Neuropathology and Applied Neurobiology最新文献

{"title":"Enhancing the Performance of a Blood-Based Diagnostic Screening Tool for Dysferlinopathy: Optimising an Immunoassay Across Continents.","authors":"G D'Este, D Cox, L Maistrello, S S Emmons, P Gaitonde, R Dastur, R Barresi","doi":"10.1111/nan.70060","DOIUrl":"10.1111/nan.70060","url":null,"abstract":"<p><strong>Aims: </strong>Dysferlin, a 237-kDa protein crucial for muscle function, is deficient in dysferlinopathy, a rare form of muscular dystrophy caused by recessive mutations in the DYSF gene. While genetic analysis is the primary diagnostic approach, protein-based studies remain essential for confirming pathogenicity, particularly for variants of uncertain significance. This study aims to validate an immunohistochemical assay for dysferlin detection in neutrophils from peripheral blood films (PBF) and to evaluate how different storage conditions affect its performance, with particular focus on refining variables that may affect assay reliability and reproducibility.</p><p><strong>Methods: </strong>We performed a follow-up assessment of a new immunoassay to detect dysferlin expression in neutrophils from PBFs, using samples from genetically confirmed dysferlinopathy patients and healthy controls in an Indian cohort.</p><p><strong>Results: </strong>The assay exhibited very high sensitivity, but its specificity was affected by sample quality and storage conditions. Protein degradation occurred in samples stored at room temperature in environments exceeding 30°C, while storage at 4°C preserved dysferlin immunoreactivity for up to 20 weeks.</p><p><strong>Conclusions: </strong>The PBF-based dysferlin assay is a rapid, cost-effective and minimally invasive screening tool, well-suited for use in resource-limited settings. It provides a viable approach for initial screening and variant assessment. As the assay's reliability is influenced by sample quality and storage conditions, proper training in collection techniques and strict adherence to storage protocols are essential for ensuring diagnostic accuracy and enabling broader clinical application.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70060"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12851850/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146093498","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":"Diagnostic Alteration Is Not Therapeutic Dependency: Lessons From Failed RET Inhibition in a PLAG-Altered CNS Embryonal Tumour.","authors":"Stjepan Škudar","doi":"10.1111/nan.70088","DOIUrl":"10.1111/nan.70088","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 4","pages":"e70088"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352757","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":"Proceedings of the 127th Meeting of the British Neuropathological Society 28-30 January 2026, London, UK.","authors":"","doi":"10.1111/nan.70050","DOIUrl":"https://doi.org/10.1111/nan.70050","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 Suppl 1 ","pages":"e70050"},"PeriodicalIF":3.4,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065635","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":"Cortical Layer-Specific Remodelling of Parvalbumin and Perineuronal Net Networks in Alcohol Use Disorder.","authors":"Tamsin Karas, Asheeta A Prasad","doi":"10.1111/nan.70066","DOIUrl":"10.1111/nan.70066","url":null,"abstract":"<p><strong>Background: </strong>Alcohol use disorder (AUD) is a chronically relapsing condition marked by a pathological shift in behaviour, where excessive motivational drive predominates over cognitive control. Brodmann area 6 (BA6) is a key cortical region that integrates cognitive control with motor output and striatal circuits. Cellular alterations in the BA6 can shift from flexible, goal-directed planning to habitual, compulsive behaviours.</p><p><strong>Method: </strong>Here, we examined cellular changes in the human post-mortem cortex from AUD cases (n = 9) and age-matched controls (n = 10). The density of parvalbumin (PV) neurons and perineuronal nets (PNN) was analysed from immunofluorescent-stained sections. The number of PV neurons, PNN-positive cells, and PV neurons colocalised with PNN across cortical layers II-VI in BA6 regions was quantified.</p><p><strong>Results: </strong>Across layers II/VI, the density of PV neurons and PNN was similar in the control and AUD groups, indicative of no cellular loss in the BA6. Analysis of the colocalisation of PV neurons with PNN revealed no effect in layers II/III (p = 0.720). However, there was a significant increase in colocalisation of PV neurons with PNN in layers IV (p = 0.043) and V/VI (p = 0.025) in the AUD compared to the control group.</p><p><strong>Conclusion: </strong>This study reveals layer-specific remodelling of PNN and PV networks in the human cortex in AUD cases, suggesting shifts in AUD behaviours are potentially attributed to PV neuronal activity regulated by PNN in specific cortical layers. Together, this study identifies AUD-related neuropathology and provides insight into the mechanisms underlying persistent alcohol-seeking behaviour.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70066"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12872299/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119557","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":"Respone to Škudar.","authors":"King David, Keck Michaela-Kristina","doi":"10.1111/nan.70089","DOIUrl":"10.1111/nan.70089","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 4","pages":"e70089"},"PeriodicalIF":3.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13428381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148352712","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":"Correction to \"Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System\".","authors":"","doi":"10.1111/nan.70047","DOIUrl":"10.1111/nan.70047","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 6","pages":"e20004"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12862672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431840","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":"Central Nervous System Kinase-Altered Spindle Cell Neoplasm: A Case Series of an Emerging Tumour Type.","authors":"Faizan Malik, Julieann C Lee, Soniya Pinto, Maria Cardenas, Melanie Hakar, Matthew D Wood, Amy Smith, Samuel Hwang, Aditi Bagchi, Paul C Klimo, Lu Wang, David W Ellison","doi":"10.1111/nan.70048","DOIUrl":"10.1111/nan.70048","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 6","pages":"e70048"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669165","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":"Neuropathological Characterisation of McLeod Syndrome With a Proposed New Grading System.","authors":"Anna Maria Reuss, Klavs Renerts, Tibor Hortobágyi, Felix Geser, Johannes Haybaeck, Adrian Danek, Peter Fuhr, Bjarne Udd, Adam Zeman, Reichard R Ross, Elisabeth J Rushing, Hans H Jung","doi":"10.1111/nan.70039","DOIUrl":"10.1111/nan.70039","url":null,"abstract":"<p><strong>Aims: </strong>X-linked McLeod neuroacanthocytosis syndrome (MLS) is a rare neurodegenerative disorder characterised by the presence of red blood cell acanthocytosis and a chorea syndrome. Analogous to Huntington's disease (HD), MLS displays cognitive and behavioural symptoms besides the progressive movement disorder. This study aimed to describe the neuropathology of MLS in the largest case series to date.</p><p><strong>Methods: </strong>Clinical data were collected, and neuropathological assessments were performed on eight male MLS patients originating from Finland, New Zealand, Switzerland, Scotland and the United States.</p><p><strong>Results: </strong>Macroscopic data were available from six patients, with five showing atrophy of the basal ganglia, which was more pronounced in the caudate nucleus and to a lesser extent in the putamen and pallidum. Histology revealed neuronal loss and accompanying gliosis in the basal ganglia of all patients. The extent of these alterations varied widely, with a decreasing gradient of severity from the caudate nucleus to the putamen and the pallidum, mirroring the macroscopic findings. In addition, we detected intraneuronal vacuoles in the striatum in half of the patients.</p><p><strong>Conclusions: </strong>MLS neuropathology is characterised macroscopically by atrophy and microscopically by neuronal loss and gliosis of the basal ganglia, with a decreasing gradient of severity from the caudate nucleus, the putamen to the pallidum. Analogous to the grading system for HD, we propose a neuropathological grading system for MLS based on the current observations in the largest MLS cohort examined to date. Standardised criteria are crucial for neuropathological assessment of this extremely rare disease.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 5","pages":"e70039"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12547491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144962522","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":"A Variant of OTUD3 in Early-Onset Parkinsonism.","authors":"S Rehan Ahmad, Nazim Nasir, Anupriya Kumari, Atiq Ul Hassan","doi":"10.1111/nan.70046","DOIUrl":"10.1111/nan.70046","url":null,"abstract":"<p><p>Early-onset Parkinsonism is a neurodegenerative disorder that can arise from rare genetic variants. We report a 21-year-old female proband with progressive bradykinesia, symmetrical rigidity, resting tremors, postural instability, executive dysfunction, and behavioural disturbances. Brain MRI revealed asymmetric thinning of the substantia nigra pars compacta, consistent with dopaminergic neuronal loss in early-onset Parkinsonism. Exome sequencing identified a novel homozygous missense variant in OTUD3 (c.559C>T; p.Arg187Trp), ultra-rarely present as a heterozygous allele in gnomAD and absent in ClinVar, and inherited in an autosomal recessive manner. The substituted arginine at position 187 lies within a β-sheet of the highly conserved OTU deubiquitinase domain. In silico predictions classified the variant as deleterious, disease-causing, and structurally destabilising. Molecular dynamics simulations additionally predicted R187W-induced destabilisation, including increased backbone flexibility, loss of hydrogen bonding, solvent exposure of the hydrophobic tryptophan residue, and partial collapse of the catalytic domain. In proband-derived fibroblasts, OTUD3-R187W exhibited cytosolic aggregation and failed to regulate its substrate IRP2, resulting in IRP2 accumulation and intracellular iron overload. These cells also showed increased cell death. OTUD3 protein interaction networks and gene ontology analyses revealed involvement in ubiquitin signalling, cytoskeletal organisation, and transcriptional regulation. Together, these data demonstrate that the OTUD3-R187W variant compromises structural integrity and cellular function, contributing to early-onset Parkinsonism. This study implicates OTUD3 as a novel gene linked to neurodegeneration and highlights its role in maintaining midbrain neuronal integrity.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 5","pages":"e70046"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145377884","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":"Quantification of Exercise-Induced Sarcomeric Damage in R349P Desmin Knock-In Mice: A New Approach in Myofibrillar Myopathy Research.","authors":"Christian Holtzhausen, Dorothea Schultheis, Carolin Berwanger, Julia Schuld, Ursula Schlötzer-Schrehardt, Marion Riehl-Nestler, Sabrina Batonnet-Pichon, Alain Lilienbaum, Esther Mahabir, Peter F M van der Ven, Dieter O Fürst, Rolf Schröder, Christoph S Clemen","doi":"10.1111/nan.70038","DOIUrl":"10.1111/nan.70038","url":null,"abstract":"<p><strong>Aims: </strong>The classical morphological hallmarks of the clinically and genetically diverse group of human myofibrillar myopathies are signs of myofibrillar degeneration and desmin-positive protein aggregates. The local sarcomeric enrichment of filamin-C and xin actin-binding repeat-containing proteins 1 and 2 (xirp 1 and xirp 2) is a marker of myofibrillar damage. This work aimed to (i) address filamin-C- and xirp 1/2-positive sarcomeric lesions in desminopathy mouse models, (ii) develop an approach to quantifying xirp 1/2-positive sarcomeric lesions, and (iii) study the effects of acute physical exercise on sarcomeric lesion formation in R349P desmin knock-in mice, which are a model of human R350P desminopathy.</p><p><strong>Methods: </strong>Sarcomeric lesions were visualised by xirp 1/2 and filamin-C immunofluorescence in soleus muscles from R349P and R405W desmin knock-in, desmin knock-out and W2711X filamin-C knock-in mice. The open-source software QuPath was used to analyse xirp 1/2 confocal immunofluorescence images of soleus muscle from nonexercised and treadmill-exercised R349P desmin knock-in mice.</p><p><strong>Results: </strong>Filamin-C and xirp 1/2 stained muscles revealed the presence of congenerous sarcomeric lesions in heterozygous and homozygous R349P and R405W desmin knock-in, homozygous desmin knock-out and heterozygous and homozygous W2711X filamin-C knock-in mice. Quantitative analysis of R349P desmin knock-in mice showed (i) significantly more lesions in nonexercised heterozygous mice, with an even more pronounced increase in homozygous animals, as compared to wild-type, and (ii) a significant increase in sarcomeric lesions per mm² in heterozygous mice and wild-type siblings subjected to strenuous treadmilling.</p><p><strong>Conclusions: </strong>A QuPath workflow to quantify sarcomeric lesions using xirp 1/2 immunofluorescence images showed augmented densities of lesions in R349P desminopathy mice and after treadmill exercise. Eccentric and high-intensity physical activity may exhibit a disease-promoting effect on skeletal muscles in desminopathy.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"51 5","pages":"e70038"},"PeriodicalIF":3.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12433831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145065298","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}