Acta Neuropathologica Communications最新文献

{"title":"Astrocyte-neuron combined targeting for CYP46A1 gene therapy in Huntington's disease.","authors":"Louis-Habib Parsai, Farah Chali, Enejda Subashi, Caroline Zeitouny, Emilie Rey, A Berniard, William Bitton, Laureline Urli, Lisa Rousselot, Nadège Sarrazin, Véronique Blouin, Wilfried F A Den Dunnen, Kristin Michaelsen-Preusse, Martin Korte, Sandro Alves, Nathalie Cartier","doi":"10.1186/s40478-025-02054-4","DOIUrl":"https://doi.org/10.1186/s40478-025-02054-4","url":null,"abstract":"<p><p>Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by an abnormal expansion of cytosine-adenine-guanosine (CAG) trinucleotidein the huntingtin gene. Mutant huntingtin (mHTT) expression in neurons and glial cells affects neuron and astrocyte functions and leads to the loss of medium spiny neurons of the striatum. Brain cholesterol pathway is severely affected by HTT mutation in neurons and astrocytes, contributing to HD pathogenesis. Decreased cholesterol production and transport by astrocytes impair synapse maturation and neurotransmission. Brain cholesterol metabolism is maintained by cholesterol hydroxylation into 24-hydroxycholesterol by the neuronal enzyme cholesterol 24-hydroxylase (CYP46A1). CYP46A1 is decreased in affected brain regions in HD patients and mice. AAV-CYP46A1 striatal delivery was shown to restore cholesterol metabolism with neuroprotective effects in two mouse models of HD, characterized by mHTT aggregates' reduction, improved transcriptomic profile, and Brain-Derived Neurotrophic Factor (BDNF) signaling, and preservation of striatal neurons. From a therapeutic perspective, we intended to clarify the detailed mechanisms and the specific role of neurons and astrocytes in the therapeutic effects of AAV-CYP46A1 delivery. We first evaluated CYP46A1 expression in astrocytes in HD post-mortem putamen at a late stage of disease progression. To determine the specific contribution of CYP46A1 expression in astrocytes compared to neurons on the HD phenotype, we assessed the effects of AAV-CYP46A1 striatal injection under the control of astrocytic (GFA2) or neuronal (hSYN) promoters in R6/2 mice. Overall, equivalent transgenic CYP46A1 protein levels, both astrocytic and neuronal targeting, mitigate medium ppiny neuron (MSN) atrophy and improve spine density in R6/2 mice. Reduction of mHTT aggregates in neurons is similar when CYP46A1 is overexpressed in neurons or in astrocytes. However, astrocyte targeting reduces mHTT aggregates in neurons and astrocytes, while restricted neuronal targeting reduces mHTT aggregates in neurons only. Altogether, astrocytic targeting of CYP46A1 expression in CYP46A1-tested animals combines cell-autonomous and non-cell-autonomous mechanisms of action, with improved phenotypic correction compared to neuronal-restricted targeting. Allowing expression in both cell types with higher expression levels of CYP46A1 showed overall better efficacy. We demonstrate that astrocyte-neuron combined targeting with AAV-CAG-CYP46A1 delivery increases therapeutic efficacy. This study brings new evidence that CAG-mediated CYP46A1 striatal overexpression significantly modifies the transcriptome in R6/2 mice for pathways involved in synaptogenesis and inflammation, suggesting targeting both astrocytes and neurons provides benefits for HD phenotypic correction.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"184"},"PeriodicalIF":5.7,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938085","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":"H3F3B p.K27I-mutant diffuse midline glioma is a distinct subtype of H3K27-altered diffuse midline glioma.","authors":"Lei Cheng, Min Zhou, Tao Luo, Rongfang Dong, Ni Chen, Xinyong Cai, Xingwen Wang, Hao Wu, Zan Chen, Zuowei Wang, Xueling Qi, Dehong Lu, Lianghong Teng, Fengzeng Jian, Leiming Wang","doi":"10.1186/s40478-025-02101-0","DOIUrl":"https://doi.org/10.1186/s40478-025-02101-0","url":null,"abstract":"<p><p>H3K27-altered diffuse midline glioma (DMG) is a fatal disease, including four subtypes H3.3-mutant, H3.1/H3.2-mutant, H3-wildtype with EZHIP overexpression, and EGFR-mutant. H3F3B, another gene encoding histone H3.3 in addition to H3F3A, was ever reported to be mutated in DMGs. However, the clinical and molecular characteristics of H3F3B-mutant DMGs is yet understood. The clinical and radiological information of 9 patients with H3F3B-mutant DMG were retrospectively collected. Tumor specimens underwent DNA methylation profiling and next-generation sequencing. All tumors harbored somatic H3F3B p.K27I mutation. Average patient age was 46 ± 6.86 years, 6 tumors located in spinal cord, 5 tumors involved brainstem and 2 arose in the thalamus. Immunohistochemistry showed these tumors exhibited completely or mosaic-like loss of H3K27me3 expression. Unsupervised t-distributed stochastic neighbor embedding (t-SNE) analysis of DNA methylation profiles showed that H3F3B-mutant DMGs formed a unique methylation cluster separate from other gliomas with H3K27me3 loss and DMGs with canonical histone H3 mutation. PPM1D and NF1 were frequently mutated in H3F3B-mutant DMGs. Survival analysis showed that H3F3B-mutant DMGs had poor prognosis comparable to H3K27M-mutant DMGs. Taken together, H3F3B mutation also cause a loss of H3K27 trimethylation in DMGs and result in poor prognosis. The distinct characteristics of DNA methylation and mutational spectrum between H3F3B-mutant DMGs and canonical H3K27M-mutant DMGs might suggest divergent underlying mechanism of gliomagenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"183"},"PeriodicalIF":5.7,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12374277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938270","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":"Endothelial transdifferentiation of glioma stem cells: a literature review.","authors":"Andrei Buruiana, Stefan Ioan Florian, Alexandru Ioan Florian, Olga Soritau, Sergiu Susman","doi":"10.1186/s40478-025-02031-x","DOIUrl":"https://doi.org/10.1186/s40478-025-02031-x","url":null,"abstract":"<p><p>Endothelial transdifferentiation represents a multifaceted process wherein glioma stem cells (GSCs) gradually adopt endothelial characteristics, marked by the expression of endothelial markers (CD31, CD34) and functional traits, while concurrently relinquishing their stem-like properties. This phenomenon is heterogenous in glioblastoma (GBM) samples, but holds importance in terms of prognosis. Typically occurring within hypoxic environments, particularly in perinecrotic regions, endothelial transdifferentiation is influenced by the secretome of neighboring cells, which orchestrates the activation of various signaling pathways including Notch during endothelial lineage commitment, PI3K/AKT, Wnt/β-catenin and epithelial-mesenchymal transition (EMT) during both commitment and maturation. Initially, GSCs organize into vascular-like channels resembling vasculogenic mimicry and express CD144; however, this signature diminishes as endothelial maturation progresses. GSC-derived endothelial cells (ECs) eventually integrate with normal ECs from the tumor periphery, yielding a mosaic pattern. Endothelial transdifferentiation plays a role in response to standard treatments such as temozolomide chemotherapy and radiotherapy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"181"},"PeriodicalIF":5.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372203/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938245","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":"Non-invasive and sensitive MRI assessment of radiation-induced cognitive dysfunction via voxel-based morphological and functional connectivity.","authors":"Long Zhu, Yaolei Ma, Ao Kong, Xiangjun Wu, Yanming Ren, Wei Zhou, Chaoji Huangfu, Yue Gao","doi":"10.1186/s40478-025-02092-y","DOIUrl":"https://doi.org/10.1186/s40478-025-02092-y","url":null,"abstract":"<p><strong>Background: </strong>Radiotherapy inevitably cause cognitive dysfunction. We aim to explore a non-invasive, sensitive strategy for assessing radiation-induced cognitive dysfunction, using voxel-based morphometry (VBM) and functional connectivity (FC), and to clarify the potential mechanisms from behavioral, histological, and molecular perspectives.</p><p><strong>Methods: </strong>We employed a multimodal cross-validation strategy to evaluate cognitive dysfunction of C57BL/6j mice exposed to a single dose of 5 Gy or 15 Gy using a ⁶⁰Co γ radiation source. The open field, novel object recognition, and Morris water maze tests were conducted on days 18, 19, and 21 after radiation, respectively, followed by fMRI scanning on day 27. VBM and FC analysis are used to assess cognitive function impairment after radiation. Histopathological analyses (HE and Nissl staining) and immunohistochemical assessments of neural damage markers (Iba-1 and GFAP) were conducted.</p><p><strong>Results: </strong>The radiation group (5 Gy, 15 Gy) showed an increased escape latency, decreased number of platform crossings, and no difference in exploration preference for old versus new objects. In the radiation group, the arrangement of neurons in the hippocampal DG region was disordered, and a significant reduction of Nissl bodies was observed. The expression of Iba1 (in CA1, CA2, and CA3 regions) and GFAP (in CA1 and CA3 regions) was increased after radiation. The levels of pro-inflammatory factors such as IFN-gamma and IL-1beta were increased in the hippocampal tissue, while the expression of anti-inflammatory factors (IL-4 and IL-10) were decreased. The brain region with increased gray matter volume in the 5 Gy group was the right hippocampal DG region. Functional connectivity values were increased between 24 pairs of hippocampal subregions, such as CA1.R and DG-mo.L, while decreased between 29 pairs, such as CA3.R and ENTl1.R in the 5 Gy group. In the 15 Gy group, functional connectivity values increased between 31 pairs, such as DG-mo.L and HATA.R, and decreased between 20 pairs, such as CA2.R and DG-po.L. Compared to the 5 Gy group, the 15 Gy group had 33 pairs with increased functional connectivity values and 23 pairs with decreased values.</p><p><strong>Conclusion: </strong>Functional magnetic resonance imaging can non-invasively and more efficiently assess cognitive function impairment in the brain after radiation doses using VBM and FC comparative methods. This provides new insights into the evaluation of cognitive function with non-invasive and sensitive methods.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"180"},"PeriodicalIF":5.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12369218/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938366","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: Biglycan-driven risk stratification in ZFTA-RELA fusion supratentorial ependymomas through transcriptome profiling.","authors":"Konstantin Okonechnikov, David R Ghasemi, Daniel Schrimpf, Svenja Tonn, Martin Mynarek, Jan Koster, Till Milde, Tuyu Zheng, Philipp Sievers, Felix Sahm, David T W Jones, Andreas von Deimling, Stefan M Pfister, Marcel Kool, Kristian W Pajtler, Andrey Korshunov","doi":"10.1186/s40478-025-02094-w","DOIUrl":"https://doi.org/10.1186/s40478-025-02094-w","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"182"},"PeriodicalIF":5.7,"publicationDate":"2025-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12372277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938098","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":"Germline structural variations involving the pediatric brain tumor transcriptome include disease-relevant and ancestry-related genes.","authors":"Fengju Chen, Yiqun Zhang, Luis F Paulin, Fritz J Sedlazeck, Chad J Creighton","doi":"10.1186/s40478-025-02098-6","DOIUrl":"https://doi.org/10.1186/s40478-025-02098-6","url":null,"abstract":"<p><strong>Background: </strong>Germline Structural Variants (SVs) represent an important source of genetic diversity, in large part due to their influence on gene transcription. It is necessary to systematically catalog germline SVs and their associated impacted genes across different cohorts and tissue and cellular contexts, including pediatric brain or Central Nervous System (CNS) tumors.</p><p><strong>Methods: </strong>We combined RNA with whole genome sequencing across 1430 pediatric brain or CNS tumor patients from the Children's Brain Tumor Network. We set out to systematically identify genes for which the proximity of germline SVs was recurrently and significantly associated with differential expression in the tumor sample across multiple patients.</p><p><strong>Results: </strong>For hundreds of genes, recurrent and common germline SV breakpoints within 1 Mb were associated with higher or lower expression in tumors spanning various histologic types. Some germline SV-expression associations involved gene deletion or disruption, while others represented cis-regulatory alterations. Rare and singleton SVs disrupting DNA repair-related and mitochondrial-related genes collectively involved 2.7 and 4.7% of patients, respectively. Genes with germline SV breakpoint patterns and expression associated with patients of African ancestry included ACOT1 and CRYBB2P1. Genes with germline SV breakpoint patterns and expression associated with patient survival included ACTG1 and AHRR. Genes altered in association with both somatic and germline SVs included HGF and BCOR.</p><p><strong>Conclusion: </strong>Our results capture a class of phenotypic variation at work in the setting of pediatric brain tumors, including genes with cancer roles.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"179"},"PeriodicalIF":5.7,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366115/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144938261","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":"TIMP-1 enhances Akt and BDNF signaling in neurons to reduce synaptic and cognitive deficits in 5xFAD mouse model of Alzheimer's disease.","authors":"Sukanya Sarkar, Kusumika Gharami, Ananya Mondal, Keerthana Padmanabhan, Ramesh Kumar Paidi, B N Srikumar, Subhas C Biswas","doi":"10.1186/s40478-025-02060-6","DOIUrl":"10.1186/s40478-025-02060-6","url":null,"abstract":"<p><p>Glial-secreted molecules influence neuronal function in Alzheimer's disease (AD), but their mechanisms of action are partially understood. Anti-inflammatory cytokine tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) is secreted by astrocytes early in response to amyloid-β and is suggested to have a neuroprotective function. We demonstrated that TIMP-1 levels are increased in 7-day-old 5xFAD versus wild-type mice but are drastically decreased from two months onwards. Administration of TIMP-1 protein in 5xFAD mice ameliorated AD-associated cognitive impairments. TIMP-1 regulated both neuronal apoptosis and autophagy by binding to CD63 receptors in an AD model. Synaptosomal and electrophysiological studies revealed that TIMP-1 reduces AD-related synaptic deficits, likely by promoting post-synaptic long-term potentiation in the hippocampus, independent of pre-synaptic activity. TIMP-1 induced brain-derived neurotrophic factor (BDNF) and BDNF-mediated post-synaptic signaling. These findings suggest that TIMP-1 functions as a multifunctional cytokine with protective and long-term benefits for neurons and may be a promising therapeutic candidate in AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"178"},"PeriodicalIF":5.7,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144881776","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":"Evidence of a novel α-synuclein strain isolated from a Parkinson's disease with dementia patient sample.","authors":"Sara A M Holec, Jisoo Lee, Chase R Khedmatgozar, Marcelina J Wojewska, Abby Oehler, Glenda M Halliday, Steve M Gentleman, Amanda L Woerman","doi":"10.1186/s40478-025-02093-x","DOIUrl":"10.1186/s40478-025-02093-x","url":null,"abstract":"","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"177"},"PeriodicalIF":5.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12362927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870794","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":"TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord.","authors":"Emily Feneberg, Alexander G Thompson, Philip D Charles, Iolanda Vendrell, Benedikt M Kessler, Roman Fischer, Olaf Ansorge, Elizabeth Gray, Kevin Talbot, Martin R Turner","doi":"10.1186/s40478-025-02084-y","DOIUrl":"10.1186/s40478-025-02084-y","url":null,"abstract":"<p><p>Neuronal and glial cytoplasmic inclusions positive for TAR DNA-binding protein 43 (TDP-43) are the defining pathological hallmark of 97% of amyotrophic lateral sclerosis (ALS) and 50% of frontotemporal dementia (FTD). The ALS-FTD clinicopathological spectrum variably involves cortical and spinal anterior horn cell pathology. The broader protein composition of these inclusions is of major importance to understanding pathogenesis, clinical heterogeneity and biomarker development. This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson's disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer's disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. Increased abundance of TDP-43 in the detergent-insoluble fraction of ALS cortex and spinal cord tissue confirmed disease-specific protein enrichment by serial fractionation. The most striking alterations between ALS and other conditions were found in the detergent-insoluble fraction of spinal cord, with predominant enrichment of endosomal and extracellular vesicle pathways. In the cortex mitochondrial membrane/envelope and ion transmembrane transport pathways were enriched in the detergent-insoluble fraction. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. Among proteins concordantly elevated in the detergent-insoluble fractions of spinal cord and cortex, there was greater representation of proteins encoded by ALS-associated genes, specifically Cu/Zn superoxide dismutase 1, valosin containing protein and TDP-43 (odds ratio 16.34, p = 0.002). No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex. A common upregulation of proteins encoded by ALS-causing genes implicates their role in the pathogenesis of the ALS-FTD spectrum of diseases beyond TDP-43. Data are available via ProteomeXchange with identifier PXD067060.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"175"},"PeriodicalIF":5.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12359902/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870796","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":"High-grade glioma with pleomorphic and pseudopapillary features: a single-institution series of three cases.","authors":"Eric A Goethe, Rasha Alfattal, Subhiksha Srinivasan, Pushan Dasgupta, Vinay Puduvalli, Shiao-Pei Weathers, Leomar Y Ballester, Jeffrey S Weinberg, Sujit Prabhu, Sherise D Ferguson, Maria A Gubbiotti","doi":"10.1186/s40478-025-02097-7","DOIUrl":"10.1186/s40478-025-02097-7","url":null,"abstract":"<p><strong>Introduction: </strong>Modern molecular diagnostic techniques such as DNA methylation profiling are leading to the reclassification of several central nervous system malignancies and discovery of novel diagnostic entities, such as high-grade glioma with pleomorphic and pseudopapillary features (HPAP).</p><p><strong>Methods: </strong>We performed a retrospective chart review of all patients with HPAP confirmed with methylation profiling at a single institution between 2023 and 2025. Demographic, radiographic, surgical, and outcome data were collected.</p><p><strong>Results: </strong>Three patients were identified: two females and one male with a mean age of 49.7 years (range 25-62). No patients had a prior cancer history. One patient had an incidentally discovered tumor, while the other two patients underwent imaging for symptoms of headache, vision changes and extremity weakness. Mean tumor size was 4.0 cm (range 2.8-6) with a wide variation in imaging characteristics. All patients underwent surgical resection and radiographic gross total resection was achieved in all cases. All patients underwent radiation therapy without concurrent chemotherapy. After a median 20 months follow up (range 4.5 to 108.9), two patients experienced tumor progression at 2.7 months and 86.5 months respectively. All patients were alive at last follow up.</p><p><strong>Conclusion: </strong>HPAP is a novel clinical entity demonstrating variable molecular signatures sharing a common DNA methylation profile which demonstrates a relatively favorable clinical course when compared with other high grade gliomas. Further study is needed to determine the optimal treatment and factors that influence survival.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"176"},"PeriodicalIF":5.7,"publicationDate":"2025-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12363008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144870795","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}