Acta Neuropathologica最新文献

{"title":"A quantitative Lewy-fold-specific alpha-synuclein seed amplification assay as a progression marker for Parkinson’s disease","authors":"Alexander M. Bernhardt,&nbsp;Sebastian Longen,&nbsp;Svenja V. Trossbach,&nbsp;Marcello Rossi,&nbsp;Daniel Weckbecker,&nbsp;Felix Schmidt,&nbsp;Alexander Jäck,&nbsp;Sabrina Katzdobler,&nbsp;Urban M. Fietzek,&nbsp;Endy Weidinger,&nbsp;Carla Palleis,&nbsp;Viktoria Ruf,&nbsp;Simone Baiardi,&nbsp;Piero Parchi,&nbsp;Günter U. Höglinger,&nbsp;Torsten Matthias,&nbsp;Johannes Levin,&nbsp;Armin Giese","doi":"10.1007/s00401-025-02853-y","DOIUrl":"10.1007/s00401-025-02853-y","url":null,"abstract":"<div><p>Misfolded α-synuclein (αSyn) is the hallmark of α-synucleinopathies such as Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). While seed amplification assays (SAA) have demonstrated ultrasensitive detection of misfolded αSyn, they have been primarily used reliably to provide binary (positive/negative) results for diagnostic purposes. We developed an SAA with enhanced specificity for Lewy-fold α-synucleinopathies and introduced a quantifiable measure correlating with clinical severity. Cerebrospinal fluid (CSF) of 170 patients with neurodegenerative diseases and controls was analyzed. Blinded measurements demonstrated 97.8% sensitivity and 100% specificity for Lewy-fold α-synucleinopathies, correctly identifying PD and DLB while excluding MSA. In addition, we validated the strain specificity of the assay by testing brain homogenates from 30 neuropathologically confirmed cases. A novel Lewy-fold pathology (LFP) score based on positive signals in a dilution series provided a quantitative measure of αSyn seeds. The LFP score significantly correlated with motor and cognitive impairment presented by Hoehn and Yahr stage, MDS-UPDRS III, and MoCA. Longitudinal tracking in seven PD cases showed progressive LFP score increases corresponding with clinical deterioration, highlighting the assay’s potential for monitoring disease progression at an individual level. Our Lewy-fold-specific SAA enhances ante-mortem diagnosis and differentiates Lewy-fold α-synucleinopathies from MSA. Unlike previous assays, the LFP score offers a quantitative assessment, showing promise as a progression marker and pharmacodynamic biomarker for αSyn-targeting therapies. This represents an important step toward developing an αSyn SAA that could help to track disease progression quantitatively, with potential applications in both clinical diagnostics and therapeutic trials.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02853-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446431","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":"Brain tissue metal concentrations and Alzheimer’s disease neuropathology in total joint arthroplasty patients versus controls","authors":"Blake A. Ebner,&nbsp;Sarah A. Erdahl,&nbsp;Carly S. Lundgreen,&nbsp;Maria Vassilaki,&nbsp;Walter K. Kremers,&nbsp;David S. Knopman,&nbsp;Ronald C. Petersen,&nbsp;Daniel J. Berry,&nbsp;David G. Lewallen,&nbsp;Paul J. Jannetto,&nbsp;Melissa E. Murray,&nbsp;R. Ross Reichard,&nbsp;Hilal Maradit Kremers","doi":"10.1007/s00401-025-02856-9","DOIUrl":"10.1007/s00401-025-02856-9","url":null,"abstract":"<div><p>We examined whether total joint arthroplasty (TJA) is associated with increased metal accumulation in the brain and histopathologic changes of Alzheimer’s disease. We measured ultra-trace metal concentrations (aluminum, chromium, cobalt, manganese, molybdenum, nickel, titanium, and vanadium) on postmortem frozen tissues of the occipital lobe of 177 subjects (89 non-TJA and 88 TJA) using a triple-quadrupole inductively coupled plasma mass spectrometry and correlated elemental concentrations to the degree of Alzheimer’s disease neuropathic change (ADNC). To effectively assess the relationship between TJA and brain metal concentrations, subjects with and without TJA were matched for baseline clinical characteristics and showed no difference in postmortem Alzheimer’s disease neuropathic change. TJA subjects had increased concentrations of cobalt and titanium and both metals were associated with increased amyloid plaques. In both the TJA and non-TJA subjects, increased concentrations of cobalt, titanium, manganese, and molybdenum were associated with increased odds of neuritic and diffuse plaques. Lastly, the brain’s inter-metal correlations were altered in the presence of increased neuritic plaques and/or implantable artificial joints. These findings suggest that metal concentrations and homeostasis vary in presence of TJA.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417177","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":"Microglia aggregates define distinct immune and neurodegenerative niches in Alzheimer's disease hippocampus","authors":"Sonja Fixemer,&nbsp;Mónica Miranda de la Maza,&nbsp;Gaël Paul Hammer,&nbsp;Félicia Jeannelle,&nbsp;Sophie Schreiner,&nbsp;Jean-Jacques Gérardy,&nbsp;Susana Boluda,&nbsp;Dominique Mirault,&nbsp;Naguib Mechawar,&nbsp;Michel Mittelbronn,&nbsp;David S. Bouvier","doi":"10.1007/s00401-025-02857-8","DOIUrl":"10.1007/s00401-025-02857-8","url":null,"abstract":"<div><p>In Alzheimer’s disease (AD), microglia form distinct cellular aggregates that play critical roles in disease progression, including Aβ plaque-associated microglia (PaM) and the newly identified coffin-like microglia (CoM). PaM are closely associated with amyloid-β (Aβ) plaques, while CoM are enriched in the pyramidal layer of the CA2/CA1 hippocampal subfields, where they frequently engulf neurons and associate with tau-positive tangles and phosphorylated α-synuclein. To elucidate the role of these microglial subtypes, we employed high-content neuropathology, integrating Deep Spatial Profiling (DSP), multiplex chromogenic immunohistochemistry and confocal microscopy, to comprehensively map and characterise their morphological and molecular signatures, as well as their neuropathological and astrocytic microenvironments, in AD and control post-mortem samples. PaM and PaM-associated astrocytes exhibited signatures related to complement system pathways, ErbB signalling, and metabolic and neurodegenerative processes. In contrast, CoM displayed markers associated with protein degradation and immune signalling pathways, including STING, TGF-β, and NF-κB. While no direct association between CD8 + T cells and either microglial type was observed, CD163 + perivascular macrophages were frequently incorporated into PaM. These findings provide novel insights into the heterogeneity of microglial responses, in particular their distinct interactions with astrocytes and infiltrating immune cells, and shed light on specific neurodegenerative hotspots and their implications for hippocampal deterioration in AD.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02857-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143417178","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: Co-pathology may impact outcomes of amyloid-targeting treatments: clinicopathological results from two patients treated with aducanumab","authors":"Lawren VandeVrede,&nbsp;Renaud La Joie,&nbsp;Sheena Horiki,&nbsp;Nidhi S. Mundada,&nbsp;Mary Koestler,&nbsp;Ji-Hye Hwang,&nbsp;Peter A. Ljubenkov,&nbsp;Julio C. Rojas,&nbsp;Gil D. Rabinovici,&nbsp;Adam L. Boxer,&nbsp;William W. Seeley","doi":"10.1007/s00401-025-02855-w","DOIUrl":"10.1007/s00401-025-02855-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02855-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143404210","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":"A novel TEAD1::NCOA2 fusion that potentially expands the concept of supratentorial ependymoma, YAP1 fusion-positive","authors":"Arnault Tauziède-Espariat,&nbsp;Romain Appay,&nbsp;Corinne Bouvier,&nbsp;Benoît Testud,&nbsp;Nadine Girard,&nbsp;Alice Métais,&nbsp;Euphrasie Servant,&nbsp;Didier Scavarda,&nbsp;Alexandra Meurgey,&nbsp;Daniel Pissaloux,&nbsp;Lauren Hasty,&nbsp;Pascale Varlet,&nbsp;on behalf of the RENOCLIP-LOC","doi":"10.1007/s00401-025-02852-z","DOIUrl":"10.1007/s00401-025-02852-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02852-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143375657","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":"Perivascular glial reactivity is a feature of phosphorylated tau lesions in chronic traumatic encephalopathy","authors":"Chelsie Osterman,&nbsp;Danica Hamlin,&nbsp;Catherine M. Suter,&nbsp;Andrew J. Affleck,&nbsp;Brian S. Gloss,&nbsp;Clinton P. Turner,&nbsp;Richard L. M. Faull,&nbsp;Thor D. Stein,&nbsp;Ann McKee,&nbsp;Michael E. Buckland,&nbsp;Maurice A. Curtis,&nbsp;Helen C. Murray","doi":"10.1007/s00401-025-02854-x","DOIUrl":"10.1007/s00401-025-02854-x","url":null,"abstract":"<div><p>Chronic traumatic encephalopathy (CTE), a neurodegenerative disease associated with repetitive head injuries, is characterised by perivascular hyperphosphorylated tau (p-tau) accumulations within the depths of cortical sulci. Although the majority of CTE literature focuses on p-tau pathology, other pathological features such as glial reactivity, vascular damage, and axonal damage are relatively unexplored. In this study, we aimed to characterise these other pathological features, specifically in CTE p-tau lesion areas, to better understand the microenvironment surrounding the lesion. We utilised multiplex immunohistochemistry to investigate the distribution of 32 different markers of cytoarchitecture and pathology that are relevant to both traumatic brain injury and neurodegeneration. We qualitatively assessed the multiplex images and measured the percentage area of labelling for each marker in the lesion and non-lesion areas of CTE cases. We identified perivascular glial reactivity as a prominent feature of CTE p-tau lesions, largely driven by increases in astrocyte reactivity compared to non-lesion areas. Furthermore, we identified astrocytes labelled for both NAD(P)H quinone dehydrogenase 1 (NQO1) and L-ferritin, indicating that lesion-associated glial reactivity may be a compensatory response to iron-induced oxidative stress. Our findings demonstrate that perivascular inflammation is a consistent feature of the CTE pathognomonic lesion and may contribute to the pathogenesis of brain injury-related neurodegeneration.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02854-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143361727","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":"TEAD1::NCOA2 fusion driver in primary central nervous system malignancy: case report","authors":"Agnesa Panferova,&nbsp;Maria Senchenko,&nbsp;Margarita Zaytseva,&nbsp;Yuliya Rasskazova,&nbsp;Ruslan Abasov,&nbsp;Alexandra Tarakanova,&nbsp;Natalia Usman,&nbsp;Ludmila Papusha,&nbsp;Alexander Druy","doi":"10.1007/s00401-025-02851-0","DOIUrl":"10.1007/s00401-025-02851-0","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143258296","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":"IDH-mutant astrocytomas with primitive neuronal component have a distinct methylation profile and a higher risk of leptomeningeal spread","authors":"Felix Hinz,&nbsp;Dennis Friedel,&nbsp;Andrey Korshunov,&nbsp;Franziska M. Ippen,&nbsp;Henri Bogumil,&nbsp;Rouzbeh Banan,&nbsp;Sebastian Brandner,&nbsp;Martin Hasselblatt,&nbsp;Henning B. Boldt,&nbsp;Vaidas Dirse,&nbsp;Hildegard Dohmen,&nbsp;Eleonora Aronica,&nbsp;Michael Brodhun,&nbsp;Marike L. D. Broekman,&nbsp;David Capper,&nbsp;Asan Cherkezov,&nbsp;Maximilian Y. Deng,&nbsp;Vera van Dis,&nbsp;Jörg Felsberg,&nbsp;Stephan Frank,&nbsp;Pim J. French,&nbsp;Rüdiger Gerlach,&nbsp;Kirsten Göbel,&nbsp;Eric Goold,&nbsp;Jürgen Hench,&nbsp;Sven Kantelhardt,&nbsp;Patricia Kohlhof-Meinecke,&nbsp;Sandro Krieg,&nbsp;Christian Mawrin,&nbsp;Gillian Morrison,&nbsp;Angelika Mühlebner,&nbsp;Koray Ozduman,&nbsp;Stefan M. Pfister,&nbsp;Pietro Luigi Poliani,&nbsp;Marco Prinz,&nbsp;Guido Reifenberger,&nbsp;Markus J. Riemenschneider,&nbsp;Roman Sankowski,&nbsp;Daniel Schrimpf,&nbsp;Martin Sill,&nbsp;Matija Snuderl,&nbsp;Robert M. Verdijk,&nbsp;Mathew R. Voisin,&nbsp;Pieter Wesseling,&nbsp;Wolfgang Wick,&nbsp;David E. Reuss,&nbsp;Andreas von Deimling,&nbsp;Felix Sahm,&nbsp;Sybren L. N. Maas,&nbsp;Abigail K. Suwala","doi":"10.1007/s00401-025-02849-8","DOIUrl":"10.1007/s00401-025-02849-8","url":null,"abstract":"<div><p>IDH-mutant astrocytomas are diffuse gliomas that are defined by characteristic mutations in <i>IDH1</i> or <i>IDH2</i> and do not have complete 1p/19q co-deletion. The established grading criteria include histological features of brisk mitotic activity (grade 3) and necrosis and/or microvascular proliferation (grade 4). In addition, homozygous deletion of the <i>CDKN2A/B</i> locus has recently been implemented as a molecular marker for grade 4 IDH-mutant astrocytomas. Here, we describe a subgroup of high-grade <i>IDH</i>-mutant astrocytomas characterised by a primitive neuronal component based on histology and a distinct DNA methylation profile (n = 51, ASTRO PNC). Misinterpretation as carcinoma metastasis was common, since GFAP expression was absent in the primitive neuronal component, whereas TTF-1 expression was detected in 15/19 cases (79%) based on immunohistochemistry. Apart from mutations in <i>IDH1</i>, <i>TP53</i>, and <i>ATRX</i>, we observed enrichment for alterations in <i>RB1</i> (n = 19/51, 37%) and <i>MYCN</i> (n = 14/51, 27%). Homozygous <i>CDKN2A/B</i> deletion (n = 1/51, 2%) and <i>CDK4</i> amplification (n = 3/51, 6%) were relatively rare events. Clinical (n = 31 patients) and survival data (n = 23 patients) indicate a clinical behaviour similar to other CNS WHO grade 4 IDH-mutant astrocytomas, however with an increased risk for leptomeningeal (n = 7) and extra-axial (n = 2) spread. Taken together, ASTRO PNC is defined by a distinct molecular and histological appearance that can mimic metastatic disease and typically follows an aggressive clinical course.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02849-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077483","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":"Somatic variants in SLC35A2 leading to defects in N-glycosylation in mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE)","authors":"Xianyu Liu,&nbsp;Qi Tang,&nbsp;Xiaoqian Xia,&nbsp;Qingzhu Liu,&nbsp;Jialin Liu,&nbsp;Yangyanan Jin,&nbsp;Pengxia Wu,&nbsp;Huaxia Luo,&nbsp;Kai Gao,&nbsp;Xiaoqin Ruan,&nbsp;Yu Sun,&nbsp;Taoyun Ji,&nbsp;Shuang Wang,&nbsp;Xiaoyan Liu,&nbsp;Lixin Cai,&nbsp;Yuwu Jiang,&nbsp;Peng Dai,&nbsp;Xing Chen,&nbsp;Ye Wu","doi":"10.1007/s00401-025-02850-1","DOIUrl":"10.1007/s00401-025-02850-1","url":null,"abstract":"<div><p>Mild malformation of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE) is a new histopathological entity identified in the surgically resected brain tissue of patients with drug-resistant epilepsy. Somatic variants in <i>SLC35A2</i> have been increasingly identified in MOGHE brain resections. SLC35A2 protein transports uridine 5’-diphosphogalactose (UDP-Gal) into the Golgi lumen, playing a crucial role in the process of N-glycosylation. Currently, research on the pathogenic mechanism of <i>SLC35A2</i> variants in MOGHE is limited. Here we conducted genetic testing on brain samples and paired blood samples from 28 pediatric patients pathologically diagnosed with MOGHE. We performed an in-depth functional analysis of somatic variants identified in <i>SLC35A2</i>, integrating glycan labeling and intact glycopeptide profiling to assess N-glycosylation defects. With whole-exome sequencing and validation with ultra-deep amplicon sequencing, we identified 101 potentially pathogenic somatic variants (PPSVs) across 87 genes. Nine PPSVs in <i>SLC35A2</i> were found in 10 samples. The 9 identified variants of <i>SLC35A2</i>, characterized by various mutation types (4 frameshift, 3 missense and 2 nonsense variants), were all confirmed to be loss-of-function via altered glycan chains. Intact glycopeptide analysis at the cellular level indicated an increase in truncated N-glycan glycoforms. Analysis of brain tissue revealed N-glycosylated proteins and glycosites modified with agalactosylated glycoforms, and glycoproteins bearing agalactosylated N-glycans were significantly enriched in cell adhesion and axon guidance-related pathways. Additionally, chemoenzymatic glycan labeling in lesions demonstrated N-glycan damage of heterotopic neurons, suggesting a potential diagnostic approach for MOGHE. Our findings provide a comprehensive somatic landscape of MOGHE and a rich resource of somatic <i>SLC35A2</i> variant-related glycoform and glycoprotein abnormalities, thereby unveiling valuable insights into compromised N-glycosylation and MOGHE formation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143083764","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":"MSH2, MSH6, MLH1, and PMS2 immunohistochemistry as highly sensitive screening method for DNA mismatch repair deficiency syndromes in pediatric high-grade glioma","authors":"Lea L. Friker,&nbsp;Thomas Perwein,&nbsp;Andreas Waha,&nbsp;Evelyn Dörner,&nbsp;Rebecca Klein,&nbsp;Mirjam Blattner-Johnson,&nbsp;Julian P. Layer,&nbsp;Dominik Sturm,&nbsp;Gunther Nussbaumer,&nbsp;Robert Kwiecien,&nbsp;Isabel Spier,&nbsp;Stefan Aretz,&nbsp;Kornelius Kerl,&nbsp;Ulrike Hennewig,&nbsp;Marius Rohde,&nbsp;Axel Karow,&nbsp;Ingmar Bluemcke,&nbsp;Ann Kristin Schmitz,&nbsp;Harald Reinhard,&nbsp;Pablo Hernáiz Driever,&nbsp;Susanne Wendt,&nbsp;Annette Weiser,&nbsp;Ana S. Guerreiro Stücklin,&nbsp;Nicolas U. Gerber,&nbsp;André O. von Bueren,&nbsp;Claudia Khurana,&nbsp;Norbert Jorch,&nbsp;Maria Wiese,&nbsp;Christian P. Kratz,&nbsp;Matthias Eyrich,&nbsp;Michael Karremann,&nbsp;Ulrich Herrlinger,&nbsp;Michael Hölzel,&nbsp;David T. W. Jones,&nbsp;Marion Hoffmann,&nbsp;Torsten Pietsch,&nbsp;Gerrit H. Gielen,&nbsp;Christof M. Kramm","doi":"10.1007/s00401-025-02846-x","DOIUrl":"10.1007/s00401-025-02846-x","url":null,"abstract":"<div><p>Pediatric high-grade glioma (pedHGG) can occur as first manifestation of cancer predisposition syndromes resulting from pathogenic germline variants in the DNA mismatch repair (MMR) genes <i>MSH2</i>, <i>MSH6</i>, <i>MLH1</i>, and <i>PMS2</i>. The aim of this study was to establish a generalized screening for Lynch syndrome and constitutional MMR deficiency (CMMRD) in pedHGG patients, as the detection of MMR deficiencies (MMRD) may enable the upfront therapeutic use of checkpoint inhibitors and identification of variant carriers in the patients’ families. We prospectively enrolled 155 centrally reviewed primary pedHGG patients for MMR-immunohistochemistry (IHC) as part of the HIT-HGG-2013 trial protocol. MMR-IHC results were subsequently compared to independently collected germline sequencing data (whole exome sequencing or pan-cancer DNA panel next-generation sequencing) available in the HIT-HGG-2013, INFORM, and MNP2.0 trials. MMR-IHC could be successfully performed in 127/155 tumor tissues. The screening identified all present cases with Lynch syndrome or CMMRD (5.5%). In addition, MMR-IHC also detected cases with exclusive somatic MMR gene alterations (2.3%), including <i>MSH2</i> hypermethylation as an alternative epigenetic silencing mechanism. Most of the identified pedHGG MMRD patients had no family history of MMRD, and thus, they represented index patients in their families. Cases with regular protein expression in MMR-IHC never showed evidence for MMRD in DNA sequencing. In conclusion, MMR-IHC presents a cost-effective, relatively widely available, and fast screening method for germline MMRD in pedHGG with high sensitivity (100%) and specificity (96%). Given the relatively high prevalence of previously undetected MMRD cases among pedHGG patients, we strongly recommend incorporating MMR-IHC into routine diagnostics.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-02-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02846-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143077466","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}