Yu Peng

Cardiomyopathy is a significant cause of mortality in dystrophinopathy, and early detection and intervention are critical to reduce the disease burden. Currently, cardiomyopathy detection primarily relies on echocardiography and cardiac magnetic resonance imaging (CMR), which are inconvenient for paediatric patients and those in remote areas. Uric acid (UA) is associated with various heart diseases and serves as a biomarker of injury severity, but its level changes and connection with myocardial injury in dystrophic cardiomyopathy remain unclear. Therefore, we investigated the relationship between UA and cardiomyopathy in dystrophinopathy, as its early detection may offer a more straightforward method for monitoring cardiac health. A total of 71 dystrophinopathy patients underwent biochemical, genetic, and echocardiography assessments to correlate UA, gene mutations types, and cardiac parameters. Patients with hyperuricaemia showed larger atria and ventricles, and thicker left ventricular walls compared to those with normal UA levels. This was reflected in increased left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), left atrial diameter (LAD), right ventricular diameter (RVD), left ventricular posterior wall thickness (LVPWT), and interventricular septal thickness (IVST). Multivariate linear regression analysis revealed an independent positive correlation between UA and these echocardiographic parameters. Elevated serum UA levels were independently associated with cardiac morphological changes, including cardiac dilation and left ventricular remodelling in dystrophinopathy patients. Consequently, UA may be considered as a potential biomarker for cardiomyopathy in dystrophinopathy.

Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neurons in SOD1-G93A mouse model of ALS. qPCR (Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 60, 100 and 140 days of age. We established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse. Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1β mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M delivery was an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.

Background Microglial activation plays a crucial role in the disease progression in amyotrophic lateral sclerosis (ALS). Interleukin receptor-associated kinases-M (IRAK-M) is an important negative regulatory factor in the Toll-like receptor 4 (TLR4) pathway during microglia activation, and its mechanism in this process is still unclear. In the present study, we aimed to investigate the dynamic changes of IRAK-M and its protective effects for motor neuron in SOD1-G93A mouse model of ALS. Methods qPCR(Real-time Quantitative PCR Detecting System) were used to examine the mRNA levels of IRAK-M in the spinal cord in both SOD1-G93A mice and their age-matched wild type (WT) littermates at 100 and 140 days of age. we established an adeno-associated virus 9 (AAV9)-based platform by which IRAK-M was targeted mostly to microglial cells to investigate whether this approach could provide a protection in the SOD1-G93A mouse . Results Compared with age-matched WT mice, IRAK-M mRNA level was elevated at 100 and 140 days in the anterior horn region of spinal cords in the SOD1-G93A mouse. AAV9-IRAK-M treated SOD1-G93A mice showed reduction of IL-1β mRNA levels and significant improvements in the numbers of spinal motor neurons in spinal cord. Mice also showed previously reduction of muscle atrophy. Conclusions Our data revealed the dynamic changes of IRAK-M during ALS pathological progression and demonstrated that an AAV9-IRAK-M deliverywas an effective and translatable therapeutic approach for ALS. These findings may help identify potential molecular targets for ALS therapy.

Background and purpose: Neuromyelitis optica spectrum disorder (NMOSD) is a severe neurological inflammatory disease mainly caused by pathogenic aquaporin‐4 antibodies (AQP4‐IgG). The safety and efficacy of the neonatal Fc receptor antagonist batoclimab addition to conventional intravenous methylprednisolone pulse (IVMP) therapy in patients with NMOSD acute attacks was assessed.Methods: In an open‐label, dose‐escalation phase 1b study, NMOSD patients with acute myelitis and/or optic neuritis received four doses of weekly subcutaneous injections of either 340 mg or 680 mg batoclimab with concurrent IVMP and were followed up for 27 weeks. The primary end‐points were safety and tolerability. Secondary end‐points included pharmacodynamics and efficacy, with key efficacy assessment at week 4.Results: In total nine NMOSD patients were enrolled, including two and seven in the 340 and 680 mg groups. Five patients had acute myelitis, while the remaining four had unilateral optic neuritis. Batoclimab add‐on therapy had an overall good safety profile without serious adverse events. In the 680 mg group, mean immunoglobulin G (IgG) reached its maximum reduction at the last dose (day 22). In the meantime, AQP4‐IgG was undetectable in six of seven subjects whose baseline AQP4‐IgG titers ranged from 1:32 to 1:320. Expanded Disability Status Scale score was reduced by 1.3 ± 0.4 at week 4 (2.7 ± 1.3) compared with baseline (4.0 ± 1.0).Conclusions: Batoclimab add‐on therapy to IVMP is safe and tolerated in patients with NMOSD. Preliminary evidence suggests a beneficial neurological effect. A randomized controlled trial would be needed to prove the efficacy.

Background: Limited data exists on the clinical features of patients with amyotrophic lateral sclerosis (ALS) during reproductive ages.Objective: Our study characterized the clinical features of ALS and the effects of pregnancy on disease progression in patients with ALS.Methods: We performed a retrospective study of female patients with ALS in three ALS research centers in southern China from 2009 to 2021. Data regarding fertility status, and clinical and genetic features, were collected. Age-matched male patients with ALS served as controls. The patients were divided into the following two subgroups: patients with symptom onset within 1 year of pregnancy and patients with symptom onset over 1 year group after pregnancy.Results: A total of 52 female and 52 matched male patients were enrolled. There were no differences in female and male patients in the mean age of symptom onset, the mean baseline ALSFRS-R score, or median reduction of ALSFRS-R score (p > 0.05). The mean age of first pregnancy was 25.57 ± 4.40) years. The mean age of first pregnancy in the over 1 year group was lower than that in the within 1 year group (p= 0.01). There was no difference in the median reduction of ALSFRS-R between the two subgroups. In the univariate analysis, diagnostic delay was highly correlated with the disease progression, with short delay representing rapid progress. No multicollinearity was found among every variable. In addition, 40.38% patients carried ALS-related gene variants. The proportion with gene mutations in the within 1 year group was higher than that in the over 1 year group (p < 0.01). Furthermore, SETX was the most frequently mutated gene in this cohort (16.67%) including 4 uncertain mutation.Conclusion: Pregnancy and fertility were not associated with disease progression. Diagnostic delay was correlated with disease progression in this cohort. In addition, SETX might be a gene of concern for ALS patients of childbearing age.

Background: Neuromyelitis optica (NMO), multiple sclerosis (MS) and autoimmune glial fibrillary acidic protein (GFAP) astrocytopathy are idiopathic inflammatory demyelinating diseases (IIDDs) that mainly present as encephalomyelitis. Heparan sulfate (HS) and hyaluronic acid (HA) are two components of glycocalyx, a carbohydrate-rich layer on the surface of blood vessels that mediates interaction with blood. Degradation of glycocalyx in NMO is poorly understood.Purpose: To detect the serum and cerebrospinal fluid (CSF) levels of shed HS and HA and to correlate these levels with disease severity to determine their diagnostic value.Methods: We obtained serum and CSF samples from 24 NMO patients, 15 MS patients, 10 autoimmune GFAP astrocytopathy patients, and 18 controls without non-inflammatory neurological diseases. Soluble HS and HA, and IFNγ, IL17A, and matrix metalloproteinase (MMP) 1 were detected via ELISA.Results: Serum and CSF levels of HS, HA and related cytokines but not of plasma MMP1 were significantly elevated in these diseases. Notably, HS and HA levels were positively correlated with Expanded Disability Status Scale scores.Conclusions: Our results indicate glycocalyx degradation and inflammation in NMO, MS and autoimmune GFAP astrocytopathy. Moreover, increased shedding of HS or HA may indicate a worse clinical situation. Furthermore, therapeutic strategies that protect glycocalyx may be effective in these diseases.

Introduction Turns‐amplitude, number of small segments (NSS)‐activity and envelope‐activity clouds are 3 methods of electromyography (EMG) interference pattern analysis. Our objective was to evaluate the sensitivity and specificity of each individual cloud analysis and combined clouds analysis to compare with that of quantitative motor unit potential (QMUP) analysis. Methods A total of 379 muscles from 100 patients were analyzed by both QMUP and clouds analyses. Calculation of sensitivity and specificity was based on the clinical diagnosis as the gold standard. Results For discrimination of abnormal vs. normal and neuropathic vs. non‐neuropathic, combined clouds analysis had greater sensitivity than QMUP analysis and any single cloud analysis; however, there were no differences in specificity. For discrimination of myopathic vs. non‐myopathic, combined clouds analysis and single cloud analysis had greater sensitivity than QMUP analysis; however, there were no differences in specificity. Conclusion Combined clouds analysis was superior to QMUP and each single cloud analysis for distinguishing normal, myopathic, and neuropathic muscles.

Background: Number of small segments (NSS) and activity analysis is a mature method for electromyographic automatic interference pattern analysis (IPA), but there are few reports on the application of this technique. Our objective was to establish normal reference values of NSS‐activity clouds.Methods: The NSS and activity data of the sternocleidomastoid, deltoid, biceps brachii (long head), extensor digitorum communis, abductor digiti minimi, vastus medialis, tibialis anterior, and gastrocnemius (lateral head) muscles were obtained from 34 men and 25 women, aged 15–80 years, using concentric needle electrodes. A linear regression of log(NSS) vs log(activity) was performed and the slope, intercept and standard deviation were calculated for each muscle. These variables were transformed back to the original parameters to yield clouds.Results: Normal NSS‐activity clouds for the above eight muscles were obtained.Conclusions: Normal reference values of NSS‐activity may facilitate detection of early and mild neurogenic and myogenic abnormalities.