Transient Ischemic Attack (TIA) may induce subtle tissue damage that remains undetectable on conventional magnetic resonance imaging (MRI), which has led to growing interest in blood biomarkers of neuronal and glial injury. This study examined whether plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) can distinguish patients with clinically defined, MRI-negative TIA from healthy individuals. Single-center retrospective study that included clinical TIA patients with negative MRI. Age- and sex-matched healthy controls were selected. A blood sample was collected within 24 h from admission, and plasma NfL and GFAP were measured using Simoa technology. We performed group comparisons, ROC analyses with identification of optimal thresholds, and evaluation of combined diagnostic assessment. Sensitivity analyses excluding patients with pre-existing disability, previous stroke/TIA, impaired renal function, high MRI small vessel disease burden and moderate-severe cerebral cortical atrophy were performed. 36 TIA patients and 72 controls were analyzed. TIA patients showed higher NfL (27.22 vs 10.44 pg/mL, p<0.001) and GFAP (301.99 vs 131.65 pg/mL, p<0.001) levels. Optimal thresholds were 16.83 pg/mL for NfL (sensitivity 52.8
G protein-coupled receptor (GPCR) directed regulatory autoantibodies (RABs) have previously been linked to poor functional outcome after ischemic stroke. We investigated the impact of anti-α1/α2/β1/β2 receptor, endothelin B receptor, angiotensin II receptor type 2, and CXCR3 receptor directed RABs on functional outcome and recurrent events after ischemic stroke. Data were derived from the Prospective Cohort with Incident Stroke Berlin (PROSCIS-B; NCT01363856). RABs were measured by ELISA (CellTrend) from sera collected within seven days of first-ever stroke. High RAB levels (quartile [Q]4 vs. Q1-3) and low levels (Q1 vs. Q2-4) were compared to reference groups. Quartile subgroups were characterized at baseline. Functional outcome, measured by the Modified Rankin Scale (mRS) at one year, was evaluated with ordinal logistic regression. Cox proportional hazard models were used to assess risk for a combined endpoint (stroke, myocardial infarction, death) over three years. 562 patients were included (mean age 67 (SD= 13); 38
Anti-CD20 monoclonal antibodies, such as ofatumumab, have significantly improved the management of multiple sclerosis (MS). Still, their long-term immunological effects, particularly on non-B-cell populations, remain poorly explored. We characterized longitudinal changes in circulating lymphocyte subsets and explored their clinical correlates in people with MS treated with ofatumumab. We conducted an observational cohort study including adults with MS who initiated ofatumumab and had paired baseline and on‑treatment assessments after at least 2 years (n=34). Immunophenotyping quantified total lymphocytes and subsets (CD3+, CD3+CD4+, CD3+CD8+, CD19+, CD20+, CD56+, CD27+, CD27+CD3+, CD27+CD19+, CD3+CD20 +). Longitudinal change was modeled with linear mixed‑effects regression (fixed effects: age, sex, follow‑up duration, comorbidities, BMI, previous DMT; random intercept for subject). Annualized percentage change of each laboratory measure was related to relapses, MRI activity, EDSS progression, NEDA‑3, and EDSS improvement using multivariable logistic regression with the same covariates. Over approximately 2 years of treatment, we observed increased total lymphocytes (Coeff 251.47; 95
Obesity has been associated with adverse outcomes in multiple sclerosis (MS), but whether its influence on disability progression differs according to immunogenetic background remains unclear. We investigated whether associations between obesity at diagnosis and subsequent disability progression vary by HLA-A*02:01 status. Using data from two Swedish population-based case–control studies, we included 2117 individuals with MS, disease duration ≤5 years at study inclusion, and available HLA genotyping. Obesity was defined as body mass index (BMI) >30 kg/m2. Participants were followed through the Swedish MS registry for confirmed disability worsening (CDW), time to Expanded Disability Status Scale (EDSS) 3 and 4, and longitudinal Expanded Disability Status Scale (EDSS) trajectories. Hazard ratios (HRs) were estimated using adjusted Cox regression models, and mixed-effects models were used to evaluate disability trajectories over time. Among individuals lacking HLA-A*02:01, obesity was associated with an increased risk of CDW (HR 1.49, 95
The vestibulo-ocular reflex (VOR) stabilizes gaze during head movements by generating compensatory eye movements. In bilateral vestibulopathy (BV), loss of vestibular function leads to loss of VOR and consequently, oscillopsia. Currently, no curative treatment exists. Vestibulocochlear implants (VCI) aim to restore vestibular function by modulating electrical stimulation of the ampullary nerves in response to head motion. Although prior studies have demonstrated partial VOR restoration, a comprehensive evaluation across different stimulation conditions remains limited. This study assessed the effects of multiple stimulation conditions on VOR gain in BV patients implanted with the latest VCI prototype. Nine BV patients were unilaterally implanted with an intralabyrinthine VCI. VOR responses were assessed using rotatory chair testing (mid-frequency domain) and video head impulse testing (vHIT; high-frequency domain). Five stimulation conditions were evaluated: Reference (VI off), Baseline only (constant stimulation), Default (motion modulation around baseline), Lowered baseline (motion modulation around threshold level), and Boosted stimulation (maximized modulation). Subjects were classified into subgroup A (peak eye velocity, PEV, ≥ 30°/s) during lateral ampullary nerve block stimulation and subgroup B (PEV < 30°/s). Six subjects were classified in subgroup A. In rotatory chair testing, excitatory VOR gain increased significantly under modulated stimulation at all tested frequencies (p < 0.05), with median gains rising from 0.09–0.20 (Reference) to 0.82 (Lowered baseline). No significant inhibitory improvements were observed. In vHIT, subgroup A demonstrated significant excitatory median gain improvements across all canal planes (p < 0.005). Lateral canal gains improved from 0.12 (Reference) to 0.69 (Boosted), and anterior canal median gains up to 0.74. Posterior gains improved but remained < 0.60. Inhibitory gains showed no changes. Subgroup B showed no meaningful gain improvements in any condition. Motion-modulated stimulation enhanced excitatory VOR function at mid- and high frequencies in patients who demonstrated higher PEV during block stimulations. However, baseline stimulation alone was ineffective. Lowered baseline and Boosted conditions showed the largest improvements, with gains approaching functional levels in several subjects. However, inhibitory responses remained limited, reflecting physiological and technical constraints. These findings support individualized, frequency-dependent modulation strategies to optimize gaze stabilization and potentially reduce oscillopsia in daily life.
Weight loss and malnutrition are associated with poorer outcomes in people living with amyotrophic lateral sclerosis (plwALS). This study investigated the prognostic relevance of early weight loss in plwALS and assessed whether existing energy equations provide useful guidance for nutritional management. In this prospective case–control and within-case comparison study (March 2016October 2024), 170 plwALS and 173 non-neurodegenerative disease controls completed baseline anthropometric and metabolic assessment. Participants with ALS were classified according to weight change during the first six months following study inclusion as Weight Gain, Stable Weight, or Weight Loss. Weight-change groups were compared for subsequent changes in anthropometry, functional capacity, and survival. In a nested cohort of 82 plwALS with reported energy intake and repeat assessments, we assessed whether the relationship between reported intake and equation-derived energy requirements was concordant with subsequent weight change. Early weight loss was associated with continued loss of body weight, fat mass, and fat-free mass, faster functional decline, and increased risk of earlier death relative to Weight Gain (HR=4.78 [95
In amyotrophic lateral sclerosis (ALS), the effort-dependent respiratory metrics used to determine the timing of non-invasive ventilation (NIV) lose reliability as bulbar and/or cognitive impairment progresses. We tested whether the effort-independent phrenic nerve compound muscle action potential (CMAP) amplitude predicts the timing of NIV independently of forced vital capacity (FVC) and the revised ALS Functional Rating Scale (ALSFRS-R). Pre-registered analysis of a single-centre ALS cohort (n = 1,486) contributing 2968 serial phrenic nerve conduction studies. Amplitude was expressed as percentage of an age- and sex-predicted value (per 10
Acute unilateral vestibulopathy (AUVP) and posterior circulation stroke (PCS) are the two common causes of the acute vestibular syndrome. We developed and evaluated machine learning models to differentiate AUVP and PCS using combinations of patient history, examination, and vestibular tests. We recruited 294 patients presenting to the Emergency Room (ER) with acute vestibular syndrome (AUVP: n = 163, PCS: n = 131). Data from history, bedside examination and vestibular tests (video-nystagmography (VNG), video head-impulse test (VHIT), vestibular-evoked myogenic potentials (VEMP) and subjective visual horizontal) were used for machine learning model development. Different subsets of data simulated three scenarios hierarchically reflecting different levels of clinical expertise and resources: Tier 1 represented an ER with neuro-otology support (history, neuro-otological examination, VNG, VHIT, ocular VEMP), Tier 2 an ER with VHIT (history, basic examination, VHIT) and Tier 3 an ER reliant on history and basic examination only. Model performance was also compared against the HINTS test (head impulse, nystagmus, test-of-skew). Our best-performing models used the CatBoost or XGBoost algorithms and identified PCS with accuracies of 96.6
To examine medication use trajectories from 1 year before pregnancy to 6 months postpartum in a population-based birth cohort of patients with myasthenia gravis (MG). We used harmonized and pooled national register data from Norway and Sweden (1994–2023) to identify MG pregnancies. Longitudinal dispensing records of symptomatic MG medications, oral corticosteroids (OCS), and non-steroidal immunosuppressant therapy (NSIST) were extracted from prescription registers, which were individually linked to hospital records in the national patient registers and demographic and clinical data in the medical birth registers. Group-based multi-trajectory modeling (GBMTM) was used to identify pregnancy clusters and typical mono- or polytherapy medication use trajectories until delivery. Among 339 MG pregnancies, 201 (59
Synaptic dysfunction is increasingly recognized as an early and biologically relevant component of α-synucleinopathies. However, conventional imaging biomarkers mainly assess dopaminergic dysfunction, glucose metabolism, or structural damage rather than presynaptic density itself. Synaptic vesicle glycoprotein 2A (SV2A) PET enables in vivo assessment of presynaptic terminal integrity and may provide complementary information in Parkinson's disease (PD), Parkinson's disease dementia/dementia with Lewy bodies (PDD/DLB), and multiple system atrophy (MSA). This systematic review synthesized the available evidence on SV2A-targeted PET in parkinsonian α-synucleinopathies, focusing on regional imaging patterns, clinical associations, longitudinal findings, and methodological determinants of interpretation. Seventeen reports were included. In PD, the most recurrent finding was reduced SV2A binding in the substantia nigra, although additional involvement of brainstem, caudate, striatal, thalamic, raphe, or cortical regions was reported in selected cohorts. In PDD/DLB, abnormalities appeared broader and more cortical, with evidence of association between cortical SV2A binding and cognitive performance. In MSA, one study suggested a distinct infratentorial and cerebellar pattern with potential relevance for phenotypic stratification. SV2A PET is a promising research biomarker for biological characterization of synucleinopathies. However, the field remains limited by small cohorts, methodological heterogeneity, variable quantification strategies, limited longitudinal evidence, and potential cohort overlap. Multicentre validation and harmonized protocols are required before clinical translation.
Diabetic peripheral neuropathy is a debilitating complication of type 2 diabetes mellitus (T2DM) associated with foot ulceration, amputation, Charcot neuroarthropathy, and reduced quality of life. Although glucagon-like peptide−1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase−4 (DPP-4) inhibitors are widely used therapies for T2DM, their comparative effects on neuropathy-related lower-extremity complications remain unclear. To compare diabetic foot ulcers, lower-extremity amputations, foot/ankle osteomyelitis, Charcot neuroarthropathy, and all-cause mortality in T2DM patients with neuropathy treated with GLP-1 RAs versus DPP-4 inhibitors. Using the TriNetX US Collaborative Network, we identified adults with T2DM and diabetic neuropathy, unspecified (ICD-10-CM E11.40), initiating either a GLP-1 RA or a DPP-4 inhibitor. After exclusions and 1:1 propensity score matching for demographics, comorbidities, and medications, 19,770 patients per cohort were balanced. Outcomes were assessed over 1 year and 2 years using Kaplan–Meier and Cox proportional hazards models, with Bonferroni correction (p < 0.01). After matching, GLP-1 RAs were associated with a 1-year lower risk of diabetic foot ulcers (2.2
Several modifiable factors affect Alzheimer’s disease (AD) risk. However, evidence on how these factors interact remains scarce, limiting our understanding of their role in AD development. This study aims to assess interactions between chronic stress exposure and insomnia in relation to AD biomarkers beta-amyloid (Aβ42), total tau, and phosphorylated tau. The present study included 124 memory clinic patients without dementia from the Cortisol and Stress in Alzheimer’s disease (Co-STAR) cohort study. Insomnia symptoms, stressful life events (SLEs) and current perceived stress were self-reported via questionnaires, while AD biomarkers were assessed from the cerebrospinal fluid (CSF). Cross-sectional interactions between stress and insomnia in relation to AD biomarkers were examined using linear regression models. Insomnia and SLEs interacted in relation to Aβ42. Greater stressor exposure was associated with reduced CSF Aβ42 levels, reflecting greater brain amyloid accumulation, only in those with moderate-to-high insomnia scores. No interactions were found for total or phosphorylated tau. This study suggests that chronic stress and sleep disturbances exhibit an interactive relationship in their associations with AD pathology, and highlights the need for further research into interactive effects of multiple modifiable risk factors in the development of AD.
Myotonia is delayed muscle relaxation after forceful contraction. It is due to hyperexcitability of the skeletal muscle membrane. It can arise from primary skeletal muscle ion channel dysfunction, involving chloride or sodium channels, but is also a prominent clinical feature in myotonic dystrophies where altered RNA splicing leads to secondary ion channel dysregulation amongst other systemic manifestations. Clinically, myotonia can range from delayed eye opening to a disabling symptom causing impaired mobility, functional difficulty and sometimes pain. It can also be a “hidden disability” with many patients feeling socially embarrassed by “looking healthy”, yet being unable to do everyday physical tasks or to do them as effortlessly as their peers. It is a symptom that almost always indicates a genetic diagnosis, although it can occur in acquired conditions, including metabolic and drug-induced causes. To experience myotonia without knowing what it is can be baffling. To receive a genetic diagnosis associated with it can be life changing. Although there is no cure, there are many effective and available symptomatic treatments for myotonia and currently we are in an exciting era of clinical trials for new molecular disease-modifying therapies for myotonic dystrophy type 1. In this review, we consider recent developments in the treatment of myotonic disorders and how they may change clinical practice.
Optic neuritis (ON) diagnosis is challenging due to variable clinical presentations and the limited prospective validation of current criteria. This study evaluates the 2022 international consensus criteria for optic neuritis (ICON) criteria, and the impact of adding visual evoked potentials (VEPs) and new clinical definitions to improve diagnostic accuracy. We introduced modifications to the ICON 2022 criteria, including a less strict clinical category allowing ON diagnosis with incomplete clinical features and the incorporation of VEPs as an additional paraclinical test. We then prospectively studied 46 patients with a first episode of unilateral subacute ON. Alongside standard clinical, MRI, OCT, and laboratory assessments, diagnostic classifications were compared between the original and modified criteria. Using the original ICON 2022 criteria, 20 patients (43.5
Cerebral amyloid angiopathy (CAA) has long been regarded as a hemorrhagic age-related small vessel disease (SVD). However, cerebral ischemia, indicated by symptomatic and incidental diffusion-weighted imaging (sDWI and iDWI) hyperintensities, remains controversial regarding its clinical relevance and pathological mechanisms. This study aimed to investigate the prevalence, distributing characteristics, and risk factors of sDWI and iDWI lesions in patients with CAA. Participants meeting the criteria for probable CAA (Boston criteria version 1.5) were recruited from a prospective cohort of cerebral small vessel disease at Peking Union Medical College Hospital between March 2017 and February 2026. Baseline clinical data and neuroimaging markers of SVD were collected. sDWI lesions and iDWI lesions were recorded at any MRI time point, with topography showing via lesion probability maps. Cumulative incidence was estimated using Kaplan–Meier method. The characteristics were compared between patients with sDWI lesions or iDWI lesions and those without any DWI lesion at baseline. The prospective Cox regression analyses were performed to identify risk factors for sDWI lesions and iDWI lesions, respectively. We enrolled 185 patients with probable CAA, of whom 99 underwent follow-up MRI with a total of 163 scans. sDWI lesions were detected in 29 patients and iDWI lesions in 49 patients. sDWI lesions predominantly involved deep regions (72.7
Immune-mediated necrotizing myopathy (IMNM) is a distinct entity with limited large-cohort data. We aimed to characterize clinico-serological features and treatment outcomes of anti-SRP, anti-HMGCR, and seronegative IMNM in a large Italian cohort. Retrospective multicenter study of adults diagnosed with IMNM (224th ENMC criteria) across 14 Italian neuromuscular centers between 2019 and 2022 was performed. We included 159 subjects (57
Alzheimer’s disease (AD) is increasingly conceptualised as a biological and clinical continuum that includes Subjective cognitive decline (SCD), mild cognitive impairment (MCI), and overt dementia. We conducted a systematic review and meta-analysis to assess the prevalence of APOE ε4 allele in individuals with SCD. Main databases were searched to identify studies published up to 15 April 2026, plus citation checking. Eligible studies included participants with SCD defined according to standardized criteria, with available APOE genotype data. Application of SCD-plus criteria was also recorded. Of 474 screened records, 49 studies were included in the quantitative synthesis. The pooled prevalence of APOE ε4 allele carriers was 28.3
