Acta Neuropathologica最新文献

{"title":"Liquid biopsies for the monitoring of gliomas and brain metastases in adults","authors":"Govert Dwarshuis,&nbsp;Lente L. Kroon,&nbsp;Dieta Brandsma,&nbsp;David P. Noske,&nbsp;Myron G. Best,&nbsp;Nik Sol","doi":"10.1007/s00401-025-02880-9","DOIUrl":"10.1007/s00401-025-02880-9","url":null,"abstract":"<div><p>Clinical evaluation and MR imaging are currently the cornerstone of brain tumor progression monitoring. However, this is complicated by the occurrence of treatment effects such as pseudoprogression and radionecrosis. While essential for patient management, the distinction from true progression remains a significant challenge. Moreover, MR imaging provides limited real-time insights into tumor heterogeneity, genetic divergence, and treatment resistance. Although surgical histopathological biopsies can yield additional valuable information, they are not always conclusive, invasive, and therefore, not suitable for longitudinal measurements. In the era of precision medicine, there is a critical need for minimally invasive, accurate, and cost-effective monitoring methods for both primary brain tumors and brain metastases. Liquid biopsies have emerged as a potential candidate. Various analytes, including circulating nucleic acids, extracellular vesicles, platelet RNAs, and circulating tumor cells, can be obtained from whole blood and its derivatives, as well as other body fluids such as cerebrospinal fluid. In this narrative review, we outline the potential of liquid biopsies for the management of gliomas and brain metastases in adults and emphasize their utility in monitoring disease progression and treatment response. We discuss the most studied biofluids and analytes, along with their respective advantages and downsides. Furthermore, we address key considerations for future research and biobanking to pave the way for clinical implementation. </p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02880-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875323","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":"Neuronal pSTAT1 hallmarks synaptic pathology in autoimmune encephalitis against intracellular antigens","authors":"Giovanni Di Liberto,&nbsp;Kristof Egervari,&nbsp;Alberto Vogrig,&nbsp;Marianna Spatola,&nbsp;Margot Piccinno,&nbsp;Ilena Vincenti,&nbsp;Ingrid Wagner,&nbsp;Mario Kreutzfeldt,&nbsp;Verena Endmayr,&nbsp;Karoline Ostertag,&nbsp;Jasmin Rahimi,&nbsp;Alex Vicino,&nbsp;Anne-Katrin Pröbstel,&nbsp;David Meyronet,&nbsp;Stephan Frank,&nbsp;Marco Prinz,&nbsp;Ekkehard Hewer,&nbsp;Jean-Philippe Brouland,&nbsp;Laurence de Leval,&nbsp;Laura Parkkinen,&nbsp;Bogdan Draganski,&nbsp;Virginie Desestret,&nbsp;Divyanshu Dubey,&nbsp;Sean J. Pittock,&nbsp;Shanu F. Roemer,&nbsp;Dennis W. Dickson,&nbsp;Romana Höftberger,&nbsp;Sarosh R. Irani,&nbsp;Jérôme Honnorat,&nbsp;Renaud Du Pasquier,&nbsp;Doron Merkler","doi":"10.1007/s00401-025-02882-7","DOIUrl":"10.1007/s00401-025-02882-7","url":null,"abstract":"<div><p>Autoimmune encephalitis (AE) is an inflammatory syndrome of the central nervous system (CNS) triggered by aberrant immune responses against neuronal intracellular (IC-AE) or surface (NS-AE) autoantigens. The resulting neuronal alterations and clinical trajectories differ, with IC-AE often leading to fatal outcomes. Unfortunately, the scarce availability of tissue from AE cases has hampered systematic analyses that would allow an understanding of the pathogenesis underlying neuronal alterations in T cell-mediated AE syndromes. Here, we assembled a cohort comprising both NS-AE (n = 8) and IC-AE (n = 12) from multiple institutions to delineate key histopathological features that distinguish neuronal pathology between IC-AE and NS-AE. In contrast to NS-AE, IC-AE lesions present a prominent neuronal pSTAT1 signature, accompanied by a high proportion of brain-resident memory CD8 + T cells and neurodegenerative GPNMB + phagocytes which show synaptic engulfment with little C3-complement deposition. Our findings highlight distinct histopathological features of IC-AE compared to NS-AE, providing actionable biomarkers for diagnostics and treatment strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02882-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871179","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: CSF p-tau205: a biomarker of tau pathology in Alzheimer’s disease","authors":"Juan Lantero-Rodriguez,&nbsp;Laia Montoliu-Gaya,&nbsp;Andrea L. Benedet,&nbsp;Agathe Vrillon,&nbsp;Julien Dumurgier,&nbsp;Emmanuel Cognat,&nbsp;Wagner S. Brum,&nbsp;Nesrine Rahmouni,&nbsp;Jenna Stevenson,&nbsp;Stijn Servaes,&nbsp;Joseph Therriault,&nbsp;Bruno Becker,&nbsp;Gunnar Brinkmalm,&nbsp;Anniina Snellman,&nbsp;Hanna Huber,&nbsp;Hlin Kvartsberg,&nbsp;Nicholas J. Ashton,&nbsp;Henrik Zetterberg,&nbsp;Claire Paquet,&nbsp;Pedro Rosa-Neto,&nbsp;Kaj Blennow","doi":"10.1007/s00401-025-02877-4","DOIUrl":"10.1007/s00401-025-02877-4","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02877-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143852470","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":"CNS angiocentric stromal tumor (CAST), PDGFRA-mutant, a novel entity histologically mimicking meningioangiomatosis and radiologically correlating with giant Virchow–Robin spaces","authors":"Ekin Guney,&nbsp;Kanish Mirchia,&nbsp;Simone Schmid,&nbsp;David Capper,&nbsp;Jenny Meinhardt,&nbsp;Soonmee Cha,&nbsp;Han Lee,&nbsp;Carole Brathwaite,&nbsp;Nolan Altman,&nbsp;Emily A. Sloan,&nbsp;Anousheh Sayah,&nbsp;Kevin McGrail,&nbsp;Ilay Caliskan,&nbsp;Merryl Terry,&nbsp;Sandra Perez,&nbsp;Andrew W. Bollen,&nbsp;Tarik Tihan,&nbsp;Melike Pekmezci,&nbsp;Arie Perry","doi":"10.1007/s00401-025-02870-x","DOIUrl":"10.1007/s00401-025-02870-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818111","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":"Diffuse astrocytoma, AYA-type, frequently MAPK-altered: report of 45 patients","authors":"Omkar Singh,&nbsp;Christopher Dampier,&nbsp;Zied Abdullaev,&nbsp;Karen Dazelle,&nbsp;Hye-Jung Chung,&nbsp;Kyle Conway,&nbsp;Sandra Camelo-Piragua,&nbsp;Stewart Neill,&nbsp;Daniel Brown,&nbsp;James Stephen Nix,&nbsp;Caterina Giannini,&nbsp;Robert Macaulay,&nbsp;Daniel Marker,&nbsp;John Skaugen,&nbsp;Scott Kulich,&nbsp;Han Lee,&nbsp;Orwa Aboud,&nbsp;Peter Pytel,&nbsp;Ewa Borys,&nbsp;Arie Perry,&nbsp;Laila Naqib-Osman,&nbsp;Igor Lima Fernandes,&nbsp;Qinwen Mao,&nbsp;Mouied Alashari,&nbsp;Cheddhi Thomas,&nbsp;Jeffrey Helgager,&nbsp;Maria A. Gubbiotti,&nbsp;John Newman,&nbsp;Nishant Tiwari,&nbsp;Patrick J. Cimino,&nbsp;Martha Quezado,&nbsp;Kenneth D. Aldape,&nbsp;MacLean P. Nasrallah","doi":"10.1007/s00401-025-02873-8","DOIUrl":"10.1007/s00401-025-02873-8","url":null,"abstract":"<div><p>A putative molecular subtype of IDH-wildtype diffuse glioma with recurrent MAPK pathway alterations has recently been reported. By dimensionality reduction analysis of genome-wide methylation profiling, these tumors form a distinct methylation cluster of gliomas. Characterization of 47 tumors from 45 patients reveals that these gliomas are predominantly supratentorial in young adults, are highly infiltrative, and harbor mitogen-activated protein kinase (MAPK) pathway alterations with high rates of <i>CDKN2A/2B</i> deletion, <i>PDGFRA</i> amplification, <i>MYCN</i> amplification, <i>NF1</i> variants, and <i>BRAF</i> alterations. The tumors’ epigenetics are distinct from other adult and pediatric gliomas in the 2021 World Health Organization (WHO) classification. The histology of the gliomas most often demonstrates high-grade astrocytic features, but can be variable from tumor to tumor, as well as fall into a spectrum of histologic grades. Outcomes show considerable variability based on histologic grade and molecular features, supporting grading within this group of tumors to ensure optimal care choices on an individual patient basis. These unifying epigenetic, sequencing, and infiltrative astrocytic features allow the tumors to be considered diffuse astrocytoma, adolescent, and young adult-type, with MAPK alterations (DAYA).</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02873-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143801225","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":"Seeding-competent early tau multimers are associated with cell type-specific transcriptional signatures","authors":"Rahel Feleke,&nbsp;Simona Jogaudaite,&nbsp;Elisavet Velentza-Almpani,&nbsp;Leung Yeung-Yeung,&nbsp;Daniel Clode,&nbsp;Jeong Hun Ko,&nbsp;Ben Shin,&nbsp;Steve Matthews,&nbsp;Maria Otero-Jimenez,&nbsp;Marcelina J. Wojewska,&nbsp;Sandra Gray-Rodriguez,&nbsp;Sarah J. Marzi,&nbsp;Maxwell P. Spires-Jones,&nbsp;Tara L. Spires-Jones,&nbsp;Michael R. Johnson,&nbsp;Javier Alegre-Abarrategui","doi":"10.1007/s00401-025-02869-4","DOIUrl":"10.1007/s00401-025-02869-4","url":null,"abstract":"<div><p>The initial molecular alterations of Alzheimer’s disease (AD) are unknown. Established AD is characterized by profound structural and transcriptional alterations in the human brain, with the hallmark neuropathological features being beta-amyloid (Aβ) accumulation in senile plaques and hyperphosphorylated fibrillar tau in neurofibrillary tangles (NFTs). Previous evidence indicates that tau multimerization into small aggregates is one of the earliest molecular alterations, anticipating the accumulation of hyperphosphorylated tau in NFTs. In this study, we investigated the seeding capacity of these early small tau multimers and the transcriptional changes associated with them, aiming to unveil early pathogenic processes in AD-type tau pathology. Early tau multimers visualized with tau proximity ligation assay (tau-PLA) in the post-mortem temporal cortex demonstrated high seeding activity detected by real-time quaking-induced conversion (RT-QuIC) assay and induction of aggregates in a tau biosensor cell line. Using single-nucleus transcriptomics, we showed that brain tissue harboring seeding-competent early tau multimers, but without significant NFT pathology, is associated with substantial gene expression alterations across diverse cell types when compared to control tissue lacking either multimers or NFTs. Differentially expressed genes, such as <i>APP</i>, <i>MAPT</i>, and <i>PSEN1,</i> exhibited significant enrichment of AD heritability in up-regulated genes within excitatory neurons, astrocytes, and oligodendrocytes. Pseudotime analysis exposed a positive correlation between the progression of tau pathology and the expression of genes marking reactive astrocytes. In summary, our results support the hypothesis that seeding-competent tau multimerization may initiate AD-type tau pathology cascades before the accumulation of tau in NFTs. This research contributes valuable insights into the early molecular events associated with AD, with implications for future diagnostic and therapeutic strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02869-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143775566","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":"Impaired remyelination in late-onset multiple sclerosis","authors":"Lidia Stork,&nbsp;Schirin Stephan,&nbsp;Adriane Kutllovci,&nbsp;Wolfgang Brück,&nbsp;Imke Metz","doi":"10.1007/s00401-025-02868-5","DOIUrl":"10.1007/s00401-025-02868-5","url":null,"abstract":"<div><p>A reduced regenerative capacity may contribute to faster disease progression and poorer relapse recovery in multiple sclerosis patients with disease onset after the age of 50, a condition known as late-onset multiple sclerosis (LOMS). We hypothesized that lesions in LOMS patients show more pronounced axonal damage, less remyelination and an altered inflammatory composition, and performed a detailed histopathological analysis of MS biopsies in patients with early-stage LOMS. The number of T cells, B cells, plasma cells, microglia/macrophages, different oligodendrocyte populations as well as the axonal density and acute axonal damage were assessed in 31 LOMS and 30 normal-onset MS (NOMS, 20–40 years old) patients. No major differences in the inflammatory infiltrate or axonal damage were found. BCAS1-positive oligodendrocytes indicating early myelinating oligodendrocytes, and mature oligodendrocytes were significantly lower in the normal-appearing white matter of LOMS compared to NOMS patients (<i>p</i> = 0.05; <i>p</i> = 0.01), with a negative correlation with age (r = − 0.5, <i>p</i> = 0.01). In active demyelinating lesions, the number of BCAS1-positive oligodendrocytes did not differ between LOMS and NOMS, but NOMS lesions showed a higher proportion of ramified cells indicating active remyelination. In LOMS, BCAS1-positive oligodendrocytes decreased with increasing lesion age, with the lowest numbers found in inactive demyelinated lesions. In contrast, NOMS patients showed high numbers of BCAS1-positive cells with an activated morphology, even in inactive demyelinated lesions. At the last follow-up, LOMS patients had a significantly higher EDSS score (median 3.5) than NOMS patients (median 3.0, <i>p</i> = 0.05). A higher EDSS score correlated with fewer mature and oligodendrocyte precursor cells in active demyelinating lesions (r = − 0.4, <i>p</i> = 0.01 and r = − 0.6, <i>p</i> = 0.003). These findings suggest a clinically relevant impaired oligodendrocyte differentiation and remyelination in LOMS. Since remyelination is essential for axonal protection, it will be necessary to consider the complex and dynamic tissue environment when researching therapeutics aimed at fostering the differentiation of oligodendrocyte precursor cells into myelinating oligodendrocytes.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02868-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143740795","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":"Strong nuclear expression of HOXB13 is a reliable surrogate marker for DNA methylome profiling to distinguish myxopapillary ependymoma from spinal ependymoma","authors":"Suvendu Purkait,&nbsp;Sophia Praeger,&nbsp;Jörg Felsberg,&nbsp;David Pauck,&nbsp;Kerstin Kaulich,&nbsp;Marietta Wolter,&nbsp;David Koppstein,&nbsp;Guido Reifenberger","doi":"10.1007/s00401-025-02866-7","DOIUrl":"10.1007/s00401-025-02866-7","url":null,"abstract":"<div><p>Spinal ependymoma and myxopapillary ependymoma are the two most common spinal ependymal tumor types that feature distinct histological characteristics, genetic alterations and DNA methylation profiles. Their histological distinction may be difficult in individual cases and molecular diagnostic assessment, in particular DNA methylome profiling, may then be required to assign the correct diagnosis. Expression of the homeobox gene <i>HOXB13</i> at the mRNA and protein levels has been reported as a frequent finding in myxopapillary ependymoma that may serve as a diagnostic marker for these tumors. Here, we evaluated the diagnostic role of HOXB13 immunostaining in 143 spinal neoplasms, comprising 54 histologically classified myxopapillary ependymomas, 46 histologically classified spinal ependymomas, and various other tumor types. Immunohistochemical results for HOXB13 protein were compared to molecular findings obtained by bead array-based DNA methylation and DNA copy number profiling, as well as next generation gene panel sequencing-based mutational analysis. Our findings indicate strong nuclear HOXB13 expression as a reliable diagnostic marker for molecularly confirmed myxopapillary ependymoma. Moreover, we provide evidence that differential HOXB13 protein expression is related to differential <i>HOXB13</i>-associated CpG site methylation in myxopapillary vs. spinal ependymomas, which can be assessed by targeted DNA methylation analysis. Taken together, immunohistochemistry for HOXB13 protein expression and targeted DNA methylation analysis of <i>HOXB13</i> represent useful surrogate approaches that may substitute for DNA methylome profiling in routine diagnostics and facilitate precise classification of spinal ependymal tumors. In particular, strong nuclear HOXB13 immunoreactivity may serve as a novel diagnostic criterion for the classification of myxopapillary ependymoma.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02866-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698658","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":"Chronic traumatic encephalopathy neuropathologic change in homeless","authors":"Krisztina Danics,&nbsp;Shelley L. Forrest,&nbsp;Gabor G. Kovacs","doi":"10.1007/s00401-025-02867-6","DOIUrl":"10.1007/s00401-025-02867-6","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143698676","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":"Biofluid-based staging of Alzheimer’s disease","authors":"Juan Lantero-Rodriguez,&nbsp;Laia Montoliu-Gaya,&nbsp;Nicholas J. Ashton,&nbsp;Ilaria Pola,&nbsp;Joseph Therriault,&nbsp;Nesrine Rahmouni,&nbsp;Wagner S. Brum,&nbsp;Stijn Servaes,&nbsp;Jenna Stevenson,&nbsp;Guglielmo Di Molfetta,&nbsp;Burak Arslan,&nbsp;Jesse Klostranec,&nbsp;Paolo Vitali,&nbsp;Maxime Montembeault,&nbsp;Serge Gauthier,&nbsp;Cecile Tissot,&nbsp;Arthur C. Macedo,&nbsp;Tharick A. Pascoal,&nbsp;Andreas Jeromin,&nbsp;Johan Gobom,&nbsp;Kaj Blennow,&nbsp;Henrik Zetterberg,&nbsp;Pedro Rosa-Neto,&nbsp;Andrea L. Benedet","doi":"10.1007/s00401-025-02863-w","DOIUrl":"10.1007/s00401-025-02863-w","url":null,"abstract":"<div><p>Recently, conceptual systems for the in vivo staging of Alzheimer’s disease (AD) using fluid biomarkers have been suggested. Thus, it is important to assess whether available fluid biomarkers can successfully stage AD into clinically and biologically relevant categories. In the TRIAD cohort, we explored whether p-tau217, p-tau205 and NTA-tau (biomarkers of early, intermediate and late AD pathology, respectively) have potential for biofluid-based staging in cerebrospinal fluid (CSF; <i>n</i> = 219) and plasma (<i>n</i> = 150), and compared them in a paired CSF and plasma subset (<i>n</i> = 76). Our findings suggest a good concordance between biofluid staging and underlying pathology when classifying amyloid-positivity into three categories based on neurofibrillary pathology: minimal/non-existent (p-tau217 positive), early-to-intermediate (p-tau217 and p-tau205 positivity), and advanced tau tangle deposition (p-tau217, p-tau205 and NTA-tau positive), as indexed by tau-PET. Discordant cases accounted for 4.6% and 13.3% of all CSF and plasma measurements respectively (9.2% and 11.8% in paired samples). Notably, CSF- and plasma-based staging matched one another in 61.7% of the cases, while approximately 32% of the remaining participants were one to three biofluid stages higher in CSF as compared to plasma. Overall, these exploratory results suggest that biofluid staging of AD holds potential for offering valuable insights into underlying AD hallmarks and disease severity. However, its applicability beyond molecular characterization at research settings has yet to be demonstrated.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-025-02863-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143632568","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}