Acta Neuropathologica Communications最新文献

{"title":"Melanoma antigens in pediatric medulloblastoma contribute to tumor heterogeneity and species-specificity of group 3 tumors.","authors":"Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Juan Sebastian Solano Gutierrez, Barbara Breznik, Anna K Lee, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer","doi":"10.1186/s40478-025-02055-3","DOIUrl":"10.1186/s40478-025-02055-3","url":null,"abstract":"<p><p>Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, collected between 2008 and 2015 at the Children's Medical Center in Dallas and applied our validated reverse transcription quantitative PCR (RT-qPCR) assay to measure the expression of 23 MAGE genes. To validate our data, we analyzed published datasets from pediatric MB tumors and patient-derived orthotopic xenografts, totaling 949 patients. Our RT-qPCR analysis suggested that MAGEs were expressed in G3/4MB. Further mining of bulk and single-cell RNA-sequencing datasets confirmed that 50-75% of G3 tumors activate several MAGEs. Intriguingly, single-cell data analysis showed that MAGEs are expressed in distinct subsets of cells in MAGE-positive tumors and are not activated in mouse genetic models, suggesting they contribute to the tumor heterogeneity and species-specificity of G3 MB. We then examined how MAGE expression affects the growth and oncogenic potential by CRISPR-Cas9- and siRNA-mediated gene depletion. Depletion of MAGEAs, -B2, and -Cs altered cell survival, viability, and clonogenic growth due to decreased proliferation and increased apoptosis of MAGE-positive MB cells. These findings suggested that targeting MAGEs could represent a viable therapeutic strategy for G3 MB. A deeper understanding of MAGE regulation and function is warranted and could aid in improving prognostic and therapeutic approaches for this poorly characterized subgroup of pediatric brain tumors.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"164"},"PeriodicalIF":5.7,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12302604/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144726415","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomics of the temporal cortex in semantic dementia reveals brain-region specific molecular pathology and regulation of the TDP-43-ANXA11 interactome.","authors":"Suzanne S M Miedema, Ana Rajicic, Merel O Mol, Iryna Paliukhovich, Remco V Klaassen, Renee van Buuren, Ka Wan Li, Frank T W Koopmans, Harro Seelaar, Jeroen G J van Rooij, August B Smit, John C van Swieten","doi":"10.1186/s40478-025-02077-x","DOIUrl":"10.1186/s40478-025-02077-x","url":null,"abstract":"<p><p>Semantic dementia (SD) is a clinical subtype of frontotemporal dementia characterized by impaired word comprehension and semantic memory, and occurs nearly always sporadically. Neuroimaging typically reveals asymmetric, predominantly left-sided, atrophy of the anterior temporal pole, anterior fusiform gyrus, and the hippocampus. Post-mortem pathological examination shows frontotemporal lobar degeneration TDP type C, characterized by long dystrophic neurites in the temporal cortex and typical round, TDP-43-positive neuronal inclusions in the dentate gyrus. While neuronal loss in the temporal cortex is severe in the end stage of disease, the dentate gyrus seems relatively spared. This characteristic and well-defined disease profile suggests SD patients share a specific underlying disease biology. Recently, we performed the first quantitative proteomic study of the dentate gyrus, uncovering potential SD-specific biological pathways. Here, we report on the first quantitative proteomic study of the temporal cortex in SD. We studied the same patient and non-demented control cohort, enabling comparative analysis between the two brain regions. In addition, we compared our dataset with other frontotemporal lobar degeneration subtypes and Alzheimer's disease to separate SD disease-specific changes from common neurodegenerative processes. In the temporal cortex, involvement of the ribonucleoprotein complex and presynaptic regulation of cytosolic calcium levels by voltage-gated calcium channels appear unique facets of the SD disease process. Furthermore, we observed a striking difference in the abundance of neuropathological proteins TDP-43 and ANXA11, and their interactors between the temporal cortex and dentate gyrus. The elucidation of these potentially unique disease-specific mechanisms improves our understanding of the pathophysiological processes in SD and paves the way for the discovery of novel therapeutic targets.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"162"},"PeriodicalIF":5.7,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-occurrence of multiple pathologies in a case of frontotemporal dementia with TBK1 mutation: first in vivo detection of alpha-synuclein and tau co-pathology.","authors":"Alexander M Bernhardt, Sigrun Roeber, Viktoria Ruf, Elisabeth Wlasich, Endy Weidinger, Sebastian Longen, Svenja V Trossbach, Johannes Gnörich, Matthias Brendel, Jochen Herms, Armin Giese, Günter U Höglinger, Johannes Levin","doi":"10.1186/s40478-025-02081-1","DOIUrl":"10.1186/s40478-025-02081-1","url":null,"abstract":"<p><p>We present the case of a 74-year-old woman with behavioral variant frontotemporal dementia (bvFTD) linked to a pathogenic TANK-binding kinase 1 (TBK1) mutation (c.1349_1352del; p.Ile450Lysfs*15). During clinical workup, the patient underwent comprehensive biomarker analysis, including tau positron emission tomography (PET) and cerebrospinal fluid (CSF) seed amplification assay (SAA) for α-synuclein (αSyn). While CSF biomarkers for Alzheimer's disease were normal, the αSyn SAA was clearly positive, indicating misfolded αSyn aggregates. Tau PET revealed increased [¹⁸F]PI-2620 uptake in the basal ganglia. Genetic testing confirmed autosomal dominant TBK1-associated FTD. The patient's condition deteriorated over the following year, with rapid cognitive decline and the emergence of cortical signs. Post-mortem neuropathological analysis confirmed multiple proteinopathies: FTLD-TDP43 (subtype A), Lewy body disease (limbic type, Braak stage 5), argyrophilic grain disease (AGD), aging-related tau astrogliopathy (ARTAG), and primary age-related tauopathy (PART). This is the first reported TBK1-FTD case with in vivo detection of αSyn pathology via SAA and in vivo monitoring of tau pathology. The case expands the clinical and neuropathological spectrum of TBK1-associated FTD. Our findings support a broader interpretation of TBK1-associated neurodegeneration and highlight the importance of multimodal diagnostic approaches that integrate molecular, genetic, imaging, and neuropathological tools. This case also underscores the utility of αSyn SAA and tau PET in detecting co-pathologies that may otherwise remain clinically silent and illustrates the need for further studies exploring the molecular cross-talk between TBK1, tau, and αSyn pathologies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"163"},"PeriodicalIF":5.7,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12291237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The malignant transformation of an atypical angiocentric glioma, MYB-altered.","authors":"Oumaima Aboubakr, Annika K Wefers, Volodia Dangouloff-Ros, Alice Métais, Philipp Sievers, Lauren Hasty, Raphaël Saffroy, Gaelle Pierron, Delphine Guillemot, Thomas Samoyeau, Nathalie Boddaert, Jacques Grill, Kevin Beccaria, Thomas Blauwblomme, Pascale Varlet, Arnault Tauziède-Espariat","doi":"10.1186/s40478-025-02070-4","DOIUrl":"10.1186/s40478-025-02070-4","url":null,"abstract":"<p><p>According to the current World Health Organization classification of central nervous system tumors, the angiocentric glioma (AG) assigned a grade 1, characterized by recurrent MYB fusions. However, it also mentions that increased proliferative activity and other anaplastic features have been reported, but the clinical significance of such findings is unclear as an increased proliferative activity alone does not necessarily alter the benign behavior of AGs. Most cases with \"anaplasia\" were mainly described before the molecular era. Herein, we report the case of a 3-year-old female with epilepsy symptomatic of a left temporo-parietal tumor. Histopathologically, the initial tumor displayed atypical AG morphology and a proliferation index of 1%, without mitoses, or necrosis. RNA sequencing identified a MYB::QKI fusion. After several tumor recurrences, the last tumor sample showed strong evidence of a histopathological transformation into a high-grade tumor with proliferation and mitotic indexes, necrosis and microvascular proliferation. The recurrent tumor still harbored the same MYB::QKI fusion but acquired an hTERT mutation. DNA-methylation analysis classified the initial tumor as an LGG, MYB/MYBL1-altered (AG, MYB/MYBL1-altered with a calibrated score of 0.58) while the progression clustered with glioblastoma, IDH-wildtype, RTK1 (with a calibrated score of 0.33). The copy number variation both at presentation and at last recurrence (CNV) exhibited a chromosome 6 chromothripsis. The patient died from tumor progression after an overall survival of 89 months. This novel observation raises the question of whether this case represents an aggressive form of MYB/MYBL1-altered LGGs driven by an oncogenic MYB fusion, or if they are actually high-grade gliomas that coincidentally exhibit alterations near the MYB locus. Further reports are needed to confirm the existence of malignant forms of LGG, MYB/MYBL1-altered, potentially correlated with a higher grade.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"161"},"PeriodicalIF":5.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285182/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697251","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene therapy ameliorates neuromuscular pathology in CLN3 disease.","authors":"Ewa A Ziółkowska, Albina Jablonka-Shariff, Letitia L Williams, Matthew J Jansen, Sophie H Wang, Elizabeth M Eultgen, Matthew D Wood, Daniel A Hunter, Jaiprakash Sharma, Marco Sardiello, Robyn Reese, Alan Pestronk, Mark S Sands, Alison K Snyder-Warwick, Jonathan D Cooper","doi":"10.1186/s40478-025-02059-z","DOIUrl":"10.1186/s40478-025-02059-z","url":null,"abstract":"<p><p>CLN3 disease is a neuronopathic lysosomal storage disorder that severely impacts the central nervous system (CNS) while also inducing notable peripheral neuromuscular symptoms. Although considerable attention has been directed towards the neurodegenerative consequences within the CNS, the involvement of peripheral tissues, including skeletal muscles and their innervation, has been largely neglected. We hypothesized that, CLN3 deficiency could directly influence peripheral nerves and investigated the neuromuscular system in Cln3^Δex7/8 mice. Our study found no overt loss of sciatic nerve axons or demyelination in 18-month-old Cln3^Δex7/8 mice at disease endstage, but a marked reduction of terminal Schwann cells (tSCs) at lower limb neuromuscular junctions (NMJs), culminating in progressive denervation of these NMJs which appeared abnormal. This led us to investigate skeletal muscle where we found significant myofiber atrophy and decreased and misplaced myofibril nuclei. Similar myopathic alterations were present in a muscle biopsy from an 8-year-old human CLN3 patient shortly after diagnosis. To assess a potential therapeutic intervention, we administered intravenous gene therapy using AAV9.hCLN3 to neonatal Cln3^Δex7/8 mice, which at disease endstage, entirely prevented tSC loss and NMJ abnormalities, while also averting skeletal muscle atrophy. These findings underscore the underappreciated, yet substantial effects of CLN3 disease beyond the CNS, highlighting peripheral neuromuscular pathologies as novel features of this disorder. Our findings also indicate that these manifestations could be amenable to treatment via gene therapy, opening new therapeutic strategies in the management of CLN3 disease.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"160"},"PeriodicalIF":5.7,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285172/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697250","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of LTR and LINE1 transposable elements defines atypical teratoid/rhabdoid tumor subtypes.","authors":"Martin V Hamann, Shweta Godbole, Maisha Adiba, Sabrina M Leddy, Jelena Navolić, Ghazaleh Tabatabai, Daniel J Merk, Ulrike C Lange, Julia E Neumann","doi":"10.1186/s40478-025-02078-w","DOIUrl":"10.1186/s40478-025-02078-w","url":null,"abstract":"<p><p>Atypical teratoid rhabdoid tumors (ATRTs) are aggressive central nervous system tumors mainly affecting young children. Extensive molecular characterization based on gene expression and DNA methylation patterns has solidly established three major ATRT subtypes (MYC, SHH and TYR), which show distinct clinical features, setting the basis for more effective, targeted treatment regimens. Transcriptional activity of transposable elements (TEs), like LINE1s and LTRs, is tightly linked with human cancers as a direct consequence of lifting epigenetic repression over TEs. The sole recurrent biallelic loss-of-function mutation in SMARCB1 in ATRTs, a core component of the SWI/SNF chromatin remodeling complex, raises the question of how TE transcription contributes to ATRT development. Here, we comprehensively investigate the transcriptional profiles of 1.9M LINE1 and LTR elements across ATRT subtypes in primary human samples. We find TE transcription profiles allow sample stratification into ATRT subtypes. The TE activity signature in the ATRT-MYC subtype is unique, setting these tumors apart from SHH and TYR ATRTs. More specifically, ATRT-MYC show broadly reduced transcript levels of LINE1 and ERVL-MaLR subfamilies. ATRT-MYC also displayed significantly less LTR and LINE1 loci with bidirectional promoter activity. Furthermore, we identify 849 differentially transcribed TEs in primary samples, which are predictive towards established ATRT-SHH and -MYC cell line models. In summary, including TE transcription profiles into the molecular characterization of ATRTs might reveal new tumor vulnerabilities leading to novel therapeutic interventions, such as immunotherapy.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"159"},"PeriodicalIF":5.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12285028/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of ATXN2 intermediate CAG repeats, 9bp duplication and alternative splicing on SCA3 pathogenesis.","authors":"Marilena Lauerer, Jennifer Faber, Nicolas Casadei, Magda M Santana, Georg Auburger, Michaela Pogoda, Jakob Admard, Lea Kaupp, Patricia Laura Kos, Mafalda Raposo, Manuela Lima, Luis Pereira de Almeida, Hector Garcia-Moreno, Paola Giunti, Jeroen de Vries, Bart P van de Warrenburg, Judith van Gaalen, Marcus Grobe-Einsler, Berkan Koyak, Kathrin Reetz, Friedrich Erdlenbruch, Heike Jacobi, Jon Infante, Holger Hengel, Ludger Schöls, Thomas Klockgether, Olaf Rieß, Jeannette Hübener-Schmid","doi":"10.1186/s40478-025-02074-0","DOIUrl":"10.1186/s40478-025-02074-0","url":null,"abstract":"<p><p>Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease whose exact disease pathogenesis is not yet fully understood. We performed a genetic in-depth analysis of ataxin-2 (ATXN2), a gene that has already been described as a modulator of neurodegenerative diseases. We focused on the influence of an intermediate CAG repeat, a 9bp duplication (9bp), and isoform expression of ATXN2 on the pathogenesis of SCA3.Clinical and genetic data from a large European SCA3 cohort (total 390 probands) were analyzed. Fragment analyses were performed to determine the cytosine-adenine-guanine (CAG) repeat length and the 9bp duplication in ATXN2. RNA sequencing was performed on blood and cerebellum to evaluate ATXN2 isoform profile. Cell culture and SCA3 mice were used to investigate the influence of intermediate ATXN2 length on ataxin-3 protein abundance, aggregation, and cell viability.SCA3 carriers with an intermediate ATXN2 repeat presented a significant increase in non-ataxic symptoms. A greater age at onset and faster disease progression were found in SCA3 carriers with a 9bp duplication. Co-expression of ATXN2 and ATXN3 in cell models revealed an influence of ATXN2 on ataxin-3 abundance and aggregation patterns. Determination of soluble ATXN2 abundance demonstrated a significant genotype-independent reduction in mouse brain. Aggregate analyses indicated that ataxin-2 is not co-localized with ataxin-3-containing aggregates.Our comprehensive genetic study confirmed ATXN2 as a modulator of SCA3 pathogenesis, including onset and presence of clinical symptoms. For the first time, the ATXN2 isoform profile was compared in blood and cerebellar tissue, revealing a unique profile depending on the genotype and tissue. Here, a significant higher expression of ATXN2 splice variant type I in blood and significantly lower expression in cerebellar tissue were found compared to ATXN2 splice variant type II. Molecular and biochemical analyses in SCA3 mice and cell culture provide further evidence on mechanistic aspects, including differences in protein abundance and co-aggregation propensity. In summary, our study provides new insights into the modulatory effects of ATXN2 on SCA3 pathogenesis.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"157"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the development of cutaneous neurofibromas in neurofibromatosis type 1.","authors":"Pernelle Pulh, Fanny Coulpier, Audrey Onfroy, Layna Oubrou, Wanzhen Zhang, Léa Toledano, Elie Abou Zougheib, Laura Fertitta, Pierre Wolkenstein, Piotr Topilko","doi":"10.1186/s40478-025-02075-z","DOIUrl":"10.1186/s40478-025-02075-z","url":null,"abstract":"<p><p>Neurofibromatosis type 1 (NF1) is a genetic disorder that leads to the formation of cutaneous neurofibromas (cNFs), benign nerve sheath tumors that develop in the skin and significantly impact the quality of life of patients. cNF development begins with bi-allelic NF1 loss in the Schwann cell (SC) lineage, followed by the recruitment of a complex tumor microenvironment consisting of fibroblasts, immune cells, blood vessels, axons, and a dense extracellular matrix. Despite its high prevalence and clinical impact, the molecular mechanisms underlying cNF formation remain poorly understood. Here, we used an Nf1 knockout (Nf1-KO) mouse model combined with immunohistochemistry and single cell transcriptomics in order to investigate the mechanisms driving cNF development. Our results showed that mutant SCs accumulate in the skin of young mice weeks prior to the onset of cNF. However, these cells remain quiescent until triggered by skin trauma, which induces their proliferation and the rapid formation of cNFs. Using a trauma-induced Nf1-KO model with scRNAseq, we designed a transcriptomic atlas of growing and mature cNFs, as well as adjacent apparently healthy skin. This analysis identified a population of non-myelinating Aquaporin1^highNestin^low SCs as the likely cells of origin for cNFs. These cells overexpress genes involved in axon growth and guidance, potentially driving the abnormal innervation observed in both mouse and patient cNFs. In addition, we found that tumor SCs, along with dermal and/or epineurial fibroblasts and pericytes, overexpress genes encoding collagen, contributing to the extensive fibrosis characteristic of cNFs. Notably, all of these cells exhibit high expression of periostin and tenascin C, key extracellular matrix components, highlighting them as novel therapeutic targets in view of cNF treatment.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"158"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144666774","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relationship between cerebral small vessel disease and proteinopathies in the medial temporal lobe.","authors":"Valentina Perosa, Jan Oltmer, Francesco Bax, Maarten L van den Berg, Corinne A Auger, Johanna Rotta, Romain Perbet, Jean Augustinack, Matthew P Frosch, Theresa Connors, Steven M Greenberg, Bradley T Hyman, Susanne J van Veluw","doi":"10.1186/s40478-025-02076-y","DOIUrl":"10.1186/s40478-025-02076-y","url":null,"abstract":"<p><p>The medial temporal lobe (MTL) is strategically important for cognition and the pathogenesis of Alzheimer's Disease (AD). Cerebral small vessel disease (CSVD) independently contributes to cognitive impairment and is believed to play a role in AD. CSVD and proteinopathies related to AD often coexist in the MTL but neither the severity of CSVD, nor the associations between these pathologies have been quantitatively addressed in this brain region. We hypothesized that the severity of CSVD in the MTL is associated with the local burden of proteinopathies implicated in neurodegeneration (tau-tangles, amyloid-β-plaques, phospho-Tar-DNA-Binding-Protein-43 [pTDP-43]), regardless of disease stage. One potential mechanism linking CSVD and proteinopathies is a failure in perivascular brain clearance. Therefore, the relationship between CSVD and the enlargement of perivascular spaces (PVS) was investigated. AI-models and manual ratings were applied to digitized histological MTL-sections of 152 autopsy cases with and without Alzheimer's Disease Neuropathological Changes to quantify proteinopathies and the two common forms of CSVD, cerebral amyloid angiopathy (CAA) and arteriolosclerosis. The associations between CSVD and proteinopathies were assessed using linear-mixed-effects models. The relationship between CSVD and PVS enlargement was also investigated. Regional CAA-burden increased along Braak-stages and was positively associated with amyloid-β-plaques percentage area and tau-tangles density, irrespective of Braak-stage, but not with density of pTDP-43 inclusions. Local arteriolosclerosis severity was not associated with Braak-stages and had no direct effect on parenchymal proteinopathies. However, arteriolosclerosis severity and its interaction with CAA were positively associated with PVS enlargement. These results suggest that CAA, but not arteriolosclerosis, is more directly implicated in the pathophysiology of proteinopathies in the MTL. Moreover, arteriolosclerosis may contribute to perivascular clearance dysfunction.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"156"},"PeriodicalIF":6.2,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12265290/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144648222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of neurodegenerative and cerebrovascular neuropathology with frailty in a diverse sample.","authors":"Felipe Bozi-Soares, Márlon Juliano Romero Aliberti, Alberto Fernando Oliveira Justo, Renata E P Leite, Lea T Grinberg, Vitor R Paes, Roberta D Rodriguez, Carlos A Pasqualucci, Eduardo Ferrioli, Claudia Kimie Suemoto","doi":"10.1186/s40478-025-02003-1","DOIUrl":"10.1186/s40478-025-02003-1","url":null,"abstract":"<p><p>Associations between neurodegenerative and cerebrovascular neuropathologies and frailty are not well understood, especially in diverse populations. This study investigated these associations in an admixed Brazilian cohort. This cross-sectional study included participants aged 60 + from the Brazilian Biobank for Aging Studies (2004-2024). Neuropathology data covered nine markers and a neuropathological comorbidity score (NPC). Frailty was measured using a frailty index from 33 health deficits, and cognitive impairment was defined as a Clinical Dementia Rating ≥ 0.5, both based on post-mortem informant reports with the next of kin. Linear regression models, adjusted for age, sex, education, race, and cognitive impairment, assessed associations between neuropathology and frailty. Effect modification by cognitive status was also explored. Among 1,370 participants (mean age = 78.4 ± 9.3 years; 53% women), 45% were frail, and 38% had cognitive impairment. Neurofibrillary tangles (NFT) (β = 0.005, 95%CI = 0.000-0.008, p = 0.036), Lewy body disease pathology (β = 0.008, 95%CI = 0.003-0.012, p = 0.001), lacunar infarcts (β = 0.032, 95%CI = 0.012-0.052, p = 0.002), siderocalcinosis (β = 0.015, 95%CI = 0.002-0.030, p = 0.023), and hyaline arteriolosclerosis (β = 0.034, 95%CI = 0.021-0.048, p < 0.001) were associated with frailty, independent of cognitive impairment. Higher NPC scores were linked to higher frailty with stronger associations observed among cognitively impaired participants (β = 0.007, 95%CI = 0.003-0.011, p = 0.001), as indicated by a p-value for interaction = 0.007. There was a more pronounced association between neuropathology and frailty among cognitively impaired participants for NFT (β = 0.007, 95%CI = 0.001-0.015, p = 0.020) and hyaline arteriolosclerosis (β = 0.052, 95%CI = 0.031-0.073, p < 0.001). Unlike other neuropathologies, hyaline arteriolosclerosis was associated with higher frailty levels in participants without cognitive impairment (β = 0.020, 95%CI = 0.002-0.038, p = 0.023). Our findings suggest that neuropathology affects frailty independently of cognitive status, although its impact is compounded by cognitive impairment. Moreover, cerebrovascular pathology's association with frailty in cognitively normal participants highlights the potential benefit of early cardiovascular risk management to reduce frailty risk, which is crucial in low- and middle-income countries considering the disproportionately high burden of cardiovascular and cerebrovascular conditions in these populations.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"155"},"PeriodicalIF":6.2,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12257825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}