Acta Neuropathologica最新文献

{"title":"High levels of cell-free hemoglobin and iron in cerebral thrombi of pre-Omicron COVID-19 stroke patients: novel drivers of SARS-CoV-2–induced prothrombotic state","authors":"María Payá,&nbsp;Cristian Alcahut-Rodríguez,&nbsp;Rosa A. Barbella-Aponte,&nbsp;Francisco Hernández-Fernández,&nbsp;Juan D. Molina-Nuevo,&nbsp;Gemma Barroso-García,&nbsp;Beatriz Castro-Robles,&nbsp;Susana López-López,&nbsp;Lourdes Arias-Salazar,&nbsp;Óscar Ayo-Martín,&nbsp;Jorge García-García,&nbsp;Blanca Yélamos-Sanz,&nbsp;Natalia García-Flores,&nbsp;Alba G. Arandilla,&nbsp;Rafael Moreno-Luna,&nbsp;Alicia Aliena-Valero,&nbsp;Isabel Vielba-Gómez,&nbsp;José I. Tembl,&nbsp;Juan B. Salom,&nbsp;Gemma Serrano-Heras,&nbsp;Tomás Segura","doi":"10.1007/s00401-026-03074-7","DOIUrl":"10.1007/s00401-026-03074-7","url":null,"abstract":"<div><p>The pathophysiological mechanisms underlying the hypercoagulable state and thrombotic events associated with COVID-19 remain incompletely understood. To investigate prothrombotic alterations during SARS-CoV-2 infection, we performed an exploratory and integrated analysis of cerebral thrombi retrieved, during the first wave of the pandemic, by mechanical thrombectomy from stroke patients with (n=6) and without (n=6) COVID-19. We combined histological and ultrastructural assessment with quantitative proteomics and elemental profiling to identify differences in cellular organization and in protein and metal composition. Immunohistochemical quantification revealed a trend toward increased macrophage abundance, a more diffuse CD68⁺ staining pattern, and reduced platelet content in COVID-19 thrombi. In contrast, neutrophil extracellular traps (NETs) burden, neutrophil number, and erythrocyte content did not differ significantly between groups. Transmission electron microscopy showed a disorganized ultrastructural fibrillar network in thrombi from COVID-19 stroke patients, consistent with the irregular and less densely packed extracellular matrix observed by Masson's trichrome staining. Furthermore, quantitative proteomics by liquid chromatography–tandem mass spectrometry (LC–MS/MS) identified 48 differentially expressed proteins among 720 shared proteins, with marked upregulation of hemoglobin subunits (α, β, γ, and δ), haptoglobin, biliverdin reductase and redox-regulating proteins, alongside downregulation of platelet-related proteins in COVID-19 thrombi. Total reflection X-ray fluorescence (TXRF) confirmed increased iron levels in COVID-19-associated thrombi. Notably, glycophorin A immunostaining did not indicate increased erythrocyte abundance, and erythrocyte structural proteins were not differentially expressed in proteomic analysis, suggesting that hemoglobin and iron were largely present in a cell-free form within the retrieved thrombi of COVID-19 stroke patients. In addition, acute-phase reactants, classical complement components, and immunoglobulins were detected exclusively in COVID-19 samples, consistent with a distinctive immune-inflammatory and oxidative signature. Overall, these findings support a novel pathophysiological mechanism underlying COVID-19-associated hypercoagulability and thrombosis, involving elevated circulating cell-free hemoglobin and increased iron content. Furthermore, this study highlights the potential contribution of hemoglobin/iron-related processes to the COVID-19 prothrombotic state and may provide molecular targets for future therapeutic strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148856875","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":"Distinctive properties of the prion protein in the brain and retina in the amyloidosis associated with the PRNP F198S mutation","authors":"Bernardino Ghetti,&nbsp;Bradley S. Glazier,&nbsp;Michele Fiorini,&nbsp;Kathy L. Newell,&nbsp;José M. Bonnin,&nbsp;Jill R. Murrell,&nbsp;Leah Rie Varner,&nbsp;Max Jacobsen,&nbsp;James F. Striebel,&nbsp;Suzette A. Priola,&nbsp;Gianluigi Zanusso","doi":"10.1007/s00401-026-03060-z","DOIUrl":"10.1007/s00401-026-03060-z","url":null,"abstract":"<div><p>Prion protein (PrP) deposits in the form of diffuse and cored plaques occur in most gray matter areas of the brain of individuals affected by Gerstmann–Sträussler–Scheinker disease (GSS) associated with the F198S mutation in <i>PRNP</i>; however, the PrP deposits in the retina have not been characterized. Furthermore, a comparative analysis of PrP deposits occurring in the brain and in the retina in GSS has not been carried out. We hypothesize that the PrP aggregation and seeding properties in the brain and retina differ. The aim of this study was to analyze PrP from brains and retinas of individuals affected by GSS, all carriers of the <i>PRNP</i> F198S mutation from the same pedigree. Postmortem tissues from these patients were analyzed using neuropathologic and biochemical methods including Real-Time Quaking Induced Conversion assay. PrP deposits in the retina were found only in the outer plexiform layer, did not have tinctorial property of amyloid and were immunopositive using nine antibodies recognizing epitopes throughout the PrP sequence. Biochemical analysis showed that PrP^_F198S in the retina is partially detergent-insoluble, is assembled in large-size aggregates, and has seeding property. In addition, the glycosylation of full-length PrP in the retina was more complex than that of control PrP. Furthermore, the homogenates of retina did not contain the 8 kDa PrP internal fragments (PrP^IF) as brain homogenates do; however, a PrP^IF was experimentally generated using proteinase K. In conclusion, we report for the first time the neuropathologic and biochemical properties of PrP in the retina of individuals carrying <i>PRNP</i> F198S and compare them with those in the brain of the same individuals. The fact that in GSS F198S, PrP^IF is constitutive only in the brain points to the need of identifying whether there is a difference in proteolytic mechanisms between retina and brain.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03060-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148823867","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 subtypes of multiple sclerosis severity are uncoupled from inflammatory lesion burden","authors":"Gianmarco Abbadessa,&nbsp;Karim L. Kreft,&nbsp;Owain Howell,&nbsp;Jean Victor Carlos de Oliveira,&nbsp;Benjamin Cooze,&nbsp;Artemis Papadaki,&nbsp;Joic Majo Jacinto,&nbsp;Ildiko Farkas,&nbsp;Yeung-Yeung Leung,&nbsp;Simona Bonavita,&nbsp;Emma Clare Tallantyre,&nbsp;Neil P. Robertson,&nbsp;Ai Nagano,&nbsp;Mie Rizig,&nbsp;Roberta Magliozzi,&nbsp;David Owen,&nbsp;Richard Reynolds,&nbsp;Richard Nicholas","doi":"10.1007/s00401-026-03062-x","DOIUrl":"10.1007/s00401-026-03062-x","url":null,"abstract":"<div><p>Determinants of long-term disability in multiple sclerosis (MS) remain incompletely understood, with clinical course varying greatly among individuals. Recent integrative genetic models have identified genomic clusters associated with divergent disability trajectories. Here, we integrated clinical, genetic, and postmortem neuropathological data from 291 MS brain donors from the UK MS Society Tissue Bank to test whether genomic severity clusters converge on distinct tissue phenotypes. Consistent with prior stratification, donors in genomic cluster 2 had lower age-adjusted disease duration score (ADDS) than cluster 3 (<i>β</i> = − 0.195, <i>P</i> = 0.023) and a shorter interval from progression to death than cluster 1 (<i>β</i> = − 0.225, <i>P</i> = 0.049). However, this adverse clinical profile did not reflect greater active or chronic active lesion burden. Instead, chronic active broad-rim lesions were more frequent in cluster 1 than clusters 2 and 3 (37.3% vs 24.0% and 27.2%; both FDR = 0.043), whereas chronic inactive lesions were enriched in clusters 2 and 3 relative to cluster 1 (58.2% vs 70.0% and 73.8%; FDR = 0.154 and 0.030, respectively). This dissociation was strongly influenced by HLA genetic background: cluster 1 carried the highest HLA genetic burden, which was associated with greater non-lesional HLA-D immunoreactivity (rho = 0.48, FDR &lt; 0.001), higher HLA-DRB1 (rho = 0.514, FDR &lt; 0.001) and HLA-DRB5 (rho = 0.740, FDR &lt; 0.001) mRNA expression, more active lesions (rho = 0.21, FDR = 0.007) and chronic active broad-rim lesions (rho = 0.19, FDR = 0.017), and fewer chronic inactive lesions (rho = − 0.26, FDR &lt; 0.001), but not with clinical severity. Although chronic active lesion burden remained a strong tissue correlate of severity, adjustment for it strengthened the association between cluster 2 and worse outcome (ADDS: cluster 2 vs 1: <i>β</i> = − 0.216, Holm-adjusted <i>P</i> = 0.038; cluster 2 vs 3: <i>β</i> = − 0.246, Holm-adjusted <i>P</i> = 0.012; time from progression to death: cluster 2 vs 1: <i>β</i> = − 0.288, Holm-adjusted <i>P</i> = 0.049). Overall, these findings indicate that (i) HLA genetic background shapes the neuropathological representation of inflammatory lesions, and (ii) the adverse clinical profile of cluster 2 is not fully explained by HLA-D-defined chronic active lesion burden in the sampled postmortem tissue, suggesting that genomic severity clusters and chronic active lesion burden capture complementary aspects of MS progression.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03062-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783204","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":"Tectal glioma versus pilocytic astrocytoma: revisiting tumor classification in light of molecular heterogeneity","authors":"Arnault Tauziède-Espariat,&nbsp;Alice Métais,&nbsp;Kenneth Aldape,&nbsp;Omkar Singh,&nbsp;Raphaël Saffroy,&nbsp;Kévin Beccaria,&nbsp;Aurélien Saint-Grégoire,&nbsp;Euphrasie Servant,&nbsp;Anne-Sophie Lèbre,&nbsp;Romain Appay,&nbsp;Guillaume Chotard,&nbsp;Franck Ah-Pine,&nbsp;Maxime Faisant,&nbsp;Valérie Rigau,&nbsp;Lauren Hasty,&nbsp;Farah Sassi,&nbsp;Volodia Dangouloff-Ros,&nbsp;Nathalie Boddaert,&nbsp;Pascale Varlet","doi":"10.1007/s00401-026-03066-7","DOIUrl":"10.1007/s00401-026-03066-7","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783002","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":"Correction: CTE-type tau filaments in Alzheimer’s disease with co-morbid LATE-NC","authors":"Jaimin K. Rana,&nbsp;Emile S. Pinarbasi,&nbsp;Martin G. Fernandez,&nbsp;Vikas Navratna,&nbsp;Kyle S. Conway,&nbsp;Andrew P. Lieberman,&nbsp;Sami J. Barmada,&nbsp;Shyamal Mosalaganti","doi":"10.1007/s00401-026-03069-4","DOIUrl":"10.1007/s00401-026-03069-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03069-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148783032","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":"Sellar region neurocytomas exhibit a CIMP and neuroendocrine-like epigenetic signature distinct from other intra-axial neurocytomas","authors":"Thomas M. Pearce,&nbsp;Patrick J. Cimino,&nbsp;Calixto-Hope G. Lucas,&nbsp;Daniel F. Marker,&nbsp;Scott Kulich,&nbsp;John M. Skaugen,&nbsp;Julia K. Kofler,&nbsp;Benjamin B. Cho,&nbsp;Kyle Kurek,&nbsp;Kyle Conway,&nbsp;Joshua Klonoski,&nbsp;Miguel A. Guzman,&nbsp;Sarra M. Belakhoua,&nbsp;Sofia Asioli,&nbsp;Naoko Inoshita,&nbsp;Omkar Singh,&nbsp;Zied Abdullaev,&nbsp;Katrin B. M. Frauenknecht,&nbsp;Arie Perry,&nbsp;Felipe Andreiuolo,&nbsp;Kenneth Aldape,&nbsp;Valérie Rigau,&nbsp;Romain Appay,&nbsp;Emmanuelle Uro-Coste,&nbsp;Melike Pekmezci,&nbsp;Matija Snuderl,&nbsp;Caterina Giannini,&nbsp;Leonille Schweizer,&nbsp;David Capper,&nbsp;Martha Quezado,&nbsp;M Beatriz S Lopes,&nbsp;Drew Pratt","doi":"10.1007/s00401-026-03070-x","DOIUrl":"10.1007/s00401-026-03070-x","url":null,"abstract":"<div><p>Sellar region neurocytoma (SELN) is a rare neoplasm whose relationship to other neurocytomas within the central nervous system (CNS) has remained unclear. Prior reports have variably classified SELN as a variant of extraventricular neurocytoma (EVN), while immunohistochemical and ultrastructural studies have suggested a hypothalamic origin. Here, we performed unsupervised clustering of DNA methylation data across a large pan-cancer reference set and identified SELN (<i>n</i> = 20) as distinct from other neurocytomas and regional mimics, as well as clustering with neuroendocrine tumors from other organ sites. SELN exhibited a CIMP-like phenotype, TTF1 negativity (0/8), and AVP (vasopressin) promoter hypomethylation, implicating a magnocellular hypothalamic cell of origin. In evaluable cases, a neuronal/neuroendocrine immunophenotype was observed (synaptophysin 8/8, chromogranin A 5/5) with absent pituitary transcription factor expression (PIT1 and TPIT negative 0/4). DNA sequencing (<i>n</i> = 5) and RNA-based fusion profiling (<i>n</i> = 4) did not detect recurrent mutations or gene fusions, respectively. Patients often presented with visual disturbances or headaches and spanned pediatric and older age groups (median 42 years, range 12.5–75), with no sex predilection. Despite locally aggressive imaging features in some cases (cavernous sinus invasion, carotid encasement, hydrocephalus), disease-free survival (<i>n</i> = 13) was comparable to central neurocytoma, with no disease-related deaths during the limited follow-up. Together, these findings support SELN as a molecularly distinct hypermethylated neuroendocrine-like epitype and clinicopathologic entity.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03070-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782856","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":"Emerging roles of granzymes in neurodegeneration and neuroinflammation: mechanistic insights and therapeutic opportunities","authors":"Hyung-Suk Yoo,&nbsp;Philip Yu,&nbsp;Ceres Zhou,&nbsp;Amir Hosseini,&nbsp;David J. Granville,&nbsp;Joanne A. Matsubara","doi":"10.1007/s00401-026-03061-y","DOIUrl":"10.1007/s00401-026-03061-y","url":null,"abstract":"<div><p>Neurodegenerative diseases are increasingly recognized as disorders shaped not only by intrinsic neuronal vulnerability, but also by chronic neuroinflammation mediated by maladaptive neuroimmune signaling. Granzymes, a family of serine proteases classically studied for their cytotoxic roles in anti-viral and anti-tumor immunity, are emerging as important mediators of central nervous system (CNS) pathology. In addition to their canonical intracellular functions, granzymes can act extracellularly to cleave the extracellular matrix (ECM), activate cell-surface receptors, disrupt epithelial barrier function, amplify inflammatory cascades, and alter glial and neuronal responses to injury. In this review, we synthesize current knowledge on the roles of Granzyme A (GzmA), Granzyme B (GzmB), Granzyme H (GzmH), and Granzyme K (GzmK) in neurodegeneration and neuroinflammation across diverse CNS disease and injury contexts, such as Alzheimer’s disease (AD), multiple sclerosis (MS), stroke, spinal cord injury (SCI), and age-related macular degeneration (AMD). GzmB is the most extensively characterized, with evidence supporting both intracellular neurotoxicity and extracellular pathogenic functions mediated through protease-activated receptor signaling, ECM cleavage, outer blood–retina barrier disruption, angiogenesis, fibrosis, and chronic inflammation. GzmA is implicated in tau proteolysis and structural destabilization of neurons and astrocytes, while GzmK has emerged as a context-dependent regulator of neuroinflammation through PAR-1 activation, microglial modulation, and complement cascade activation. GzmH remains the least understood but may contribute to nerve injury through mechanisms that are only beginning to be defined. We also discuss endogenous and pharmacological granzyme inhibition, highlighting the therapeutic promise of selective extracellular granzyme targeting, particularly for GzmB, while emphasizing the current lack of selective inhibitors for GzmA, GzmK, and GzmH. Collectively, these findings position granzymes as underappreciated neuroimmune effectors and potential therapeutic targets in neurodegenerative diseases and CNS injury.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03061-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148782989","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":"Distinct alpha-synuclein seeding in post-mortem skin of Lewy body disease and multiple system atrophy","authors":"Ain Kim,&nbsp;Tarig Abkur,&nbsp;Masahiro Enomoto,&nbsp;Xiaoxiao Xu,&nbsp;Anthony E. Lang,&nbsp;Carmela Tartaglia,&nbsp;Gabor G. Kovacs,&nbsp;Ivan Martinez-Valbuena","doi":"10.1007/s00401-026-03068-5","DOIUrl":"10.1007/s00401-026-03068-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148757053","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":"Cerebrospinal fluid cell-free DNA sequencing in pediatric CNS tumors: towards liquid molecular neuropathology","authors":"William Gehin,&nbsp;Marie-Sophie Merlin,&nbsp;Alexandre Harle,&nbsp;Jean-Louis Merlin","doi":"10.1007/s00401-026-03067-6","DOIUrl":"10.1007/s00401-026-03067-6","url":null,"abstract":"<div><p>Pediatric central nervous system tumors remain a leading cause of cancer-related mortality in children, while their diagnosis, risk stratification, and therapeutic management increasingly depend on integrated molecular characterization. However, representative tumor tissue is often difficult to obtain because of tumor location, surgical risk, limited biopsy material, and the impracticality of repeated sampling during disease evolution. Cerebrospinal fluid (CSF) has therefore emerged as a particularly informative liquid biopsy compartment for many CNS malignancies, enriched in tumor-derived cell-free DNA and, for tumors in contact with the CSF spaces, more directly reflective of intracranial tumor biology than plasma; its yield nonetheless varies with tumor biology and anatomical proximity to CSF pathways. Here, we review the evidence supporting CSF cell-free DNA sequencing as an emerging extension of molecular neuropathology in pediatric CNS tumors. Targeted next-generation sequencing, low-pass whole-genome sequencing, methylation-based classifiers, and nanopore sequencing now enable complementary assessment of somatic mutations, copy number alterations, epigenetic tumor class, and longitudinal tumor burden from low-input pediatric CSF samples. Recent studies have moved the field beyond analytical proof of concept towards defined clinical scenarios, including molecular diagnosis when biopsy is infeasible, molecular staging of high-CSF-shedding tumors, minimal residual disease monitoring in medulloblastoma and other embryonal tumors, and clarification of ambiguous radiological progression. CSF-based sequencing does not replace tissue neuropathology, but provides a liquid molecular layer that can complement, extend, or in selected situations partially substitute tissue-based diagnosis. Its broader adoption now depends on workflow standardization, assay-specific reporting standards, external quality assurance, and prospective evidence that CSF-guided decisions improve patient outcomes.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03067-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148700403","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":"Activated microglial phenotypes in the hippocampal CA2 subfield are implicated in Lewy body disease progression","authors":"Esteban Luna,&nbsp;Katheryn A. Q. Cousins,&nbsp;Sheina Emrani,&nbsp;Sharon X. Xie,&nbsp;Winifred Trotman,&nbsp;Noah Capp,&nbsp;Philip Sabatini,&nbsp;Parham Pouladvand,&nbsp;EunRan Suh,&nbsp;Vivianna M. Van Deerlin,&nbsp;Daniel Weintraub,&nbsp;Alice S. Chen-Plotkin,&nbsp;Edward B. Lee,&nbsp;David J. Irwin","doi":"10.1007/s00401-026-03065-8","DOIUrl":"10.1007/s00401-026-03065-8","url":null,"abstract":"<div><p>Histopathologic staging models of neuronal α-synuclein pathology (n-asyn) in Lewy body disease (LBD) seldom evaluate brain regions with direct synaptic connectivity to model the role of microglial processes. We address this gap by testing the hypothesis that, within the well-defined synaptic connectivity of the intrahippocampal circuit, n-asyn is associated with activated microglial phenotypes. We selected a cohort of autopsy-confirmed LBD patients and minimal age-related copathologies (<i>n</i> = 62) and a control cohort of cognitively healthy patients with isolated hippocampal tau accumulation (i.e., primary age-related tauopathy, PART; <i>n</i> = 12), to control for neurodegenerative pathology without amyloid plaques. We immunostained consecutive hippocampal sections for n-asyn and established markers of activated microglial phenotypes, Iba1, HLA-DR, and CD68. With validated digital histology methods, we measured percent area occupied (%AO) of each marker in 6 hippocampal subfields to compare and correlate microglial morphologic and proteomic activation phenotypes between cohorts and used linear mixed effects models to compare the %AO between subfields while covariying for demographics. We also constructed groups of n-asyn restricted to the cornu ammonis (CA) 2–3 subfields (Focal Subtype) or widespread n-asyn within additional subfields (Widespread Subtype) to model hypothesized n-asyn spread within the intrahippocampal circuit. LBD patients exhibited increased HLA-DR and CD68%AO in most hippocampal subfields compared with PART. In LBD patients, all microglial markers were the highest in the CA2. CA2 n-asyn correlated with HLA-DR and CD68 but not Iba1%AO. Patients classified as Widespread Subtype had worse cognitive impairment and increased CA2 HLA-DR and CD68%AO. CA2 HLA-DR and CD68%AO correlated with distal n-asyn in retrograde, but not anterograde connected subfields. Our data show that activated microglial phenotypes in the CA2 of LBD patients are associated with worse clinical outcomes and retrograde n-asyn transmission. These data suggest that measures of microglial states can refine LBD histopathological progression models.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13452847/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148696844","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}