Pub Date : 2026-03-01Epub Date: 2026-03-12DOI: 10.1016/j.neurot.2026.e00883
Xiao-Wen Hou , Yu Cui , Hong-Ting Yan , Fei Liu , Wen-Chu Zhao , Hui-Sheng Chen
We conducted a post hoc analysis of the ATAMIS (Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke) trial to evaluate whether diabetes mellitus (DM) status affects the efficacy of antiplatelet therapy in acute mild-to-moderate ischemic stroke. Using the modified intention-to-treat analysis set from the ATAMIS trial, patients were categorized into DM and non-DM subgroups. Outcomes were compared between the two antiplatelet treatments in each subgroup, and an interaction between DM status and treatment efficacy was assessed. The primary efficacy endpoint was early neurological deterioration (END) at 7 days, and safety endpoints included bleeding events and intracranial hemorrhage. A total of 2915 patients were included in this study. Compared with aspirin monotherapy, clopidogrel plus aspirin significantly reduced the incidence of END at 7 days in patients with DM (5.2 % versus 8.8 %; adjusted risk difference, −4.1 %; 95 % CI, −8.1 % to −0.1 %; P = 0.04), but not in those without DM (4.6 % versus 6.1 %; adjusted risk difference, −1.9 %; 95 % CI, −4.0 %–0.2 %; P = 0.07). No significant interaction was observed between DM status and treatment effect on the primary outcome (P = 0.38). Safety endpoints were similar between treatment groups, regardless of DM status. In patients with acute mild-to-moderate ischemic stroke, dual antiplatelet therapy was associated with a significant reduction in END at 7 days, specifically in the DM subgroup.
我们对ATAMIS（急性轻中度缺血性卒中抗血小板治疗）试验进行了事后分析，以评估糖尿病（DM）状态是否会影响急性轻中度缺血性卒中抗血小板治疗的疗效。使用ATAMIS试验中改进的意向治疗分析集，将患者分为糖尿病和非糖尿病亚组。比较每个亚组两种抗血小板治疗的结果，并评估糖尿病状态与治疗效果之间的相互作用。主要疗效终点是7天早期神经功能恶化（END），安全性终点包括出血事件和颅内出血。本研究共纳入2915例患者。与阿司匹林单药治疗相比，氯吡格雷加阿司匹林显著降低DM患者7天END的发生率（5.2% vs 8.8%；校正风险差，- 4.1%;95% CI, - 8.1%至- 0.1%;P = 0.04），但在无DM患者中没有（4.6% vs 6.1%；校正风险差，- 1.9%;95% CI, - 4.0% - 0.2%; P = 0.07）。糖尿病状态与治疗效果对主要结局无显著相互作用（P = 0.38）。无论糖尿病状态如何，两组间的安全终点相似。在急性轻中度缺血性卒中患者中，双重抗血小板治疗与7天时END的显著降低相关，特别是在DM亚组中。
{"title":"Diabetes mellitus and efficacy of dual antiplatelet in acute ischemic stroke: A post hoc analysis of the ATAMIS trial","authors":"Xiao-Wen Hou , Yu Cui , Hong-Ting Yan , Fei Liu , Wen-Chu Zhao , Hui-Sheng Chen","doi":"10.1016/j.neurot.2026.e00883","DOIUrl":"10.1016/j.neurot.2026.e00883","url":null,"abstract":"<div><div>We conducted a post hoc analysis of the ATAMIS (Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke) trial to evaluate whether diabetes mellitus (DM) status affects the efficacy of antiplatelet therapy in acute mild-to-moderate ischemic stroke. Using the modified intention-to-treat analysis set from the ATAMIS trial, patients were categorized into DM and non-DM subgroups. Outcomes were compared between the two antiplatelet treatments in each subgroup, and an interaction between DM status and treatment efficacy was assessed. The primary efficacy endpoint was early neurological deterioration (END) at 7 days, and safety endpoints included bleeding events and intracranial hemorrhage. A total of 2915 patients were included in this study. Compared with aspirin monotherapy, clopidogrel plus aspirin significantly reduced the incidence of END at 7 days in patients with DM (5.2 % versus 8.8 %; adjusted risk difference, −4.1 %; 95 % CI, −8.1 % to −0.1 %; P = 0.04), but not in those without DM (4.6 % versus 6.1 %; adjusted risk difference, −1.9 %; 95 % CI, −4.0 %–0.2 %; P = 0.07). No significant interaction was observed between DM status and treatment effect on the primary outcome (P = 0.38). Safety endpoints were similar between treatment groups, regardless of DM status. In patients with acute mild-to-moderate ischemic stroke, dual antiplatelet therapy was associated with a significant reduction in END at 7 days, specifically in the DM subgroup.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 2","pages":"Article e00883"},"PeriodicalIF":6.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147453108","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}
Pub Date : 2026-03-01Epub Date: 2026-02-26DOI: 10.1016/j.neurot.2026.e00860
Ying Wang , Samuel Anchipolovsky , Piplu Bhuiyan , Luna Sato , Ge Liang , De-Maw Chuang , Huafeng Wei
Alzheimer's disease (AD), particularly its sporadic form (SAD, 95 % AD patients), is strongly associated with the apolipoprotein E4 (ApoE4) genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe2+, increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation and excessive ROS production. Moreover, lithium (0.25 mM) normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP3 receptor (InsP3R-1) protein, a Ca2+ channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses and inhibition of disrupted Ca2+ signaling. Given the drug's demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.
{"title":"Lithium chloride suppresses ferroptosis of induced pluripotent stem cells with ApoE4/E4 from a sporadic Alzheimer's disease patient","authors":"Ying Wang , Samuel Anchipolovsky , Piplu Bhuiyan , Luna Sato , Ge Liang , De-Maw Chuang , Huafeng Wei","doi":"10.1016/j.neurot.2026.e00860","DOIUrl":"10.1016/j.neurot.2026.e00860","url":null,"abstract":"<div><div>Alzheimer's disease (AD), particularly its sporadic form (SAD, 95 % AD patients), is strongly associated with the apolipoprotein E4 (ApoE4) genotype and characterized by oxidative stress, iron dysregulation, and increased susceptibility to ferroptosis. Lithium, a well-established neuroprotective agent, has shown potential to mitigate several pathological mechanisms in AD, including ferroptosis. This study investigates the therapeutic potential of lithium chloride in human induced pluripotent stem cells (iPSCs) derived from a SAD patient with ApoE4/E4 genotype and compared effects with those of isogenic gene-edited ApoE3/E3 control. Lithium treatment significantly improved cell viability in ApoE4/E4 iPSCs. It also reversed key ferroptosis phenotypes, including elevated cytosolic Fe<sup>2+</sup>, increased expression of divalent metal transporter 1, reduced level of glutathione peroxidase 4, enhanced lipid peroxidation and excessive ROS production. Moreover, lithium (0.25 mM) normalized mitochondrial respiration and reduced proton leak, indicating preservation of mitochondrial function and protection against mitochondrial damage and cell death. Lithium also reduced the expression of type 1 InsP<sub>3</sub> receptor (InsP<sub>3</sub>R-1) protein, a Ca<sup>2+</sup> channel located on the endoplasmic reticulum (ER) membrane. Together, these findings highlight lithium's inhibition of ferroptosis through modulation of iron metabolism, antioxidant defenses and inhibition of disrupted Ca<sup>2+</sup> signaling. Given the drug's demonstrated efficacy in reversing ApoE4-driven cellular vulnerabilities, lithium salt warrants further investigation for the treatment of AD.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 2","pages":"Article e00860"},"PeriodicalIF":6.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147317932","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}
Pub Date : 2026-03-01Epub Date: 2026-02-27DOI: 10.1016/j.neurot.2026.e00864
Jinlong Liu , Jonas Krauss , Veronika Purrer , Valeri Borger , Markus Essler , Alexander Radbruch , Ullrich Wüllner , Neeraj Upadhyay , Henning Boecker
Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising, noninvasive therapeutic approach for essential tremor (ET), yet the effects of the respective lesions on functional brain network organization remain poorly understood. Here, we performed graph theory analysis to investigate changes in small-world properties and modular architecture in ET patients six months after unilateral MRgFUS of the thalamic ventral intermediate (VIM) nucleus. Small-worldness and normalized clustering coefficient increased significantly after MRgFUS, while clustering coefficient, characteristic path length, normalized characteristic path length, global efficiency, and local efficiency remained unchanged. Modular organization was largely preserved, but trend-level enhancements in inter-modular connectivity were observed between frontoparietal and subcortical modules, as well as between frontoparietal and frontotemporal-parietal modules. Within these modules, betweenness centrality increased significantly in specific cortical hubs, including the left superior frontal gyrus, right superior parietal lobule, and left postcentral gyrus. These findings indicate that unilateral VIM-MRgFUS induces selective functional network reorganization, particularly affecting relative clustering and nodal centrality patterns.
{"title":"Functional network reorganization following VIM-MRgFUS for essential tremor","authors":"Jinlong Liu , Jonas Krauss , Veronika Purrer , Valeri Borger , Markus Essler , Alexander Radbruch , Ullrich Wüllner , Neeraj Upadhyay , Henning Boecker","doi":"10.1016/j.neurot.2026.e00864","DOIUrl":"10.1016/j.neurot.2026.e00864","url":null,"abstract":"<div><div>Magnetic resonance-guided focused ultrasound (MRgFUS) is a promising, noninvasive therapeutic approach for essential tremor (ET), yet the effects of the respective lesions on functional brain network organization remain poorly understood. Here, we performed graph theory analysis to investigate changes in small-world properties and modular architecture in ET patients six months after unilateral MRgFUS of the thalamic ventral intermediate (VIM) nucleus. Small-worldness and normalized clustering coefficient increased significantly after MRgFUS, while clustering coefficient, characteristic path length, normalized characteristic path length, global efficiency, and local efficiency remained unchanged. Modular organization was largely preserved, but trend-level enhancements in inter-modular connectivity were observed between frontoparietal and subcortical modules, as well as between frontoparietal and frontotemporal-parietal modules. Within these modules, betweenness centrality increased significantly in specific cortical hubs, including the left superior frontal gyrus, right superior parietal lobule, and left postcentral gyrus. These findings indicate that unilateral VIM-MRgFUS induces selective functional network reorganization, particularly affecting relative clustering and nodal centrality patterns.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 2","pages":"Article e00864"},"PeriodicalIF":6.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147321886","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}
Pub Date : 2026-03-01Epub Date: 2026-03-12DOI: 10.1016/j.neurot.2026.e00867
Hunter B. Dean , Ryan A. Tuckey , Rory A. Greer , Jessica A. Greven , Shan-Zhong Yang , Daniel S. Elston , Gunnar N. Eastep , Yuwei Song , Thomas J. Brett , Yuhua Song , Erik D. Roberson
Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at hydrophobic residues in an apical site previously associated with TREM2's ability to bind apolipoprotein E, and in biophysical studies cholecalciferol enhanced TREM2–apolipoprotein E binding. Functionally, cholecalciferol induced TREM2-dependent signaling in human, rat, and mouse cells. As expected with TREM2 activation, cholecalciferol stimulated phagocytosis in cultured macrophages and microglia, and induced resistance to multiple cytotoxic agents, including pathologic amyloid-β species. These findings identify a novel TREM2 ligand that may inform therapeutic strategies for AD, and a previously unrecognized receptor for cholecalciferol that provides a potential mechanistic link between vitamin D3 deficiency and increased AD risk.
{"title":"Cholecalciferol (vitamin D3) is an agonist of the Alzheimer's disease–associated immune receptor TREM2","authors":"Hunter B. Dean , Ryan A. Tuckey , Rory A. Greer , Jessica A. Greven , Shan-Zhong Yang , Daniel S. Elston , Gunnar N. Eastep , Yuwei Song , Thomas J. Brett , Yuhua Song , Erik D. Roberson","doi":"10.1016/j.neurot.2026.e00867","DOIUrl":"10.1016/j.neurot.2026.e00867","url":null,"abstract":"<div><div>Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) is one of the strongest genetic risk factors for late-onset Alzheimer's disease (AD). Several TREM2 ligands are known, including charged lipids and AD-associated proteins like apolipoprotein E and amyloid-β, but the full range of endogenous ligands for TREM2 remains unknown. Here we combined virtual screening of the Human Metabolome Database with molecular dynamics simulations, binding free energy estimation, and biolayer interferometry to identify novel TREM2 ligands and map their binding sites. Cholecalciferol, the unmodified parent form of vitamin D3, emerged as a top candidate. Structural modeling indicated that cholecalciferol binds TREM2 at hydrophobic residues in an apical site previously associated with TREM2's ability to bind apolipoprotein E, and in biophysical studies cholecalciferol enhanced TREM2–apolipoprotein E binding. Functionally, cholecalciferol induced TREM2-dependent signaling in human, rat, and mouse cells. As expected with TREM2 activation, cholecalciferol stimulated phagocytosis in cultured macrophages and microglia, and induced resistance to multiple cytotoxic agents, including pathologic amyloid-β species. These findings identify a novel TREM2 ligand that may inform therapeutic strategies for AD, and a previously unrecognized receptor for cholecalciferol that provides a potential mechanistic link between vitamin D3 deficiency and increased AD risk.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 2","pages":"Article e00867"},"PeriodicalIF":6.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147453107","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}
Pub Date : 2026-03-01Epub Date: 2026-03-12DOI: 10.1016/j.neurot.2026.e00868
Qiujiang Qiao , Qing Gong , Ning Li , Haowei Sun , Xufang Ru , Ning Mu , Beike Chen , Wenyan Li , Tunan Chen , Hua Feng , Yujie Chen , Huilin Cheng
Scar formation is a critical determinant of neurological recovery following spinal cord injury (SCI) because scars act as a physical support and barrier that influences axonal regeneration and remyelination. However, the regulatory mechanisms governing scar formation remain incompletely understood. Integrated multiomics analysis of publicly available single-cell RNA-seq and ATAC-seq data (GSE230765) from adult mice during the subacute/chronic phases of SCI revealed epigenetic mechanisms underlying microglial activation. Cell communication analysis revealed a connection between persistent microglial activation and excessive scar formation after SCI. Pharmacological inhibition of histone acetylation using L002 was employed to validate the H3K27ac-mediated regulation of the microglial phenotype, scar formation, and functional recovery. Persistent microglial activation post-SCI resulted in characteristic cholesterol metabolic reprogramming, with intracellular cholesterol accumulation correlated with sustained microglial activation. Single-cell ATAC-seq revealed chromatin accessibility-mediated epigenetic control of cholesterol metabolism gene expression, identifying H3K27ac as a pivotal regulator. L002-mediated H3K27ac inhibition attenuated cholesterol accumulation, mitigated neuroinflammation, and reduced scar formation through the disruption of microglia–astrocyte–fibroblast communication. Mechanistically, SPP1 secretion from activated microglia drove excessive scar formation, and inhibition of H3K27ac reduced the level of SPP1. Our study suggests that H3K27ac mediates the epigenetic regulation of myeloid cell activation in SCI pathogenesis. Targeted modulation of this histone modification site attenuates chronic microglial activation and subsequent scar formation, suggesting an innovative therapeutic strategy for neural repair. These findings establish chromatin remodeling as a promising target for improving functional recovery post-SCI.
{"title":"Persistent histone H3K27 acetylation contributes to excessive scar formation after spinal cord injury through the regulation of microglial cholesterol accumulation","authors":"Qiujiang Qiao , Qing Gong , Ning Li , Haowei Sun , Xufang Ru , Ning Mu , Beike Chen , Wenyan Li , Tunan Chen , Hua Feng , Yujie Chen , Huilin Cheng","doi":"10.1016/j.neurot.2026.e00868","DOIUrl":"10.1016/j.neurot.2026.e00868","url":null,"abstract":"<div><div>Scar formation is a critical determinant of neurological recovery following spinal cord injury (SCI) because scars act as a physical support and barrier that influences axonal regeneration and remyelination. However, the regulatory mechanisms governing scar formation remain incompletely understood. Integrated multiomics analysis of publicly available single-cell RNA-seq and ATAC-seq data (GSE230765) from adult mice during the subacute/chronic phases of SCI revealed epigenetic mechanisms underlying microglial activation. Cell communication analysis revealed a connection between persistent microglial activation and excessive scar formation after SCI. Pharmacological inhibition of histone acetylation using L002 was employed to validate the H3K27ac-mediated regulation of the microglial phenotype, scar formation, and functional recovery. Persistent microglial activation post-SCI resulted in characteristic cholesterol metabolic reprogramming, with intracellular cholesterol accumulation correlated with sustained microglial activation. Single-cell ATAC-seq revealed chromatin accessibility-mediated epigenetic control of cholesterol metabolism gene expression, identifying H3K27ac as a pivotal regulator. L002-mediated H3K27ac inhibition attenuated cholesterol accumulation, mitigated neuroinflammation, and reduced scar formation through the disruption of microglia–astrocyte–fibroblast communication. Mechanistically, SPP1 secretion from activated microglia drove excessive scar formation, and inhibition of H3K27ac reduced the level of SPP1. Our study suggests that H3K27ac mediates the epigenetic regulation of myeloid cell activation in SCI pathogenesis. Targeted modulation of this histone modification site attenuates chronic microglial activation and subsequent scar formation, suggesting an innovative therapeutic strategy for neural repair. These findings establish chromatin remodeling as a promising target for improving functional recovery post-SCI.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 2","pages":"Article e00868"},"PeriodicalIF":6.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147453111","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}
Rituximab (RTX) is increasingly used off-label for the treatment of multiple sclerosis (MS), yet real-world evidence from Middle Eastern populations remains limited. This multicenter, retrospective observational study evaluated the effectiveness and safety of RTX using data from the MENACTRIMS registry across seven Middle Eastern countries (Iraq, Kuwait, Lebanon, Oman, Saudi Arabia, Tunisia, and the United Arab Emirates). A total of 774 MS patients were included: 482 with relapsing-remitting MS (RRMS) and 292 with active secondary progressive MS (aSPMS). Patients received intravenous RTX at doses of 500 mg or 1000 mg every 6–12 months. The cohort was predominantly female (72.1%), with a mean age of 39.6 years and a mean disease duration of 11.9 years from symptom onset. RTX treatment was associated with a significant reduction in annualized relapse rate (ARR), decreasing from 1.65 to 0.08 in RRMS and from 2.03 to 0.02 in aSPMS (p < 0.001). Expanded Disability Status Scale (EDSS) scores remained stable in RRMS but increased by 1.0 point in aSPMS (p < 0.001). MRI activity was suppressed in most RRMS patients, with 89.1% showing no new or enlarging lesions, whereas only 8.1% of aSPMS patients demonstrated similar stability. NEDA-3 was achieved in 47.3% of RRMS patients. A total of 491 adverse events were reported, predominantly mild infusion-related reactions (92.5%). Overall, off-label RTX demonstrated substantial real-world effectiveness and a favorable safety profile in Middle Eastern MS patients, particularly in RRMS.
{"title":"The real-world effectiveness and safety of off-label rituximab in a large cohort of Middle Eastern multiple sclerosis patients","authors":"Ghida Ismail , Maya Zeineddine , Raed Al-Roughani , Samar Farouk Ahmed , Akram Al-Mahdawi , Samia Khoury , Nabil El-Ayoubi , Jihad Inshasi , Jaber Al-Khabouri , Abdullah Al-Asmi , Riadh Gouider , Salman Aljarallah , Nuha Alkhawajah , Yaser Al Malik , Ahmad Abulaban , Seraj Makkawi , Osama Khojah , Taghrid El-Hajj , Joelle Massouh , Husam AlSalamat , Bassem Yamout","doi":"10.1016/j.neurot.2026.e00861","DOIUrl":"10.1016/j.neurot.2026.e00861","url":null,"abstract":"<div><div>Rituximab (RTX) is increasingly used off-label for the treatment of multiple sclerosis (MS), yet real-world evidence from Middle Eastern populations remains limited. This multicenter, retrospective observational study evaluated the effectiveness and safety of RTX using data from the MENACTRIMS registry across seven Middle Eastern countries (Iraq, Kuwait, Lebanon, Oman, Saudi Arabia, Tunisia, and the United Arab Emirates). A total of 774 MS patients were included: 482 with relapsing-remitting MS (RRMS) and 292 with active secondary progressive MS (aSPMS). Patients received intravenous RTX at doses of 500 mg or 1000 mg every 6–12 months. The cohort was predominantly female (72.1%), with a mean age of 39.6 years and a mean disease duration of 11.9 years from symptom onset. RTX treatment was associated with a significant reduction in annualized relapse rate (ARR), decreasing from 1.65 to 0.08 in RRMS and from 2.03 to 0.02 in aSPMS (p < 0.001). Expanded Disability Status Scale (EDSS) scores remained stable in RRMS but increased by 1.0 point in aSPMS (p < 0.001). MRI activity was suppressed in most RRMS patients, with 89.1% showing no new or enlarging lesions, whereas only 8.1% of aSPMS patients demonstrated similar stability. NEDA-3 was achieved in 47.3% of RRMS patients. A total of 491 adverse events were reported, predominantly mild infusion-related reactions (92.5%). Overall, off-label RTX demonstrated substantial real-world effectiveness and a favorable safety profile in Middle Eastern MS patients, particularly in RRMS.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 2","pages":"Article e00861"},"PeriodicalIF":6.9,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147453105","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}
Pub Date : 2026-01-01Epub Date: 2025-11-30DOI: 10.1016/j.neurot.2025.e00808
Lorenzo Muccioli , Maria Tappatà , Andrea Farolfi , Pankaj K. Singh , Elena Pasini , Serena Mazzone , Erika Esposito , Lorenzo Motta , Olivia M. D'Agati , Sofia Angeloni , Alice Caravelli , Chiara Cancellerini , Raffaella Minardi , Eleonora Pizzi , Valerio Carelli , Caterina Tonon , Jessica Fiori , Matthew S. Gentry , Luca Vignatelli , Roberto Michelucci , Francesca Bisulli
Lafora disease (LD) is a fatal progressive myoclonus epilepsy that affects previously healthy adolescents and lacks effective treatments. It is caused by pathogenic variants in EPM2A or NHLRC1, leading to the accumulation of polyglucosan in the brain and other tissues. This study is the first to evaluate the administration of a potentially disease-modifying drug – VAL-1221, a glycogen-degrading antibody-enzyme fusion – in LD patients through a 12-month compassionate use program. Five patients (aged 17–24 years; three females) with intermediate to advanced LD received VAL-1221 intravenous infusions (20 mg/kg every other week). Safety was monitored through treatment-emergent adverse events (TEAEs), whereas efficacy was assessed using clinical scales, EEG and neuroimaging. Drug concentration profile was studied via liquid chromatography-high resolution mass spectrometry (LC-HRMS) of plasma and cerebrospinal fluid (CSF), and metabolomics via gas chromatography-MS of CSF. Four patients completed the full treatment course: one discontinued after eight months following status epilepticus. VAL-1221 was well tolerated, with five mild infusion-related TEAEs (skin rash in one, hypotension in four). Efficacy measures showed continued disease progression across patients. LC-HRMS analysis revealed no detectable levels of VAL-1221 in CSF. CSF metabolic profiling revealed no difference between untreated and VAL-1221-treated samples. These findings demonstrate that intravenous VAL-1221 is safe but ineffective, providing an important negative result that prevents further patient exposure to this approach and redirects efforts toward direct central nervous system delivery methods. The study also demonstrates the feasibility of assessing disease progression using clinical and neuroimaging measures, providing a valuable framework for clinical trials in LD.
{"title":"New therapeutic strategies for Lafora disease: Evaluation of the safety, efficacy, pharmacokinetics and metabolomic profile of intravenous VAL-1221 treatment","authors":"Lorenzo Muccioli , Maria Tappatà , Andrea Farolfi , Pankaj K. Singh , Elena Pasini , Serena Mazzone , Erika Esposito , Lorenzo Motta , Olivia M. D'Agati , Sofia Angeloni , Alice Caravelli , Chiara Cancellerini , Raffaella Minardi , Eleonora Pizzi , Valerio Carelli , Caterina Tonon , Jessica Fiori , Matthew S. Gentry , Luca Vignatelli , Roberto Michelucci , Francesca Bisulli","doi":"10.1016/j.neurot.2025.e00808","DOIUrl":"10.1016/j.neurot.2025.e00808","url":null,"abstract":"<div><div>Lafora disease (LD) is a fatal progressive myoclonus epilepsy that affects previously healthy adolescents and lacks effective treatments. It is caused by pathogenic variants in <em>EPM2A</em> or <em>NHLRC1</em>, leading to the accumulation of polyglucosan in the brain and other tissues. This study is the first to evaluate the administration of a potentially disease-modifying drug – VAL-1221, a glycogen-degrading antibody-enzyme fusion – in LD patients through a 12-month compassionate use program. Five patients (aged 17–24 years; three females) with intermediate to advanced LD received VAL-1221 intravenous infusions (20 mg/kg every other week). Safety was monitored through treatment-emergent adverse events (TEAEs), whereas efficacy was assessed using clinical scales, EEG and neuroimaging. Drug concentration profile was studied via liquid chromatography-high resolution mass spectrometry (LC-HRMS) of plasma and cerebrospinal fluid (CSF), and metabolomics via gas chromatography-MS of CSF. Four patients completed the full treatment course: one discontinued after eight months following status epilepticus. VAL-1221 was well tolerated, with five mild infusion-related TEAEs (skin rash in one, hypotension in four). Efficacy measures showed continued disease progression across patients. LC-HRMS analysis revealed no detectable levels of VAL-1221 in CSF. CSF metabolic profiling revealed no difference between untreated and VAL-1221-treated samples. These findings demonstrate that intravenous VAL-1221 is safe but ineffective, providing an important negative result that prevents further patient exposure to this approach and redirects efforts toward direct central nervous system delivery methods. The study also demonstrates the feasibility of assessing disease progression using clinical and neuroimaging measures, providing a valuable framework for clinical trials in LD.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00808"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655185","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}
Pub Date : 2026-01-01Epub Date: 2025-12-04DOI: 10.1016/j.neurot.2025.e00812
Franz Felix Konen , Steffen Pfeuffer , Konstantin Fritz Jendretzky , Klaus Gehring , Birte Elias-Hamp , Kurt-Wolfram Sühs , Stephan Halle , Korbinian Brand , Ralf Lichtinghagen , Eline Willemse , Marc Pawlitzki , Jens Kuhle , Sven G. Meuth , Christoph Kleinschnitz , Refik Pul , Thomas Skripuletz
Anti-CD20 antibodies and cladribine are established therapies for active relapsing multiple sclerosis (RMS). Increasing evidence suggests that switching between these therapies may be beneficial in patients with ongoing disease activity under current treatment. In this multicenter retrospective study across six German MS centres, a total of 90 patients with active RMS were considered for inclusion, of whom 71 patients were switched either from anti-CD20 antibodies to cladribine (n = 31) or from cladribine to anti-CD20 antibodies (n = 40), with a minimum follow-up of 12 months. At treatment initiation, patients switching from anti-CD20 antibodies were older, had a longer disease duration, and a higher disability score compared to those switching from cladribine (p = 0.0040, p = 0.0447, p = 0.0028, respectively). The primary reason for switching was disease activity. Following the switch, the proportion of patients with relapsing disease activity was markedly reduced (from 55 % to 16 % for anti-CD20 to cladribine, and from 83 % to 25 % for cladribine to anti-CD20). Clinical outcomes improved, while serum biomarkers such as neurofilament light chain and glial fibrillary acidic protein remained stable over six months. Notably, the prevalence of hypogammaglobulinemia decreased after switching from anti-CD20 therapies to cladribine. These results indicate that patients with active RMS can achieve clinical stabilization after switching therapies in either direction, underscoring the complementary mechanisms of action and the safety of such an approach in real-world practice.
抗cd20抗体和克拉德滨是治疗活动性复发性多发性硬化症（RMS）的既定疗法。越来越多的证据表明，在目前的治疗下，在这些疗法之间切换可能对正在进行疾病活动的患者有益。在这项横跨6个德国MS中心的多中心回顾性研究中，共纳入了90例活动性RMS患者，其中71例患者从抗cd20抗体切换到cladriine （n = 31）或从cladriine切换到抗cd20抗体（n = 40），随访时间至少为12个月。在治疗开始时，与改用克拉德滨的患者相比，改用抗cd20抗体的患者年龄更大，病程更长，残疾评分更高（p = 0.0040, p = 0.0447, p = 0.0028）。转换的主要原因是疾病活动。转换后，复发疾病活动的患者比例显著降低（抗cd20到克拉德里宾的比例从55%降至16%，克拉德里宾到抗cd20的比例从83%降至25%）。临床结果得到改善，而血清生物标志物如神经丝轻链和胶质纤维酸性蛋白在6个月内保持稳定。值得注意的是，从抗cd20治疗转为克拉宾治疗后，低γ -球蛋白血症的患病率下降。这些结果表明，活动性RMS患者在转换治疗方向后可以达到临床稳定，强调了这种方法在现实实践中的互补机制和安全性。
{"title":"Switching from anti-CD20 therapies to cladribine and vice versa – Analysis of a German relapsing multiple sclerosis cohort","authors":"Franz Felix Konen , Steffen Pfeuffer , Konstantin Fritz Jendretzky , Klaus Gehring , Birte Elias-Hamp , Kurt-Wolfram Sühs , Stephan Halle , Korbinian Brand , Ralf Lichtinghagen , Eline Willemse , Marc Pawlitzki , Jens Kuhle , Sven G. Meuth , Christoph Kleinschnitz , Refik Pul , Thomas Skripuletz","doi":"10.1016/j.neurot.2025.e00812","DOIUrl":"10.1016/j.neurot.2025.e00812","url":null,"abstract":"<div><div>Anti-CD20 antibodies and cladribine are established therapies for active relapsing multiple sclerosis (RMS). Increasing evidence suggests that switching between these therapies may be beneficial in patients with ongoing disease activity under current treatment. In this multicenter retrospective study across six German MS centres, a total of 90 patients with active RMS were considered for inclusion, of whom 71 patients were switched either from anti-CD20 antibodies to cladribine (n = 31) or from cladribine to anti-CD20 antibodies (n = 40), with a minimum follow-up of 12 months. At treatment initiation, patients switching from anti-CD20 antibodies were older, had a longer disease duration, and a higher disability score compared to those switching from cladribine (p = 0.0040, p = 0.0447, p = 0.0028, respectively). The primary reason for switching was disease activity. Following the switch, the proportion of patients with relapsing disease activity was markedly reduced (from 55 % to 16 % for anti-CD20 to cladribine, and from 83 % to 25 % for cladribine to anti-CD20). Clinical outcomes improved, while serum biomarkers such as neurofilament light chain and glial fibrillary acidic protein remained stable over six months. Notably, the prevalence of hypogammaglobulinemia decreased after switching from anti-CD20 therapies to cladribine. These results indicate that patients with active RMS can achieve clinical stabilization after switching therapies in either direction, underscoring the complementary mechanisms of action and the safety of such an approach in real-world practice.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00812"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678208","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}
α-Synuclein is a small presynaptic protein whose aggregation is one of the hallmarks of Parkinson’s disease (PD). In our quest to identify novel preventive or therapeutic treatments for PD, we collected 60 Italian plant species, representative of part of the Mediterranean flora, which were screened by a phylogenetic analysis in conjunction with a high-throughput screening in a yeast model of PD expressing human α-synuclein. The integration of these approaches led to the identification of four plants, Allium lusitanicum, Salvia pratensis, Verbascum thapsus and Glaucium flavum, whose extracts, characterized by a metabolomic analysis, exhibit robust inhibitory activity against the amyloid aggregation of α-synuclein in vitro, as well as in neuroblastoma cells overexpressing the protein. By employing a size exclusion chromatography affinity approach coupled to mass spectrometry, we identified the phenylpropanoid glycoside acteoside from the extract of the edible plant V. thapsus as the metabolite that directly binds α-synuclein and effectively inhibits its fibril formation. In addition, acteoside reduces oxidative stress in neuroblastoma cells exposed to α-synuclein fibrils and activates the NRF2 pathway. Notably, acteoside improves motor performance in a Drosophila model of PD and exhibits a significant reduction of protein carbonyl groups, suggesting that this compound may mitigate oxidative stress-induced protein damage. Our findings could pave the way for the development of new strategies aimed at discovering novel neuroprotective agents targeting PD-related diseases.
α-突触核蛋白是一种小的突触前蛋白，其聚集是帕金森病（PD）的标志之一。为了寻找新的PD预防或治疗方法，我们收集了60种意大利植物，这些植物代表了地中海植物群的一部分，通过系统发育分析和高通量筛选在表达人α-突触核蛋白的PD酵母模型中进行筛选。综合这些方法，鉴定出四种植物，Allium lusitanicum, Salvia pratensis， Verbascum thapsus和Glaucium flavum，通过代谢组学分析，其提取物在体外对α-突触核蛋白淀粉样蛋白聚集以及过度表达α-突触核蛋白的神经母细胞瘤细胞表现出强大的抑制活性。采用大小排斥层析亲和法结合质谱法，鉴定了可食用植物V. thapsus提取物中的苯丙醇苷（phenylpropanoid glycoside actioside）为直接结合α-synuclein并有效抑制其纤维形成的代谢物。此外，毛蕊花苷还能降低α-突触核蛋白原纤维暴露的神经母细胞瘤细胞的氧化应激，激活NRF2通路。值得注意的是，毛苷改善了帕金森病果蝇模型的运动表现，并显示出蛋白质羰基的显著减少，这表明该化合物可能减轻氧化应激诱导的蛋白质损伤。我们的发现可能为开发新的策略铺平道路，旨在发现针对pd相关疾病的新型神经保护剂。
{"title":"Acteoside exerts neuroprotective effects by preventing α-synuclein aggregation and oxidative stress in models of Parkinson’s disease","authors":"Alessia Lambiase , Giorgia Spandri , Hind Moukham , Elisa Toini , Annalisa D’Urzo , Giovanni Zecca , Mauro Commisso , Flavia Guzzo , Valentina Santoro , Anna Lisa Piccinelli , Enrica Calleri , Sofia Salerno , Francesca Rinaldi , Stefano Negri , Carlo Santambrogio , Maura Brioschi , Cristina Solana-Manrique , Massimo Labra , Fabrizio Grassi , Nuria Paricio , Paola Coccetti","doi":"10.1016/j.neurot.2025.e00825","DOIUrl":"10.1016/j.neurot.2025.e00825","url":null,"abstract":"<div><div>α-Synuclein is a small presynaptic protein whose aggregation is one of the hallmarks of Parkinson’s disease (PD). In our quest to identify novel preventive or therapeutic treatments for PD, we collected 60 Italian plant species, representative of part of the Mediterranean flora, which were screened by a phylogenetic analysis in conjunction with a high-throughput screening in a yeast model of PD expressing human α-synuclein. The integration of these approaches led to the identification of four plants, <em>Allium lusitanicum</em>, <em>Salvia pratensis</em>, <em>Verbascum thapsus</em> and <em>Glaucium flavum,</em> whose extracts, characterized by a metabolomic analysis, exhibit robust inhibitory activity against the amyloid aggregation of α-synuclein <em>in vitro</em>, as well as in neuroblastoma cells overexpressing the protein. By employing a size exclusion chromatography affinity approach coupled to mass spectrometry, we identified the phenylpropanoid glycoside acteoside from the extract of the edible plant <em>V. thapsus</em> as the metabolite that directly binds α-synuclein and effectively inhibits its fibril formation. In addition, acteoside reduces oxidative stress in neuroblastoma cells exposed to α-synuclein fibrils and activates the NRF2 pathway. Notably, acteoside improves motor performance in a <em>Drosophila</em> model of PD and exhibits a significant reduction of protein carbonyl groups, suggesting that this compound may mitigate oxidative stress-induced protein damage. Our findings could pave the way for the development of new strategies aimed at discovering novel neuroprotective agents targeting PD-related diseases.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00825"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145820384","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}
Pub Date : 2026-01-01Epub Date: 2025-11-18DOI: 10.1016/j.neurot.2025.e00783
Shabnam Babakry , Jana V.P. Devos , Catharine A. Hellingman , Linda Ackermans , Jasper V. Smit , Michelle Moerel , Carsten Leue , Annelien A. Duits , Yasin Temel , Marcus L.F. Janssen
Tinnitus disorder can have a significant negative impact on quality of life, especially when refractory to standard care. Deep brain stimulation (DBS) of the medial geniculate body (MGB) attenuates pathological neuronal activity in the central auditory pathway and is a potential treatment for severe tinnitus. The aim of this pilot study was to assess the safety and feasibility of bilateral MGB DBS in patients with refractory tinnitus disorder. This randomised double-blind 2 × 2 cross-over study was conducted at Maastricht University Medical Centre, Maastricht, the Netherlands. The included patients had treatment refractory, severe, and chronic tinnitus without an anatomical substrate. Patients with bilateral MGB DBS were randomised to an ON-OFF or OFF-ON stimulation order for two cross-over phases. Primary outcomes consisted of safety and feasibility. Secondary outcomes on tinnitus severity, psychiatric and cognitive functioning and quality of life were assessed at screening, after both cross-over phases and at one-year follow-up. Four patients were included. No irreversible stimulation-induced side effects were observed. Surgical-related side effects were transient and resolved within two weeks. All patients experienced DBS as an acceptable treatment. Three of four patients showed improvement of tinnitus complaints based on the Tinnitus Functional Index. In the non-responder, electrodes had the largest distance from the centre of the MGB. To conclude, this study shows that bilateral MGB DBS is safe and feasible for patients with refractory tinnitus. Findings suggest the potential for clinically meaningful reduction in tinnitus burden through DBS. Effectiveness needs to be further evaluated in a follow-up study.
{"title":"Deep brain stimulation of the medial geniculate body for refractory tinnitus: A feasibility study","authors":"Shabnam Babakry , Jana V.P. Devos , Catharine A. Hellingman , Linda Ackermans , Jasper V. Smit , Michelle Moerel , Carsten Leue , Annelien A. Duits , Yasin Temel , Marcus L.F. Janssen","doi":"10.1016/j.neurot.2025.e00783","DOIUrl":"10.1016/j.neurot.2025.e00783","url":null,"abstract":"<div><div>Tinnitus disorder can have a significant negative impact on quality of life, especially when refractory to standard care. Deep brain stimulation (DBS) of the medial geniculate body (MGB) attenuates pathological neuronal activity in the central auditory pathway and is a potential treatment for severe tinnitus. The aim of this pilot study was to assess the safety and feasibility of bilateral MGB DBS in patients with refractory tinnitus disorder. This randomised double-blind 2 × 2 cross-over study was conducted at Maastricht University Medical Centre, Maastricht, the Netherlands. The included patients had treatment refractory, severe, and chronic tinnitus without an anatomical substrate. Patients with bilateral MGB DBS were randomised to an ON-OFF or OFF-ON stimulation order for two cross-over phases. Primary outcomes consisted of safety and feasibility. Secondary outcomes on tinnitus severity, psychiatric and cognitive functioning and quality of life were assessed at screening, after both cross-over phases and at one-year follow-up. Four patients were included. No irreversible stimulation-induced side effects were observed. Surgical-related side effects were transient and resolved within two weeks. All patients experienced DBS as an acceptable treatment. Three of four patients showed improvement of tinnitus complaints based on the Tinnitus Functional Index. In the non-responder, electrodes had the largest distance from the centre of the MGB. To conclude, this study shows that bilateral MGB DBS is safe and feasible for patients with refractory tinnitus. Findings suggest the potential for clinically meaningful reduction in tinnitus burden through DBS. Effectiveness needs to be further evaluated in a follow-up study.</div></div>","PeriodicalId":19159,"journal":{"name":"Neurotherapeutics","volume":"23 1","pages":"Article e00783"},"PeriodicalIF":6.9,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557618","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}
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