Neuropathology and Applied Neurobiology最新文献

{"title":"CNS Embryonal Tumour With PLAG Family Gene Alteration: Failure of Response to RET Inhibition.","authors":"David King, Annika Schneider, Bernhard Küster, David T W Jones, Daniel J A Connolly, Stephen Wharton, Michaela-Kristina Keck","doi":"10.1111/nan.70076","DOIUrl":"https://doi.org/10.1111/nan.70076","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 2","pages":"e70076"},"PeriodicalIF":3.4,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147691254","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":"Challenge of Diagnostic Criteria for Diffuse Hemispheric Glioma (DHG), H3 G34-Mutant: A Case of DHG Without H3.3 Gene Alteration.","authors":"Tianran Hu, Xiaojia Liu, Yang Lan, Jia Ge, Lihong Wang, Jiao Wang, Sen Wei, Hong Chen, Tao Luo","doi":"10.1111/nan.70073","DOIUrl":"10.1111/nan.70073","url":null,"abstract":"<p><p>We present a case of diffuse hemispheric glioma (DHG), H3 G34-mutant, NEC. Postoperative histological examination and DNA sequencing detected some features consistent with DHG, H3 G34-mutant; however, no canonical H3 alterations or ATRX variants were detected. The diagnosis could only be established based on the DNA methylation profiling result. In light of these distinctive molecular findings, we propose some insights into the current WHO diagnostic criteria for DHG H3-G34 and emphasise the value of comprehensive molecular diagnosis.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 2","pages":"e70073"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147623425","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":"Commitment to Myogenic Differentiation Significantly Aggravates the RNA Phenotype in Myotonic Dystrophy Type 1.","authors":"Lise Ripken, Walther J A A van den Broek, Remco T P van Cruchten, Jos G A Smits, Tabea V Riepe, Peter A C 't Hoen, Derick G Wansink","doi":"10.1111/nan.70069","DOIUrl":"10.1111/nan.70069","url":null,"abstract":"<p><strong>Aims: </strong>Myotonic dystrophy type 1 (DM1) is a severe neuromuscular disorder classified as a spliceopathy, caused by a (CTG)n repeat expansion in the 3' UTR of the DMPK gene. The expansion in DMPK transcripts sequesters key splicing regulators of the MBNL family, leading to dysregulated alternative splicing. DM1 presents heterogeneous symptoms, with prevalent muscle weakness and myotonia, highlighting the need to understand its impact on the myogenesis process in more detail. This study aims to understand the impact of myotonic dystrophy type 1 (DM1) on myogenesis by investigating RNA expression during the differentiation of DM1 and isogenic CRISPR/Cas9-corrected DM∆ myoblast cell lines into myotubes.</p><p><strong>Methods: </strong>RNA samples were collected at various stages of myogenesis from DM1 and control DM∆ myoblast cell lines. Gene expression patterns and alternative splicing signatures were analysed using high-coverage sequencing.</p><p><strong>Results: </strong>Proliferating myoblasts exhibited a mild phenotype, with only a few differentially expressed genes and aberrant splicing events. However, upon commitment to fusion in differentiating cultures, there was a marked increase in differentially expressed genes between DM1 and corrected cells, particularly those related to muscle function and ion transport. Notably, aberrant alternative splicing, enriched for MBNL1 binding motifs, aggravated during differentiation, affecting genes associated with muscle organization, contraction and cell junctions.</p><p><strong>Conclusions: </strong>These findings highlight that the disturbance of myogenesis becomes particularly evident upon commitment to differentiation, emphasising the critical role of differentiation- and MBNL1-dependent splicing throughout myogenesis.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 2","pages":"e70069"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12997521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147474819","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":"Lipofuscin Accumulation in Dysmorphic Neurons in FCDIIa Focal Epilepsy: A Case Report and Literature Review.","authors":"Rita Garbelli, Dalia De Santis, Cinzia Cagnoli, Laura Rossini, Gianluca Marucci, Fabio Martino Doniselli, Valeria Cuccarini, Michele Rizzi, Ester Cifaldi, Rachele Colombo, Annalisa Parente, Barbara Castellotti, Elena Freri, Giuseppe Didato, Francesco Deleo, Giulia Battaglia, Marco de Curtis, Roberta Di Giacomo","doi":"10.1111/nan.70061","DOIUrl":"10.1111/nan.70061","url":null,"abstract":"<p><p>We describe the case of a 29-year-old woman with focal drug-resistant epilepsy and an unusual Focal Cortical Dysplasia (FCD) IIa with lipofuscin accumulation in dysmorphic neurons. We discuss the commonalities and discrepancies between the present case and FCDIIa cases without lipofuscin accumulation at the clinical, histopathological and proteomic levels. (a) Coronal 3D-FLAIR imaging demonstrates an unusually deep F1-F2 sulcus associated with subtle signal alteration (arrowhead). (b) Coronal FDG-PET coregistered with T1 3D MRI reveals marked hypometabolism of the same sulcus (arrowhead). (c-f) Histological images of the surgical specimen show numerous dysmorphic neurons (DN), a typical hallmark of FCD type IIa. Notably, DN (green arrows) exhibit cytoplasmic PAS-positive granular material identified as lipofuscin (c), neurofilament accumulation with peculiar 'ring-like' aspect (d,e) and occasional ubiquitin-binding protein p62 labelling (f). (g-h) Matrix-assisted laser desorption/ionisation imaging mass spectrometry (MALDI-IMS) further supports differences at proteomic level between the present case and classic FCDIIa without lipofuscin accumulation.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70061"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119590","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":"Myopathy With Exercise-Induced Intolerance due to Novel Biallelic Variants in OBSCN-A Clinical, Morphological and Molecular Analysis.","authors":"Heidrun H Krämer-Best, Marlen C Reis, Andreas Hentschel, Michaela Weiß, Alexander Schaiter, Klaus-Dieter Böhm, Andreas Roos, Dagmar Nolte, Anne Schänzer","doi":"10.1111/nan.70065","DOIUrl":"10.1111/nan.70065","url":null,"abstract":"<p><p>The phenotype of OBSCN variants consists of exercise intolerance ranging from myalgia and cramps to rhabdomyolysis. Symptoms are mainly induced by high-intensity sports. Molecular analysis showing a deregulation of muscle processes associated with Ca²⁺ regulation, extrasarcolemmal integrity and autophagy emphasised the critical role of obscurin in skeletal muscle function.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70065"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12877425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125545","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":"Truncating GAS6 Variant Disrupts Neuroglial Homeostasis in a Childhood-Onset Demyelinating Disorder.","authors":"Diksha, Abhishek Kumar, Vishal Gaurav, Yogendra Pratap Mathuria, Shailesh Kumar Gupta, Debasish Kumar Ghosh","doi":"10.1111/nan.70063","DOIUrl":"10.1111/nan.70063","url":null,"abstract":"<p><p>Growth arrest-specific 6 (GAS6) protein is required for cell survival through its role in TAM receptor signalling. Here, we investigate a novel autosomal recessive demyelinating disorder in a 9-year-old male presenting with progressive motor dysfunction, spasticity, seizures and cognitive decline. MRI revealed multifocal T2/FLAIR hyperintensities in periventricular, juxtacortical and brainstem white matter regions. Exome sequencing uncovered a homozygous stop-gain variant in GAS6 (c.444G>A; p.Trp148Ter). The variant results in nonsense-mediated decay and loss of protein expression and secretion. Functional assays in patient fibroblasts and HOG oligodendrocytes showed downregulation of neurotrophic and myelin-related genes (NTRK2, CNTF, EGR1, MBP, PLP), defective oligodendrocyte-process formation and increased G₀/G₁ cell cycle arrest. Rescue experiments confirmed that wild-type GAS6, but not the truncated variant, restored cellular function. These findings establish GAS6 as a critical regulator of neuro-glial homeostasis and identify its deficiency as the cause of a previously unreported childhood-onset demyelinating disease.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70063"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146086561","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":"Evaluating Basigin as a Potential Biomarker of Blood-Brain Barrier Dysfunction in Cerebral Amyloid Angiopathy.","authors":"Arno Stellingwerf, Davita Bosveld, Lieke Jäkel, Anna M De Kort, Benno Küsters, Catharina J M Klijn, Floris H B M Schreuder, H Bea Kuiperij, Marcel M Verbeek","doi":"10.1111/nan.70064","DOIUrl":"10.1111/nan.70064","url":null,"abstract":"<p><strong>Aims: </strong>Blood-brain barrier (BBB) dysfunction may be involved in the pathophysiology of neurodegenerative disorders, including sporadic cerebral amyloid angiopathy (CAA). Because basigin (BSG) may induce activity of matrix metalloproteinases and thereby BBB breakdown, we investigated BSG expression in CAA brain tissue with immunohistochemistry and as cerebrospinal fluid biomarker for BBB dysfunction in patients with CAA.</p><p><strong>Methods: </strong>Using immunohistochemistry, we quantified BSG expression within the cortical microvasculature of the temporal lobe of 50 CAA patients (16 with intracerebral haemorrhage [CAA-ICH] and 34 without intracerebral haemorrhage [CAA-NH]) and 35 controls. To investigate whether BSG is expressed at another brain barrier, choroid plexus tissue was qualitatively assessed. Additionally, we compared cerebrospinal fluid levels of BSG between 40 CAA patients and 27 healthy controls using ELISA.</p><p><strong>Results: </strong>Cortical vessels, in particular capillaries, were positive for BSG. Median %area of BSG expression was increased in CAA cases (1.02%, IQR [0.63-1.68]) compared with controls (0.65%, IQR [0.43-1.01], p = 0.013). Moreover, we observed more BSG staining in CAA-NH (1.23%, IQR [0.90-2.0]) than in CAA-ICH (0.58%, IQR [0.24-1.00], p = 0.001) and controls (p < 0.001). Choroid plexus epithelial cells showed apical BSG expression, whereas endothelial cells were negative. The median BSG concentration in CSF was decreased in CAA (11.0 ng/mL, IQR [10.1-13.8]) compared with controls (13.00 ng/mL, IQR [11.5-14.5], p = 0.02).</p><p><strong>Conclusions: </strong>CSF concentrations of BSG may be related to altered expression at the BBB; the BSG concentrations in CSF may thus serve as a biomarker of BBB function, although a contribution of choroid plexus epithelial BSG cannot be entirely excluded. Independent cohorts are needed to replicate these observations before we can conclude that reduced CSF concentrations of BSG may indicate an alteration of the BBB in patients with CAA.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70064"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12916252/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146219135","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":"G Protein-Coupled Receptor 32 Contributes to Inflammation Resolution and Neuronal Excitability Dysfunction in Patients With Focal Cortical Dysplasia IIb and Tuberous Sclerosis Complex.","authors":"Kaixuan Huang, Jie Li, Zeng He, Yang Li, Xingye Liu, Yuhe Wan, Xiaolin Yang, Dongxue Sang, Shujing Li, Zhongke Wang, Shiyong Liu","doi":"10.1111/nan.70062","DOIUrl":"10.1111/nan.70062","url":null,"abstract":"<p><strong>Background: </strong>Focal cortical dysplasia IIb (FCDIIb) and tuberous sclerosis complex (TSC) show persistent neuroinflammation that promotes epileptogenesis and epilepsy progression, suggesting that endogenous resolution of inflammation is inadequate to relieve neuronal network hyperexcitability. G-protein-coupled receptor 32 (GPR32) is a key regulator of inflammation resolution and we aimed to explore the roles of GPR32 in cortical lesions of patients with FCDIIb and TSC.</p><p><strong>Method: </strong>We examined the expression and distribution of GPR32 in patients with FCDIIb and TSC and its effects on human microglial cell activation, inflammation and the electrophysiological properties of neurons.</p><p><strong>Results: </strong>GPR32 and Resolvin D1 expression was significantly lower in cortical lesions of patients with FCDIIb and TSC than in controls and were negatively correlated with seizure frequency. GPR32 was widely distributed in neurons and microglia and was nearly absent in astrocytes. Furthermore, the Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) pathway was downregulated in patients with FCDIIb and TSC. The GPR32/SHP2/nuclear factor-kappa B pathway inhibited the M1 transformation of microglia to produce numerous pro-inflammatory mediators and promoted M2 polarisation. GPR32 also regulated neuronal excitability by reducing the amplitude and frequency of spontaneous excitatory postsynaptic currents.</p><p><strong>Conclusion: </strong>Our results suggest that GPR32 may help control epilepsy in patients with FCDIIb and TSC.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70062"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146046835","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":"Analyses of the Effects of Wild-Type TDP-43 Overexpression in Oxytocin Neurons in Mice.","authors":"Sofia Bergh, Oskar Simonsson, Åsa Petersén","doi":"10.1111/nan.70059","DOIUrl":"10.1111/nan.70059","url":null,"abstract":"<p><p>Selective TDP-43 overexpression in oxytocin neurons in the paraventricular nucleus of the hypothalamus causes a decrease in oxytocin-immunopositive cells compared to uninjected mice. AAV-mediated TDP-43 overexpression in oxytocin neurons does not appear to be a major driver of behavioural and metabolic phenotypes in mice.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70059"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12822521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146011358","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Diagnostic Value of Confocal Laser Endomicroscopy in Brain Tumours When Performed by Blinded, Untrained Neuropathologists.","authors":"Ilona Iff, Marielena Gutt-Will, Theoni Maragkou, Andrea Mathis, Kathleen Seidel, David Capper, Elisabeth G Hain, Jenny Meinhardt, Regina Von Manitius, Carsten Dittmayer, Simone Schmid, Ekkehard Hewer, Andreas Raabe, Philippe Schucht","doi":"10.1111/nan.70049","DOIUrl":"10.1111/nan.70049","url":null,"abstract":"<p><strong>Aim: </strong>Achieving maximal and safe tumour resection is a key goal in brain tumour surgery. Confocal laser endomicroscopy (CLE) enables real-time visualisation of the tissue microstructure at a cellular level, potentially helping neurosurgeons distinguish non-neoplastic from neoplastic tissue. The core aim of this study was to determine the baseline diagnostic accuracy that can be achieved with CLE alone, when assessed by neuropathologists without prior CLE training and without any additional clinical or contextual information, and to compare these findings to standard haematoxylin and eosin (H & E)-based histology in a blinded setting.</p><p><strong>Methods: </strong>CLE images and corresponding H & E-stained slides from 100 brain tumour patients treated at the University Hospital Bern over a 22-month period were analysed. Five blinded neuropathologists with no prior CLE experience independently evaluated the data sets.</p><p><strong>Results: </strong>Based on CLE images, neuropathologists differentiated neoplastic from non-neoplastic tissue in 70.7%. The specific tumour type was correctly identified in 47.5%: gliomas in 59.8%, meningiomas in 43.8%, and metastases in 25.7%. In contrast, H & E slides were correctly classified as neoplastic in 87.6%, with 89.1% tumour-type-level accuracy (gliomas 85.6%, meningiomas 94.6%, metastases 88.2%). Confidence levels for CLE diagnoses were generally low, and no learning curve was observed.</p><p><strong>Conclusions: </strong>CLE shows potential to distinguish between neoplastic and non-neoplastic tissue, but diagnostic accuracy remains lower than with H & E-stained slides. Training in CLE image interpretation is recommended to improve diagnostic accuracy. CLE imaging may have the potential to become a valuable tool for delineating brain tumour borders.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"52 1","pages":"e70049"},"PeriodicalIF":3.0,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12811067/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990119","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}