Search Results (119)

Neurodegenerative diseases (NDDs), including Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), are becoming more prevalent and still lack effective disease-modifying therapies (DMTs). However, translational efficiency remains critically low. For example, a ClinicalTrials.gov analysis of AD programs (2002–2012) estimated ~99.6% attrition, while PD programs (1999–2019) achieved an overall success rate of ~14.9%. In vitro platforms are assessed, ranging from immortalized neuronal lines and primary cultures to human-induced pluripotent stem cell (iPSC)-derived neurons/glia, neuron–glia co-cultures (including neuroinflammation paradigms), 3D spheroids, organoids, and blood–brain barrier (BBB)-on-chip systems. Complementary in vivo toxin, pharmacological, and genetic models are discussed for systems-level validation and central nervous system (CNS) exposure realism. The therapeutic synthesis focuses on AD, covering symptomatic drugs, anti-amyloid immunotherapies, tau-directed approaches, and repurposed drug classes that target metabolism, neuroinflammation, and network dysfunction. This review links experimental models to translational decision-making, focusing primarily on AD and providing a brief comparative context from other NDDs. It also covers emerging targeted protein degradation (PROTACs). Key priorities include neuroimmune/neurovascular human models, biomarker-anchored adaptive trials, mechanism-guided combination DMTs, and CNS PK/PD-driven development for brain-directed degraders. Full article

Multiple sclerosis (MS) is a chronic neuroinflammatory and autoimmune disorder of the central nervous system (CNS) whose cause remains unknown. Disease-modifying therapies (DMTs) are the current standard of care, yet growing evidence highlights the importance of complementary lifestyle-based interventions, including nutrition, in modulating disease activity. Given the influence of diet on immune function, several studies have examined its effects in MS, with particular attention to specific dietary patterns and macronutrients. However, fewer studies have focused on micronutrients, bioactive compounds, and minerals and their influence in MS. In this narrative review, we report the latest evidence on micronutrients such as vitamins and essential metals, along with polyphenols and minerals like salt, in both experimental autoimmune encephalomyelitis (EAE) and MS. We also discuss how these dietary components may influence the gut microbiota, which is considered a contributor to disease onset due to its interaction with the immune system in the gut–brain axis. While findings for vitamins B, C, E, and K remain heterogeneous, vitamins A and D show the most consistent immunological and clinical effects, with immunomodulatory, antioxidative, and neuroprotective effects in both EAE and MS. Polyphenols also display anti-inflammatory and neuroprotective properties in EAE and, to a lesser extent, in clinical studies. Lastly, evidence suggests the importance of balanced salt intake and adequate levels of essential metals, as dysregulation may contribute to comorbidities or enhance inflammatory pathways relevant to MS. Although only a limited number of studies have explored these aspects, the gut microbiota appears to be differentially affected by these dietary factors. Overall, advancing our understanding of how these components interact with immune and microbial pathways may support the development of personalized nutritional strategies to complement current therapies and improve patient outcomes. Full article

Background: Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS), characterised by inflammation, demyelination, and progressive neurodegeneration. Although current disease-modifying therapies (DMTs) can reduce relapse rates and inflammatory activity, they rarely stop long-term progression or repair neurological damage. In recent years, cell-based therapies have emerged as promising approaches to promote immune regulation and neuroregeneration in MS. Methods: This review summarises the current clinical evidence from studies in humans investigating cell-based treatments for MS, including autologous haematopoietic stem cell transplantation (AHSCT), mesenchymal stem cells (MSCs), and neural stem or progenitor cells (NSCs). A systematic literature search was performed using PubMed, Scopus, and ClinicalTrials.gov, focusing on human clinical trials that met specific inclusion criteria. Results: Prevailing findings show that AHSCT provides the most consistent benefit, achieving long-term immune reconstitution and remission in patients with highly active relapsing–remitting MS (RRMS), although it carries procedural risks. MSC therapies have demonstrated good safety and biological activity, especially when delivered intrathecally (IT) in progressive MS, though clinical results remain variable. Conclusions: NSC-based treatments are still at an early stage of clinical research but show potential for CNS repair. The main limitations across studies include differences in protocols, small sample sizes, and short follow-up periods. Further large-scale, randomised controlled trials are needed to confirm long-term efficacy, define optimal delivery methods, and establish standardised clinical protocols. Full article

Background/Objectives: Very early pediatric-onset multiple sclerosis (POMS) is rare; clinical studies using disease-modifying treatments (DMTs) have not been performed. Clinicians rely on studies performed at older ages. This review resulted from difficulties faced by clinicians and the off-label use of DMTs at this age. Methods: A literature review of studies dated between 1982 and 2025 on very early POMS, specifically with onset before age 5, has been performed, searching for outcomes without or with DMTs. The curated database of the selected patients was analyzed using computed descriptive and integrated cohort-level estimates. The clinical, paraclinical, treatment, and outcome characteristics were analyzed. Statistical analysis used JASP, with GenAI-assisted verification. The treatment outcome of a 16-year-old patient with very early POMS starting at 2 years 4 months that consecutively received interferon, immunoglobulin, and Natalizumab is presented. Results: A total of 101 patients with very early POMS presented, at onset, with ataxic syndrome (57.4%), pyramidal syndrome (41.4%), ophthalmoplegia (10.3%), and optic neuritis (6.9%). In evolution, 22.7% had seizures. Half of the patients were not treated. Among those treated, acute steroid therapy was administered; 11 received the DMTs interferon, Glatiramer acetate, Dimethyl fumarate, and Azathioprine (three), with only two high-efficacy therapies (Natalizumab and Rituximab). Our patient had partial remission under interferon, relapses when stopped and replaced by immunoglobulin and 9 years relapse-free interval when Natalizumab was introduced. Conclusions: Early treatment with high-efficiency DMTs should be considered in very early POMS; association with known increased neuroplasticity at this age may improve prognosis, allowing good recovery of acquired disability. Full article

Background: The role of age and time-dependent variables in determining the response to disease-modifying therapies (DMTs) has aroused growing interest in the Multiple Sclerosis (MS) field. Although it is a very hot topic, related literature on the subject is considerably lacking. Objectives: The aim of this study is to deepen the understanding of how time-dependent variables influence disability accumulation and drug response in an MS population, assuming DMF as the first-line treatment, and to expand our knowledge of the risk–benefit evaluation of DMF. Methods: We investigated, in a real-world setting, the efficacy of Dimethyl Fumarate (DMF) in naive versus switcher MS patients, correlated with age, in preventing disability accumulation. Starting from an initial population of 234 DMF-treated patients, we selected 169 of them based on their similar time in therapy (TinT) with DMF of 5.9 ± 2.3 year and sex ratio. Of these, 74 were naive and 95 were lateral switchers at the start of treatment. The mean Expanded Disability Status Scale (EDSS), Disease Duration (DD), age and age at onset were compared between groups. Results: The switcher group showed higher EDSS and age compared to the naive group (2.7 vs. 1.8, p < 0.001; 40.2 vs. 35.5, p = 0.005, respectively). Age correlated with DD, EDSS and age at onset in both naive (r = 0.39, p = 0.007; r = 0.53, p = 0.000; r = 0.63, p = 0.000, respectively) and switcher (r = 0.46, p = 0.002; r = 0.49, p = 0.000; r = 0.61, p = 0.000, respectively) groups. Kaplan–Meier curves, adjusted for age, also indicated that the naive group retained an EDSS score status of 0.5–3.5 more frequently (p < 0.001) and reached elevated disability less frequently (p = 0.002) than switchers. The mean EDSS percentage ratio between paired naive and switcher patients, representing the differential neurological impairment (DNI), was 69%, inversely correlating with age in both naive (r = −0.52, p < 0.001) and switcher patients (r = −0.47, p < 0.001). Finally, logistic regression analysis indicated age as an independent and predictive variable with respect to EDSS. Conclusions: We conclude that age is the main contributor to disability progression and the primary predictive factor for treatment effectiveness for DMF in both naive and switcher MS patients. Full article

Background/Objectives: Gaucher disease (GD) is a lysosomal disorder caused by a deficiency of β-glucosidase. Disease-modifying therapies (DMTs) include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). Glucosylsphingosine (lyso-Gb1) is a biomarker with high sensitivity and specificity in GD. Methods: In GD patients attending a specialist centre, we evaluated dried blood spot lyso-Gb1 levels (normal values ≤ 6.8 ng/mL) by treatment status, sex, GD type and genotype, ERT dose, DMT type and duration, spleen status, and association with other GD biomarkers. Results: A total of 111 patients were screened; 100 (54M:46F; 93 GD1 and 7 GD3; median age 45.2 years, IQR 34.2–57.2; 7 naive and 93 patients on DMTs for a median of 10.4 years, IQR 5.7–21.2) had at least one lyso-Gb1 measurement. Median lyso-Gb1 values were higher in naïve (195, IQR 48.6–388) patients than treated patients (47.1, IQR 23.1–89.7), p = 0.015; higher in those treated ≥ 15 years (62.9, IQR 36.6–103) than in those treated < 15 years (35.1, IQR 20.3–73.9), p = 0.006; and higher in splenectomised (83.4, IQR 34.7–224.5) patients than non-splenectomised patients (40.7, IQR 21.4–77.1), p = 0.044. ERT dose > 60 U/kg had high median lyso-Gb1 values (87.3, IQR 19.7–126), reflecting greater disease burden, and this high dose was only used in patients with GD3. Lyso-Gb1 correlated with chitotriosidase (r = 0.495; p < 0.001) and haemoglobin (r = −0.231; p = 0.022). In a subset of 50 patients with paired values, lyso-Gb1 decreased from baseline (median −1.7 ng/mL, IQR −24.5–14.8). Conclusions: Whilst there was a modest decrease in lyso-Gb1 over time on DMTs, the values remained significantly above the normal range, which may be driven by underlying mechanisms such as inflammation. Full article

Background: Sleep disturbances in the multiple sclerosis (MS) population are increasingly recognized, but the factors driving this association remain understudied. This study aimed to determine the prevalence and associations of poor sleep quality in the relapsing–remitting MS (RRMS) population receiving disease-modifying therapy (DMT). Methods: We conducted a cross-sectional study that enrolled 399 individuals diagnosed with RRMS on DMT. Data on patient demographics, clinical presentation, and treatment were systematically evaluated. Sleep-related outcomes were assessed using validated questionnaires—the Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), STOP-Bang questionnaire, and Hamilton Anxiety Rating Scale (HAM-A). Independent associations of poor sleep were examined using log-binomial regression to estimate risk ratios (RR). Results: Poor sleep was reported in 42% of the participants in our cohort. In multivariable analysis, only insomnia severity (RR = 1.07; 95% CI 1.05–1.09, p < 0.001) and anxiety (RR = 1.02; 95% CI 1.01–1.04, p = 0.001) remained independently associated with poor sleep. Conclusions: Sleep disturbances are common among patients with RRMS. Insomnia severity and anxiety, rather than demographic or disease-related characteristics, showed independent associations with impaired sleep. Routine screening and targeted interventions addressing insomnia and anxiety may improve sleep quality and, consequently, overall quality of life in this population. Full article

Background: Current disease-modifying therapies (DMTs) for multiple sclerosis (MS) attenuate pathogenic immune responses but are limited by safety and tolerability concerns. Antigen-specific tolerance approaches provide targeted immunomodulation yet remain constrained by their dependence on known autoantigens. LPX-TI641, an orally bioavailable, clinical-stage small-molecule agonist of Tim-3/4, represents an antigen-independent strategy to restore immune tolerance by expanding regulatory T cells (Tregs). Methods: LPX-TI641 was evaluated in vitro for its ability to induce Treg populations in murine splenocytes. Therapeutic efficacy was assessed in vivo using MOG_35–55- and PLP_139–151-induced experimental autoimmune encephalomyelitis (EAE) mouse models. Ex vivo, peripheral blood mononuclear cells (PBMCs) from people with MS (PwMS) were analyzed for Treg phenotype and function in response to LPX-TI641. Results: LPX-TI641 induced dose-dependent expansion of CD4⁺Foxp3⁺ and CD4⁺Foxp3⁺Tim-3⁺ Tregs in vitro. In EAE models, treatment significantly reduced disease severity, prevented relapses, and maintained clinical benefit after discontinuation. In PBMCs from patients with MS, LPX-TI641 restored diminished Tim-3⁺ Treg populations and reversed Treg dysfunction in recall assays. Efficacy in animal models was comparable to or exceeded that of high-efficacy DMTs, including natalizumab. Conclusions: LPX-TI641 promotes antigen-independent immune tolerance through Tim receptor agonism and Treg expansion. These findings support its potential as a novel therapeutic candidate for MS, addressing the limitations of current DMTs. Full article

Background: Multiple sclerosis (MS) is a chronic auto-immune neuroinflammatory disorder presenting as a range of systemic and neurological symptoms, including cognitive impairment. Emerging evidence suggests that diets targeting brain health—such as the Mediterranean (MED) and Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diets—may improve cognitive function; however, studies examining their role in people living with MS are limited. Methods: We examined cross-sectional associations between diet and cognition data from 967 participants in the United Kingdom Multiple Sclerosis Register (UKMSR). Dietary pattern scores (alternate Mediterranean; aMED, and MIND) were derived from the 130-item EPIC-Norfolk food frequency questionnaire. Cognition was assessed using the MS-specific Cognitron-MS (C-MS) battery (13 tasks) and summarised as overall cognition (global G factor) and four domains (object memory, problem solving, information processing speed [IPS], and words memory). Cognitive outcomes were expressed as Deviation-from-Expected (DfE) scores standardised to demographic and device characteristics using external regression-based norms. Linear models were adjusted for total energy intake, MS phenotype, disease duration since diagnosis, and current disease-modifying therapy (DMT) use. Interactions tested moderation by MS phenotype (relapsing vs. progressive MS) and current DMT use (yes vs. no). Sensitivity analyses included within-domain multiple-comparison control, rank-based inverse-normal transformation, and winsorisation. Results: Greater alignment with aMED and MIND dietary patterns were associated with higher scores in specific cognitive domains but not in overall cognition. Higher aMED scores were associated most consistently with better IPS, while higher MIND scores were additionally associated with better words memory. In categorical models, participants with the middle or highest tertiles of aMED or MIND scores performed up to ~0.4 SD better on tasks of Verbal Analogies, Word Definitions, Simple Reaction Time, Words Memory Immediate, or Words Memory Delays compared with those in the lowest tertile. These findings were robust across sensitivity analyses. Stratified analyses showed differential cognitive performance and diet-cognition associations by MS phenotype and DMT use. Conclusions: Mediterranean and MIND dietary patterns showed modest cross-sectional associations with specific cognition domains, with differential cognitive performance in different subgroups according to MS phenotype and DMT use. Although causal inference is not possible, our findings indicate future MS-related dietary studies (longitudinal and/or randomised controlled trials) examining cognitive function domains across different MS subgroups are warranted. Full article

Background: Spinal Muscular Atrophy type 1 (SMA type 1) is a genetic neuromuscular disease that typically presents before 6 months of age and is characterized by profound hypotonia, progressive muscle weakness, and early involvement of respiratory and bulbar musculature. Swallowing impairment (dysphagia) is a hallmark of SMA type 1 and significantly contributes to morbidity. Despite the documented benefits of disease-modifying therapies (DMTs) in terms of enhanced survival and motor outcomes, their impact on swallowing remains understudied. Aim: This study aims to longitudinally characterize swallowing function in children with SMA type 1 treated with DMTs, while contextualizing these findings in relation to the patients’ current motor abilities and cognitive performance. Materials and Methods: A single-center, longitudinal, observational study was conducted at IRCCS Besta, Milan, Italy, from 2021 to 2025. Swallowing function was evaluated using four validated scales (MAS, OrSAT, FILS, and p-FOIS), while motor and cognitive functions were assessed using CHOP-INTEND and age-appropriate cognitive tests (DQ/IQ). Patients were stratified by baseline swallowing status, pharmacological therapy, and age at DMT administration. Non-parametric statistical tests were applied. Results: No statistically significant changes in swallowing function were observed over one year in the overall cohort or its subgroups, despite significant improvements in motor function. MAS/e, FILS, and p-FOIS showed moderate associations with CHOP-INTEND and DQ/IQ scores. Conclusions: Swallowing function in children with SMA type 1 remained largely stable, while motor function significantly improved over one year, regardless of baseline swallowing status, DMT type, and age at administration. These findings underscore the need for standardized, longitudinal assessments of swallowing, motor, and cognitive functions in the management of SMA type 1. Full article

Background/Objectives: Multiple sclerosis (MS) is an autoimmune disorder affecting the central nervous system, characterised by the degradation of myelin, which results in various neurological symptoms. This study aims to utilise radiomics features to evaluate the predictive value of IVIM diffusion parameters, namely, the true diffusion coefficient (D), pseudo-diffusion coefficient (D*), and perfusion fraction (f), in relation to disability severity, assessed using the Expanded Disability Status Scale (EDSS), and mobility in patients with relapsing–remitting MS. Methods: This retrospective cross-sectional study analysed MRI data from 197 patients diagnosed with multiple sclerosis (MS). Quantitative intravoxel incoherent motion (IVIM) parameters were obtained using a 1.5 Tesla MRI scanner. Clinical information collected included age, disease duration, number of relapses, status of disease-modifying therapy (DMT), and the need for mobility assistance. Machine learning (ML) techniques, such as XGB, Random Forest, and ANN, were employed to explore the relationships between radiomic IVIM parameters and these clinical variables. Results: IVIM radiomics achieved high accuracy in lesion phenotyping. Random Forest distinguished enhancements from non-enhancing lesions with 96% accuracy and AUC = 0.99 with IVIM-f and D* maps. CNN also reached ~92% accuracy (AUC 0.97) with IVIM-f. For disability prediction, IVIM-D and D* radiomics strongly correlated with EDSS: Random Forest achieved 89% accuracy (AUC = 0.90), while CNN achieved 90% accuracy (AUC = 0.95). Mobility impairment was predicted with the highest performance—RNN achieved 96% accuracy (AUC = 0.99) across IVIM-f features. In contrast, relapse history, disease duration, and treatment status were poorly predicted (<75% accuracy). Conclusions: ML analyses of IVIM metrics provided independent predictors of functional impairment and disability in MS. Our novel approach may be used to improve diagnostic accuracy and develop personalised treatment strategies for MS patients. Full article

Pruritus (itching) is an underrecognized but often debilitating symptom in patients with central nervous system (CNS) demyelinating diseases, including multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). It is often considered a paroxysmal symptom. Although less studied than pain or spasticity, pruritus can significantly impair the quality of life. This review aims to provide a comprehensive overview of the pathophysiological mechanisms underlying pruritus in demyelinating CNS disorders, its clinical presentations, and the available treatment options. We explore the central origins of neuropathic itch, focusing on spinal cord, brainstem, and cerebral lesions, with particular emphasis on white matter involvement and spinothalamic tract dysfunction. In addition, we review pruritus triggered or exacerbated by disease-modifying therapies (DMTs) used in MS and NMOSD. Full article

Background and Objectives: Ofatumumab (OFA) is the first fully human anti-CD20 monoclonal antibody approved for the treatment of RRMS classified as a high-efficacy treatment agent. Real-world evidence is essential for evaluating the effectiveness and safety of OFA. Materials and Methods: A total of 184 patients (72.3% women, mean age 38 years (±10.9), 51 naïve patients and 133 after switch. Among them, 142 patients were evaluated after first 12-months of treatment according to relapse rate, neurological status expressed by Expanded Disability Status Scale (EDSS), new T2-weighted (T2-w) lesions and gadolinium-enhancing lesions (GELs) in magnetic resonance imaging (MRI), confirmed disability progression, as well as adverse events. Logistic regression identified factors associated with disease activity at ofatumumab initiation, including age, sex, disease duration, prior treatment, and baseline EDSS. Results: After the first 12 months of OFA treatment, relapses occurred in 12.0% of patients; new or enlarging T2-w lesions were observed in 12.7%; GELs in 3.5%; EDSS progression in 12.7%; and EDSS improvement in 14.2%. The No Evidence of Disease Activity-3 (NEDA-3) status was achieved in 76.1% of patients overall—75.8% in those who switched from another disease-modifying therapy (DMT), and 76.6% in treatment-naïve individuals. No significant differences were observed between the naïve and switch groups. Baseline EDSS at ofatumumab initiation was a significant predictor of relapse activity, while age was significantly associated with MRI activity (GELs) at 12 months. Conclusions: Real-world data confirmed high efficacy and safety of ofatumumab in RRMS. NEDA-3 was achieved more often than in registration trials. No efficacy differences between naïve and switch patients were observed. Full article

Background/Objectives: Quantitative intravoxel incoherent motion (IVIM) imaging, incorporating both diffusion- and perfusion-derived metrics, offers a promising non-invasive approach for assessing tissue microstructure and clinical disability in multiple sclerosis (MS). This study aimed to investigate the correlation and predictive values of the IVIM apparent diffusion coefficient (ADC), true diffusion coefficient (D), and perfusion-derived pseudo-diffusion coefficient (D*) and perfusion fraction (f) parameters with disability status, measured using the Expanded Disability Status Scale (EDSS), in relapsing–remitting MS patients. Methods: This cross-sectional study retrospectively analyzed MRI data from 197 MS patients. Quantitative IVIM parameters were extracted from scans obtained using a 1.5 T MRI scanner. Clinical data were also obtained, including age, disease duration, number of relapses, disease-modifying therapy (DMT) status, and need for mobility assistance. Bivariate analyses were conducted to compare mean values across subgroups. Pearson correlation was used to examine associations between EDSS score and imaging/clinical variables. Multiple linear regression was applied to identify independent predictors of EDSS score. Results: The bivariate analyses revealed that ADC, D, D*, and EDSS values were higher in patients over 50 years old, those with a longer disease duration, and those who required mobility assistance. f was higher in females and DMT-treated patients, but it had no effect on EDSS score. Patients with longer disease duration and limited mobility had a higher number of MS lesions and relapses. EDSS score exhibited positive Pearson correlations with ADC, D, D*, the number of MS lesions, and the number of relapses (p-value < 0.001). In the multivariate regression analysis, only the number of MS lesions and relapses emerged as independent predictors of EDSS score (p-value < 0.001). Other variables, including ADC, D, D*, f, age, and disease duration, were not independently associated with EDSS score (p-value > 0.05). Conclusions: This study demonstrates the utility of IVIM parameters in detecting microstructural alterations associated with MS impairment. Despite relapse frequency and lesion count being the strongest predictors of EDSS score, IVIM metrics showed meaningful clinical correlations. The findings support combining IVIM biomarkers with clinical data for better disability assessment. Full article

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article