Brain Pathology最新文献

{"title":"Human amyotrophic lateral sclerosis/motor neuron disease: The disease-associated microglial pathway is upregulated while APOE genotype governs risk and survival.","authors":"Bridget A Ashford, Julie E Simpson, Charlotte Dawson, Delphine Boche, Johnathan Cooper-Knock, Paul R Heath, Daniel Fillingham, Charlie Appleby-Mallinder, Wenbin Wei, Mark Dunning, J Robin Highley","doi":"10.1111/bpa.70019","DOIUrl":"https://doi.org/10.1111/bpa.70019","url":null,"abstract":"<p><p>A key role for inflammation in amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) has been identified. It is vital to assess which central nervous system structures are most affected and which inflammatory processes are responsible in humans. The inflammatory transcriptome was characterized in the cervical spinal cord and motor cortex in post-mortem frozen and formalin-fixed paraffin-embedded specimens from human sporadic ALS/MND and control cases using the nCounter® Neuroinflammation Panel. Archival data were reanalyzed and compared with the nCounter data. Immunohistochemistry was used to examine the inflammatory response in the spinal cord and motor cortex and validate changes found during transcriptomic analyses. In the spinal cord, marked inflammation was observed, while less inflammation was detected in the motor cortex. Examination of differentially expressed genes in the spinal cord highlighted TREM2, TYROBP, APOE, and CD163, as well as phagocytic pathways. In sporadic ALS/MND spinal cord, significant microglial reactivity and involvement of TREM2, ApoE (encoded by APOE), and TYROBP were confirmed, suggesting the involvement of the disease-associated microglial (DAM) phenotype. The corticospinal tracts showed greater inflammation than the ventral horns. The precentral gyrus of ALS/MND again showed less immune reactivity to disease when compared to controls. Finally, in the largest cohort assessed to date, we demonstrate an association between the APOE variant and ALS/MND risk, age of onset, and survival. We find confirmed associations between APOE ε3/ε3 and disease and between ε2/ε2 and absence of disease. Further, ε4/ε4 appears to be associated with earlier disease onset and a more aggressive course. We conclude that while there is widespread inflammation in the CNS in sporadic ALS/MND, this is more marked in the spinal cord, especially the corticospinal tract. The specific markers stress the DAM phenotype as having a key role together with a possible influx of somatic macrophages. In addition, APOE function and genotype may be relevant in ALS/MND.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70019"},"PeriodicalIF":5.8,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144282384","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":"Targeting TRPV4 to restore glymphatic system function and alleviate cerebral edema in ischemic stroke.","authors":"Yongchuan Li, Haiping Zhou, Jiaxin Xie, Mingjia Yu, Guanyu Ye, Yuzhen Zhang, Zhentong Li, Kunxue Zhang, Jingwen Wu, Sheng Xiao, Shuxin Zeng, Yuan Chang, Kaibin Huang, Suyue Pan","doi":"10.1111/bpa.70022","DOIUrl":"https://doi.org/10.1111/bpa.70022","url":null,"abstract":"<p><p>Emerging studies underscore the pivotal role of glymphatic system (GS) dysfunction in the pathogenesis of cerebral edema following brain injury. The transient receptor potential vanilloid 4 (TRPV4) channels have been implicated in modulating the polarization of aquaporin-4 (AQP4), a key protein involved in GS function. This study investigates the potential of targeting TRPV4 to alleviate GS dysfunction and reduce cerebral edema following ischemic stroke. TRPV4 inhibitor HC067047 or a vehicle was administered via lateral ventricle cannulation in a mouse model of middle cerebral artery occlusion and reperfusion (MCAO/R). The function of the GS was assessed through tracer injection experiments, including in vivo transcranial imaging, ex vivo brain tissue and section analysis, and fluorescence retention in deep cervical lymph nodes (dCLNs). Cerebral edema was quantified using magnetic resonance imaging. AQP4 polarization and β-dystroglycan (β-DG) expression were evaluated by immunofluorescence. Western blotting was employed to measure protein levels of β-DG, matrix metalloproteinase-9 (MMP9), and Ras homolog family member A (RhoA). Long-term neurological outcomes were assessed via behavioral testing. MCAO/R mice exhibited significant GS dysfunction, cerebral edema, and disrupted AQP4 polarization. Additionally, β-DG expression was markedly reduced, while TRPV4 expression was elevated in the ischemic penumbra. Western blotting revealed increased expression of MMP9 and RhoA. The inhibition of TRPV4 by HC067047 significantly improved GS function, reduced cerebral edema, and enhanced neurological recovery. Mechanistically, HC067047 partially restored AQP4 polarization, upregulated β-DG expression, and suppressed the expression of MMP9 and RhoA. These findings highlight the therapeutic potential of TRPV4 inhibition in ischemic stroke by restoring GS function, mitigating cerebral edema, and promoting neurological recovery, thereby positioning TRPV4 as a promising target for future interventions.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70022"},"PeriodicalIF":5.8,"publicationDate":"2025-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144246572","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":"Hippo pathway effectors are associated with glioma patient survival, control cell proliferation and sterol metabolism through TEAD3.","authors":"Konstantin Masliantsev, Amandine Desette, Anne-Alicia Gonzalez, Inès Garrouche, Anaïs Noblanc, Maleaume Soulard, Mathis Triquard, Serge Milin, Michel Wager, Lucie Karayan-Tapon, Pierre-Olivier Guichet","doi":"10.1111/bpa.70021","DOIUrl":"https://doi.org/10.1111/bpa.70021","url":null,"abstract":"<p><p>Glioblastomas represent the most common and lethal primary brain tumors in the world. Despite therapeutic advances during the last two decades, patient prognosis remains very poor. The Hippo signaling pathway effectors YAP/TAZ-TEADs play a crucial role in tumor progression and represent promising therapeutic targets in gliomas. In this study, we identified and investigated the clinical and biological significance of TEAD transcription factors. Through comprehensive analyses of TCGA glioma data and patient samples, we identified TEAD3-4 transcription factors as robust prognostic markers of patient outcome. Using up to five different patient-derived glioblastoma stem cell cultures, we confirmed the preferential expression and activation of TEAD3-4 along with their transcriptional coactivators YAP/TAZ. Pharmacological inhibition of YAP/TAZ-TEAD interaction by Verteporfin significantly decreased tumor cell growth, whereas specific inhibition of TEAD3 did not impact cell proliferation but affected sterol/cholesterol biosynthetic and metabolic processes. This study contributes to a better understanding of the role of Hippo effectors in glioblastoma pathophysiology. These transcription factors, particularly TEAD3, could potentially serve as therapeutic targets, especially considering recent data on cholesterol homeostasis in glioblastomas.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70021"},"PeriodicalIF":5.8,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144207777","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":"SOCIETY NEWS","authors":"Audrey Rousseau","doi":"10.1111/bpa.70020","DOIUrl":"10.1111/bpa.70020","url":null,"abstract":"&lt;p&gt;&lt;b&gt;The ISN is looking for a group of young motivated neuropathologists&lt;/b&gt; to promote the specialty via the ISN website. If you are interested in participating, please contact Audrey Rousseau (&lt;span&gt;[email protected]&lt;/span&gt;) or Monika Hofer (&lt;span&gt;[email protected]&lt;/span&gt;).&lt;/p&gt;&lt;p&gt;&lt;b&gt;The International Congress of Neuropathology (ICN)&lt;/b&gt; will be held in Edinburgh, Scotland, in 2027 (ICN27). The Congress President will be Prof Colin Smith and the ICN27 will be hosted by the British Neuropathological Society (BNS).&lt;/p&gt;&lt;p&gt;“On behalf of the British Neuropathological Society I am delighted to extend a warm invitation to all our colleagues across the world to join us in Edinburgh for the International Congress of Neuropathology 2027. Edinburgh is an easily accessible centre, surrounded by 1000 years of living history. We will develop a strong academic programme covering all aspects of neuropathology with world leading plenary speakers, supported by a social programme highlighting some of Edinburgh's historic charms. For those wishing to explore further, Edinburgh offers access to many of Scotland's highlights, be it touring the Highlands, sampling our famous whisky or golfing on some of our picturesque courses. I do hope you will be able to join us for what I am sure will be a memorable meeting showcasing the best in international neuropathology.&lt;/p&gt;&lt;p&gt;Colin Smith&lt;/p&gt;&lt;p&gt;Congress President ISN 2027”&lt;/p&gt;&lt;p&gt;Summary report for ICN23 Berlin (our most recent International Congress of Neuropathology, September 2023) now available in the Society's journal Brain Pathology (see link: https://doi.org/10.1111/bpa.13249).&lt;/p&gt;&lt;p&gt;We are delighted to start the bidding process for holding the &lt;b&gt;2031 XXII International Congress of Neuropathology (ICN)&lt;/b&gt;. As you know, the 2027 XXI ICN Congress will be in Edinburgh and we now need to think ahead to 2031 and find a new home for our much-loved congress.&lt;/p&gt;&lt;p&gt;The Invitation Letter calling for bids and outlining the process can be found on the ISN website (www.intsocneuropathol.com). Please note that the deadline is the &lt;b&gt;31st August 2025&lt;/b&gt;.&lt;/p&gt;&lt;p&gt;The &lt;b&gt;7th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies&lt;/b&gt; will be held in conjunction with the 30th Annual Meeting &amp; Education Day of the Society for Neuro-Oncology &lt;b&gt;November 19-23, 2025&lt;/b&gt; in Honolulu, Hawaii.&lt;/p&gt;&lt;p&gt;&lt;b&gt;&lt;i&gt;Brain Pathology has joined Wiley's Open Access&lt;/i&gt;&lt;/b&gt; portfolio as of January 2021. As a result, all submissions are subject to an Article Publication Charge (APC) if accepted and published in the journal. ISN members are eligible for a 10% discount off the Open Access APC. For more information on the fees, please click here.&lt;/p&gt;&lt;p&gt;&lt;b&gt;Free resource: digital microscopy platform for neurodegenerative diseases curated in Munich&lt;/b&gt;. Prof Jochen Herms and his team have been setting up a digital microscopy platform for neurodegenerative diseases in their department in Munich. Registration is free. ISN members and interested","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"35 4","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70020","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198290","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":"Complement dysregulation in human tauopathies.","authors":"Jacqui Nimmo, Samuel Keat, Louis De Muynck, B Paul Morgan","doi":"10.1111/bpa.70017","DOIUrl":"https://doi.org/10.1111/bpa.70017","url":null,"abstract":"<p><p>Dysregulation of the complement system plays an important role in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). In post-mortem AD brains, complement is deposited in and around amyloid plaques, and peri-plaque complement activation drives synapse loss in AD mouse models. Studies to date have focused on amyloid pathology; however, aggregated tau is also involved in neuronal loss in AD. Primary tauopathies are characterised by tau pathology in the absence of amyloid. The role of complement in human tauopathies remains largely unexplored. Here, we address this knowledge gap by assessing complement activation in human tauopathy brains using immunohistochemistry and well-characterised detection tools. Post-mortem pre-frontal cortex was obtained from three tauopathy subtypes, Pick's disease (PiD), globular glial tauopathy (GGT) and corticobasal degeneration (CBD) (3-5 cases each). C1q and the complement activation markers iC3b and terminal complement complex (TCC) were assessed by immunohistochemistry and were elevated in all tauopathy cases compared to controls, with C1q and C3b/iC3b deposition particularly prominent on neurons, demonstrating complement activation on these cells. TCC deposits were present on and adjacent neurons in all tauopathy brains examined and were significantly increased compared to controls in CBD and GGT. Uniquely in GGT, abundant deposition of C3b/iC3b on myelin was also observed, implicating complement in GGT-associated demyelination. To validate these findings, complement proteins (C1q, C3, factor B), regulators (factor I, clusterin) and activation products (Ba, C3b/iC3b, and TCC) were measured in brain homogenates by ELISA, revealing significant elevation in C3b/iC3b, Ba, and FI in CBD and GGT cases compared to controls. Together, our data demonstrate complement activation on and adjacent neurons in post-mortem brains from all tauopathy subtypes.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70017"},"PeriodicalIF":5.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149404","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":"cIMPACT-NOW update 10: Recommendations for defining new types for central nervous system tumor classification.","authors":"Cynthia Hawkins, Kenneth Aldape, David Capper, Andreas von Deimling, Caterina Giannini, Mark R Gilbert, Thomas S Jacques, David Jones, Takashi Komori, David N Louis, Sabine Mueller, MacLean Nasrallah, Brent A Orr, Arie Perry, Stefan M Pfister, Felix Sahm, Chitra Sarkar, Matija Snuderl, David Solomon, Pascale Varlet, Pieter Wesseling, Guido Reifenberger","doi":"10.1111/bpa.70018","DOIUrl":"https://doi.org/10.1111/bpa.70018","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70018"},"PeriodicalIF":5.8,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144149398","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":"Late-onset multiple system atrophy: Neuropathological features associated with slow disease progression.","authors":"Misato Ozawa, Rie Saito, Takuya Konno, Yasuko Kuroha, Tetsuhiko Ikeda, Akio Yokoseki, Takashi Tani, Tomoe Sato, Jiro Idezuka, Reiji Koide, Shigeru Fujimoto, Osamu Onodera, Mari Tada, Akiyoshi Kakita","doi":"10.1111/bpa.70016","DOIUrl":"https://doi.org/10.1111/bpa.70016","url":null,"abstract":"<p><p>Patients with late-onset (LO) multiple system atrophy (MSA), whose initial symptoms appear at age 75 years or older, are more common than previously assumed, but their clinicopathological characteristics remain unclear. We aimed to clarify the clinicopathological features of LO-MSA. Of 102 patients with autopsy-confirmed MSA, 5 were identified as having LO-MSA and 24 as having usual-age-onset MSA (UO-MSA) with a similar disease duration. On the basis of previous reports, we defined UO-MSA as the appearance of initial symptoms between the ages of 55 and 65 years. We compared the clinical pictures of the two groups and assessed their histopathological features using quantitative and semi-quantitative methods. The investigated features included the severity of degeneration in the striatonigral (StrN) and olivopontocerebellar (OPC) systems, the numbers of neurons in the brainstem autonomic and spinal intermediolateral nuclei, and the density of α-synuclein-immunopositive inclusions in the putamen, inferior olivary nucleus, and ventrolateral medulla (VLM). Most patients with both LO-MSA and UO-MSA exhibited the MSA-olivopontocerebellar atrophy (OPCA) subtype (3/5 and 18/24, respectively). The median disease duration for LO-MSA patients was 5.5 years, which was comparable to that for patients in our cohort who had developed symptoms below 75 years of age. Pathologically, degeneration of the StrN and OPC systems in LO-MSA was less severe than that observed in UO-MSA. Quantitative analysis revealed better preservation of neuron numbers in the brainstem autonomic nuclei in LO-MSA than in UO-MSA, with a significantly higher number of serotonergic neurons in the VLM (p = 0.013). The density of α-synuclein-positive inclusions in the putamen was significantly lower in LO-MSA than in UO-MSA (p < 0.001). Neuronal degeneration in LO-MSA may progress more slowly than in UO-MSA. Accordingly, the prognosis of LO-MSA may not necessarily be less favorable than that of MSA generally, especially with appropriate care.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70016"},"PeriodicalIF":5.8,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144101424","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":"Comments to the \"Letter to the Editor\" for the manuscript titled \"Clinico-sero-pathological characteristics of anti-Ha antisynthetase syndrome\".","authors":"Bing Zhao, Lining Zhang, Tingjun Dai","doi":"10.1111/bpa.70014","DOIUrl":"https://doi.org/10.1111/bpa.70014","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70014"},"PeriodicalIF":5.8,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076081","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":"Correspondence to: Clinico-sero-pathological characteristics of anti-Ha antisynthetase syndrome.","authors":"Marie-Therese Holzer, Robert Biesen, Sarah Tansley, Carsten Dittmayer, Werner Stenzel, Udo Schneider","doi":"10.1111/bpa.70015","DOIUrl":"https://doi.org/10.1111/bpa.70015","url":null,"abstract":"","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70015"},"PeriodicalIF":5.8,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143970525","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":"Comparative pathology boards facilitate the translation of knowledge between canine and human cancer patients.","authors":"Jessica A Beck, Christina Mazcko, Sara Belluco, Mireille Bitar, Daniel Brat, Jonathan W Bush, Rati Chkheidze, Kara N Corps, Chad Frank, Caterina Giannini, Craig Horbinski, Jason T Huse, Jennifer W Koehler, Andrew D Miller, C Ryan Miller, M Gerard O'Sullivan, Joanna J Phillips, Daniel R Rissi, Courtney R Schott, Anat Stemmer-Rachamimov, Stephen Yip, Amy K LeBlanc","doi":"10.1111/bpa.70013","DOIUrl":"https://doi.org/10.1111/bpa.70013","url":null,"abstract":"<p><p>Comparative pathology boards bring together anatomic pathologists with expertise in canine and human histology to identify shared features, including immune or TME components, tumor subtypes, or prognostic tissue biomarkers. This article summarizes feedback to improve future initiatives and enhance the translational relevance of comparative oncology for human patients.</p>","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":" ","pages":"e70013"},"PeriodicalIF":5.8,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953795","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}