Acta Neuropathologica最新文献

{"title":"Expansion of the spectrum of tumors diagnosed as myxopapillary ependymomas","authors":"Fuat Kaan Aras, Dennis Friedel, Felix Keller, Ferdinand Zettl, Rouzbeh Banan, Philipp Sievers, Abigail K. Suwala, Felix Hinz, Lukas Friedrich, Ivan Abdulrazak, Mozhgan Esmaeilibenvidi, Nima Etminan, Christel Herold-Mende, Wolfgang Wick, Sandro Krieg, Stefan M. Pfister, Andrey Korshunov, Isabell Bludau, Felix Sahm, David E. Reuss, Gianluca Sigismondo, Andreas von Deimling","doi":"10.1007/s00401-025-02944-w","DOIUrl":"10.1007/s00401-025-02944-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02944-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194520","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":"Neuropathological changes in the nucleus basalis of Meynert in people with type 1 or type 2 diabetes mellitus","authors":"Wei Jiang,&nbsp;Martin J. Kalsbeek,&nbsp;Felipe Correa-da-Silva,&nbsp;Han Jiao,&nbsp;Andries Kalsbeek,&nbsp;Dick F. Swaab,&nbsp;Sarah E. Siegelaar,&nbsp;Chun-Xia Yi","doi":"10.1007/s00401-025-02942-y","DOIUrl":"10.1007/s00401-025-02942-y","url":null,"abstract":"<div><p>People with type 1 or type 2 diabetes mellitus (T1DM or T2DM) often experience cognitive impairment. We profiled cells in the nucleus basalis of Meynert (NBM) in postmortem human brain tissue to investigate the neuropathological changes. Sixty-eight postmortem NBM samples were grouped as T1DM, T2DM, and controls without diabetes, with Braak stage 0–II or III–VI. T1DM subjects had only Braak stage 0–II and were thus compared only to controls with a similar Braak stage and not subjects with Braak stage III–VI. We analyzed neurons expressing choline acetyltransferase (ChAT), phosphorylated tau, amyloid-beta, glial cells, and vasculature with their respective markers. We found significantly lower neuronal expression of ChAT in T1DM individuals than in controls and T2DM individuals with Braak stage 0–II. Later-stage hyperphosphorylated tau levels were higher in T2DM compared to controls with Braak stage III–VI. Our results suggest that reduced acetylcholine production by NBM neurons may underlie the cognitive complaints of people with T1DM. In contrast, T2DM may exacerbate neuropathological changes associated with Alzheimer’s disease-like alterations.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12479689/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190627","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":"Reversible tau hyperphosphorylation in hibernation: a blood biomarker and brain tissue study","authors":"Wagner S. Brum,&nbsp;Laia Montoliu-Gaya,&nbsp;Gunnar Brinkmalm,&nbsp;Diana Piotrowska,&nbsp;Elena Camporesi,&nbsp;Carsten Jäger,&nbsp;Helena S. Isaksson,&nbsp;Sven Martin,&nbsp;Jonas Kindberg,&nbsp;Juan Lantero-Rodriguez,&nbsp;João Pedro Ferrari-Souza,&nbsp;Alexis Moscoso,&nbsp;Andrea L. Benedet,&nbsp;Shorena Janelidze,&nbsp;Johan Gobom,&nbsp;Henrik Zetterberg,&nbsp;Oskar Hansson,&nbsp;Eduardo R. Zimmer,&nbsp;Nicholas J. Ashton,&nbsp;Thomas Arendt,&nbsp;Tammaryn Lashley,&nbsp;Jens T. Stieler,&nbsp;Max Holzer,&nbsp;Ole Fröbert,&nbsp;Kaj Blennow","doi":"10.1007/s00401-025-02930-2","DOIUrl":"10.1007/s00401-025-02930-2","url":null,"abstract":"<div><p>Tau hyperphosphorylation, a key neuropathological feature of tauopathies such as Alzheimer’s disease (AD), also occurs physiologically during mammalian hibernation and is fully reversed upon arousal, offering a unique translational model to study tau metabolism. However, limited data exist on insoluble and soluble tau alterations during hibernation and on patterns of tau fragment concentrations in the hibernating mammalian brain. We quantified tau biomarkers in plasma samples from ten free-ranging brown bears (<i>Ursus arctos</i>), captured during both their active summer period and hibernation in the winter, using clinically validated immunoassays and immunoprecipitation mass spectrometry (IP-MS) techniques. We also analyzed brain tissue from ten golden Syrian hamsters (<i>Mesocricetus auratus</i>) subjected to induced torpor (hibernation) versus euthermic (non-hibernating) states by quantifying multiple phosphorylated and non-phosphorylated tau peptides with an IP-MS method previously applied in human brain tissue. In brown bears, plasma levels of phosphorylated tau (p-tau) biomarkers p-tau181 and p-tau217 significantly increased during hibernation compared to summer (median increases of 362% and 294% by IP-MS, respectively), with similar increases found with immunoassays. Additional plasma p-tau biomarkers associated with AD pathology, including p-tau205 and p-tau231, were also increased during bear hibernation. In hamster brains, p-tau217, and p-tau231 were similarly elevated during torpor, while tau fragments from the microtubule-binding region (MTBR), associated with tangle aggregation, were not increased. In contrast, brain tissue from <i>n</i> = 10 AD patients, analyzed with the same IP-MS method, exhibited striking increases in p-tau (~ 50,000% for p-tau217) and MTBR fragments (~ 20,000% for MTBR tau354-369) compared with <i>n</i> = 10 human controls. We show that hibernation-linked tau hyperphosphorylation involves some of the same phospho-sites altered in AD, but occurs without MTBR tau aggregation. This highlights hibernation as a reversible, non-pathological model to study tau biology and mechanisms underlying AD due to its reversibility and lack of tau aggregation despite hyperphosphorylation in key AD tau phospho-sites.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02930-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189314","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":"In silico purification improves DNA methylation-based classification rates of pediatric low-grade gliomas","authors":"Liv Jürgensen,&nbsp;Salvatore Benfatto,&nbsp;Simone Schmid,&nbsp;Bjarne Daenekas,&nbsp;Julia Großer,&nbsp;Pablo Hernáiz Driever,&nbsp;Arend Koch,&nbsp;David Capper,&nbsp;Volker Hovestadt","doi":"10.1007/s00401-025-02939-7","DOIUrl":"10.1007/s00401-025-02939-7","url":null,"abstract":"<div><p>DNA methylation-based classification using the Heidelberg Classifier is a state-of-the-art data-driven method for molecular diagnosis of central nervous system (CNS) tumors. However, many pediatric low-grade glioma (pLGG) samples fail to yield a confident methylation-based classification, often suspected due to low tumor cell content. Here, we present a rapid, reference-based in silico purification framework that systematically removes the epigenetic signatures of five non-malignant cell types—microglia, monocytes, neutrophils, T cells, and neurons—from tumor profiles to enable classification of previously non-classifiable pLGG samples. To validate our approach, we analyzed paired DNA methylation profiles from the same biopsy, where one was initially classifiable and the other was not. After purification, predictions for all newly classifiable samples matched the classification of their corresponding initially classifiable counterparts (9/9, 100%). Application of our method to two independent pLGG cohorts allowed confident classification in 24.1% (26/108) and 22.7% (5/22) of previously non-classifiable cases. In conclusion, our in silico purification framework enables confident classification of previously non-classifiable pLGG samples, supporting accurate molecular diagnosis and timely clinical decision-making, and can seamlessly be integrated into current classification workflows. Its independence from tumor type, classifier, and reference signatures further suggests the potential for broader application to other low-purity tumor types.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02939-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145153394","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":"Complement profiling of sural nerves in chronic-inflammatory demyelinating polyneuropathy","authors":"Frauke Stascheit,&nbsp;Andreas Roos,&nbsp;Christina B. Schroeter,&nbsp;Johanna Katrin Thomas,&nbsp;Katrin Hahn,&nbsp;Hannah Preßler,&nbsp;Andreas Hentschel,&nbsp;Beate Schlotter-Weigel,&nbsp;Benedikt Schoser,&nbsp;Tobias Ruck,&nbsp;Andreas Meisel,&nbsp;Werner Stenzel,&nbsp;Corinna Preusse","doi":"10.1007/s00401-025-02936-w","DOIUrl":"10.1007/s00401-025-02936-w","url":null,"abstract":"<div><p>Chronic-inflammatory demyelinating polyneuropathy (CIDP) is a rare immune-mediated polyneuropathy causing substantial disability. While both cell-mediated and humoral mechanisms contribute to CIDP, the role of complement remains poorly understood. Considering the rise of complement-targeted treatment, it is crucial to examine the role of complement in CIDP. In this cross-sectional, study, sural nerve biopsies from 55 CIDP patients were analyzed using histopathology, gene- and protein-based techniques, comparing them to two non-diseased controls (NDCs), as well as 8 patients with hereditary neuropathy (HN) and idiopathic axonal neuropathy (IPN). Overall, 94% (n = 52) revealed abnormal and prominent deposition of terminal complement complex C5b-9 on endoneurial capillaries. Patients with significant complement deposition presented with a progressive disease course (n = 52) and the number and distribution of infiltrating CD8 + T cells and CD68 + macrophages, since a basic immunological paradigm holds that those two may form an immunological synapse, correlated with clinical disease severity as measured by inflammatory neuropathy cause and treatment sensory sum (INCAT) score (<i>p</i> &lt; 0.001). Furthermore, changes in abundances of complement proteins as unveiled by untargeted proteomics accord with changes on transcript level as identified by targeted gene expression studies. In contrast, there was no complement deposition in NDC nor DC. This study provides an extensive evaluation of sural nerve specimens of CIDP patients finding a marked involvement of complement supporting the postulated concept of complement mediated demyelination in CIDP. Our results support the approach of targeting the complement system as a new and promising therapeutic strategy—at least in a subgroup of CIDP. Further research is warranted to unravel the functional implications and role of complement in CIDP progression and optimize patient care. <i>Clinical Trial Registration</i>: The study is registered under the German clinical trial registry (https://www.drks.de), DRKS0003245.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02936-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083537","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":"Alpha synuclein-mediated cytoskeletal dysfunction impairs myelination in human oligodendrocytes","authors":"Jeanette Wihan,&nbsp;Kristina Battis,&nbsp;Alana Hoffmann,&nbsp;Farina Windener,&nbsp;Marcus Himmler,&nbsp;Anish Varghese,&nbsp;Aron Koller,&nbsp;Isabell Karnatz,&nbsp;Dirk W. Schubert,&nbsp;Friederike Zunke,&nbsp;Wei Xiang,&nbsp;Tanja Kuhlmann,&nbsp;Jürgen Winkler","doi":"10.1007/s00401-025-02933-z","DOIUrl":"10.1007/s00401-025-02933-z","url":null,"abstract":"<div><p>Oligodendroglial alpha-synuclein (aSyn) deposits are a key feature in the atypical parkinsonian disorder, multiple system atrophy (MSA) linked to profound myelin loss and neurodegeneration while precise cellular and molecular mechanisms remain unclear. We generated human oligodendrocytes (hOLs) from induced pluripotent stem cells to investigate the impact of aSyn on oligodendroglial morphology, differentiation, and function. We observed an aSyn-induced myelinogenic dysfunction characterized by impaired oligodendroglial process outgrowth, altered cell shape, and increased perinuclear accumulation of the tubulin polymerization promoting protein TPPP/p25α. These changes were associated with a reduced capacity to ensheath axons and were linked to compromised actin remodeling machinery. Actin imbalances were confirmed in <i>post-mortem</i> putaminal tissue from MSA patients. Treatment with a rho-associated protein kinase inhibitor rescued oligodendroglial process formation and improved ensheathment in aSyn-expressing hOLs. Our work emphasizes the aSyn-mediated interference with actin dynamics as a key pathogenic mechanism in MSA, pointing toward a novel therapeutic target for improving myelin maintenance.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02933-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145089814","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":"Genetic and clinical characteristics of cranial nerve schwannoma harboring SH3PXD2A-HTRA1 fusion gene","authors":"Junki Sogano,&nbsp;Ryota Tamura,&nbsp;Masahiro Yo,&nbsp;Kohei Nakamura,&nbsp;Ippei Fukada,&nbsp;Takayuki Ueno,&nbsp;Utaro Hino,&nbsp;Azuna Tomioka,&nbsp;Kosuke Karatsu,&nbsp;Aya Nagao,&nbsp;Ryo Ueda,&nbsp;Hiroshi Nishihara,&nbsp;Masahiro Toda","doi":"10.1007/s00401-025-02941-z","DOIUrl":"10.1007/s00401-025-02941-z","url":null,"abstract":"<div><p>The <i>SH3PXD2A-HTRA1</i> fusion gene has recently been identified in a subset of schwannomas, but its frequency and clinical significance remain unclear. This study aimed to investigate the prevalence and clinical relevance of this fusion gene in intracranial schwannomas, stratified by cranial nerve of origin. We retrospectively investigated the fusion gene in 237 intracranial schwannomas. Fusion detection was performed using reverse transcription polymerase chain reaction and confirmed by Sanger sequencing. Somatic <i>NF2</i> status was evaluated using whole-genome sequencing or Merlin immunohistochemistry in fusion gene-positive cases. Clinical characteristics and postoperative tumor recurrence were compared between fusion gene-positive and fusion gene-negative tumors, and subgroup analyses were performed by cranial nerve of origin. The fusion gene was detected in 30 tumors (12.7%), with the highest frequency observed in trigeminal schwannomas (25.9%). Tumors classified as recurrent at baseline (odds ratio [OR], 3.74; <i>P</i> = 0.012), trigeminal nerve origin (OR, 2.88; <i>P</i> = 0.042), and intratumoral hemorrhage (OR, 18.61; <i>P</i> = 0.028) were significantly associated with fusion gene-positive tumors. In the trigeminal schwannomas, fusion gene-positive cases were significantly younger (<i>P</i> = 0.029). In the vestibular schwannomas, recurrence status was found to be independently associated with positive fusion gene status (OR, 4.53; <i>P</i> = 0.010). Furthermore, even after gross or nearly total resection, fusion gene-positive vestibular schwannomas exhibited a significantly higher incidence of recurrence after surgery (<i>P</i> = 0.046). Only 33% of fusion gene-positive tumors indicated somatic <i>NF2</i> alteration. The <i>SH3PXD2A-HTRA1</i> fusion gene may define a molecular subset of intracranial schwannomas with distinctive anatomical distribution and biological aggressiveness. It may contribute to tumorigenesis through an alternative pathway independent of <i>NF2</i>. Our findings provide a basis for future clinical investigations.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079024","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":"Limbic Alzheimer’s co-pathology in multiple system atrophy is associated with cognitive impairment and diagnostic inaccuracy","authors":"Janna van Wetering,&nbsp;Natasja A. C. Deshayes,&nbsp;Joëlle Boone,&nbsp;Inês Rodrigues Fernandes,&nbsp;Dagmar H. Hepp,&nbsp;Henk W. Berendse,&nbsp;Laura E. Jonkman,&nbsp;Annemieke J. M. Rozemuller,&nbsp;Wilma D. J. van de Berg","doi":"10.1007/s00401-025-02940-0","DOIUrl":"10.1007/s00401-025-02940-0","url":null,"abstract":"<div><p>The clinical heterogeneity of multiple system atrophy (MSA) may, along with the primary aggregation of alpha-synuclein (α-syn), partly be shaped by co-pathologies, such as amyloid-beta (Aβ), phosphorylated (p)-tau, and pTDP-43, though their relevance remains unclear. Here, we aimed to characterize the prevalence, morphology, regional patterns, and clinical relevance of co-pathologies in a well-characterized MSA autopsy cohort. Regional load (%area) and morphological characterization of α-syn (KM51), Aβ (6F/3D), p-tau (AT8), and pTDP-43 (pSer409) pathology were assessed in limbic regions of MSA (<i>n</i> = 70) donors from the Netherlands Brain Bank. APOE-ε4 genotyping and clinical parameters of the cohort were collected. Associations with clinical features were analyzed using ANCOVA and mixed linear models, adjusted for age and sex. Aβ, p-tau, and pTDP-43 pathology were detected in 31%, 91%, and 11% of all MSA cases, respectively, with the highest burdens in the entorhinal cortex and amygdala. Mixed MSA + AD cases had a higher age at death (75 ± 7 vs. 64 ± 7, <i>p</i> &lt; 0.001), and more frequently APOE-ε4 alleles (<i>p</i> &lt; 0.001) than pure MSA. Cognitive impairment (CDR scores) was associated with diffuse and compact Aβ plaques across all regions (r ≥ 0.24, <i>p</i> ≤ 0.015), p-tau pathology in CA1 and CA3 + 4 (r ≥ 0.32, <i>p</i> ≤ 0.020), and neuronal α-syn inclusions in the amygdala (r = 0.54, <i>p</i> &lt; 0.001). No robust correlations were found between total α-syn burden and Aβ or p-tau. Misdiagnoses increased with co-pathology burden (Aβ: <i>p</i> = 0.040; p-tau: <i>p</i> = 0.020) and age at onset (80% in those with onset &gt; 75 years). Our results demonstrate that limbic Aβ, p-tau, and neuronal α-syn pathologies occur in a substantial proportion of MSA donors and are independently associated with cognitive decline and diagnostic inaccuracy, particularly among those with older age at onset. By providing a systematic quantitative and morphological assessment of co-pathologies in limbic regions of MSA, our study advances beyond prior prevalence reports and highlights their direct clinical relevance. These findings highlight the need for refined diagnostic criteria and co-pathology-informed biomarker strategies for MSA.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02940-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079023","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":"Spatial transcriptomic analysis reveals lack of response to PD-1 blockade in recurrent glioblastoma","authors":"Sara Blaabjerg Artzi,&nbsp;Marc Nihøj Klausen,&nbsp;Dylan Scott Lykke Harwood,&nbsp;Signe Regner Michaelsen,&nbsp;Simone Bendix Maarup,&nbsp;Alessio Locallo,&nbsp;Vincent Fougner,&nbsp;Nicolai Schou Bager,&nbsp;Nadine Margaretha Hammouda,&nbsp;Dorte Schou Nørøxe,&nbsp;Benedikte Hasselbalch,&nbsp;Ulrik Lassen,&nbsp;Joachim Weischenfeldt,&nbsp;Bjarne Winther Kristensen","doi":"10.1007/s00401-025-02937-9","DOIUrl":"10.1007/s00401-025-02937-9","url":null,"abstract":"<div><p>Immune checkpoint inhibitors have transformed treatment for several cancers, yet clinical trials of programmed cell death protein 1 (PD-1) blockade in glioblastoma (GBM) have consistently failed to show therapeutic benefit. While some studies have reported treatment-related transcriptional changes, particularly in T cells, findings remain limited and inconsistent. The aim of this study was to investigate changes in tumor cells and tumor-associated macrophages (TAMs) after PD-1 blockade in recurrent GBM using spatial transcriptomics. We performed Digital Spatial Profiling (GeoMx, NanoString) on FFPE tumor samples from 26 patients with matched primary and recurrent IDH-wildtype GBM, including 16 patients who received neoadjuvant nivolumab at recurrence. Tumor (SOX2⁺) and TAM (IBA1⁺) segments were selected for targeted spatial analysis. Following quality control and filtering, transcriptomic profiles were compared between nivolumab-treated and untreated recurrent tumors. PD-1 blockade did not induce detectable gene expression changes in either tumor cells or TAMs. There were no significant differences in global expression profiles or in more targeted analyses of malignant cell states, cell cycle activity, interferon signaling, or myeloid transcriptional programs. These results consistently indicate that neoadjuvant PD-1 blockade does not elicit measurable responses at the spatial transcriptomic level in tumor cells or TAMs in recurrent GBM. These findings align with the lack of clinical benefit observed in trials and highlight the need for alternative strategies to improve immunotherapy outcomes in GBM.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02937-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145071803","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":"Differences and overlaps in TDP-43 pathology of ‘pure’ LATE-NC compared to LATE-NC coexisting with Alzheimer’s disease","authors":"Sandra O. Tomé,&nbsp;Klara Gawor,&nbsp;Simona Ospitalieri,&nbsp;Alicja Ronisz,&nbsp;Markus Otto,&nbsp;Christine A. F. von Arnim,&nbsp;Estifanos Ghebremedhin,&nbsp;Celeste Laureyssen,&nbsp;Kristel Sleegers,&nbsp;Rik Vandenberghe,&nbsp;Peter T. Nelson,&nbsp;Dietmar Rudolf Thal","doi":"10.1007/s00401-025-02929-9","DOIUrl":"10.1007/s00401-025-02929-9","url":null,"abstract":"<div><p>Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a common substrate of dementia in the elderly. LATE and Alzheimer’s disease (AD) share similar clinical features, and their underlying neuropathological changes—LATE-NC and ADNC—commonly co-occur. However, the histomorphological and molecular features of TDP-43 pathology in LATE-NC with or without coexisting ADNC are not yet well understood. We performed immunohistochemistry in paraffin-embedded tissue from the hippocampus, amygdala, and temporal and frontal cortices of 108 human autopsy cases including 20 cognitively unimpaired controls, 20 AD dementia cases with moderate-high severity of ADNC without LATE-NC (ADNC group), 34 AD dementia cases with LATE-NC (ADNC + LATE-NC group), 17 dementia cases with LATE-NC but no/low ADNC (pure LATE-NC group), and 17 FTLD-TDP Type A cases. We assessed TDP-43 aggregate morphology and composition using antibodies against different TDP-43 epitopes: pS409/410, pS403/pS404, and C- and N-terminal TDP-43. We also investigated nuclear clearance of physiological TDP-43 and cytoplasmic colocalization of TDP-43 and tau proteins. Pure LATE-NC cases were on average 10 years older at death than ADNC + LATE-NC, had less cognitive impairment, higher prevalence of argyrophilic grain disease (AGD) pathology, aging-related tau astrogliopathy (ARTAG), and <i>APOE</i>ε2 allele. They also tended to show lower <i>APOEε4</i> frequencies, but similar frequencies of hippocampal sclerosis and LATE-NC stages. Importantly, LATE-NC predominantly displayed a mesh-like neuritic TDP-43 pattern in the hippocampus, extending from CA1/2 to subiculum. This mesh-like pattern was present in 81% of pure LATE-NC cases and only in 18% of ADNC + LATE-NC. This pattern was also observed in 53% of FTLD-TDP Type A cases. Moreover, the aggregate composition differed in pure LATE-NC and ADNC + LATE-NC, with LATE-NC cases exhibiting increased burdens of several phosphorylated and non-phosphorylated TDP-43 species, while only the pS409/pS410 epitope was significantly associated with ADNC + LATE-NC in the amygdala. Nuclear clearance patterns also tended to differ between pure LATE-NC and ADNC + LATE-NC. Similar to ADNC + LATE-NC, TDP-43 and tau proteinopathies colocalized in pure LATE-NC with comorbid primary age-related tauopathy (PART) or low ADNC. These data suggest that LATE-NC tends to be modified in the presence of moderate–high ADNC. These differences may reflect upstream influences (age, genetics, and environmental risk factors), direct protein–protein interactions, and/or other impacts of ADNC-related mechanisms on TDP-43 proteinopathy, potentially relevant for clinical trial design and future therapeutic applications.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"150 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145057545","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}