Acta Neuropathologica最新文献

筛选
英文 中文
Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants. 在临床异质性参与者的神经病理尸检队列中,脑脊液终点稀释RT-QuIC量化路易体病理。
IF 12.7 1区 医学
Acta Neuropathologica Pub Date : 2025-06-23 DOI: 10.1007/s00401-025-02904-4
Andrea Mastrangelo,Serena Caldera,Sophie E Mastenbroek,Erica Vittoriosi,Shorena Janelidze,Geidy E Serrano,Alireza Atri,Holly Shill,Erika Driver-Dunckley,Shyamal Mehta,Charles H Adler,Angela Mammana,Franco Magliocchetti,Simone Baiardi,Thomas G Beach,Oskar Hansson,Piero Parchi
{"title":"Quantification of Lewy body pathology by cerebrospinal fluid endpoint dilution RT-QuIC in a neuropathological autopsy cohort of clinically heterogeneous participants.","authors":"Andrea Mastrangelo,Serena Caldera,Sophie E Mastenbroek,Erica Vittoriosi,Shorena Janelidze,Geidy E Serrano,Alireza Atri,Holly Shill,Erika Driver-Dunckley,Shyamal Mehta,Charles H Adler,Angela Mammana,Franco Magliocchetti,Simone Baiardi,Thomas G Beach,Oskar Hansson,Piero Parchi","doi":"10.1007/s00401-025-02904-4","DOIUrl":"https://doi.org/10.1007/s00401-025-02904-4","url":null,"abstract":"The identification of biomarkers predicting the burden of brain alpha-synuclein (α-syn) pathology in vivo represents a research priority in Lewy body disease (LBD). Recently, some kinetic parameters of seed amplification assays (SAAs) for α-syn showed associations with measures of clinical progression. However, preanalytical and analytical factors significantly affect these parameters, reducing reproducibility. The Endpoint Dilution (ED) SAA Real-time Quaking-induced Conversion (RT-QuIC) is emerging as an alternative, more accurate tool for seed quantification. Still, the approach needs validation in large patient cohorts. We applied the ED RT-QuIC to postmortem ventricular cerebrospinal fluid (CSF) samples from 357 brain donors, including 168 who showed LBD at neuropathologic examination. We estimated the seeding dose, yielding positive responses in 50% of replicate reactions (SD50), using the midSIN algorithm and correlated these values with postmortem synuclein pathology burden and clinical severity measures. LBD was staged through the Unified Staging System for Lewy Body Disorders and the Lewy pathology consensus criteria. The SD50 values (expressed in log10SD/ml) differed significantly among participants at different LBD stages (p < 0.0001), with those at a neocortical stage demonstrating higher values than those at a brainstem-predominant stage (p < 0.0001). The SD50 values were significantly associated with the LBD load evaluated through immunohistochemistry (Rho = 0.62, p < 0.0001). Participants showing higher SD50 values performed worse at the last available scores on clinical scales evaluating motor (Rho = 0.33, p < 0.0001) and olfactory functions (Rho = - 0.33, p < 0.0001). The SD50 scores accurately distinguished neocortical LBD participants from those at lower stages (area under the curve, 0.86; 95% confidence interval, 0.79-0.92). The CSF ED RT-QuIC measure of α-syn seeds correlated significantly with LBD burden and clinical severity scores. These findings validate the CSF ED RT-QuIC as a quantitative assay for misfolded brain α-syn in LBD. This novel approach may be clinically applied to identify individuals at different stages of LBD pathology in research settings.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"19 1","pages":"67"},"PeriodicalIF":12.7,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370316","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}
引用次数: 0
The olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system. 嗅觉上皮:病理tau蛋白繁殖的关键通道和减轻中枢神经系统tau病的靶标。
IF 12.7 1区 医学
Acta Neuropathologica Pub Date : 2025-06-19 DOI: 10.1007/s00401-025-02902-6
Marion Dourte,Esther Paître,Mongia Bouchoucha,Emilien Boyer,Sandra O Tomé,Emilie Doeraene,Caroline Huart,Karelle Leroy,Dietmar Rudolf Thal,Anabelle Decottignies,Bernard Hanseeuw,Nuria Suelves,Pascal Kienlen-Campard
{"title":"The olfactory epithelium: a critical gateway for pathological tau propagation and a target for mitigating tauopathy in the central nervous system.","authors":"Marion Dourte,Esther Paître,Mongia Bouchoucha,Emilien Boyer,Sandra O Tomé,Emilie Doeraene,Caroline Huart,Karelle Leroy,Dietmar Rudolf Thal,Anabelle Decottignies,Bernard Hanseeuw,Nuria Suelves,Pascal Kienlen-Campard","doi":"10.1007/s00401-025-02902-6","DOIUrl":"https://doi.org/10.1007/s00401-025-02902-6","url":null,"abstract":"Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimer's disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g., EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OE's middle stratum and in the OB's olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Targeted treatments (ZnSO4 and AAVs) were applied at the OE level to assess the impact on tau pathology in the CNS. Complete stripping of the OE by intranasal administration of ZnSO4 led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human postmortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to aging or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"319 1","pages":"64"},"PeriodicalIF":12.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320337","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}
引用次数: 0
Role of CSF flow and meningeal barriers in the development of inflammatory lesions at the CNS-PNS transition zone of cranial nerves in autoimmune demyelinating diseases. 自身免疫性脱髓鞘疾病中脑神经CNS-PNS过渡区炎性病变发展中脑脊液流动和脑膜屏障的作用
IF 12.7 1区 医学
Acta Neuropathologica Pub Date : 2025-06-19 DOI: 10.1007/s00401-025-02896-1
Li Xin,Hideaki Nishihara,Adrian Madarasz,Petr Pleskac,Linh Tran,Daniela C Ivan,Fumitaka Shimizu,Simone Aleandri,Giuseppe Locatelli,Paola Luciani,Steven T Proulx
{"title":"Role of CSF flow and meningeal barriers in the development of inflammatory lesions at the CNS-PNS transition zone of cranial nerves in autoimmune demyelinating diseases.","authors":"Li Xin,Hideaki Nishihara,Adrian Madarasz,Petr Pleskac,Linh Tran,Daniela C Ivan,Fumitaka Shimizu,Simone Aleandri,Giuseppe Locatelli,Paola Luciani,Steven T Proulx","doi":"10.1007/s00401-025-02896-1","DOIUrl":"https://doi.org/10.1007/s00401-025-02896-1","url":null,"abstract":"Patients with autoimmune inflammatory demyelinating diseases have been shown to present with trigeminal and cochlear nerve lesions restricted at the root transition zone, which contrasts with the relatively extensive distribution of lesions in optic neuritis. To better understand the mechanism underlying the different distribution pattern for cranial nerve lesions in these autoimmune neuroinflammatory diseases, we focused on the CNS-PNS transition zone (TZ) of the trigeminal and cochlear nerves in a MOG-driven active EAE model. These nerves were found to exhibit unique arrangements of anatomical barrier layers including the arachnoid and glia limitans, which affected cerebrospinal fluid (CSF) tracer distribution as well as CCR2+ immune cell infiltration. Our data demonstrated that CCR2+ immune cells accumulate at the TZ on both CNS side and PNS side of the trigeminal nerve and cochlear nerve, which mirror the locations of cranial nerve pathology observed clinically in patients with inflammatory demyelinating disease. On the other hand, the optic and olfactory nerves, which both lack a TZ, did not exhibit restrictions in immune cell localization. Overall, our results reconcile with the hypothesis that the segment of the cranial nerve that is exposed to CSF flow is more susceptible to CCR2+ immune cell infiltration.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"240 1","pages":"65"},"PeriodicalIF":12.7,"publicationDate":"2025-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144320379","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}
引用次数: 0
Characterization of prion strains and peripheral prion infectivity patterns in E200K genetic CJD patients. E200K遗传性CJD患者朊病毒株及外周血朊病毒感染模式的研究。
IF 12.7 1区 医学
Acta Neuropathologica Pub Date : 2025-06-16 DOI: 10.1007/s00401-025-02903-5
Tomás Barrio,Jean-Yves Douet,Dana Žáková,Hasier Eraña,Alvina Huor,Hervé Cassard,Oihane Alzuguren,Séverine Lugan,Naïma Aron,Patrice Péran,Joaquín Castilla,Olivier Andréoletti
{"title":"Characterization of prion strains and peripheral prion infectivity patterns in E200K genetic CJD patients.","authors":"Tomás Barrio,Jean-Yves Douet,Dana Žáková,Hasier Eraña,Alvina Huor,Hervé Cassard,Oihane Alzuguren,Séverine Lugan,Naïma Aron,Patrice Péran,Joaquín Castilla,Olivier Andréoletti","doi":"10.1007/s00401-025-02903-5","DOIUrl":"https://doi.org/10.1007/s00401-025-02903-5","url":null,"abstract":"The mutation E200K in the prion protein gene (PRNP) is the most common variant in genetic Creutzfeldt-Jakob disease (gCJD). The clinical and pathological features observed in patients with E200K gCJD led to the hypothesis that the prion strains responsible for this form of the disease may be related to those involved in sporadic CJD (sCJD). In this study, we characterized the prion strains responsible for E200K gCJD cases from Slovakia (n = 12), Spain (n = 9), and France (n = 3) using transgenic mouse models expressing human prion protein (PrP). The cohort included patients with various PRNP genotypes: E200K-Met129/Met129, E200K-Met129/E200K-Met129, E200K-Met129/Val129, and E200K-Val129/Val129. Prion strain characterization revealed that the strains isolated from E200K gCJD cases corresponded to the two most common strains identified in sCJD cases: M1CJD and V2CJD. Depending on the individual, these strains were either present as pure M1CJD or V2CJD, or as a mixture of both (M1CJD + V2CJD). Additionally, peripheral tissues from E200K-Met129/Met129 patients (n = 4) and one E200K-Met129/Val129 case were analyzed for prion infectivity and seeding activity. Similar to sCJD patients, low but detectable levels of prions were found in various peripheral tissues of E200K gCJD cases. Overall, our findings suggest that the prion strains and their distribution in the body are highly similar between E200K gCJD and sCJD patients. These similarities indicate that individuals carrying the E200K mutation may serve as a valuable model for understanding CJD pathogenesis during the preclinical phase of the disease.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"31 1","pages":"62"},"PeriodicalIF":12.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295667","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}
引用次数: 0
Divergent host-pathogen interactions in neurolisteriosis: cytosolic replication vs. phagosomal dormancy of Listeria monocytogenes in CNS macrophages. 神经李斯特菌病中不同宿主-病原体的相互作用:单核增生李斯特菌在中枢神经系统巨噬细胞中的胞质复制与吞噬体休眠。
IF 12.7 1区 医学
Acta Neuropathologica Pub Date : 2025-06-16 DOI: 10.1007/s00401-025-02900-8
Leticia Tavares-Gomes,Margherita Polidori,Camille Monney,Géraldine Neuhaus,Beatriz Vidondo,Guillaume Witz,Andrew Hemphill,Anna Oevermann
{"title":"Divergent host-pathogen interactions in neurolisteriosis: cytosolic replication vs. phagosomal dormancy of Listeria monocytogenes in CNS macrophages.","authors":"Leticia Tavares-Gomes,Margherita Polidori,Camille Monney,Géraldine Neuhaus,Beatriz Vidondo,Guillaume Witz,Andrew Hemphill,Anna Oevermann","doi":"10.1007/s00401-025-02900-8","DOIUrl":"https://doi.org/10.1007/s00401-025-02900-8","url":null,"abstract":"Bacterial infections of the central nervous system (CNS) pose a significant threat to public health, especially with the growing challenge of antimicrobial resistance. Among these, Listeria monocytogenes (Lm) stands out as a key pathogen, responsible for often fatal neurolisteriosis in humans and cattle. Emerging evidence highlights the distinct roles played by microglia, the resident macrophages of the CNS, and infiltrating monocyte-derived macrophages (MDM) during neuroinflammation. Using bovine models, we investigated the interactions between these two macrophage populations and Lm during infection. Our results show that Lm thrives in the cytosol of microglia, driving productive infection and facilitating bacterial spread. In contrast, MDM effectively sequesters Lm within the phagolysosomal system, limiting its replication and inducing a viable but non-culturable (VBNC) state without completely eliminating the pathogen. Listeriolysin O contributes to the dichotomy of Lm fate, determining whether Lm escapes into the cytosol or transitions to the VBNC state. These findings underscore the complexity of Lm-host dynamics in neurolisteriosis, emphasizing the distinct yet complementary roles of microglia and MDM in shaping CNS infection. By elucidating these mechanisms, our study offers new perspectives on the neurolisteriosis pathogenesis and opens avenues for innovative therapeutic approaches to combat bacterial neuroinfections.","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"51 1","pages":"63"},"PeriodicalIF":12.7,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144295669","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}
引用次数: 0
Outcome-associated factors in a molecularly defined cohort of central neurocytoma. 中枢神经细胞瘤分子定义队列的结果相关因素。
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2025-06-11 DOI: 10.1007/s00401-025-02894-3
Maja Krech, Amos Muench, Daniel Teichmann, Peter Kuzman, Abigail K Suwala, Franziska M Ippen, Michael Müther, Katharina J Weber, Katharina Wenger-Alakmeh, Julia Onken, Peter Vajkoczy, Felix Behling, Sven-Axel May, Georgios Ntoulias, Joachim K Krauss, Oday Atallah, Majid Esmaeilzadeh, Wolf C Mueller, Frank L Heppner, Helena Radbruch, Carsten Dittmayer, Werner Stenzel, Arend Koch, David Capper, David Kaul, Werner Paulus, Karl H Plate, Joachim P Steinbach, Markus Czabanka, Rudi Beschorner, Andreas von Deimling, Michael Bockmayr, Julia E Neumann, Sebastian Brandner, Teresa Krieger, Christian Hartmann, Christian Thomas, Leonille Schweizer
{"title":"Outcome-associated factors in a molecularly defined cohort of central neurocytoma.","authors":"Maja Krech, Amos Muench, Daniel Teichmann, Peter Kuzman, Abigail K Suwala, Franziska M Ippen, Michael Müther, Katharina J Weber, Katharina Wenger-Alakmeh, Julia Onken, Peter Vajkoczy, Felix Behling, Sven-Axel May, Georgios Ntoulias, Joachim K Krauss, Oday Atallah, Majid Esmaeilzadeh, Wolf C Mueller, Frank L Heppner, Helena Radbruch, Carsten Dittmayer, Werner Stenzel, Arend Koch, David Capper, David Kaul, Werner Paulus, Karl H Plate, Joachim P Steinbach, Markus Czabanka, Rudi Beschorner, Andreas von Deimling, Michael Bockmayr, Julia E Neumann, Sebastian Brandner, Teresa Krieger, Christian Hartmann, Christian Thomas, Leonille Schweizer","doi":"10.1007/s00401-025-02894-3","DOIUrl":"10.1007/s00401-025-02894-3","url":null,"abstract":"<p><p>Central neurocytomas (CN) are intraventricular brain tumors predominantly occurring in young adults. Although prognosis is usually favorable, tumor recurrence is common, particularly following subtotal resection (STR). Currently, the risk of progression is evaluated using atypical features and an elevated Ki67 proliferation index. However, these markers lack consistent definitions, raising the need for objective criteria. Genome-wide DNA methylation profiles were examined in 136 tumors histologically classified as CN. Clinical/histopathological characteristics were assessed in 93/90 cases, and whole-exome sequencing was conducted in 12 cases. Clinical and molecular characteristics were integrated into a survival model to predict progression-free survival (PFS). A diagnosis of CN was epigenetically confirmed in 125 of 136 cases (92%). No DNA methylation subgroups were identified, but global DNA hypomethylation emerged as a hallmark feature of CN associated with higher recurrence risk. Risk stratification based on histological features of atypia and Ki67 proliferation index was not reproducible across neuropathologists. Hypomethylation at the FGFR3 locus, accompanied by increased FGFR3 protein expression, was observed in 97% of cases. Gross total resection was associated with significantly improved PFS compared to STR, while patients undergoing STR receiving radiotherapy had a better outcome (p = 0.0001). Younger patients were identified as having a higher risk of recurrence (p = 0.026). Patient age and treatment strategy were key factors associated with survival outcomes in this cohort. These findings underscore the importance of closer follow-up for younger patients and radiotherapy for STR cases. Furthermore, FGFR3 represents a hallmark feature and potential therapeutic target, warranting further investigation.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"61"},"PeriodicalIF":9.3,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12158839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144265031","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}
引用次数: 0
Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons. 兴奋性皮质神经元脑损伤区域易感性的分子特征。
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2025-06-07 DOI: 10.1007/s00401-025-02879-2
Diede W M Broekaart, Abhijeet Sharma, Aarthi Ramakrishnan, Anjalika Chongtham, Dorothee M Günther, Saraswathi Subramaniyan, Minghui Wang, Vishwendra Patel, Bin Zhang, Lea T Grinberg, Robert D Blitzer, Eric F Schmidt, Li Shen, Patrick R Hof, Ana C Pereira
{"title":"Molecular signatures of regional vulnerability to tauopathy in excitatory cortical neurons.","authors":"Diede W M Broekaart, Abhijeet Sharma, Aarthi Ramakrishnan, Anjalika Chongtham, Dorothee M Günther, Saraswathi Subramaniyan, Minghui Wang, Vishwendra Patel, Bin Zhang, Lea T Grinberg, Robert D Blitzer, Eric F Schmidt, Li Shen, Patrick R Hof, Ana C Pereira","doi":"10.1007/s00401-025-02879-2","DOIUrl":"10.1007/s00401-025-02879-2","url":null,"abstract":"<p><p>Tauopathies are characterized by the aggregation and accumulation of hyperphosphorylated tau proteins that correlates with cognitive impairment in affected individuals. The presence of tauopathy follows a temporospatial spreading pattern in which certain neuronal cell types in specific brain regions are more vulnerable to tau accumulation and atrophy. However, the mechanisms underlying the selective vulnerability of these neurons and regions to pathological tau accumulation are not fully understood. Here, we characterized the presence of phosphorylated tau in excitatory and inhibitory neurons in post-mortem prefrontal cortex of tauopathy patients, including Alzheimer's disease, progressive supranuclear palsy, corticobasal degeneration, and frontotemporal lobar dementia due to a MAPT mutation. We observed that neuronal tau accumulation across these tauopathies occurs predominantly in excitatory neurons compared to inhibitory neurons. Next, we performed viral translating ribosome affinity purification (vTRAP) from vulnerable and resistant brain regions on vGLUT1<sup>CRE+</sup> and GAD2<sup>CRE+</sup> PS19 mice to understand molecular signatures of tau vulnerability. We observed that both vulnerable regions and vulnerable neurons are characterized by alterations in synaptic transmission and neuronal excitability. Transcription factor Mef2c (myocyte enhancer factor 2c) was identified as an upstream regulator affecting myelination and synaptic organization in vulnerable brain regions in PS19 mice. The relevance of these findings was validated in human tauopathies via coexpression network analysis. Concordantly, we observed tau-induced changes in spontaneous postsynaptic currents of excitatory neurons in mice especially in the prefrontal cortex. Taken together, we conclude that selective vulnerability to tau could arise from changes in neurotransmission and synaptic compositions, potentially due to an altered Mef2c transcriptional network.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"60"},"PeriodicalIF":9.3,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144245599","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}
引用次数: 0
Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing. 对FTLD-TDP患者额叶皮层剪接景观的分析揭示了亚型特异性模式和隐性剪接。
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2025-06-06 DOI: 10.1007/s00401-025-02901-7
Júlia Faura, Bavo Heeman, Cyril Pottier, Matthew C Baker, Mariely DeJesus-Hernandez, Fahri Küçükali, Laura Heiß, Sarah Wynants, Marleen Van den Broeck, Peter De Rijk, Tim De Pooter, Geert Joris, NiCole A Finch, Yan Asmann, Mojca Strazisar, Melissa E Murray, Leonard Petrucelli, Björn Oskarsson, Kristel Sleegers, Keith A Josephs, Aivi T Nguyen, R Ross Reichard, Ronald C Petersen, Bradley F Boeve, Neill R Graff-Radford, Dennis W Dickson, Marka van Blitterswijk, Rosa Rademakers
{"title":"Analysis of the splicing landscape of the frontal cortex in FTLD-TDP reveals subtype specific patterns and cryptic splicing.","authors":"Júlia Faura, Bavo Heeman, Cyril Pottier, Matthew C Baker, Mariely DeJesus-Hernandez, Fahri Küçükali, Laura Heiß, Sarah Wynants, Marleen Van den Broeck, Peter De Rijk, Tim De Pooter, Geert Joris, NiCole A Finch, Yan Asmann, Mojca Strazisar, Melissa E Murray, Leonard Petrucelli, Björn Oskarsson, Kristel Sleegers, Keith A Josephs, Aivi T Nguyen, R Ross Reichard, Ronald C Petersen, Bradley F Boeve, Neill R Graff-Radford, Dennis W Dickson, Marka van Blitterswijk, Rosa Rademakers","doi":"10.1007/s00401-025-02901-7","DOIUrl":"10.1007/s00401-025-02901-7","url":null,"abstract":"<p><p>Dysregulation of TDP-43 as seen in TDP-43 proteinopathies leads to specific RNA splicing dysfunction. While discovery studies have explored novel TDP-43-driven splicing events in induced pluripotent stem cell (iPSC)-derived neurons and TDP-43 negative neuronal nuclei, transcriptome-wide investigations in frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP) brains remain unexplored. Such studies hold promise for identifying widespread novel and relevant splicing alterations in FTLD-TDP patient brains. We conducted the largest differential splicing analysis (DSA) using bulk short-read RNAseq data from frontal cortex (FCX) tissue of 127 FTLD-TDP (A, B, C, GRN and C9orf72 carriers) and 22 control subjects (Mayo Clinic Brain Bank), using Leafcutter. In addition, long-read bulk cDNA sequencing data were generated from FCX of 9 FTLD-TDP and 7 controls and human TARDBP wildtype and knock-down iPSC-derived neurons. Publicly available RNAseq data (MayoRNAseq, MSBB and ROSMAP studies) from Alzheimer's disease patients (AD) was also analyzed. Our DSA revealed extensive splicing alterations in FTLD-TDP patients with 1881 differentially spliced events, in 892 unique genes. When evaluating differences between FTLD-TDP subtypes, we found that C9orf72 repeat expansion carriers carried the most splicing alterations after accounting for differences in cell-type proportions. Focusing on cryptic splicing events, we identified STMN2 and ARHGAP32 as genes with the most abundant and differentially expressed cryptic exons between FTLD-TDP patients and controls in the brain, and we uncovered a set of 17 cryptic events consistently observed across studies, highlighting their potential relevance as biomarkers for TDP-43 proteinopathies. We also identified 16 cryptic events shared between FTLD-TDP and AD brains, suggesting potential common splicing dysregulation pathways in neurodegenerative diseases. Overall, this study provides a comprehensive map of splicing alterations in FTLD-TDP brains, revealing subtype-specific differences and identifying promising candidates for biomarker development and potential common pathogenic mechanisms between FTLD-TDP and AD.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"59"},"PeriodicalIF":9.3,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12143990/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144232851","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}
引用次数: 0
Multifactorial etiology of progressive supranuclear palsy (PSP): the genetic component. 进行性核上性麻痹(PSP)的多因素病因:遗传成分。
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2025-06-04 DOI: 10.1007/s00401-025-02898-z
Ulrich Müller, Günter Höglinger, Dennis W Dickson
{"title":"Multifactorial etiology of progressive supranuclear palsy (PSP): the genetic component.","authors":"Ulrich Müller, Günter Höglinger, Dennis W Dickson","doi":"10.1007/s00401-025-02898-z","DOIUrl":"10.1007/s00401-025-02898-z","url":null,"abstract":"<p><p>Progressive supranuclear palsy (PSP) is mainly a sporadic disease. It has a multifactorial etiology and an interaction between environmental and genetic factors causes disease. While elucidation of environmental risks for PSP is still in its infancy, much has been learned about the genetic etiological component of PSP during the past few years. This article reviews genes that convey risk for PSP. All genes have been identified in association studies. Only those genes with the standard threshold for genome-wide significance of P < 5E-8 are covered. These genes include MAPT, KANSL1, PLEKHM1, STX6, MOBP, EIF2AK3, SLC01 A2, DUSP10, APOE, RUNX2, TRIM11, NFASC/CNTN2 and LRRK2. The physiologic function of these genes is described and their potential role in the etiology of PSP is discussed.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"58"},"PeriodicalIF":9.3,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12137433/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144214530","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}
引用次数: 0
Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease. gantenerumab或solanezumab治疗显性遗传性阿尔茨海默病的免疫组化评价
IF 9.3 1区 医学
Acta Neuropathologica Pub Date : 2025-06-03 DOI: 10.1007/s00401-025-02890-7
Charles D Chen, Erin E Franklin, Yan Li, Nelly Joseph-Mathurin, Aime L Burns, Diana A Hobbs, Austin A McCullough, Stephanie A Schultz, Chengjie Xiong, Guoqiao Wang, Mario Masellis, Ging-Yuek Robin Hsiung, Serge Gauthier, Sarah B Berman, Erik D Roberson, Lawrence S Honig, Roger Clarnette, John M Ringman, James E Galvin, William Brooks, Kazushi Suzuki, Sandra Black, Johannes Levin, Neelum T Aggarwal, Mathias Jucker, Matthew P Frosch, Julia K Kofler, Charles White, C Dirk Keene, Jie Chen, Alisha Daniels, Brian A Gordon, Laura Ibanez, Celeste M Karch, Jorge Llibre-Guerra, Eric McDade, John C Morris, Charlene Supnet-Bell, Ricardo F Allegri, Jae-Hong Lee, Gregory S Day, Francisco Lopera, Jee Hoon Roh, Peter R Schofield, Susan Mills, Tammie L S Benzinger, Randall J Bateman, Richard J Perrin
{"title":"Immunohistochemical evaluation of a trial of gantenerumab or solanezumab in dominantly inherited Alzheimer disease.","authors":"Charles D Chen, Erin E Franklin, Yan Li, Nelly Joseph-Mathurin, Aime L Burns, Diana A Hobbs, Austin A McCullough, Stephanie A Schultz, Chengjie Xiong, Guoqiao Wang, Mario Masellis, Ging-Yuek Robin Hsiung, Serge Gauthier, Sarah B Berman, Erik D Roberson, Lawrence S Honig, Roger Clarnette, John M Ringman, James E Galvin, William Brooks, Kazushi Suzuki, Sandra Black, Johannes Levin, Neelum T Aggarwal, Mathias Jucker, Matthew P Frosch, Julia K Kofler, Charles White, C Dirk Keene, Jie Chen, Alisha Daniels, Brian A Gordon, Laura Ibanez, Celeste M Karch, Jorge Llibre-Guerra, Eric McDade, John C Morris, Charlene Supnet-Bell, Ricardo F Allegri, Jae-Hong Lee, Gregory S Day, Francisco Lopera, Jee Hoon Roh, Peter R Schofield, Susan Mills, Tammie L S Benzinger, Randall J Bateman, Richard J Perrin","doi":"10.1007/s00401-025-02890-7","DOIUrl":"10.1007/s00401-025-02890-7","url":null,"abstract":"<p><p>Clinical trials of anti-amyloid-β (Aβ) monoclonal antibodies in Alzheimer disease (AD) infer target engagement from Aβ positron emission tomography (PET) and/or fluid biomarkers such as cerebrospinal fluid (CSF) Aβ42/40. However, these biomarkers measure brain Aβ deposits indirectly and/or incompletely. In contrast, neuropathologic assessments allow direct investigation of treatment effects on brain Aβ deposits-and on potentially myriad 'downstream' pathologic features. From a clinical trial of anti-Aβ monoclonal antibodies in dominantly inherited AD (DIAD), in the largest study of its kind, we measured immunohistochemistry area fractions (AFs) for Aβ deposits (10D5), tauopathy (PHF1), microgliosis (IBA1), and astrocytosis (GFAP) in 10 brain regions from 10 trial cases-gantenerumab (n = 4), solanezumab (n = 4), placebo/no treatment (n = 2)-and 10 DIAD observational study cases. Strikingly, in proportion to total drug received, Aβ deposit AFs were significantly lower in the gantenerumab arm versus controls in almost all areas examined, including frontal, temporal, parietal, and occipital cortices, anterior cingulate, hippocampus, caudate, putamen, thalamus, and cerebellar gray matter; only posterior cingulate and cerebellar white matter comparisons were non-significant. In contrast, AFs of tauopathy, microgliosis, and astrocytosis showed no differences across groups. Our results demonstrate with direct histologic evidence that gantenerumab treatment in DIAD can reduce parenchymal Aβ deposits throughout the brain in a dose-dependent manner, suggesting that more complete removal may be possible with earlier and more aggressive treatment regimens. Although AFs of tauopathy, microgliosis, and astrocytosis showed no clear response to partial Aβ removal in this limited autopsy cohort, future examination of these cases with more sensitive techniques (e.g., mass spectrometry) may reveal more subtle 'downstream' effects.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"57"},"PeriodicalIF":9.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12133910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207352","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}
引用次数: 0
0
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
相关产品
×
本文献相关产品
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:604180095
Book学术官方微信