Acta Neuropathologica最新文献

{"title":"CALB1 expression in meningioma: associations with progression-free survival and chromosome arm 6q loss","authors":"Lukas S. Friedrich,&nbsp;Friederike Liesche-Starnecker,&nbsp;Philipp Sievers,&nbsp;Claire Ertelt-Delbridge,&nbsp;Katharina J. Weber,&nbsp;Daniel Schrimpf,&nbsp;Nicole Pfarr,&nbsp;Patrick N. Harter,&nbsp;Jürgen Schlegel,&nbsp;Michael Meyer","doi":"10.1007/s00401-026-03113-3","DOIUrl":"10.1007/s00401-026-03113-3","url":null,"abstract":"<div><p>Molecular profiling has refined risk stratification in meningioma, but the biological relevance of associated transcriptional changes remains incompletely understood. Calbindin D28K (Calb), encoded by <i>CALB1</i>, is a calcium-binding protein with reported anti-apoptotic and cytoprotective functions. Previous unsupervised transcriptomic analysis identified <i>CALB1</i> upregulation in meningiomas with aggressive cellular features, but its biological and clinical relevance remains unresolved. We analysed Calb immunoreactivity in 231 meningioma tissue microarray (TMA) cores from 147 patients and evaluated <i>CALB1</i> transcript expression, DNA methylation and copy-number alterations in an independent cohort of 110 primary meningiomas. Calb immunoreactivity was detected in approximately 30% of primary tumours, and elevated <i>CALB1</i> transcript levels were observed at a similar frequency in the molecular cohort. High Calb protein expression was associated with shorter progression-free survival (PFS) after adjustment for the included clinical variables in the primary cohort. This association was also observed in restricted analyses of histological WHO grade 2 meningiomas. Lower methylation of selected exonic and intronic <i>CALB1</i> CpG sites correlated with a higher transcript expression, consistent with an epigenetic contribution to deregulation. Multivariable analyses identified associations of <i>CALB1</i> transcript expression with chromosome arm 6q loss, histological WHO grade, <i>CALB1</i> hypo-methylation and specific methylation subclasses in the secondary cohort. Differential expression analysis of tumours harbouring 6q loss identified expression differences in <i>CALB1</i> and transcription factors, including <i>NKX2-5</i> and <i>SOX11</i>. In contrast, expression of a related calcium-binding protein Calretinin (Calr) and the Progesterone Receptor (PR) was not significantly associated with PFS in the primary cohort. Together, these findings support the potential prognostic relevance of Calb protein expression, particularly in histological WHO grade 2 meningiomas, and associate <i>CALB1</i> transcript expression with selected molecular features in complementary cohorts. Calb immunohistochemistry may therefore provide a practical tool for refining risk stratification in this clinically heterogeneous tumour type prior to integrative molecular testing.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03113-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149338128","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":"CSF cytology: core principles, diagnostic pitfalls and emerging digital tools including artificial intelligence and telecytology","authors":"Sandra Nay,&nbsp;Franz Felix Konen,&nbsp;Franziska Bachhuber,&nbsp;Alexander Dressel,&nbsp;Deborah Erhart,&nbsp;Andreas Gerritzen,&nbsp;Catharina C. Gross,&nbsp;Andrea Harrer,&nbsp;Andrea Hinger,&nbsp;Piotr Lewczuk,&nbsp;Jan Lewerenz,&nbsp;Michael Khalil,&nbsp;Mirjam Korporal-Kuhnke,&nbsp;Frank Leypoldt,&nbsp;Thiemo M. Möllenkamp,&nbsp;Markus Otto,&nbsp;Astrid Petersmann,&nbsp;Axel Regeniter,&nbsp;Martin Roskos,&nbsp;Klemens Ruprecht,&nbsp;Annette Spreer,&nbsp;Herwig Strik,&nbsp;Marie Süße,&nbsp;Hayrettin Tumani,&nbsp;Manfred Uhr,&nbsp;Manfred Wick,&nbsp;Brigitte Wildemann,&nbsp;Jens Wiltfang,&nbsp;Thomas Zimmermann,&nbsp;Thomas Skripuletz,&nbsp;Stefan Isenmann","doi":"10.1007/s00401-026-03101-7","DOIUrl":"10.1007/s00401-026-03101-7","url":null,"abstract":"<div><p>Cerebrospinal fluid cytology remains a cornerstone of diagnostic evaluation in infectious, autoimmune, haemorrhagic, and neoplastic disorders of the central nervous system despite advances in neuroimaging, molecular diagnostics, and digital technologies. This narrative review summarises established principles of cerebrospinal fluid cytology, highlights methodological limitations and diagnostic pitfalls, and integrates emerging developments, including automated cell counting, artificial intelligence, and telecytology. Pre-analytical factors are critical determinants of diagnostic accuracy. Delayed sample processing promotes pH-dependent autolysis and substantial cell loss, whereas rapid cytocentrifugation preserves cellular morphology and facilitates reliable assessment. Automated cell counters are increasingly implemented in routine laboratories and offer advantages in settings with limited technical staffing. However, current systems show limited precision in samples with low and slightly elevated cell counts and limited morphological evaluation. Manual chamber counting, particularly in the normal and low-cell-count range, remains the gold standard for quantitative CSF cell assessment, whereas expert microscopic examination remains the reference standard for qualitative cytomorphological assessment. Although the sensitivity of neuroimaging continues to improve, cerebrospinal fluid cytology retains a unique diagnostic role in the detection of infectious and neoplastic conditions and in the evaluation of subarachnoid haemorrhage. Cytological detection of erythrophages, siderophages, and haematoidin crystals can reveal haemorrhage and provide clues to its temporal stage. Overall, cerebrospinal fluid cytology remains a valuable diagnostic tool when integrated with clinical, laboratory, microbiological, immunological, and imaging findings. Careful recognition of common pitfalls is essential. We recommend rapid cerebrospinal fluid processing, routine preparation of cytospin-based stained slides with expert microscopic review, and the implementation of automated or digital methods only within clearly validated workflows.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722749/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293948","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":"SNP rs11618521 modifies transcription factor NANOG-mediated expression of KPNA3 and the age at onset of spinocerebellar ataxia type 3","authors":"Hezhou Han,&nbsp;Leah Czisch,&nbsp;Manuel Pascal Wanner,&nbsp;Jonasz Jeremiasz Weber,&nbsp;Miriam Christina Dieterle,&nbsp;Carolina Alexandra Licia Schroeder,&nbsp;Pengfei Qi,&nbsp;Junbo Zhou,&nbsp;Jaqueline Jung,&nbsp;Wenxu Zheng,&nbsp;Fubo Cheng,&nbsp;Priscila Pereira Sena,&nbsp;Florian Fath,&nbsp;Gunnar Blumenstock,&nbsp;Carlos R. Gordon,&nbsp;Roy Zaltzman,&nbsp;Marcondes C. França Jr.,&nbsp;Maria-Luiza Saraiva-Pereira,&nbsp;Laura Bannach Jardim,&nbsp;Mario R. Cornejo-Olivas,&nbsp;Peter Bauer,&nbsp;Ludger Schöls,&nbsp;Bart P. C. van de Warrenburg,&nbsp;Alexandra Durr,&nbsp;Alexis Brice,&nbsp;Thomas Klockgether,&nbsp;Olaf Riess,&nbsp;The EUROSCA Network,&nbsp;Thorsten Schmidt","doi":"10.1007/s00401-026-03051-0","DOIUrl":"10.1007/s00401-026-03051-0","url":null,"abstract":"<div><p>Intranuclear localization of the affected protein ataxin-3 is critical for the pathogenesis of spinocerebellar ataxia type 3 (SCA3). The nuclear–cytoplasmic transporter karyopherin alpha 3 (KPNA3) has been demonstrated to play an essential role in the pathophysiology of this disorder. In this study, we characterized the single nucleotide polymorphism (SNP) rs11618521, located in the <i>KPNA3</i> promoter, as a genetic modifier of the age at onset in SCA3 and a regulator of the <i>KPNA3</i> promoter activity. Moreover, we identified the transcription factor Nanog homeobox (NANOG) as a key regulator exerting allele-specific modulatory effects on the <i>KPNA3</i> promoter activity, thereby modulating expression and contributing to SCA3-associated pathogenic mechanisms. Pharmacological inhibition of NANOG reduced KPNA3 levels and ameliorated aggregate formation. In conclusion, we identified variant rs11618521 as a regulator of <i>KPNA3</i> promoter activity and as a genetic modifier of SCA3. Moreover, we provide mechanistic insights that may guide future-targeted therapeutic strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722750/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293925","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":"From dosage alteration to amplification strategies: mechanistically defined alpha-synuclein mouse models for Parkinson’s disease therapy development","authors":"Silke Nuber,&nbsp;Saranna Fanning,&nbsp;Ulf Dettmer","doi":"10.1007/s00401-026-03112-4","DOIUrl":"10.1007/s00401-026-03112-4","url":null,"abstract":"<div><p>A major challenge for identifying a disease-modifying cure for Parkinson’s disease (PD) is creating models resembling key features of the disease including resting tremor, bradykinesia, muscle rigidity and gait disturbances. In addition, PD patients often develop cognitive symptoms that are associated with pathology in neocortical areas. Initially, PD rodent models were generated primarily by chemical neurotoxins that induce an acute loss of dopaminergic neurons. Upon discovery of familial-PD-linked genetic mutations in the SNCA gene—encoding α-synuclein (αS)—mice carrying these mutations provided deeper insight into the pathologic role of this synaptic protein throughout the brain. αS transgenic mouse models stand out for their ability to develop intraneuronal lesions that are rich in αS phospho-serine 129, a histopathological signature of the human PD brain. Recent advances in αS protein biochemistry led to the generation of mice carrying strategic amplifications of familial-PD-linked αS mutants, resulting in more pronounced neurodegeneration and progressive phenotype development. Here we review advances of αS transgenic mouse model development with a focus on strategic mutations that may have greater potential for identifying underlying disease mechanisms than classical single-mutant and wild-type αS overexpressing mice. We also present how the mice are currently used in testing drug efficacy and target engagement for PD drug discovery and outline strategies for utilizing such mice in basic and translational research.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13722733/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149293945","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":"Identification and characterization of a novel distinct Pineal Neoplasm with Neuroendocrine and Epithelial Differentiation (PINNED)","authors":"Helena Bode,&nbsp;Abigail K. Suwala,&nbsp;Brian Gudenas,&nbsp;Alicia Fürst,&nbsp;Neal Geisemeyer,&nbsp;Lea Altendorf,&nbsp;Karoline Hack,&nbsp;Caterina Giannini,&nbsp;Ziedulla Abdullaev,&nbsp;Sebastian Brandner,&nbsp;Jan Beckervordersandforth,&nbsp;Matija Snuderl,&nbsp;Josefine Radke,&nbsp;Carlos Rodríguez-Antolín,&nbsp;Chiara Villa,&nbsp;Catherine Godfraind,&nbsp;Lindsey Lowder,&nbsp;Aaron Mammoser,&nbsp;Tyler J. Kenning,&nbsp;Kay Hertel,&nbsp;Michael Brodhun,&nbsp;Rüdiger Gerlach,&nbsp;Christian Mawrin,&nbsp;Guntis Karelis,&nbsp;Paul Kerbs,&nbsp;Isabell Bludau,&nbsp;Andreas von Deimling,&nbsp;Stefan M. Pfister,&nbsp;Felix Sahm,&nbsp;Alexandre Vasiljevic,&nbsp;Christian Thomas,&nbsp;Martin Hasselblatt,&nbsp;Paul Northcott,&nbsp;Marcel Kool,&nbsp;Ulrich Schüller","doi":"10.1007/s00401-026-03111-5","DOIUrl":"10.1007/s00401-026-03111-5","url":null,"abstract":"<div><p>Pineal region tumors are rare neoplasms that occur in all ages and account for less than 1% of all central nervous system (CNS) tumors in adults but are more frequent in children. Here, we describe a previously unrecognized tumor type of pineal origin characterized by a unique and consistent DNA methylation profile that does not match any known CNS tumor class and is distinct from all currently recognized pineal tumor entities. The presented cohort (<i>n</i> = 27) displayed a balanced sex distribution with a mean patient age of 35 years (range 7–75 years). The histopathological analyses demonstrated a highly cellular tumor showing various degrees of necrosis, mitotic activity, papillary structures, rosettes, epithelioid cytology, or signet-ring cells. The tumors consistently expressed cytokeratin 18, synaptophysin, chromogranin A, and OTX2, whereas CRX expression was absent. Four out of 16 tumors (25%) showed <i>ATRX</i> mutations and/or loss of protein expression as revealed by immunohistochemistry. Single-nucleus RNA sequencing confirmed molecular distinctiveness from other pineal neoplasms but revealed the closest similarities to papillary tumors of the pineal region (PTPR). Projection of the transcriptome data onto the cellular trajectory of the developing murine pineal gland suggests that pinealocyte progenitors are the cellular origins. Taken together, our findings define a novel type of pineal region tumor that we provisionally named ‘<i>Pi</i>neal <i>N</i>eoplasm with <i>N</i>euroendocrine and <i>E</i>pithelial <i>D</i>ifferentiation’ (PINNED). Recognition of this tumor type appears to be important for the accurate diagnosis of pineal region tumors and may have implications for future tumor classification and treatment strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13710622/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149260555","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":"Sex differences in the association of late-life blood pressure decline with postmortem brain vessel pathology","authors":"Nicholas W. Baumgartner,&nbsp;Lianlian Du,&nbsp;Rupal I. Mehta,&nbsp;Kaitlin B. Casaletto,&nbsp;Madeline Wood Alexander,&nbsp;Jennifer S. Rabin,&nbsp;Thomas van Sloten,&nbsp;David A. Bennett,&nbsp;Ana W. Capuano,&nbsp;Zoe Arvanitakis","doi":"10.1007/s00401-026-03107-1","DOIUrl":"10.1007/s00401-026-03107-1","url":null,"abstract":"<div><p>Although hypertension is the leading modifiable risk factor for cerebrovascular disease, less is known about the relation of late-life change in blood pressure (BP) and cerebrovascular pathology beyond brain infarcts. Our previous work found sex-specific associations between declining systolic BP (SBP) and cognitive decline in late-life, suggesting that cerebrovascular pathology may be an upstream contributor to these sex differences. However, postmortem studies have not examined whether BP change differentially relates to vascular brain pathology in men and women, despite well-established sex differences in BP trajectories and cerebrovascular pathology. We examined associations between change in late-life BP and postmortem cerebrovascular (arteriolosclerosis, atherosclerosis, and cerebral amyloid angiopathy) pathology from 2033 community-dwelling older adults (mean baseline age = 79.7 [SD = 7.1] years; 69% women) from four longitudinal cohort studies with brain autopsy (mean age-at-death = 89.8 [6.6] years). Person-specific late-life BP slopes estimated from annual clinical evaluations over an average of 9.1 [5.7] years were entered in ordinal regressions adjusted for age-at-death, sex, antihypertensive medication use, and BP slope × sex, age-at-death × sex, and BP slope × age-at-death interactions. Faster SBP decline was associated with greater severity of arteriolosclerosis (OR = 1.24, 95%CI 1.08–1.42) and atherosclerosis (OR = 1.41, 95%CI 1.22–1.63). A sex × SBP slope interaction (<i>p</i> = 0.01) revealed a stronger association of SBP decline with arteriolosclerosis severity in women than men. This longitudinal, clinical-pathologic study of older decedents showed sex differences in the association of declining SBP in late-life with severity of arteriolosclerosis, extending prior associations with cognitive decline to cerebrovascular pathology, and suggests potential for longitudinal BP monitoring for precision medicine approaches in cerebrovascular disease risk stratification.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03107-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149235031","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":"Tau A152T risk variant drives distinct cell type transcriptional signatures in AD and PSP","authors":"Meredith T. Lilley,&nbsp;Yingxue Ren,&nbsp;Disha Soni,&nbsp;Emily C. Sanborn,&nbsp;Jordan D. Marks,&nbsp;Yunfei Chen,&nbsp;Yan Yan,&nbsp;Michael DeTure,&nbsp;Bailey Rawlinson,&nbsp;Dennis W. Dickson,&nbsp;Casey N. Cook","doi":"10.1007/s00401-026-03110-6","DOIUrl":"10.1007/s00401-026-03110-6","url":null,"abstract":"<div><p>The A152T point mutation is a rare genetic variant in the tau gene (<i>MAPT</i>) that is linked to risk of Alzheimer’s disease (AD) and frontotemporal dementia spectrum disorders, including progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). To uncover mechanisms through which the A152T variant contributes to risk of tauopathy, we performed single-nucleus RNA sequencing (snRNA-seq) on postmortem brain tissue collected from A152T carriers and pathology-matched non-carriers with either AD or PSP, along with age-matched controls. These efforts revealed that despite similar cell type composition across groups, A152T carriers exhibited distinct cell type-specific transcriptional changes in both AD and PSP. Differential expression analysis identified excitatory neurons, oligodendrocytes, and astrocytes as the most affected cell populations in AD and PSP, and these same cell types showed the strongest A152T-specific changes. These findings identify transcriptional alterations that differentiate sporadic AD and sporadic PSP from AD-A152T and PSP-A152T, as well as shared molecular signatures unique to A152T carriers in both PSP and AD. Donor-level pseudo-bulk analyses showed broad directional support with the single-nucleus findings although the proportion of donor-supported genes varied across cell type and comparison. Importantly, merging sporadic and A152T cases into a single disease group was found to mask transcriptional differences in several cell types in both AD and PSP, indicating divergence in transcriptional signature and highlighting the importance of screening for genetic risk variants like A152T in snRNA-seq data from human cohorts.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03110-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149235056","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":"TSPO–PET binding in vivo reflects increased phagocytic microglia at post mortem in people with frontotemporal dementia","authors":"Davi S. Vontobel,&nbsp;Kei Onn Lai,&nbsp;Mehtap Bacioglu,&nbsp;George Nolan,&nbsp;Daniel C. Maddison,&nbsp;Amelie Adamski,&nbsp;Julia Goddard,&nbsp;Noah L. Shapiro,&nbsp;Harry Crook,&nbsp;Tim Fryer,&nbsp;Young Hong,&nbsp;Sasvi Wijesinghe,&nbsp;Franklin Aigbirhio,&nbsp;Edward Avezov,&nbsp;Kieren S. J. Allinson,&nbsp;Annelies Quaegebeur,&nbsp;John T. O’Brien,&nbsp;James B. Rowe,&nbsp;Maria Grazia Spillantini,&nbsp;Maura Malpetti","doi":"10.1007/s00401-026-03103-5","DOIUrl":"10.1007/s00401-026-03103-5","url":null,"abstract":"<div><p>Brain inflammation is a key feature of frontotemporal dementia (FTD). Positron emission tomography (PET) of the 18 kDa translocator protein (TSPO) is widely used as an in vivo proxy for neuroinflammation, but whether the elevated signal reflects microglial, astrocytic or vascular pathology remains controversial, and this has not previously been resolved in FTD using matched <i>ante mortem</i> imaging and <i>post-mortem</i> tissue. We paired <i>ante mortem</i> [¹¹C]PK11195 TSPO–PET with quantitative <i>post-mortem</i> neuropathology in 10 individuals with FTD (5 FTLD-tau, 5 FTLD–TDP) and 5 age- and sex-matched controls, combining CD68 immunohistochemistry across 17 brain regions, multiplex immunofluorescence pairing TSPO with microglial/macrophagic (IBA1, CD68), astrocytic (GFAP) and endothelial (CD31) markers in three frontotemporal cortical regions, and three-dimensional single-cell reconstruction of individual microglia. CD68 area fraction was elevated in FTD relative to controls, predominantly in white matter, and was positively associated with regional TSPO–PET-binding potential across the cohort (<i>β</i> = 8.66, <i>P</i> &lt; 0.001), with comparable slopes in FTLD-tau and FTLD–TDP. Total tissue TSPO-area fraction was likewise increased in FTD and tracked regional PET binding in two independently processed slide sets. Of the four cell-type markers, only the CD68–TSPO co-localised fraction was positively associated with the PET signal (<i>β</i> = +0.0041, <i>P</i> = 0.015, <i>P</i>_FDR = 0.062), with null or negative associations for IBA1, GFAP and CD31. At single-cell resolution, IBA1+ microglia that were also CD68+ carried more absolute TSPO and were larger than CD68− microglia, without an increase in the TSPO fraction of cell volume. The elevated TSPO–PET signal in FTD, therefore, likely reflects an increased burden of CD68+ phagocytic microglia rather than TSPO expression in other cell types, supporting TSPO–PET as a microglial-burden biomarker across both FTLD-tau and FTLD–TDP.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03103-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234927","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":"Prevalence of alpha-synuclein seeding activity in the Olfactory Mucosa following SARS-CoV-2 infection: results from a pilot study","authors":"Beatrice Heim,&nbsp;Klaus Seppi,&nbsp;Nicolas De Cleene,&nbsp;Matilde Bongianni,&nbsp;Erika Bronzato,&nbsp;Clancy Cerejo,&nbsp;Frank Jagusch,&nbsp;Philipp Kindl,&nbsp;Judith Löffler-Ragg,&nbsp;Günter Weiss,&nbsp;Timo Gottfried,&nbsp;Joachim Schmutzhard,&nbsp;Gianluigi Zanusso,&nbsp;Werner Poewe","doi":"10.1007/s00401-026-03104-4","DOIUrl":"10.1007/s00401-026-03104-4","url":null,"abstract":"<div><p>Olfactory dysfunction (OD) is a hallmark of SARS-CoV-2-infection where it is believed to result from neuroinflammation induced by viral invasion via the olfactory mucosa (OM). Hyposmia also affects the majority of patients with Parkinson’s disease (PD) where it is caused by α-synuclein (aSyn) pathology in the olfactory system, and aSyn-seeding-activity can be detected in the OM using aSyn-seeding-amplification-assays (aSyn-SAA). The present pilot study aimed to investigate whether SARS-CoV-2-infection induces local aSyn-misfolding and -aggregation in OM samples using aSyn-SAA. We conducted an observational study including PD patients (n = 51), individuals with a history of documented symptomatic SARS-CoV-2-infection (post-COVID; n = 95), and healthy controls (HC; n = 42). Post-COVID-participants were stratified based on persistent OD (COVID+OD; n = 42) or normal olfaction (COVID–OD; n = 53) using Sniffin’-Sticks-Identification (SSI) and -Discrimination (SSD) tests. OM samples were obtained by ENT specialists and analyzed by aSyn-SAA at the University of Verona. Clinical phenotyping included MDS-UPDRS, MoCA, and the Innsbruck-RBD-Inventory. OM-SAA positivity rates were significantly different between PD and both post-COVID-participants and HCs (80.4% vs 24.2% vs 11.9%; <i>p</i> &lt; 0.001). Within the post-COVID-group, positivity rates were higher in COVID+OD vs COVID–OD (35.7% vs 15.1%; <i>p</i> = 0.030), and COVID+OD differed from HC (<i>p</i> = 0.030), while COVID–OD did not (<i>p</i> = 0.65). Among post-COVID-participants, aSyn-SAA positivity was associated with lower SSI (<i>p</i> = 0.007) and SSD (<i>p</i> &lt; 0.001) scores, but not with MDS-UPDRS, MoCA, or RBD measures. OM-SAA-positivity was enriched among individuals with persistent post-COVID-OD and correlated with olfactory impairment. These findings support the hypothesis that neuroinflammation following SARS-COV-2-infection might promote local aSyn-aggregation. The biological and prognostic relevance of OM-SAA positivity is unknown and needs further prospective investigation.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03104-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234926","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: Tau oligomerization induces nuclear lamina invagination and chromatin remodeling in Alzheimer’s disease","authors":"Shuo Yuan,&nbsp;Nicholas Essepian,&nbsp;Rebecca Roberts,&nbsp;Eliana Sherman,&nbsp;Weronika M. Gniadzik,&nbsp;Qingbo Wang,&nbsp;Alev Erisir,&nbsp;Lulu Jiang","doi":"10.1007/s00401-026-03092-5","DOIUrl":"10.1007/s00401-026-03092-5","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"152 1","pages":""},"PeriodicalIF":10.3,"publicationDate":"2026-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-026-03092-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149234780","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}