Brain Pathology最新文献

{"title":"SOCIETY NEWS","authors":"Audrey Rousseau","doi":"10.1111/bpa.70122","DOIUrl":"https://doi.org/10.1111/bpa.70122","url":null,"abstract":"<p><b><i>Future International Congresses of Neuropathology (ICNs) ICN27 Edinburgh</i></b>. The International Congress of Neuropathology (ICN) will be held in Edinburgh, Scotland, in 2027 (ICN27). The Congress President will be Prof Colin Smith and the ICN27 will be hosted by the British Neuropathological Society (BNS).</p><p>“On behalf of the British Neuropathological Society I am delighted to extend a warm invitation to all our colleagues across the world to join us in Edinburgh for the International Congress of Neuropathology 2027. Edinburgh is an easily accessible centre, surrounded by 1000 years of living history. We will develop a strong academic programme covering all aspects of neuropathology with world leading plenary speakers, supported by a social programme highlighting some of Edinburgh's historic charms. For those wishing to explore further, Edinburgh offers access to many of Scotland's highlights, be it touring the Highlands, sampling our famous whisky or golfing on some of our picturesque courses. I do hope you will be able to join us for what I am sure will be a memorable meeting showcasing the best in international neuropathology.</p><p>Colin Smith</p><p>Congress President ISN 2027”</p><p><b><i>ICN31 Bangalore / Bengaluru</i></b>. ISN is pleased to announce that the International Congress of Neuropathology 2031 (ICN31) will be hosted in Bangalore/Bengaluru, India, following a successful bid from the Neuropathology Society of India (NPSI). The congress is planned for the beginning of October 2031 (final dates to be confirmed). It will be the first time for the International Congress of Neuropathology to take place in India and we very much look forward to it. Congratulations to NPSI for preparing to host the first International Congress of Neuropathology in India. We will be receiving regular updates on congress planning and preparations including more formal updates at our Joint ISN Council & Executive meetings in the coming years.</p><p>Summary report for ICN23 Berlin (our most recent International Congress of Neuropathology, September 2023) now available in the Society's journal Brain Pathology (see link: https://doi.org/10.1111/bpa.13249).</p><p><b><i>Brain Pathology has joined Wiley's Open Access</i></b> portfolio as of January 2021. As a result, all submissions are subject to an Article Publication Charge (APC) if accepted and published in the journal. ISN members are eligible for a 10% discount off the Open Access APC. For more information on the fees, please click here.</p><p><b><i>Free resource: digital microscopy platform for neurodegenerative diseases curated in Munich</i></b>. Prof Jochen Herms and his team have been setting up a digital microscopy platform for neurodegenerative diseases in their department in Munich. Registration is free. ISN members and interested colleagues are invited to use this resource, which will be particularly useful for teaching and training (see link below). Colleagues are invited to con","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70122","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652457","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":"The DNA/RNA autophagy protein SIDT2 as a novel neuropathological hallmark in Huntington disease","authors":"Sanaz Gabery,&nbsp;Sofia Bergh,&nbsp;Chrisovalantou Huridou,&nbsp;Rachel Y. Cheong,&nbsp;Barbara Baldo,&nbsp;Paul Günther Scheunemann,&nbsp;Marie-Louisa Schoebel,&nbsp;Linda Holmquist Mengelbier,&nbsp;Elisabet Englund,&nbsp;Catriona McLean,&nbsp;Carsten Saft,&nbsp;Deniz Kirik,&nbsp;Maria Björkqvist,&nbsp;Glenda Halliday,&nbsp;Elisabeth Petrasch-Parwez,&nbsp;Huu Phuc Nguyen,&nbsp;Jonasz Jeremiasz Weber,&nbsp;Åsa Petersén","doi":"10.1111/bpa.70088","DOIUrl":"10.1111/bpa.70088","url":null,"abstract":"<p>The pathogenic mechanisms leading to neurodegeneration in Huntington disease (HD) are not fully understood but involve accumulation of toxic mRNA and protein products in the brain. Recent studies described an unconventional autophagic pathway involving DNA and RNA degradation through DNautophagy and RNautophagy that is regulated by the lysosomal protein SID1 transmembrane family member 2 (SIDT2). Interestingly, SIDT2 has been shown to bind to the expanded CAG repeat in the mutant huntingtin (mHTT) transcript and lower mHTT in vitro. The aim of the present study was to determine whether SIDT2 levels are altered in HD and whether manipulation of SIDT2-mediated RNautophagy can alter HD pathology. We demonstrate a significant reduction of SIDT2 protein levels in the striatum and in the lateral hypothalamic area in postmortem HD brains compared to control cases without effects on SIDT2 mRNA levels. In frontal cortical postmortem HD tissue, we show a CAG-repeat-length-dependent increase in the frequency of SIDT2-immunoreactive intranuclear inclusions. In postmortem tissue of an HD case with Vonsattel grade 0, we demonstrate SIDT2- and mHTT-immunoreactive inclusions not only in the frontal cortex, but also in the striatum and the lateral hypothalamic area. In the R6/2 mouse model of HD, we show that SIDT2 inclusions form at later stages than mHTT inclusions. Overexpression of SIDT2 using adeno-associated viral vectors injected into the hypothalamus of R6/2 mice led to a reduction of mHTT inclusions in the lateral hypothalamic area. Similarly, in a neuronal cell model, overexpression of SIDT2 reduced soluble and insoluble mHTT exon 1 protein levels. Taken together, our results reveal novel pathology in clinical HD cases and in experimental models, characterized by the accumulation of SIDT2-immunoreactive inclusions, while demonstrating the efficacy of overexpressing SIDT2 for lowering detrimental mHTT species. Targeting SIDT2-mediated RNautophagy may offer a potential strategy to ameliorate the molecular pathology in HD.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70088","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282649","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":"Increased expression of inflammasome signaling genes and proteins in selective brain regions in the intermediate stage of Alzheimer's disease","authors":"Juan Pablo de Rivero Vaccari,&nbsp;David A. Davis,&nbsp;Andrew P. Sawaya,&nbsp;Susanna P. Garamszegi,&nbsp;Xiaoyan Sun,&nbsp;Ayled Barreda,&nbsp;Helen M. Bramlett,&nbsp;Sakir Humayun Gultekin,&nbsp;W. Dalton Dietrich,&nbsp;Robert W. Keane,&nbsp;Regina T. Vontell","doi":"10.1111/bpa.70086","DOIUrl":"10.1111/bpa.70086","url":null,"abstract":"<p>Neuritic plaques (NP) are a key component of Alzheimer disease (AD) pathology composed of dystrophic neurites that form neurofibrillary tangles (NFTs) and amyloid-<i>β</i> (A<i>β</i>) proteins. NP accumulation is one fundamental feature seen in the intermediate stage of AD neuropathological pathology change. NPs are sites for cellular degeneration and can induce the upregulation of inflammatory signals including the inflammasome complex. We analyzed 758 genes using multiplex genomics in samples from the hippocampal, temporal and frontal brain regions that had intermediate AD neuropathological changes and aged-matched controls. In addition, we analyzed NP formation using <i>phosphorylated tau at threonine 217</i> (pTau217) and A<i>β</i> antibodies along with inflammasome sensors using NOD-like receptor protein (NLRP) antibodies, <i>apoptosis-associated speck like protein containing a caspase recruitment domain</i> (ASC) and <i>absent in melanoma-like receptor 2</i> (AIM2). Finally, we investigated if cell death is occurring cells by pyroptosis using Gasdermin D (GSDMD) antibody to detect pore formation on the membrane. Analyses show that inflammasome signaling genes and proteins are significantly increased in the hippocampus rather than the temporal and frontal lobe at the intermediate stage of AD. NPs are more prevalent in the hippocampus and temporal lobe in cases with intermediate AD pathology. ASC (1C100) immunostaining is colocalized with NLRP1, NLRP3 and AIM2. GSDMD immunostaining detected pericellular pores forming around the membrane of NFTs and in NPs. Messenger RNA and protein analyses demonstrate that inflammasome signaling molecules are elevated in AD suggesting that neuronal death occurs by the induction of pyroptosis.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147269778","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":"Right medial temporal lobe mass in a 25-year-old male","authors":"Jorge Samanamud,&nbsp;Cheyanne C. Slocum,&nbsp;Michael Christian Virata,&nbsp;Zied Abdullaev,&nbsp;Kenneth Aldape,&nbsp;Melissa Umphlett,&nbsp;Raymund L. Yong,&nbsp;Thomas P. Naidich,&nbsp;Nadejda M. Tsankova,&nbsp;Jamie M. Walker,&nbsp;Timothy E. Richardson","doi":"10.1111/bpa.70093","DOIUrl":"10.1111/bpa.70093","url":null,"abstract":"&lt;p&gt;A 25-year-old male with no significant past medical, surgical, or neurologic history presented with a new-onset seizure, which occurred while driving and led to a motor vehicle accident. His family history was notable for a paternal grandfather who died of glioblastoma at the age of 56. Brain magnetic resonance imaging (MRI) demonstrated a 3.4 × 3.2 × 3.1 cm expansile mass in the right medial temporal lobe with extension into adjacent basal forebrain structures. The lesion showed diffusion restriction, hyperintensity on T2-Fluid-Attenuated Inversion Recovery (T2-FLAIR), and absence of significant contrast enhancement on T1-weighted MRI (Figure 1). The patient subsequently underwent a right frontotemporal craniotomy with gross total resection confirmed by post-contrast MRI and was discharged 2 days after surgery.&lt;/p&gt;&lt;p&gt;H&amp;E-stained sections demonstrated a diffusely infiltrating neoplasm composed of small to medium-sized cells with scant cytoplasm and perinuclear halos (Box 1). There was perineuronal satellitosis (Figure 2A), scattered nuclear clusters and multinucleated cells (Figure 2B), microcalcifications, and focally frequent mitotic figures (up to 13/10 high power fields) (Figure 2C). Microvascular proliferation and necrosis were not identified. GFAP was focally strongly positive (Figure 2D). Synaptophysin was strongly and diffusely positive (Figure 2D [left insert]) and OLIG2 was strongly positive in tumor cell nuclei (Figure 2D [right insert]). Immunohistochemistry was negative for IDH1 R132H, H3K27M, and BRAFV600E. The Ki-67 proliferation index was highly variable, ranging from less than 5% to over 30%. Fluorescent in situ hybridization (FISH) demonstrated retained 1p/19q and pyrosequencing demonstrated unmethylated &lt;i&gt;MGMT&lt;/i&gt; promoter. Next-generation sequencing revealed loss of chromosome 14, as well as two variants of uncertain significance, &lt;i&gt;FGFR1&lt;/i&gt; p.E592G and &lt;i&gt;NOTCH1&lt;/i&gt; p.L1805P, neither of which is predicted to be oncogenic (https://www.ncbi.nlm.nih.gov/clinvar/). Copy number profiling redemonstrated the loss of chromosome 14 along with other focal chromosomal losses (Figure 2E). DNA methylation profiling matched with high confidence (0.999 by Bethesda Classifier [v2] and &gt;0.999 by Molecular Neuropathology classifier [v12b6]) to diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC).&lt;/p&gt;&lt;p&gt;Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), with high-grade features.&lt;/p&gt;&lt;p&gt;Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC) is a rare, methylation-defined entity with only a limited number of cases reported in the literature to date. DGONC was initially recognized as a distinct DNA methylation cluster, then subsequently delineated as a histopathologically and molecularly distinct tumor type by Deng et al., who described its characteristic morphology and recurrent monosomy of chromosome 14 [&lt;span&gt;1&lt;/s","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70093","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147466996","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":"Clinical and molecular features of primary gliosarcoma with digital spatial whole-transcriptome analysis of glial and mesenchymal components","authors":"Matthew D. Wood,&nbsp;Gabriel Zangirolani,&nbsp;Jinho Lee,&nbsp;Melanie H. Hakar,&nbsp;Tanaya Neff,&nbsp;Kevin Y. Zhang,&nbsp;Christopher L. Corless","doi":"10.1111/bpa.70091","DOIUrl":"10.1111/bpa.70091","url":null,"abstract":"<p>Gliosarcoma is a rare subtype of IDH-wildtype glioblastoma defined by mixed malignant glial and high-grade sarcomatous histological elements. Gliosarcoma is clinically managed similarly to glioblastoma and has a poor outcome. The sarcoma-like regions of gliosarcoma are thought to represent extreme mesenchymal metaplasia of neoplastic glial cells. Factors contributing to this phenomenon are not completely understood. Here we report a single-institution series of 37 gliosarcomas including next-generation sequencing data on 25 cases and digital spatial whole-transcriptome analysis on four cases to characterize differential gene expression between glial and mesenchymal components. Gliosarcoma demographic and genetic features were compared to a cohort of 75 primary adult hemispheric IDH-wildtype non-sarcomatous glioblastomas. Patient age, tumor location, sex, and overall survival in gliosarcoma were similar to glioblastoma. Gliosarcomas showed a significantly lower rate of <i>EGFR</i> amplification and a higher rate of <i>NF1</i> mutation compared to glioblastomas in next-generation sequencing analysis. Digital spatial whole-transcriptome analysis showed a distinct transcriptomic profile in sarcomatous regions with over-expression of genes involved in extracellular matrix development and remodeling. Selected differentially expressed transcripts were examined further by immunohistochemistry. The glial elements of gliosarcomas showed higher immunoreactivity for Chitinase-3-like protein 1 (CHI3L1) than glioblastomas, and low to absent immunoreactivity within the sarcomatous elements. Lymphoid Enhancer-Binding Factor 1 (LEF1) immunoreactivity was identified within sarcomatous regions of gliosarcoma without detectable nuclear β-catenin, suggesting a role for β-catenin independent wingless (WNT) effector signaling in sarcomatous transformation. This study adds to the growing literature demonstrating differences in the genetic underpinning of gliosarcoma and glioblastoma, establishes feasibility of spatial transcriptomic approaches in gliosarcoma, and builds on digital spatial profiling-based results as a discovery platform to identify pathways and immunohistochemical markers for further study.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70091","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147479682","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":"Alpha-B-crystallin immunohistochemistry: A sensitive but non-specific marker for epileptogenic lesions","authors":"Ekin Güney,&nbsp;Ilay Caliskan,&nbsp;Tara Saunders,&nbsp;Mercedes Paredes,&nbsp;Calixto-Hope Lucas,&nbsp;Kanish Mirchia,&nbsp;Rufei Lu,&nbsp;Merryl Terry,&nbsp;Erika Cagampan,&nbsp;Melike Pekmezci,&nbsp;Andrew Bollen,&nbsp;Arie Perry,&nbsp;Cathryn R. Cadwell,&nbsp;Tarık Tihan","doi":"10.1111/bpa.70087","DOIUrl":"10.1111/bpa.70087","url":null,"abstract":"&lt;p&gt;Epilepsy is a common neurological disorder associated with a broad spectrum of underlying pathologies. These include neoplastic lesions such as oligodendrogliomas, dysembryoplastic neuroepithelial tumors (DNTs), and gangliogliomas (GGs), as well as non-neoplastic conditions including genetic syndromes, malformations, infections, metabolic disturbances, immune-mediated processes, hypoxic–ischemic injury, and/or trauma [&lt;span&gt;1&lt;/span&gt;]. The overlapping clinical and radiologic findings of non-neoplastic and neoplastic epileptogenic entities render histopathologic evaluation of seizure surgery specimens critical for definitive diagnosis.&lt;/p&gt;&lt;p&gt;In surgical neuropathology, the most frequently encountered non-neoplastic lesions in chronic epilepsy are malformations of cortical development (most commonly focal cortical dysplasias, or FCDs) and mesial temporal sclerosis (MTS). These are classified according to guidelines from the International League Against Epilepsy (ILAE) [&lt;span&gt;2&lt;/span&gt;]. Recent advances in the genetic and epigenetic understanding of FCDs have led to recommendations that integrate molecular analysis with histopathologic evaluation [&lt;span&gt;2, 3&lt;/span&gt;]. However, due to the limited availability and high cost of molecular studies, histopathology remains the gold standard in many clinical settings.&lt;/p&gt;&lt;p&gt;To date, no single immunohistochemical marker has reliably distinguished between various non-neoplastic epileptogenic pathologies. Thus, comprehensive diagnostic evaluation remains necessary for accurate classification [&lt;span&gt;2&lt;/span&gt;]. Alpha-B-crystallin (ABC, also known as CRYAB or HSPB5), a small heat shock protein, and p16, a key regulator of cellular senescence through cyclin-dependent kinase inhibition, have recently been proposed as useful adjunct markers. Previous studies have reported upregulation of these proteins in balloon cells in FCD ILAE type IIb (FCD IIb) cases [&lt;span&gt;4-6&lt;/span&gt;]. Here, we conducted a systematic evaluation of ABC and p16 immunohistochemical staining patterns to assess their utility in the histopathologic work-up of epilepsy surgery specimens.&lt;/p&gt;&lt;p&gt;In this study, immunohistochemistry (IHC) for ABC (polyclonal; platform: Ventana Ultra; vendor: Millipore; incubation time: 32 min; dilution: 1:4000) was performed on 77 non-neoplastic and 42 neoplastic surgical specimens from epilepsy patients. p16 IHC (clone: E6H4; platform: Leica Bond; vendor: Ventana; incubation time: 30 min; undiluted) was applied to 50 of the non-neoplastic and 40 of the neoplastic surgical specimens. Clinical and radiologic data for the non-neoplastic and neoplastic cohort are detailed in Tables S1–S5. ABC IHC was scored as: 0 (absent), 1 (rare), 2 (occasional), and 3 (frequent) positive cells. p16 IHC was scored as: 0 (absent), 1 (rare), 2 (occasional), and 3 (frequent) positivity. The scoring was performed independently by two neuropathologists, with detailed scoring presented in Table S5 and Figure S1.&lt;/p&gt;&lt;p&gt;ABC showed cytoplasmic imm","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146218641","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 19-year-old woman with intermittent headache and dizziness and a large temporal lobe mass","authors":"Sha-Sha Hu,&nbsp;Wei Yan,&nbsp;Bo Wang","doi":"10.1111/bpa.70085","DOIUrl":"10.1111/bpa.70085","url":null,"abstract":"&lt;p&gt;A 19-year-old woman had a 3-month history of intermittent headaches and dizziness. MRI revealed a 7.7 × 6.8 × 6.2 cm right temporal lobe mass involving the choroid plexus, compressing the lateral ventricle with midline shift. The lesion was T1-hypointense (Figure 1), T2-hyperintense, heterogeneously enhancing with mild diffusion restriction. Intraoperatively, the tumor was located in the temporal lobe parenchyma, extending into the lateral ventricle without a capsule. Subsequently, the patient underwent microscopic total tumor resection.&lt;/p&gt;&lt;p&gt;Pathological examination revealed an ependymoma-like pattern, characterized by perivascular pseudorosettes (Figure 2A, Box 1) and microcystic areas containing basophilic secretions (Figure 2B). The tumor exhibited high cellularity, nuclear atypia, and increased mitoses (up to 6/mm&lt;sup&gt;2&lt;/sup&gt; in hotspots) in ependymoma-like pattern regions. Necrosis (Figure 2A, inset) and hyalinized stroma (Figure 2B, inset) were seen locally. Although supratentorial ependymoma was initially suspected, the diagnosis was not fully supported by the minimal focal expression of GFAP, EMA, and S100, along with negative FISH testing for &lt;i&gt;ZFTA::RELA&lt;/i&gt;. Meanwhile, RNA-seq identified only a &lt;i&gt;SAMD5::SASH1&lt;/i&gt; fusion transcript (Figure 2F). An extensive immunohistochemical panel showed diffuse positivity for BCOR (Figure 2C), vimentin (Figure 2C, inset), CD56 (Figure 2D, inset), and CD99, and a Ki-67 index of 40% (Figure 2D), suggesting a CNS tumor with &lt;i&gt;BCOR&lt;/i&gt; internal tandem duplication (ITD). Subsequent whole-genome sequencing confirmed a heterozygous ITD in &lt;i&gt;BCOR&lt;/i&gt; exon 15 (Figure 2E). No hotspot mutations (e.g., in &lt;i&gt;IDH1/2&lt;/i&gt;, &lt;i&gt;TERT&lt;/i&gt;, &lt;i&gt;ATRX&lt;/i&gt;, &lt;i&gt;TP53&lt;/i&gt;, &lt;i&gt;CDKN2A/B&lt;/i&gt;) or structural variations (e.g., in &lt;i&gt;MN1&lt;/i&gt; or &lt;i&gt;CIC&lt;/i&gt;) were detected.&lt;/p&gt;&lt;p&gt;Postoperatively, she underwent radiotherapy (56Gy/28f) for 1 year without signs of local recurrence. One year after radiotherapy, she began to experience a persistent cough, dyspnea, and CT scan showed multiple lung nodules and left pleural effusion, pathologically confirmed as metastases. Despite aggressive treatment and chemotherapy, she succumbed to respiratory failure 1 month later.&lt;/p&gt;&lt;p&gt;CNS tumor with &lt;i&gt;BCOR&lt;/i&gt; internal tandem duplication (ITD).&lt;/p&gt;&lt;p&gt;The 2021 WHO classification defines CNS tumors with &lt;i&gt;BCOR&lt;/i&gt; ITD as malignant embryonal neoplasms of uncertain origin, characterized by a heterozygous ITD in &lt;i&gt;BCOR&lt;/i&gt; exon 15 and a solid growth patterns of oval-spindle cells with a dense capillary network and focal pseudorosettes [&lt;span&gt;1&lt;/span&gt;]. &lt;i&gt;BCOR&lt;/i&gt; ITDs also occur in certain sarcomas, such as primitive myxoid mesenchymal tumor of infancy, clear cell sarcoma of the kidney, and undifferentiated round cell sarcomas in infants, and the nosological relationship among these entities continues to be debated [&lt;span&gt;1&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Somatic heterozygous &lt;i&gt;BCOR&lt;/i&gt; ITD is a key oncogenic driver, often as the sole alteration, although addit","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70085","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147282685","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":"New perspectives on VEGF signalling in Alzheimer's disease","authors":"Cherelle E. G. Emery,&nbsp;Seth Love,&nbsp;J. Scott Miners","doi":"10.1111/bpa.70100","DOIUrl":"10.1111/bpa.70100","url":null,"abstract":"<p>Vascular endothelial growth factor (VEGF) signalling mediates pleiotropic effects within the brain, encompassing angiogenesis, neuronal survival, and immune signalling. There is growing interest in the role of VEGF signalling in the pathophysiology of Alzheimer's disease (AD). The generation of single-cell brain atlases and recent large multi-omic studies, including analysis of CSF and bloods alongside post-mortem brain tissue, have provided novel insights into the role of VEGF signalling in AD. Disruption of the VEGF-A/VEGFR2 signalling pathway, due in part to elevated soluble VEGFR1 expression may contribute to pathogenic angiogenesis, BBB leakiness, and neuronal loss in AD. Induction of VEGF-B/VEGFR1 signalling in microglia suggests that dysregulated VEGF-mediated immune cell signalling is a further influence on AD pathogenesis. A reduction in expression of the ‘protective’ VEGFR3 and co-receptors neuropilin 1 and 2 has also been recently linked to cognitive decline in AD. In large clinical studies, lower VEGF-A levels in CSF and serum, raised soluble VEGFR1in CSF and elevated PlGF in CSF and serum, are predictive of more rapid cognitive decline and accelerated Alzheimer's disease neuropathological change (ADNC). This review discusses findings from recent multi-omic studies of large clinical and neuropathological studies that prompt reconsideration of the nature of VEGF signalling in AD and shed light on some of the complexities and previous conflicts within the field.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70100","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147670503","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":"TANC1::HTRA1 fusion in schwannomas","authors":"Ilay Caliskan,&nbsp;Kanish Mirchia,&nbsp;Walter Patrick Devine,&nbsp;Melike Pekmezci","doi":"10.1111/bpa.70084","DOIUrl":"10.1111/bpa.70084","url":null,"abstract":"&lt;p&gt;Schwannomas are benign peripheral nerve sheath tumors that can arise either sporadically, frequently involving somatic alterations in &lt;i&gt;NF2&lt;/i&gt;, &lt;i&gt;ARID1A&lt;/i&gt;, &lt;i&gt;ARID1B&lt;/i&gt;, and &lt;i&gt;DDR1&lt;/i&gt; genes [&lt;span&gt;1&lt;/span&gt;], or in the context of schwannomatosis, which is associated with germline &lt;i&gt;SMARCB1&lt;/i&gt; or &lt;i&gt;LZTR1&lt;/i&gt; mutations [&lt;span&gt;2&lt;/span&gt;]. A distinct subset of schwannomas has been shown to harbor an &lt;i&gt;SH3PXD2A::HTRA1&lt;/i&gt; fusion, including both sporadic cases [&lt;span&gt;3&lt;/span&gt;] and those associated with &lt;i&gt;LZTR1&lt;/i&gt; germline mutations [&lt;span&gt;2&lt;/span&gt;]. These fusion-positive tumors have a younger age of onset, preference for somatic sites over intracranial/spinal locations, and display a serpentine morphology [&lt;span&gt;3&lt;/span&gt;]. Functional studies have demonstrated increased phosphorylated ERK (pERK) levels in vivo and in vitro [&lt;span&gt;1&lt;/span&gt;], providing support for Ras/MEK/ERK pathway activation in &lt;i&gt;SH3PXD2A::HTRA1&lt;/i&gt; fusion schwannomas. We describe two schwannomas harboring a fusion involving HTRA1 and an alternative partner, TANC1, which further supports that the HTRA1 portion of the fusion protein drives its tumorigenic activity.&lt;/p&gt;&lt;p&gt;Patient #1 is a 45-year-old male who presented with a palpable mass of the right medial upper thigh, found to have a 3 cm T2-hyperintense heterogeneously enhancing tumor originating from the right obturator nerve on MR imaging (Figure 1A). Patient #2 is a 34-year-old female who presented with bilateral upper extremity paresthesia. MR imaging revealed a 4.5 cm homogenously enhancing tumor in the left C2–C3 neural foramen (Figure 1E).&lt;/p&gt;&lt;p&gt;The histologic sections from both tumors showed a variably cellular proliferation of bland spindle cells, arranged in fascicles and focally forming twisting nuclear palisades with intervening areas of compact eosinophilic nuclear-free zones (Figure 1B,C,F,G), a pattern reminiscent but not classical for Verocay bodies. Mitotic activity was inconspicuous, with no cytologic atypia or necrosis.&lt;/p&gt;&lt;p&gt;Targeted DNA-based next generation sequencing (NGS) was performed as previously described [&lt;span&gt;4&lt;/span&gt;], which showed a solitary in-frame gene fusion involving the &lt;i&gt;TANC1&lt;/i&gt; and &lt;i&gt;HTRA1&lt;/i&gt; genes as a result of a balanced translocation between chromosome 2q24 and chromosome 10q26 with breakpoints involving intron 3 of &lt;i&gt;TANC1&lt;/i&gt; and intron 1 of &lt;i&gt;HTRA1&lt;/i&gt; in tumor #1. Tumor #2 underwent a tumor-normal paired targeted next-generation sequencing which revealed no pathogenic or likely pathogenic somatic or germline alterations or copy number changes.&lt;/p&gt;&lt;p&gt;Whole transcriptome RNA sequencing demonstrated an in-frame fusion (Figure 1I), where the N-terminal portion is composed of exons 1–3 of &lt;i&gt;TANC1&lt;/i&gt; and the C-terminal is composed of exons 2–9 of &lt;i&gt;HTRA1&lt;/i&gt;. The fusion proteins retain the functional trypsin and PDZ domains of the HTRA1, similar to what was described in the pathogenic &lt;i&gt;SH3PXD2A::HTRA1&lt;/i&gt; fusion [&lt;span&gt;3, 5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;&lt;i&gt;HTRA1&lt;/i&gt; encodes a se","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70084","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146177932","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":"Artificial intelligence-based statistical modeling delineates architectural distortion in focal cortical dysplasia","authors":"Andrew Cannon,&nbsp;Roland Tian,&nbsp;Blake Ebner,&nbsp;Robert E. Watson Jr.,&nbsp;Brian Burkett,&nbsp;Jamie Van Gompel,&nbsp;Lily C. Wong-Kisiel,&nbsp;Christopher P. Hartley,&nbsp;Roger K. Moreira,&nbsp;Aditya Raghunathan","doi":"10.1111/bpa.70096","DOIUrl":"https://doi.org/10.1111/bpa.70096","url":null,"abstract":"<p>In epilepsy patients lacking magnetic resonance imaging-visible lesions such as focal cortical dysplasia (FCD), surgical resections target regions with abnormal electroencephalographic (EEG) activity. However, histopathological identification of subtle cortical architectural abnormalities in these specimens remains challenging. We investigated whether artificial intelligence (AI)-based morphometric and spatial analysis of NeuN-stained cortical sections could detect neuronal architectural disorganization in epilepsy resections, including regions without definitive histologic dysplasia. Whole slide images were generated from 83 FCD regions and 19 neurologically normal autopsy controls. Regions of interest were annotated in QuPath as FCD, FCD-adjacent, FCD-distant, apparently normal (abnormal EEG without histologic dysplasia), and true normal (autopsy controls). NeuN-positive neurons were detected using QuPath (90% sensitivity, 12% false positive rate). Spatial and morphometric features—including neuronal clustering, distribution inhomogeneity, and nuclear morphology—were extracted and used to train a multinomial, Least Absolute Shrinkage and Selection Operator-regularized regression classifier. The classifier achieved 70.6% accuracy in subregion classification and 88.2% accuracy in overall specimen diagnosis. Notably, regions with abnormal EEG but lacking histologic dysplasia exhibited quantifiable architectural disorganization similar to those seen in areas adjacent to FCD and distinct from control tissue. AI-driven analysis of neuronal morphology and spatial distribution reveals subtle cortical disorganization in epilepsy resections, including in histologically ambiguous regions. Further investigation is warranted to determine if this methodology can enhance the diagnostic yield of neuropathological evaluation and support more precise surgical targeting in epilepsy.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"36 5","pages":""},"PeriodicalIF":5.0,"publicationDate":"2026-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70096","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148652447","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}