Journal of Neuropathology and Experimental Neurology最新文献

{"title":"An open-source application for automated quantification of Ki-67 proliferative index in meningiomas.","authors":"Aaishah R Raquib, Steven N Schwartz, Shan H Siddiqi, Hemant Varma","doi":"10.1093/jnen/nlag083","DOIUrl":"https://doi.org/10.1093/jnen/nlag083","url":null,"abstract":"<p><p>Ki-67 is a proliferative biomarker used for diagnosis, grading, and prognosis of various cancer types. This involves manually counting up to 1000 cells, a laborious and error-prone process due to interobserver variability. We developed and validated an open access automated tool for quantification of Ki-67-positive cells in meningiomas, the most common primary brain tumor. The automated counting algorithm was trained using immunohistochemical Ki-67-stained sections from 10 meningioma samples and tested on another 50 meningioma samples. Automated counts were compared to manual counts from 2 independent observers using intraclass correlations (ICC) and Pearson correlation. The 2 observers yielded similar counts across all 50 slides (ICC = 0.802, Pearson r = 0.77). The automated count showed significantly greater correlation with both manual counts (ICC = 0.94, P = 2.5×10-5; ICC = 0.90, P = 0.011). The Pearson correlation between the automated count and both manual counts (r = 0.89 in both cases) was significantly stronger than the correlation between the 2 manual counts (P < 10-6 in each case). Thus, the automated Ki-67 count predicted both manual counts better than manual counts predicted each other. The algorithm is freely available as a web application (https://Ki67.app) and as open-source code (https://github.com/aaishahraquib/Ki67-counter). This freely available counter will provide a user-friendly, time efficient, and accurate resource for practicing pathologists.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"When muscles matter in SORD neuropathy.","authors":"Heike Kölbel, Andreas Hentschel, Corinna Preuße, May Tiet, Maike F Dohrn, David Muhmann, Jelle van den Ameele, Lei Chen, Ulrike Schara-Schmidt, Joachim Weis, Rita Horvath, Alexander Mensch, Andreas Roos","doi":"10.1093/jnen/nlag057","DOIUrl":"https://doi.org/10.1093/jnen/nlag057","url":null,"abstract":"<p><p>Biallelic pathogenic variants in SORD (Sorbitoldehydrongenase gene), encoding sorbitol dehydrogenase, are a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease type 2 (CMT2). Recent evidence suggests direct involvement of skeletal muscle in addition to peripheral nerve degeneration. We investigated muscle biopsies from 4 genetically confirmed CMT-SORD patients using an integrative approach. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, ie, non-specific neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum (SR). Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement and immunomodulatory factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodeling. Despite mitochondrial vulnerability, serum studies indicated that GDF-15 and FGF-21 did not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as intrinsic myopathic features of SORD-related CMT2. They indicate the need for therapeutic strategies targeting both neuronal and muscular compartments.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148794539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proliferation patterns across meningioma locations: A WHO grade-based analysis.","authors":"Neşe Yeldir, Mohammad Sargolzaeimoghaddam, Maral Sargolzaeimoghaddam, Aslı Çakır, Zeki Şekerci","doi":"10.1093/jnen/nlag090","DOIUrl":"10.1093/jnen/nlag090","url":null,"abstract":"<p><p>Meningiomas are the most common primary central nervous system tumors and their biological behavior is closely related to histopathological grade and proliferative activity. This study investigated the associations between World Health Organization (WHO) grade, tumor location, mitotic activity, and Ki-67 labeling index in previously untreated meningiomas. We retrospectively analyzed 298 surgically treated primary meningiomas diagnosed between 2013 and 2025, re-evaluated according to the 2021 WHO Classification of Central Nervous System Tumors. Mitotic counts and Ki-67 labeling indices were assessed in hotspot areas. Associations between proliferation markers, grade, and anatomical location were analyzed statistically, and receiver operating characteristic (ROC) analyses determined optimal cut-off values. Of the tumors, 55.0% were WHO Grade 1, 41.6% Grade 2, and 3.4% Grade 3. Both markers increased significantly with grade and showed a strong positive correlation (ρ = 0.79, P < .001). Convexity meningiomas were associated with higher grades and increased proliferative activity, whereas skull base and spinal tumors predominantly exhibited lower grades and lower proliferation indices. ROC analyses demonstrated comparable discriminatory performance for Ki-67 and mitotic counts across WHO grades. In summary, proliferation markers strongly correlate with WHO grade and vary by tumor location, supporting their combined value in meningioma risk stratification.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148723006","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Drug-induced autophagic myopathies: Exploring pathophysiology with immunolabelling and proteomics.","authors":"Beatrice Labella, Sarah Leonard-Louis, Emmanuelle Lacene, Maud Beuvin, Anaïs Chanut, Angeline Madelaine, Guy Brochier, Clémence Labasse, Thierry Maisonobe, Olivier Benveniste, Claire Lefeuvre, Clément Guémy, Pascal Laforêt, Angèle N Merlet, Léonard Féasson, Andreas Hentschel, Andreas Roos, Teresinha Evangelista","doi":"10.1093/jnen/nlag074","DOIUrl":"https://doi.org/10.1093/jnen/nlag074","url":null,"abstract":"<p><p>Hydroxychloroquine (HCQ), chloroquine (CQ), and colchicine are widely used to treat autoimmune and inflammatory diseases but can cause toxic autophagic vacuolar myopathies. This study investigates the pathological mechanisms of HCQ/CQ- and colchicine-induced myopathies through integrated clinical, histopathological, ultrastructural, and proteomic analyses. Nine patients with clinicopathologically defined toxic myopathy (HCQ/CQ, n = 4; colchicine, n = 5) were included. Muscle biopsies were analyzed using histoenzymology, immunohistochemistry for autophagic and immune markers, electron microscopy, and proteomic profiling in selected cases. Clinically, both groups presented with proximal muscle weakness and myalgia after variable drug exposure. Histology revealed rimmed and non-rimmed vacuoles, especially in HCQ/CQ cases, and myofibrillar disorganization; the latter predominated in colchicine-treated patients. Electron microscopy confirmed myofibrillar disruption in colchicine-treated patients and autophagosomes with curvilinear bodies in HCQ/CQ cases. Immunohistochemistry showed MHC-I upregulation, heterogeneous C5b-9 deposition, and accumulation of LC3 and p62, with evidence of endoplasmic reticulum stress and transcriptional dysregulation by GRP170 overexpression and cytoplasmic MeCP2 redistribution. Proteomic analysis revealed a shared molecular signature involving immune activation, extracellular matrix remodeling, cytoskeletal stress, mitochondrial dysfunction, and dysregulation of the autophagy-lysosome pathway. Overall, HCQ/CQ- and colchicine-induced myopathies converge on common mechanisms of autophagic impairment, immune activation, and disrupted muscle homeostasis.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148697534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phosphorylation‑independent monoclonal antibody improves detection of TDP‑43 pathology across frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and limbic predominant age related TDP‑43 encephalopathy neuropathological change.","authors":"Xiaojing Zheng, Ning Zhang, Lixia Wang, Hongjuan Zhao, ChengGang Liu, Jiayu Wang, Wanli Zhao, Junli Zhao, Peiyan Yang, Lorraina Robinson, Lindsay Hunt, Alex Lokken, Leo Lin, Peter T Nelson, Julia Kofler, Hehuang Xie, Haibin Xia, Qinwen Mao","doi":"10.1093/jnen/nlag085","DOIUrl":"10.1093/jnen/nlag085","url":null,"abstract":"<p><p>TDP-43 proteinopathies encompass frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP), amyotrophic lateral sclerosis (ALS-TDP), and limbic predominant age related TDP-43 encephalopathy neuropathological change (LATE-NC). These proteinopathies exhibit subtype-specific aggregate architectures that may constrain epitope accessibility in situ. We compared a phosphorylation-independent monoclonal antibody targeting a C-terminal epitope (MAb No. 9) with the phospho-specific pSer409/410 antibody to determine whether its signal relates to regional neurodegeneration in a multicenter autopsy cohort spanning FTLD-TDP types A-C, ALS-TDP, and Alzheimer disease neuropathologic change (ADNC) with or without LATE-NC. Immunolabeling with MAb No. 9 detected pathological TDP-43 across all diagnostic groups with enhanced labeling of dystrophic neurites and thread/dot-like pathology in FTLD-TDP types A/B and in ALS-TDP. MAb No. 9 performance was equivalent to p409/410 in FTLD-TDP type C. In ADNC with stage 3 LATE-NC, MAb No. 9 revealed a greater limbic burden and labeled both α type and β type inclusions. Dual label immunofluorescence demonstrated strong spatial overlap with p409/410 but additionally highlighted fine punctate pathology. MAb No. 9 burden in FTLD-TDP type A correlated strongly with cortical neurodegeneration but showed weaker and variable associations, particularly in severely atrophic cortex. These findings indicate that filament architecture governs C-terminal epitope accessibility and that MAb No. 9 may be a complementary tool for subtype refinement, clinicopathologic correlation and translational biomarker development in TDP-43 proteinopathies.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13589412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148685110","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MN1 rearrangement detected by FISH analysis in a neuroepithelial tumor with EWSR1::PATZ1 demonstrating ependymoma-like and astroblastoma-like histology: A diagnostic pitfall.","authors":"Takahiro Shirakura, Hajime Yonezawa, Yasuhito Arai, Natsuko Hama, Kohei Fukuoka, Ayako Yamazaki, Mari Kirishima, Akihiko Yoshida, Hideaki Yokoo, Tatsuhiro Shibata, Ryosuke Hanaya, Sumihito Nobusawa","doi":"10.1093/jnen/nlag087","DOIUrl":"https://doi.org/10.1093/jnen/nlag087","url":null,"abstract":"","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.3,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148701524","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal neuropathologic and molecular characterization of a retroperitoneal ependymoma.","authors":"Emily Ling-Lin Pai, Matthew N Nazarian, Alicia L Kenyon, Zied Abdullaev, Maria Arisi, Erika S Johnson, Lea F Surrey, Martha Quezado, Lauren E Schwartz, Kimberly L Dumoff, Kumarasen Cooper, Kenneth Aldape, Lawrence Kenyon, MacLean P Nasrallah, Arati S Desai","doi":"10.1093/jnen/nlaf143","DOIUrl":"10.1093/jnen/nlaf143","url":null,"abstract":"","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":"913-917"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145819775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced nuclear TDP-43 and cytoplasmic DLK1 as markers of motor neuron degeneration in amyotrophic lateral sclerosis.","authors":"Takahiro Takeda, Ai Ishikawa, Sayuri Kokubun, Yumiko Saito, Sagiri Isose, Kimiko Ito, Kimihito Arai, Satoshi Kuwabara, Kazuhiro Honda","doi":"10.1093/jnen/nlag017","DOIUrl":"10.1093/jnen/nlag017","url":null,"abstract":"<p><p>Loss of upper and lower motor neurons (MNs) is a defining pathological feature underlying the clinical manifestations of amyotrophic lateral sclerosis (ALS). However, the differences in MN loss and TDP-43 pathology between these areas in ALS patients remain unclear. This study included 7 patients with ALS and 3 controls from consecutive autopsies. The cell density and regional density of TDP-43-positive inclusions in 4 upper MN areas and their anatomically corresponding lower MN areas were measured. The numbers of large cells with loss of nuclear TDP-43 and cytoplasmic delta-like-1 homolog (DLK1) were counted. The results showed severe MN loss in both upper and lower MN areas. However, TDP-43-positive inclusions differed markedly, that is they were rare in upper MNs but abundant in lower MN. In upper MN areas, TDP-43 density was not associated with the residual rate of MNs, whereas in lower MN areas, the density in MNs was associated with the cell residual rate. Significantly higher numbers of MNs lacking nuclear TDP-43 and cytoplasmic DLK1 were observed in the upper and lower MN regions in ALS vs controls. These findings suggest that these morphological changes may be closely related to motor neuron vulnerability and may be mechanistic contributors to ALS development.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":"881-893"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147480964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of concurrent neuropathologies with Alzheimer disease neuropathologic change on cognitive decline: Minimal impact of vascular brain injury compared with other combinations.","authors":"Sarah M Yasuda, Charles Mock, Kathryn Gauthreaux, Kwun C G Chan, C Dirk Keene, Jessica E Culhane, Yen-Chi Chen, Walter Kukull","doi":"10.1093/jnen/nlag033","DOIUrl":"10.1093/jnen/nlag033","url":null,"abstract":"<p><p>We examined cognitive changes associated with several neuropathologic entities, alone and in combination. We studied 808 participants from the National Alzheimer's Coordinating Center to assess associations between neuropathologic diagnoses (from autopsy) and neuropsychologic test scores (trajectories over time for 5 domains: overall cognition, episodic memory, attention, language, executive function). Neuropathologies included: Alzheimer disease neuropathologic change (ADNC), Lewy body disease (LBD), vascular brain injury (VBI), and limbic-predominant age-related TDP43 encephalopathy neuropathologic change (LATE-NC). Using linear mixed-effects models, we examined trajectories of cognitive decline for ADNC alone compared to ADNC plus LBD, VBI, or LATE-NC. We also examined differences between observed trajectories and trajectories that would be expected if the neuropathologic entities exerted their effects independently (additively). ADNC+LBD had worse decline than ADNC alone for 4 of the 5 domains with rate of decline consistent with an additive model for all 4 domains. ADNC+LATE-NC had worse decline than ADNC alone for 3 domains with rate of decline additive for only one and <additive for 2. ADNC+VBI had worse decline than ADNC alone for only one domain, with rate of decline <additive. These findings are relevant for prognostication in clinical practice and for clinical trial design.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":"857-867"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13374727/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147774525","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer neuropathological change, α-synuclein and transactive response DNA-binding protein of 43 kDa expression in children and young adult brains from forensic autopsies: Value for early measurement of abnormal protein expression prevalence in neurodegenerative diseases.","authors":"Lilian Calderón-Garcidueñas, Ozkan Ufuk Nalbantoglu, Angélica González-Maciel, Ricardo Torres-Jardón","doi":"10.1093/jnen/nlag028","DOIUrl":"10.1093/jnen/nlag028","url":null,"abstract":"<p><p>Alzheimer disease (AD) neuropathologic change (ADNPC), Parkinson disease (PD) α-synuclein (α-Syn), and TAR DNA-binding protein 43 (TDP-43) pathology overlap in a continuum in fine particulate matter (PM2.5)-exposed Metropolitan Mexico City (MMC) children and young adult forensic autopsy brains. This report focuses on a forensic targeted immunohistochemistry protocol to assess ADNPC, α-Syn and TDP-43 in ≤40y subjects, and to define their relationship with cumulative PM2.5 (CPM) exposures. We proposed an early measurement of abnormal protein expression to evaluate neurodegenerative disease prevalence in exposed PM2.5 urban young populations. We studied 189 autopsies average age 26±10y, including 179 MMC ≤40y olds and 10 low pollution controls. Among MMC adults 18-40y, 11.3% exhibited ADNPC alone; 50% had ADNPC + PD, 32.0% had ADNPC + PD + TDP-43 and 6.7% had ADNPC + TDP-43 pathology. In 37 children (13.0±4.8y), 24.3% had ADNPC, 37.8% had ADNPC + PD, 32.4% had ADNPC + PD + TDP-43; 5.4% had ADNPC + TDP-43 pathology. The overlapping children's neuropathology was documented under low CPM. We suggest that measurements of abnormal protein expression to evaluate neurodegenerative disease in young PM2.5-exposed young urban populations in US autopsies will define the prevalence and overlap of early neurodegenerative biological markers. This information guide preventive medicine, health services, environmental PM2.5 emission control and early neuroprotection from potentially preventable air pollution-associated neurodegenerative diseases.</p>","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":"894-902"},"PeriodicalIF":3.3,"publicationDate":"2026-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13440675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147729201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}