Patients with generalized myasthenia gravis (gMG) frequently have variable and fluctuating symptoms. Treatments providing long-term, sustained disease control are essential for improving function and health-related quality of life. In the phase 3 Vivacity-MG3study, nipocalimab improved clinical outcomes in adults with gMG when added to standard-of-care (SOC) therapy. These post hoc analyses further assessed the ability of nipocalimab to produce sustained responses over 24 weeks, using the following response categories for total score improvements in Myasthenia Gravis-Activities of Daily Living (MG-ADL) and Quantitative Myasthenia Gravis (QMG), respectively: Meaningful Clinical Improvement (MCI; ≥ 2- and ≥ 3-point), Substantial Improvement (SI; ≥ 3- and ≥ 4-point), Considerable Improvement (CIP; ≥ 4- and ≥ 5), Composite Response (CR; MG-ADL improvement ≥ 2-points plus QMG improvement ≥ 3-points), and Minimal Symptom Expression (MSE; MG-ADL 0 or 1). Significantly higher percentages of nipocalimab-treated than placebo-treated participants achieved MG-ADL MCI, SI, and CIP, sustained for ≥ 12 consecutive weeks; achievement of these outcomes occurred as early as week 1 among nipocalimab-treated participants. Similar results were observed for QMG MCI, SI, and CIP. Significantly higher percentages of nipocalimab-treated participants achieved CR, sustained for ≥ 8 consecutive weeks versus placebo; the likelihood of achieving sustained CR for ≥ 8 weeks was higher with nipocalimab (odds ratio = 6.3). Nipocalimab-treated participants were 4-fold more likely to achieve MSE, sustained for ≥ 8 consecutive weeks versus placebo (p = 0.022). MSE and CR were achieved earlier among nipocalimab-treated participants. Nipocalimab treatment improves gMG symptoms earlier than placebo and provides meaningful and long-term sustained disease control over 24 weeks among participants with gMG.

Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive disorder caused by variants in the NTRK1 gene (encoding TrkA). The identification and functional analysis of these variants are essential for elucidating the genetic basis of the disease and improving diagnostic efficiency. In this study, we investigated four unrelated Chinese families with CIPA. We employed next-generation sequencing to identify the causative genetic variants in 13 individuals (5 affected and 8 unaffected) from four unrelated Chinese families. A comprehensive bioinformatics and invitro functional analyses were subsequently performed to assess the pathogenicity of the identified variants. We identified seven variants in the NTRK1 gene, including two novel variants (c.2285C > A and c.1990_1993delinsTGCT). Functional characterization of five variants (four missense: c.632 T > A, c.1942C > T, c.2122G > A and c.2285C > A; and one indel: c.1990_1993delinsTGCT) revealed that they disrupted distinct steps within the nerve growth factor (NGF)-TrkA pathway, including TrkA glycosylation and phosphorylation, NGF-TrkA binding, and downstream signaling pathway. Our findings expand the mutational spectrum of NTRK1 with two novel variants associated with CIPA and delineate the specific step(s) within the NGF-TrkA pathway affected by each variant, thereby establishing a link between genotype and the observed phenotypic severity. This study provides a crucial theoretical and experimental foundation for the future development of personalized therapies for CIPA patients.

ABSTRACTBackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease. We assessed changes in the mortality from ALS in Finland from 1987 to 2022.MethodsNumbers of deaths caused by ALS (ICD‐10 code G12.2) and population sizes by sex, age group, and year were obtained from Statistics Finland. Crude and age‐standardized mortality rates were calculated. The annual percentage change was estimated using Poisson regression, and joinpoint regression was used to identify changes in trend during the study period.ResultsMortality from ALS increased in Finland from 1987 to 2022. The age‐standardized ALS mortality in the entire population was 2.24/100,000 in 1987 and 4.21/100,000 in 2022. The male: female ratio in mortality was 1.18. The age‐standardized mortality increased on average by 1.7% (95% CI 1.5%–2.0%) annually. In men, the age‐standardized mortality increased on average by 1.2% (95% CI 0.9%–1.6%) annually and in women by 2.0% (95% CI 1.6%–2.3%). The largest increase occurred in the oldest age group (70+ years), with an average annual increase of 2.4% (95% CI 2.0%–2.8%). In joinpoint regression, no changes in trend were identified overall or in men, but in women, the annual percentage change (APC) was 5.5% (95% CI 3.0%–8.0%) in 1987–1997 and 1.0% (95% CI 0.5%–1.4%) during 1997–2022.ConclusionSimilar to some other countries, mortality from ALS has increased in Finland, nearly doubling in 35 years. Further research on possible reasons is needed.

Although treatment goals in migraine prevention have moved beyond the benchmark of a 50% reduction in monthly attacks, residual disease burden is still evaluated based on residual headache frequency. However, migraine-related symptoms can persist despite headache freedom, leading to so-called unclear days that may meaningfully contribute to interictal burden. In this prospective, real-world study, patients with chronic or high-frequency episodic migraine treated with CGRP-monoclonal antibodies (CGRP-mAbs) were followed for six months. Interictal burden was assessed using the Migraine Interictal Burden Scale (MIBS-4) alongside the monthly unclear and crystal clear days. Patients achieving optimal (< 4 monthly attacks) or modest (4-6 monthly attacks) migraine control were stratified according to the presence of "residual interictal burden" (MIBS-4 ≥ 3). Two hundred patients were included. CGRP-mAbs treatment was associated with a reduction in MIBS-4 scores and an increase in crystal clear days (p < 0.001). Despite optimal or modest migraine control, 45.1% of patients at month 3 and 27.2% at month 6 continued to exhibit a substantial "residual interictal burden". Patients with "residual interictal burden" showed significantly more unclear days and fewer crystal clear days compared with those without residual interictal migraine burden, while no differences were observed in residual headache days, concomitant preventive treatments, or cephalalgiophobia. Even when migraine attacks are adequately controlled, residual interictal burden may remain and seems to be predominantly associated with unclear days rather than with residual attacks. Assessing crystal clear and unclear days provides a complementary, patient-centered perspective on treatment response and interictal recovery in migraine.

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy characterized by early postural instability and vertical gaze palsy. Mitochondrial dysfunctions have been increasingly implicated in the pathogenesis of neurodegenerative disorders, including PSP. We investigated mitochondrial DNA copy number (mtDNA-CN) alterations in the peripheral blood of PSP patients, assessing its potential as a biomarker for disease onset and progression. We measured mtDNA-CN in a cohort of clinically diagnosed PSP patients and age-matched healthy controls using quantitative real-time PCR. We evaluated differences across clinical phenotypes and age groups. PSP patients exhibited a significant reduction in ND3-CN compared to healthy controls (p < 0.0001). This depletion remained consistent across age groups, suggesting that mitochondrial impairment in PSP is independent of physiological aging. Although not statistically significant, ND3-CN levels were lower in PSP-parkinsonism (PSP-P) patients compared to those with Richardson's syndrome (PSP-RS). Interestingly, in PSP-RS patients, ND3-CN levels tended to increase with age, potentially reflecting an age-related compensatory mitochondrial response to chronic neuroinflammation. Our findings support the involvement of mitochondrial dysfunction in PSP pathogenesis, suggesting that peripheral mtDNA-CN may serve as a non-invasive biomarker for disease monitoring. Further studies in larger cohorts are warranted to validate its prognostic potential in different PSP phenotypes.

The French National Rare Diseases Registry (BNDMR) was established in 2007 to ensure access to optimal care standards for all patients with rare diseases in dedicated reference centres. The objective of this retrospective cohort study was to describe patients with myasthenia gravis (MG) in the BNDMR. All patients aged ≥ 18 years in the BNDMR with a confirmed diagnosis of MG visiting a reference centre at least once between 2007 and 2021 (inclusive) were included. Diagnosis was defined through ORPHA:589 or ORPHA:391490 disease codes. Patients were followed for ≥ 12 months until 31 December 2022 (or until death). Data were collected on demographics and disease history. Mortality was estimated using Kaplan-Meier survival analysis. Healthcare resource utilisation at the reference centre was documented. Overall, 3963 patients were analysed. Mean follow-up duration was 6.1 ± 3.8 years. The median interval between diagnosis and inclusion was 3.8 months [IQR: 1.5-7.5] and the median age at symptom onset was 52.0 [IQR: 34.0-69.0] years. Survival probability was 82.7% at 10 years, and higher in women than men (p < 0.001; logrank test). The mean interval between visits was 4.1 months. The mean number of overnight or day hospitalisations per patient was 2.6 ± 3.4 and the mean number of physician consultations per patient per year was 1.7 ± 1.1. This national registry study provides reference data for patients in France with a confirmed diagnosis of MG. However, all patients with MG are still not managed in dedicated reference centres.

Cerebral small vessel disease (CSVD) is a common incidental MRI finding in patients with transient ischemic attack (TIA) and stroke and has been linked to cognitive decline. This study investigated the prevalence of CSVD imaging biomarkers in TIA patients and their association with cognitive performance over 3 years. We included 246 TIA patients from the INSPiRE-TMS study (ClinicalTrials.gov: NCT01586702). CSVD was assessed on baseline 3 T MRI using a composite score (0-4) including white matter hyperintensities (WMH), lacunes, cerebral microbleeds (CMBs), and enlarged perivascular spaces (PVS). Cognitive performance was evaluated using the Montreal Cognitive Assessment (MoCA) at baseline and annually for 3 years. At least one CSVD imaging biomarker was present in 58.5% of patients. Lacunes (36.6%) were the most common, followed by PVS (28.1%), WMH (19.5%), and CMBs (17.9%). Higher CSVD-score was independently associated with greater cognitive decline over 3 years (β = -0.52, 95% CI -0.95- -0.08, p = 0.020), along with older age (β = -0.08, 95% CI -0.13 to -0.03, p = 0.001). CMB burden was the strongest predictive component of the CSVD-score (β = 0.42, 95% CI -0.63 to -0.22, p < 0.001). CSVD-score was particularly associated with decline in the memory domain (adjusted β of -0.18, 95% CI -0.32 to -0.04, p = 0.015). CSVD imaging markers are present in over half of TIA patients and are independently associated with cognitive decline up to 3 years, with the strongest effect on memory. Whether the presence of CMBs is the strongest predictive imaging biomarker of cognitive decline in TIA patients requires confirmation in further studies.

Characterizing the gene-environment interactions with early pathological changes in Alzheimer's disease (AD) is critical to precision medicine. We recruited 1007 cognitively normal participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study. Multiple linear regression models were applied to explore the associations between polygenic risk scores (PRSs) and cerebrospinal fluid (CSF) biomarkers of AD, the interactions between PRSs and potentially modifiable risk factors, and the relationships between lifestyle categories and CSF AD biomarkers. A higher AD-PRS was associated with more severe amyloidosis, as indicated by pTau/Aβ42 (β = 0.091, p = 0.005) and tTau/Aβ42 (β = 0.092, p = 0.004). There were significant interactions between AD-PRS and three modifiable risk factors (anemia, gingivitis, and anxiety) in AD biomarker ratios. Stratified analyses by AD-PRS indicated that anemia was associated with higher pTau/Aβ42 and tTau/Aβ42 in the first and second quartiles, while gingivitis and anxiety correlated with amyloidosis in the fourth quartile (all p < 0.05). Additionally, a favorable lifestyle was associated with milder amyloidosis in the high genetic risk group. AD-PRS was associated with amyloidosis severity. The associations between modified risk factors (anemia, gingivitis, and anxiety) and biomarker ratios differed by genetic risk strata. Moreover, a healthy lifestyle was associated with less amyloid burden in individuals with high genetic risk. These findings can be used to generate hypotheses for future longitudinal studies to investigate whether targeted management of these factors influences AD pathological progression.