Journal of Neurology最新文献

{"title":"Advancements in genetic research and RNA therapy strategies for amyotrophic lateral sclerosis (ALS): current progress and future prospects.","authors":"Paola Ruffo, Bryan J Traynor, Francesca Luisa Conforti","doi":"10.1007/s00415-025-12975-8","DOIUrl":"10.1007/s00415-025-12975-8","url":null,"abstract":"<p><p>This review explores the intricate landscape of neurodegenerative disease research, focusing on Amyotrophic Lateral Sclerosis (ALS) and the intersection of genetics and RNA biology to investigate the causative pathogenetic basis of this fatal disease. ALS is a severe neurodegenerative disease characterized by the progressive loss of motor neurons, leading to muscle weakness and paralysis. Despite significant research advances, the exact cause of ALS remains largely unknown. Thanks to the application of next-generation sequencing (NGS) approaches, it was possible to highlight the fundamental role of rare variants with large effect sizes and involvement of portions of non-coding RNA, providing valuable information on risk prediction, diagnosis, and treatment of age-related diseases, such as ALS. Genetic research has provided valuable insights into the pathophysiology of ALS, leading to the development of targeted therapies such as antisense oligonucleotides (ASOs). Regulatory agencies in several countries are evaluating the commercialization of Qalsody (Tofersen) for SOD1-associated ALS, highlighting the potential of gene-targeted therapies. Furthermore, the emerging significance of microRNAs (miRNAs) and long RNAs are of great interest. MiRNAs have emerged as promising biomarkers for diagnosing ALS and monitoring disease progression. Understanding the role of lncRNAs in the pathogenesis of ALS opens new avenues for therapeutic intervention. However, challenges remain in delivering RNA-based therapeutics to the central nervous system. Advances in genetic screening and personalized medicine hold promise for improving the management of ALS. Ongoing clinical trials use genomic approaches for patient stratification and drug targeting. Further research into the role of non-coding RNAs in the pathogenesis of ALS and their potential as therapeutic targets is crucial to the development of effective treatments for this devastating disease.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"233"},"PeriodicalIF":4.8,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865122/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cervical spinal cord gray matter damage predicts disability worsening in multiple sclerosis: a longitudinal study.","authors":"Matteo Azzimonti, Paolo Preziosa, Elisabetta Pagani, Alessandro Meani, Monica Margoni, Martina Rubin, Mor Gueye, Federica Esposito, Massimo Filippi, Maria A Rocca","doi":"10.1007/s00415-025-12979-4","DOIUrl":"https://doi.org/10.1007/s00415-025-12979-4","url":null,"abstract":"<p><strong>Objective: </strong>Cervical spinal cord (cSC) gray matter (GM) damage is associated with current disability in multiple sclerosis (MS), but its prognostic value remains unexplored. We aimed to investigate whether cSC GM damage may predict disability worsening in MS.</p><p><strong>Materials and methods: </strong>Seventy-nine MS patients and 49 healthy controls (HC) underwent 3 T brain and cSC MRI at baseline and two neurological evaluations after median follow-up of 1.3 years. Total and GM cSC lesions were identified on axial T2-weighted sequences, whereas global and GM cSC cross-sectional areas (CSAs) at C3-C4 level were quantified on phase-sensitive inversion recovery sequences. Brain lesional and volumetric measures were also assessed. At follow-up, disability worsening was defined as deterioration on ≥ 1/3 components of the Expanded Disability Status Scale (EDSS)-plus score (EDSS worsening or ≥ 20% change in timed 25-foot walk [T25FWT] or 9-hole peg test [9-HPT]).</p><p><strong>Results: </strong>At follow-up, 40/79 (50.6%) patients showed EDSS-plus worsening, with 13/79 (16.4%) worsening at EDSS score, 13/79 (16.4%) at 9-HPT, and 29/79 (36.7%) at T25FWT. Progressive phenotype (odds ratio [OR] = 8.65) predicted EDSS worsening (p = 0.001, C-index = 0.79). Progressive phenotype (OR = 5.56), lower cortical volume (OR = 0.41), and higher cSC GM T2-hyperintense lesion volume (OR = 2.28) (p ≤ 0.035, C-index = 0.88) predicted 9-HPT worsening. Longer disease duration (OR = 1.64), progressive phenotype (OR = 4.74), and lower cSC GM CSA (OR = 0.51) predicted T25FWT worsening (p ≤ 0.050, C-index = 0.77). Male sex (OR = 6.12), older age (OR = 1.71), progressive phenotype (OR = 7.40), and lower cSC GM CSA (OR = 0.47) predicted EDSS-plus worsening (p ≤ 0.055, C-index = 0.83).</p><p><strong>Conclusions: </strong>cSC GM damage emerged as a relevant MRI predictor of disability worsening in MS, highlighting its prognostic relevance.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"228"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Familial vs sporadic normal pressure hydrocephalus: a comparative study.","authors":"Alice J M Jelmoni, Ghada Albuainain, Gianfranco Gaudiano, Gianluca Sorrento, David F Tang-Wai, Alfonso Fasano","doi":"10.1007/s00415-025-12970-z","DOIUrl":"https://doi.org/10.1007/s00415-025-12970-z","url":null,"abstract":"<p><strong>Introduction: </strong>Normal pressure hydrocephalus (NPH) is a syndrome characterized by the buildup of cerebrospinal fluid that results in the clinic triad of gait impairment, urinary incontinence, and cognitive impairment. NPH can be categorized as secondary, idiopathic, or familial. Here, we report a comparison of sporadic to familial types from clinical, radiological, and surgery response aspects as well as a novel gene mutation as a cause of familial NPH.</p><p><strong>Method: </strong>We analyzed 139 patients evaluated for NPH at our center from 2010 to 2022. Ninety-five patients diagnosed with probable (n = 26) or definite (n = 69) iNPH were included. Clinical, radiological, and gait data were retrospectively collected. In patients with a positive familial history of NPH, we defined the inheritance pattern when possible. The results of performed genetic tests were reported.</p><p><strong>Result: </strong>Nine patients (9.5%) had a familial history of NPH. Familial and sporadic groups were largely comparable in age, sex, and disease duration. However, familial cases had better cognitive scores (p = 0.022) and a higher prevalence of upper-limb action tremor (56% vs. 14%; p = 0.008). No significant differences were noted in radiological markers, and both groups showed a positive response to ventriculoperitoneal shunting (VPS). Whole exome sequencing identified a novel pathogenic NEIL1 variant in twin patients with familial NPH.</p><p><strong>Conclusions: </strong>Familial NPH occurred in roughly 1 in 10 reviewed iNPH cases and demonstrates better cognition and increased tremor incidence compared to sporadic cases but otherwise similar characteristics. The genetic underpinning of these cases is heterogeneous and NEIL1 might represent another associated gene.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"229"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Giuseppe Levi (1872-1965).","authors":"Ugo Borello, Erica Lucia Crapanzano","doi":"10.1007/s00415-025-12963-y","DOIUrl":"https://doi.org/10.1007/s00415-025-12963-y","url":null,"abstract":"","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"231"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492427","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Upper motor neuron-predominant motor neuron disease: a novel immunotherapy-responsive association of GAD65 autoimmunity.","authors":"Naveen Kumar Paramasivan, Pallab Sarker, Anastasia Zekeridou, Nathan P Staff, Christopher J Klein, Andrew McKeon, Sean J Pittock, Divyanshu Dubey","doi":"10.1007/s00415-025-12968-7","DOIUrl":"https://doi.org/10.1007/s00415-025-12968-7","url":null,"abstract":"<p><strong>Background: </strong>Autoimmune disorders can present as motor neuronopathies and need to be excluded prior to the diagnosis of amyotrophic lateral sclerosis (ALS). We aimed to characterize the clinical phenotypes of patients with motor neuron disease (MND) in the context of high-titer serum/CSF GAD65 antibodies (radioimmunoassay).</p><p><strong>Methods: </strong>A retrospective review of all Mayo patients (between 1/1/2003 and 12/31/2023) with motor neuronopathy and co-existing high-titer GAD65 antibodies (≥ 20 nmol/L in serum [equivalent to > 10,000 IU, ELISA] or detection in CSF) was performed. Clinical phenotypes and outcomes were compared with ALS patients diagnosed in the last 5 years (1/1/2019-12/31/2023) who tested negative for GAD65 IgG.</p><p><strong>Results: </strong>We identified 12 patients with high-titer GAD65 IgG and motor neuronopathy, who often had lower back spasms, history of an exaggerated startle response with immunotherapy responsiveness as compared to ALS patients. On further analysis, a subgroup of these patients with neurogenic changes on EMG, had an upper motor neuron (UMN) predominant syndrome (58%), with history of exaggerated startle (57%), lower back spasms (43%), tandem gait impairment (86%) and UMN bladder symptoms (71%) that were significantly different from the ALS controls. The UMN predominant GAD65 MN responded favorably to immunotherapy with stable electromyography; significantly lesser worsening in mRS and mortality on long-term follow-up.</p><p><strong>Discussion: </strong>An upper motor neuron predominant motor neuronopathy is a distinct manifestation of GAD65 autoimmunity. Co-existing symptoms like exaggerated startle response, lower back spasms, impaired tandem gait, and UMN bladder signs might warrant consideration of an immunotherapy trial, which could yield favorable results.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"230"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elevated suicide risk in individuals with epilepsy: a systematic review and meta-analysis.","authors":"Ali Rafati, Yeganeh Pasebani, Churl-Su Kwon","doi":"10.1007/s00415-025-12961-0","DOIUrl":"https://doi.org/10.1007/s00415-025-12961-0","url":null,"abstract":"<p><strong>Objective: </strong>Suicide is among the top 10 leading causes of death. Epilepsy is associated with increased diagnoses of psychiatric conditions. Approximately 5% of deaths in people with epilepsy (PwE) are caused by suicide. We aim to compare the suicide incidence in PwE vs. people without epilepsy.</p><p><strong>Methods: </strong>A systematic review was performed looking at suicide incidence among PwE compared to persons without epilepsy. The reporting guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses standards were followed in this study. The search included records until February 2024 in Ovid® MEDLINE, Embase®, and PsycINFO. Abstracts were screened in duplicate and extracted using standard proforma. Data were recorded on the incidence of suicide ideation, attempt, or completed suicide in PwE compared to persons without epilepsy. Meta-analyses were performed along with descriptive analyses.</p><p><strong>Results: </strong>Out of a total of 7,371 records identified from the systematic search, 13 met the eligibility criteria. Meta-analysis showed a significantly higher incidence proportion of suicide ideation in PwE than those without epilepsy (risk ratio [RR]: 2.06, 95% CI 1.47-2.89). For suicide attempts, incidence proportion (RR: 3.62, 95% CI 2.88-4.55), incidence rate (incidence rate ratio [IRR]: 4.94, 95% CI 4.44-5.50) and hazard (adjusted hazard ratio [HR]: 2.32, 95% CI 2.17-2.48) were all significantly higher in PwE vs. people without epilepsy. Lastly, incidence proportion (RR: 2.39, 95% CI 1.28-4.47), incidence rate (IRR: 2.26, 95% CI 2.13-2.40), and hazard (adjusted HR: 2.50, 95% CI 1.99-3.16) of completed suicide were all significantly higher in PwE than those without epilepsy.</p><p><strong>Significance: </strong>The incidence of suicide ideation, suicide attempt, and completed suicide were significantly higher in PwE compared to people without epilepsy. Comprehensive support systems to educate, diagnose, and manage epilepsy and concurrent psychiatric conditions in PwE are highly suggested.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"232"},"PeriodicalIF":4.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heinrich Obersteiner (1847-1922).","authors":"Andrew J Larner, Lazaros C Triarhou","doi":"10.1007/s00415-025-12981-w","DOIUrl":"https://doi.org/10.1007/s00415-025-12981-w","url":null,"abstract":"","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"227"},"PeriodicalIF":4.8,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143483419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A disproportionality analysis of surgical site infections across multiple sclerosis disease modifying therapies.","authors":"Alexandra Balshi, John Dempsey, Nova Manning, Grace Leuenberger, Ursela Baber, Jacob A Sloane","doi":"10.1007/s00415-025-12980-x","DOIUrl":"https://doi.org/10.1007/s00415-025-12980-x","url":null,"abstract":"<p><strong>Background and objective: </strong>People with multiple sclerosis (PwMS) may be at an increased risk of surgical site infections (SSIs). However, the role of specific MS disease-modifying therapies (DMTs) in modulating this risk remains underexplored.</p><p><strong>Methods: </strong>The FDA Adverse Event Reporting System (FAERS) was used to investigate if MS DMTs are associated with disproportionally higher SSI reporting compared to other FAERS medications for individuals of all ages and those over the age of 50.</p><p><strong>Results: </strong>We identified 769 reports of SSIs across MS DMTs (352 in PwMS aged 50 or older) and 21 SSI-associated deaths. A pooled analysis of all DMTs revealed increased risks of SSIs (reporting odds ratio [ROR] of 1.95, 95% confidence interval [CI] 1.80-2.12) for all age groups and for those 50 or older (ROR of 2.58, 95% CI 2.27-2.92). For both age groups, ocrelizumab and interferon beta-1a met Evan's threshold for disproportionally high SSI reporting compared to all other FAERS medications.</p><p><strong>Conclusion: </strong>MS DMTs are collectively associated with disproportionately high SSI reporting, especially for PwMS over the age of 50, with ocrelizumab and interferon beta-1a increasing SSI reporting risk in both age groups. These findings reveal a need to take extra precautions when caring for PwMS in a surgical setting, such as engaging wound care teams to minimize SSI risk.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"223"},"PeriodicalIF":4.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476558","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Myasthenia gravis in 2025: five new things and four hopes for the future.","authors":"S N M Binks, I M Morse, Mohammad Ashraghi, A Vincent, Patrick Waters, M Isabel Leite","doi":"10.1007/s00415-025-12922-7","DOIUrl":"10.1007/s00415-025-12922-7","url":null,"abstract":"<p><p>The last 10 years has brought transformative developments in the effective treatment of myasthenia gravis (MG). Beginning with the randomized trial of thymectomy in myasthenia gravis that demonstrated efficacy of thymectomy in nonthymomatous MG, several new treatment approaches have completed successful clinical trials and regulatory launch. These modalities, including B cell depletion, complement inhibition, and blockade of the neonatal Fc receptor, are now in use, offering prospects of sustained remission and neuromuscular protection in what is a long-term disease. In this review, we update our clinico-immunological review of 2016 with these important advances, examine their role in treatment algorithms, and focus attention on key issues of biomarkers for prognostication and the growing cohort of older patients, both those with long-term disease, and late-onset MG ('LOMG'). We close by expressing our four hopes for the next 5-10 years: improvements in laboratory medicine to facilitate rapid diagnosis, effective strategies for neuromuscular protection, more research into and better understanding of pathophysiology and treatment response in older individuals, and the potentially transformative role of therapies aimed at delivering a durable response such as chimeric antigen receptor (CAR) T cells. Our postscript summarizes some emerging themes in the field of serological and online biomarkers, which may develop greater stature in the next epoch.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"226"},"PeriodicalIF":4.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846739/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476589","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smartphone-based gait analysis in the assessment of fatigue and fatigability in people with multiple sclerosis: a supervised cohort study.","authors":"Carolin Schönherr, Julian Ziegler, Ton Zentek, Asarnush Rashid, Sebastian Strauss, Alexander Tallner, Matthias Grothe","doi":"10.1007/s00415-025-12906-7","DOIUrl":"10.1007/s00415-025-12906-7","url":null,"abstract":"<p><strong>Background: </strong>Gait impairments and fatigue are the most common and disabling symptoms in people with multiple sclerosis (PwMS). Objective 6-min walk test (6MWT) gait testing can be improved through body-worn accelerometers, but its association to subjective fatigue and objective fatigability is contradictory. This study aims to validate an algorithm using smartphone sensor data for spatial-temporal gait parameters in PwMS and healthy controls, and evaluate its accuracy in detecting fatigability, and quantify its association with fatigue in PwMS.</p><p><strong>Methods: </strong>We recruited PwMS with mild to moderate disability (EDSS 0.0-6.5) and healthy controls in a supervised, lab-based cohort study. All participants performed the 6MWT while wearing a smartphone at the hip, which collected acceleration data of step count, cadence and walking speed. Algorithm validation included the mean absolute percentage error (MAPE) and Bland-Altman analysis. Fatigability and fatigue were measured in PwMS, with fatigability defined as a 10% decline in gait performance, and fatigue using the fatigue scale for motor and cognitive functions (FSMC). Further, correlations between gait parameters and FSMC were assessed.</p><p><strong>Results: </strong>A total of 38 PwMS and 24 healthy controls were included. The algorithm demonstrated high validity for step count (MAPE < 3%) and cadence (MAPE < 10%). Gait analyses revealed fatigability in between 2.6 and 15.8% of PwMS, with large differences between the gait parameter assessed. Significant correlations were found especially between FSMC motor fatigue scores and step count (r = - 0.50), cadence (r = 0.51) and walking speed (r = 0.50).</p><p><strong>Conclusion: </strong>Smartphone-based gait analysis provides an accessible and valid method for detecting steps and cadence. There are major differences in the assessment of fatigability, but an allover association to subjective motor fatigue.</p>","PeriodicalId":16558,"journal":{"name":"Journal of Neurology","volume":"272 3","pages":"217"},"PeriodicalIF":4.8,"publicationDate":"2025-02-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11846754/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143476598","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}