Acta Neuropathologica Communications最新文献

{"title":"Inflammation alters myeloid cell and oligodendroglial iron-handling in multiple sclerosis.","authors":"Christian J Riedl, Daniel Bormann, Anja Steinmaurer, Anja Novak, Giulia Testa, Elena Poldlehner, Carmen Haider, Thomas Berger, Michael Mildner, Romana Höftberger, Ferdinand Schweser, Simon Hametner","doi":"10.1186/s40478-025-02020-0","DOIUrl":"10.1186/s40478-025-02020-0","url":null,"abstract":"<p><p>Changes in brain iron levels are a consistent feature of multiple sclerosis (MS) over its disease course. They encompass iron loss in oligodendrocytes in myelinated brain regions and iron accumulation in myeloid cells at so-called paramagnetic rims of chronic active lesions. Here, we explore the mechanisms behind this overall shift of iron from oligodendrocytes (OLs) to myeloid cells (MCs) and the loss of total brain-iron in MS. We investigated the expression of various iron importers and exporters, applying immunohistochemistry to a sample of control and MS autopsy cases. Additionally, we studied the transcriptional response of iron-related genes in primary rodent OL progenitor cells (OPCs) and microglia (MG) to various combinations of known MS-relevant pro-inflammatory stimuli together with iron loading. Histologically, we identified a correlation of OL-iron accumulation and the expression of the ferritin receptor TIM1 in myelinated white matter and observed an increase in the expression of iron-related proteins in myeloid cells at the lesion rims of MS plaques. qPCR revealed a marked increase of the heme scavenging and degradation machinery of MG under IFN-γ exposure, while OPCs changed to a more iron-inert phenotype with apparent decreased iron handling capabilities under MS-like inflammatory stimulation. Collectively, our data suggest that OL iron loss in MS is mainly due to a decrease in ferritin iron import. Iron accumulation in MCs at rims of chronic active lesions is in part driven by up-regulation of heme import and metabolism, while these cells also actively export ferritin.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"124"},"PeriodicalIF":6.2,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12135419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144223974","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 comprehensive, multi-center, immunogenomic analysis of melanoma brain metastases.","authors":"Lucy Boyce Kennedy, Amanda E D Van Swearingen, Marissa R Lee, Layne W Rogers, Alexander B Sibley, Jeff Sheng, Dadong Zhang, Xiaodi Qin, Eric S Lipp, Swaminathan Kumar, Aron Joon, Pixu Shi, Michael A Davies, Kouros Owzar, Carey K Anders, April K S Salama","doi":"10.1186/s40478-025-02035-7","DOIUrl":"10.1186/s40478-025-02035-7","url":null,"abstract":"<p><strong>Background: </strong>Melanoma brain metastases (MBM) have a unique molecular profile compared to extracranial metastases (ECM). Description of the biological features and clinical outcomes of MBM will facilitate the design of rational therapies.</p><p><strong>Methods: </strong>We examined the mutational landscape and gene expression profiles of MBM (74 patients) and ECM (34 patients) in paired patient samples from a previously published dataset with whole-exome sequencing (WES) and RNA sequencing (RNAseq) data from MD Anderson Cancer Center (MDACC). We also present findings from MBM from a new cohort of 14 patients from Duke University to strengthen investigation of somatic mutations and gene expression profiles. Gene Set Enrichment Analysis (GSEA) was used to compare paired MBM versus lymph node (LN) metastases and skin metastases. Relative immune cell abundance was inferred using deconvolution methods. Survival outcomes from craniotomy and associations with biological features, BRAF mutation status, and PTEN expression were assessed.</p><p><strong>Results: </strong>GSEA found that autophagy signaling pathways are enriched in MBM versus LN and skin metastases. BRAF was the most frequently mutated clinically relevant gene in MBM and ECM, with NRAS and PTEN also frequently altered in MBM. The most strongly upregulated genes in autophagy pathways were glial fibrillary acidic protein (GFAP) and hemoglobin beta (HBB). An increased proportion of immune-suppressive M2 compared to tumor-suppressive M1 macrophages in MBM and ECM was identified. There was not sufficient evidence for an association between BRAF V600 mutation status or expression and overall survival (OS) from craniotomy.</p><p><strong>Conclusions: </strong>The mutational landscape and gene expression of MBM from the Duke cohort resembled those previously reported in the MDACC cohort. Upregulation of autophagy pathways was observed in patient-matched MBM versus LN and skin metastases due to upregulation of two genes, GFAP and HBB. In MBM, higher M2:M1 ratio may contribute to a therapeutically relevant immune-suppressive tumor microenvironment (TME).</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"123"},"PeriodicalIF":6.2,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12128383/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207344","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":"Oedematic-atrophic astrocytes in hepatic encephalopathy.","authors":"Mariusz Popek, Marta Obara-Michlewska, Łukasz Mateusz Szewczyk, Marcin Kołodziej, Karol Perlejewski, Alexei Verkhratsky, Jan Albrecht, Magdalena Zielińska","doi":"10.1186/s40478-025-02045-5","DOIUrl":"10.1186/s40478-025-02045-5","url":null,"abstract":"<p><p>Hepatic encephalopathy (HE) following acute liver failure (ALF) is considered as a primary toxic astrocytopathy, but in-depth characterisation of astrocytic contribution to the pathogenesis of this disease is far from complete. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF and post-mortem cortical tissue of patients at grade IV of HE. In both mice and post-mortem human tissues astrocytic primary branches demonstrated the territory occupied by astrocytes was increased, confirming astrocytic oedema. Astrocytic primary branches demonstrated swelling, while terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. In mice these morphological changes develop in parallel with decreased expression of proteins critical for astrocytic modelling and function: the water channel aquaporin 4 (AQP4), the phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1 (PFN1). Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in EEG power and by excessive glutamate in the brain microdialysates. We propose that HE evokes disease-specific remodelling of astrocytes to a \"mixed\", oedematic/atrophic phenotype. Concurrence of HE-specific phenotype with alterations in the expression of astrocytic proteins are a likely cause of aberrant astrocyte synaptic support resulting in severe, often fatal brain malfunction in HE.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"122"},"PeriodicalIF":6.2,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12125882/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191360","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":"Acute targeting of N-terminal tau protein has long-lasting beneficial effects in Tg2576 APP/Aβ mouse model by reducing cognitive impairment, cerebral Aβ-amyloidosis, synaptic remodeling and microgliosis later in life.","authors":"Valentina Latina, Margherita De Introna, Francesca Malerba, Rita Florio, Bijorn Omar Balzamino, Giuseppe Di Natale, Michele Francesco Maria Sciacca, Giuseppe Pappalardo, Alessandra Micera, Annabella Pignataro, Pietro Calissano, Giuseppina Amadoro","doi":"10.1186/s40478-025-02022-y","DOIUrl":"10.1186/s40478-025-02022-y","url":null,"abstract":"<p><p>Even though the number of patients suffering from Alzheimer's Disease (AD) is rapidly growing worldwide, only a few symptomatic treatments have been approved for clinical use, pointing out the urgent need for more effective disease-modifying therapies that actually alter the progression of this neurodegenerative disorder which is characterized by co-occurence of both Amyloid beta (Aβ) and tau neuropathologies. Preclinical and clinical evidence suggests that a link between Aβ and tau drives the entire continuum of AD pathobiology. 12A12 is a monoclonal antibody (mAb) which offers neuroprotection into two transgenic lines of AD, including Tg2576 that overexpresses Swedish mutation (KM670/671NL) of Amyloid Precursor Protein (APP, isoform 695) and 3xTg (APP Swedish, MAPT P301L, and PSEN1 M146V), by targeting the 20-22kDa N-terminal tau fragments (NH₂htau). In particular, acute (over 14 days with 4 doses), intravenous injection of 12A12mAb leads to significant improvement of cognitive, biochemical and histopathological AD signs in symptomatic 6-month-old Tg2576, a well-established transgenic mouse model that mimics the human amyloidosis with an age-dependent Aβ accumulation/aggregation and plaque deposition. Here, we report that Tg2576 mice, immunized with 12A12mAb at 6 months of age and returned to their home cage for additional 3 months, exhibit preserved spatial memory despite the anticipated interruption of antibody administration (discontinuous treatment). This enduring beneficial effect on memory deficit (up to 90 days after the last injection) is accompanied by normalization in the synaptic imbalance and microgliosis along with decrease of the most toxic A11-positive prefibrillar oligomers and inverse increase in 4kDa monomeric form(s) of Aβ 1-42. These findings reveal that: (i) soluble, pathogenetic tau specie(s) located at the N-terminal domain of protein early synergizes with Aβ in driving the progression of AD neuropathology; (ii) transient immunoneutralization of the NH₂htau following short-term treatment with 12A12mAb exerts preventive, long-lasting neuroprotective effects, at least in part by interfering at \"pre-plaque\" stage with the progressive deposition of insoluble, fibrillar Aβ via a shift of its aggregation pathway into its less harmful, unaggregated monomeric forms. Taken together, these findings represent a strong rationale for the advancement of 12A12mAb to clinical stage aiming at preventing the Aβ-dependent neurodegeneration by lowering the cerebral levels of NH₂htau in humans suffering from chronic, slow-progressing AD.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"121"},"PeriodicalIF":6.2,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12123992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179959","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":"Operationalizing postmortem pathology-MRI association studies in Alzheimer's disease and related disorders with MRI-guided histology sampling.","authors":"Chinmayee Athalye, Alejandra Bahena, Pulkit Khandelwal, Sheina Emrani, Winifred Trotman, Lisa M Levorse, Zahra Khodakarami, Daniel T Ohm, Eric Teunissen-Bermeo, Noah Capp, Shokufeh Sadaghiani, Sanaz Arezoumandan, Sydney A Lim, Karthik Prabhakaran, Ranjit Ittyerah, John L Robinson, Theresa Schuck, Edward B Lee, M Dylan Tisdall, Sandhitsu R Das, David A Wolk, David J Irwin, Paul A Yushkevich","doi":"10.1186/s40478-025-02030-y","DOIUrl":"10.1186/s40478-025-02030-y","url":null,"abstract":"<p><p>Postmortem neuropathological examination, while the gold standard for diagnosing neurodegenerative diseases, often relies on limited regional sampling that may miss critical areas affected by Alzheimer's disease and related disorders. Ultra-high resolution postmortem MRI can help identify regions that fall outside the diagnostic sampling criteria for additional histopathologic evaluation. However, there are no standardized guidelines for integrating histology and MRI in a traditional brain bank. We developed a comprehensive protocol for whole hemisphere postmortem 7T MRI-guided histopathological sampling with whole-slide digital imaging and histopathological analysis, providing a reliable pipeline for high-volume brain banking in heterogeneous brain tissue. Our method uses patient-specific 3D printed molds built from postmortem MRI, allowing standardized tissue processing with a permanent spatial reference frame. To facilitate pathology-MRI association studies, we created a semi-automated MRI to histology registration pipeline and developed a quantitative pathology scoring system using weakly supervised deep learning. We validated this protocol on a cohort of 29 brains with diagnosis on the AD spectrum that revealed correlations between cortical thickness and phosphorylated tau accumulation. This pipeline has broad applicability across neuropathological research and brain banking, facilitating large-scale studies that integrate histology with neuroimaging. The innovations presented here provide a scalable and reproducible approach to studying postmortem brain pathology, with implications for advancing diagnostic and therapeutic strategies for Alzheimer's disease and related disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"120"},"PeriodicalIF":6.2,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12121285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144172175","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":"Therapeutic potential of NGF-enriched extracellular vesicles in modulating neuroinflammation and enhancing peripheral nerve remyelination.","authors":"Hancheol Yeo, Yoo Jung Kim, Jaekwon Seok, Yeonjoo Kwak, Soo Bin Jang, Na Hee Lim, Kwonwoo Song, Junghoon Lee, Min Chul Cho, Soo Woong Kim, Ssang-Goo Cho","doi":"10.1186/s40478-025-02033-9","DOIUrl":"10.1186/s40478-025-02033-9","url":null,"abstract":"<p><p>Neurological damage caused by peripheral nerve injury can be devastating and is a common neurological disorder that, along with muscle disorders, reduces the quality of life. Neural crest cells (NCCs) are a transient cell population that occurs during embryogenesis, can differentiate into various cells upon transplantation, and has potential therapeutic effects on neurological diseases. However, there are limitations to cell therapy, such as uncontrolled differentiation and tumor formation. Extracellular vesicles (EVs), which are non-cellular potential therapeutic candidates, are nanosized membrane-bound vesicles. Studies have been reported using starch cells derived from neural cells, such as neural stem cells, because they are involved in cell-to-cell communication and carry a variety of bioactive molecules. We investigated the effects of EVs isolated from NCCs on neuronal cell death and inflammation. Additionally, we overexpressed the nerve growth factor (NGF), which is involved in neural cell growth and proliferation, in NCCs to further investigate the effects of EVs containing NGF. NCC^oe-NGF-EVs showed neuroprotective and regenerative properties by modulating inflammatory pathway, promoting Schwann cell activation, and enhancing remyelination. In vitro studies on NCC^oe-NGF-EVs suppressed pro-inflammatory cytokines and reduced oxidative stress-induced neuronal apoptosis through NF-κB pathway inhibition and ERK, AKT signal activation. We also evaluated the effect of EVs on neuropathy by performing in vivo study. Our results suggest that NCC^oe-NGF-EV had neuroprotective effects by reducing neuronal apoptosis and promoting neuronal proliferation based on neurite outgrowth and anti-inflammation effects treated with NCC^oe-NGF-EVs. In addition, NCC^oe-NGF-EVs were protected muscle loss caused by peripheral nerve injury. NCC^oe-NGF-EV induced regeneration of damaged nerves and inhibited cell death through anti-inflammatory effects. This study suggests the potential of NGF-enriched EVs as non-cellular therapeutic platform for peripheral neuropathies and other neuroinflammatory disorders.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"118"},"PeriodicalIF":6.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12107788/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148996","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":"TDP-43 overexpression in the hypothalamus drives neuropathology, dysregulates metabolism and impairs behavior in mice.","authors":"Sofia Bergh, Nicolas Casadei, Sanaz Gabery, Oskar Simonsson, João M N Duarte, Deniz Kirik, Huu Phuc Nguyen, Åsa Petersén","doi":"10.1186/s40478-025-02018-8","DOIUrl":"10.1186/s40478-025-02018-8","url":null,"abstract":"<p><p>TAR DNA-binding protein 43 (TDP-43) pathology is linked to the neurodegenerative disorders amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and Huntington disease (HD). Dysregulation of metabolism and emotion is shared across these disorders and may be caused by hypothalamic pathology. Inclusions with TDP-43 are present in the hypothalamus in clinical ALS, as well as selective loss of hypothalamic neurons expressing the metabolism and emotion regulating neuropeptides hypocretin (orexin), melanin-concentrating hormone (MCH) and oxytocin. We aimed to investigate whether there is a casual link between the effects of TDP-43 in the hypothalamus and the development of neuropathology, as well as changes in metabolism and behavior. We generated an adeno-associated viral (AAV) vector expressing human TDP-43 under the neuronal-specific synapsin promoter, which was injected bilaterally into the hypothalamus of wild-type FVB/N mice. TDP-43 overexpression resulted in hypothalamic pathology in a dose-dependent fashion replicating clinical pathology with hypothalamic atrophy and loss of hypocretin-, MCH- and oxytocin-expressing neurons. Nuclear and cytoplasmic inclusions of TDP-43 were found in the hypothalamus. Mice overexpressing TDP-43 in the hypothalamus developed metabolic dysregulation with hyperglycaemia independent of food intake. Additionally, mice overexpressing TDP-43 in the hypothalamus exhibited reduced motor activity and nesting ability, suggesting the development of an apathy-like phenotype. Taken together, AAV-vector mediated TDP-43 overexpression in the hypothalamus leads to neuropathology with the development of metabolic dysfunction and apathy-like behavior. These results indicate that TDP-43 can exert direct pathological effects in the hypothalamus, which may contribute to the development of the non-motor phenotype in TDP-43 proteinopathies.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"119"},"PeriodicalIF":6.2,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12108026/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144155407","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":"Lack of junctional adhesion molecule (JAM)-B traps CD8 T cells in CNS border zones and ameliorates autoimmune neuroinflammation.","authors":"Javier Pareja, Sidar Aydin, Mara Zbinden, Elisa Bouillet, Niklas Zollinger, Vidusiya Theivendram, Amal Fahmi, Petr Pleskač, Sara Barcos, Felix Paas, Florencia Kloster, Aida Muñoz Blázquez, Nicolas Fonta, Doron Merkler, Urban Deutsch, Britta Engelhardt","doi":"10.1186/s40478-025-02021-z","DOIUrl":"10.1186/s40478-025-02021-z","url":null,"abstract":"<p><p>The endothelial blood-brain barrier (BBB) tightly controls T cell entry into the central nervous system (CNS). T cell extravasation across the BBB involves a multi-step cascade with a predominant role of α4β1-integrins. In contrast to CD4 T cells, α4β1-integrin mediated CD8 T cell interaction with the BBB was proposed to involve the tight junction protein junctional adhesion molecule (JAM)-B. Here, we made use of ODC-OVA mice expressing ovalbumin as neo-self-antigen in oligodendrocytes that is solely visible to CD8 T cells, allowing to investigate CD8 T cell-mediated autoimmune neuroinflammation. We generated JAM-B-deficient ODC-OVA mice (ODC-OVA; JAM-B^KO mice) and compared CD8 T cell mediated autoimmune neuroinflammation to their ODC-OVA; JAM-B^WT littermates. ODC-OVA; JAM-B^KO mice developed ameliorated clinical disease, which was associated with a marked reduction in CD8 T cell infiltration into the CNS parenchyma. Surprisingly, lack of JAM-B did not affect CD8 T cell arrest or extravasation in spinal cord microvessels but rather resulted in CD8 T cell accumulation in the subarachnoid space and perivascular spaces in ODC-OVA; JAM-B^KO mice. Detection of Jam-2 RNA expression in cells other than BBB endothelial cells contributing to CNS barriers including astrocytes forming the glia limitans, Bergmann glial cells, meningeal fibroblasts and choroid plexus epithelial cells suggests that JAM-B may regulate CD8 T cell entry into the CNS at barriers other than the BBB, particularly at the glia limitans. Thus, targeting JAM-B could provide a therapeutic strategy for treating neuroinflammation without disrupting T cell-mediated immune surveillance in CNS border compartments.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"117"},"PeriodicalIF":6.2,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12105289/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144148981","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":"Evaluation of aggrephagy markers in myofibrillar myopathies.","authors":"Eliana Iannibelli, Alessandra Ruggieri, Antonello Maruotti, Franco Salerno, Marta Cheli, Alessandra Carnazzi, Lucia Nicolini De Gaetano, Giorgia Riolo, Sara Bortolani, Pietro Riguzzi, Sara Vianello, Gioia Merlonghi, Luca Bello, Matteo Garibaldi, Massimiliano Filosto, Stefano Carlo Previtali, Giorgio Tasca, Gaetano Vattemi, Paola Tonin, Elena Pegoraro, Sara Gibertini, Lorenzo Maggi","doi":"10.1186/s40478-025-02041-9","DOIUrl":"10.1186/s40478-025-02041-9","url":null,"abstract":"<p><p>Myofibrillar Myopathies (MFMs) are a growing group of muscular disorders genetically determined, whose diagnosis is based on histological features as myofibrillar degeneration, Z-disk disorganization and protein aggregates' accumulation. Protein aggregates that do not fit the proteasome's narrow pore are targeted for removal via a specialized form of autophagy, called aggrephagy. Our study aims to investigate the potential pathogenic role of aggrephagy in 52 muscle samples from an Italian MFM multicentric cohort. We measured, the percentage of positive areas of key aggrephagy proteins by immunofluorescence staining, of sequestosome 1 (p62/SQSTM1), Neighbor of BRCA1 Gene 1 (NBR1), and ubiquitinated proteins (FK2) in 11 DES-, 6 DNAJB6-, 5 FLNC-, 18 MYOT- and 12 TTN-mutated patients. We showed that all aggrephagy markers are increased in these patients, regardless of the mutated genes, suggesting a possible common pathomechanism; no positive signal was found in healthy, age-matched controls. We analyzed the association between positivity levels of these markers, measured as percentage of positive areas, and selected clinical features utilizing generalized linear mixed models with gamma distribution as the probability model and center-specific random effects to better capture possible heterogeneity across participating centers. Our findings indicate significant associations between levels of p62, NBR1, and FK2 with age at biopsy (p62 and NBR1 p-values < 0.001, FK2 p-value < 0.05), age of onset (p62 and NBR1 p-values < 0.001, FK2 p-value < 0.01) and disease severity through Walton & Gardner-Medwin (WGM) score at biopsy (all p-values < 0.001) and at the last visit (all p-values < 0.05). Noteworthy, the aggrephagic pathway is mostly activated in MYOT-mutated patients compared to the other subgroups. Moreover, the association between aggrephagy and WGM score at biopsy is stronger in this subgroup. Overall, our study emphasizes the role of aggrephagy in MFMs across all patients, and its association with specific clinical parameters.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"115"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141096","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":"Accurate detection of pathologic α-synuclein in CSF, skin, olfactory mucosa, and urine with a uniform seeding amplification assay.","authors":"Remarh Bsoul, Oskar H McWilliam, Gunhild Waldemar, Steen G Hasselbalch, Anja H Simonsen, Christian von Buchwald, Magne Bech, Clara H Pinborg, Christian K Pedersen, Sara O Baungaard, José Lombardía, Patrick Ejlerskov, Matilde Bongianni, Erika Bronzato, Gianluigi Zanusso, Kristian S Frederiksen, Eva L Lund, Aušrinė Areškevičiūtė","doi":"10.1186/s40478-025-02034-8","DOIUrl":"10.1186/s40478-025-02034-8","url":null,"abstract":"<p><p>Currently, early diagnosis of dementia with Lewy bodies (DLB) is based on clinical criteria, which is challenging due to overlapping symptoms with other neurodegenerative diseases. Seeding amplification assays, detecting minute amounts of disease causing α-synuclein (αSyn^D), are emerging as a promising diagnostic tool for α-synucleinopathies including DLB and Parkinson's disease. This study aimed to test whether the same seeding amplification assay established for αSyn^D detection in cerebrospinal fluid (CSF) could be applied to other biospecimens, including skin, olfactory mucosa, saliva, and urine, obtained from the same patients. A total of 31 patients with probable DLB and 53 healthy controls were recruited. When evaluating the assays' applicability to different biospecimens, only those collected from participants with a positive CSF αSyn^D result were considered. Seeding amplification assay results were evaluated based on the αSyn^D amplification rate over 48 h and the value of the area under the curve. The sensitivity and specificity were 94% and 98% for skin, 47% and 100% for olfactory mucosa, and 22% and 100% for urine, respectively for the CSF positive DLB and healthy controls. αSyn^D was undetectable in saliva. Cohen's Kappa analysis (κ) showed almost perfect agreement between CSF and skin assays (κ = 0.86) but slight to no agreement for CSF versus olfactory mucosa (κ = 0.12) and urine (κ = 0.094). In summary, the seeding amplification assay established for αSyn^D detection in CSF demonstrated comparable diagnostic performance in minimally invasive skin biopsies. Olfactory mucosa, saliva, and urine sample preparation pose technical challenges resulting in the established assays' low diagnostic accuracy, for now, limiting their use in diagnostics. Nevertheless, the proof-of-concept for αSyn^D detection in urine expands the potential for non-invasive diagnostics of α-synucleinopathies in the future.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"13 1","pages":"113"},"PeriodicalIF":6.2,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12102825/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144141092","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}