Annals of Neurology最新文献

{"title":"Reply to \"CSF Amyloid-β Risk Stratification in CAA: A Missing Link for Anti-Amyloid Therapy Safety\".","authors":"Philipp Arndt, Stefanie Schreiber","doi":"10.1002/ana.78339","DOIUrl":"https://doi.org/10.1002/ana.78339","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823509","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":"Cerebrospinal Fluid Amyloid-β Risk Stratification in Cerebral Amyloid Angiopathy: A Missing Link for Anti-Amyloid Therapy Safety.","authors":"Hajime Takase","doi":"10.1002/ana.78337","DOIUrl":"https://doi.org/10.1002/ana.78337","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823504","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":"Cortical Thickness and White Matter Surface Morphology in Tourette Syndrome: A Cohort Study.","authors":"Sahar Delavari, Adam C Frank, Ravi Bansal, Flora M Vaccarino, Robert A King, Paul Lombroso, Lawrence Scahill, James F Leckman, Bradley S Peterson","doi":"10.1002/ana.78340","DOIUrl":"https://doi.org/10.1002/ana.78340","url":null,"abstract":"<p><strong>Objective: </strong>To examine cortical thickness and white matter surface morphology in a large sample of individuals with Tourette syndrome (TS) and neurotypical controls across the lifespan, and to assess associations with symptom severity, comorbidities, and medication use.</p><p><strong>Methods: </strong>Cross-sectional neuroimaging cohort study utilizing high-resolution, T1-weighted magnetic resonance imaging scans obtained in 264 participants (151 TS, 113 neurotypical controls), aged 6-63 years. Image processing included rigorous quality control and deformation-based morphometry. Voxel-wise measures of cortical thickness and white matter surface displacement from a template brain were calculated. General linear models applied voxel-wise tested group differences adjusted for age, sex, and socioeconomic status. Additional covariates in sensitivity analyses included full-scale IQ, comorbid illnesses, and medication use. Interactions of group with age and sex, as well as associations with symptom severity, were also evaluated.</p><p><strong>Results: </strong>Compared with controls, TS participants showed extensive cortical thinning in precentral and postcentral gyri, inferior and middle frontal gyri, and inferior parietal lobule, as well as white matter surface displacement in overlapping regions. These effects remained significant after covarying for IQ, comorbidity, and medication use. Neither age nor sex significantly moderated these group differences. Attention deficit hyperactivity disorder symptom severity was associated with additional frontoparietal cortical thinning; obsessive-compulsive disorder severity showed no effect. Tic symptom severity did not associate significantly with brain measures anywhere.</p><p><strong>Interpretation: </strong>These findings suggest that cortical thinning and associated white matter reductions in TS reflect stable neurodevelopmental traits rather than transient symptom states. These cortical portions of cortico-striato-thalamo-cortical circuits may serve as targets for future therapeutic interventions. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811650","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":"Accelerated Brain Atrophy in Epilepsy: A Prospective Population-Based Study.","authors":"Marian Galovic, Rebecca S N Liu, Alex D Everitt, Robert Terziev, Louis Lemieux, Matthias J Koepp, John S Duncan","doi":"10.1002/ana.78319","DOIUrl":"https://doi.org/10.1002/ana.78319","url":null,"abstract":"<p><strong>Objective: </strong>Previous longitudinal neuroimaging studies suggest that epilepsy is a progressive disorder. To date, these findings have relied largely on populations from tertiary centers, resulting in ascertainment bias, as severely affected individuals are more likely to be rescanned. We aimed to determine rates of progressive brain atrophy in a prospective, population-based cohort.</p><p><strong>Methods: </strong>We analyzed longitudinal magnetic resonance imaging (MRI) data from 116 individuals with epilepsy and 89 age- and sex-matched healthy controls recruited from a prospective, longitudinal, community-based cohort in the United Kingdom. All participants underwent 2 scans 3.5 years apart, regardless of seizure status. We quantified progressive changes in cortical thickness and subcortical volumes using state-of-the-art longitudinal morphometry.</p><p><strong>Results: </strong>People with epilepsy exhibited accelerated but modest global grey matter volume (GMV) loss compared with controls (2.7 vs 2.4 ml/year; p = 0.01). This acceleration was associated with specific phenotypes: focal epilepsy, MRI-identifiable lesions, and ongoing seizures. In contrast, generalized epilepsy and seizure-free periods were associated with more stable global trajectories. Cortical regions identified as vulnerable were characterized by markedly accelerated thinning compared to controls (5.3 vs 3.4 μm/year; p < 0.001) and were pervasive across most epilepsy phenotypes.</p><p><strong>Interpretation: </strong>Epilepsy is associated with progressive structural brain damage that exceeds normal aging, but the trajectory is heterogeneous. These prospective population-based data confirm that vulnerable regions show progressive atrophy, particularly in focal and lesional epilepsy and individuals with ongoing seizures. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.5,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148811594","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":"Gut–Brain Axis Modulation by Short-Chain Fatty Acids Exerts Disease-Modifying Effects in a Murine Model of Drug-Resistant Epilepsy","authors":"Akash A. Bera MSc,&nbsp;Rossella Di Sapia PhD,&nbsp;Greta Volpedo PhD,&nbsp;Sneha Anand MSc,&nbsp;Eray Sahin PhD,&nbsp;Pasquale Baldassarre BS,&nbsp;Francesca Buffelli MSc,&nbsp;Andrea Petretto PhD,&nbsp;Chiara Lavarello PhD,&nbsp;James D. Mills PhD,&nbsp;Gabriele Cattaneo MSc,&nbsp;Ilaria Craparotta PhD,&nbsp;Eleonora Aronica MD, PhD,&nbsp;Antonella Riva MD, PhD,&nbsp;Pasquale Striano MD, PhD,&nbsp;Annamaria Vezzani PhD,&nbsp;Teresa Ravizza PhD","doi":"10.1002/ana.78283","DOIUrl":"10.1002/ana.78283","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Drug-resistant epilepsy (DRE) remains a clinical challenge, as therapies modifying disease trajectory are lacking. Increasing evidence implicates gut microbiota dysbiosis in epilepsy pathophysiology, with short-chain fatty acids (SCFAs) emerging as key microbial metabolites with neuroprotective and anti-inflammatory properties. Clinical studies show that people with DRE exhibit gut microbiota alterations that may impair fecal SCFAs production. Here, we investigated whether supplementation of SCFAs confers disease-modifying effects in a preclinical model of DRE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Adult male mice were subjected to status epilepticus (SE) and subsequently treated with a balanced mixture of acetate, propionate, and butyrate, or vehicle. Seizure frequency and temporal progression were monitored for 70 days by electroencephalography (EEG). At the study end point, cognitive performance, brain and gut histopathology, and neuroinflammation were assessed, together with metabolomic profiling of feces and blood. Brain SCFA levels and receptor expression were also analyzed in mice and in brain tissue from individuals with DRE.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>SCFA supplementation reduced the proportion of mice exhibiting a progressive phenotype and decreased the overall progression index (PI) 3-fold, without significantly altering overall daily seizure frequency. Treatment reduced seizure clustering, improved cognitive deficits, restored hippocampal and intestinal alterations, and partially normalized cerebral SCFAs levels. Metabolomic profiling in epileptic mice and analysis of human epilepsy brain tissue support a mechanistic contribution of gut-brain axis dysfunction to disease progression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These findings identify SCFAs supplementation as a therapeutic strategy capable of modifying disease trajectory in experimental DRE, with clear translational relevance. ANN NEUROL 2026;100:613–627</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"100 3","pages":"613-627"},"PeriodicalIF":7.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78283","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148292578","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}

{"title":"Five Issues of Artificial Intelligence in Science: Sailing the Ship of Theseus","authors":"S. Thomas Carmichael MD, PhD","doi":"10.1002/ana.78298","DOIUrl":"10.1002/ana.78298","url":null,"abstract":"<p>Artificial intelligence (AI) is becoming part of the working infrastructure of academic medicine. Because grants convert scientific ideas into protected time, infrastructure, and institutional priority, they provide a revealing test case for AI's effects on biomedicine. Five issues are emerging: language, agency, review, doership, and identity. AI can polish weak proposals, shift the origin of ideas, align proposal and review language around fundability, and create feasibility theater, projects that sound executable, but exceed a laboratory's capacity. The challenge is to keep AI anchored to lived expertise, the experience of failure, and the formative work by which faculty become scientists. ANN NEUROL 2026;100:453–457</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"100 3","pages":"453-457"},"PeriodicalIF":7.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78298","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374014","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}

{"title":"The IL-1β-STING Signaling Axis Drives Neuromyelitis Optica Pathogenesis in a Murine Model","authors":"Siyu Han MS,&nbsp;Ziqi Liang PhD,&nbsp;Chongyou Zhang MS,&nbsp;Siyu Yang MB,&nbsp;Jiade Li MS,&nbsp;Wei Jiang MD,&nbsp;Huiming Xu MD,&nbsp;Haoyang Li MD,&nbsp;Xiaoxin Xiang MD,&nbsp;Ruoyi Guo MD,&nbsp;Wenjing Luo MD,&nbsp;Bin Li MD,&nbsp;Changyong Tang PhD,&nbsp;Yuhong Zhang PhD,&nbsp;Shanshan Yang MD,&nbsp;Guangyou Wang PhD","doi":"10.1002/ana.78233","DOIUrl":"10.1002/ana.78233","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Neuromyelitis optica (NMO) is a severe autoimmune disorder of the central nervous system (CNS) characterized by aquaporin-4 antibody (AQP4-IgG)-mediated astrocyte injury. IL-1β–mediated inflammatory signaling plays a critical role in amplifying astrocyte damage and propagating CNS inflammation in NMO. However, the astrocyte-intrinsic mechanisms linking IL-1β signaling to downstream pathways, such as STING activation, remain poorly understood. To address this knowledge gap, in this study, we aim to elucidate the astrocyte-intrinsic mechanisms, specifically the IL-1β–IL-1R STING signaling axis, that contribute to NMO pathogenesis, and to evaluate the therapeutic potential of IL-1β-targeting antisense oligonucleotides (ASOs).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Using a multi-level experimental system comprising in vitro primary astrocytes, ex vivo organotypic cerebellar slices, and in vivo NMO mouse models, we systematically investigated the critical role of the astrocytic IL-1β–IL-1R STING signaling axis in NMO pathogenesis. Utilizing diverse interventions—including an IL-1β–neutralizing antibody, astrocyte-specific IL-1β knockout, the IL-1R inhibitor Anakinra, STING genetic ablation, and IL-1β ASOs—in conjunction with behavioral, histopathological, and molecular analyses, we comprehensively delineated the impact of this signaling pathway on NMO pathology. These data support the translation of targeted therapeutic strategies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>IL-1β signals through the IL-1 receptor (IL-1R) to induce STING-dependent proinflammatory cytokine production in astrocytes. This inflammatory cascade can be suppressed by the IL-1R antagonist anakinra or genetic ablation of STING. Therapeutic administration of lead IL-1β targeting ASO reduces IL-1β expression, preserves AQP4 levels and myelin integrity, and improves functional outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>The IL-1β–IL-1R STING signaling axis is a central contributor to NMO pathogenesis and supports IL-1β ASO therapy as a promising potential disease-modifying approach. ANN NEUROL 2026;100:487–510</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"100 3","pages":"487-510"},"PeriodicalIF":7.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147757998","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":"Assessing Progression Independent of Relapse Activity in Multiple Sclerosis Using a Patient-Reported Disability Measure and Self-Administered Neuroperformance Outcomes","authors":"Evy M. Reinders MD,&nbsp;Ariadna Masot-Llima MSc,&nbsp;Susana Otero-Romero MD, PhD,&nbsp;René Carvajal MD,&nbsp;Álvaro Cobo-Calvo MD, PhD,&nbsp;Pere Carbonell-Mirabent MSc,&nbsp;Jordina Beltran HT,&nbsp;Maria Jesús Arévalo PhD,&nbsp;Helena Ariño MD, PhD,&nbsp;Georgina Arrambide MD, PhD,&nbsp;Cristina Auger MD,&nbsp;Luca Bollo MD,&nbsp;Joaquín Castilló MD, PhD,&nbsp;Manuel Comabella MD, PhD,&nbsp;Ingrid Galán MD,&nbsp;Alexis García-Sarreón MD,&nbsp;Andrew Goodman MD,&nbsp;Carrie M. Hersh DO, MSc, FAAN,&nbsp;Delon La Puma MD,&nbsp;Le H. Hua MD,&nbsp;Luciana Midaglia MD, PhD,&nbsp;Neus Mongay-Ochoa MD, PhD,&nbsp;Ellen M. Mowry MD,&nbsp;Agustín Pappolla MD,&nbsp;Breogán Rodríguez-Acevedo MD,&nbsp;Jordi Río MD, PhD,&nbsp;Paula Tagliani MD,&nbsp;Ángela Vidal-Jordana MD, PhD,&nbsp;Andreu Vilaseca MD,&nbsp;Ana Zabalza MD, PhD,&nbsp;Deborah Pareto PhD,&nbsp;Carlos Nos MD,&nbsp;Menno Schoonheim PhD,&nbsp;Eva Strijbis MD, PhD,&nbsp;Jaume Sastre-Garriga MD, PhD,&nbsp;Madalina Tivarus PhD,&nbsp;Tjalf Ziemssen MD,&nbsp;Àlex Rovira MD,&nbsp;Xavier Montalban MD, PhD,&nbsp;Mar Tintoré MD, PhD,&nbsp;Carmen Tur MD, PhD","doi":"10.1002/ana.78275","DOIUrl":"10.1002/ana.78275","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>The objective of this study was to investigate the ability of patient-reported/administered outcomes to capture disability worsening and progression independent of relapse activity (PIRA) in multiple sclerosis (MS).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We included patients from the longitudinal multicenter MS PATHS cohort with ≥3 assessments and &gt;6 months follow-up. PIRA was defined on the patient-determined disease steps (PDDS) and self-administered tests assessing walking speed, manual dexterity, and processing speed, in the absence of self-reported relapses. We assessed (i) prevalence of PDDS/self-administered test-based disability worsening and PIRA definitions; (ii) their concurrent validity, through the association with worsening and PIRA definitions based on the expanded disability status scale (EDSS; Barcelona subcohort); and (iii) their clinical meaningfulness, through the correlation with brain magnetic resonance imaging (MRI) and quality-of-life (QoL) data trajectories.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We included 9,088 patients (73% female patients; age = 46.8 years; disease duration = 14.2 years). Over a 3-year follow-up, 4,066 (45%) patients worsened on ≥1 patient-reported/administered outcome, of which 2,357 (58%) developed PIRA. In the Barcelona subcohort (N = 279), 68 (24%) patients developed EDSS-based worsening, of which 30 (44%) developed EDSS-based PIRA; 99 of 279 (35%) worsened on ≥1 patient-reported/administered test, of which 78 of 99 (79%) had PIRA. Worsening (but not PIRA) on PDDS was associated with EDSS-based worsening (odds ratio = 3.03 [1.42; 6.43], <i>p</i> = 0.004). PDDS/self-administered-test-based worsening or PIRA strongly correlated with accelerated brain atrophy and T2 lesion volume increase compared to non-worseners (<i>p</i> &lt; 0.05), and showed worse QoL (<i>p</i> &lt; 0.05).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Despite only partial agreement with EDSS-based definitions, PDDS/self-administered test-based worsening and PIRA definitions were clinically meaningful, by identifying patients with greater brain damage and poorer QoL, supporting their use in clinical practice. ANN NEUROL 2026;100:525–546</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"100 3","pages":"525-546"},"PeriodicalIF":7.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78275","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389480","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}

{"title":"Diabetes and the Metabolic Syndrome as Drivers of Neurodegeneration: Convergent Mechanisms Linking Peripheral Neuropathy and Dementia","authors":"Masha G. Savelieff,&nbsp;David L. Bennett,&nbsp;Troels S. Jensen,&nbsp;Eva L. Feldman","doi":"10.1002/ana.78289","DOIUrl":"10.1002/ana.78289","url":null,"abstract":"<p>The metabolic syndrome, a state of progressive metabolic dysfunction, injures the peripheral and central nervous systems, promoting peripheral neuropathy (PN) and cognitive impairment (CI), respectively. We posit PN and CI are connected in the metabolic syndrome framework, built on the premise that neurons, whether in the peripheral or central nervous systems, are susceptible to similar injury from shared metabolic risk factors and pathophysiological processes. We highlight future studies for determining the relative evolution of PN and CI in metabolic syndrome, and propose revising the “stocking–glove” description of PN to “stocking–glove–hat” encompassing CI, concluding with research, therapeutic, and clinical implications. ANN NEUROL 2026;100:458–476</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"100 3","pages":"458-476"},"PeriodicalIF":7.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78289","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148403056","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}

{"title":"Maternal-Fetal Administration of Risdiplam Partially Rescues the SMNΔ7 Mouse Model of Spinal Muscular Atrophy","authors":"Emma R. Sutton PhD,&nbsp;Ariane Beauvais MSc,&nbsp;Rebecca Yaworski MSc,&nbsp;Hugh J. McMillan MD,&nbsp;Rashmi Kothary PhD","doi":"10.1002/ana.78302","DOIUrl":"10.1002/ana.78302","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Spinal muscular atrophy (SMA) is caused by deletions or mutations in the <i>survival motor neuron 1</i> (<i>SMN1</i>) gene and subsequent reduction in the expression of survival motor neuron (SMN) protein. The disease is characterized by degeneration of α motor neurons and subsequent muscle atrophy. Postnatal disease modifying therapies improve outcomes yet fall short of a cure. We have investigated a prenatal therapeutic strategy using the SMNΔ7 mouse model of SMA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A risdiplam-like compound was administrated by oral gavage to pregnant mice with treatment initiated mid-gestation and halted on day of birth. Reproductive metrics, liver toxicology, and immune function were assessed in the pregnant dams during gestation and post-birth. Progeny were monitored phenotypically, and pathological hallmarks of SMA were investigated including, but not limited to motor neuron, neuromuscular junction, and muscle health.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Maternal-fetal drug transfer was safe for the pregnant dam and substantially increased weight, motor function, and survival of severe SMA mice. It also rescued and maintained myofiber area. Presynaptic components of the neuromuscular junction were marginally improved in SMNΔ7 pups, whereas postsynaptic endplate size was increased following prenatal risdiplam treatment. Motor neuron pathology was not fully rescued by prenatal exposure to SMN protein, likely because of the lack of continued postnatal intervention. By restricting risdiplam treatment to the prenatal period, we have isolated and assessed therapeutic effects attributable solely to embryo exposure of the therapeutic.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Our efforts demonstrate a combination of prenatal and postnatal therapy must be used for optimum therapeutic outcomes in the treatment of patients with SMA. ANN NEUROL 2026;100:584–599</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"100 3","pages":"584-599"},"PeriodicalIF":7.5,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.78302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454021","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}