Annals of Neurology最新文献

{"title":"Hematoma Interleukin-1 Receptor Antagonist Concentrations Predict Long-Term Outcome in Acute Human Intracerebral Hemorrhage.","authors":"Adrian R Parry-Jones, Blessing Nyakutsikwa, Michael H Askenase, Matthew Gittins, Mary Newland, Siobhan Crilly, Paul R Kasher, Yvonne Davidson, Federico Roncaroli, Stuart M Allan, Lauren H Sansing, Wendy Ziai, Daniel F Hanley","doi":"10.1002/ana.78237","DOIUrl":"https://doi.org/10.1002/ana.78237","url":null,"abstract":"<p><strong>Objectives: </strong>The interleukin (IL)-1, IL-6, and C-reactive protein (CRP) pathway is central to the immune response after intracerebral hemorrhage (ICH). We tested for associations between hematoma and plasma cytokine concentrations and patient outcomes in Minimally Invasive Surgery Plus Rt-PA for ICH Evacuation Phase III (MISTIE III) participants.</p><p><strong>Methods: </strong>Inflammation after minimally invasive evacuation of ICH (INFLAME)-ICH was a sub-study nested in MISTIE III. Daily hematoma fluid was collected from surgical patients and peripheral blood for all patients. Multiple regression models compared hematoma cytokine concentrations to the modified Rankin scale (mRS) score at 1 year. Correlations between hematoma and plasma cytokine concentrations were tested. We compared plasma cytokines in patients randomized to surgery (vs medical). Gene expression in monocyte/macrophages and neutrophils were compared in a subset of participants.</p><p><strong>Results: </strong>A total of 89 patients were recruited (47 surgical, 42 medical). Mean hematoma IL-1 receptor antagonist (IL-1Ra) (odds ratio [OR]: 5.92; 95% confidence interval [CI]: 1.08-32.54; n = 38) and mean hematoma IL-6 (OR: 3.23; 95% CI: 1.33-7.81; n = 45) were independently associated with good outcome (mRS, 0-3) at 1 year. Higher hematoma IL-1β was associated with higher plasma CRP (β-coefficient: 21.0; 95% CI: 4.4-37.5; n = 117 paired samples). No differences were seen in plasma IL-6, CRP and IL-1Ra in patients by treatment group. IL1B, IL6, and IL1RN transcripts in monocyte/macrophages correlated with respective protein concentrations in hematoma fluid.</p><p><strong>Interpretation: </strong>Hematomal IL-1Ra within a week of ICH is independently associated with a good outcome at 1 year, supporting further investigation of IL-1Ra in ICH. IL-6 is independently associated with a good outcome at 1 year, which might suggest a role in enhancing repair and recovery. ANN NEUROL 2026.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":7.7,"publicationDate":"2026-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147809005","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":"Clot Composition Profiling in Large Vessel Occlusion Stroke Via Radiomics.","authors":"Andres Gudino, Elena Sagues, Carlos Dier, Diego Ojeda, Samantha Saenz-Hinojosa, Sebastian Sanchez, Ariel Vargas, Linder Wendt, Maria Belen Torres, Emily Garces, Alex Hanson, Navami Shenoy, Connor Aamot, Susan A Walsh, Anil K Chauhan, Gowri Anil-Peethambar, Santiago Ortega-Gutierrez, Jay Kinariwala, Mohamed Elshikh, Amir Shaban, Enrique C Leira, Osorio Lopes Abath Neto, Malik Ghannam, Edgar A Samaniego","doi":"10.1002/ana.78160","DOIUrl":"10.1002/ana.78160","url":null,"abstract":"<p><strong>Objective: </strong>Clot composition may offer insights into the mechanism of ischemic stroke. Radiomics, a noninvasive imaging technique, enables tissue characterization through radiomic features (RFs). We aimed to evaluate clot composition using radiomics on non-contrast computed tomography (NCCT).</p><p><strong>Methods: </strong>In the first phase, we conducted a prospective study comparing RFs with histopathology in thrombi retrieved via mechanical thrombectomy (MT). Thrombi were imaged using micro-computed tomography (micro-CT) and analyzed histologically. Matched micro-CT and histological slices identified red blood cells (RBCs) and fibrin-rich regions. RFs were extracted, and multivariate logistic regression identified features associated with each component. Spearman's correlation was used to assess associations between RFs and percentage composition. The same clots were localized on pre-MT NCCT, and RFs were extracted. Micro-CT and NCCT RFs were correlated to enable histology-informed interpretation. Receiver operating characteristic analysis evaluated the ability of NCCT RFs to discriminate clot composition. In the second phase, radiomics was applied to a retrospective NCCT dataset from patients with ischemic stroke with varying etiologies.</p><p><strong>Results: </strong>Ten thrombi were analyzed using micro-CT. Total energy (odds ratio [OR] = 1.35, 95% confidence interval [CI] = 1.20-1.54, p < 0.001) and large dependence high gray level emphasis (OR = 1.18, 95% CI = 1.07-1.32, p = 0.01) were associated with RBCs and correlated with >70% RBCs composition on NCCT (Rho = 0.752 and Rho = 0.815). Subsequently, 150 NCCT scans were analyzed, including 50 cardioembolic, 50 large artery atherosclerosis (LAA), and 50 cryptogenic strokes. Radiomic analysis indicated RBCs-predominant composition in 72% of cardioembolic, 30% of LAA, and 50% of cryptogenic clots.</p><p><strong>Interpretation: </strong>Radiomics is a promising, noninvasive technique for characterizing clot composition. ANN NEUROL 2026;99:1179-1188.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1179-1188"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145987391","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":"Tau Pathology in Alzheimer's Disease Uniquely Affects Sulcal Depths.","authors":"Samira A Maboudian, Corrina S Fonseca, Adam C Martersteck, Yishu Chao, Yuheng Chen, Daniela Ushizima, Duygu Tosun, Lea T Grinberg, Kevin S Weiner, William J Jagust","doi":"10.1002/ana.78166","DOIUrl":"10.1002/ana.78166","url":null,"abstract":"<p><strong>Objective: </strong>Though it is widely known that tau deposition affects brain structure, the precise localization of these effects is poorly understood, especially in relation to gyral and sulcal anatomy. We investigated whether tau pathology in Alzheimer's disease (AD) preferentially affects sulci, and particularly sulcal depths.</p><p><strong>Methods: </strong>We analyzed 675 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) with magnetic resonance imaging (MRI) and positron emission tomography (PET) data to investigate relationships between neocortical tau PET signal and cortical thickness. We then examined an advanced AD case with postmortem MRI and coregistered whole-brain phospho-tau staining for evidence of sulcal tau distribution in AD. Finally, in a sample of 187 cognitively unimpaired young and older adults with resting-state functional MRI, we examined connectivity strength between tau-vulnerable regions and the hippocampus across adulthood, prior to disease-related cognitive decline.</p><p><strong>Results: </strong>Our findings revealed that tau-related cortical thinning predominantly occurs in sulcal regions, especially the deepest parts. Postmortem histology confirmed preferential tau accumulation in sulcal depths. Additionally, connectivity analyses revealed that, across adulthood, these primarily sulcal regions most susceptible to tau-related thinning also have stronger connectivity to the hippocampus, suggesting a role for network connectivity in the vulnerability of sulci to the effects of tau pathology later in life.</p><p><strong>Interpretation: </strong>These findings support the hypothesis that sulci, and particularly their depths, represent structurally and functionally vulnerable regions for tau deposition in AD. Understanding the mechanisms underlying this sulcal vulnerability provides insight into general principles driving regional susceptibility to pathology, and sheds light on the detrimental functional and cognitive effects of tau pathology. ANN NEUROL 2026;99:1343-1353.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1343-1353"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092793/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146040084","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":"Diverse Genetic Etiologies of Unilateral Polymicrogyria.","authors":"Abbe Lai, Jennifer E Neil, Shyam K Akula, Dina Amrom, Eva Andermann, Ann Bergin, Roberto Caraballo, Allen Y Chen, John Gaitanis, Ganeshwaran H Mochida, Jill M Gotoff, Giorgi Kuchukhidze, Daphna Marom, Christelle Moufawad ElAchkar, Miriam Regev, Lance H Rodan, Heather Olson, Bo Zhang, Annapurna Poduri, Diane D Shao, Christopher A Walsh, Edward Yang","doi":"10.1002/ana.78169","DOIUrl":"10.1002/ana.78169","url":null,"abstract":"<p><strong>Objective: </strong>Polymicrogyria (PMG) is one of the most common human malformations of cortical development and is often classified by its radiographic pattern of distribution. Unilateral polymicrogyria (uPMG) is a subtype of PMG affecting a portion or all of one cerebral hemisphere. As most PMGs occur bilaterally, there has been no specific investigation as to whether the genetic underpinnings of uPMG comprise a subset of or a distinct entity from bilateral PMG. In this study, our goal was to assess both the genetic etiology of uPMG and the value of diagnostic genetic testing in this setting.</p><p><strong>Methods: </strong>We conducted a retrospective analysis of clinical data from individuals with uPMG seen in the Brain Development and Genetics Clinic and/or research participants of the Walsh Laboratory at Boston Children's Hospital. The final study cohort included 35 individuals from 30 families who were diagnosed with uPMG on brain magnetic resonance imaging (MRI) and also underwent genetic testing.</p><p><strong>Results: </strong>A likely genetic cause was identified in 26.7% (8/30) of unrelated individuals with uPMG in this cohort and segregated within one family (10/35 total subjects). Recessive genetic causes included ASPM, WDR62, and TMEM216. Dominant causes included 22q deletion syndrome, DYNC1H1, SCN3A, and hereditary hemorrhagic telangiectasia (HHT) genes, ACVRL1 and ENG. This is the first report of variants in DYNC1H1, TMEM216, and ACVRL1 in association with uPMG.</p><p><strong>Interpretation: </strong>The genetic causes of bilateral PMG and uPMG can overlap, but some are unique to certain distributions of the malformation. Genetic explanations for uPMG are found at comparable rates to bilateral PMG, suggesting that germline testing for this unique presentation is warranted. ANN NEUROL 2026;99:1277-1286.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1277-1286"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13033188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155457","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":"Reframing the Risks of Deep Brain Stimulation: A Comparison of 2.8 Million Elective Surgeries From the NSQIP Database.","authors":"Lucas R Philipp, Kevin Hines, Justin Williams, Jingya Miao, Chengyuan Wu","doi":"10.1002/ana.78154","DOIUrl":"10.1002/ana.78154","url":null,"abstract":"<p><strong>Objective: </strong>Deep brain stimulation (DBS) is an established surgical therapy for movement disorders, epilepsy, and psychiatric conditions, yet remains underutilized due to perceived risks. We therefore endeavored to compare the safety of DBS to other common elective procedures to provide context for its relative risk.</p><p><strong>Methods: </strong>This retrospective cohort study utilized the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database, encompassing diverse referral and community hospitals across the United States from 2015 to 2021. Patients with DBS were compared with those receiving one of the 16 most common elective procedures. The primary outcome of interest was the weighted odds of any postoperative complication at 30 days. Secondary outcomes included risk of readmission, reoperation, and discharge disposition. Logistic regression with inverse probability of treatment weighting (IPTW) based on propensity scores adjusted for baseline group heterogeneity.</p><p><strong>Results: </strong>We identified 2,853,662 patients for analysis, including 4,749 DBS procedures. After IPTW adjustment, patients with DBS experienced lower 30-day complication rates compared with other procedures (1.3% vs 4.1%, OR = 0.32, 95% confidence interval [CI] = 0.25-0.41, p < 0.0001). Readmission rates did not differ significantly (2.2% vs 2.6%, OR = 0.84, 95% CI = 0.69-1.02, p = 0.08). DBS cases had higher odds of discharge home (98.7% vs 96.3%, OR = 2.94, 95% CI = 2.27-3.82, p < 0.0001) and lower reoperation rates (0.7% vs 1.3%, OR = 0.50, 95% CI = 0.35-0.72, p = 0.0002).</p><p><strong>Interpretation: </strong>DBS demonstrates a favorable safety profile with substantially lower complication rates compared with the most widely performed elective surgeries. These findings support broader consideration of surgical referral for appropriate DBS candidates. ANN NEUROL 2026;99:1239-1250.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1239-1250"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996731","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":"Conditioning Electrical Stimulation for Patients with Moderate or Severe Carpal Tunnel Syndrome: Double Blinded Randomized Controlled Trial.","authors":"Yusuke Osaki, Jaret L Olson, Michael J Morhart, Matthew W Curran, Douglas W Zochodne, K Ming Chan","doi":"10.1002/ana.78155","DOIUrl":"10.1002/ana.78155","url":null,"abstract":"<p><strong>Objective: </strong>Carpal tunnel syndrome (CTS) can drastically impair one's ability to work and interferes with activities of daily living. We recently demonstrated that, in rodents, conditioning electrical stimulation (CES) delivered to the nerve 7 days prior to surgery imparts a conditioning lesion-like effect by accelerating the rate of regeneration along the entire length of the nerve. The goal of this study is to test the hypothesis that CES could accelerate nerve regeneration and improve function in patients with moderate or severe CTS.</p><p><strong>Methods: </strong>Using a double-blind randomized controlled study design, patients received surgery + CES or surgery + sham stimulation. They were evaluated at regular intervals for 12 months following intervention. Primary outcome was motor unit number estimation (MUNE), supplemented with secondary outcomes including motor and sensory nerve conduction studies, Semmes Weinstein Monofilaments, and Moberg Pick-Up Test.</p><p><strong>Results: </strong>Sixty-four participants were randomized to either the treatment or control groups. There was no significant demographic or physiological difference at baseline between the groups. No major adverse event was found with treatment. Following intervention, there was significantly greater increase in MUNE of 62 ± 71 in the treatment group compared to 25 ± 66 in the controls after 12 months. In the treatment group, there was correspondingly better physiological and functional recovery and hand dexterity compared with the controls.</p><p><strong>Interpretation: </strong>CES is a safe, feasible, and efficacious treatment to improve nerve reinnervation and functional outcomes in patients with moderate or severe CTS. This may open future possibilities for more effective treatment for other peripheral nerve injuries. ANN NEUROL 2026;99:1251-1262.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1251-1262"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092794/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145916155","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":"Increased Numbers of CD4⁺ T-Cells in the Hypocretin/Orexin Region of Narcolepsy Type 1.","authors":"Ling Shan, Milo Fonville, Mabel Hoekstra, Rolf Fronczek, Joost Smolders, Dick F Swaab","doi":"10.1002/ana.78199","DOIUrl":"10.1002/ana.78199","url":null,"abstract":"<p><p>Narcolepsy type 1 (NT1) is presumed to be an autoimmune disorder caused by hypothalamic loss of hypocretin (Hcrt; orexin). In postmortem NT1 brains, we observed an 11-fold increase of CD4⁺ T-cells in the Hcrt region compared with control hypothalami, without a corresponding rise in CD8⁺ T-cells. CD4⁺ and CD8⁺ T-cell numbers were unchanged in other hypothalamic regions, including the paraventricular nucleus and median eminence, and in extra-hypothalamic areas such as the substantia nigra and locus coeruleus. Hcrt-region CD4⁺ T-cells expressed the tissue-resident memory markers CD49a and CXCR6. These findings support the autoimmune hypothesis of NT1. ANN NEUROL 2026;99:1173-1178.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1173-1178"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092791/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147454833","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":"Brain-Computer Interface-Controlled Exoskeleton Training for Lower-Limb Rehabilitation in Spinal Cord Injury: A Pilot Randomized Clinical Trial.","authors":"Xuantao Hu, Na Li, Mao Pang, Shuwen Bai, Jian Mo, Senyu Yao, Yubao Lu, Mudan Huang, Jiawei Di, Yu Kang, Juliang Tang, Haojie Zhang, Tianlun Zhao, Jiale He, Lei He, Renjie Xie, Bin Liu, Guanghua Xu, Xiquan Hu, Limin Rong","doi":"10.1002/ana.78144","DOIUrl":"10.1002/ana.78144","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to evaluate the efficacy of brain-computer interface (BCI)-controlled exoskeleton training on lower-limb functional recovery, psychological outcomes, and neural plasticity in patients with spinal cord injury (SCI).</p><p><strong>Methods: </strong>We conducted a single-center, prospective, randomized, single-blind pilot trial (ChiCTR2300074503) including 21 patients with SCI. Participants were randomized to a BCI-exoskeleton group (B + E, n = 10) or an exoskeleton-only group (E, n = 11) for lower-limb training. Both groups received conventional rehabilitation plus 30 minutes of training, 6 days per week, for 4 weeks. The primary outcomes were Walking Index for Spinal Cord Injury II (WISCI II) scoring. Secondary outcomes included Lower Extremity Motor Score (LEMS), Spinal Cord Independence Measure version III (SCIM III), International Association of Neurorestoratology Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS), 10-Meter Walk Test (10MWT), 6-Minute Walk Test (6MWT), and Hospital Anxiety and Depression Scale (HADS). Cortical plasticity was assessed by electroencephalography (EEG) and magnetic resonance imaging (MRI).</p><p><strong>Results: </strong>The B + E group showed a significant improvement in LEMS (p = 0.003), whereas both groups improved in IANR-SCIFRS (p < 0.05). The B + E group demonstrated significant within-group gains in walking speed (10MWT, p < 0.001) and endurance (6MWT, p = 0.031), although between-group differences were not significant. Compared with the E group, the B + E group had larger reductions in HADS scores (p = 0.003). EEG analyses revealed stronger μ/β desynchronization and increased network efficiency, whereas MRI showed no structural changes.</p><p><strong>Interpretation: </strong>BCI-controlled exoskeleton training enhanced motor function, walking performance, and depressive symptoms more than exoskeleton training alone, likely through cortical reorganization. Extended training may further consolidate these benefits, supporting BCI-exoskeleton integration as a promising rehabilitation strategy for SCI. ANN NEUROL 2026;99:1124-1138.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1124-1138"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888277","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":"DNase1 RS1053874 Polymorphism is Associated with Early Neurological Recovery through NET Modulation and with Long-Term Survival in Ischemic Stroke: A Prospective Cohort Study.","authors":"B Díaz-Benito, P Calleja, L Alzamora, A Ruiz-García, A Martínez-Salio, M Muñoz-García, F Ostos, A García-Culebras, A Moraga, M A Moro, I Lizasoain","doi":"10.1002/ana.78156","DOIUrl":"10.1002/ana.78156","url":null,"abstract":"<p><strong>Objective: </strong>Immunothrombosis contributes to ischemic stroke pathophysiology through neutrophil extracellular trap (NET) formation, which promotes thrombus stabilization and microvascular dysfunction. DNase1 is the principal endonuclease responsible for NET degradation. The rs1053874 polymorphism in DNase1 gene influences enzymatic activity and protein stability in vitro, but its clinical relevance in ischemic stroke remains unexplored. We investigated whether this variant modulates systemic NET burden and impacts stroke-related outcomes.</p><p><strong>Methods: </strong>We conducted a prospective observational cohort study including 492 patients with acute ischemic stroke. Genotyping of rs1053874 was performed via Sanger sequencing and categorized into AA versus GG + GA genotypes (dominant model). Clinical variables, NET biomarkers (elastase, myeloperoxidase [MPO], and dsDNA), DNAse1 activity, infarct volume, thrombectomy metrics, and survival were assessed. Multivariable regression and Cox proportional hazards models were used to explore associations between genotype and outcomes.</p><p><strong>Results: </strong>AA genotype carriers (7.9%) had a significantly lower burden of prior vascular events compared to GG + GA carriers. At admission, they exhibited higher DNAse1 activity, reduced levels of circulating NET markers (elastase, MPO, and dsDNA), and lower neutrophil and monocyte counts. Despite similar initial stroke severity, AA carriers required fewer thrombectomy passes and had significantly better early neurological recovery and smaller infarcts. In adjusted models, both the AA genotype and dyslipidemia were independently associated with improved long-term survival. However, stratified analyses revealed the most robust survival benefit among AA carriers without dyslipidemia. No significant interaction was observed.</p><p><strong>Interpretation: </strong>DNase1 rs1053874 polymorphism influences NET-related inflammation and is associated with improved vascular profile, procedural efficiency, and long-term outcomes in ischemic stroke. These findings support the potential of DNase1 as a therapeutic and prognostic target in personalized stroke care. ANN NEUROL 2026;99:1210-1223.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1210-1223"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13092784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958401","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":"Longitudinal Trajectories of Brain Health Risk Factors Measured by the Brain Care Score and Risk of Stroke, Dementia, and Depression.","authors":"Tamara N Kimball, Reinier W P Tack, Livia Parodi, Savvina Prapiadou, Jasper R Senff, Benjamin Y Q Tan, Marie-Gabrielle Duperron, Devanshi Choksi, Evy M Reinders, Cyprien A Rivier, Guido J Falcone, Nirupama Yechoor, Sanjula D Singh, Jonathan Rosand, Ernst Mayerhofer, Christopher D Anderson","doi":"10.1002/ana.78145","DOIUrl":"10.1002/ana.78145","url":null,"abstract":"<p><strong>Objective: </strong>Evidence linking modifiable risk factors to age-related brain diseases, such as dementia, stroke, and depression (DSD), is robust, yet limited regarding long-term change in modifiable risk factors in association with these conditions, particularly in real-world settings. This study aimed to assess whether longitudinal changes in modifiable brain health risk factors were associated with reduced risk of DSD.</p><p><strong>Methods: </strong>We analyzed UK Biobank data (2006-2019) from 155,469 participants with general practitioner-linked data. The Brain Care Score (BCS) assesses 12 modifiable risk factors across lifestyle, physical, and social-emotional domains. Longitudinal BCS measurements were derived from repeated general practitioner (GP)-recorded measurements. Changes in the BCS were modeled using linear mixed-effects models, and associations with DSD were evaluated using multivariable Cox models, adjusting for baseline BCS and genetic risk (polygenic risk scores for stroke and depression, and APOE genotype for dementia).</p><p><strong>Results: </strong>Among 155,469 participants (median age = 51 years, 54.3% women), the median annual BCS change was 0.14 (Q1-Q3 = 0.008-0.30) points over a median follow-up of 12.3 years (Q1-Q3 = 11.5-13.1 years). Over time, 82.1% improved their BCS, 12.9% remained stable, and 5.0% worsened over time. Each 1-point annual increase in the BCS was associated with 4% lower risk of incident age-related brain diseases (hazard ratio [HR] = 0.96, 95% confidence interval [CI] = 0.95-0.97).</p><p><strong>Interpretation: </strong>In this large real-world cohort, improvements in modifiable risk factor profiles were associated with lower incidence of DSD, regardless of genetic risk or baseline BCS. Our results provide important information for communicating with patients about the brain health benefits of improving risk factor profiles. ANN NEUROL 2026;99:1113-1123.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":"1113-1123"},"PeriodicalIF":7.7,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145931525","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}