Spinal muscular atrophy (SMA) types III and IV are the most common late-onset forms, and they progress slowly, making the identification of sensitive biomarkers critical. The Motor Unit Number Index (MUNIX) estimates motor unit loss and may complement traditional electrophysiological measurements such as Compound Muscle Action Potential amplitudes (CMAP). However, their respective performances have never been directly compared in adult SMA. In a French multicenter study (NCT04690998), 71 adult patients with SMA and 24 healthy controls underwent clinical and electrophysiological evaluation. MUNIX, CMAP, and Motor Unit Size Index (MUSIX) were recorded in four muscles, and sum scores (SumMUNIX, SumCMAP, SumMUSIX) were calculated. Reliability was assessed using intraclass correlation coefficients (ICCs), and associations with functional outcomes were explored. MUNIX and CMAP effectively distinguished SMA patients from controls, showing strong test - retest reliability. MUNIX showed the highest discriminative performance (AUC = 0.92), while CMAP demonstrated the strongest and most consistent associations with clinical severity. In multivariate analyses, only CMAP remained independently associated with all functional and strength measures, whereas MUNIX and MUSIX lost significance. MUNIX demonstrated the highest discriminative performance among biomarkers for differentiating SMA from controls, indicating early motor unit loss even when CMAP values were within normal limits. However, disease burden and functional impairment were better reflected by CMAP, probably due to it integrating both motor unit loss and reinnervation. The complementary nature of these profiles supports their combined use (concurrent application), and longitudinal studies are warranted to assess their responsiveness in adult SMA as well as their appropriateness for clinical trial settings.

Acute vertigo and dizziness are among the most frequent complaints presenting to the emergency department (ED). If acute-onset and persistent vertigo/dizziness (lasting > 24h) are accompanied by motion intolerance, gait imbalance, nausea/vomitus, and (usually also) nystagmus, this refers to the acute vestibular syndrome (AVS). We aimed at collecting epidemiologic data about the frequency of AVS etiologies for improving the diagnostic workup. We conducted a Prospero-registered systematic literature search (MEDLINE, Embase - in June 2024) retrieving information on AVS's clinical presentation, differential diagnosis, and stroke frequency. Two independent reviewers screened abstracts and full texts. Studies were rated with QUADAS-2 for risk of bias. Due to heterogeneity, we refrained from meta-analysis. We identified 6731 unique articles and 45 manuscripts (reporting on > 5 Mio. dizzy patients) that were included. 3.45% of all ED visits were related to dizziness/vertigo. One tenth (i.e., 0.3%) met the diagnostic criteria for an AVS. Only about 74% of AVS patients received peripheral or central vestibular diagnoses, while 26% were non-specific. Stroke was the second most common cause (21% in our dedicated review) after acute unilateral vestibulopathy (38%). Selected studies assessing infarction location showed posterior-inferior cerebellar artery (36%) involvement most commonly. Stroke cases were seen at similar rates in patients with or without nystagmus (22 vs. 25%). Representing 10% of all dizzy patients, AVS in the ED is frequent. With a stroke fraction among all AVS cases of approximately 21%, profound clinical training to differentiate peripheral from central causes reliably should be prioritized.

Primary CNS vasculitis (PCNSV) is uncommon, difficult to diagnose, and potentially fatal or at least likely to cause major and persistent neurological deficits, and yet appears highly treatable (although controlled clinical trials remain to be done). Here, we summarize recent advances in the recognition and diagnosis of PCNSV, the crucial role of biopsy and histopathological confirmation of the diagnosis, and currently recommended approaches to treatment. We also sign post areas of potentially fruitful future collaborative study that might advance this difficult disease.

Thalamic atrophy is a highly common and disabling consequence of multiple sclerosis (MS) that occurs early in the disease process, progressively worsens over time, and negatively impacts functional and quality of life outcomes in patients. Long-term aerobic walking exercise training (ET), in particular, represents a promising approach for mitigating MS-related thalamic atrophy and its downstream consequences in persons with MS. The present early-stage trial examined the feasibility of two different doses of a 12-month remotely delivered and supported aerobic walking ET program on thalamic volume and its downstream outcomes of cognitive processing speed, walking performance, and quality of life in 25 fully-ambulatory persons with MS who were pre-screened for slowed cognitive processing speed. The 12-month trial was feasible in terms of process, resource, and management metrics, and the 12-month exercise prescriptions were both safe and associated with high adherence rates. However, the higher-dose walking ET prescription was too difficult in terms of duration and intensity. Regarding scientific feasibility, with the data pooled across conditions, 12-months of remotely delivered and supported aerobic walking ET was associated with preservation of thalamic volume (d = 1.01), along with benefits on cognitive processing speed (d = 0.41), walking endurance (d = 0.33), and aerobic fitness overall (d = 0.48). Collectively, the present feasibility data support the design and testing of a subsequent randomized controlled trial of 12-months of remotely delivered and supported aerobic walking ET on thalamic volume/atrophy and its downstream consequences in persons with MS.

This study aimed to investigate the influence of different obesity-metabolic syndrome (MetS) statuses on mild cognitive impairment (MCI) and to explore the modifying roles of related factors. Data were obtained from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2015) and a real-world cohort (RWC). Binary logistic regression and restricted cubic spline models were used to examine the associations between obesity, MetS, and MCI, adjusting for covariates. In the RWC, the effects of obesity-metabolic phenotypes on cognitive function were further explored using structural magnetic resonance imaging (MRI) to evaluate brain atrophy. A total of 6079 participants from CHARLS and 522 from the RWC were included. Each additional MetS component increased the risk of MCI in females aged < 60 and 60-70years. Low high-density lipoprotein (HDL) levels in older males negatively affected cognition, and elevated fasting glucose was significantly associated with poorer cognitive performance. Metabolically unhealthy non-obesity (MUNO) and metabolically unhealthy obesity (MUO) were associated with higher MCI risk both in males and females, while metabolically healthy obesity (MHO) in males aged 60-70years was also linked to increased risk. RWC further revealed that MHO, MUNO, and MUO groups exhibited varying degrees of brain atrophy compared with healthy controls. Findings from both cohorts suggest that obesity and metabolic health jointly influence cognitive impairment risk. Structural MRI results highlight that metabolic dysregulation may exacerbate obesity-related neurodegeneration.

Depending on the methodology used, the prevalence of restless legs syndrome (RLS) in people with multiple sclerosis (PwMS) ranges from 13 to 65%. This study aimed to evaluate the prevalence of RLS in PwMS using a case-control design, with each case confirmed by a sleep disorder specialist. Prevalence of RLS was analyzed in a hospital cohort of 440 PwMS and 241 age- and sex-matched control subjects. Cases were identified through two interviews. First, participants answered to a structured questionnaire, and second, those who met the criteria for any cardinal RLS symptoms were interviewed by a sleep disorder specialist to confirm the diagnosis. Multivariate regression was used to analyze the clinical and radiological characteristics of MS associated with RLS. Of the 86 PwMS who tested positive for RLS using the questionnaire, 67 were diagnosed by a sleep specialist, corresponding to a prevalence of 15.23% (95% CI 11.80-19.34) compared to 19.55% (95% CI 15.63-24.14) based solely on the questionnaire (false positive: 22.09%). PwMS were twice as likely to suffer from this syndrome as the control group (OR 2.148, 95% CI 1.218-3.788, p = 0.008). Family history of RLS (OR 5.291, 95% CI 2.407-11.629, p < 0.0001) and pyramidal tract involvement (OR 4.208 95% CI 1.940-9.128, p < 0.0001) were the only factors associated with RLS. PwMS are twice as likely to develop RLS as the general population. Pyramidal tract involvement appears to be a risk factor for developing RLS in this disease.

Eculizumab as C5 complement protein inhibitor has been approved for the maintenance treatment of neuromyelitis optica spectrum disorder (NMOSD). However, evidence regarding its efficacy in the acute phase remain limited. This study enrolled six patients with aquaporin-4 (AQP4)-IgG-seropositive neuromyelitis optica, including five cases of optic neuritis and one case of long-segment transverse myelitis. These patients exhibited no or partial symptomatic improvement following glucocorticoid pulse therapy, and two patient experienced further deterioration. Subsequently, eculizumab was added to the treatment regimen, and all patients achieved rapid symptom improvement without adverse events reported post-infusion. The addition of eculizumab to glucocorticoid therapy during the acute phase may significantly ameliorate symptoms in AQP4-IgG-positive NMOSD patients with rapid onset of action and favorable safety profile. This may provide a new treatment option for patients with poor response to glucocorticoids in the acute phase, while mitigating glucocorticoid-related adverse effects to a certain degree.

IntroductionGenetic studies have identified the GBA1 gene as a significant genetic risk factor for Parkinson’s disease (PD), with 10–15% of PD patients carrying GBA1 variants. GBA1 variants affect the glucocerebrosidase (GCase) enzyme, often leading to reduced GCase activity and associated altered lysosomal function, implicated in PD pathogenesis. Ambroxol, a small molecule widely used for respiratory diseases, has emerged as a potential therapeutic agent for PD, acting by increasing GCase activity. A phase 2 trial demonstrated ambroxol’s safety and efficacy in penetrating cerebrospinal fluid (CSF) and engaging with its target in PD patients, including those with GBA1 variants.MethodsWe present the protocol of the ASPro-PD trial, a phase 3, multicentre, randomised, double-blind, placebo-controlled trial, aimed at evaluating whether high-dose ambroxol improves motor and non-motor function in PD patients. The trial will enrol 330 PD patients with confirmed GBA1 status and the primary outcome will be the combined score of parts I, II, and III of the Movement Disorders Society–Unified Parkinson’s Disease Rating Scale (MDS-UPDRS). The secondary outcomes include safety, impact on PD symptoms, and quality of life. Mechanistic and exploratory outcomes include biomarkers related to GCase activity, blood, and CSF biomarkers.ConclusionsThis trial is the largest to date to study the effect of ambroxol in PD, utilise a genetically stratified PD population and will provide robust estimates of the efficacy of ambroxol in slowing PD clinical progression.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-026-13683-7.

BackgroundParkinson's disease dementia (PDD) and dementia with Lewy bodies (DLB) are two synucleinopathies that share considerable overlap in their clinical and pathological characteristics.ObjectiveThis study aimed to evaluate the profile of phenotypic features across PDD and DLB to highlight their shared and distinctive features to explore any possible neurobiological underpinnings.MethodsPatients diagnosed with Parkinson's disease dementia (PDD) (n=31) and dementia with Lewy bodies (DLB) (n=30) underwent evaluation for motor and non-motor symptoms using the International Parkinson and Movement Disorder Society -Unified Parkinson's Disease Rating Scale, the Scales for Outcomes in Parkinson’s Disease-Psychiatric Complications, the Montreal Cognitive Assessment, the Hospital Anxiety and Depression Scale and the Epworth Sleepiness Scale.ResultsPatients with PDD showed a more severe phenotype than those with DLB, with higher scores in motor severity, hallucinations, delusions, somnolence, and urinary dysfunction (all p≤0.01). The correlations between neuropsychiatric symptoms differed between groups. In both PDD and DLB, depression correlated with anxiety (PDD ρ=0.54; DLB ρ=0.65; both p<0.001). In PDD, depression was additionally correlated with delusions (ρ=0.47; p<0.001), apathy (ρ=0.41; p<0.001), and sexual preoccupation (ρ=0.35; p<0.001), whereas in DLB depression correlated with hallucinations (ρ=0.38; p<0.001). PDD patients showed greater impairment in activities of daily living (ADLs) than DLB patients (p<0.001), correlating with motor severity (ρ=0.65; p<0.001) and fatigue (ρ=0.58; p<0.001). In DLB, impaired ADLs were linked to hallucinations (ρ=0.39; p<0.05), poorer cognition (ρ=0.47; p<0.01), urinary dysfunction (ρ=0.38; p<0.001), and fatigue (ρ=0.45; p<0.001).ConclusionDespite being grouped under Lewy body dementias, these findings show PDD and DLB have distinct phenotypes reflecting their neurobiological underpinnings. This has implications for symptomatic and disease-modifying management. Future research should explore pathological mechanisms of these characteristics to improve diagnosis and treatment strategies.

BackgroundBiallelic intronic repeat expansions in the RFC1 gene are associated with the cerebellar ataxia, neuropathy, and vestibular areflexia (bilateral vestibulopathy) syndrome (CANVAS). Oculomotor abnormalities may serve as a state marker exclusively reflecting the midline cerebellar involvement in CANVAS, i.e., independent of the combined disorders affecting the patient’s postural control stance and gait.MethodsSlow and fast eye movements of 15 CANVAS patients and 14 healthy subjects were compared using a high-resolution video-based eye tracker allowing to record visually-guided saccades, gaze-holding function and smooth pursuit paradigms. Scores of cognitive impairment were related to oculomotor performance.ResultsSaccades (latency, metria, velocity) were normal. Small amplitude omnidirectional gaze-holding deficit was found in 70% of patients, with downbeat nystagmus (60%) being more common than upbeat nystagmus (13%). Latency of initial acceleration of smooth pursuit was prolonged and there was severe impairment of smooth pursuit eye movements. Montreal Cognitive Assessment (MoCA) scores were lower in patients and correlated with saccade and pursuit latency and initial acceleration. Disease duration and vestibulopathy correlated with no oculomotor abnormalities.ConclusionCerebellar oculomotor dysfunction affected mainly smooth pursuit and gaze holding function at eccentric gaze positions, but it did neither comprise spontaneous nystagmus nor saccade abnormalities. Prolonged latencies in initial pursuit acceleration might be related to the patient’s cognitive decline, but normal saccade latencies point to cerebellar oculomotor neurodegeneration. Smooth pursuit impairment was not related to disease duration and vestibulopathy, contrariwise pursuit impairment became worse with larger functional impairment. Oculomotor abnormalities in CANVAS are in line with midline cerebellar impairment without evidence for extracerebellar (brainstem) brain involvement.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00415-026-13678-4.