Brain Pathology最新文献

{"title":"Astrocyte-derived Interleukin-31 causes poor prognosis in elderly patients with intracerebral hemorrhage","authors":"Rui Jiang,&nbsp;Zhichao Lu,&nbsp;Chenxing Wang,&nbsp;WenJun Tu,&nbsp;Qi Yao,&nbsp;Jiabing Shen,&nbsp;Xingjia Zhu,&nbsp;Ziheng Wang,&nbsp;Yixun Chen,&nbsp;Yang Yang,&nbsp;Kaijiang Kang,&nbsp;Peipei Gong","doi":"10.1111/bpa.13245","DOIUrl":"10.1111/bpa.13245","url":null,"abstract":"<p>The incidence of intracerebral hemorrhage (ICH) is increasing every year, with very high rates of mortality and disability. The prognosis of elderly ICH patients is extremely unfavorable. Interleukin, as an important participant in building the inflammatory microenvironment of the central nervous system after ICH, has long been the focus of neuroimmunology research. However, there are no studies on the role IL31 play in the pathologic process of ICH. We collected para-lesion tissue for immunofluorescence and flow cytometry from the elderly and young ICH patients who underwent surgery. Here, we found that IL31 expression in the lesion of elderly ICH patients was significantly higher than that of young patients. The activation of astrocytes after ICH releases a large amount of IL31, which binds to microglia through IL31R, causing a large number of microglia to converge to the hematoma area, leading to the spread of neuroinflammation, apoptosis of neurons, and ultimately resulting in poorer recovery of nerve function. Interfering with IL31 expression suppresses neuroinflammation and promotes the recovery of neurological function. Our study demonstrated that elderly patients release more IL31 after ICH than young patients. IL31 promotes the progression of neuroinflammation, leading to neuronal apoptosis as well as neurological decline. Suppression of high IL31 concentrations in the brain after ICH may be a promising therapeutic strategy for ICH.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13245","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139734511","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 24-year-old woman with a recurrent intracranial mass","authors":"Yan Peng,&nbsp;Wei Zhao,&nbsp;Dachuan Zhang,&nbsp;Xie Gao,&nbsp;Yongqiang Shi,&nbsp;Qing Li,&nbsp;Jian Wang","doi":"10.1111/bpa.13242","DOIUrl":"10.1111/bpa.13242","url":null,"abstract":"&lt;p&gt;A 24-year-old woman presented with headache, dizziness, and tinnitus that had lasted for 3 months. Pre-operative magnetic resonance imaging (MRI) demonstrated a 6 × 4.9 × 4.3 cm well-circumscribed mass located in the right frontal lobe adjacent to the cerebral falx. The mass showed heterogeneous signal intensity and both solid and cystic components with perilesional brain edema on T1-weighted (Figure 1A) and T2-weighted images. Microsurgical tumor resection was performed. During the operation, it was found that the tumor originated from the falx and had infiltrated the opposite side. Gross total resection of the tumor was achieved with the adherent falx. The patient received no adjuvant treatment after the operation and had local recurrence 26 months after surgery, marked by the presence of headache. MRI demonstrated a 4.5 × 3.0 × 2.9 cm cystic-solid mass at the local recurrence (Figure 1B). The patient underwent gross total resection again and had a disease-free survival time of 14 months.&lt;/p&gt;&lt;p&gt;Histopathological examination revealed similar morphological features in both primary and recurrent tumors (Box 1). A fibrous pseudocapsule was present at the periphery of both tumors, which showed solid tumor cell nodules. A dense lymphoplasmacytic infiltrate with lymphoid follicles was present along the pseudocapsule and the periphery of the nodules (Figure 2A), which led to our first consideration of angiomatoid fibrous histiocytoma (AFH). Blood-filled pseudoangiomatoid cystic spaces and intratumor hemorrhage with hemosiderin were identified. Tumor cell morphology mainly included epithelioid, rhabdoid (Figure 2B), oval, and spindle morphology. Epithelioid cells embedded in a dense sclerotic stroma were seen (Figure 2C). The tumor cells had indistinct cell borders and inconspicuous nucleoli. Mitotic activity was low. Immunohistochemistry, the tumor cells were diffusely positive for desmin (Figure 2D) and CD99, and some were positive for EMA (Figure 2E) and MUC4. Few cells presented weak expression of ALK. The tumor cells were negative for S100, CD34, CD31, STAT6, HMB45, CD21, CD68, Synaptophysin, Chromogranin, WT1. The Ki-67 index was 5%. Next-generation sequencing (NGS) revealed that the tumor harbored exon 7 of the FUS gene and exon 6 of the CREM gene fusion (Figure 2F).&lt;/p&gt;&lt;p&gt;Intracranial mesenchymal tumor, &lt;i&gt;FET::CREB&lt;/i&gt; fusion-positive.&lt;/p&gt;&lt;p&gt;FET family (EWSR1 and FUS) fusions with CREB family (CREB1, CREM, and ATF1) are found in a wide variety of tumor entities. Kao et al [&lt;span&gt;1&lt;/span&gt;] first reported the occurrence of a unique myxoid mesenchymal tumor with &lt;i&gt;EWSR1&lt;/i&gt; fusions with &lt;i&gt;CREB&lt;/i&gt; family members in young patients with intracranial predilection in 2017. Previous studies speculated that these tumors may represent a myxoid variant of AFH occurring intracranially or a novel intracranial myxoid mesenchymal tumor (IMMT). Sloan et al. [&lt;span&gt;2&lt;/span&gt;] studied the largest numbers of these tumors, reviewed previously reported cases, a","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 2","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13242","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691268","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":"Transient receptor potential vanilloid 1 inhibition reduces brain damage by suppressing neuronal apoptosis after intracerebral hemorrhage","authors":"Chien-Cheng Chen,&nbsp;Chia-Hua Ke,&nbsp;Chun-Hu Wu,&nbsp;Hung-Fu Lee,&nbsp;Yuan Chao,&nbsp;Min-Chien Tsai,&nbsp;Song-Kun Shyue,&nbsp;Szu-Fu Chen","doi":"10.1111/bpa.13244","DOIUrl":"10.1111/bpa.13244","url":null,"abstract":"<p>Intracerebral hemorrhage (ICH) induces a complex sequence of apoptotic cascades and inflammatory responses, leading to neurological impairment. Transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel with high calcium permeability, has been implicated in neuronal apoptosis and inflammatory responses. This study used a mouse ICH model and neuronal cultures to examine whether TRPV1 activation exacerbates brain damage and neurological deficits by promoting neuronal apoptosis and neuroinflammation. ICH was induced by injecting collagenase in both wild-type (WT) C57BL/6 mice and TRPV1^−/− mice. Capsaicin (CAP; a TRPV1 agonist) or capsazepine (a TRPV1 antagonist) was administered by intracerebroventricular injection 30 min before ICH induction in WT mice. The effects of genetic deletion or pharmacological inhibition of TRPV1 using CAP or capsazepine on motor deficits, histological damage, apoptotic responses, blood–brain barrier (BBB) permeability, and neuroinflammatory reactions were explored. The antiapoptotic mechanisms and calcium influx induced by TRPV1 inactivation were investigated in cultured hemin-stimulated neurons. TRPV1 expression was upregulated in the hemorrhagic brain, and TRPV1 was expressed in neurons, microglia, and astrocytes after ICH. Genetic deletion of TRPV1 significantly attenuated motor deficits and brain atrophy for up to 28 days. Deletion of TRPV1 also reduced brain damage, neurodegeneration, microglial activation, cytokine expression, and cell apoptosis at 1 day post-ICH. Similarly, the administration of CAP ameliorated brain damage, neurodegeneration, brain edema, BBB permeability, and cytokine expression at 1 day post-ICH. In primary neuronal cultures, pharmacological inactivation of TRPV1 by CAP attenuated neuronal vulnerability to hemin-induced injury, suppressed apoptosis, and preserved mitochondrial integrity in vitro. Mechanistically, CAP reduced hemin-stimulated calcium influx and prevented the phosphorylation of CaMKII in cultured neurons, which was associated with reduced activation of P38 and c-Jun NH₂-terminal kinase mitogen-activated protein kinase signaling. Our results suggest that TRPV1 inhibition may be a potential therapy for ICH by suppressing mitochondria-related neuronal apoptosis.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13244","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139671314","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":"Apolipoprotein-E genotyping in formalin-fixed and paraffin-embedded post-mortem brain tissue","authors":"James Minshull,&nbsp;Yvonne Davidson,&nbsp;Federico Roncaroli,&nbsp;Andrew C. Robinson","doi":"10.1111/bpa.13243","DOIUrl":"10.1111/bpa.13243","url":null,"abstract":"<p>Formalin-fixed paraffin-embedded (FFPE) brain tissue held in tissue banks constitutes a valuable research resource, especially when associated with clinical annotations and longitudinal psychometric testing. Apolipoprotein-E (APOE) genotyping is important to fully characterise this resource, however older FFPE tissue may not be suitable for genotyping. We performed polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) assays on DNA extracted from post-mortem FFPE brain tissue ranging from 2-19 years old. A maximum of three years in paraffin was determined for robust APOE genotyping of FFPE tissue using PCR-RFLP which may suggest prolonged storage of fixed tissue as FFPE blocks may have deleterious effects on DNA.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13243","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139545727","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 relation between BTK expression and iron accumulation of myeloid cells in multiple sclerosis","authors":"Anja Steinmaurer,&nbsp;Christian Riedl,&nbsp;Theresa König,&nbsp;Giulia Testa,&nbsp;Ulrike Köck,&nbsp;Jan Bauer,&nbsp;Hans Lassmann,&nbsp;Romana Höftberger,&nbsp;Thomas Berger,&nbsp;Isabella Wimmer,&nbsp;Simon Hametner","doi":"10.1111/bpa.13240","DOIUrl":"10.1111/bpa.13240","url":null,"abstract":"<p>Activation of Bruton's tyrosine kinase (BTK) has been shown to play a crucial role in the proinflammatory response of B cells and myeloid cells upon engagement with B cell, Fc, Toll-like receptor, and distinct chemokine receptors. Previous reports suggest BTK actively contributes to the pathogenesis of multiple sclerosis (MS). The BTK inhibitor Evobrutinib has been shown to reduce the numbers of gadolinium-enhancing lesions and relapses in relapsing–remitting MS patients. In vitro, BTK inhibition resulted in reduced phagocytic activity and modulated BTK-dependent inflammatory signaling of microglia and macrophages. Here, we investigated the protein expression of BTK and CD68 as well as iron accumulation in postmortem control (<i>n</i> = 10) and MS (<i>n</i> = 23) brain tissue, focusing on microglia and macrophages. MS cases encompassed active, chronic active, and inactive lesions. BTK⁺ and iron⁺ cells positively correlated across all regions of interests and, along with CD68, revealed highest numbers in the center of active and at the rim of chronic active lesions. We then studied the effect of BTK inhibition in the human immortalized microglia-like HMC3 cell line in vitro. In particular, we loaded HMC3 cells with iron-dextran and subsequently administered the BTK inhibitor Evobrutinib. Iron treatment alone induced a proinflammatory phenotype and increased the expression of iron importers as well as the intracellular iron storage protein ferritin light chain (FTL). BTK inhibition of iron-laden cells dampened the expression of microglia-related inflammatory genes as well as iron-importers, whereas the iron-exporter ferroportin was upregulated. Our data suggest that BTK inhibition not only dampens the proinflammatory response but also reduces iron import and storage in activated microglia and macrophages with possible implications on microglial iron accumulation in chronic active lesions in MS.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13240","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139520201","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":"Proteomic analysis identifies HSP90AA1, PTK2B, and ANXA2 in the human entorhinal cortex in Alzheimer's disease: Potential role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells","authors":"Veronica Astillero-Lopez,&nbsp;Sandra Villar-Conde,&nbsp;Melania Gonzalez-Rodriguez,&nbsp;Alicia Flores-Cuadrado,&nbsp;Isabel Ubeda-Banon,&nbsp;Daniel Saiz-Sanchez,&nbsp;Alino Martinez-Marcos","doi":"10.1111/bpa.13235","DOIUrl":"10.1111/bpa.13235","url":null,"abstract":"<p>Alzheimer's disease (AD), the most prevalent neurodegenerative disorder worldwide, is clinically characterized by cognitive deficits. Neuropathologically, AD brains accumulate deposits of amyloid-β (Aβ) and tau proteins. Furthermore, these misfolded proteins can propagate from cell to cell in a prion-like manner and induce native proteins to become pathological. The entorhinal cortex (EC) is among the earliest areas affected by tau accumulation along with volume reduction and neurodegeneration. Neuron–glia interactions have recently come into focus; however, the role of microglia and astroglia in the pathogenesis of AD remains unclear. Proteomic approaches allow the determination of changes in the proteome to better understand the pathology underlying AD. Bioinformatic analysis of proteomic data was performed to compare ECs from AD and non-AD human brain tissue. To validate the proteomic results, western blot, immunofluorescence, and confocal studies were carried out. The findings revealed that the most disturbed signaling pathway was synaptogenesis. Because of their involvement in synapse function, relationship with Aβ and tau proteins and interactions in the pathway analysis, three proteins were selected for in-depth study: HSP90AA1, PTK2B, and ANXA2. All these proteins showed colocalization with neurons and/or astroglia and microglia and with pathological Aβ and tau proteins. In particular, ANXA2, which is overexpressed in AD, colocalized with amoeboid microglial cells and Aβ plaques surrounded by astrocytes. Taken together, the evidence suggests that unbalanced expression of HSP90AA1, PTK2B, and ANXA2 may play a significant role in synaptic homeostasis and Aβ pathology through microglial and astroglial cells in the human EC in AD.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13235","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139511862","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":"Induced pluripotent stem cell models as a tool to investigate and test fluid biomarkers in Alzheimer's disease and frontotemporal dementia","authors":"Julie J. McInvale,&nbsp;Peter Canoll,&nbsp;Gunnar Hargus","doi":"10.1111/bpa.13231","DOIUrl":"10.1111/bpa.13231","url":null,"abstract":"<p>Neurodegenerative diseases are increasing in prevalence and comprise a large socioeconomic burden on patients and their caretakers. The need for effective therapies and avenues for disease prevention and monitoring is of paramount importance. Fluid biomarkers for neurodegenerative diseases have gained a variety of uses, including informing participant selection for clinical trials, lending confidence to clinical diagnosis and disease staging, determining prognosis, and monitoring therapeutic response. Their role is expected to grow as disease-modifying therapies start to be available to a broader range of patients and as prevention strategies become established. Many of the underlying molecular mechanisms of currently used biomarkers are incompletely understood. Animal models and in vitro systems using cell lines have been extensively employed but face important translatability limitations. Induced pluripotent stem cell (iPSC) technology, where a theoretically unlimited range of cell types can be reprogrammed from peripheral cells sampled from patients or healthy individuals, has gained prominence over the last decade. It is a promising avenue to study physiological and pathological biomarker function and response to experimental therapeutics. Such systems are amenable to high-throughput drug screening or multiomics readouts such as transcriptomics, lipidomics, and proteomics for biomarker discovery, investigation, and validation. The present review describes the current state of biomarkers in the clinical context of neurodegenerative diseases, with a focus on Alzheimer's disease and frontotemporal dementia. We include a discussion of how iPSC models have been used to investigate and test biomarkers such as amyloid-β, phosphorylated tau, neurofilament light chain or complement proteins, and even nominate novel biomarkers. We discuss the limitations of current iPSC methods, mentioning alternatives such as coculture systems and three-dimensional organoids which address some of these concerns. Finally, we propose exciting prospects for stem cell transplantation paradigms using animal models as a preclinical tool to study biomarkers in the in vivo context.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13231","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139511860","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":"Phenotype parallels protein seeding capacity in neurodegenerative diseases","authors":"Ivan Martinez-Valbuena","doi":"10.1111/bpa.13238","DOIUrl":"10.1111/bpa.13238","url":null,"abstract":"<p>With the new era of disease-modifying therapies for neurodegenerative diseases, a novel approach for the molecular classification of neurodegenerative diseases is needed. In this research letter, there is a summary of the advances made in Alzheimer's disease, Lewy body disorders, and progressive supranuclear palsy toward this classification.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 2","pages":""},"PeriodicalIF":6.4,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13238","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139429262","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":"Diagnostic utility of genetic alterations in distinguishing IDH-wildtype glioblastoma from lower-grade gliomas: Insight from next-generation sequencing analysis of 479 cases","authors":"Boram Lee,&nbsp;Soohyun Hwang,&nbsp;Hyunsik Bae,&nbsp;Kyue-Hee Choi,&nbsp;Yeon-Lim Suh","doi":"10.1111/bpa.13234","DOIUrl":"10.1111/bpa.13234","url":null,"abstract":"<p>The accurate diagnosis and classification of gliomas are essential for appropriate treatment planning and prognosis prediction. This study aimed to investigate the molecular diagnostics of IDH-wildtype diffuse astrocytic gliomas and identify potential genetic variants that could differentiate glioblastoma (GBM) from lower-grade gliomas when DNA methylation analysis is not feasible. In total, 479 H3-and IDH-wildtype diffuse astrocytic gliomas were included in this study. All the cases were diagnosed according to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Panel sequencing data were collected, and clinicopathological information was retrieved from medical records. Genetic alterations and histological findings were analyzed to determine their diagnostic utility and prognostic implications. Out of 479 cases, 439 (91.6%) were diagnosed with GBM, including 28 cases that were molecularly diagnosed as GBM. However, 40 (8.4%) cases could not be classified according to the 2021 WHO classification and were diagnosed as lower-grade diffuse astrocytic glioma, IDH-wildtype, not elsewhere classified (LGNEC). In addition to the three genetic alterations included in the diagnostic criteria of GBM, <i>PTEN</i> and <i>EGFR</i> mutations were found to be enriched in GBM. Patients harboring mTOR pathway mutations demonstrated a more favorable prognosis and often exhibited morphology resembling subependymal giant cell astrocytoma, along with a high tumor mutational burden. Among patients with mTOR pathway mutations, those lacking molecular diagnostic features of GBM exhibited outstanding survival outcomes, even in the presence of grade 4 histology. Integration of molecular features enhanced the diagnostic accuracy of IDH-wildtype gliomas. Some molecular alterations enriched in GBM offer valuable insights for molecular diagnosis and glioma classification. Furthermore, high-grade diffuse astrocytic gliomas featuring mTOR pathway mutations in the absence of molecular diagnostic features of GBM could represent more favorable tumor types distinct from GBM.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13234","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139461725","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":"Morphology-based molecular classification of spinal cord ependymomas using deep neural networks","authors":"Yannis Schumann,&nbsp;Matthias Dottermusch,&nbsp;Leonille Schweizer,&nbsp;Maja Krech,&nbsp;Tasja Lempertz,&nbsp;Ulrich Schüller,&nbsp;Philipp Neumann,&nbsp;Julia E. Neumann","doi":"10.1111/bpa.13239","DOIUrl":"10.1111/bpa.13239","url":null,"abstract":"<p>Based on DNA-methylation, ependymomas growing in the spinal cord comprise two major molecular types termed spinal (SP-EPN) and myxopapillary ependymomas (MPE(-A/B)), which differ with respect to their clinical features and prognosis. Due to the existing discrepancy between histomorphogical diagnoses and classification using methylation data, we asked whether deep neural networks can predict the DNA methylation class of spinal cord ependymomas from hematoxylin and eosin stained whole-slide images. Using explainable AI, we further aimed to prospectively improve the consistency of histology-based diagnoses with DNA methylation profiling by identifying and quantifying distinct morphological patterns of these molecular ependymoma types. We assembled a case series of 139 molecularly characterized spinal cord ependymomas (<i>n</i>_MPE = 84, <i>n</i>_SP-EPN = 55). Self-supervised and weakly-supervised neural networks were used for classification. We employed attention analysis and supervised machine-learning methods for the discovery and quantification of morphological features and their correlation to the diagnoses of experienced neuropathologists. Our best performing model predicted the DNA methylation class with 98% test accuracy and used self-supervised learning to outperform pretrained encoder-networks (86% test accuracy). In contrast, the diagnoses of neuropathologists matched the DNA methylation class in only 83% of cases. Domain-adaptation techniques improved model generalization to an external validation cohort by up to 22%. Statistically significant morphological features were identified per molecular type and quantitatively correlated to human diagnoses. The approach was extended to recently defined subtypes of myxopapillary ependymomas (MPE-(A/B), 80% test accuracy). In summary, we demonstrated the accurate prediction of the DNA methylation class of spinal cord ependymomas (SP-EPN, MPE(-A/B)) using hematoxylin and eosin stained whole-slide images. Our approach may prospectively serve as a supplementary resource for integrated diagnostics and may even help to establish a standardized, high-quality level of histology-based diagnostics across institutions—in particular in low-income countries, where expensive DNA-methylation analyses may not be readily available.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"34 5","pages":""},"PeriodicalIF":5.8,"publicationDate":"2024-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.13239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139416413","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}