Acta Neuropathologica最新文献

{"title":"Targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded neuropathology specimens","authors":"Charlotte Gorißen, Anne Albers, Viktoria Ruf, Emil Chteinberg, Reiner Siebert, Leonille Schweizer, Lukas Kaufmann, Joachim E. Kühn, Dennis Tappe, Tanja Kuhlmann, Christian Thomas","doi":"10.1007/s00401-024-02812-z","DOIUrl":"10.1007/s00401-024-02812-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02812-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma","authors":"Santoesha A. Ghisai,&nbsp;Levi van Hijfte,&nbsp;Wies R. Vallentgoed,&nbsp;C. Mircea S. Tesileanu,&nbsp;Iris de Heer,&nbsp;Johan M. Kros,&nbsp;Marc Sanson,&nbsp;Thierry Gorlia,&nbsp;Wolfgang Wick,&nbsp;Michael A. Vogelbaum,&nbsp;Alba A. Brandes,&nbsp;Enrico Franceschi,&nbsp;Paul M. Clement,&nbsp;Anna K. Nowak,&nbsp;Vassilis Golfinopoulos,&nbsp;Martin J. van den Bent,&nbsp;Pim J. French,&nbsp;Youri Hoogstrate","doi":"10.1007/s00401-024-02811-0","DOIUrl":"10.1007/s00401-024-02811-0","url":null,"abstract":"<div><p>Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from <i>CDKN2A/B</i> homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (<i>n</i> = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. <i>HOX</i>, <i>PAX,</i> and <i>TBX</i>) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02811-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline","authors":"Joan Liu,&nbsp;Lawrence Binding,&nbsp;Isha Puntambekar,&nbsp;Smriti Patodia,&nbsp;Yau Mun Lim,&nbsp;Alicja Mryzyglod,&nbsp;Fenglai Xiao,&nbsp;Shengning Pan,&nbsp;Remika Mito,&nbsp;Jane de Tisi,&nbsp;John S. Duncan,&nbsp;Sallie Baxendale,&nbsp;Matthias Koepp,&nbsp;Maria Thom","doi":"10.1007/s00401-024-02809-8","DOIUrl":"10.1007/s00401-024-02809-8","url":null,"abstract":"<div><p>White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, <i>p</i> &lt; 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, <i>p</i> &lt; 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, <i>p</i> &lt; 0.01) which was more marked the longer the duration of epilepsy (<i>p</i> &lt; 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (<i>p</i> &lt; 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02809-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins","authors":"Kohji Mori,&nbsp;Thomas Arzberger,&nbsp;Friedrich A. Grässer,&nbsp;Ilse Gijselinck,&nbsp;Stephanie May,&nbsp;Kristin Rentzsch,&nbsp;Shih‑Ming Weng,&nbsp;Martin H. Schludi,&nbsp;Julie van der Zee,&nbsp;Marc Cruts,&nbsp;Christine Van Broeckhoven,&nbsp;Elisabeth Kremmer,&nbsp;Hans A. Kretzschmar,&nbsp;Christian Haass,&nbsp;Dieter Edbauer","doi":"10.1007/s00401-024-02806-x","DOIUrl":"10.1007/s00401-024-02806-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulated cell death in neurodegeneration: pathways and therapeutic horizons","authors":"Dietmar Rudolf Thal,&nbsp;Bart De Strooper","doi":"10.1007/s00401-024-02808-9","DOIUrl":"10.1007/s00401-024-02808-9","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142317205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau accumulation is cleared by the induced expression of VCP via autophagy","authors":"Hoi-Khoanh Giong,&nbsp;Seung Jae Hyeon,&nbsp;Jae-Geun Lee,&nbsp;Hyun-Ju Cho,&nbsp;Uiyeol Park,&nbsp;Thor D. Stein,&nbsp;Junghee Lee,&nbsp;Kweon Yu,&nbsp;Hoon Ryu,&nbsp;Jeong-Soo Lee","doi":"10.1007/s00401-024-02804-z","DOIUrl":"10.1007/s00401-024-02804-z","url":null,"abstract":"<div><p>Tauopathy, including frontotemporal lobar dementia and Alzheimer’s disease, describes a class of neurodegenerative diseases characterized by the aberrant accumulation of Tau protein due to defects in proteostasis. Upon generating and characterizing a stable transgenic zebrafish that expresses the human <i>TAU</i>^P301L mutant in a neuron-specific manner, we found that accumulating Tau protein was efficiently cleared via an enhanced autophagy activity despite constant Tau mRNA expression; apparent tauopathy-like phenotypes were revealed only when the autophagy was genetically or chemically inhibited. We performed RNA-seq analysis, genetic knockdown, and rescue experiments with clinically relevant point mutations of valosin-containing protein (VCP), and showed that induced expression of VCP, an essential cytosolic chaperone for the protein quality system, was a key factor for Tau degradation via its facilitation of the autophagy flux. This novel function of VCP in Tau clearance was further confirmed in a tauopathy mouse model where <i>VCP</i> overexpression significantly decreased the level of phosphorylated and oligomeric/aggregate Tau and rescued Tau-induced cognitive behavioral phenotypes, which were reversed when the autophagy was blocked. Importantly, VCP expression in the brains of human Alzheimer’s disease patients was severely downregulated, consistent with its proposed role in Tau clearance. Taken together, these results suggest that enhancing the expression and activity of VCP in a spatiotemporal manner to facilitate the autophagy pathway is a potential therapeutic approach for treating tauopathy.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11422276/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142306917","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TDP-43 regulates LC3ylation in neural tissue through ATG4B cryptic splicing inhibition","authors":"Pascual Torres,&nbsp;Santiago Rico-Rios,&nbsp;Miriam Ceron-Codorniu,&nbsp;Marta Santacreu-Vilaseca,&nbsp;David Seoane-Miraz,&nbsp;Yahya Jad,&nbsp;Victòria Ayala,&nbsp;Guillermo Mariño,&nbsp;Maria Beltran,&nbsp;Maria P. Miralles,&nbsp;Pol Andrés-Benito,&nbsp;Joaquin Fernandez-Irigoyen,&nbsp;Enrique Santamaria,&nbsp;Carlos López-Otín,&nbsp;Rosa M. Soler,&nbsp;Monica Povedano,&nbsp;Isidro Ferrer,&nbsp;Reinald Pamplona,&nbsp;Matthew J. A. Wood,&nbsp;Miguel A. Varela,&nbsp;Manuel Portero-Otin","doi":"10.1007/s00401-024-02780-4","DOIUrl":"10.1007/s00401-024-02780-4","url":null,"abstract":"<div><p>Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease with a mean survival time of three years. The 97% of the cases have TDP-43 nuclear depletion and cytoplasmic aggregation in motor neurons. TDP-43 prevents non-conserved cryptic exon splicing in certain genes, maintaining transcript stability, including <i>ATG4B</i>, which is crucial for autophagosome maturation and Microtubule-associated proteins 1A/1B light chain 3B (LC3B) homeostasis. In ALS mice (G93A), <i>Atg4b</i> depletion worsens survival rates and autophagy function. For the first time, we observed an elevation of LC3ylation in the CNS of both ALS patients and <i>atg4b</i>^{<i>−/−</i>} mouse spinal cords. Furthermore, LC3ylation modulates the distribution of ATG3 across membrane compartments. Antisense oligonucleotides (ASOs) targeting cryptic exon restore <i>ATG4B</i> mRNA in <i>TARDBP</i> knockdown cells. We further developed multi-target ASOs targeting TDP-43 binding sequences for a broader effect. Importantly, our ASO based in peptide-PMO conjugates show brain distribution post-IV administration, offering a non-invasive ASO-based treatment avenue for neurodegenerative diseases.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02780-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142275595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of in vivo retention of [18f] flortaucipir pet with tau neuropathology in corresponding brain regions","authors":"Tove Freiburghaus,&nbsp;Daria Pawlik,&nbsp;Kevin Oliveira Hauer,&nbsp;Rik Ossenkoppele,&nbsp;Olof Strandberg,&nbsp;Antoine Leuzy,&nbsp;Jonathan Rittmo,&nbsp;Cécilia Tremblay,&nbsp;Geidy E. Serrano,&nbsp;Michael J. Pontecorvo,&nbsp;Thomas G. Beach,&nbsp;Ruben Smith,&nbsp;Oskar Hansson","doi":"10.1007/s00401-024-02801-2","DOIUrl":"10.1007/s00401-024-02801-2","url":null,"abstract":"<div><p>[¹⁸F]Flortaucipir is an FDA-approved tau-PET tracer that is increasingly utilized in clinical settings for the diagnosis of Alzheimer’s disease. Still, a large-scale comparison of the in vivo PET uptake to quantitative <i>post-mortem</i> tau pathology and to other co-pathologies is lacking. Here, we examined the correlation between in vivo [¹⁸F]flortaucipir PET uptake and quantitative <i>post-mortem</i> tau pathology in corresponding brain regions from the AVID A16 end-of-life study (<i>n</i> = 63). All participants underwent [¹⁸F]flortaucipir PET scans prior to death, followed by a detailed <i>post-mortem</i> neuropathological examination using AT8 (tau) immunohistochemistry. Correlations between [¹⁸F]flortaucipir standardized uptake value ratios (SUVRs) and AT8 immunohistochemistry were assessed across 18 regions-of-interest (ROIs). To assess [¹⁸F]flortaucipir specificity and level of detection for tau pathology, correlations between [¹⁸F]flortaucipir SUVR and neuritic plaque score and TDP-43 stage were also computed and retention was further assessed in individuals with possible primary age-related tauopathy (PART), defined as Thal phase ≤ 2 and Braak stage I–IV. We found modest-to-strong correlations between in vivo [¹⁸F]flortaucipir SUVR and <i>post-mortem</i> tau pathology density in corresponding brain regions in all neocortical regions analyzed (rho-range = 0.61–0.79, p &lt; 0.0001 for all). The detection threshold of [¹⁸F]flortaucipir PET was determined to be 0.85% of surface area affected by tau pathology in a temporal meta-ROI, and 0.15% in a larger cortical meta-ROI. No significant associations were found between [¹⁸F]flortaucipir SUVRs and <i>post-mortem</i> tau pathology in individuals with possible PART. Further, there was no correlation observed between [¹⁸F]flortaucipir and level of amyloid-β neuritic plaque load (rho-range =  – 0.16–0.12; <i>p</i> = 0.48–0.61) or TDP-43 stage (rho-range =  – 0.10 to  – 0.30; <i>p</i> = 0.18–0.65). In conclusion, our in vivo vs <i>post-mortem</i> study shows that the in vivo [¹⁸F]flortaucipir PET signal primarily reflects tau pathology, also at relatively low densities of tau proteinopathy, and does not bind substantially to tau neurites in neuritic plaques or in individuals with PART.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02801-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dysregulated FOXO1 activity drives skeletal muscle intrinsic dysfunction in amyotrophic lateral sclerosis","authors":"Mónica Zufiría,&nbsp;Oihane Pikatza-Menoio,&nbsp;Maddi Garciandia-Arcelus,&nbsp;Xabier Bengoetxea,&nbsp;Andrés Jiménez,&nbsp;Amaia Elicegui,&nbsp;María Levchuk,&nbsp;Olatz Arnold-García,&nbsp;Jon Ondaro,&nbsp;Pablo Iruzubieta,&nbsp;Laura Rodríguez-Gómez,&nbsp;Uxoa Fernández-Pelayo,&nbsp;Mikel Muñoz-Oreja,&nbsp;Ana Aiastui,&nbsp;José Manuel García-Verdugo,&nbsp;Vicente Herranz-Pérez,&nbsp;Miren Zulaica,&nbsp;Juan José Poza,&nbsp;Rebeca Ruiz-Onandi,&nbsp;Roberto Fernández-Torrón,&nbsp;Juan Bautista Espinal,&nbsp;Mario Bonilla,&nbsp;Ana Lersundi,&nbsp;Gorka Fernández-Eulate,&nbsp;Javier Riancho,&nbsp;Ainara Vallejo-Illarramendi,&nbsp;Ian James Holt,&nbsp;Amets Sáenz,&nbsp;Edoardo Malfatti,&nbsp;Stéphanie Duguez,&nbsp;Lorea Blázquez,&nbsp;Adolfo López de Munain,&nbsp;Gorka Gerenu,&nbsp;Francisco Gil-Bea,&nbsp;Sonia Alonso-Martín","doi":"10.1007/s00401-024-02794-y","DOIUrl":"10.1007/s00401-024-02794-y","url":null,"abstract":"<div><p>Amyotrophic Lateral Sclerosis (ALS) is a multisystemic neurodegenerative disorder, with accumulating evidence indicating metabolic disruptions in the skeletal muscle preceding disease symptoms, rather than them manifesting as a secondary consequence of motor neuron (MN) degeneration. Hence, energy homeostasis is deeply implicated in the complex physiopathology of ALS and skeletal muscle has emerged as a key therapeutic target. Here, we describe intrinsic abnormalities in ALS skeletal muscle, both in patient-derived muscle cells and in muscle cell lines with genetic knockdown of genes related to familial ALS, such as <i>TARDBP</i> (TDP-43) and <i>FUS</i>. We found a functional impairment of myogenesis that parallels defects of glucose oxidation in ALS muscle cells. We identified FOXO1 transcription factor as a key mediator of these metabolic and functional features in ALS muscle, via gene expression profiling and biochemical surveys in TDP-43 and FUS-silenced muscle progenitors. Strikingly, inhibition of FOXO1 mitigated the impaired myogenesis in both the genetically modified and the primary ALS myoblasts. In addition, specific in vivo conditional knockdown of TDP-43 or FUS orthologs (<i>TBPH</i> or <i>caz</i>) in <i>Drosophila</i> muscle precursor cells resulted in decreased innervation and profound dysfunction of motor nerve terminals and neuromuscular synapses, accompanied by motor abnormalities and reduced lifespan. Remarkably, these phenotypes were partially corrected by <i>foxo</i> inhibition, bolstering the potential pharmacological management of muscle intrinsic abnormalities associated with ALS. The findings demonstrate an intrinsic muscle dysfunction in ALS, which can be modulated by targeting FOXO factors, paving the way for novel therapeutic approaches that focus on the skeletal muscle as complementary target tissue.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02794-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234479","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HOXD12 defines an age-related aggressive subtype of oligodendroglioma","authors":"Nicholas Nuechterlein,&nbsp;Sadie Cimino,&nbsp;Allison Shelbourn,&nbsp;Vinny Ha,&nbsp;Sonali Arora,&nbsp;Sharika Rajan,&nbsp;Linda G. Shapiro,&nbsp;Eric C. Holland,&nbsp;Kenneth Aldape,&nbsp;Tresa McGranahan,&nbsp;Mark R. Gilbert,&nbsp;Patrick J. Cimino","doi":"10.1007/s00401-024-02802-1","DOIUrl":"10.1007/s00401-024-02802-1","url":null,"abstract":"<div><p>Oligodendroglioma, IDH-mutant and 1p/19q-codeleted has highly variable outcomes that are strongly influenced by patient age. The distribution of oligodendroglioma age is non-Gaussian and reportedly bimodal, which motivated our investigation of age-associated molecular alterations that may drive poorer outcomes. We found that elevated HOXD12 expression was associated with both older patient age and shorter survival in the TCGA (FDR &lt; 0.01, FDR = 1e−5) and the CGGA (<i>p</i> = 0.03, <i>p</i> &lt; 1e−3). <i>HOXD12</i> gene body hypermethylation was associated with older age, higher WHO grade, and shorter survival in the TCGA (<i>p</i> &lt; 1e−6, <i>p</i> &lt; 0.001, <i>p</i> &lt; 1e−3) and with older age and higher WHO grade in Capper et al. (<i>p</i> &lt; 0.002, <i>p</i> = 0.014). In the TCGA, <i>HOXD12</i> gene body hypermethylation and elevated expression were independently prognostic of <i>NOTCH1</i> and <i>PIK3CA</i> mutations, loss of 15q, MYC activation, and standard histopathological features. Single-nucleus RNA and ATAC sequencing data showed that HOXD12 activity was elevated in neoplastic tissue, particularly within cycling and OPC-like cells, and was associated with a stem-like phenotype. A pan-HOX DNA methylation analysis revealed an age and survival-associated HOX-high signature that was tightly associated with <i>HOXD12</i> gene body methylation. Overall, HOXD12 expression and gene body hypermethylation were associated with an older, atypically aggressive subtype of oligodendroglioma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02802-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142166235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}