Neuropathology and Applied Neurobiology最新文献

{"title":"Multiplex Immunofluorescent Analysis of Alpha-Synuclein in Nigral Lewy Bodies With Heat-Induced Antibody Stripping Reveals an Intricate Multilayered Structure.","authors":"Dominik Hrabos, Satomi Hasegawa, Dorota Konickova","doi":"10.1111/nan.70024","DOIUrl":"https://doi.org/10.1111/nan.70024","url":null,"abstract":"<p><p>In the study, we employ an affordable, tissue-saving, and precise simultaneous multiplex immunofluorescence method with heat-induced antibody stripping to identify and structurally analyse nigral Lewy bodies in dopaminergic neurones. Analysis of different alpha-synuclein epitopes and proteoforms reveals an almost uniform, onion-like morphology of the Lewy bodies. The N-terminal and C-terminal domains are predominantly accessible to antibody binding in the peripheral shell of the bodies.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 3","pages":"e70024"},"PeriodicalIF":4.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Computational Analysis of SOD1-G93A Mouse Muscle Biomarkers for Comprehensive Assessment of ALS Progression.","authors":"Pedro Gómez-Gálvez, Victoria Navarro, Ana M Castro, Carmen Paradas, Luis M Escudero","doi":"10.1111/nan.70014","DOIUrl":"10.1111/nan.70014","url":null,"abstract":"<p><strong>Aims: </strong>To identify potential image biomarkers of neuromuscular disease by analysing morphological and network-derived features in skeletal muscle biopsies from a murine model of amyotrophic lateral sclerosis (ALS), the SOD1^G93A mouse and wild-type (WT) controls at distinct stages of disease progression.</p><p><strong>Methods: </strong>Using the NDICIA computational framework, we quantitatively evaluated histological differences between skeletal muscle biopsies from SOD1^G93A and WT mice. The process involved the selection of a subset of features revealing these differences. A subset of discriminative features was selected to characterise these differences, and their temporal dynamics were assessed across disease stages.</p><p><strong>Results: </strong>Our findings demonstrate that muscle pathology in the mutant model evolves from early alterations in muscle fibre arrangement, detectable at the presymptomatic stage through graph theory features, to the subsequent development of the typical morphological pattern of neurogenic atrophy at more advanced disease stages.</p><p><strong>Conclusions: </strong>Our assay identifies a neurogenic signature in mutant muscle biopsies, even when the disease is phenotypically imperceptible.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70014"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143753640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identical Seeding Characteristics and Cryo-EM Filament Structures in FTLD-Synuclein and Typical Multiple System Atrophy.","authors":"Patrick W Cullinane, Yang Yang, Viorica Chelban, Yee Yen Goh, Kirsten Ebanks, Toby Curless, Sarah Wrigley, Eduardo de Pablo-Fernández, Janice Holton, Sew Peak-Chew, Catarina Franco, Amanda L Woerman, Henry Houlden, Thomas T Warner, Sjors H W Scheres, Michel Goedert, Zane Jaunmuktane","doi":"10.1111/nan.70013","DOIUrl":"10.1111/nan.70013","url":null,"abstract":"<p><strong>Aims: </strong>The aim of this study is to identify the prevalence of frontotemporal dementia (FTD)/corticobasal syndrome (CBS) in a large cohort of pathologically confirmed cases of multiple system atrophy (MSA) and to determine the α-synuclein seeding characteristics and electron cryo-microscopy (cryo-EM) filament structure in frontotemporal lobar degeneration with MSA-type α-synuclein pathology (FTLD-synuclein).</p><p><strong>Methods: </strong>The archives of the Queen Square Brain Bank (1989-2023) were searched for histologically confirmed MSA cases, and those with a clinical diagnosis of FTD/CBS were reviewed for pathological features of FTLD-synuclein. Phosphotungstic acid (PTA)-precipitated brain homogenates from FTLD-synuclein, dementia with Lewy bodies (DLB) and G51D SNCA synucleinopathy cases were used to seed aggregation in α-syn140*A53T-YFP HEK293T cells. The structure of α-synuclein filaments from an FTLD-synuclein case was determined by cryo-EM.</p><p><strong>Results: </strong>We identified 283 cases of MSA. Four cases had a clinical diagnosis of CBS, one of which met pathological criteria for FTLD-synuclein. Genetic studies in this case were negative for SNCA variants, and PTA-precipitated brain homogenates seeded abundant cytoplasmic α-synuclein inclusions that were morphologically indistinguishable from those of typical MSA but distinct from those of G51D SNCA and DLB. MSA Type II α-synuclein filaments were identified by cryo-EM.</p><p><strong>Conclusions: </strong>FTD/CBS is rarely associated with MSA pathology. The cell seeding characteristics and cryo-EM findings support the classification of FTLD-synuclein as a subtype of MSA, differentiating it from genetic synucleinopathies, such as those with SNCA variants G51D and A53E, which have neuropathological features overlapping with MSA and Lewy body diseases. These cases expand the clinicopathological spectrum of MSA and FTLD and have implications for our understanding of selective neuronal vulnerability in MSA and the interpretation of α-synuclein biomarker studies.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70013"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11937994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143710730","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":"Enhancing Lateral Resolution Using Two-Colour Direct Stochastic Optical Reconstruction Microscopy to Unravel Synaptic Tau Pathology in Alzheimer's Disease.","authors":"Érika Sánchez-Aced, Borja Moya-Llamas, Joaquim Aumatell Escabias, Soraya Torres, Martí Colom-Cadena, Jordi Pegueroles, Cristian de Quintana-Schmidt, Àlex Bayés, Laura Molina-Porcel, Iban Aldecoa, Olivia Belbin, Juan Fortea, Tara Spires-Jones, Sílvia Pujals, Sònia Sirisi, Alberto Lleó","doi":"10.1111/nan.70010","DOIUrl":"10.1111/nan.70010","url":null,"abstract":"<p><strong>Aims: </strong>In Alzheimer's disease (AD), the pathological accumulation of tau in synapses contributes to synapse dysfunction and loss. However, the small and complex structure of synapses limits the investigation when using conventional techniques. In this work, we describe the combination of array tomography (AT) with two-colour direct stochastic optical reconstruction microscopy (dSTORM) to enhance lateral resolution for resolving synaptic terminals in human postmortem brain.</p><p><strong>Methods: </strong>We applied this combination to study synapses in brain samples (from biopsy and postmortem) from healthy subjects and pathological synaptic tau (aggregates and oligomers) in samples from AD patients.</p><p><strong>Results: </strong>AT combined with dSTORM allowed the characterisation of the orientation and shape of the synaptic terminals and the synaptic cleft. In addition, this combination confirmed the presence of oligomeric tau in synaptic terminals in AD.</p><p><strong>Conclusions: </strong>Overall, we found that the combination of AT and two-colour dSTORM provides optimal resolution to detect pathological synaptic tau and its spatial relationship with presynaptic and postsynaptic terminals.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70010"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537473","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PLAG-Family Amplified CNS Embryonal Tumour With PLAG1 Immunohistochemical Expression: Expanding the Spectrum of Diagnostic Tools.","authors":"Antonio d'Amati, Flavia Adotti, Francesca Gianno, Domenico Cicala, Eugenio Covelli, Giuseppe Cinalli, Vittoria D'Onofrio, Maria Elena Errico, Lucia Quaglietta, Sabina Barresi, Sabrina Rossi, Evelina Miele, Manila Antonelli","doi":"10.1111/nan.70017","DOIUrl":"https://doi.org/10.1111/nan.70017","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70017"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11984066/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014052","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":"Glial Alterations in the Glutamatergic and GABAergic Signalling Pathways in a Mouse Model of Lafora Disease, a Severe Form of Progressive Myoclonus Epilepsy.","authors":"Rosa Viana, Teresa Rubio, Ángela Campos-Rodríguez, Pascual Sanz","doi":"10.1111/nan.70009","DOIUrl":"10.1111/nan.70009","url":null,"abstract":"<p><strong>Aims: </strong>Lafora disease (LD; OMIM#254780) is a rare form of progressive myoclonus epilepsy characterised by the accumulation of insoluble deposits of glycogen in the brain and peripheral tissues. In mouse models of LD, we have identified neuroinflammation as a secondary hallmark of the disease, characterised by increased levels of reactive astrocytes and activated microglia. Our previous work demonstrated that the TNF and IL-6 inflammatory signalling pathways are the primary drivers of this neuroinflammatory phenotype. In this work, we aimed to investigate whether TNF and IL-6 pathway activation contributes to alterations in the glutamatergic and GABAergic signalling pathways.</p><p><strong>Methods: </strong>We performed immunofluorescence and western blot analyses on the hippocampus of a mouse model of LD to evaluate potential changes in proteins associated with glutamatergic and GABAergic signalling pathways.</p><p><strong>Results: </strong>Our findings reveal dysregulation in the expression of subunits of excitatory glutamatergic receptors (phospho-GluN2B and GluK2), as well as an increase in the levels of the GABA transporter GAT1. In addition, we detected activated forms of the Src and Lyn protein kinases in the hippocampus. More importantly, these alterations predominantly occur in nonneuronal cells, such as reactive astrocytes and microglia, underscoring the critical involvement of glial cells in the pathophysiology of LD.</p><p><strong>Conclusions: </strong>The observed upregulation of glutamatergic receptor subunits likely amplifies excitatory glutamatergic signalling, whereas the increased expression of GAT1 may reduce the inhibitory GABAergic tone. These changes contribute to the characteristic hyperexcitability of LD.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70009"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143542555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pathological Characterisation of Posterior Cortical Atrophy in Comparison With Amnestic Alzheimer's Disease.","authors":"Z Abdi, K X Yong, J M Schott, A Gatt, T Revesz, S J Crutch, T Lashley","doi":"10.1111/nan.70007","DOIUrl":"10.1111/nan.70007","url":null,"abstract":"<p><strong>Aims: </strong>Posterior cortical atrophy (PCA) is a predominantly young-onset neurodegenerative syndrome, typically caused by Alzheimer's disease (PCA-AD). PCA-AD presents with visual and spatial dysfunction attributed to occipito-parietal or 'posterior' brain regions rather than memory difficulties characteristic of typical amnestic-led Alzheimer's disease (a-AD) attributed to medial temporal regions. Imaging and neuropathological studies suggest that PCA-AD is associated with a more posterior distribution of tau neurofibrillary tangles (NFTs), whereas β-amyloid pathology (Aβ) is diffusely deposited throughout the cortex. This study characterised the neuropathological substrates of PCA-AD in comparison with a-AD, to further understanding of the biological basis of phenotypical heterogeneity in AD.</p><p><strong>Methods: </strong>Immunohistochemistry for Aβ; tau; the microglial markers CD68, CR3-43 and Iba1; α-synuclein; and TDP-43 was carried out on 26 PCA-AD and 27 age and gender-matched a-AD cases at the Queen Square Brain Bank. Aβ, tau and the three microglial markers were quantified in the superior frontal, superior temporal, superior parietal and occipital (primary visual cortex) cortices, with α-synuclein and TDP-43 assessed using formal staging criteria. In addition, microglial circularity, a morphological indicator of microglial activation state, was calculated.</p><p><strong>Results: </strong>There was a higher load of Aβ and tau in the parietal region of PCA-AD compared to a-AD. In the PCA-AD compared to the a-AD group, there were significant increases in tau load in parietal and frontal relative to temporal regions. There was no difference in cerebral amyloid angiopathy (CAA) severity between PCA-AD and a-AD. There was a significantly lower temporal CD68 load in a-AD compared with PCA-AD. In a-AD, CD68 load was lowest and tau load highest in the temporal relative to all other regions.</p><p><strong>Conclusions: </strong>This study demonstrates differences in the distribution of Aβ and tau and variations in regional neuroinflammatory response in PCA-AD and a-AD. These findings extend our understanding of the biological substrates underpinning PCA-AD and highlight the potential for exploring phenotypic variants to understand selective vulnerability in neurodegenerative diseases.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70007"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11964714/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772940","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":"Refining Muscle Morphometry Through Machine Learning and Spatial Analysis.","authors":"Daisuke Ono, Honami Kawai, Hiroya Kuwahara, Takanori Yokota","doi":"10.1111/nan.70012","DOIUrl":"10.1111/nan.70012","url":null,"abstract":"<p><strong>Aims: </strong>Muscle morphology provides important information in differentiating disease aetiology, but its measurement remains challenging because of the lack of an efficient and objective method. This study aimed to quantitatively refine the morphological features of muscle fibres in neuromuscular diseases using machine learning.</p><p><strong>Methods: </strong>In this retrospective study, we analysed muscle biopsy specimens on haematoxylin and eosin-staining. Machine learning-based software was developed to segment muscle fibre contours and perform automated muscle morphometry and subsequent graph theory-based spatial analysis of atrophied fibre grouping. A decision tree-based framework, LightGBM, was trained to predict underlying aetiologies based on morphometric and spatial variables.</p><p><strong>Results: </strong>The study included 100 muscle samples, including 20 normal muscles, 49 myopathies and 19 neuropathies. The fine-tuned segmentation model, YOLOv8, achieved a mask average precision of 0.819. The muscle morphometry revealed the significance of fibre circularity. The mean circularity was higher in the myopathy group, and the SD of circularity was elevated in the neuropathy group. Although most cases were consistent with textbook findings, atypical presentations, such as dermatomyositis with angular atrophy and amyotrophic lateral sclerosis with round atrophy, were objectively documented. Spatial analysis quantified grouped atrophy, showing the potential to feature specific atrophy patterns. The LightGBM model successfully predicted the final clinical diagnosis of the myopathies and neuropathies with an accuracy of 0.852, which exceeded that of 0.808 by human annotation.</p><p><strong>Conclusion: </strong>Automated muscle morphometry and spatial analysis provide quantification of muscle morphology and patterns of atrophy, which will facilitate objective and efficient investigation of neuromuscular diseases.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70012"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143692749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Atrophy and Higher Levels of Inflammatory-Related Markers in the Posterior Cerebellar Lobe Cortex in Chronic Alcohol Use Disorder: A Cross-Sectional Study.","authors":"Fernando García-Dolores, Mirielle Adelina Hernández-Torres, Estefania Fuentes-Medel, Alfonso Díaz, Jorge Guevara, Eduardo Baltazar-Gaytan, Leonardo Aguilar-Hernández, Humberto Nicolini, Julio César Morales-Medina, Sonia Irais González-Cano, Fidel de la Cruz, Alicia Gil-Velazco, Hiram Tendilla-Beltrán, Gonzalo Flores","doi":"10.1111/nan.70011","DOIUrl":"10.1111/nan.70011","url":null,"abstract":"<p><strong>Aims: </strong>Alcohol use disorder (AUD) involves excessive and chronic ethanol consumption, leading to various health issues, including cerebellar atrophy. The cerebellum is particularly susceptible to ethanol-induced damage through neuroinflammation, oxidative stress and excitotoxicity. This damage has been documented predominantly in the anterior lobe, primarily due to its role in motor function, which is often impaired in patients with AUD. However, less is known about the impact of AUD on the posterior cerebellar lobes. In contrast, alterations in the posterior lobe have been associated with cerebellar cognitive affective syndrome (CCAS). Moreover, the cerebellum is an asymmetric structure with spatial functions being left-lateralised. We hypothesised that the posterior cerebellar lobe in AUD cases would show increased inflammation compared with healthy controls.</p><p><strong>Methods: </strong>This cross-sectional study examined the structural integrity and neuroinflammatory state of the left posterior cerebellar lobe cortex in post-mortem samples from nine males with chronic AUD and 9 control cases.</p><p><strong>Results: </strong>Chronic AUD cases showed significant cerebellar damage. Immunohistochemistry revealed higher levels of reactive astrogliosis (GFAP), increased T_reg cell markers (CD45 and FOXP3), increased mitochondria marker (MitoTracker^TM), elevated COX2 (indicating inflammation and T_reg cell activity), increased cFos protein (cell activity marker), and higher caspase 3 (Casp3) levels, suggesting excessive cell death. These findings indicate that chronic AUD leads to atrophy in the left posterior cerebellar lobe cortex due to neuroinflammation driven by reactive astrogliosis, T_reg cell infiltration, and COX2 activity.</p><p><strong>Conclusions: </strong>The study highlights the inflammatory consequences of chronic AUD, potentially linked to cerebellar atrophy and subsequent motor and cognitive impairments. Targeting neuroinflammation could help mitigate the neurodegenerative effects of chronic AUD.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70011"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143720786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intramuscular Nerve Bundles Reflect TDP-43 Pathology in the Medulla and Spinal Cord of ALS Patients.","authors":"Takashi Kurashige, Tomomi Murao, Yuhei Kanaya, Yoriko Dodo, Tomohito Sugiura, Kazuya Kuraoka, Tomohiko Ohshita","doi":"10.1111/nan.70016","DOIUrl":"10.1111/nan.70016","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 2","pages":"e70016"},"PeriodicalIF":4.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11974360/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143796021","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}