Annie T G Chiu, Mark F Bennett, Harshini Thiyagarajah, Amy L Schneider, Sian M W Macdonald, Tom Witkowski, Edith P Almanza Fuerte, Talia J Allan, Nico Lieffering, Blake Robinson, Christy W LaFlamme, Soham Sengupta, Clara W T Chung, Michael Cardamone, Cassandra Gray, Piero Perucca, Samuel F Berkovic, Heather C Mefford, Michael S Hildebrand, Ingrid E Scheffer
RNU2-2 is a non-coding small nuclear RNA (snRNA) that forms part of the spliceosome. We identified recurrent pathogenic RNU2-2 variants in 4 of 672 (0.6%) patients with developmental and epileptic encephalopathies (DEEs) of unknown cause. An additional patient was subsequently included. Patients with RNU2-2 DEE had median seizure onset age of 24 months, focal and generalized seizures, status epilepticus (n = 5), severe to profound impairment, hyperventilation (n = 3), and obstructive sleep apnea (n = 3). Electroencephalography showed sleep-activated multifocal epileptiform discharges (n = 4) and hippocampal sclerosis on magnetic resonance imaging (n = 3). Pathogenic variants in RNU2-2 cause a distinctive severe DEE.SnRNAs are emerging as an important cause of genetic DEEs. ANN NEUROL 2025.
{"title":"Pathogenic Variants in RNU2-2, a Non-coding Spliceosomal RNA, Cause a Distinctive Developmental and Epileptic Encephalopathy.","authors":"Annie T G Chiu, Mark F Bennett, Harshini Thiyagarajah, Amy L Schneider, Sian M W Macdonald, Tom Witkowski, Edith P Almanza Fuerte, Talia J Allan, Nico Lieffering, Blake Robinson, Christy W LaFlamme, Soham Sengupta, Clara W T Chung, Michael Cardamone, Cassandra Gray, Piero Perucca, Samuel F Berkovic, Heather C Mefford, Michael S Hildebrand, Ingrid E Scheffer","doi":"10.1002/ana.78071","DOIUrl":"https://doi.org/10.1002/ana.78071","url":null,"abstract":"<p><p>RNU2-2 is a non-coding small nuclear RNA (snRNA) that forms part of the spliceosome. We identified recurrent pathogenic RNU2-2 variants in 4 of 672 (0.6%) patients with developmental and epileptic encephalopathies (DEEs) of unknown cause. An additional patient was subsequently included. Patients with RNU2-2 DEE had median seizure onset age of 24 months, focal and generalized seizures, status epilepticus (n = 5), severe to profound impairment, hyperventilation (n = 3), and obstructive sleep apnea (n = 3). Electroencephalography showed sleep-activated multifocal epileptiform discharges (n = 4) and hippocampal sclerosis on magnetic resonance imaging (n = 3). Pathogenic variants in RNU2-2 cause a distinctive severe DEE.SnRNAs are emerging as an important cause of genetic DEEs. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Large Class of Neurodevelopmental Disorders Requires Genome Sequencing for Diagnosis.","authors":"Seth I Berger, Anne O'Donnell-Luria","doi":"10.1002/ana.78108","DOIUrl":"https://doi.org/10.1002/ana.78108","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145547474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Margaux E. Miller BSc, Benjamin E. Zusman MD, Chia-Ling Phuah MD, MSc, Erin McNally BSc, David O. Okonkwo MD, PhD, Matthew Pease MD, Shashvat M. Desai MBBS, Anupama Rani PhD, Nasathapot Namphol MD, Aditya Kumar MD, Raemier A. Javelosa BSc, Adam T. Eberle BSc, Semeon Afework BSc, Joshua Catapano MD, Charles S. Cox Jr MD, Patrick M. Kochanek MD, Yvette P. Conley PhD, Ava M. Puccio PhD, Ruchira M. Jha MD, MSc, the BRAIN Investigators
Objective
Growing evidence underscores the importance of host-response/secondary-injury—likely influenced by genetics—in outcome variability post-traumatic brain injury (TBI). Intracranial hypertension and hemorrhage progression are critical secondary injuries in severe TBI; these are mediated by the SUR1-TRPM4 channel (a target in clinical trials). We aimed to deconstruct the complex network surrounding SUR1-TRPM4 and define the cumulative impact of key genetic variants on mechanistically connected secondary injuries/outcomes after severe TBI.
Methods
This exploratory study analyzed 492 prospectively enrolled patients with severe TBI. A network of regulators, mediators, and effectors upstream/downstream of SUR1-TRPM4 was bioinformatically constructed. Single nucleotide variants (SNVs) were evaluated for multivariable model association with intracranial pressure, intraparenchymal hemorrhage progression, and Glasgow Outcome Scale (GOS) score. Weighted/unweighted polygenic-risk scores (PRS) were constructed and interrogated. Spatial modeling and functional predictions were determined. Single-cell cortical transcriptomic differences were assessed in a parallel murine TBI model.
Results
Ninety-seven genes (625 SNVs) were analyzed. Nineteen genes contained variants associated with all outcomes (intracranial pressure, hemorrhage progression, and GOS score; p < 0.05). Twenty-two genes (42 SNVs) retained significance for ≥ 1 outcome, with overlap across outcomes. Functions included Ca2+-transport/signaling, glutamate-clearance, neuroinflammation, and cell death. Single-cell analyses revealed cell-specific gene-expression differences. SNVs were brain-specific cis-expression quantitative trait locus (eQTLs)/missense/frameshift mutations suggesting high likelihood of biological impact. PRSs were associated with all outcomes with large effects, and markedly improved model explanatory power/performance (R2, receiver operating characteristic [ROC]).
Interpretation
Polygenic variability in key nodes linked to SUR1-TRPM4 were associated with mechanistically related secondary injuries and outcome after severe TBI; findings suggest a major role of heritability. Functional implications indicate biological plausibility and identify novel targets. The data, whereas requiring validation, support a shift toward incorporating biologically relevant genetics in advancing precision medicine. ANN NEUROL 2026;99:459–477
{"title":"Polygenic Vulnerability to Intracranial Hypertension, Hemorrhage Progression, and Outcome in Traumatic Brain Injury","authors":"Margaux E. Miller BSc, Benjamin E. Zusman MD, Chia-Ling Phuah MD, MSc, Erin McNally BSc, David O. Okonkwo MD, PhD, Matthew Pease MD, Shashvat M. Desai MBBS, Anupama Rani PhD, Nasathapot Namphol MD, Aditya Kumar MD, Raemier A. Javelosa BSc, Adam T. Eberle BSc, Semeon Afework BSc, Joshua Catapano MD, Charles S. Cox Jr MD, Patrick M. Kochanek MD, Yvette P. Conley PhD, Ava M. Puccio PhD, Ruchira M. Jha MD, MSc, the BRAIN Investigators","doi":"10.1002/ana.78064","DOIUrl":"10.1002/ana.78064","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Growing evidence underscores the importance of host-response/secondary-injury—likely influenced by genetics—in outcome variability post-traumatic brain injury (TBI). Intracranial hypertension and hemorrhage progression are critical secondary injuries in severe TBI; these are mediated by the SUR1-TRPM4 channel (a target in clinical trials). We aimed to deconstruct the complex network surrounding SUR1-TRPM4 and define the cumulative impact of key genetic variants on mechanistically connected secondary injuries/outcomes after severe TBI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This exploratory study analyzed 492 prospectively enrolled patients with severe TBI. A network of regulators, mediators, and effectors upstream/downstream of SUR1-TRPM4 was bioinformatically constructed. Single nucleotide variants (SNVs) were evaluated for multivariable model association with intracranial pressure, intraparenchymal hemorrhage progression, and Glasgow Outcome Scale (GOS) score. Weighted/unweighted polygenic-risk scores (PRS) were constructed and interrogated. Spatial modeling and functional predictions were determined. Single-cell cortical transcriptomic differences were assessed in a parallel murine TBI model.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Ninety-seven genes (625 SNVs) were analyzed. Nineteen genes contained variants associated with all outcomes (intracranial pressure, hemorrhage progression, and GOS score; <i>p</i> < 0.05). Twenty-two genes (42 SNVs) retained significance for ≥ 1 outcome, with overlap across outcomes. Functions included Ca<sup>2+</sup>-transport/signaling, glutamate-clearance, neuroinflammation, and cell death. Single-cell analyses revealed cell-specific gene-expression differences. SNVs were brain-specific cis-expression quantitative trait locus (eQTLs)/missense/frameshift mutations suggesting high likelihood of biological impact. PRSs were associated with all outcomes with large effects, and markedly improved model explanatory power/performance (<i>R</i><sup>2</sup>, receiver operating characteristic [ROC]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Polygenic variability in key nodes linked to SUR1-TRPM4 were associated with mechanistically related secondary injuries and outcome after severe TBI; findings suggest a major role of heritability. Functional implications indicate biological plausibility and identify novel targets. The data, whereas requiring validation, support a shift toward incorporating biologically relevant genetics in advancing precision medicine. ANN NEUROL 2026;99:459–477</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 2","pages":"459-477"},"PeriodicalIF":7.7,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145511263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Neurological Performance is not Evolutionary Fitness in Huntington's Disease.","authors":"Simon Okholm","doi":"10.1002/ana.78088","DOIUrl":"https://doi.org/10.1002/ana.78088","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145470268","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marios Gavrielatos MSc, Michael G. Heckman MS, Alexandra I. Soto-Beasley MS, Sophia G. Blumenfeld BSc, Xu Hou PhD, Shunsuke Koga MD, PhD, Melissa E. Murray PhD, Koji Kasanuki MD, PhD, Daisuke Ono MD, PhD, Fabienne C. Fiesel PhD, Ryan J. Uitti MD, Julie A. Fields PhD LP, Hugo Botha MB ChB, Vijay K. Ramanan MD PhD, Kejal Kantarci MD, Val J. Lowe MD, Clifford R. Jack MD, Nilufer Ertekin-Taner MD PhD, J. Raphael Gibbs PhD, Bryan J. Traynor MD PhD, Clifton L. Dalgard PhD, Rodolfo Savica MD PhD, Jonathan Graff-Radford MD, Ronald C. Petersen MD PhD, R. Ross Reichard MD, Neill R. Graff-Radford MD, Tanis J. Ferman PhD, Bradley F. Boeve MD, Zbigniew K. Wszolek MD, Wolfdieter Springer PhD, Ziv Gan-Or MD PhD, Emmanuel Mignot MD PhD, Sonja W. Scholz MD PhD, Dennis W. Dickson MD, Owen A. Ross PhD
Objective
Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically-defined series of LBD cases.
Methods
We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High-resolution whole-genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes.
Results
Our analysis identified 1 significant (P < 3.43 × 10−5) and 4 suggestive (P < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA-mediated immune mechanisms in disease progression and subtype differentiation. Specifically, HLA-DPB1*06:01 was significantly associated with lower Lewy body counts in the parahippocampal gyrus (P = 3.30 × 10−5), with weaker and suggestive associations observed in the middle frontal (P = 1.80 × 10−4) and inferior parietal gyrus (P = 6.33 × 10−4). Additionally, although only suggestive, HLA-DRB1*11:01 correlated with a lower Thal amyloid phase (P = 1.56 x 10−4), and HLA-B*15:01 correlated with an increased risk of diffuse LBD (P = 7.58 x 10−4).
Interpretation
This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune-related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501
{"title":"Association between Human Leukocyte Antigen Alleles and Neuropathological Outcomes in Lewy Body Disease","authors":"Marios Gavrielatos MSc, Michael G. Heckman MS, Alexandra I. Soto-Beasley MS, Sophia G. Blumenfeld BSc, Xu Hou PhD, Shunsuke Koga MD, PhD, Melissa E. Murray PhD, Koji Kasanuki MD, PhD, Daisuke Ono MD, PhD, Fabienne C. Fiesel PhD, Ryan J. Uitti MD, Julie A. Fields PhD LP, Hugo Botha MB ChB, Vijay K. Ramanan MD PhD, Kejal Kantarci MD, Val J. Lowe MD, Clifford R. Jack MD, Nilufer Ertekin-Taner MD PhD, J. Raphael Gibbs PhD, Bryan J. Traynor MD PhD, Clifton L. Dalgard PhD, Rodolfo Savica MD PhD, Jonathan Graff-Radford MD, Ronald C. Petersen MD PhD, R. Ross Reichard MD, Neill R. Graff-Radford MD, Tanis J. Ferman PhD, Bradley F. Boeve MD, Zbigniew K. Wszolek MD, Wolfdieter Springer PhD, Ziv Gan-Or MD PhD, Emmanuel Mignot MD PhD, Sonja W. Scholz MD PhD, Dennis W. Dickson MD, Owen A. Ross PhD","doi":"10.1002/ana.78075","DOIUrl":"10.1002/ana.78075","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Lewy body disease (LBD) is a complex neurodegenerative disorder characterized by the accumulation of misfolded α-synuclein in the brain. Neuroinflammation has long been implicated in LBD pathogenesis, and recent genetic studies in Parkinson's disease (a clinical manifestation of LBD) have shown consistent association with the human leukocyte antigen (HLA) gene complex. Here, we assessed whether variation in HLA alleles influences neuropathological burden in a neuropathologically-defined series of LBD cases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted a comprehensive analysis of HLA allelic variants in a cohort of 539 LBD cases of European descent from the Mayo Clinic brain bank. High-resolution whole-genome sequencing was used, and the HLA alleles of each sample were called using the HLA*LA tool and assessed for association with neuropathological outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our analysis identified 1 significant (<i>P</i> < 3.43 × 10<sup>−5</sup>) and 4 suggestive (<i>P</i> < 0.001) associations between certain HLA alleles and specific neuropathological outcomes in LBD, suggesting a potential role for HLA-mediated immune mechanisms in disease progression and subtype differentiation. Specifically, <i>HLA-DPB1*06:01</i> was significantly associated with lower Lewy body counts in the parahippocampal gyrus (<i>P</i> = 3.30 × 10<sup>−5</sup>), with weaker and suggestive associations observed in the middle frontal (<i>P</i> = 1.80 × 10<sup>−4</sup>) and inferior parietal gyrus (<i>P</i> = 6.33 × 10<sup>−4</sup>). Additionally, although only suggestive, <i>HLA-DRB1*11:01</i> correlated with a lower Thal amyloid phase (<i>P</i> = 1.56 x 10<sup>−4</sup>), and <i>HLA-B*15:01</i> correlated with an increased risk of diffuse LBD (<i>P</i> = 7.58 x 10<sup>−4</sup>).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study provides a detailed evaluation of the relationship between HLA alleles and LBD pathology, highlighting the importance of immune-related genetic factors in the etiology of LBD. ANN NEUROL 2026;99:492–501</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 2","pages":"492-501"},"PeriodicalIF":7.7,"publicationDate":"2025-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12814941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145457089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aaron W Abrams, Michael Waltz, T Charles Casper, Gregory Aaen, Leslie A Benson, Eva-Chava M Bernfeld, Leigh E Charvet, Tanuja Chitnis, Carla Francisco, Mark P Gorman, Jennifer S Graves, Lauren Krupp, Kimberly O'Neill, Timothy E Lotze, Soe Mar, Jayne Ness, Mary Rensel, Moses Rodriguez, John Rose, Alice Rutatangwa, Teri Schreiner, Nikita Shukla, Jan-Mendelt Tillema, Bianca Weinstock-Guttman, Yolanda Wheeler, Emmanuelle Waubant, Kristen M Krysko
Objective: To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity.
Methods: Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders.
Results: A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88).
Interpretation: Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.
目的：评估儿童多发性硬化症（MS）和临床孤立综合征（CIS）最初使用平台注射剂治疗的转换疾病改善疗法（DMT）对疾病活动性的实际有效性。方法：在美国（US）儿科多发性硬化症中心网络的12个诊所的2615例儿科发病脱髓鞘疾病患者中，对那些最初使用平台注射治疗的MS/CIS患者转换为另一类平台注射、口服或输注DMT进行分析。复发率采用负二项回归模型，并根据预先确定的混杂因素进行调整。结果：共有212名儿童在18岁前切换DMT（67%为女性，95%为MS）。93人从注射改为注射，76人从注射改为口服，43人从注射改为输液。转入口服或输液的患者发病年龄较大（可注射12.3年，口服13.5年，输液14.2年），转入口服或输液的患者发病年龄较大（可注射14.6年，口服16.0年，输液15.7年）。切换到输注DMT更有可能出现强化病变（注射45%，口服28%，输注67%）。与注射组（年化复发率[ARR] = 0.88, 95%可信区间[CI] = 0.52-1.48）相比，注射组到口服组（ARR = 0.34, 95% CI = 0.20-0.57；比率：0.38,95% CI = 0.21-0.69）和注射组到输液组(ARR = 0.18, 95% CI = 0.09-0.37；比值：0.21,95% CI = 0.10-0.44) (p)解释：与其他平台注射DMT相比，从平台注射切换到口服或输注可以更好地控制儿科ms的疾病。Ann neurol 2025。
{"title":"Real-World Effectiveness of Switching to Oral or Infusion Versus Injectable Disease-Modifying Therapy in Pediatric Multiple Sclerosis.","authors":"Aaron W Abrams, Michael Waltz, T Charles Casper, Gregory Aaen, Leslie A Benson, Eva-Chava M Bernfeld, Leigh E Charvet, Tanuja Chitnis, Carla Francisco, Mark P Gorman, Jennifer S Graves, Lauren Krupp, Kimberly O'Neill, Timothy E Lotze, Soe Mar, Jayne Ness, Mary Rensel, Moses Rodriguez, John Rose, Alice Rutatangwa, Teri Schreiner, Nikita Shukla, Jan-Mendelt Tillema, Bianca Weinstock-Guttman, Yolanda Wheeler, Emmanuelle Waubant, Kristen M Krysko","doi":"10.1002/ana.78086","DOIUrl":"https://doi.org/10.1002/ana.78086","url":null,"abstract":"<p><strong>Objective: </strong>To assess real-world effectiveness of switching disease-modifying therapy (DMT) in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS) initially treated with platform injectables on disease activity.</p><p><strong>Methods: </strong>Of 2615 pediatric-onset demyelinating disease patients at 12 clinics in the United States (US) Network of Pediatric MS Centers, those with MS/CIS on initial therapy with a platform injectable who switched to another class of platform injectable, oral or infusion DMT were analyzed. Relapse rate was modeled with negative binomial regression, adjusted for preidentified confounders.</p><p><strong>Results: </strong>A total of 212 children switched DMT before age 18 (67% female, 95% MS). Ninety-three switched from injectable to injectable, 76 injectable to oral, and 43 injectable to infusion. Switchers to oral or infusion were older at onset (injectable 12.3 years, oral 13.5 years, and infusion 14.2 years) and switch (injectable 14.6 years, oral 16.0 years, and infusion 15.7 years). Switchers to infusion DMT were more likely to have enhancing lesions (injectable 45%, oral 28%, and infusion 67%). Compared to injectable (annualized relapse rate [ARR] = 0.88, 95% confidence interval [CI] = 0.52-1.48), relapse rates were lower for injectable to oral (ARR = 0.34, 95% CI = 0.20-0.57; rate ratio: 0.38, 95% CI = 0.21-0.69) and injectable to infusion (ARR = 0.18, 95% CI = 0.09-0.37; rate ratio: 0.21, 95% CI = 0.10-0.44) (p < 0.001). Adjusted number needed to treat in person-years to prevent 1 relapse with oral over injectable was 1.84 (95% CI = 1.03-8.69) and infusion over injectable 1.43 (95% CI = 1.00-3.88).</p><p><strong>Interpretation: </strong>Switching from platform injectable to oral or infusion compared to other platform injectable DMT led to better disease control in pediatric MS. Long-term safety data are required. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145450384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jeevan K. Jadapalli MS, Joseph Olson PhD, Zachary T. Irwin PhD, Arie Nakhmani PhD, Christopher P. Hurt PhD, Christopher L. Gonzalez MS, Melissa H. Wade CRNP, Bart L. Guthrie MD, Harrison C. Walker MD
Objective
To investigate whether deep brain stimulation (DBS) lead implant in the subthalamic nucleus and its associated “microlesion” effect impacts oscillatory activity in the hand area of motor cortex.
Methods
We examined cortical local field potentials in 31 patients before and after subthalamic nucleus lead implant at rest and during repetitive voluntary and passive contralateral upper limb movements. We computed continuous wavelet transforms of the signals and correlated (1) baseline spectral power and motor symptom severity and (2) changes in spectral power and contralateral motor symptoms related to microlesion.
Results
Baseline motor symptom severity correlated with high-frequency broadband power in primary motor cortex during voluntary movements (200–300Hz: Pearson's r = 0.51, p = 0.014, 95% confidence interval [CI]: [0.15, 0.75]; and 300–500Hz: r = 0.44, p = 0.038, 95% CI: [0.06, 0.70]). Motor improvements from lead implant correlated with decreases in high gamma power in primary sensory cortex during voluntary movements (70–200Hz: r = 0.44, p = 0.035, 95% CI: [−0.07, 0.62]).
Interpretation
How motor parkinsonism alters electrophysiology in cerebral cortex is unclear. Our findings suggest that both the severity of parkinsonism and its improvement from the microlesion effect are associated most closely with changes in high-frequency oscillatory activity in primary sensorimotor cortex. Better understanding the cortical dynamics of movement disorders could guide novel paradigms for adaptive DBS. ANN NEUROL 2026;99:480–491
目的：探讨脑深部电刺激（DBS）在丘脑底核植入铅及其相关的“微损伤”效应是否影响运动皮层手区振荡活动。方法：对31例丘脑下核铅植入前后、对侧上肢重复自主和被动运动时的皮质局部场电位进行检测。我们计算了信号的连续小波变换，并将(1)基线谱功率与运动症状严重程度以及(2)与微病变相关的谱功率与对侧运动症状的变化相关联。结果：基线运动症状严重程度与自主运动时初级运动皮层高频宽带功率相关（200-300Hz: Pearson’s r = 0.51, p = 0.014, 95%可信区间[CI]: [0.15, 0.75]; 300-500Hz: r = 0.44, p = 0.038, 95% CI:[0.06, 0.70]）。植入铅的运动改善与自主运动时初级感觉皮层高伽马能量的降低相关（70-200Hz: r = 0.44, p = 0.035, 95% CI:[-0.07, 0.62]）。解释：运动帕金森病如何改变大脑皮层的电生理尚不清楚。我们的研究结果表明，帕金森病的严重程度和微损伤效应的改善与初级感觉运动皮层高频振荡活动的变化密切相关。更好地了解运动障碍的皮质动力学可以指导适应性脑深部脑刺激的新范式。Ann neurol 2025。
{"title":"Sensorimotor Cortex High Frequency Oscillations Characterize Motor Symptom Severity during Deep Brain Stimulation Surgery for Parkinson's Disease","authors":"Jeevan K. Jadapalli MS, Joseph Olson PhD, Zachary T. Irwin PhD, Arie Nakhmani PhD, Christopher P. Hurt PhD, Christopher L. Gonzalez MS, Melissa H. Wade CRNP, Bart L. Guthrie MD, Harrison C. Walker MD","doi":"10.1002/ana.78077","DOIUrl":"10.1002/ana.78077","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To investigate whether deep brain stimulation (DBS) lead implant in the subthalamic nucleus and its associated “microlesion” effect impacts oscillatory activity in the hand area of motor cortex.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We examined cortical local field potentials in 31 patients before and after subthalamic nucleus lead implant at rest and during repetitive voluntary and passive contralateral upper limb movements. We computed continuous wavelet transforms of the signals and correlated (1) baseline spectral power and motor symptom severity and (2) changes in spectral power and contralateral motor symptoms related to microlesion.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Baseline motor symptom severity correlated with high-frequency broadband power in primary motor cortex during voluntary movements (200–300Hz: Pearson's r = 0.51, <i>p</i> = 0.014, 95% confidence interval [CI]: [0.15, 0.75]; and 300–500Hz: r = 0.44, <i>p</i> = 0.038, 95% CI: [0.06, 0.70]). Motor improvements from lead implant correlated with decreases in high gamma power in primary sensory cortex during voluntary movements (70–200Hz: r = 0.44, <i>p</i> = 0.035, 95% CI: [−0.07, 0.62]).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>How motor parkinsonism alters electrophysiology in cerebral cortex is unclear. Our findings suggest that both the severity of parkinsonism and its improvement from the microlesion effect are associated most closely with changes in high-frequency oscillatory activity in primary sensorimotor cortex. Better understanding the cortical dynamics of movement disorders could guide novel paradigms for adaptive DBS. ANN NEUROL 2026;99:480–491</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 2","pages":"480-491"},"PeriodicalIF":7.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145420925","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Annals of Neurology: Volume 98, Number 5, November 2025","authors":"","doi":"10.1002/ana.26993","DOIUrl":"https://doi.org/10.1002/ana.26993","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"98 5","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26993","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145407384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christos V Chalitsios, Jiali Gao, Carol A C Coupland, Julia Hippisley Cox, Martin R Turner, Alexander G Thompson
Objective: Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited.
Methods: We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers.
Results: There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]per 1-SD = 1.07, 95% confidence interval [CI] = 1.02-1.11) and total cholesterol levels (HRper 1-SD = 1.06, 95% CI = 1.02-1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HRper 1-SD = 1.08, 95% CI = 1.04-1.13, Pinteraction = 0.003). Higher creatinine was inversely associated with FTD risk (HRper 1-SD = 0.90, 95% CI = 0.83-0.97), supported by MR (odds ratio [OR] inverse variance weighted (IVW), per 1-SD = 0.73, 95% CI = 0.56-0.96). HbA1c showed a U-shaped association with FTD (Pnon-linearity = 0.006).
Interpretation: LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2025.
目的：确定影响肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）风险的可改变因素对预防具有重要意义。血液生物标志物，特别是胆固醇，与神经退行性风险相关，但在ALS中的发现不一致，FTD的数据有限。方法：我们进行了一项基于人群的队列研究，使用了QResearch与医院事件统计相关的英国初级保健记录。研究对象包括1998年至2023年间记录有生物标志物数据的成年人。我们研究了低脂蛋白胆固醇和高密度脂蛋白胆固醇（LDL-C和HDL-C）、总胆固醇、甘油三酯、肌酐、肌酸激酶和HbA1c与ALS和FTD风险的关系。Cox比例风险模型用于估计相关性。应用双样本孟德尔随机化（MR）来探索所选生物标志物的遗传预测关联。结果：有多达2695例ALS和781例FTD诊断，中位随访时间分别为9.4年和10.5年。较高的LDL-C（每1-SD风险比[HR] = 1.07, 95%可信区间[CI] = 1.02-1.11）和总胆固醇水平（每1-SD风险比[HR] = 1.06, 95% CI = 1.02-1.10）与较高的ALS风险呈线性相关。年龄分层分析显示，总胆固醇与≥60岁人群的相关性更强（HRper 1-SD = 1.08, 95% CI = 1.04-1.13, p - interaction = 0.003）。较高的肌酐与FTD风险呈负相关（HRper 1-SD = 0.90, 95% CI = 0.83-0.97）， MR（比值比[OR]逆方差加权（IVW）， per 1-SD = 0.73, 95% CI = 0.56-0.96）也支持这一观点。HbA1c与FTD呈u型相关（p非线性= 0.006）。解释：LDL和总胆固醇可能为ALS的早期疾病变化或病因提供见解，而肌酐和HbA1c可能与FTD有关。需要对单基因ALS和FTD进行研究，以确定这些生物标志物是否为有针对性的预防或干预策略提供信息。Ann neurol 2025。
{"title":"Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Have Distinct Prediagnostic Blood Biochemical Profiles.","authors":"Christos V Chalitsios, Jiali Gao, Carol A C Coupland, Julia Hippisley Cox, Martin R Turner, Alexander G Thompson","doi":"10.1002/ana.78082","DOIUrl":"https://doi.org/10.1002/ana.78082","url":null,"abstract":"<p><strong>Objective: </strong>Identifying modifiable factors influencing amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) risk is important for prevention. Blood biomarkers, particularly cholesterol, have been associated with neurodegenerative risk, but findings in ALS are inconsistent, and data on FTD are limited.</p><p><strong>Methods: </strong>We conducted a population-based cohort study using UK primary care records from QResearch linked with Hospital Episode Statistics. Adults with biomarker data recorded between 1998 and 2023 were included. We examined associations of low- and high-density lipoprotein cholesterol (LDL-C and HDL-C), total cholesterol, triglycerides, creatinine, creatine kinase, and HbA1c with ALS and FTD risk. Cox proportional hazards models were used to estimate associations. Two-sample Mendelian randomization (MR) was applied to explore genetically predicted associations of selected biomarkers.</p><p><strong>Results: </strong>There were up to 2,695 ALS and 781 FTD diagnoses, with a median follow-up duration of 9.4 and 10.5 years, respectively. Higher LDL-C (hazard ratio [HR]<sub>per 1-SD</sub> = 1.07, 95% confidence interval [CI] = 1.02-1.11) and total cholesterol levels (HR<sub>per 1-SD</sub> = 1.06, 95% CI = 1.02-1.10) were linearly associated with higher ALS risk. Age-stratified analysis showed a stronger association for total cholesterol in those ≥ 60 years (HR<sub>per 1-SD</sub> = 1.08, 95% CI = 1.04-1.13, P<sub>interaction</sub> = 0.003). Higher creatinine was inversely associated with FTD risk (HR<sub>per 1-SD</sub> = 0.90, 95% CI = 0.83-0.97), supported by MR (odds ratio [OR] inverse variance weighted (<sub>IVW</sub>)<sub>, per 1-SD</sub> = 0.73, 95% CI = 0.56-0.96). HbA1c showed a U-shaped association with FTD (P<sub>non-linearity</sub> = 0.006).</p><p><strong>Interpretation: </strong>LDL and total cholesterol may provide insights into early disease changes or the etiology of ALS, whereas creatinine and HbA1c may be relevant for FTD. Research in monogenic ALS and FTD is needed to determine whether these biomarkers inform targeted prevention or intervention strategies. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eva Michael MD, Carola Hedberg-Oldfors PhD, Mar Tulinius MD, PhD, Sara Nordström MD, Anders Oldfors MD, PhD, Niklas Darin MD, PhD
Objective
Congenital myopathies are a group of rare genetic muscle disorders. Previous studies have estimated point prevalences which only include surviving individuals. Our aim was to perform an epidemiological study with strict inclusion criteria, using modern diagnostic technology to present both incidences and prevalences, and to describe the genetic and muscle pathological characteristics of these disorders.
Methods
A retrospective, population-based epidemiological study was conducted in western Sweden between 1985 and 2022. All patients diagnosed with congenital myopathies during this period were included.
Results
In total, 104 patients were identified whereas 25 died during the follow-up. The total birth prevalence (estimated lifetime risk) was 14.9 per 100,000 live births, whereas the total cumulative incidence by age 35 years was 12.3 per 100,000 inhabitants, and the total point prevalence was 3.9 per 100,000 inhabitants. The most common histopathological type was congenital myopathy with nonspecific changes (birth prevalence 4.1 per 100,000 live births), followed by core myopathy and centronuclear myopathy (2.1 per 100,000). The most common causative genes were MYH2 (3.9 per 100,000) and RYR1 (2.0 per 100,000). Despite using next-generation sequencing, 1 in 5 cases lacked a genetic diagnosis. Among those without a genetic cause, 4 of 5 had nonspecific histopathological changes.
Interpretation
By including all patients identified, both alive and deceased, our estimated incidence figures are considerably higher than estimates of point prevalence, which only includes living patients. As the mortality in these diseases is significant, incidence figures better reflect the occurrence in the population and are important for evidence-based health care planning and resource allocation. ANN NEUROL 2026;99:382–392
{"title":"Incidence and Prevalence of Congenital Myopathies - A Population-Based Study From Western Sweden","authors":"Eva Michael MD, Carola Hedberg-Oldfors PhD, Mar Tulinius MD, PhD, Sara Nordström MD, Anders Oldfors MD, PhD, Niklas Darin MD, PhD","doi":"10.1002/ana.78078","DOIUrl":"10.1002/ana.78078","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Congenital myopathies are a group of rare genetic muscle disorders. Previous studies have estimated point prevalences which only include surviving individuals. Our aim was to perform an epidemiological study with strict inclusion criteria, using modern diagnostic technology to present both incidences and prevalences, and to describe the genetic and muscle pathological characteristics of these disorders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A retrospective, population-based epidemiological study was conducted in western Sweden between 1985 and 2022. All patients diagnosed with congenital myopathies during this period were included.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In total, 104 patients were identified whereas 25 died during the follow-up. The total birth prevalence (estimated lifetime risk) was 14.9 per 100,000 live births, whereas the total cumulative incidence by age 35 years was 12.3 per 100,000 inhabitants, and the total point prevalence was 3.9 per 100,000 inhabitants. The most common histopathological type was congenital myopathy with nonspecific changes (birth prevalence 4.1 per 100,000 live births), followed by core myopathy and centronuclear myopathy (2.1 per 100,000). The most common causative genes were <i>MYH2</i> (3.9 per 100,000) and <i>RYR1</i> (2.0 per 100,000). Despite using next-generation sequencing, 1 in 5 cases lacked a genetic diagnosis. Among those without a genetic cause, 4 of 5 had nonspecific histopathological changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>By including all patients identified, both alive and deceased, our estimated incidence figures are considerably higher than estimates of point prevalence, which only includes living patients. As the mortality in these diseases is significant, incidence figures better reflect the occurrence in the population and are important for evidence-based health care planning and resource allocation. ANN NEUROL 2026;99:382–392</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"99 2","pages":"382-392"},"PeriodicalIF":7.7,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145385510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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