Acta Neuropathologica Communications最新文献

{"title":"Spatial transcriptomics in focal cortical dysplasia type IIb.","authors":"Yujiao Wang, Yihe Wang, Linai Guo, Chunhao Shen, Yongjuan Fu, Penghu Wei, Yongzhi Shan, Qian Wu, Yue-Shan Piao, Guoguang Zhao","doi":"10.1186/s40478-024-01897-7","DOIUrl":"10.1186/s40478-024-01897-7","url":null,"abstract":"<p><p>Focal cortical dysplasia (FCD) type IIb (FCD IIb) is an epileptogenic malformation of the neocortex that is characterized by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). Approximately 30-60% of lesions are associated with brain somatic mutations in the mTOR pathway. Herein, we investigated the transcriptional changes around the DNs and BCs regions in freshly frozen brain samples from three patients with FCD IIb by using spatial transcriptomics. We demonstrated that the DNs region in a gene enrichment network enriched for the mTOR signalling pathway, autophagy and the ubiquitin‒proteasome system, additionally which are involved in regulating membrane potential, may contribute to epileptic discharge. Moreover, differential expression analysis further demonstrated stronger expression of components of the inflammatory response and complement activation in the BCs region. And the DNs and BCs regions exhibited common functional modules, including regulation of cell morphogenesis and developmental growth. Furthermore, the expression of representative proteins in the functional enrichment module mentioned above was increased in the lesions of FCD IIb, such as p62 in DNs and BCs, UCHL1 in DNs, and C3 and CLU in BCs, which was confirmed via immunohistochemistry. Collectively, we constructed a spatial map showing the potential effects and functions of the DNs and BCs regions at the transcriptomic level and generated publicly available data on human FCD IIb to facilitate future research on human epileptogenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"185"},"PeriodicalIF":6.2,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754449","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":"Retinal cytoarchitecture is preserved in an organotypic perfused human and porcine eye model.","authors":"Darren Chan, Jenny Wanyu Zhang, Gah-Jone Won, Jeremy M Sivak","doi":"10.1186/s40478-024-01892-y","DOIUrl":"https://doi.org/10.1186/s40478-024-01892-y","url":null,"abstract":"<p><p>Pathobiology of the intact human retina has been challenging to study due to its relative inaccessibility and limited sample availability. Thus, there is a great need for new translational models that can maintain human retinal integrity and cytoarchitecture. The role of physiologic intraocular pressure (IOP) and fluid flow on retinal tissue has not been well studied. Here, we present an ex vivo organotypic model to assess the impact of physiological intraocular perfusion on retinal cytoarchitecture and cell survival. We demonstrate that retinal cytoarchitecture is remarkably well preserved following re-establishment of physiological IOP and aqueous humor dynamics for up to 24 h in ex vivo whole globe porcine and human eyes, comparable to freshly preserved control eyes. Accordingly, cell death was minimized in the perfused retinas, which also displayed normal markers of cellular metabolism and astrogliosis. These results are in marked contrast to contralateral control eyes without active perfusion, which displayed excessive cell death and disrupted cytoarchitecture at the same time point. These experiments demonstrate the critical impact that physiological pressure and fluid flow have on retinal tissue, and introduce a new pre-clinical model to study human and porcine retinal health and degeneration in a relevant biomechanical setting.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"186"},"PeriodicalIF":6.2,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11607936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765333","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":"ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice.","authors":"Mai Horiuchi, Seiji Watanabe, Okiru Komine, Eiki Takahashi, Kumi Kaneko, Shigeyoshi Itohara, Mayuko Shimada, Tomoo Ogi, Koji Yamanaka","doi":"10.1186/s40478-024-01893-x","DOIUrl":"10.1186/s40478-024-01893-x","url":null,"abstract":"<p><p>Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43^M337V in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43^M337V and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43^M337V with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43^M337V. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43^M337V overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"184"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737920","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":"Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals.","authors":"Melissa J Alldred, Kyrillos W Ibrahim, Harshitha Pidikiti, Gabriela Chiosis, Elliott J Mufson, Grace E Stutzmann, Stephen D Ginsberg","doi":"10.1186/s40478-024-01891-z","DOIUrl":"10.1186/s40478-024-01891-z","url":null,"abstract":"<p><p>Selective vulnerability of neuronal populations occurs in both Down syndrome (DS) and Alzheimer's disease (AD), resulting in disproportional degeneration of pyramidal neurons (PNs) affecting memory and executive function. Elucidating the cellular mechanisms underlying the selective vulnerability of these populations will provide pivotal insights for disease progression in DS and AD. Single population RNA-sequencing analysis was performed on neurons critical for executive function, prefrontal cortex Brodmann area 9 (BA9) layer III (L3) and layer V (L5) excitatory PNs in postmortem human DS and age- and sex-matched control (CTR) brains. Data mining was performed on differentially expressed genes (DEGs) from PNs in each lamina with DEGs divergent between lamina identified and interrogated. Bioinformatic inquiry of L3 PNs revealed more unique/differentially expressed DEGs (uDEGs) than in L5 PNs in DS compared to CTR subjects, indicating gene dysregulation shows both spatial and cortical laminar projection neuron dependent dysregulation. DS triplicated human chromosome 21 (HSA21) comprised a subset of DEGs only dysregulated in L3 or L5 neurons, demonstrating partial cellular specificity in HSA21 expression. These HSA21 uDEGs had a disproportionally high number of noncoding RNAs, suggesting lamina specific dysfunctional gene regulation. L3 uDEGs revealed overall more dysregulation of cellular pathways and processes, many relevant to early AD pathogenesis, while L5 revealed processes suggestive of frank AD pathology. These findings indicate that trisomy differentially affects a subpopulation of uDEGs in L3 and L5 BA9 projection neurons in aged individuals with DS, which may inform circuit specific pathogenesis underlying DS and AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"182"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603868/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737929","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":"Towards integrating imaging and immunology in glioblastoma: mapping blood immune system metrics to tumor magnetic resonance image data.","authors":"Johanna Heugenhauser, Carmen Visus, Johanna Buchroithner, Christine Marosi, Karl Rössler, Thomas Felzmann, Georg Widhalm, Sarah Iglseder, Martha Nowosielski, Friedrich Erhart","doi":"10.1186/s40478-024-01888-8","DOIUrl":"10.1186/s40478-024-01888-8","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is the most frequent and aggressive brain cancer. It is a highly immunology-driven disease as up to a third of its mass is composed of immune cells. Apart from immunology, imaging is a major research frontier. The VASARI (Visually AcceSAble Rembrandt Images) MRI feature set is a system designed to enable consistent description of gliomas using a set of defined visual features and controlled vocabulary. Even though imaging and immunology are both indispensable for glioblastoma phenotyping, a comprehensive integration of these two disciplines has not been performed so far.</p><p><strong>Material and methods: </strong>76 patients from a previous glioblastoma immunotherapy clinical trial were retrospectively screened for the availability of peripheral blood immunology and tumor imaging data at baseline, i.e. at the start of the study. For 41 patients both were available. MRI were then analyzed via volumetry and VASARI morphometry. The resulting 27 imaging variables were linked with 67 peripheral blood immunology variables from flow cytometry and PCR and all potential relations were mapped.</p><p><strong>Results: </strong>In an initial broad screening, 94 imaging-immunology associations were discovered. Notably, features of the contrast-enhancing margin like its thickness and its shape were positively correlated with various T cell species including activated cytotoxic CD8+ T cells and central memory CD8+ T cells. The T2-volume was correlated with CD56+CD16- natural killer cells, and the necrosis volume was correlated with immunopolarizing mRNAs in the blood (IFN-γ, GATA3, ROR-gt). After multiple testing correction, two imaging-immunology associations were confirmed as significant: a thick contrast-enhancing margin was correlated with lower regulatory T cell markers in the blood and invasion of deep white matter was correlated with less T helper 17 factors.</p><p><strong>Conclusion: </strong>We here provide first evidence that imaging and peripheral blood immunology features can go hand in hand and that imaging variables can correlate with systemic immunophenotypes. Especially a thick contrast-enhancing margin seems to indicate a pro-inflammatory immune state. Via pioneering the integration of imaging and immunology, we not only advance basic glioblastoma science but we also open up novel avenues for research. In the future, e.g. patient stratification for therapy development could be based on imaging-guided immunophenotyping.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"183"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737932","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":"An immune scoring system predicts prognosis and immune characteristics in lung adenocarcinoma brain metastases by RNA sequencing.","authors":"Gang Xiao, Guilong Tanzhu, Xuan Gao, Lifeng Li, Zhiyuan Liu, Xuefeng Xia, Rongrong Zhou","doi":"10.1186/s40478-024-01895-9","DOIUrl":"10.1186/s40478-024-01895-9","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have reported that the tumor immune microenvironment (TIME) was associated with the prognosis of lung cancer patients and the efficacy of immunotherapy. However, given the significant challenges in obtaining specimens of brain metastases (BrMs), few studies explored the correlation between the TIME and the prognosis in patients with BrMs from lung adenocarcinoma (LUAD).</p><p><strong>Methods: </strong>Transcript profiling of archival formalin-fixed and paraffin-embedded specimens of BrMs from 70 LUAD patients with surgically resected BrMs was carried out using RNA sequencing. An immune scoring system, the green-yellow module score (GYMS), was developed to predict prognosis and immune characteristics in both BrMs and primary LUAD using Weighted Correlation Network analysis (WGCNA) and GSVA analysis. We comprehensively evaluated the immunological role of GYMS based on gene expression profile of LUAD BrMs by systematically correlating GYMS with immunological characteristics and immunotherapy responsiveness in the BrMs. Immunohistochemistry was applied for validation.</p><p><strong>Results: </strong>We found that the high-GYMS group had better clinical prognosis and inflamed immune landscape including high infiltrations of various immune cells, increased immunomodulatory expression, and enriched immune-related pathways by using RNA-seq and immunohistochemical analysis. Low-GYMS group presented a lacked immune infiltration characteristic. Besides, the high-GYMS group had lower TIDE score and higher T-cell inflamed score than low-GYMS group. The GYMS has been validated in independent BrMs cohorts and primary NSCLC cohort treated with anti-PD-1/PD-L1, showing strong reproducibility and stability in both primary LUAD and BrMs. In addition, we construct a GYMS-related risk signature for patients with LUAD BrMs to predict prognosis.</p><p><strong>Conclusions: </strong>We identified two immune-related subtypes which used to estimate prognosis and immune characteristics and developed a reliable GYMS-related risk signature in LUAD BrMs. These results will enhance the understanding of the immune microenvironment in LUAD BrMs and lay the theoretical foundation for the development of personalized therapies for LUAD patients with BrMs.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"181"},"PeriodicalIF":6.2,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724369","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":"Homozygous CDKN2A/B deletions in low- and high-grade glioma: a meta-analysis of individual patient data and predictive values of p16 immunohistochemistry testing.","authors":"Darius Noack, Johannes Wach, Alonso Barrantes-Freer, Nils H Nicolay, Erdem Güresir, Clemens Seidel","doi":"10.1186/s40478-024-01889-7","DOIUrl":"10.1186/s40478-024-01889-7","url":null,"abstract":"<p><p>CDKN2A/B deletions are prognostically relevant in low- and high-grade gliomas. Data on this is derived from heterogeneous series, an accurate estimation of survival risk from homozygous CDKN2A/B deletion is missing. Besides genetic testing, p16-immunohistochemistry (IHC) as a less cost intensive means for indirect detection of CDKN2A/B alterations is possible but not validated in larger datasets. The present meta-analysis aimed to (1) reconstruct individual patient data (IPD) and estimate overall survival (OS) stratified by CDKN2A/B status from all literature and to (2) determine accuracy of p16 testing for CDKNA2/B detection from published studies. For survival analysis according to CDKN2A/B status 460 records were screened, four articles with 714 participants were included. In IDH-wildtype (IDH-wt) gliomas, 57.07% harbored the deletion compared to 9.76% in IDH-mutant (IDH-mut) gliomas. Median OS of patients with IDH-wt gliomas and homozygous CDKN2A/B deletion was 13.0 months compared to 18.0 months with non-deleted CDKN2A/B (p = 0.014, Log-Rank). With homozygous deletion of CDKN2A/B the risk of death was increased by 1.5 (95%-CI 1.1-2.1). Median OS in patients with IDH-mut gliomas without CDKN2A/B deletion was 92.0 months compared to 40.0 months with CDKN2A/B deletion (p < 0.001, Log-Rank). CDKN2A/B deletions were associated with a significantly shorter OS (HR = 3.2; 95%-CI 2.2-5.5). For p16 IHC analysis, 10 eligible studies with 1087 examined samples were included. The cut-off for retention differed between the studies. In 588/662 p16 retained cases CDKN2A/B deletions was not detected, implying a negative predictive value (NPV) of p16 staining of 88.8%. Conversely, 279/425 p16 absent cases showed a CDKN2A/B deletion resulting in a positive predictive value (PPV) of 65.6%. Sensitivity of p16 staining for CDKN2A/B detection was 79.0%, specificity 80.1%. Highest diagnostic accuracy of p16 IHC was reached with a cut-off of > 5% and within IDH-mut glioma.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"180"},"PeriodicalIF":6.2,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11590270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724384","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":"Inhibition of RtTg neurons reverses methamphetamine-induced attention deficits.","authors":"Xiaotian Qu, Pingyuan Yang, Rongwei Zhai, Zhi-Qi Xiong","doi":"10.1186/s40478-024-01890-0","DOIUrl":"10.1186/s40478-024-01890-0","url":null,"abstract":"<p><p>Chronic methamphetamine (METH) use, a prevalent psychostimulant, is known to impair attention, yet the cellular mechanisms driving these deficits remain poorly understood. Here, we employed a rat model of repeated passive METH injections and evaluated attentional performance using the 5-choice serial reaction time task (5-CSRTT). Using single-nucleus RNA sequencing, immunofluorescence and in situ hybridization, we characterized the response of neurons in the reticulotegmental nucleus (RtTg) to METH exposure. Our results indicate that METH exposure disrupts RtTg neurons at the transcriptional level and results in an increased activation ratio of RtTg under 5-CSRTT conditions. Crucially, chemogenetic inactivation of these neurons or RtTg lesion attenuated METH-induced attention deficits, whereas their activation reproduced the deficits. These findings underscore the critical role of RtTg neurons in mediating METH-induced attention deficits, positioning RtTg as a promising therapeutic target for the treatment of attention deficits linked to chronic METH use.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"179"},"PeriodicalIF":6.2,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11585149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142692531","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 detection rate of circulating-tumor DNA from cerebrospinal fluid of children with central nervous system germ cell tumors.","authors":"Yoshiko Nakano, Ian Burns, Liana Nobre, Robert Siddaway, Mansuba Rana, Cody Nesvick, Andrew Bondoc, Michelle Ku, Richard Yuditskiy, Dennis T L Ku, Matthew M K Shing, Kevin K F Cheng, Ho-Keung Ng, Anirban Das, Julie Bennett, Vijay Ramaswamy, Annie Huang, David Malkin, Birgit Ertl-Wagner, Peter Dirks, Eric Bouffet, Ute Bartels, Uri Tabori, Cynthia Hawkins, Anthony P Y Liu","doi":"10.1186/s40478-024-01886-w","DOIUrl":"10.1186/s40478-024-01886-w","url":null,"abstract":"<p><p>Central nervous system germ cell tumors (CNS-GCT) are malignant neoplasms that arise predominantly during adolescence and young adulthood. These tumors are typically sensitive to treatment, but resulting long-term health deficits are common. Additional clinical challenges include surgical risks associated with tumor biopsy, and need to determine treatment response for adapting radiotherapy protocols. The aim of this study was to establish the detectability of circulating-tumor DNA (ctDNA) from cerebrospinal fluid (CSF) of children with CNS-GCT as a potential biomarker. We obtained CSF from patients with CNS-GCT by lumbar puncture or intra-operatively. Cell-free DNA (cfDNA) was extracted and subjected to low-pass whole genome sequencing (LP-WGS). Copy-number alterations (CNAs) were inferred and served as a marker of measurable residual disease (MRD). Comparisons with imaging findings and tumor marker levels were made. A total of 29 CSF samples from 21 patients (16 with germinoma, 5 with non-germinomatous GCT) were sequenced. Twenty samples from 19 patients were collected at diagnosis, and 9 samples from 7 patients were collected during or after therapy. Among the diagnostic samples, CNAs were detected in samples from 17/19 patients (89%), which included 8 with marker-negative tumors. Specific clinical scenarios suggested that serial cfDNA analysis may carry utility in tracking treatment responses as well as clarifying indeterminate imaging findings. Our results provide evidence for the high-sensitivity in detecting ctDNA from CSF of CNS-GCT patients using LP-WGS, with potential utility for non-invasive diagnosis and disease monitoring in upcoming CNS-GCT studies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"178"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580361/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680063","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":"Detection of diagnostic somatic copy number alterations from cerebrospinal fluid cell-free DNA in brain tumor patients.","authors":"Svenja Klinsing, Julia Beck, Katharina J Weber, Kirsten Bornemann-Kolatzki, Mareike Dettki, Hans Urban, Bastian Roller, Kai U Chow, Henning Reis, Peter J Wild, Ekkehard Schuetz, Philipp Euskirchen, Joachim P Steinbach, Michael W Ronellenfitsch, Patrick N Harter, Pia S Zeiner","doi":"10.1186/s40478-024-01887-9","DOIUrl":"10.1186/s40478-024-01887-9","url":null,"abstract":"<p><p>The gold standard for precise diagnostic classification of brain tumors requires tissue sampling, which carries relevant procedural risks. Brain biopsies often have limited sensitivity and fail to address tumor heterogeneity, because small tissue parts are being examined. This study aims to explore the detection and quantification of diagnostically relevant somatic copy number aberrations (SCNAs) in cell-free DNA (cfDNA) extracted from cerebrospinal fluid (CSF) in a real-world cohort of patients with defined brain tumor subtypes. A total of 33 CSF samples were collected from 30 patients for cfDNA extraction. Shallow whole-genome sequencing was conducted on CSF samples containing > 3ng of cfDNA and corresponding tissue DNA from nine patients. The sequencing cohort encompassed 26 samples of 23 patients, comprising 12 with confirmed CNS cancer as compared to 11 patients with either ambiguous CNS lesions (n = 5) or non-cancer CNS lesions (n = 6). After mapping and quality filtering SCNAs were called by depth-of-coverage analyses with a binning of 5.5 Mbp. SCNAs were exclusively identified in CSF cfDNA from brain tumor patients (10/12, 83%). In tumor patients, SCNAs were detectable in cfDNA from all patients with, but also in five of seven patients without tumor cells detected by CSF cytopathology. A substantial number of shared SCNAs were traceable between tissue and CSF in matched pair analyses. Additionally, some SCNAs unique to either CSF or tissue indicating spatial heterogeneity or tumor evolution. Also, diagnostically relevant genomic alterations as well as essential and desirable SCNAs as implemented in the current WHO classification of CNS tumors for certain primary brain tumor subtypes were traceable. In summary, this minimally invasive cfDNA-based LB approach employing shallow whole genome sequencing demonstrates potential for providing a molecularly informed diagnosis of CNS cancers, mapping tumor heterogeneity, tracking tumor evolution, and surveilling tumor patients. Further prospective trials are warranted.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"177"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11580493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680080","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}