Annals of Clinical and Translational Neurology最新文献

{"title":"CSF Cytokine Network Organization Predicts Progression Independent of Relapse and MRI Activity in Multiple Sclerosis.","authors":"Antonio Bruno, Matteo Conti, Ettore Dolcetti, Federica Azzolini, Angela Borrelli, Roberta Fantozzi, Mario Stampanoni Bassi, Giovanni Galifi, Giuseppe Maccarrone, Luca Montaguti, Marco Cervigni, Maddalena Dal Pozzo, Roberto Furlan, Annamaria Finardi, Girolama Alessandra Marfia, Marco Salvetti, Antonella Conte, Fabio Buttari, Diego Centonze, Luana Gilio","doi":"10.1002/acn3.70502","DOIUrl":"https://doi.org/10.1002/acn3.70502","url":null,"abstract":"<p><strong>Objective: </strong>Progression independent of relapse activity is a major determinant of long-term disability in multiple sclerosis, but its immunopathologic basis remains incompletely understood. We investigated whether relapse-independent progression in radiologically stable relapsing-remitting multiple sclerosis is associated with distinct cerebrospinal fluid inflammatory profiles and whether cytokine-network features provide information beyond single-mediator levels.</p><p><strong>Methods: </strong>In this prospective observational cohort study, baseline cerebrospinal fluid cytokine and chemokine profiling was performed in 346 RRMS patients, 61 primary progressive multiple sclerosis (PPMS) patients, and 196 neurological controls without inflammatory or neurodegenerative central nervous system disease. After 2-year clinical and MRI follow-up, 37 RRMS patients with clinical relapse and/or MRI activity were excluded, leaving 309 relapse-free and MRI-stable RRMS patients classified as stable RRMS (n = 241) or RRMS with PIRMA (n = 68). Cytokines were analyzed using two-part hurdle models, cytokine interactomes, and machine-learning classifiers.</p><p><strong>Results: </strong>Quantitative cytokine analyses distinguished multiple sclerosis from controls but showed substantial overlap across multiple sclerosis phenotypes. RRMS with PIRMA showed higher cerebrospinal fluid levels of tumor necrosis factor-α, interleukin-17, and RANTES than stable RRMS. Network analyses showed a more integrated cytokine interactome in RRMS with PIRMA. The network-level model best distinguished RRMS with PIRMA from stable RRMS, with an area under the curve of 0.86, sensitivity of 77%, and specificity of 76%.</p><p><strong>Interpretation: </strong>Relapse-independent progression in multiple sclerosis is associated with selective cytokine changes and broader reorganization of inflammatory network architecture, supporting cerebrospinal fluid cytokine interactome profiling as a translational approach to immune stratification.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13490313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148786099","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":"Normal-Appearing White Matter Injury Mediates Chronic Deep Venous Hypoxia and Disease Progression in Multiple Sclerosis","authors":"Xinli Wang,&nbsp;Huiying Wang,&nbsp;Zhizheng Zhuo,&nbsp;Ai Guo,&nbsp;Ke Lv,&nbsp;Decai Tian,&nbsp;Chao Chai,&nbsp;Yunyun Duan,&nbsp;Shuang Xia","doi":"10.1002/acn3.70354","DOIUrl":"10.1002/acn3.70354","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To explore how cerebral hypoxia and Normal-Appearing White Matter (NAWM) integrity affect MS lesion burden and clinical course.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Seventy-nine MS patients, including 13 clinically isolated syndrome (CIS) patients and 66 relapsing–remitting multiple sclerosis (RRMS) patients, and 44 healthy controls (HCs) were recruited from CLUE, NCT04106830. Quantitative susceptibility mapping (QSM) was employed to evaluate the changes of cerebral venous oxygen saturation (SvO₂) in deep cerebral veins. Diffusion tensor imaging (DTI) and neurite orientation dispersion and density imaging analyzes (NODDI) were employed to evaluate microstructural alterations in deep brain white matter (WM), including WM lesion and NAWM between MS and HCs. Partial correlations analyzes were conducted to examine associations between imaging biomarkers and clinical indicators. Mediation analysis was used to evaluate the relationship among SvO₂, microstructural alterations, lesion volumes, and clinical indicators.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with HCs, patients with MS showed significantly decreased SvO₂ in the internal cerebral vein (76.56% ± 1.34% vs. 78.80% ± 0.86%, <i>p</i> &lt; 0.001). Advanced diffusion metrics revealed extensive microstructural disruption in both WM lesions and NAWM (NAWM mean diffusivity [MD]: 1.03 ± 0.12 vs. 0.90 ± 0.04 [×10⁻³ mm²/s], <i>p</i> &lt; 0.001). Furthermore, microstructural disruption of NAWM (MD and orientation dispersion index [ODI]) significantly correlated with SvO₂ of the ICV (MD: <i>r</i> = −0.307, <i>p</i> = 0.036; ODI: <i>r</i> = −0.279, <i>p</i> = 0.036). Critically, mediation analysis demonstrated that deep brain WM hypoxia (ICV SvO₂) associated with greater lesion burden and clinical disability via NAWM damage as an intermediate pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>In MS patients, lower cerebral SvO₂ (compared with HCs) is statistically associated with microstructural alterations in the NAWM. Our mediation models are consistent with a pathway whereby lower SvO₂ is associated with greater lesion burden and worse functional scores via its association with NAWM damage. These findings support the exploratory value of SvO₂ and NAWM integrity as potential biomarkers for monitoring MS progression, which warrants validation in further longitudinal studies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1686-1696"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147300351","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":"Baseline Regional Cholinergic Denervation Predicts Cognitive Trajectories in Moderate Parkinson Disease","authors":"Taylor Brown,&nbsp;Giulia Carli,&nbsp;Prabesh Kanel,&nbsp;Stiven Roytman,&nbsp;Jaimie Barr,&nbsp;Nicolaas I. Bohnen,&nbsp;Roger L. Albin","doi":"10.1002/acn3.70335","DOIUrl":"10.1002/acn3.70335","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Cognitive decline is a disabling and variable feature of Parkinson disease (PD). While cholinergic system degeneration is linked to cognitive impairments in PD, most prior research reported cross-sectional associations. We aimed to fill this gap by investigating whether baseline regional cerebral vesicular acetylcholine transporter ligand [¹⁸F]-fluoroethoxybenzovesamicol ([¹⁸F]-FEOBV) binding predicts longitudinal cognitive changes in mild–moderate, non-demented PD subjects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Seventy-five non-demented, mild–moderate PD subjects underwent baseline [¹⁸F]-FEOBV PET and standardized cognitive evaluations, with repeat cognitive testing after 2 years. Participants were classified into four cognitive classes: persistent normal (no MCI at either time point; <i>N</i> = 41), persistent MCI (MCI at both; <i>N</i> = 21), MCI conversion (normal to MCI; <i>N</i> = 6), and MCI reversion (MCI to normal; <i>N</i> = 7). We performed whole-brain voxel comparisons (controls and between classes) and used linear and multinomial regression to predict follow-up cognitive status.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Whole-brain voxel analyses revealed class-specific [¹⁸F]-FEOBV binding deficits. Persistent MCI showed the most widespread reductions, extending into frontal regions. Compared with MCI reverter and persistently normal groups, persistent MCI had lower binding in occipito-temporal and temporo-parieto-frontal regions, respectively, while MCI reverters showed higher occipital binding than converters. Binding in occipital, temporo-parietal, and medial frontal regions predicted follow-up cognitive decline, with medial frontal binding showing the strongest association (esp. global cognition, memory, and visuospatial domains).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Baseline cholinergic system changes associate with varying cognitive trajectories in mild–moderate PD. Assessment of regional cholinergic deficits may be useful for prediction of cognitive trajectories in this population, enhancing subject selection and stratification for intervention trials aimed at improving cognition in PD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1569-1580"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394599/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176829","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":"Validity of a Wearable Digital Insole for Assessing Gait ON and OFF in Parkinson's Disease","authors":"Deborah A. Hall,&nbsp;Kimberly Kwei,&nbsp;Rolando J. Acosta,&nbsp;Bharatkumar Koyani,&nbsp;Erin Robertson,&nbsp;Pratyush Rai,&nbsp;Roland Barge,&nbsp;Emily Timm,&nbsp;Nicollette L. Purcell,&nbsp;Natasha Desai,&nbsp;Dhanesh Patel,&nbsp;Ana-Maria Visoiu-Knapp,&nbsp;Samuel Stuart,&nbsp;Rinol Alaj,&nbsp;Matthew F. Wipperman,&nbsp;Oren Levy,&nbsp;Joan A. O'Keefe","doi":"10.1002/acn3.70333","DOIUrl":"10.1002/acn3.70333","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Gait impairment is a distinctive symptom of Parkinson's disease that negatively impact mobility. We assessed the validity of wearable digital insoles against a validated reference gait analysis system for measuring select gait characteristics in patients with Parkinson's disease.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>A comparative analysis between digital insoles (Moticon ReGo Insole) and the GAITRite system was conducted in patients with Parkinson's disease. Patients were assessed in both the OFF and ON medication states. Gait characteristics were measured simultaneously with both systems during two 10 m walk tests. Patients also completed a patient experience survey following the use of the digital insoles.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Overall, 21 patients with Parkinson's disease were included in the study. Analytical validation for gait cadence, speed, and stride length showed excellent agreement (intraclass correlation coefficients between 0.93–0.97) in both the OFF and ON states. Stance, swing, and double support times exhibited lower validity with moderate agreement (intraclass correlation coefficients from 0.48–0.57). Gait speed and stride length were significantly associated with scores on the Movement Disorders Society's Unified Parkinson's Disease Rating Scale (<i>p</i> = 0.0085 and 0.013, respectively). Mean differences in all parameters measured with the insoles, except cadence, were significantly different between OFF and ON states (<i>p</i> &lt; 0.003). The majority of patients liked wearing the digital insoles and found them comfortable and user-friendly.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These findings support the validity of Moticon ReGo digital insoles for the assessment of several important gait characteristics in Parkinson's disease.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1662-1672"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275278","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":"Movement Disorders in Aicardi–Goutières Syndrome and Response to Immunomodulation","authors":"Enrique Gonzalez Saez-Diez,&nbsp;Monica Ferrer Socorro,&nbsp;Kathryn Yang,&nbsp;Nicole Battaglia,&nbsp;Zainab Zaman,&nbsp;Mariko Bennett,&nbsp;Adeline Vanderver,&nbsp;Pui Y. Lee,&nbsp;Lauren A. Henderson,&nbsp;Milena M. Andzelm,&nbsp;Darius Ebrahimi-Fakhari","doi":"10.1002/acn3.70407","DOIUrl":"10.1002/acn3.70407","url":null,"abstract":"<p>This study characterizes movement disorders and treatment responses in seven children with Aicardi–Goutières syndrome (AGS). We retrospectively evaluated motor phenotypes, neuroimaging, and interferon signatures in patients treated with baricitinib or anifrolumab. Spasticity affected all patients, while dystonia was present in 4/7. GMFCS levels ranged from I to V. Following immunomodulation, interferon signatures normalized in 6/7 of patients, and 6/7 showed clinical stabilization or improvement, with no further regression events. These findings indicate that targeted therapy was associated with reduced systemic inflammation and stabilized disease. However, motor outcomes varied, suggesting that established CNS injury may limit functional recovery despite a biochemical response.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1702-1710"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395044/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147757709","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":"Impact of Plasma p-tau181 on Cognition, Motor Phenotypes, and Disease Course in ALS","authors":"Elisabeth Kasper,&nbsp;Annaliis Lehto,&nbsp;Nina Nordmann,&nbsp;Oliver Peters,&nbsp;Julian Hellmann,&nbsp;Josef Priller,&nbsp;Eike Jakob Spruth,&nbsp;Gabor C. Petzold,&nbsp;Ina Vogt,&nbsp;Patrick Weydt,&nbsp;Sarah Bernsen,&nbsp;Elisabeth Dinter,&nbsp;Björn Falkenburger,&nbsp;René Günther,&nbsp;Emrah Düzel,&nbsp;Wenzel Glanz,&nbsp;Matthis Synofzik,&nbsp;Lukas Beichert,&nbsp;Annika Spottke,&nbsp;Michael Wagner,&nbsp;Frederic Brosseron,&nbsp;Matthias C. Schmid,&nbsp;Anja Schneider,&nbsp;Stefan Teipel,&nbsp;Johannes Prudlo,&nbsp;Andreas Hermann","doi":"10.1002/acn3.70423","DOIUrl":"10.1002/acn3.70423","url":null,"abstract":"<p>Phosphorylated tau181 (p-tau181), an Alzheimer's disease biomarker, was recently evaluated in amyotrophic lateral sclerosis (ALS). We investigated plasma p-tau181 in 202 ALS/ALS-FTD patients and 94 healthy controls, assessing cognitive performance, motor function, and longitudinal dynamics. Plasma p-tau181 and NfL were significantly elevated in ALS, with p-tau181 increasing over 1 year while NfL remained stable. Neither marker correlated with cognitive performance, and only NfL was associated with disease severity and progression. Plasma p-tau181 was higher in patients with predominant lower motor neuron involvement. The results indicate that p-tau181 reflects peripheral processes in ALS, providing a complementary, mechanistically distinct biomarker from NfL.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1711-1718"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395029/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147808961","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":"Innate Immune Reprogramming Mediated by Endogenous Retroelement Dysregulation Drives Multiple Sclerosis Progression","authors":"Li-Mei Xiao,&nbsp;Qiu-Ping Zhao,&nbsp;Run-Yun Li,&nbsp;Wei Chen,&nbsp;Huan-Huan Song,&nbsp;Wan-Jin Chen,&nbsp;Ying Fu","doi":"10.1002/acn3.70350","DOIUrl":"10.1002/acn3.70350","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Skewed myelopoiesis in the bone marrow has been identified as a key driver of multiple sclerosis (MS) progression. Interestingly, SARS-CoV-2 infection, which has a severe impact on MS patients, can also induce similar skewed myelopoiesis. This shared phenotype raises the question of whether a common mechanism underlies the skewed myelopoiesis in both diseases. Previous studies in mice have demonstrated that the dysregulation of endogenous retroelements (EREs) in HSPCs leads to skewed myelopoiesis. Building on this, we sought to determine whether ERE dysregulation contributes to the skewed myelopoiesis observed in MS and after COVID-19, which remains challenging.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We undertook a joint investigation of two public single-cell/nuclei cohorts respectively representing MS and following COVID-19. Both cohorts were processed through an identical bioinformatic pipeline to ensure comparable assessment of gene and ERE expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We observed enhanced myelopoiesis in the bone marrow of MS patients compared to healthy controls, along with downregulation of the ERE repressor H3.3 and concomitant EREs overexpression. Notably, a similar epigenetic and transcript feature was found in post-COVID-19 individuals.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The H3.3^low/ERE^high signature may not only explain the common skewed myelopoiesis in MS and post-COVID-19 conditions, but also provide a mechanistic link between infection and the innate immune reprogramming that drives MS progression. This offers a novel therapeutic insight for MS.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1673-1685"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13395003/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147275323","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":"Super-Refractory Status Epilepticus (SRSE) in a Patient With Compound Heterozygous OPA1 Variants: Case Report and Literature Review","authors":"Pouria Mohammadi,&nbsp;Lara Basovic,&nbsp;Christopher Michael McGraw","doi":"10.1002/acn3.70287","DOIUrl":"10.1002/acn3.70287","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Super-Refractory Status Epilepticus (SRSE) is a rare, life-threatening neurological emergency with unclear etiology in many cases. Mitochondrial dysfunction, often due to disease-causing genetic variants, is increasingly recognized as a cause, with each gene producing distinct pathophysiological mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We describe the detailed clinical, neurophysiological, neuroimaging, and molecular findings of a 19-year-old female with SRSE associated with compound heterozygous variants in <i>OPA1</i>, a key gene for mitochondrial inner membrane fusion and cristae maintenance. In addition, a literature review was performed, identifying 16 previously published cases reporting one or both of the variants observed in the present case.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Despite a longstanding history of generalized hypotonia, celiac disease, optic atrophy, cerebellar ataxia, and progressive motor decline, the proband had no prior history of seizures. She developed super-refractory status epilepticus with occipital-predominant epileptiform activity and MRI showing transient diffusion restriction in the right parieto-occipital cortex and cerebellum. Genetic testing revealed a frameshift variant (p.Val903GlyfsTer3) and a missense variant (p.Ile382Met) in the GTPase domain, known to impair mitochondrial fusion. Unlike <i>POLG</i> or MELAS-associated seizures, typically driven by severe mtDNA depletion and respiratory chain failure, <i>OPA1</i> dysfunction usually spares mtDNA copy number but disrupts mitochondrial dynamics. In severe biallelic loss-of-function, a “second-hit” stressor may trigger a diffuse energy crisis and catastrophic seizures.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>This case of mitochondrial SRSE in a patient with no known infectious, autoimmune, or structural cause emphasizes the possible role of genetic background and mitochondrial disorders in the development of the disease. This case highlights a rare mitochondrial subtype of RSE, emphasizing the need to consider energy metabolism defects in unexplained refractory status epilepticus.</p>\u0000 </section>\u0000 </div>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1543-1557"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146155430","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":"Structure–Function Decoupling of the Sensorimotor and Default Mode Networks in Black Americans With MS","authors":"Emilio Cipriano,&nbsp;Giacomo Boffa,&nbsp;Maria Petracca,&nbsp;Marta Ponzano,&nbsp;Nicole Graziano,&nbsp;Claire Wigley,&nbsp;Claire Riley,&nbsp;Jonathan Howard,&nbsp;Pietro Bontempi,&nbsp;Sylvia Klineova,&nbsp;Fred Lublin,&nbsp;Matilde Inglese","doi":"10.1002/acn3.70331","DOIUrl":"10.1002/acn3.70331","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background and Objectives&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Multiple sclerosis (MS) exhibits racially disparate rates of disease progression. Black people with MS (B-PwMS) experience a more severe disease course than non-Hispanic White people with MS (NHW-PwMS). Here we investigated structural and functional connectivity as well as structure–function decoupling in the sensorimotor and default mode networks (SMN and DMN, respectively), which play a key role in determining physical and cognitive disability in people with MS.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;A total of 176 participants (50 B-PwMS, 50 NHW-PwMS, 41 Black healthy controls (B-HCs), and 35 NHW-HCs) underwent 3T-MRI with T1, resting-state functional, &amp; diffusion imaging, and clinical assessment with Expanded-Disability-Status-Scale (EDSS) &amp; Symbol-Digit-Modalities-Test (SDMT). T1-weighted images were lesion-filled and segmented to obtain cortical, subcortical, and cerebellar structures. Diffusion and functional MRI datasets were preprocessed, and structural and functional connectivity were extracted between regions defined by the AAL3 atlas. Global and local network measures were extracted for both structural and functional connectivity, and structure–function decoupling was quantified by calculating the correlation between the strengths of the two networks, considering only edges with non-zero structural connectivity. Network measures were compared between subgroups, accounting for the impact of demographics and social determinants of health, with correction for multiple comparisons.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Despite similar disease duration, treatment exposure, lesion load and brain volumes, B-PwMS exhibited higher EDSS and lower SDMT scores compared to NHW-PwMS, which were influenced by total income and body mass index. In both B- and NHW-PwMS, structural global efficiency and streamline density were lower in the SMN and DMN compared to their respective HCs. Structural characteristic path length in SMN was significantly higher in B-PwMS versus B-HCs, whereas no significant differences were observed in NHW groups. Extensive local rearrangements of structural and functional hubs were observed in the SMN and DMN of B-PwMS compared to B-HCs and NHW-PwMS. B-PwMS showed greater structure–function decoupling in the SMN as compared to the other groups. There was a trend towards a higher decoupling in the DMN with lower SDMT scores (&lt;i&gt;ρ&lt;/i&gt; = −0.20, &lt;i&gt;p&lt;/i&gt; = 0.05), and higher decoupling in the SMN with higher EDSS scores (&lt;i&gt;ρ&lt;/i&gt; = 0.20, &lt;i&gt;p&lt;/i&gt; = 0.06).&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Di","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1558-1568"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146176881","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":"Histopathological Evidence of Neurodegenerative Pathology in Epilepsy: A Systematic Review","authors":"Syeda Amrah Hashmi,&nbsp;Aleksander Luniewski,&nbsp;Vanessa Smith,&nbsp;Matthew McCord,&nbsp;Jaideep Kapur,&nbsp;Mark Quigg,&nbsp;Catherine Joshua,&nbsp;Ifrah Zawar","doi":"10.1002/acn3.70486","DOIUrl":"10.1002/acn3.70486","url":null,"abstract":"<p>Epilepsy affects &gt; 50 million people worldwide and is associated with a disproportionate burden of cognitive impairment. Emerging evidence suggests that neurodegenerative proteinopathies, particularly hyperphosphorylated tau (p-tau) and amyloid-β (Aβ), may contribute to cognitive dysfunction in people with epilepsy (PWE), even in the absence of dementia. However, the prevalence, distribution, and clinical significance of these proteins in epilepsy remain unclear. We conducted a systematic review of neuropathological studies examining neurodegenerative pathology in PWE without primary neurodegenerative disease. The review followed PRISMA guidelines and was registered with PROSPERO (CRD42024612990). A search of PubMed/MEDLINE, Ovid MEDLINE, Ovid Embase, and the Cochrane was performed from database inception to 7/8/2024. Eligible studies included human observational studies, case series, and post-mortem or surgical pathology assessing p-tau, amyloid, TDP-43, or related proteinopathies in PWE. Two reviewers independently screened studies, extracted data, and assessed risk of bias. Forty-two studies met the inclusion criteria. Most studies involved drug-resistant temporal lobe epilepsy (TLE) with hippocampal sclerosis. P-Tau was the most consistently reported finding, identified across multiple epilepsy types with a prevalence ranging from 3%–95%. Amyloid was detected less consistently but occurred in both temporal and extratemporal epilepsies. Several studies reported associations between p-tau burden and seizure frequency, epilepsy duration, and cognitive impairment, particularly in mesial TLE, although findings were heterogeneous. Neurodegenerative pathology, especially p-tau, is frequently observed in epilepsy and may represent a biological link between seizures, hyperexcitability, and cognition. These findings suggest that epilepsy may intersect with neurodegenerative mechanisms and underscore the need for studies integrating neuropathology, biomarkers, and cognitive outcomes.</p>","PeriodicalId":126,"journal":{"name":"Annals of Clinical and Translational Neurology","volume":"13 8","pages":"1530-1542"},"PeriodicalIF":3.9,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13394345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148454023","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}