Annals of Clinical and Translational Neurology最新文献

{"title":"Cracking the Code: Genotype–Phenotype Correlation Models in Sarcoglycanopathies","authors":"Leonela Luce,&nbsp;Goknur Selen Kocak,&nbsp;José Verdú-Díaz,&nbsp;Jorge Alonso-Pérez,&nbsp;Kristl G. Claeys,&nbsp;Tanya Stojkovic,&nbsp;Gorka Fernández-Eulate,&nbsp;Pascal Laforêt,&nbsp;Najoua Miladi,&nbsp;Filipe Di Pace,&nbsp;Cristiane Araujo Martins Moreno,&nbsp;Edmar Zanoteli,&nbsp;Conrad C. Weihl,&nbsp;Volker Straub,&nbsp;Ana Töpf,&nbsp;Jordi Díaz-Manera,&nbsp;Sarcoglycan European Cohort Consortium","doi":"10.1002/acn3.70361","DOIUrl":"10.1002/acn3.70361","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Sarcoglycanopathies are among the most severe limb-girdle muscular dystrophies (LGMD), though milder presentations have been described. These diseases are primarily caused by missense variants, but the limited predictability of their effect on protein maturation, complex formation, and transport has hindered reliable genotype–phenotype correlations. This study aimed to establish accurate genotype–phenotype correlations for LGMDR3, LGMDR4, and LGMDR5.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed the largest sarcoglycanopathy cohort to date (<i>n</i> = 541). Clinical data, including age at symptom onset and loss of ambulation, were collected and used to define phenotype severity. Predictive models were developed considering the impact of non-truncating variants on secondary structure, functional domains, evolutionary conservation, and intra-complex protein–protein interactions. Patients carrying two variants predicted to disrupt membrane trafficking were expected to present with severe phenotypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>For LGMDR3, the best-performing model classified variants affecting β-sheets, cadherin-like, and ATP-binding domains as disruptive to membrane translocation, achieving 89% predictive power, 0.867 balanced accuracy, and 2.4% false-negative rate (clinically severe patients who were wrongly classified by the model as mild). For LGMDR4 and LGMDR5, the best-performing model involved conserved residues, β-sheets, EGF-like domain, and protein–protein interactions—reaching 80% predictive power, 0.689 balanced accuracy, and 3.1% false-negative rate (LGMDR4), and 90% predictive power, 0.536 balanced accuracy, with no false negatives (LGMDR5). Additionally, we developed an open-access predictive tool for clinical and research application.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study provides a robust genotype–phenotype correlation for sarcoglycanopathies, improving prognosis, patient management, and clinical trial recruitment.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1851-1865"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395032/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paramagnetic Rim Lesions Are Associated With Trans-Synaptic Degeneration of the Visual Pathway in Multiple Sclerosis","authors":"Abdul Jaber Tayem,&nbsp;Angel Liu,&nbsp;Sargis Manukyan,&nbsp;Mustafa Subhi,&nbsp;Elaina Luskin,&nbsp;Bryan Quah,&nbsp;Sreekanth Madhusoodhanan Nair,&nbsp;Arzu C. Has Silemek,&nbsp;Gabriela Zabala,&nbsp;Yujie Cui,&nbsp;Laura Locke,&nbsp;Paula Barreras,&nbsp;Marwa Kaisey,&nbsp;Vinicius Calsavara,&nbsp;Daniel S. Reich,&nbsp;Nancy L. Sicotte,&nbsp;Pascal Sati,&nbsp;Omar Al-Louzi","doi":"10.1002/acn3.70352","DOIUrl":"10.1002/acn3.70352","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objectives</h3>\u0000 \u0000 <p>Retrograde trans-synaptic degeneration (rTSD) from posterior visual pathway lesions in multiple sclerosis (MS) is characterized by hemi-macular ganglion cell-inner plexiform layer (GCIPL) thinning and contralateral visual field loss. We investigated associations between rTSD, paramagnetic rim lesions (PRL), and longitudinal visual disability in people with MS (pwMS) using a novel optical coherence tomography (OCT) based biomarker of rTSD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>PwMS, non-MS neurological disease controls, and healthy controls underwent OCT, multiparametric brain MRI, and clinical assessments. A quantitative rTSD index was developed to capture hemispheric GCIPL asymmetry, with absolute values reflecting rTSD severity. Generalized linear models were used to investigate MRI and clinical predictors of rTSD. Longitudinal changes in rTSD were evaluated using mixed-effects linear regression models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>A total of 170 pwMS and 49 controls were included. PwMS had higher rTSD than healthy (<i>p</i> = 0.006) and non-MS controls (<i>p</i> = 0.009). African American race (<i>p</i> = 0.02) and longer disease duration (<i>p</i> = 0.005) were associated with higher baseline rTSD. PRL in the optic radiations (OR) was linked to a 4.5-fold increase in rTSD (<i>p</i> = 0.037; <i>n</i> = 37) and −1.18 dB reduction in hemifield sensitivity (<i>p</i> = 0.018). Longitudinally, each unit/year progression in rTSD was associated with a −0.07 dB/year decline in hemifield sensitivity (<i>p</i> = 0.005) and a 10.8-fold increase in the odds of expanded disability status scale score progression (<i>p</i> = 0.022). Higher body mass index was associated with faster rTSD progression longitudinally (<i>p</i> = 0.02).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>PRL in the OR, African American race, disease duration, and higher BMI are associated with rTSD in pwMS. Longitudinal increase in rTSD is associated with worsening visual loss and clinical disability progression in MS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Trial Registration</h3>\u0000 \u0000 <p>ClinicalTrials.gov identifier: NCT05204459</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1831-1841"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394915/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466368","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF Monoamine Metabolites and Cognitive Trajectory in Early Parkinson's Disease","authors":"Jing-Yu Shao,&nbsp;Rong Li,&nbsp;Yu-Xiang Jiao,&nbsp;Kai Ma,&nbsp;Hong-Qi Yang,&nbsp;Zheng-Yu Sun,&nbsp;Jie-Wen Zhang,&nbsp;Shuai Chen","doi":"10.1002/acn3.70367","DOIUrl":"10.1002/acn3.70367","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Imaging and postmortem studies indicate that abnormalities in monoaminergic neurotransmission contribute to cognitive impairment in Parkinson's disease (PD). However, it remains uncertain if cerebrospinal fluid (CSF) monoamine metabolites can serve as biomarkers of cognitive decline in early PD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>We therefore examined associations of CSF 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylglycol (DOPEG), and 5-hydroxyindoleacetic acid (5-HIAA) with baseline Montreal Cognitive Assessment (MoCA) scores and with longitudinal rates of change.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Ninety-five patients with early PD and fifty-six demographically matched healthy controls (HCs) were included from the Parkinson's Progression Markers Initiative cohort. Baseline CSF concentrations of monoamine metabolites were measured by liquid chromatography coupled with tandem mass spectrometry (LC–MS/MS). In PD patients, multivariable linear regression and linear mixed-effects models were used to evaluate the cross-sectional and longitudinal associations, respectively, between baseline CSF metabolites and MoCA scores. To facilitate comparison, the levels of monoamine metabolites were converted into Z-scores to attain standardized β coefficients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with HCs, PD patients had lower baseline CSF concentrations of DOPAC, HVA, and 5-HIAA. After adjustment for relevant covariates, any standardized CSF metabolite was not associated with baseline MoCA scores. Lower baseline CSF DOPAC and HVA were significantly associated with more rapid cognitive decline over time (z-DOPAC: β = 0.17, <i>p</i> &lt; 0.001; z-HVA: β = 0.14, <i>p</i> = 0.009). Neither DOPEG nor 5-HIAA was associated with longitudinal cognitive decline.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Taken together, our results indicated that baseline CSF DOPAC and HVA may serve as promising longitudinal predictors of cognitive decline in patients with PD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1842-1850"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394995/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466357","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Validation of Plasma p-217tau in Neurological Diseases","authors":"Takeshi Kawarabayashi,&nbsp;Takumi Nakamura,&nbsp;Ryoma Takahashi,&nbsp;Tetsuya Ueda,&nbsp;Seiji Kinoshita,&nbsp;Chikage Uchida,&nbsp;Takashi Sugawara,&nbsp;Kentaro Hashimoto,&nbsp;Kunihiko Ishizawa,&nbsp;Masakuni Amari,&nbsp;Hiroo Kasahara,&nbsp;Yoshio Ikeda,&nbsp;Masamitsu Takatama,&nbsp;Mikio Shoji","doi":"10.1002/acn3.70359","DOIUrl":"10.1002/acn3.70359","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Plasma p-217tau is a minimally invasive but specific biomarker for diagnosing Alzheimer's disease (AD). However, its disease specificity remains to be clinically evaluated. We validated the reliability of the p-217tau biomarker in 12 other neurological diseases.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Plasma p-217tau levels were measured in 298 participants, consisting of 81 AD patients, 204 patients with 12 other neurological diseases, and 13 healthy and cognitively unimpaired controls (HCU), using an assay system from Meso Scale Diagnostics. Cerebrospinal fluid (CSF) tau and Aß levels were simultaneously evaluated in AD, amyotrophic lateral sclerosis (ALS), and idiopathic normal pressure hydrocephalus (iNPH).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Plasma p-217tau levels increased in AD with the clinical stage, but also in ALS and iNPH, leading to them having decreased sensitivity and specificity for diagnosing AD. No increases in plasma p-217tau levels were seen in possible tauopathies or synucleinopathies. CSF and plasma p-217tau levels were strongly correlated in AD, but not in ALS. The plasma p-217tau/CSF p-217tau ratio was inversely higher in ALS than in AD. Active and chronic denervation potentials were associated with plasma p-217tau levels. In iNPH, plasma p-217tau was associated with cognitive dysfunction, but not with gait disturbance or urinary incontinence. CSF p-181tau, total tau, and Aß1-40 levels and the Aß1-40/1–42 ratio were reduced in iNPH.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>ALS and iNPH are two major pitfalls for the clinical application of plasma p-217tau as a biomarker of AD. Lower motor neuron injury in ALS and cognitive dysfunction in iNPH were both found to be associated with elevated plasma p-217tau levels.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1780-1790"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147375561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Problematic Internet Use in Frontotemporal Dementia: A Case Series","authors":"Daniele Urso,&nbsp;Giuseppe Volpe,&nbsp;Agnese Valguarnera,&nbsp;Davide Vilella,&nbsp;Alessandra Vitulli,&nbsp;Valentina Gnoni,&nbsp;Alessia Giugno,&nbsp;Eleonora Rollo,&nbsp;Mark D. Griffiths,&nbsp;Giancarlo Logroscino","doi":"10.1002/acn3.70417","DOIUrl":"10.1002/acn3.70417","url":null,"abstract":"<p>The present study investigated problematic internet use (PIU) among 61 patients with frontotemporal dementia (FTD) compared to a cohort of 354 patients with mild cognitive impairment (MCI) and Alzheimer's dementia. PIU was identified in 22.9% of FTD patients compared to only 0.8% of AD patients (<i>p</i> &lt; 0.001). Behaviors included compulsive social media use, gaming, and online shopping. These findings suggest that PIU may represent an emerging behavioral feature associated with FTD, significantly more prevalent than in MCI and Alzheimer's dementia. Recognizing these digital behaviors could provide valuable clinical insights for diagnosis and management in the digital age.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1947-1950"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969088","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Claustrum Involvement in New Onset Refractory Status Epilepticus: A Systematic Review","authors":"Margherita Burani,&nbsp;Lorenzo Muccioli,&nbsp;Giada Giovannini,&nbsp;Niccolò Orlandi,&nbsp;Francesca Bisulli,&nbsp;Stefano Meletti","doi":"10.1002/acn3.70490","DOIUrl":"10.1002/acn3.70490","url":null,"abstract":"<p>The claustrum sign is a distinctive neuroimaging finding characterized by bilateral T2/FLAIR hyperintensity of the claustrum, one of the most interconnected regions of the human brain. It was first described in new-onset refractory status epilepticus (NORSE) and febrile infection–related epilepsy syndrome (FIRES). A systematic search was conducted according to PRISMA guidelines from 2018 (formal definition of NORSE) to February 2026 (PROSPERO 2026 CRD420261307306). We included peer-reviewed original studies reporting MRI findings and patient-level data, and compared clinical characteristics, treatments, and outcomes of patients with claustrum alteration versus NORSE/FIRES patients without this finding. Of 785 records identified, 65 studies met inclusion criteria; 41 provided individual patient data, yielding 206 NORSE cases (72 with the claustrum sign, 134 without). All but one patient with the claustrum sign met criteria for cryptogenic NORSE. Patients were predominantly young (mean age 24.9 years) and had a febrile prodrome in 93% of cases. Convulsive status epilepticus (SE) occurred in 98%, progressing to super-refractory SE (SRSE) in more than half reported cases. Bilateral claustrum hyperintensity was detected in 68/71 patients during the acute phase, typically emerging 7 days after SE onset. Immunotherapy was administered in 92% of patients. In-hospital mortality was 9%, while 74% of patients developed chronic epilepsy. Compared with patients without claustrum involvement, those with the claustrum sign more often had febrile onset (93% vs. 51%, <i>p</i> &lt; 0.001) and convulsive SE (98% vs. 81.5%, <i>p</i> = 0.008), lower rates of SRSE (51% vs. 96.5%, <i>p</i> &lt; 0.001), and ICU admission (71% vs. 99%, <i>p</i> &lt; 0.001), and a trend toward lower mortality (9% vs. 16%, <i>p</i> = 0.240). Recognition of the claustrum sign may support early diagnosis and targeted treatment.</p><p><b>Trial Registration:</b> PROSPERO 2026 [CRD420261307306]</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1750-1758"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13438007/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148672886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALDOA Promotes Glycolysis and NLRP3/GSDMD Pyroptosis to Accelerate ALS Progression","authors":"Kaixin Yan,&nbsp;Yan Jiang,&nbsp;Yuxuan Yong,&nbsp;Tianshuo Zhang,&nbsp;Niannian Zhang,&nbsp;Qianqian Zeng,&nbsp;Xue Gong,&nbsp;Li Meng,&nbsp;Fangfang Bi,&nbsp;Yongmin Liu","doi":"10.1002/acn3.70372","DOIUrl":"10.1002/acn3.70372","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Amyotrophic lateral sclerosis (ALS) is characterized by progressive motor neuron degeneration. Glycolytic dysregulation is implicated in disease progression, yet the underlying mechanisms remain unclear. This study investigates how Aldolase A (ALDOA) drives ALS progression through glycolysis-mediated motor neuron pyroptosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In vivo, tamoxifen-induced TDP-43 cKO mice were assessed for motor function (rotarod/suspension tests), motor cortex L-lactic acid, and ALDOA/NLRP3/GSDMD expression. The ALDOA inhibitor Aldometanib was administered. In vitro, TDP-43 KO NSC34 cells were used to measure viability, glucose uptake, and L-lactic acid.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>ALS model mice exhibited significant motor deficits, progressive weight loss, and reduced survival. Their motor cortex showed elevated ALDOA expression, L-lactic acid accumulation, and NLRP3/GSDMD inflammasome activation. Aldometanib treatment suppressed glycolysis, prolonged survival, and slowed disease progression by inhibiting NLRP3/GSDMD-mediated pyroptosis. In vitro, TDP-43-deficient NSC34 cells displayed increased ALDOA levels, enhanced glycolytic flux, NLRP3/GSDMD pathway activation, and impaired proliferation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>We show that ALDOA-mediated glycolytic dysregulation activates the NLRP3/GSDMD inflammasome, leading to pyroptosis in motor neurons. Pharmacological inhibition of ALDOA alleviates glycolytic dysregulation and extends survival, identifying ALDOA as a potential therapeutic target.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1903-1918"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Five-Year Disease Progression in Synuclein Seeding Positive Sporadic Parkinson's Disease","authors":"Paulina Gonzalez-Latapi,&nbsp;Caroline Gochanour,&nbsp;Seung Ho Choi,&nbsp;Hyunkeun Cho,&nbsp;Chelsea Caspell-Garcia,&nbsp;Christopher Coffey,&nbsp;Michael Brumm,&nbsp;David-Erick Lafontant,&nbsp;Yuge Xiao,&nbsp;Thomas Tropea,&nbsp;John Seibyl,&nbsp;Caroline Tanner,&nbsp;Charles S. Venuto,&nbsp;Karl Kieburtz,&nbsp;Lana M. Chahine,&nbsp;Kathleen L. Poston,&nbsp;Andrew Siderowf,&nbsp;Kenneth Marek,&nbsp;Tanya Simuni,&nbsp;The Parkinson's Progression Markers Initiative","doi":"10.1002/acn3.70323","DOIUrl":"10.1002/acn3.70323","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To provide a comprehensive description of disease progression in synuclein seeding assay (SAA) positive sporadic Parkinson Disease participants, using Neuronal Synuclein Disease integrated biological and functional impairment staging framework.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed 5-year longitudinal data from 345 participants recruited in the Parkinson's Progression Markers Initiative with the diagnosis of early (less than 2 years of clinical diagnosis at baseline and untreated) sporadic Parkinson's Disease, who were synuclein seeding assay positive. We assessed 5-year progression in a spectrum of clinical and biomarker measures. We used Cox proportional hazards models to assess the association between baseline stage and time to survival, postural instability, cognitive impairment, and other meaningful milestones. Biomarker analysis included dopamine transporter binding measures, CSF-SAA, amyloid-beta, phosphorylated tau and total tau, as well as serum urate, and neurofilament light chain.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>At baseline there was clear separation of participants by Neuronal Synuclein Disease Stages (23% Stage 2b, 67% Stage 3, 10% Stage 4). Participants in stage 4 at baseline had a significantly higher rate of reaching disability, postural instability, cognitive decline, and the autonomic dysfunction milestones. There was a stage-dependent increase in dopamine deficit at baseline. There was no difference in fluid biomarkers between the stages at baseline and longitudinally.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This study highlights the heterogeneity in the early Parkinson's Disease population defined by clinical diagnostic criteria and underscores the importance of shifting from clinical to biologically and functional impairment defined inclusion criteria for clinical trials. Biological drivers of stage heterogeneity must be further explored.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1791-1806"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147429443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reperfusion-Dependent Outcomes After Endovascular Thrombectomy Stratified by NIHSS-ASPECTS Clinical-Core Mismatch","authors":"Felix Schlicht,&nbsp;Lukas Meyer,&nbsp;Gabriel Broocks,&nbsp;Matthias Bechstein,&nbsp;Christian Thaler,&nbsp;Christian Heitkamp,&nbsp;Laurens Winkelmeier,&nbsp;Vincent Geest,&nbsp;Alexander Heitkamp,&nbsp;Maximilian Jungnitz,&nbsp;Gregor Peter,&nbsp;Luca Meucci,&nbsp;Tobias Faizy,&nbsp;Jawed Nawabi,&nbsp;Caspar Brekenfeld,&nbsp;Fabian Flottmann,&nbsp;Maximilian Schell,&nbsp;Alexandros Hadjilaou,&nbsp;Uta Hanning,&nbsp;Götz Thomalla,&nbsp;Jens Fiehler,&nbsp;Susanne Gellißen,&nbsp;Helge C. Kniep,&nbsp;German Stroke Registry Endovascular Treatment","doi":"10.1002/acn3.70358","DOIUrl":"10.1002/acn3.70358","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This analysis evaluates the effect of successful reperfusion on functional outcomes after MT, stratified by admission National Institutes of Health Stroke Scale (NIHSS) and Alberta Stroke Program Early CT Score (ASPECTS) as surrogates for clinical-core mismatch, using multicenter registry data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Retrospective analysis of patients with anterior circulation stroke undergoing MT enrolled in the German Stroke Registry (2015–2023). Patients were stratified into nine subgroups according to ASPECTS (10; 9–8; ≤ 7) and NIHSS (0–10; 11–15; ≥ 16). The primary endpoint was the rate of good functional outcome (modified Rankin Scale [mRS] of 0–2) at 90 days. Safety outcomes included symptomatic intracranial hemorrhage and mortality. Inverse-probability-weighted regression adjustment (IPWRA) was used to control confounders in observational data.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>18,069 patients were screened, 5448 met the inclusion criteria (mean age 71.2; 48% female). Successful reperfusion (mTICI 2b-3) was associated with improved functional outcomes in all subgroups, including patients with low NIHSS and high ASPECTS or high NIHSS and low ASPECTS. Largest effects were observed for high clinical-core mismatch (ASPECTS = 10; NIHSS ≥ 16) with 47% (95% Confidence Interval [CI]: 42%–53%) mRS 0–2 after mTICI 3 recanalization compared to 9% (95% CI: 3%–16%) after persistent occlusion, a 38-percentage point increase in good outcome. mTICI 3 was associated with superior outcomes compared to mTICI 2b, particularly in patients with high NIHSS and high ASPECTS.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Patients with pronounced clinical-core mismatch derive the greatest benefit from successful reperfusion. Nonetheless, significant functional improvements across all subgroups support more individualized treatment considerations and highlight the need for refined selection criteria.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1807-1816"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147442054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness of rTMS on Working Memory and Inhibitory Impairments in Patients With Post-Stroke Executive Deficits","authors":"Mengting Lao,&nbsp;Rongwei Du,&nbsp;Zhujun Wang,&nbsp;Yang Gao,&nbsp;Meiling Cheng,&nbsp;Xianglong Wang,&nbsp;Wen Wu","doi":"10.1002/acn3.70376","DOIUrl":"10.1002/acn3.70376","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Considerable efforts have been dedicated to developing effective treatments for post-stroke executive impairment (PSEI), among which repetitive transcranial magnetic stimulation (rTMS) has shown great potential. This study aimed to investigate the therapeutic effects of high-frequency rTMS on working memory (WM) and response inhibition (RI) of executive functions in PSEI patients and the potential neural mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In a randomized, double-blind trial, 10 Hz rTMS was applied to the left dorsolateral prefrontal cortex (DLPFC) in 32 PSEI patients for 10 days, who were divided into real and sham rTMS groups. The Stroop color-word test (SCWT), digit span test (DST), and functional near-infrared spectroscopy (fNIRS) were used for assessment before and after the intervention. Resting-state functional connectivity (rsFC) and graph theory methods were used to analyze changes in brain function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared to the sham rTMS group, the real rTMS group showed significant reductions in SCWT response time (<i>F</i> = 4.223, <i>p</i> = 0.049) and improvements in DST forward scores (<i>F</i> = 4.739, <i>p</i> = 0.037) after the intervention. Moreover, the real rTMS group demonstrated significant enhancements in rsFC from left DLPFC to the right DLPFC (<i>F</i> = 8.538, <i>p</i> = 0.007) and the right posterior parietal cortex (<i>F</i> = 9.905, <i>p</i> = 0.004), as well as in the Degree Centrality of the left DLPFC (<i>F</i> = 7.144, <i>p</i> = 0.012), which were respectively significantly correlated with reduced SCWT response time and increased DST forward scores.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>High-frequency rTMS effectively improves WM and RI performance in patients with PSEI, which may be attributed to the remodeling of specific connectivity patterns and enhancement of local communication efficiency within the frontoparietal network.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 9","pages":"1919-1929"},"PeriodicalIF":3.9,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}