Acta Neuropathologica Communications最新文献

{"title":"Accurate detection of pathologic α-synuclein in CSF, skin, olfactory mucosa, and urine with a uniform seeding amplification assay.","authors":"Remarh Bsoul, Oskar H McWilliam, Gunhild Waldemar, Steen G Hasselbalch, Anja H Simonsen, Christian von Buchwald, Magne Bech, Clara H Pinborg, Christian K Pedersen, Sara O Baungaard, José Lombardía, Patrick Ejlerskov, Matilde Bongianni, Erika Bronzato, Gianluigi Zanusso, Kristian S Frederiksen, Eva L Lund, Aušrinė Areškevičiūtė","doi":"10.1186/s40478-025-02034-8","DOIUrl":"10.1186/s40478-025-02034-8","url":null,"abstract":"<p><p>Currently, early diagnosis of dementia with Lewy bodies (DLB) is based on clinical criteria, which is challenging due to overlapping symptoms with other neurodegenerative diseases. Seeding amplification assays, detecting minute amounts of disease causing α-synuclein (αSyn^D), are emerging as a promising diagnostic tool for α-synucleinopathies including DLB and Parkinson's disease. This study aimed to test whether the same seeding amplification assay established for αSyn^D detection in cerebrospinal fluid (CSF) could be applied to other biospecimens, including skin, olfactory mucosa, saliva, and urine, obtained from the same patients. A total of 31 patients with probable DLB and 53 healthy controls were recruited. When evaluating the assays' applicability to different biospecimens, only those collected from participants with a positive CSF αSyn^D result were considered. Seeding amplification assay results were evaluated based on the αSyn^D amplification rate over 48 h and the value of the area under the curve. The sensitivity and specificity were 94% and 98% for skin, 47% and 100% for olfactory mucosa, and 22% and 100% for urine, respectively for the CSF positive DLB and healthy controls. αSyn^D was undetectable in saliva. Cohen's Kappa analysis (κ) showed almost perfect agreement between CSF and skin assays (κ = 0.86) but slight to no agreement for CSF versus olfactory mucosa (κ = 0.12) and urine (κ = 0.094). In summary, the seeding amplification assay established for αSyn^D detection in CSF demonstrated comparable diagnostic performance in minimally invasive skin biopsies. Olfactory mucosa, saliva, and urine sample preparation pose technical challenges resulting in the established assays' low diagnostic accuracy, for now, limiting their use in diagnostics. Nevertheless, the proof-of-concept for αSyn^D detection in urine expands the potential for non-invasive diagnostics of α-synucleinopathies in the future.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"113"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141092","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":"Glioneuronal tumors PATZ1-fused: clinico-molecular and DNA methylation signatures for a variety of morphological and radiological profiles.","authors":"Arnault Tauziède-Espariat, Volodia Dangouloff-Ros, Philipp Sievers, Mathilde Duchesne, Aurore Siegfried, Yvan Nicaise, Nathalie Boddaert, Lauren Hasty, Alice Métais, Carine Ngo, François le Loarer, Corinne Bouvier, Alix Fontaine, Audrey Rousseau, Florent Marguet, Kévin Beccaria, Thomas Blauwblomme, Emmanuelle Uro-Coste, Pascale Varlet","doi":"10.1186/s40478-025-02037-5","DOIUrl":"10.1186/s40478-025-02037-5","url":null,"abstract":"<p><p>The neuroepithelial tumor, PATZ1-fused (NET-PATZ1), has been recently isolated as a distinct methylation class by DNA-methylation profiling and is characterized by recurrent PATZ1 fusions, in association with the EWSR1 or MN1 genes and a chromosome 22 chromothripsis. The clinical phenotype is mainly pediatric and features circumscribed supratentorial tumors. However, the histopathology is vastly heterogeneous (glial, glioneuronal, sarcomatous, multiphenotypic) and a cell of origin has not yet been identified, explaining the previsionary imprecise terminology of \"NET\". Moreover, extra-central nervous system (CNS) sarcomas also harboring the EWSR1::PATZ1 fusion have been reported and added to the current World Health Organization (WHO) Classification of Soft Tissue and Bone Tumors, in the chapter on undifferentiated small round cell sarcomas. However, their relationship to their CNS counterparts has not yet been studied. Herein, we analyzed a cohort of twelve CNS tumors with PATZ1 fusions in terms of clinical presentation, radiology, histopathology, immunohistochemistry, ultrastructure and DNA-methylation profiling and compared them to five extra-CNS sarcomas-PATZ1. Based on the reported GATA2 overexpression in NET-PATZ1, we also studied the potential interest of GATA2 immunoexpression as a diagnostic tool. We confirmed their distinct molecular characteristics and clinical phenotype but evidenced a morphological intratumoral heterogeneity with three recurrent morphological patterns (oligodendroglial-like, pleomorphic xanthoastrocytoma-like and spindle cells). Despite the unusual spindle and proliferative component in a CD34 + glioneuronal tumor (using electronic microscopy), these tumors present a favorable prognosis. Their histopathological features were all clearly distinct from their soft tissue counterparts. GATA2 immunostaining is highly specific for CNS tumors PATZ1-fused, but its sensitivity is perfectible and further studies are needed to confirm its use as a diagnostic tool. To conclude, our work highlights that CNS tumors, PATZ1-fused seem to represent a novel pediatric glioneuronal tumor type exhibiting a polymorphous morphology and provides new support for its addition as a provisional emerging pediatric circumscribed glioneuronal tumor type, low grade.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"114"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141054","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":"Experimental evidence that readily diffusible forms of Aβ from Alzheimer's disease brain have seeding activity.","authors":"Simin Song, Qianmin Liu, Ruixiang Chen, Ping Chen, Min Tao, Siyao Li, Liping Guo, Xixi Zhu, Yan Liu, Lu Liu, Hiroki Sasaguri, Takashi Saito, Takaomi C Saido, Dominic M Walsh, Zhangjin Zhang, Wei Hong","doi":"10.1186/s40478-025-02032-w","DOIUrl":"10.1186/s40478-025-02032-w","url":null,"abstract":"<p><p>Significant data suggest that cerebral accumulation of the amyloid β-protein (Aβ) plays an initiating role in Alzheimer's disease (AD), however, Aβ can exist in multiple different forms and it is not clear which of these contribute to the propagation of amyloid or toxicity. When injected into animal models, Aβ-containing homogenates from AD or APP transgenic mouse brain accelerate amyloid pathology, but the nature of the seeding species remain ill-defined. In this study, we took advantage of well-characterized brain extracts from human AD cases and App^NL-F/NL-F mice, to assess the seeding activity of diffusible forms of Aβ. Extracts containing readily diffusible forms of Aβ, (which we refer to as S extracts) are obtained by soaking tissue slices in physiological buffer and removing large non-diffusing material by centrifugation. Such AD brain S extracts are potent neuritotoxins and contain a broad range of different sized forms Aβ. When tested at approximately ten months after a single intracerebral injection of AD brain S extract, App^NL-F/NL-F mice exhibited a significant perturbation of learned behavior, together with accelerated cerebral amyloid deposition, microgliosis, astrocytosis, neuronal dystrophy and synaptic loss. Importantly, inoculation of App^NL-F/NL-F mice with S extract from a human control brain altered neither the memory of learned behavior nor the appearance of amyloid and associated pathologies. These results indicate that diffusible forms of Aβ derived from AD brain can readily induce aggregation of endogenous Aβ and accelerate negative outcomes associated with Aβ accumulation.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"112"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102860/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144131971","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":"Viral-mediated knockdown of Atxn2 attenuates TDP-43 pathology and muscle dysfunction in the PFN1^C71G ALS mouse model.","authors":"Zachary C E Hawley, Xueying Li, Dora Bodnar, Yuanzheng Gu, Yi Luo, Daniel Ferretti, Adam Sheehy, Rachelle Driscoll, Maria I Zavodszky, Shaolong Cao, Isabel Isaza, Luke Jandreski, Yuqing Liu, Thomas Carlile, Shih-Ching Lo, Anna Grimard, Shawn Bourque, Aditya Utturkar, Samantha Desmarais, H Moore Arnold, Dann Huh, Edward Guilmette, Deborah Y Kwon","doi":"10.1186/s40478-025-02005-z","DOIUrl":"10.1186/s40478-025-02005-z","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron loss and muscle atrophy. Hyperphosphorylated aggregation of the RNA-binding protein, TDP-43, in the motor cortex and spinal cord are defining molecular features of ALS, suggesting TDP-43 dysfunction underlies disease pathogenesis. This phenomenon, however, has been difficult to recapitulate endogenously in animal models, impeding characterization of TDP-43 pathobiology in neurodegeneration. In this study, we report age-dependent accumulation of TDP-43 pathology in the spinal cord and progressive muscle-related deficits in transgenic mice expressing the ALS-associated PFN1^C71G mutant protein. We show that transgenic neuronal expression of PFN1^C71G induces early hyperphosphorylation of endogenous TDP-43 in the spinal cord that augments over time, preceding accumulation of insoluble non-phosphorylated TDP-43 and the manifestation of muscle denervation and motor dysfunction. Sustained knockdown of Atxn2 in the central nervous system (CNS) in pre-symptomatic PFN1^C71G mice by AAV-driven expression of an artificial microRNA (AAV-amiR-Atxn2) reduces aberrant TDP-43 in the spinal cord, while delaying neurodegeneration and improving muscle and motor function. RNA-sequencing analysis of spinal cord samples from PFN1^C71G mice and ALS donors show shared patterns of transcriptional perturbation, including a pro-inflammatory gene signature that is attenuated by AAV-amiR-Atxn2. Notably, impaired regulation of the PFN1^C71G skeletal muscle transcriptome exceeds that of the spinal cord and is also improved by Atxn2 reduction in the CNS. Lastly, we find significant gene co-expression network homology between PFN1^C71G mice and human ALS, with shared dysregulation of modules related to neuroinflammation and neuronal function and uncover novel hub genes that provide biological insight into ALS and potential drug targets that can be further investigated in this mouse model.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"116"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102926/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141058","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":"Dose-dependent CHCHD10 dysregulation dictates motor neuron disease severity and alters creatine metabolism.","authors":"Sandra Harjuhaahto, Manu Jokela, Jayasimman Rajendran, Minea Rokka, Bowen Hu, Jouni Kvist, Fuping Zhang, Tomáš Zárybnický, Kimmo Haimilahti, Liliya Euro, Eija Pirinen, Nadine Huber, Sanna-Kaisa Herukka, Annakaisa Haapasalo, Emilia Kuuluvainen, Swetha Gopalakrishnan, Pekka Katajisto, Ville Hietakangas, Thibaut Burg, Ludo Van Den Bosch, Xiaoping Huang, Derek P Narendra, Satu Kuure, Emil Ylikallio, Henna Tyynismaa","doi":"10.1186/s40478-025-02039-3","DOIUrl":"10.1186/s40478-025-02039-3","url":null,"abstract":"<p><p>Dominant defects in CHCHD10, a mitochondrial intermembrane space protein, lead to a range of neurological and muscle disease phenotypes including amyotrophic lateral sclerosis. Many patients present with spinal muscular atrophy Jokela type (SMAJ), which is caused by heterozygous p.G66V variant. While most disease variants lead to aggregation of CHCHD10 and activation of proteotoxic stress responses, the pathogenic mechanisms of the p.G66V variant are less clear. Here we report the first homozygous CHCHD10 patient, and show that the variant dosage dictates the severity of the motor neuron disease in SMAJ. We demonstrate that the amount of the mutant CHCHD10 is reduced, but the disease mechanism of p.G66V is not full haploinsufficiency as residual mutant CHCHD10 protein is present even in a homozygous state. Novel knock-in mouse model recapitulates the dose-dependent reduction of mutant CHCHD10 protein and the slow disease progression of SMAJ. With metabolome analysis of patients' primary fibroblasts and patient-specific motor neurons, we show that CHCHD10 p.G66V dysregulates energy metabolism, leading to altered redox balance and energy buffering by creatine metabolism.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"111"},"PeriodicalIF":6.2,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096803/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118446","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":"Distinct characteristics of brain metastasis in lung adenocarcinoma: development of high-confidence cell lines.","authors":"Jintao He, Zen-Ichi Tanei, Dao-Sian Wu, Lei Wang, Yoshitaka Oda, Masumi Tsuda, Shinya Tanaka","doi":"10.1186/s40478-025-02038-4","DOIUrl":"10.1186/s40478-025-02038-4","url":null,"abstract":"<p><p>Lung cancer is a leading cause of cancer-related deaths worldwide, with brain metastasis occurring in approximately 30-55% of patients, particularly in lung adenocarcinoma. Due to the challenges in obtaining genuine brain metastasis tumor cells, researchers commonly use nude mouse models to establish brain metastasis cell lines, though traditional methods have limitations such as high costs, lengthy timeframes, and the need for specialized imaging equipment. To address these issues, we developed an improved approach by performing low cell number circulating intracranial injections (500-4000 cells) in nude mice, successfully establishing the H1975-BM1, BM2, and BM3 cell lines. Through RNA sequencing and bioinformatics analyses, we identified transcriptomic differences among these cell lines, revealing that H1975-BM1 cells primarily exhibit stem cell function and migration characteristics, while H1975-BM3 cells display enhanced chemotaxis, cell adhesion, and cytokine secretion associated with interactions. Experimental validation, including Transwell assays, CCK8, cell adhesion assays, and subcutaneous tumor implantation in nude mice, further confirmed these findings, with H1975-BM3 forming larger tumors and a more pronounced secretion cystic cavity. In conclusion, our improved methodology successfully established high-confidence brain metastasis lung adenocarcinoma cell lines, elucidating distinct transcriptomic and functional characteristics at different stages of brain metastasis progression.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"109"},"PeriodicalIF":6.2,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12093710/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118445","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":"A comprehensive spatiotemporal map of dystrophin isoform expression in the developing and adult human brain.","authors":"Francesco Catapano, Reem Alkharji, Darren Chambers, Simran Singh, Artadokht Aghaeipour, Jyoti Malhotra, Patrizia Ferretti, Rahul Phadke, Francesco Muntoni","doi":"10.1186/s40478-025-01996-z","DOIUrl":"10.1186/s40478-025-01996-z","url":null,"abstract":"<p><p>Mutations in the dystrophin gene (DMD) cause the severe muscle-wasting disease Duchenne muscular dystrophy (DMD). Additionally, there is a high incidence of intellectual disability and neurobehavioural comorbidities in individuals with DMD. Similar behavioural abnormalities are found in mdx dystrophic mouse models. Unlike muscle, several dystrophin isoforms are expressed in the human brain, but a detailed map of regional and cellular localisation of dystrophin isoforms is missing. This is crucial in understanding the neuropathology of DMD individuals, and for evaluating the translatability of pre-clinical findings in DMD mouse models receiving genetic therapy interventions. Here, we provide a comprehensive dystrophin expression profile in human brains from early development to adulthood. We reveal expression of dp427p2, dp427c, dp427m and dp40 isoforms in human embryonic brains, not previously reported. We also detected dp427p2 expression and developmental regulation in human brain across the lifespan. In addition we showed by in situ hybridisation that dp140 was greatly downregulated in adult brains. Importantly, our data also demonstrate expression of DMD transcripts in human motor neurons and co-expression of different dystrophin isoforms within single neurons in both developing and adult brains. Finally, we show localisation of DMD transcripts with GAD1+ GABAergic-associated transcripts in neurons including cerebellar Purkinje cells and interneurons, as well as in the majority of neocortical and hippocampal SLC17A7+ glutamatergic neurons, suggesting a role for dystrophin in signalling at the neuronal inhibitory and excitatory synapses.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"110"},"PeriodicalIF":6.2,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12096690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144118443","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":"Microglial repopulation reverses radiation-induced cognitive dysfunction by restoring medial prefrontal cortex activity and modulating leukotriene-C4 synthesis.","authors":"Yubo Hu, Zhe Li, Yafeng Zhu, Mengdan Xing, Xiaoru Xie, Panwu Zhao, Xin Cheng, Chuan Xiao, Yuting Xia, Jingru Wu, Yuan Luo, Ho Ko, Yamei Tang, Xiaojing Ye, Wei-Jye Lin","doi":"10.1186/s40478-025-02026-8","DOIUrl":"10.1186/s40478-025-02026-8","url":null,"abstract":"<p><p>Cranial radiotherapy and environmental radiation exposure are associated with increased risk of cognitive dysfunction, including memory deficits and mood disorders, yet the underlying mechanisms remain poorly understood. In this study, we demonstrate that cranial irradiation induces hypoactivity in the medial prefrontal cortex (mPFC) of mice, leading to anxiety-like behaviors and memory impairments, which can be prevented by optogenetic activation of mPFC excitatory neurons. Radiaiton exposure also causes a significant reduction in microglial density within the mPFC, accompanied by morphological and transcriptional alterations in the remaining microglia. Notably, microglial repopulation, achieved through CSF1R antagonist-mediated depletion prior to irradiation and subsequent repopulation, restores mPFC neuronal acitivity and reverses cognitive and behavioral deficits. Integrated bulk RNA sequencing and microglial proteomic analysis of the mPFC reveal that microglial repopulation specifically modulates the leukotriene-C4 biosynthesis pathway, without significant changes in canonical pro-inflammatory cytokines or chemokines. Importantly, pharmacological inhibition of leukotriene-C4 synthase ameliorates radiation-induced anxiety and memory impairments. These findings identify leukotriene-C4 signaling as a critical mechanism underlying radiation-induced cognitive dysfunction and suggest that microglial repopulation and targted inhibition of leukotriene-C4 represent potential therapeutic strategies for mitigating radiation-associated cognitive disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"105"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087111/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101293","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":"Correction: Small molecule treatment alleviates photoreceptor cilia defects in LCA5-deficient human retinal organoids.","authors":"Dimitra Athanasiou, Tess A V Afanasyeva, Niuzheng Chai, Kalliopi Ziaka, Katarina Jovanovic, Rosellina Guarascio, Karsten Boldt, Julio C Corral-Serrano, Naheed Kanuga, Ronald Roepman, Rob W J Collin, Michael E Cheetham","doi":"10.1186/s40478-025-02010-2","DOIUrl":"10.1186/s40478-025-02010-2","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"104"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087157/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101290","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":"Histomorphological variations in progressive multifocal leukoencephalopathy correlated with JCV replication in brain lesions: insights from 91 patients.","authors":"Kenta Takahashi, Yuko Sato, Hideki Hasegawa, Harutaka Katano, Tadaki Suzuki","doi":"10.1186/s40478-025-02027-7","DOIUrl":"10.1186/s40478-025-02027-7","url":null,"abstract":"<p><p>Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease caused by JC polyomavirus (JCV). The histopathology of PML is morphologically diverse and characterized by the classical triad of demyelination, enlarged oligodendroglial nuclei, and bizarre astrocytes. Pathological diagnostic criteria for PML require both the classical triad and viral detection in brain tissue. However, the frequency of this triad in surgical pathology specimens and its correlation with disease progression and viral loads remain unclear. In this study, 117 brain tissues from 91 pathologically confirmed PML patients were investigated. PML histopathology was found to be spatially and temporally pleomorphic, and not all brain tissues exhibited the complete classical triad. The sensitivity of quantitative PCR for detecting JCV in brain tissues was 100%, whereas that of immunohistochemistry (IHC) was 83.5-87.8%. Viral loads in biopsy samples were significantly higher than those in autopsy samples and decreased over time after disease onset. To systematically characterize PML lesions from the outer border to the demyelinated center, we developed a histological classification based on the classical triad and macrophage infiltration. This classification correlated with viral loads, with subtypes characterized by abundant enlarged oligodendroglial nuclei at the demyelination border exhibiting the highest levels of JCV DNA. Pathological variability was influenced by spatial and temporal factors rather than by underlying diseases, although PML associated with acquired immunodeficiency syndrome exhibited more severe demyelination. In conclusion, histomorphological variability in PML reflects viral replication activity, emphasizing the importance of comprehensive pathological evaluation. Combining histomorphology, tissue-based PCR for viral DNA detection, and IHC for viral antigens is crucial for assessing disease progression. Early brain biopsy from the demyelination border offers the best opportunity for a definitive diagnosis of PML and may guide therapy targeting active lesions.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"106"},"PeriodicalIF":6.2,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12087142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101292","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}