Acta Neuropathologica最新文献

{"title":"Histopathologic correlates of opioid-associated injury in CHANTER syndrome: first report of a post-mortem examination","authors":"Katherine E. Schwetye,&nbsp;Lakshmi Ramachandran Nair,&nbsp;Joseph Boyle,&nbsp;Jed A. Barash","doi":"10.1007/s00401-024-02797-9","DOIUrl":"10.1007/s00401-024-02797-9","url":null,"abstract":"<div><p>Opioid-associated brain injury may involve selective regions, including the hippocampi alone, globi pallidi, and cerebellar hemispheres. Opioid-associated amnestic syndrome, for example, is one clinical correlate of hippocampal injury as manifest by MRI abnormality. When all three regions are involved in what may be a more fulminant injury, the syndrome is termed “cerebellar, hippocampal, and basal nuclei transient edema with restricted diffusion (CHANTER)”, initially described in 2019. Until now, to our knowledge, there have been no histopathologic correlates to the imaging findings specifically in CHANTER syndrome. Here, for the first time, we present histopathologic findings of the post-mortem brain from a patient who died from complications of CHANTER syndrome following fentanyl intoxication. These observations included microhemorrhage, reactive and necrotic vasculature, eosinophilic neuronal necrosis, axonal swelling and spheroids, and frank infarction. The findings support previous experimental models implicating both hypoxic–ischemic and cytotoxic mechanisms in the tissue damage associated with CHANTER syndrome, though further work is needed to better characterize the exact cellular pathways involved to develop targeted treatments.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02797-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100617","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disability independent of cerebral white matter demyelination in progressive multiple sclerosis","authors":"Vikas Singh,&nbsp;Yufan Zheng,&nbsp;Daniel Ontaneda,&nbsp;Kedar R Mahajan,&nbsp;Jameson Holloman,&nbsp;Robert J Fox,&nbsp;Kunio Nakamura,&nbsp;Bruce D Trapp","doi":"10.1007/s00401-024-02796-w","DOIUrl":"10.1007/s00401-024-02796-w","url":null,"abstract":"<div><p>The pathogenic mechanisms contributing to neurological disability in progressive multiple sclerosis (PMS) are poorly understood. Cortical neuronal loss independent of cerebral white matter (WM) demyelination in myelocortical MS (MCMS) and identification of MS patients with widespread cortical atrophy and disability progression independent of relapse activity (PIRA) support pathogenic mechanisms other than cerebral WM demyelination. The three-dimensional distribution and underlying pathology of myelinated T2 lesions were investigated in postmortem MCMS brains. Postmortem brain slices from previously characterized MCMS (10 cases) and typical MS (TMS) cases (12 cases) were co-registered with <i>in situ</i> postmortem T2 hyperintensities and T1 hypointensities. T1 intensity thresholds were used to establish a classifier that differentiates MCMS from TMS. The classifier was validated in 36 uncharacterized postmortem brains and applied to baseline MRIs from 255 living PMS participants enrolled in SPRINT-MS. Myelinated T2 hyperintensities in postmortem MCMS brains have a contiguous periventricular distribution that expands at the occipital poles of the lateral ventricles where a surface-in gradient of myelinated axonal degeneration was observed. The MRI classifier distinguished pathologically confirmed postmortem MCMS and TMS cases with an accuracy of 94%. For SPRINT-MS patients, the MRI classifier identified 78% as TMS, 10% as MCMS, and 12% with a paucity of cerebral T1 and T2 intensities. In SPRINT-MS, expanded disability status scale and brain atrophy measures were similar in MCMS and TMS cohorts. A paucity of cerebral WM demyelination in 22% of living PMS patients raises questions regarding a primary role for cerebral WM demyelination in disability progression in all MS patients and has implications for clinical management of MS patients and clinical trial outcomes in PMS. Periventricular myelinated fiber degeneration provides additional support for surface-in gradients of neurodegeneration in MS.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02796-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142100616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRDM16-DT is a novel lncRNA that regulates astrocyte function in Alzheimer’s disease","authors":"Sophie Schröder,&nbsp;Ulrike Fuchs,&nbsp;Verena Gisa,&nbsp;Tonatiuh Pena,&nbsp;Dennis M. Krüger,&nbsp;Nina Hempel,&nbsp;Susanne Burkhardt,&nbsp;Gabriela Salinas,&nbsp;Anna-Lena Schütz,&nbsp;Ivana Delalle,&nbsp;Farahnaz Sananbenesi,&nbsp;Andre Fischer","doi":"10.1007/s00401-024-02787-x","DOIUrl":"10.1007/s00401-024-02787-x","url":null,"abstract":"<div><p>Astrocytes provide crucial support for neurons, contributing to synaptogenesis, synaptic maintenance, and neurotransmitter recycling. Under pathological conditions, deregulation of astrocytes contributes to neurodegenerative diseases such as Alzheimer’s disease (AD). While most research in this field has focused on protein-coding genes, non-coding RNAs, particularly long non-coding RNAs (lncRNAs), have emerged as significant regulatory molecules. In this study, we identified the lncRNA <i>PRDM16-DT</i> as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. <i>PRDM16-DT</i> and its murine homolog, <i>Prdm16os</i>, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of <i>PRDM16-DT</i> and <i>Prdm16os</i> revealed its critical role in maintaining astrocyte homeostasis and supporting neuronal function by regulating genes essential for glutamate uptake, lactate release, and neuronal spine density through interactions with the RE1-Silencing Transcription factor (Rest) and Polycomb Repressive Complex 2 (PRC2). Notably, CRISPR-mediated overexpression of <i>Prdm16os</i> mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of <i>PRDM16-DT</i> in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02787-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory aspects of Alzheimer’s disease","authors":"Pablo Botella Lucena,&nbsp;Michael T. Heneka","doi":"10.1007/s00401-024-02790-2","DOIUrl":"10.1007/s00401-024-02790-2","url":null,"abstract":"<div><p>Alzheimer´s disease (AD) stands out as the most common chronic neurodegenerative disorder. AD is characterized by progressive cognitive decline and memory loss, with neurodegeneration as its primary pathological feature. The role of neuroinflammation in the disease course has become a focus of intense research. While microglia, the brain’s resident macrophages, have been pivotal to study central immune inflammation, recent evidence underscores the contributions of other cellular entities to the neuroinflammatory process. In this article, we review the inflammatory role of microglia and astrocytes, focusing on their interactions with AD’s core pathologies, amyloid beta deposition, and tau tangle formation. Additionally, we also discuss how different modes of regulated cell death in AD may impact the chronic neuroinflammatory environment. This review aims to highlight the evolving landscape of neuroinflammatory research in AD and underscores the importance of considering multiple cellular contributors when developing new therapeutic strategies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correlation between natural history and multi-omics profiling of meningiomas in NF2-related schwannomatosis suggests role of methylation group and immune microenvironment in tumor growth rate","authors":"Yu Teranishi,&nbsp;Andrey Yurchenko,&nbsp;Suzanne Tran,&nbsp;Philipp Sievers,&nbsp;Fatemeh Rajabi,&nbsp;Singhabahu Ruchith,&nbsp;Samiya Abi-Jaoude,&nbsp;Antoine Blouin,&nbsp;Franck Bielle,&nbsp;Dominique Cazals-Hatem,&nbsp;Felix Sahm,&nbsp;Sergey Nikolaev,&nbsp;Michel Kalamarides,&nbsp;Matthieu Peyre","doi":"10.1007/s00401-024-02791-1","DOIUrl":"10.1007/s00401-024-02791-1","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02791-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylation profiling of plasma cell-free DNA in pediatric brain tumor patients","authors":"Shejuan An,&nbsp;Kathleen McCortney,&nbsp;Jordain Walshon,&nbsp;Kaethe Leonard,&nbsp;Brian Wray,&nbsp;Matthew McCord,&nbsp;Michael DeCuypere,&nbsp;Craig Horbinski","doi":"10.1007/s00401-024-02795-x","DOIUrl":"10.1007/s00401-024-02795-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02795-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142074941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The RNA-binding protein IGF2BP1 regulates stability of mRNA transcribed from FOXM1 target genes in hypermitotic meningiomas","authors":"Nathan K. Leclair,&nbsp;Calixto-Hope G. Lucas,&nbsp;Kanish Mirchia,&nbsp;Kathleen McCortney,&nbsp;Craig M. Horbinski,&nbsp;David R. Raleigh,&nbsp;Olga Anczukow","doi":"10.1007/s00401-024-02788-w","DOIUrl":"10.1007/s00401-024-02788-w","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02788-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142045645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups","authors":"Yiyi Ma,&nbsp;Dolly Reyes-Dumeyer,&nbsp;Angel Piriz,&nbsp;Patricia Recio,&nbsp;Diones Rivera Mejia,&nbsp;Martin Medrano,&nbsp;Rafael A. Lantigua,&nbsp;Jean Paul G. Vonsattel,&nbsp;Giuseppe Tosto,&nbsp;Andrew F. Teich,&nbsp;Benjamin Ciener,&nbsp;Sandra Leskinen,&nbsp;Sharanya Sivakumar,&nbsp;Michael DeTure,&nbsp;Duara Ranjan,&nbsp;Dennis Dickson,&nbsp;Melissa Murray,&nbsp;Edward Lee,&nbsp;David A. Wolk,&nbsp;Lee-Way Jin,&nbsp;Brittany N. Dugger,&nbsp;Annie Hiniker,&nbsp;Robert A. Rissman,&nbsp;Richard Mayeux,&nbsp;Badri N. Vardarajan","doi":"10.1007/s00401-024-02778-y","DOIUrl":"10.1007/s00401-024-02778-y","url":null,"abstract":"<div><p> Genetic variants and epigenetic features both contribute to the risk of Alzheimer’s disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: <i>ADAM20</i> (Score = 55.19, <i>P</i> = 4.06 × 10^–8), the intergenic region between <i>VRTN</i> and <i>SYNDIG1L</i> (Score = − 37.67, <i>P</i> = 2.25 × 10^–9), <i>SPG7</i> (16q24.3) (Score = 40.51, <i>P</i> = 2.23 × 10^–8), <i>PVRL2</i> (Score = 125.86, <i>P</i> = 1.64 × 10^–9), <i>TOMM40</i> (Score = − 18.58, <i>P</i> = 4.61 × 10^–8), and <i>APOE</i> (Score = 75.12, <i>P</i> = 7.26 × 10^–26). CGSes in <i>PVRL2</i> and <i>APOE</i> were also significant in NHW. Except for <i>ADAM20</i>, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in <i>SPG7, PVRL2,</i> and <i>APOE</i> were also mQTLs in NHW. Except for <i>SYNDIG1L</i> (<i>P</i> = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (<i>P</i> &lt; 0.05), and methylation at <i>VRTN</i> and <i>TOMM40</i> were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR &lt; 0.05). DNA methylation at all six loci and mRNA expression of <i>SYNDIG1</i> and <i>TOMM40</i> were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11343944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142034912","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FGFR1 wild-type rosette-forming glioneuronal tumours","authors":"Mégane Le Quang,&nbsp;Aude Trinquet,&nbsp;Aurore Siegfried,&nbsp;Amaury de Barros,&nbsp;Luc Bauchet,&nbsp;Sam Ng,&nbsp;Vincent Jecko,&nbsp;Guillaume Chotard,&nbsp;Morgan Ollivier,&nbsp;Gilles Adam,&nbsp;Fabrice Bonneville,&nbsp;Julien Masliah-Planchon,&nbsp;Yvan Nicaise,&nbsp;Clémentine Decamps,&nbsp;Valérie Rigau,&nbsp;Emmanuelle Uro-Coste","doi":"10.1007/s00401-024-02779-x","DOIUrl":"10.1007/s00401-024-02779-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02779-x.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142013840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Severe neurodegeneration in brains of transgenic rats producing human tau prions","authors":"Jacob Ayers,&nbsp;T. Peter Lopez,&nbsp;Ian T. Steele,&nbsp;Abby Oehler,&nbsp;Rigo Roman-Albarran,&nbsp;Elisa Cleveland,&nbsp;Alex Chong,&nbsp;George A. Carlson,&nbsp;Carlo Condello,&nbsp;Stanley B. Prusiner","doi":"10.1007/s00401-024-02771-5","DOIUrl":"10.1007/s00401-024-02771-5","url":null,"abstract":"<div><p>Both wild-type and mutant tau proteins can misfold into prions and self-propagate in the central nervous system of animals and people. To extend the work of others, we investigated the molecular basis of tau prion–mediated neurodegeneration in transgenic (Tg) rats expressing mutant human tau (P301S); this line of Tg rats is denoted Tg12099. We used the rat <i>Prnp</i> promoter to drive the overexpression of mutant tau (P301S) in the human 0N4R isoform. In Tg12099(+/+) rats homozygous for the transgene, ubiquitous expression of mutant human tau resulted in the progressive accumulation of phosphorylated tau inclusions, including silver-positive tangles in the frontal cortices and limbic system. Signs of central nervous system dysfunction were found in terminal Tg12099(+/+) rats exhibiting severe neurodegeneration and profound atrophy of the amygdala and piriform cortex. The greatest increases in tau prion activity were found in the corticolimbic structures. In contrast to the homozygous Tg12099(+/+) rats, we found lower levels of mutant tau in the hemizygous rats, resulting in few neuropathologic changes up to 2 years of age. Notably, these hemizygous rats could be infected by intracerebral inoculation with recombinant tau fibrils or precipitated tau prions from the brain homogenates of sick, aged homozygous Tg12099(+/+) rats. Our studies argue that the regional propagation of tau prions and neurodegeneration in the Tg12099 rats resembles that found in human primary tauopathies. These findings seem likely to advance our understanding of human tauopathies and may lead to effective therapeutics for Alzheimer’s disease and other tau prion disorders.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11333523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142003326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}