BACKGROUND:Alzheimer's disease (AD)-related pathology may co-occur in progressive supranuclear palsy (PSP), although its clinical and prognostic impact is unclear. OBJECTIVES:To assess whether cerebrospinal fluid (CSF) AD biomarker profiles at diagnosis predict severity and survival in PSP. METHODS:CSF amyloid-β42 (Aβ42), total and phosphorylated tau (t-tau, p-tau) levels from 85 newly-diagnosed PSP patients and 59 controls were assessed by the amyloid/tau/neurodegeneration (AT[N]) framework, and the p-tau/Aβ42 ratio (AD+ if ≥0.08), and implemented in a survival analysis through Kaplan-Meier, Cox regression, and LASSO-Cox modeling. RESULTS:AD CSF signature was identified in 5.9% and 18.8% of PSP patients, according to AT(N) and ratio, respectively. It was unrelated to phenotype or severity but strongly predicted survival, with AD+ patients showing markedly shorter survival. The p-tau/Aβ42 ratio was the strongest independent predictor of mortality, together with phenotype and smoking. CONCLUSIONS:AD-related CSF signature defines a biological PSP subgroup with shortened survival. The p-tau/Aβ42 ratio offers a pragmatic prognostic tool for patient stratification. © 2026 International Parkinson and Movement Disorder Society.

OBJECTIVE:Progression independent of relapse activity is a major determinant of long-term disability in multiple sclerosis, but its immunopathologic basis remains incompletely understood. We investigated whether relapse-independent progression in radiologically stable relapsing-remitting multiple sclerosis is associated with distinct cerebrospinal fluid inflammatory profiles and whether cytokine-network features provide information beyond single-mediator levels. METHODS:In this prospective observational cohort study, baseline cerebrospinal fluid cytokine and chemokine profiling was performed in 346 RRMS patients, 61 primary progressive multiple sclerosis (PPMS) patients, and 196 neurological controls without inflammatory or neurodegenerative central nervous system disease. After 2-year clinical and MRI follow-up, 37 RRMS patients with clinical relapse and/or MRI activity were excluded, leaving 309 relapse-free and MRI-stable RRMS patients classified as stable RRMS (n = 241) or RRMS with PIRMA (n = 68). Cytokines were analyzed using two-part hurdle models, cytokine interactomes, and machine-learning classifiers. RESULTS:Quantitative cytokine analyses distinguished multiple sclerosis from controls but showed substantial overlap across multiple sclerosis phenotypes. RRMS with PIRMA showed higher cerebrospinal fluid levels of tumor necrosis factor-α, interleukin-17, and RANTES than stable RRMS. Network analyses showed a more integrated cytokine interactome in RRMS with PIRMA. The network-level model best distinguished RRMS with PIRMA from stable RRMS, with an area under the curve of 0.86, sensitivity of 77%, and specificity of 76%. INTERPRETATION:Relapse-independent progression in multiple sclerosis is associated with selective cytokine changes and broader reorganization of inflammatory network architecture, supporting cerebrospinal fluid cytokine interactome profiling as a translational approach to immune stratification.

[This corrects the article DOI: 10.3389/fneur.2026.1747131.].

Background: A substantial proportion of patients with chronic migraine (CM) with previous failures among oral standard-of-care migraine medications do not respond to monoclonal antibodies targeting the calcitonine gene related peptide pathway (CGRP-mAbs), leaving limited evidence-based options for subsequent preventive strategies. The present multicentre real-world study evaluated the effectiveness of onabotulinumtoxin-A (BoNT-A) in CM patients with previous CGRP-mAb failure and multiple prior oral preventive failures. Methods: This prospective, observational, non-randomized multicentre study enrolled patients with CM who had failed ≥3 classes of oral preventive treatments and ≥1 CGRP-mAb due to lack of efficacy or intolerance. Participants received BoNT-A according to the PREEMPT “follow-the-pain” paradigm every three months and were followed for 6 months. Co-primary outcomes were change in monthly headache days (MHD) after three and six months and ≥50% MHD responder rates at both time points. Results: Fifty-three patients were analysed (85% female, aged 48.5 ± 15.2 years, range 20–73). Compared to the baseline, at the third month and sixth month, MHD decreased from 22.83 (SD 6.74) to 15.38 (SD 7.91; p < 0.001) and 14.55 (SD 9.35; p < 0.001), respectively. The percentages of participants achieving the response status in MMD at the third month and sixth month were 30% and 45%, respectively. In the third and sixth months, 22 patients (41.5%) and 27 patients (50.9%), respectively, converted from chronic to episodic migraine, while the prevalence of medication-overuse headache decreased from 81.1% of patients at baseline to 45.3% and 43.4%, respectively. Migraine-related impact and disability scores improved over follow-up, alongside improvements in anxiety and depressive symptoms and in migraine-specific quality of life. Conclusions: The present findings support the use of BoNT-A in difficult-to-treat patients with CM following CGRP-mAb failure and provide further evidence that its therapeutic effects may rely on mechanisms that are at least partially distinct from, and potentially complementary to, those of CGRP-targeted therapies.

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.

Introduction OCARINA II a montré qu’ocr2lizumab (OCR) sous-cutané (SC) 920mg (avec hyaluronidase humaine recombinante PH20 [rHuPH20]) était non-inférieur à OCR intraveineux (IV) 600mg chez les personnes atteintes de SEP. Objectifs Caractériser davantage le profil bénéfice-risque d’OCR SC sur la base de l’analyse finale issue de l’étude OCARINA II (juin 2025, semaine 96 ; les données semaine 72 sont décrites ici). Méthodes Les patients atteints de SEP récurrente ou primaire progressive (18–65 ans ; EDSS [Expanded Disability Status Scale] : 0–6,5) n’ayant jamais reçu d’OCR ont été randomisés pour recevoir 600mg d’OCR IV ou 920mg d’OCR SC (période contrôlée). Semaine 24, tous les patients pouvaient entrer dans la phase OCR SC jusqu’à semaine 96. Les critères d’évaluation comprenaient EDSS, poussées, lésions IRM, sécurité et questionnaire d’impression globale de satisfaction rapportée par le patient (PGI-SF). Résultats OCR SC a entraîné une suppression quasi complète d’activité IRM et poussées semaine 72. L’EDSS était stable. Les patients ont été 84,1 % à présenter un événement indésirable, 4,3 % grave et 57,5 % une réaction liée à l’injection. Les RLI étaient légères ou modérées ; 99,4 % ont disparu. Incidence et sévérité ont diminué avec le temps. Aucun anticorps anti-médicament OCR n’a été signalé ; un contre rHuPH20. Les données semaine 96 seront présentées. Discussion L’administration sous-cutanée d’ocrélizumab continue de présenter un profil bénéfice-risque favorable qui se maintient au fil du temps, similaire à celui de la voie d’administration intraveineuse bien établie. Conclusion L’ocrélizumab SC peut offrir une flexibilité et une commodité d’administration pour les personnes atteintes de SEP récurrente ou de SEP primaire progressive.

The recent introduction of High-Efficacy Therapies (HETs) in clinical practice has drastically reduced the frequency of acute inflammatory episodes and relapses, in patients with Multiple Sclerosis (MS), gradually shifting the interest of clinicians toward preventing disease progression and treating symptoms associated with the residual disease. This article summarizes the output of a recent meeting (June 2025, in Rome) among an Italian group of neurologists, who discussed about published evidence supporting the involvement of the endocannabinoid system (ECS) in MS spasticity and its associated symptoms. Sharing their clinical experiences about the silent progression of the disease, in patients with Relapse-Free Multiple Sclerosis (RFMS), treated with HETs, authors propose a new algorithm to treat residual disease in RFMS, by enhancing ECS with both cannabinoid agents and lifestyle interventions (diet and physical activity).

Migraine is common in people with multiple sclerosis (PwMS) and substantially contributes to disability and impaired quality of life. Although (CGRP)–targeting therapies have reshaped migraine prevention, evidence on their use in PwMS remains scarce, particularly in people receiving concomitant disease-modifying therapies (DMTs). We retrospectively collected data from 17 Italian multiple sclerosis (MS) centers on adult PwMS with comorbid migraine treated with anti-CGRP monoclonal antibodies or gepants in addition to stable DMTs. Monthly headache days (MHDs) and total number of analgesics per month were compared between treatment initiation and last follow-up. MS activity was assessed through clinical relapses, Expanded Disability Status Scale (EDSS), and MRI findings. A ≥ 50

Exercise is increasingly recognized as a disease-modifying intervention in multiple sclerosis. A new study published in Nature Metabolism shows that the muscle-derived hormone irisin promotes neuronal survival in an inflammation-driven neurodegenerative model.

INTRODUCTION:Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath-holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype. METHODS:We enrolled 64 patients with cerebrospinal fluid (CSF)-confirmed AD (30 APOE ε3, 34 APOE ε4) and 28 age-matched healthy controls in a cross-sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p-tau181], amyloid beta [Aβ]42/Aβ40 ratio - AmyR). Multivariate regressions examined associations between BHI and AD-related parameters, stratified by APOE genotype. RESULTS:BHI was significantly reduced in both AD groups compared to controls (p < 0.001), with no difference between ε3 and ε4 carriers. In ε3 patients, lower BHI was independently associated with higher plasma p-tau181. In the MRI subgroup analysis, ε3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in ε4 carriers. DISCUSSION:Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular-metabolic dysfunction in APOE ε3 carriers. CVR may represent a non-invasive biomarker of early vascular contributions to cognitive decline in AD.

Anti-amyloid monoclonal antibodies have increased the need for scalable, minimally invasive biomarkers for Alzheimer’s disease (AD). In this single-center cohort study, we evaluated plasma biomarkers performance in detecting biologically defined AD, assessing diagnostic accuracy and generalizability outside dedicated laboratory settings and exploring suitability for clinical implementation. We enrolled 204 outpatients referred to the memory clinic of Policlinico “Rome Tor Vergata” who underwent standard work-up, lumbar puncture for cerebrospinal fluid (CSF) biomarkers and paired blood sampling. Among plasma biomarkers, phosphorylated tau (p-tau) 181, p-tau217, and their ratios adjusted for Aβ42 were measured on the Lumipulse platform. AD pathology was defined by CSF p-tau181/Aβ42 ≥ 0.069. ROC analyses estimated AUCs, and a two-cut-off approach targeting 90

BACKGROUND:Citicoline is a promising therapeutic option for improving both motor and non-motor symptoms in Parkinson's disease (PD) beyond levodopa and other standard dopaminergic treatments. OBJECTIVES:The CITIPARK study evaluated the efficacy and safety of citicoline in improving clinical outcomes and quality of life (QOL) in PD patients on dopaminergic therapies. METHODS:The randomized, double-blind, multicenter trial compared citicoline (1000 mg/day intramuscular, two six-week cycles) with placebo for 24 weeks in PD under stable medications. The primary endpoint was change in Movement Disorder Society-Unified PD Rating Scale (MDS-UPDRS) total score; secondary endpoints included motor and non-motor subscores, QOL, clinical global impression (CGI) and safety. RESULTS:The study enrolled 485 participants, randomizing 474 (citicoline: 303; placebo: 171). Citicoline significantly increased the likelihood of achieving a minimal clinically important difference compared with placebo (OR 2.06, 95% CI 1.06-3.99; P = 0.031) on the MDS-UDPRS total score in the modified intention-to-treat population. Among secondary outcomes, the citicoline group showed greater improvement in motor function (MDS-UPDRS III -2.97 vs -0.13; p = 0.009) and a greater improvement on CGI -II and CGI-III (3.26 vs 3.59; p = 0.021 and 9.30 vs 10.38; p = 0.018, respectively). AEs occurred in 22.1% and 27.1% of the citicoline and placebo groups, respectively. CONCLUSIONS:Citicoline was well tolerated and associated with motor benefits compared with placebo in a highly compliant population. The results suggest a role of citicoline as a safe and possibly effective supportive therapy in PD treated with concomitant dopaminergic agents.

OBJECTIVE:Parkinson's disease (PD) is increasingly conceptualized as a disorder of large-scale brain networks, yet whether and how frequency-specific functional connectivity reorganizes across stages remains poorly understood. In this study, we used high-density electroencephalography (EEG) to characterize cortico-cortical functional connectivity across the clinical spectrum of PD. METHODS:We performed high-density EEG in a cross-sectional cohort of 140 PD patients spanning early, intermediate, and advanced stages and 57 healthy controls. Cortico-cortical functional connectivity was reconstructed in source space across multiple frequency bands and analyzed using network-based statistics combined with machine-learning models to identify stage-dependent network alterations and evaluate their diagnostic and prognostic relevance. RESULTS:We detected 3 distinct large-scale networks showing divergent trajectories across disease stages. An α-band network involving prefrontal and parieto-temporal regions exhibited progressive hypoconnectivity and was associated with cognitive and axial impairment. A β-band sensorimotor network showed progressive hyperconnectivity, paralleling bradykinesia severity. A high-γ network demonstrated increased connectivity in early PD, followed by a progressive connectivity breakdown, and was inversely associated with motor complications. Multiband integration achieved near-perfect discrimination between early PD and healthy controls and robust stratification across disease stages. Band-specific networks also predicted clinical milestones of disease progression, with preserved α connectivity identifying patients at lower risk for cognitive and axial impairment, and stronger high-γ connectivity indicating reduced vulnerability to motor complications. INTERPRETATION:Together, these results identify frequency-specific cortical networks as markers of disease stage and clinical vulnerability and support high-density EEG connectivity as a scalable systems-level biomarker for diagnosis, staging, and risk stratification in PD. ANN NEUROL 2026;100:319-333.

Physical exercise (PE) exerts beneficial effects in people with multiple sclerosis (pwMS). Preclinical studies in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS, indicate that PE may attenuate key pathological features of the disease, including immune dysregulation and inflammation-driven synaptotoxicity, although the underlying mechanisms remain unclear. Clinical evidence, however, is still limited and fragmented, leaving the disease-modifying potential of PE in MS largely unresolved. Here, we investigated the impact of PE on T cell immunometabolic function and its downstream consequences on synaptotoxicity in both EAE mice and progressive MS (PMS) subjects, also assessing the contribution of vagal innervation to PE-mediated effects in the EAE model. Specifically, we found that PE improved EAE clinical course, by mitigating neuronal damage and modulating peripheral T cell proliferation, activation, and metabolic activity. These beneficial effects were partially blunted by preventive cervical vagotomy, suggesting a role for vagal integrity in mediating PE-driven neuroimmune modulation. In PMS subjects, a structured PE program improved clinical functional outcomes and enhanced mitochondrial respiration in peripheral T cells. Moreover, patch-clamp recordings revealed that glutamatergic synaptotoxicity induced by PMS-derived T cells was abolished following PE. Together, these findings highlight the therapeutic potential and disease-modifying value of PE in MS and suggest the vagal pathway as a key modulator of exercise-induced neuroimmune benefits.

Late-onset epilepsy (LOE) remains of unknown aetiology (LOEU) in around 20% of cases. Longitudinal studies have demonstrated the presence of early cognitive impairment at seizure onset, progressive memory decline and a substantially elevated risk of dementia within a decade of diagnosis, with an increased risk of subsequent neurodegenerative disorders, particularly Alzheimer's disease (AD). LOEU is associated with cognitive network alterations and epileptiform activity, although links remain unclear. Further emerging data suggest that neurodegenerative processes related to β-amyloid and tau pathology may precede the onset of epilepsy. Although epilepsy is highly prevalent among older adults, its impact on quality of life remains unclear, with affective symptoms and sleep disturbances as key determinants of subjective well-being. These findings suggest that LOEU should be reconceptualised as a multidimensional neurological condition.This protocol advocates an integrated approach, combining neuropsychological assessment, advanced biomarkers, neurophysiological measures and systematic sleep evaluation to identify high-risk phenotypes and define optimal windows for neuroprotective interventions in LOEU. This strategy could improve the early detection of cognitive decline, guide personalised management, and ultimately enhance quality of life, while contributing to the long-term sustainability of healthcare systems in an ageing population, focusing on LOEU as a model for dementia prevention.

Dementia with Lewy bodies (DLB) has a prolonged prodromal stage marked by heterogeneous onset presentations (OPs). However, the distribution, co-occurrence, and prognostic implications of core and supportive clinical features at onset remain underexplored. We aimed to characterize prodromal OPs and associated clinical features in a longitudinally confirmed DLB cohort and to examine their relationship with cognitive decline. Patients were enrolled from the CLIMB-DLB observational cohort at the Memory Clinic of Policlinico Tor Vergata (Rome), upon fulfilling consensus criteria for probable DLB. Patients were stratified by main OP (MCI-LB, psychiatric-onset, delirium-onset). Core (cognitive fluctuations [CF], visual hallucinations [VH], REM sleep behavior disorder [RBD], parkinsonism) and supportive (hyposmia, dysautonomia) features were coded at the prodromal stage. Pairwise associations were assessed using φ coefficients and odds ratios (ORs). Longitudinal cognitive trajectories were examined using linear mixed-effects models with random intercepts and slopes, adjusted for age and sex. Among 75 patients (mean age 73.2 ± 6.4 years; 26.7

Background:Adverse life events are frequent in patients with functional neurological disorder (FND), although their prevalence is highly variable when assessed using standardized methods. We explored whether an extended multimodal evaluation with a personalized approach may yield additional insights. Methods:This cross-sectional study included 83 newly diagnosed FND patients and 82 organic neurological disorder (OND) patients. All participants underwent: (1) a standardized psychological/psychometric evaluation of mood, fatigue, sleep, personality disorders. Adverse life events were specifically investigated using the Life Stressor Checklist-R (LSCL-R); (2) a brief psychotherapeutic intervention consisting in five-eight sessions of psychodynamic psychotherapy. We compared the prevalence of adverse life events in the two evaluations. Results:Increased prevalence of adverse life events was found in FND compared with OND patients using both the LSCL-R (66.3% vs 36.6%) and the brief psychotherapeutic intervention (87.9% vs 45.1%). While in the OND group the two evaluations demonstrated a significant agreement, the brief psychotherapeutic intervention showed traumatic events in a consistent proportion of FND patients reporting no adverse life experiences in the LSCL-R. Traumatic events evaluated using both the LSCL-R and the brief psychotherapeutic intervention were significantly associated with FND group controlling for other clinical characteristics (OR=3.625, 95%CI 1.812-7.250, p<0.001; OR=10.731, 95%CI 4.417-26.071, p<0.001, respectively). Conclusions:A brief psychotherapeutic intervention uncovered a high prevalence of adverse life events in patients with FND, suggesting that a significant number of traumatic experiences remain undetected during standard evaluations. These findings have important implications for the pathogenesis and treatment of FND, and support the inclusion of psychotherapeutic assessment as part of a multidisciplinary approach.