Acta Neuropathologica最新文献

{"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":"https://doi.org/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":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"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":"https://doi.org/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^CRE+ and GAD2^CRE+ 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}

{"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}

{"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}

{"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}

{"title":"Anti-pyroglutamate-3 Aβ immunotherapy engages microglia and inhibits amyloid accumulation in transgenic mouse models of Aβ amyloidosis.","authors":"Fan Liao, Maria Calvo-Rodriguez, Meha Chhaya, Julian P Sefrin, Erik I Charych, Mario Mezler, Diana Clausznitzer, Emily J McGlame, Karen Zhao, Allison Rodgers, Yang Cao, Philipp F Secker, Laura Fernandez Garcia-Agudo, Lili Huang, Corinna Klein, Tammy Dellovade, Eric Karran","doi":"10.1007/s00401-025-02892-5","DOIUrl":"10.1007/s00401-025-02892-5","url":null,"abstract":"<p><p>Alzheimer disease (AD) is the most common form of dementia affecting more than 6 million people in the United States. Currently, 3 monospecific antibodies targeting different Amyloid β (Aβ) species have been approved by the US FDA as disease modifying therapeutics for treatment in early AD patients with amyloid pathology. ABBV-916 is a clinical stage human IgG1 monoclonal antibody which binds to N-terminal truncated, pyroglutamate-modified at amino acid position 3, Aβ (Aβ_pE3). The current study characterized ABBV-916 using human tissue samples and amyloid precursor protein (APP) transgenic mice. ABBV-916 selectively bound to recombinant Aβ_pE3-42 fibrils and native amyloid plaques in unfixed AD brain tissue but did not bind targets in human CSF. ABBV-916 significantly reduced dense plaques from brain tissue that were co-cultured with hiPSC-derived phagocytes. In APPPS1-21 mice, ABBV‑916 bound plaques in a dose-dependent manner after a single intravenous injection. In addition, three months of weekly administration of ABBV-916 murine surrogate antibody significantly decreased amyloid plaques in APPPS1-21 mice. In vivo two-photon imaging revealed that the murine version of ABBV-916 inhibited the growth of the plaques in APPPS1-21 mice. ABBV-916 murine surrogate antibody recruited microglia to plaques within 24-48 hours after a single intraperitoneal injection in Cx3cr1-tdTomato/APPPS1-21 mice. Importantly, in contrast to a positive control antibody, ABBV‑916 murine precursor antibody did not cause microhemorrhage in aged APPPS1-21 mice. Taken together, our results suggest that ABBV-916 is a promising drug candidate. Clinical testing is on-going to evaluate the plaque removal and safety profiles of ABBV-916 in AD patients.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"55"},"PeriodicalIF":9.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130127/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198028","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":"Synaptotoxic effects of extracellular tau are mediated by its microtubule-binding region.","authors":"Tomas Ondrejcak, Neng-Wei Hu, Emily Coode, Tom Campbell, Grant T Corbett, Ivan Doykov, Kevin Mills, Dominic M Walsh, Frederick J Livesey, Michael J Rowan, Igor Klyubin","doi":"10.1007/s00401-025-02897-0","DOIUrl":"10.1007/s00401-025-02897-0","url":null,"abstract":"<p><p>Immunotherapies targeting extracellular tau share the premise that interrupting cell-to-cell spread of tau pathology in Alzheimer's disease (AD) will slow dementia pathogenesis. Whether these interventions affect the actions of synaptotoxic, extracellular tau species that may contribute to cognitive impairment is relatively unknown. Here, we assayed synaptic plasticity disruption in anaesthetised live rats caused by intracerebral injection of synaptotoxic tau present either in (a) secretomes of induced pluripotent stem cell-derived neurons (iNs) from people with Trisomy 21, the most common genetic cause of AD, or (b) aqueous extracts of human AD brain. Extracellular tau in iN secretomes was found to include fragments that contain the extended microtubule-binding regions of tau, MTBR/R' and adjacent C-terminal sequences. Immunodepletion or co-injection with antibodies targeting epitopes within these fragments prevented the acute disruption of synaptic plasticity by these patient-derived synaptotoxic tau preparations. Moreover, a recombinant human tau fragment encompassing the core MTBR/R'-region present in tau fibrils, tau_297-391, potently mimicked the deleterious action of patient-derived tau. MTBR/R'-directed antibodies also rapidly reversed a very persistent synaptotoxic effect of soluble brain tau. Our findings reveal a hitherto relatively unexplored potential benefit of targeting extracellular MTBR/R' tau on correcting synaptic dysfunction.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"56"},"PeriodicalIF":9.3,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12130085/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198029","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":"SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex: insights from a Down syndrome in vitro model.","authors":"Maria I Lioudyno, Evgueni A Sevrioukov, Gema M Olivarria, Lauren Hitchcock, Dominic I Javonillo, Sydney M Campos, Isabel Rivera, Sierra T Wright, Elizabeth Head, Juan Fortea, Thomas Wisniewski, A Claudio Cuello, Sonia Do Carmo, Thomas E Lane, Jorge Busciglio","doi":"10.1007/s00401-025-02895-2","DOIUrl":"10.1007/s00401-025-02895-2","url":null,"abstract":"<p><p>Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g., TMPRSS2) or indirectly influence the SARS-CoV-2 entry into central nervous system (CNS) cells. The anti-viral immune response may also be altered in cells with trisomy-21 (T21) due to triplication of genes encoding for several interferon receptor subunits and interferon-stimulated genes (ISGs). Here, we demonstrate that human cells derived from fetal cortical specimens and maintained in primary cultures are susceptible to infection with a molecular clone of vesicular stomatitis virus engineered to express the Spike protein of SARS-CoV-2 (VSV-eGFP-SARS-CoV-2) and to authentic SARS-CoV-2. The level of SARS-CoV-2 infectivity in cultures originated from different cortical specimens varied, seemingly depending on ploidy and chromosomal sex of the cells. We confirmed the presence of ACE2 and TMPRSS2 in cultures and found that XY T21 group had the highest TMPRSS2 mRNA levels, which was associated with increased infectivity in XY-compared to XX T21 cultures. The XX T21 cultures exhibited elevated expression of several ISGs (MX1, STAT1, and STAT2) which was associated with lower infectivity. The comparisons of postmortem aged brain specimens revealed reduced ACE2, TMPRSS2, but elevated STAT2 protein levels in individuals with DS and Alzheimer's disease (DS-AD) compared to control and Alzheimer's disease (AD) group. Collectively, these results suggest multifactorial regulation of SARS-CoV-2 infectivity in cortical cells that involves ploidy, chromosomal sex, and the expression of genes implicated in regulation of virus entry and anti-viral response as contributing factors.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"54"},"PeriodicalIF":9.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125050/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186242","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":"Delineating the mechanisms of cerebellar degeneration in paediatric and adult primary mitochondrial disease.","authors":"Laura A Smith, Elizaveta A Olkhova, Nichola Z Lax, Yi Shiau Ng, Robert W Taylor, Grainne S Gorman, Daniel Erskine, Robert McFarland","doi":"10.1007/s00401-025-02891-6","DOIUrl":"10.1007/s00401-025-02891-6","url":null,"abstract":"<p><p>Cerebellar ataxia is a frequent, debilitating neurological manifestation of primary mitochondrial disease and is associated with extensive neurodegeneration of the cerebellar cortical circuitry. However, the precise neuropathological mechanisms resulting in cerebellar degeneration in paediatric and adult forms of mitochondrial disease remain unclear. We therefore sought to perform a comparative neuropathological study using post-mortem cerebellar tissues from 28 paediatric and adult patients with pathogenic bi-allelic POLG variants and pathogenic mitochondrial DNA variants (m.3243A > G, m.8344A > G, m.13094T > C, and m.14709T > C), in addition to 18 neurologically normal control cases. We also sought to assess the prevalence and progression of cerebellar ataxia in an adult mitochondrial disease patient clinical cohort (n = 310) harbouring the same pathogenic variants as the post-mortem cases. Analysis of the clinical patient cohort revealed that at least 23.5-39.7% of adult patients with primary mitochondrial disease had predominantly cerebellar ataxia, with disease progression evident in 38.8% of patients. In the mitochondrial disease post-mortem tissue cohort, there was clear evidence of selective loss of inhibitory Purkinje cells, with corresponding oxidative phosphorylation protein deficiencies, which were more severe in comparison to mainly excitatory neuronal populations of the granule cell layer and dentate nucleus. Remaining Purkinje cells also demonstrated an increased expression of mitophagy-related proteins, including LC3B and BNIP3. Focal necrotic cerebellar cortical lesions, identified in eight patients, were characterised by decreased parvalbumin immunoreactivity, and sporadic c-Fos immunoreactivity was observed throughout the cerebellar cortices of 14 patients, suggestive of cerebellar cortical hyperactivity. Overall, these neuropathological features were more severe in the early onset POLG-related disease group and patients who had epilepsy. Our findings provide an important insight to the pathological mechanisms contributing to the degeneration of the cerebellar cortex in paediatric and adult forms of primary mitochondrial disease, highlighting an increased burden of pathology in early onset POLG-related disease which may have important prognostic and therapeutic implications.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"53"},"PeriodicalIF":9.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125081/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186241","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":"Thalamic atrophy in multiple sclerosis is associated with tract disconnection and altered microglia.","authors":"Carla Rodriguez-Mogeda, Ismail Koubiyr, Stefanos E Prouskas, Margarita Georgallidou, Susanne M A van der Pol, Rosalia Franco Fernandez, Yvon Galis de Graaf, Ysbrand D van der Werf, Laura E Jonkman, Geert J Schenk, Frederik Barkhof, Hanneke E Hulst, Maarten E Witte, Menno M Schoonheim, Helga E de Vries","doi":"10.1007/s00401-025-02893-4","DOIUrl":"10.1007/s00401-025-02893-4","url":null,"abstract":"<p><p>Thalamic atrophy already occurs in the early stages of multiple sclerosis (MS) and continues progressively throughout the disease. Demyelination is one of the main pathological hallmarks of MS and yet, thalamic demyelination does not correlate well with thalamic atrophy. By combining post-mortem magnetic resonance imaging with immunohistochemistry of thalami from 13 control and 13 MS donors, we investigated the underlying pathological contributors of thalamic atrophy and pathology. We first assessed the volumes of four thalamic nuclei groups (anterior, lateral, medial and posterior). Then, diffusion weighted imaging was used to assess the microstructural integrity of white matter tracts connecting each thalamic nuclei group. In addition, we studied myelination, inflammation, neurodegeneration and microglial activation by immunohistochemistry. We uncovered that medial and posterior thalamic nuclei were more atrophic compared to the anterior and lateral nuclei. Bilateral posterior nuclei and the right medial and anterior nuclei showed reduced fractional anisotropy in connected white matter tracks. We further show that microglial cells in the mediodorsal nuclei have an increased density and morphological complexity in MS compared to control donors. Microglia show signs of phagocytosis of pre-synapses, although we did not observe an overall synaptic loss in the thalamus of MS donors. These microglial changes within mediodorsal nuclei correlated with lower medial thalamic volume. Taken together, this study provides evidence that thalamic (subnuclear) atrophy relates tostructural thalamic network disconnection and within-thalamic microglial changes, but not thalamic demyelination. These findings could impact future treatment strategies aimed at thalamic neuroprotection.</p>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"149 1","pages":"52"},"PeriodicalIF":9.3,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119693/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155468","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}