Annals of Neurology最新文献

{"title":"Subventricular Zone Microstructure in Pediatric-Onset Multiple Sclerosis.","authors":"Monica Margoni, Loredana Storelli, Elisabetta Pagani, Paolo Preziosa, Damiano Mistri, Mor Gueye, Martina Rubin, Lucia Moiola, Massimo Filippi, Maria Assunta Rocca","doi":"10.1002/ana.27180","DOIUrl":"https://doi.org/10.1002/ana.27180","url":null,"abstract":"<p><strong>Objective: </strong>The aim of this study was to explore the microstructural dynamics of the subventricular zone (SVZ) with aging and their associations with clinical disability and brain structural damage in pediatric-onset multiple sclerosis (MS) patients.</p><p><strong>Methods: </strong>One-hundred and forty-one pediatric-onset MS patients (67 pediatric and 74 adults with pediatric-onset) and 233 healthy controls (HC) underwent neurological and 3.0 T MRI assessment. Fractional anisotropy (FA) and mean diffusivity (MD) were extracted from the SVZ and the thalamus (as control region).</p><p><strong>Results: </strong>In HC, SVZ FA was higher until age 40 then declined, whereas MD was lower until age 35 before rising (false discovery rate p value [pFDR] ≤ 0.008). Thalamic FA was higher until age 30 and then declined, whereas MD was higher until age 50 (pFDR ≤ 0.007). Pediatric MS patients showed significantly higher SVZ FA than pediatric HC (pFDR < 0.001), while adult patients showed no differences compared to adult HC (pFDR ≤ 0.724). Adult patients had lower thalamic FA and higher MD (pFDR < 0.001). Adults had lower SVZ FA and MD, but higher thalamic MD compared to pediatric patients (pFDR < 0.001). In pediatric MS, higher SVZ FA and MD were associated with higher white matter (WM) lesion volume (LV) and choroid plexus volume and lower brain and thalamic volumes (pFDR ≤ 0.047). In adult patients, higher SVZ MD associated with higher WM LV, lower brain volumes, and lower z-SDMT (pFDR≤0.019). Thalamic microstructural abnormalities were associated with more severe disability and brain damage in both groups (pFDR ≤ 0.018).</p><p><strong>Interpretation: </strong>Our findings suggest that microstructural changes in the SVZ occur early in pediatric MS and are associated with brain structural damage but not with clinical impairment. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996769","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":"Clinical Relevance of 'Cap' and 'Track' Development after Recent Small Subcortical Infarct.","authors":"Yajun Cheng, Carmen Arteaga-Reyes, Una Clancy, Daniela Jaime Garcia, Maria Del C Valdés Hernández, Michael J Thrippleton, Michael S Stringer, Gordon W Blair, Stewart Wiseman, Francesca M Chappell, Junfang Zhang, Xiaodi Liu, Angela C C Jochems, Susana Muñoz Maniega, Eleni Sakka, Mark E Bastin, Rosalind Brown, Caroline M J Loos, Stephen D J Makin, Ming Liu, Bo Wu, Fergus N Doubal, Joanna M Wardlaw","doi":"10.1002/ana.27182","DOIUrl":"https://doi.org/10.1002/ana.27182","url":null,"abstract":"<p><strong>Objective: </strong>After a recent small subcortical infarct (RSSI), some patients develop perilesional or remote hyperintensities ('caps/tracks') to the index infarct on T2/FLAIR MRI. However, their clinical relevance remains unclear. We investigated the clinicoradiological correlates of 'caps/tracks', and their impact on long-term outcomes following RSSI.</p><p><strong>Methods: </strong>We identified participants with lacunar stroke and MRI-confirmed RSSI from 3 prospective studies. At baseline, we collected risk factors, RSSI characteristics, small vessel disease (SVD) features, and microstructural integrity on diffusion imaging. Over 1-year, we repeated MRI and recorded 'caps/tracks' blinded to other data. We evaluated predictors of 'caps/tracks', and their association with 1-year functional (modified Rankin Scale score ≥2), mobility (Timed Up-and-Go), cognitive outcomes (Montreal Cognitive Assessment [MoCA] score <26), and recurrent cerebrovascular events (stroke/transient ischemic attack/incident infarct) using multivariable regression.</p><p><strong>Results: </strong>Among 185 participants, 93 (50.3%) developed 'caps/tracks' first detected at median 198 days after stroke. 'Caps/tracks' were independently predicted by baseline factors: larger RSSI, RSSI located in white matter, higher SVD score, and higher mean diffusivity in normal-appearing white matter (odds ratio [OR] [95% confidence interval {CI}], 1.15 [1.07-1.25], 6.01 [2.80-13.57], 1.77 [1.31-2.44], 1.42 [1.01-2.03]). At 1 year, 'cap/track' formation was associated with worse functional outcome (OR: 3.17, 95% CI: 1.28-8.22), slower gait speed (β: 0.13, 95% CI: 0.01-0.25), and recurrent cerebrovascular events (hazard ratio [HR]: 2.05, 95% CI: 1.05-4.02), but not with cognitive impairment.</p><p><strong>Interpretation: </strong>'Caps/tracks' after RSSI are associated with worse clinical outcomes, and may reflect vulnerability to progressive SVD-related injury. Reducing 'caps/tracks' may offer early efficacy markers in trials aiming to improve outcome after lacunar stroke. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996755","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Annals of Neurology: Volume 97, Number 2, February 2025","authors":"","doi":"10.1002/ana.26975","DOIUrl":"https://doi.org/10.1002/ana.26975","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 2","pages":"C1"},"PeriodicalIF":8.1,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.26975","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143116111","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":"Diagnosing Epilepsy with Normal Interictal EEG Using Dynamic Network Models.","authors":"Patrick Myers, Kristin M Gunnarsdottir, Adam Li, Vlad Razskazovskiy, Jeff Craley, Alana Chandler, Dale Wyeth, Edmund Wyeth, Kareem A Zaghloul, Sara K Inati, Jennifer L Hopp, Babitha Haridas, Jorge Gonzalez-Martinez, Anto Bagíc, Joon-Yi Kang, Michael R Sperling, Niravkumar Barot, Sridevi V Sarma, Khalil S Husari","doi":"10.1002/ana.27168","DOIUrl":"10.1002/ana.27168","url":null,"abstract":"<p><strong>Objective: </strong>Whereas a scalp electroencephalogram (EEG) is important for diagnosing epilepsy, a single routine EEG is limited in its diagnostic value. Only a small percentage of routine EEGs show interictal epileptiform discharges (IEDs) and overall misdiagnosis rates of epilepsy are 20% to 30%. We aim to demonstrate how network properties in EEG recordings can be used to improve the speed and accuracy differentiating epilepsy from mimics, such as functional seizures - even in the absence of IEDs.</p><p><strong>Methods: </strong>In this multicenter study, we analyzed routine scalp EEGs from 218 patients with suspected epilepsy and normal initial EEGs. The patients' diagnoses were later confirmed based on an epilepsy monitoring unit (EMU) admission. About 46% ultimately being diagnosed with epilepsy and 54% with non-epileptic conditions. A logistic regression model was trained using spectral and network-derived EEG features to differentiate between epilepsy and non-epilepsy. Of the 218 patients, 90% were used for training and 10% were held out for testing. Within the training set, 10-fold cross validation was performed. The resulting tool was named \"EpiScalp.\"</p><p><strong>Results: </strong>EpiScalp achieved an area under the curve (AUC) of 0.940, an accuracy of 0.904, a sensitivity of 0.835, and a specificity of 0.963 in classifying patients as having epilepsy or not.</p><p><strong>Interpretation: </strong>EpiScalp provides an accurate diagnostic aid from a single initial EEG recording, even in more challenging epilepsy cases with normal initial EEGs. This may represent a paradigm shift in epilepsy diagnosis by deriving an objective measure of epilepsy likelihood from previously uninformative EEGs. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142996758","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":"ANA Podcasts and Webinars: Minimally Invasive Epilepsy Surgery","authors":"Ioannis Karakis MD, PhD, MSc,&nbsp;Adeline L. Goss MD,&nbsp;Jessica W. Templer MD,&nbsp;Michelle C. Johansen MD, PhD,&nbsp;Jon T. Willie MD, PhD, FAANS","doi":"10.1002/ana.27183","DOIUrl":"https://doi.org/10.1002/ana.27183","url":null,"abstract":"","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"407-408"},"PeriodicalIF":8.1,"publicationDate":"2025-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143423540","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":"Genetic Ablation of Sarm1 Mitigates Disease Acceleration after Traumatic Brain Injury in the SOD1^G93A Transgenic Mouse Model of Amyotrophic Lateral Sclerosis.","authors":"Elif O Dogan, Sean R Simonini, James Bouley, Alexandra Weiss, Robert H Brown, Nils Henninger","doi":"10.1002/ana.27174","DOIUrl":"https://doi.org/10.1002/ana.27174","url":null,"abstract":"<p><strong>Objective: </strong>Approximately 20% of familial cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Epidemiological data have identified traumatic brain injury (TBI) as an exogenous risk factor for ALS; however, the mechanisms by which TBI may worsen SOD1 ALS remain largely undefined.</p><p><strong>Methods: </strong>We sought to determine whether repetitive TBI (rTBI) accelerates disease onset and progression in the transgenic SOD1^G93A mouse ALS model, and whether loss of the primary regulator of axonal degeneration sterile alpha and TIR motif containing 1 (Sarm1) mitigates the histological and behavioral pathophysiology. We subjected wild-type (n = 23), Sarm1 knockout (KO; n = 17), SOD1^G93A (n = 19), and SOD1^G93AxSarm1^KO (n = 26) mice of both sexes to rTBI or sham surgery at age 64 days (62-68 days). Body weight and ALS-deficit score were serially assessed up to 17 weeks after surgery and histopathology assessed in layer V of the primary motor cortex at the study end point.</p><p><strong>Results: </strong>In sham injured SOD1^G93A mice, genetic ablation of Sarm1 did not attenuate axonal loss, improve neurological deficits, or survival. The rTBI accelerated onset of G93A-SOD1 ALS, as indicated by accentuated body weight loss, earlier onset of hindlimb tremor, and shortened survival. The rTBI also triggered TDP-43 mislocalization, enhanced axonal and neuronal loss, microgliosis, and astrocytosis. Loss of Sarm1 significantly diminished the impact of rTBI on disease progression and rescued rTBI-associated neuropathology.</p><p><strong>Interpretation: </strong>SARM1-mediated axonal death pathway promotes pathogenesis after TBI in SOD1^G93A mice suggesting that anti-SARM1 therapeutics are a viable approach to preserve neurological function in injury-accelerated G93A-SOD1 ALS. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941771","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":"Early-Life Adversity Predicts Markers of Aging-Related Neuroinflammation, Neurodegeneration, and Cognitive Impairment in Women","authors":"Lara Fleck MSc,&nbsp;Claudia Buss PhD,&nbsp;Martin Bauer MSc,&nbsp;Maike Stein MD,&nbsp;Ralf Mekle PhD,&nbsp;Lena Kock MSc,&nbsp;Heiko Klawitter MSc,&nbsp;Malvika Godara PhD,&nbsp;Judith Ramler MSc,&nbsp;Sonja Entringer PhD,&nbsp;Matthias Endres MD,&nbsp;Christine Heim PhD","doi":"10.1002/ana.27161","DOIUrl":"10.1002/ana.27161","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Despite the overwhelming evidence for profound and longstanding effects of early-life stress (ELS) on inflammation, brain structure, and molecular aging, its impact on human brain aging and risk for neurodegenerative disease is poorly understood. We examined the impact of ELS severity in interaction with age on blood-based markers of neuroinflammation and neurodegeneration, brain volumes, and cognitive function in middle-aged women.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We recruited 179 women (aged 30–60 years) with and without ELS exposure before the onset of puberty. Using Simoa technology, we assessed blood-based markers of neuroinflammation and neurodegeneration, including serum concentrations of glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL). We further obtained T1-weighted and T2-weighted magnetic resonance images to assess brain volumes and we assessed cognitive performance sensitive to early impairments associated with the development of dementia, using the Cambridge Neuropsychological Automated Test Battery. We used generalized additive models to examine nonlinear interaction effects of ELS severity and age on these outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Analyses revealed significant nonlinear interaction effects of ELS severity and age on NfL and GFAP serum concentrations, total and subcortical gray matter volume loss, increased third ventricular volume, and cognitive impairment.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>These findings suggest that ELS profoundly exacerbates peripheral, neurostructural, and cognitive markers of brain aging. Our results are critical for the development of novel early prevention strategies that target the impact of developmental stress on the brain to mitigate aging-related neurological diseases. ANN NEUROL 2025;97:642–656</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 4","pages":"642-656"},"PeriodicalIF":8.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27161","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941768","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":"Automated Detection of Isolated REM Sleep Behavior Disorder Using Computer Vision.","authors":"Mohamed Abdelfattah, Li Zhou, Oliver Sum-Ping, Anahid Hekmat, Joanna Galati, Niraj Gupta, George Adaimi, Salonee Marwaha, Ankit Parekh, Emmanuel Mignot, Alexandre Alahi, Emmanuel During","doi":"10.1002/ana.27170","DOIUrl":"10.1002/ana.27170","url":null,"abstract":"<p><strong>Objective: </strong>Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) is, in most cases, an early stage of Parkinson's disease or related disorders. Diagnosis requires an overnight video-polysomnogram (vPSG), however, even for sleep experts, interpreting vPSG data is challenging. Using a 3D camera, automated analysis of movements has yielded high accuracy. We aimed to replicate and extend prior work using a conventional 2D camera.</p><p><strong>Methods: </strong>The dataset included 172 vPSG recordings from a clinical sleep center, 81 patients with iRBD and 91 non-RBD healthy controls (63 with a range of other sleep disorders and 28 healthy sleepers). An optical flow computer vision algorithm automatically detected movements during rapid eye movement (REM) sleep, from which features of rate, ratio, magnitude and velocity of movements, and ratio of immobility were extracted.</p><p><strong>Results: </strong>Patients with iRBD exhibited an increased number of shorter movements and immobility periods. Accuracies for detecting iRBD ranged from 84.9% (with 2 features) to 87.2% (with 5 features). Combining all 5 features but only analyzing short (0.1-2 second duration) movements achieved the highest accuracy at 91.9%. Of the 11 patients with iRBD without noticeable movements during vPSG, 7 were correctly identified.</p><p><strong>Interpretation: </strong>This work improves prior art by using a 2D camera routinely used in sleep laboratories and improving performance by adding only 3 features. This approach could be implemented in clinical sleep laboratories to facilitate and improve the diagnosis of iRBD. Coupled with automated detection of REM sleep, it should also be tested in the home environment using conventional infrared cameras to detect and/or monitor RBD. ANN NEUROL 2025.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941766","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":"Inflammation in Cerebral Amyloid Angiopathy-Related Transient Focal Neurological Episodes","authors":"Amina Sellimi MD,&nbsp;Larysa Panteleienko MD, PhD,&nbsp;Dermot Mallon MD, PhD,&nbsp;Simon Fandler-Höfler MD, PhD,&nbsp;Rupert Oliver MD, PhD,&nbsp;Victoria Harvey Sc, PGDip,&nbsp;Michael S. Zandi PhD,&nbsp;Gargi Banerjee MD, PhD,&nbsp;David J. Werring MD, PhD","doi":"10.1002/ana.27164","DOIUrl":"10.1002/ana.27164","url":null,"abstract":"<p>Transient focal neurological episodes (TFNE), often associated with convexity subarachnoid hemorrhage (cSAH), are common in cerebral amyloid angiopathy (CAA), but their pathophysiology remains incompletely understood. In six patients with unremitting TFNE, using high-resolution post-contrast magnetic resonance imaging and vessel wall imaging (VWI), we found various combinations of transient leptomeningeal, parenchymal and vessel wall enhancement; in 5 of 6 the enhancement included regions corresponding anatomically to symptoms. Three patients had resolution of TFNE and enhancement (2 with corticosteroid treatment, 1 without). Our observations suggest that inflammation might contribute to the pathophysiology of CAA-related TFNE and cSAH, with potential wider relevance for the associated high risks of recurrent ICH in CAA more generally. ANN NEUROL 2025;97:475–482</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 3","pages":"475-482"},"PeriodicalIF":8.1,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ana.27164","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142941773","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":"Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients","authors":"Chiseko Ikenaga MD, PhD,&nbsp;Andrew B. Wilson PhD,&nbsp;Katherine E. Irwin MS,&nbsp;Aswathy Peethambaran Mallika PhD,&nbsp;Collin Kilgore MS,&nbsp;Irika R. Sinha MS,&nbsp;Elizabeth H. Michelle MD,&nbsp;Jonathan P. Ling PhD,&nbsp;Philip C. Wong PhD,&nbsp;Thomas E. Lloyd MD, PhD","doi":"10.1002/ana.27167","DOIUrl":"10.1002/ana.27167","url":null,"abstract":"<div>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by endomysial inflammation, rimmed vacuoles, and cytoplasmic mislocalization of transactive response DNA-binding protein 43 (TDP-43). We aimed to determine whether loss of TDP-43 splicing repression led to the production of “cryptic peptides” that could be detected in muscle biopsies as a useful biomarker for IBM.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used an antisera against a neoepitope encoded by a TDP-43-dependent cryptic exon within hepatoma-derived growth factor-like protein 2 (<i>HDGFL2</i>) for immunohistochemical analysis on muscle biopsy samples of 122 patients with IBM, 181 disease controls, and 16 healthy controls without abnormal muscle pathology. In situ hybridization was also utilized to detect the localization of cryptic <i>HDGFL2</i> transcripts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>We found cryptic <i>HDGFL2</i> peptides localized within myonuclei from muscle biopsies in 79 of 122 patients with IBM (65%), and this staining correlated with TDP-43 depletion. In contrast, cryptic <i>HDGFL2</i> immunoreactivity was absent in 197 muscle biopsies from a variety of disease controls, except for 2 patients with vacuolar myopathies. Notably, we show that cryptic <i>HDGFL2</i> transcripts are accompanied by the detection of cryptic <i>HDGFL2</i> in muscle fibers of IBM without rimmed vacuoles and TDP-43 aggregates.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Interpretation</h3>\u0000 \u0000 <p>Together, our findings establish that loss of TDP-43 splicing repression occurs in myonuclei of IBM skeletal muscle and suggest that detection of cryptic peptides in muscle biopsies may be a useful biomarker. We suggest that a therapeutic strategy designed to restore TDP-43 function should be considered to attenuate the degeneration of skeletal muscle in this devastating disease. ANN NEUROL 2025;97:629–641</p>\u0000 </section>\u0000 </div>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":"97 4","pages":"629-641"},"PeriodicalIF":8.1,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930092","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}