{"title":"Nosferatu and the cinematic unglory of hysteria","authors":"Eelco F Wijdicks","doi":"10.1016/s1474-4422(25)00282-0","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00282-0","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"17 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840155","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Thomas O Crawford, Laurent Servais, Eugenio Mercuri, Heike Kölbel, Nancy Kuntz, Richard S Finkel, Jena Krueger, Kaitlin Batley, Sally Dunaway Young, Jing L Marantz, Guochen Song, Bert Yao, Guolin Zhao, Jose Rossello, Giridhar S Tirucherai, Elena Stacy Mazzone, Russell J Butterfield, Marta Gomez Garcia de la Banda, Andreea M Seferian, Valeria A Sansone, Inmaculada Pitarch Castellano
{"title":"Safety and efficacy of apitegromab in nonambulatory type 2 or type 3 spinal muscular atrophy (SAPPHIRE): a phase 3, double-blind, randomised, placebo-controlled trial","authors":"Thomas O Crawford, Laurent Servais, Eugenio Mercuri, Heike Kölbel, Nancy Kuntz, Richard S Finkel, Jena Krueger, Kaitlin Batley, Sally Dunaway Young, Jing L Marantz, Guochen Song, Bert Yao, Guolin Zhao, Jose Rossello, Giridhar S Tirucherai, Elena Stacy Mazzone, Russell J Butterfield, Marta Gomez Garcia de la Banda, Andreea M Seferian, Valeria A Sansone, Inmaculada Pitarch Castellano","doi":"10.1016/s1474-4422(25)00225-x","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00225-x","url":null,"abstract":"<h3>Background</h3>Approved spinal muscular atrophy therapies greatly improve clinical outcomes; however, substantial motor function deficits persist. Apitegromab, a fully human monoclonal antibody, selectively inhibits myostatin activation, improving muscle function. We aimed to assess the safety and efficacy of apitegromab in patients with nonambulatory type 2 or type 3 spinal muscular atrophy receiving nusinersen or risdiplam.<h3>Methods</h3>SAPPHIRE, a double-blind, placebo-controlled, phase 3 trial, was done in 48 hospitals in Belgium, France, Germany, Italy, Poland, Spain, the Netherlands, the UK, and the USA. Eligible participants were aged 2–21 years, had genetically documented SMN-deficient nonambulatory type 2 or type 3 spinal muscular atrophy, an estimated life expectancy greater than 2 years, Hammersmith Functional Motor Scale-Expanded (HFMSE) scores 10–45, and had received at least 10 months’ nusinersen or at least 6 months’ risdiplam therapy at screening. Participants aged 2–12 years were randomly assigned 1:1:1 to receive apitegromab 20 mg/kg, apitegromab 10 mg/kg, or placebo every 4 weeks; participants aged 13–21 years were randomly assigned 2:1 to receive apitegromab 20 mg/kg or placebo every 4 weeks. All participants, parents or caregivers, investigators, and site personnel were unaware of the treatment assignment. The primary endpoint, change from baseline in HFMSE at 12 months, was assessed in participants aged 2–12 years who received at least one dose of apitegromab or placebo and had at least one post-baseline evaluable HFMSE assessment (modified intention-to-treat set). Comparisons of the combined apitegromab dose (20 mg/kg and 10 mg/kg) versus placebo and the 20 mg/kg dose versus placebo were done with a mixed-effects model with repeated measurement. Safety was analysed in all participants who received at least one dose of apitegromab or placebo through evaluation of adverse events, physical examinations, vital signs and cardiac assessments, laboratory evaluations, and concomitant medications. SAPPHIRE is registered with <span><span>ClinicalTrials.gov</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, <span><span>NCT05156320</span><svg aria-label=\"Opens in new window\" focusable=\"false\" height=\"20\" viewbox=\"0 0 8 8\"><path d=\"M1.12949 2.1072V1H7V6.85795H5.89111V2.90281L0.784057 8L0 7.21635L5.11902 2.1072H1.12949Z\"></path></svg></span>, and is completed.<h3>Findings</h3>From March 28, 2022, to Sept 4, 2024, we enrolled 188 patients (156 in the population aged 2–12 years and 32 in the population aged 13–21 years); of whom 128 participants received apitegromab and 60 participants received placebo. At 12 months, least squares mean difference in HFMSE change from baseline was 1·8 (95% CI 0·30 to 3·32, p=0·019) points for participants aged 2–12 years receiving apitegromab","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer E Fugate, Maximiliano A Hawkes, Alejandro A Rabinstein
{"title":"Posterior reversible encephalopathy syndrome: evolving insights in diagnosis, management, and outcomes","authors":"Jennifer E Fugate, Maximiliano A Hawkes, Alejandro A Rabinstein","doi":"10.1016/s1474-4422(25)00232-7","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00232-7","url":null,"abstract":"Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome characterised by acute or subacute neurological symptoms—including encephalopathy, seizures, headache, and visual disturbances. Recent advances in neuroimaging, biomarker research, and the increasing use of cytotoxic agents and novel immunotherapies, such as tyrosine kinase inhibitors and anti-CD19 chimeric antigen receptor T-cell therapies, have expanded the spectrum of PRES presentations and associated risk factors. PRES is thought to result from endothelial dysfunction and blood–brain barrier disruption. Emerging research into inflammatory cytokines and biomarkers, such as IL-6, IL-10, and VEGF, offers promising avenues for improved diagnosis and prognosis. Treatment is focused on removing precipitating factors and controlling blood pressure, but evidence from randomised trials is absent. Although prognosis is generally favourable, severe and recurrent PRES can occur, and complications such as epilepsy and stroke can follow. More robust observational studies with large sample sizes, prospective designs, and with more systemic imaging approaches are required to refine diagnostic criteria, clarify pathophysiological mechanisms, and identify optimal management strategies to improve outcomes in this complex and evolving syndrome.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Joost Raaphorst, Anneke J van der Kooi, Christopher A Mecoli, Conrad C Weihl, Sander W Tas, Jens Schmidt, Marianne de Visser
{"title":"Advances in the classification and management of idiopathic inflammatory myopathies","authors":"Joost Raaphorst, Anneke J van der Kooi, Christopher A Mecoli, Conrad C Weihl, Sander W Tas, Jens Schmidt, Marianne de Visser","doi":"10.1016/s1474-4422(25)00233-9","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00233-9","url":null,"abstract":"Idiopathic inflammatory myopathies are a group of immune-mediated disorders characterised by multisystem involvement and a chronic disease course in two-thirds of adult patients. Autoantibodies can aid in the identification of disease subtypes and their associated severe complications, such as cancer or interstitial lung disease. Patients with idiopathic inflammatory myopathies need to be managed in a multidisciplinary setting. Treatment with intravenous immunoglobulins is efficacious in patients with refractory dermatomyositis, and can result in improvements in disease activity in the skin and muscle. Numerous randomised controlled trials are underway testing potential therapeutic agents that hold promise for the treatment of idiopathic inflammatory myopathies. Other advances include the identification of pathophysiological mechanisms. Induction of interferons in patients with dermatomyositis leads to the upregulation of interferon-stimulated genes in blood, skin, and muscle tissue. The interferon-induced transcripts could yield diagnostic biomarkers and biomarkers for monitoring disease activity. The identification of these potential biomarkers has also propelled the development of therapies targeting the interferon pathway—either upstream by using monoclonal autoantibodies or by blocking downstream signalling pathways via JAK inhibitors. A promising strategy for patients with refractory disease is targeting B cells with CD19-targeting chimeric antigen receptor T-cell therapy. Treatments targeting T cell lymphocytes and specific T-cell subsets are also under investigation.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The evolving landscape of spinal muscular atrophy treatment","authors":"Aicee Dawn Calma, Steve Vucic, Michelle A Farrar","doi":"10.1016/s1474-4422(25)00268-6","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00268-6","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840044","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Michael S Rafii, Zinayida Schlachetzki, Isabel Barroeta, Elizabeth Head, Juan Fortea, Beau M Ances
{"title":"Down syndrome and Alzheimer's disease: insights into biomarkers, clinical symptoms, and pathology","authors":"Michael S Rafii, Zinayida Schlachetzki, Isabel Barroeta, Elizabeth Head, Juan Fortea, Beau M Ances","doi":"10.1016/s1474-4422(25)00237-6","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00237-6","url":null,"abstract":"<h3>Background</h3>Individuals with Down syndrome have a genetically determined form of Alzheimer's disease, due to an additional copy of the APP gene. Nearly all individuals with Down syndrome develop Alzheimer's disease pathology by age 40 years, and approximately 70% are diagnosed with dementia by around age 54 years, with an overall lifetime risk of 95%. Moreover, Alzheimer's disease is the leading cause of death in adults with Down syndrome older than 35 years.<h3>Recent developments</h3>The intersection of Down syndrome and Alzheimer's disease has garnered substantial attention in the past 10 years as research indicates that the trajectory of clinical symptoms and biomarker changes in adults with Down syndrome closely resembles that seen in late-onset Alzheimer's disease and autosomal-dominant Alzheimer's disease (ADAD). The predictive nature of dementia onset in genetically determined populations allows precise staging of disease in individuals along the Alzheimer's disease continuum. The high prevalence of Alzheimer's disease pathology combined with the few age-related comorbidities in these cohorts, makes them ideal for understanding the biological mechanisms related to late-onset Alzheimer's disease. The more rapid disease progression seen in people with Down syndrome-related Alzheimer's disease compared with people with ADAD or late-onset Alzheimer's disease provides important insights and supports the rationale for new clinical trials.<h3>Where next?</h3>The Alzheimer's Clinical Trials Consortium–Down Syndrome is ushering in a new era of therapies for individuals with Down syndrome. Three ongoing clinical trials, in close collaboration with industry partners, specifically designed for this population, are focused on testing disease-modifying treatments. These innovative efforts mark a considerable stride in bringing groundbreaking therapies to a group that has long been excluded from clinical trials in Alzheimer's disease.","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Alzheimer's disease in Down syndrome: progress and promise","authors":"Natalie S Ryan","doi":"10.1016/s1474-4422(25)00276-5","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00276-5","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"An emerging theory of sentience | Todd E Feinberg, From sensing to sentience: how feeling emerges from the brain, The MIT Press (2024), p. 216, $35.00, ISBN: 978-0-262-55095-6","authors":"Robert Stirrups","doi":"10.1016/s1474-4422(25)00283-2","DOIUrl":"https://doi.org/10.1016/s1474-4422(25)00283-2","url":null,"abstract":"No Abstract","PeriodicalId":22676,"journal":{"name":"The Lancet Neurology","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144840052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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