needed before a systematic clinical application.

The management of multiple sclerosis (MS) in patients with significant comorbidities such as severe asthma presents unique therapeutic challenges. We report a case of successful combined biologic therapy with ofatumumab and mepolizumab in a patient with relapsing MS and pre-existing severe eosinophilic asthma, highlighting the feasibility and safety of dual biologic therapy. To our knowledge, this is the first report of concomitant use of ofatumumab and mepolizumab in a patient with MS and severe eosinophilic asthma, documenting the safety of a non-standard combination strategy in a real-world clinical scenario.

BackgroundCirculating microRNAs (MiRNAs) have been investigated for their role in fine-tuning the adaptive immune response to inflammatory factors and in Multiple Sclerosis (MS). They have been investigated as possible biomarkers for the diagnosis and prognosis of the disease.MethodsA cross sectional study conducted at the MS centre of Foggia, Italy. We enrolled patients with (1) an age between 18 and 55 years, (2) a definitive diagnosis of relapsing remitting MS (RRMS) as per the revised McDonald criteria, and (3) naïve to any disease modifying therapy (DMTs), as well as (4) patients with other neurological disorders (OND). The aim of the study was to compare the levels of expression of miRNA 21-5p, miRNA 106a-5p, miRNA 146a-5p, and miRNA223-3p in cell-free cerebrospinal fluid (CSF) in RRMS patients and OND. Investigated MiRNAs were extracted, retrotranscribed, and then assessed by real-time polymerase chain reaction assay (q-PCR). A receiver-operator characteristic (ROC) curve was used to test MiRNAs as a biomarker for diagnosing MS. A linear regression analysis was done to find any association with disease characteristics at the time of diagnosis.ResultsA total cohort of 70 subjects (70% women) was analyzed. Out of them, 35 had a RRMS diagnosis. MiRNA 106a-5p (7.8 ± 3.8 vs 1.3 ± 0.9, p=0.03) had higher levels in RRMS patients when compared to OND. The ROC curve indicated that MiRNA 106a-5p could be considered as a disease biomarker with an area under the curve of 0.812 (p<.001; 95% CI 0.686-0.937). Linear regression analysis showed an association between the number of oligoclonal bands and MiRNA 106a-5p levels (B-coeff 2.6, p<.001; 95% CI 1.3-4.9).ConclusionWe described miRNA 106a-5p as a possible signature in the CSF of RRMS patients in early phases of the disease. Further studies are needed to characterize its role in early MS as a disease biomarker.

Background: Multiple sclerosis (MS) is a complex and heterogeneous disease characterized by variable clinical outcomes. Objective: We aimed to develop a predictive model combining principal component analysis (PCA) and clustering techniques to identify biomarker sets associated with MS and characterize distinct phenotypes. Design: A monocentric, cross-sectional study on treatment naïve patients at the time of MS diagnosis. Methods: Clinical, laboratory, and neuroimaging data were collected, including retinal layer measurements via optical coherence tomography and neurofilament light (NFL) chains levels. Results: The cohort included 71 MS patients with mean age 35.7 years (SD = 9.8). PCA yielded five components with eigenvalues >1.0, explaining 68.1% of total variance. Component 1 showed strong negative coefficients for retinal thickness (ganglion cell-inner plexiform layer: −0.82, peripapillary retinal nerve fiber layer (RNFL): −0.79, macular RNFL: −0.75) and moderate positive coefficient for serum NFL (0.45). Component 2 featured high positive coefficients for NFL in cerebrospinal fluid (0.88) and serum (0.56). K-means clustering identified two distinct groups: one (n = 33) with thicker retinal layers, better cognitive performance, and unexpectedly higher serum NFL levels compared to the other group (n = 38). Conclusion: These findings suggest that MS may present with distinct phenotypic profiles even at diagnosis. Future longitudinal studies are needed to validate these early biomarkers and refine personalized treatment approaches.