To evaluate the long-term safety and potential neuroprotective effects of human fetal neural precursor cell transplantation in individuals with progressive multiple sclerosis. This retrospective observational study assessed long-term follow-up data (median 5.7 years) from participants in a first-in-human phase I trial (NCT03269071) investigating neural cell transplantation in progressive multiple sclerosis. Clinical and radiological available data were collected and compared to baseline values and reference populations. Long-term follow-up data were available for 11 of 12 patients. No serious adverse events related to cell transplantation occurred, confirming long-term safety. Although physical disability progressed over time, cognition remained stable compared to baseline. Five patients developed new T2-hyperintense brain lesions without associated contrast enhancement. Long-term gray matter atrophy rates were lower than those observed during the initial two years post-transplantation. Rates of gray and white matter atrophy approximated those of age-matched healthy individuals and patients with early-stage multiple sclerosis, with a trend for a lower atrophy rate compared to a control cohort with progressive disease. These structural findings were consistent with stable levels of circulating biomarkers of neurodegeneration. The findings support the long-term safety of fetal neural cell transplantation in progressive multiple sclerosis. Although exploratory in nature, the stability of cognitive function, reduced brain atrophy, and consistent biomarker profiles support the hypothesis of a possible neuroprotective effect that warrants further investigation in a controlled clinical trial setting.

People with multiple sclerosis (MS) often present with cognitive deficits that cannot fully be attributed to focal brain alterations. Whole-brain network changes show stronger relations, but MS network insights have mostly focused on either structural or functional (single-layer) networks, while recent work has shown the importance of multilayer frontoparietal network integration for cognition. Here, we explored the cognitive relevance of multilayer integration of the frontoparietal network in relapsing-remitting MS (n = 780) using diffusion and resting-state fMRI. Cognitive relations were first assessed for nodal multilayer eigenvector centrality, averaged over frontoparietal network nodes as a measure of integration, and post hoc for mean eccentricity for both single layer and multilayers. Higher multilayer frontoparietal network centrality was associated with worse Symbol Digit Modalities Test (SDMT) performance (β = -.117, p = .005). Mean eccentricity of single-layer diffusion (β = -.123, p < .001) and multilayer networks (β = .085, p = .018) were associated with SDMT performance. However, results could not be replicated using a different anatomical parcellation. This study showed that cognition in MS is related to multilayer network parameters. Nevertheless, correlations were weak and atlas specific, suggesting that a binary structure-function multilayer network approach is not particularly relevant as a correlate of cognition in MS.

Altered cerebellar resting-state functional connectivity (FC) may contribute to hand motor impairment in People with Multiple Sclerosis (PwMS). We aimed to assess whether: 1. FC abnormalities of the sensorimotor and cognitive cerebellum (smCb, cCb) are associated with impaired hand dexterity; 2. these alterations contribute to impaired hand dexterity beyond structural brain and spinal cord damage. Six hundred and sixty-seven subjects from the Italian Neuroimaging Network Initiative database were included: two hundred forty-eight PwMS with impaired (iPwMS) and two hundred forty-eight with preserved hand dexterity (pPwMS), and one hundred seventy-one healthy controls (HC). We obtained measures of white matter lesion load, cortical, deep gray matter and cerebellar volumes, and C2–C3 spinal cord area. Cerebellar FC of the smCb and cCb was evaluated using voxel-wise seed-based analyses. Group comparisons were performed using ANCOVA models, with and without adjusting for global and regional structural measures. Compared to HC and pPwMS, iPwMS showed widespread FC reductions of both smCb and cCb in several cortical, subcortical, and cerebellar regions (p < 0.05, FDR-corrected), whereas pPwMS did not differ significantly from HC. After adjusting for structural measures, FC reductions in iPwMS persisted, although to a lesser extent, particularly in cortical and cerebellar regions. Cerebellar FC reductions involving both sensorimotor and cognitive domains are robustly associated with impaired hand dexterity in PwMS and remain significant even after controlling for brain and spinal cord structural damage. This suggests that cerebellar FC alterations are a key, only partly structure-dependent contributor to dexterity impairment, highlighting cerebellar connectivity as a promising target for motor rehabilitation in MS.

INTRODUCTION:Recent randomised trials have questioned the benefit of endovascular therapy (EVT) for MeVO stroke, but data from clinical practice are limited. This study aimed to assess the effectiveness and safety of EVT, with or without intravenous thrombolysis (IVT), vs IVT alone in MeVO stroke using registry-based real-world data. PATIENTS AND METHODS:This retrospective multicentre study included patients from 82 Italian centres in the Safe Implementation of Treatments in Stroke (SITS) registry (January 2020-December 2023). Adults with acute ischaemic stroke due to MeVO (ACA A1/A2, MCA M2/M3 or more distal or PCA P1/P2), treated with IVT or EVT ± IVT, and with available 90-day mRS scores were included. Patients with tandem occlusions were excluded. Propensity score matching (1:1) was used to balance baseline variables. Primary outcome was functional independence (mRS 0-2) at 90 days. Secondary outcomes included in-hospital mortality, intracranial haemorrhage incidence and recanalisation status. RESULTS:Among 1375 total patients, 780 were included and matched (390 per group) by propensity score. Baseline characteristics were balanced. Functional independence at 90 days was achieved in 60.6% of EVT ± IVT patients vs 60.9% in the IVT-only group (odds ratio [OR] 0.99; 95% CI, 0.73-1.34; P = .939). When restricted to patients with baseline mRS < 2, functional independence rates remained comparable between groups, confirming the primary findings. In-hospital mortality was non-significantly lower in the EVT ± IVT group (5.4% vs 8.7%, P = .069). Symptomatic intracranial haemorrhage rates were comparable between groups, although overall haemorrhagic complications were higher with EVT (18.4% vs 11.2%, P < .0001). Stratified analyses by stroke severity and treatment timing showed consistent lack of benefit across all subgroups (all interaction P-values > .05). DISCUSSION:The absence of functional benefit from EVT observed in this real-world cohort is consistent with the results of the ESCAPE-MeVO and DISTAL randomized trials. Notably, the higher rate of any intracranial haemorrhage in the EVT group (18.4% vs 11.2%), driven primarily by minor haemorrhagic events, represents a clinically meaningful safety concern that must be weighed against the lack of demonstrated efficacy. A hypothesis-generating signal was observed in patients treated within 180 minutes (OR 2.16, 95% CI 1.06-4.38), warranting prospective investigation. The retrospective design and the limitations inherent to registry-based data, including incomplete procedural data and anatomical heterogeneity in MeVO classification, should be considered when interpreting these findings. CONCLUSIONS:Endovascular therapy did not improve long-term functional outcomes compared to IVT alone in MeVO stroke but was associated with higher haemorrhagic risk. These findings support a cautious approach to EVT in this setting, in line with recent trial evidence.

BACKGROUND/OBJECTIVES:Characterizing spinal cord multiple sclerosis (MS) lesions in MRI is critical for diagnosis, monitoring, and treatment evaluation. However, current automated approaches for lesion detection and segmentation are typically designed for specific MRI contrasts or acquisition sites, limiting their generalizability in real-world clinical settings where imaging protocols vary widely. This work proposes a robust multi-site, multi-contrast segmentation framework for spinal cord lesions. METHODS:The segmentation model was trained and evaluated on a large-scale dataset comprising 4428 annotated images from 1849 persons with MS across 23 imaging centers, encompassing six MRI contrasts (T1w, T2w, T2*w, PSIR, STIR, and UNIT1) acquired at 1.5 tesla (T), 3 T, and 7 T. RESULTS:Likert-type assessment performed by neuroradiologist ratings demonstrated superior generalization of the model compared to existing contrast-specific pipelines (p < 0.01). Additional experiments evaluated robustness across spinal levels, acquisition resolutions, binarization thresholds, and quantitative evaluation on external labeled datasets. CONCLUSIONS:The proposed model can achieve accurate and reliable spinal cord MS lesion segmentation across heterogeneous MRI data, addressing a key barrier to clinical translation. The model is available in the Spinal Cord Toolbox v7.2 and higher.Code repository: https://github.com/ivadomed/seg-sc-ms-lesion-multicontrast.

Background. RehaCom, a computerized cognitive rehabilitation program for people with multiple sclerosis (PwMS), has been studied primarily in relation to treatment "dose" (duration, frequency, and adherence), with less focus on which training modules drive improvement or which participant factors predict responsiveness. This secondary analysis of the CogEx trial investigated whether progression within specific RehaCom modules was associated with processing speed improvement, measured by the SDMT, and whether baseline characteristics predicted response in participants with progressive MS. Methods. A total of 153 participants completed 12 weeks of RehaCom training across 5 attention-based modules. Cognition was assessed at baseline, 12 weeks, and 6 months using the SDMT. Correlation and regression analyses evaluated associations between module progression and cognitive outcomes. Results. Progression correlated significantly with SDMT improvement in 4 modules, with the strongest effects for Attention/Concentration (r = .37, P < .001) and Divided Attention-2 (r = .36, P < .001). Higher baseline SDMT, higher premorbid IQ, older age, and greater module progression independently predicted better SDMT performance at12-weeks (adjusted R-2 = .73). At 6 months, higher baseline SDMT, greater progression in Attention/Concentration and Divided Attention-2, older age, and female sex predicted better SDMT performance (adjusted R-2 = .71). Conclusion. Processing speed gains in progressive MS were related to both module-specific progression and participant characteristics, supporting a precision approach to cognitive rehabilitation that tailors training content to individual cognitive profiles. This study is a secondary analysis of the CogEx trial (ClinicalTrials.gov Identifier: NCT03679468; https://clinicaltrials.gov/ct2/show/NCT03679468).

BackgroundSecondary progressive multiple sclerosis (SPMS) encompasses heterogeneous phenotypes that may or may not exhibit disease activity.ObjectivesTo characterize a cohort of non-relapsing SPMS (nrSPMS) identified through a data-driven definition adapted from the HERCULES trial criteria, compared with neurologist-defined (ND) SPMS.MethodsRelapsing MS patients were retrospectively extracted from the Italian Multiple Sclerosis Register (RISM). ND was defined according to clinical criteria for SPMS and the HERCULES cohort adapting the trial inclusion criteria. Progression independent from relapse activity (PIRA) and relapse-associated worsening (RAW) events were assessed. Diagnostic performances of SPMS definitions were evaluated.ResultsAmong 20,306 patients, 866 (4.26%) were classified as SPMS by ND and 1603 (7.89%) by HERCULES criteria. The HERCULES group included older patients, less likely to relapse post-conversion. PIRA occurred in 88.8% of ND and 88.5% of HERCULES-defined cases, with a shorter median time to first PIRA in the latter. The HERCULES definition showed high specificity (93.4%) and low sensitivity (37.6%).ConclusionsHERCULES-adapted criteria identified a subgroup of 7.9% nrSPMS patients in the real-world cohort of RISM, characterized by fewer post-conversion relapses and earlier PIRA onset. These findings reinforce the value of applying standardized algorithmic definitions of SPMS in registry-based studies.

Background Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by JC polyomavirus (JCV), affecting immunocompromised individuals. We describe PML demographic, clinical, radiological, and laboratory characteristics and survival over time and according to underlying condition in a large retrospective patient cohort. Methods This is a retrospective cohort including Italian PML patients observed between 1987 and 2024, with known year of diagnosis and underlying disease. Results We included 456 cases with either a definite (n = 376, 82.4%) or clinico-radiological (n = 80, 17.6%) PML diagnosis. The relative frequency of human immunodeficiency virus (HIV)-associated cases decreased through four time periods (1987-1996; 1997-2004; 2005-2012; 2013-2024) from 99% to 43%, in parallel with increasing age (P < .0001), proportion of women (P < .001) and CD4(+) counts (P < .001) but not cerebrospinal fluid (CSF) or plasma JCV-DNA levels at diagnosis. One-year survival probability increased from 23.8% in 1987-1996 to 59.2% in 2013-2024, with highest values in natalizumab-treated multiple sclerosis (93.8%), followed by combination antiretroviral treatment (cART)-treated HIV infection (55%), hematological malignancies (50.8%), primary immunodeficiencies (41.3%), and cART-untreated HIV infection (11.9%). At multivariate analysis excluding cART-untreated people with HIV, JCV-DNA levels in both CSF and plasma were independently associated with an increased mortality risk of 2.9% and 7.2%, respectively, for each Log increase in JCV-DNA. Conclusions This observational study showed a changing epidemiological context over 37 years. Although survival improved over time, it remained poor even in the last decade, with a one-year survival probability of 59.2%

Demyelinating diseases, particularly multiple sclerosis (MS), present a unique therapeutic challenge in the management of inflammatory bowel disease (IBD). Although rare, the co-occurrence of IBD and demyelinating disorders is well-documented and may reflect shared immune, genetic, and environmental risk factors. As the therapeutic landscape of IBD expands to include biologics and small molecules that target immune pathways also implicated in MS, concerns around neurological safety have grown. In particular, anti-tumor necrosis factor agents have been consistently linked to new-onset or worsening demyelinating events, while other treatments such as sphingosine-1-phosphate receptor modulators and natali­zumab are licensed for both IBD and MS, though real-world data in patients with coexisting disease remain limited. This review synthesizes current evidence regarding the neurological safety and efficacy of IBD therapies in the context of demyelinating disease. It proposes a practical framework for clinicians, addressing management strategies for patients with confirmed MS, those at increased risk, and individuals who develop neurological symptoms during treatment. In the absence of formal guidelines, multidisciplinary collaboration, early recognition of symptoms, and careful treatment selection are important to optimize both gastrointestinal and neurological outcomes.

Emerging therapies for progressive multiple sclerosis (PMS) increasingly target CNS-compartmentalized inflammation driving progression independent of relapse activity. Six pivotal trials are evaluating Bruton's tyrosine kinase inhibitors, CD40-CD40L blockade, and CD19-directed CAR-T cells. Together, these studies may establish mechanism-based strategies to modulate microglia and B cell pathology, redefining treatment of progression and addressing a major unmet clinical need.

Cues are specific references that support motor performance by improving speed, timing, and amplitude while reducing variability. This study aimed at investigating the effects of external auditory cueing on bradykinesia-related kinematic deficits and their neural correlates during a hand-tapping task in people with Parkinson’s disease (pwPD) and healthy controls (HC). Twenty-six pwPD and 20 HC performed a right hand-tapping fMRI task either in a self-paced condition (NOCue) or following an auditory cue (Cue). Hand-tapping kinematics were objectively quantified using an optical-fiber glove. PwPD showed reduced hand-tapping amplitude and a greater sequence effect on amplitude than HC during NOCue condition. Cueing attenuated the sequence effect on amplitude in pwPD. During the NOCue condition, pwPD showed reduced activity of pallidum/thalamus relative to HC. No group differences emerged during Cue condition. During Cue relative to NOCue condition, pwPD showed higher activity of pallidum, parietal, temporal, sensorimotor, insular, and cerebellar regions, alongside reduced activation in of paracentral gyrus and cerebellum. Higher activity of pallidum correlated with better motor performance and higher positive effects of cueing. Our results demonstrated that auditory cueing reduces bradykinesia in pwPD possibly by facilitating basal ganglia activity and reducing the need of movement programming.

BACKGROUND:Identifying long-term outcome substrates in pediatric multiple sclerosis (Ped-MS) can inform treatment selection. We investigated clinical/magnetic resonance imaging (MRI) correlates over a median 12.3-year follow-up. METHODS:Fifty-two Ped-MS patients and 23 healthy controls underwent baseline 3.0 T MRI. Neurological evaluations were performed every 6 months. MRI metrics included regional lesion burden, brain and choroid plexus (CP) volumes, diffusion tensor-derived fractional anisotropy (FA), averaged in normal-appearing white matter (NAWM). Multivariable Cox, Andersen-Gill, linear regression models identified long-term outcome correlates. RESULTS:At follow-up, 69% relapsed, 21% had 6-month confirmed disability worsening (6m-CDW), and 35% showed EDSS worsening. Infratentorial lesion number (hazard ratio (HR) = 1.09, 95% confidence interval (CI) = 1.02 to 1.18), spinal cord lesion presence (HR = 2.45, 95% CI = 1.18 to 5.10), and thalamic volume (HR = 0.77, 95% CI = 0.60 to 0.99) were associated with shorter time to first relapse; high-efficacy treatment (HET) exposure with longer (HR = 0.20, 95% CI = 0.06 to 0.68), and CP volume (HR = 1.58, 95% CI = 0.93 to 2.68) was associated marginally. WM lesion volume (HR = 1.04, 95% CI = 1.01 to 1.06) and HET exposure (HR = 0.21, 95% CI = 0.11 to 0.40) were associated with higher/lower overall relapse risk, respectively; baseline EDSS (HR = 1.29, 95% CI = 0.96 to 1.73), spinal cord lesion presence (HR = 1.52, 95% CI = 0.95 to 2.44), and CP volume (HR = 1.35, 95% CI = 1.00 to 1.83) contributed marginally. Younger age (HR = 0.82, 95% CI = 0.68 to 0.98) and NAWM FA (HR = 0.67, 95% CI = 0.51 to 0.88) were associated with earlier 6m-CDW; NAWM FA with EDSS worsening (β = -0.26, 95% CI = -0.50 to -0.03). CONCLUSION:Advanced MRI markers and HET exposure associate with long-term outcomes in Ped-MS.

The therapeutic scenario for multiple sclerosis (MS) has expanded rapidly over the last few years. Among the available treatments, anti-CD20 monoclonal antibodies, including rituximab, ocrelizumab, ofatumumab, and ublituximab, have shown significant results in reducing disease activity and slowing progression, particularly in relapsing MS. The distinct mechanisms of action, including the pharmacokinetic and pharmacodynamic profiles as well as the immunogenicity of these drugs, require careful consideration to tailor treatment for individual patients. A comprehensive review of the literature was conducted by searching PubMed and evaluating key studies, trials, and congress abstracts related to the use of anti-CD20 monoclonal antibodies. The analysis focused on the pharmacokinetic and pharmacodynamic profiles, as well as the immunogenicity, of anti-CD20 therapies currently available, with particular emphasis on the recently approved ublituximab. Ocrelizumab is effective in both relapsing-remitting and primary-progressive MS, using antibodydependent cellular cytotoxicity (ADCC) as its primary mechanism of action, with intravenous and subcutaneous administration options ensuring flexible treatment delivery. Ofatumumab depletes B-cells through enhanced complement-dependent cytotoxicity, offering convenient monthly subcutaneous self-administration. Ublituximab's unique glycoengineered fragment crystallizable region enhances ADCC, resulting in rapid B-cell depletion and potentially improving its safety profile. Ublituximab allows for a shorter infusion time without requiring post-infusion monitoring after the second dose, provided there have been no prior reactions. Understanding the characteristics of different anti-CD20 monoclonal antibodies is critical for optimizing treatment, enhancing patient outcomes, and minimizing treatment burden. Ublituximab represents a promising option, offering a shorter infusion time and higher ADCC activity, which complements existing treatments such as ocrelizumab and ofatumumab.