Neuropathology and Applied Neurobiology最新文献

{"title":"Interferon‐gamma contributes to disease progression in the Ndufs4(−/−) model of Leigh syndrome","authors":"Allison R. Hanaford, Asheema Khanna, Katerina James, Vivian Truong, Ryan Liao, Yihan Chen, Michael Mulholland, Ernst‐Bernhard Kayser, Kino Watanabe, Erin Shien Hsieh, Margaret Sedensky, Philip G. Morgan, Vandana Kalia, Surojit Sarkar, Simon C. Johnson","doi":"10.1111/nan.12977","DOIUrl":"https://doi.org/10.1111/nan.12977","url":null,"abstract":"AimLeigh syndrome (LS), the most common paediatric presentation of genetic mitochondrial dysfunction, is a multi‐system disorder characterised by severe neurologic and metabolic abnormalities. Symmetric, bilateral, progressive necrotizing lesions in the brainstem are defining features of the disease. Patients are often symptom free in early life but typically develop symptoms by about 2 years of age. The mechanisms underlying disease onset and progression in LS remain obscure. Recent studies have shown that the immune system causally drives disease in the <jats:italic>Ndufs4</jats:italic>(−/−) mouse model of LS: treatment of <jats:italic>Ndufs4</jats:italic>(−/−) mice with the macrophage‐depleting Csf1r inhibitor pexidartinib prevents disease. While the precise mechanisms leading to immune activation and immune factors involved in disease progression have not yet been determined, interferon‐gamma (IFNγ) and interferon gamma‐induced protein 10 (IP10) were found to be significantly elevated in <jats:italic>Ndufs4</jats:italic>(−/−) brainstem, implicating these factors in disease. Here, we aimed to explore the role of IFNγ and IP10 in LS.MethodsTo establish the role of IFNγ and IP10 in LS, we generated IFNγ and IP10 deficient <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>Ifng</jats:italic>(−/−) and <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>IP10</jats:italic>(−/−) double knockout animals, as well as IFNγ and IP10 heterozygous, <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>Ifng</jats:italic>(+/−) and <jats:italic>Ndufs4</jats:italic>(−/−)/<jats:italic>IP10</jats:italic>(+/−), animals. We monitored disease onset and progression to define the impact of heterozygous or homozygous loss of IFNγ and IP10 in LS.ResultsLoss of IP10 does not significantly impact the onset or progression of disease in the <jats:italic>Ndufs4</jats:italic>(−/−) model. IFNγ loss significantly extends survival and delays disease progression in a gene dosage‐dependent manner, though the benefits are modest compared to Csf1r inhibition.ConclusionsIFNγ contributes to disease onset and progression in LS. Our findings suggest that IFNγ targeting therapies may provide some benefits in genetic mitochondrial disease, but targeting IFNγ alone would likely yield only modest benefits in LS.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"167 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140828331","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":"Revisiting the relevance of Hirano bodies in neurodegenerative diseases","authors":"Koji Yoshida, Shelley L. Forrest, Shojiro Ichimata, Hidetomo Tanaka, Tomoya Kon, Maria Carmela Tartaglia, Charles H. Tator, Anthony E. Lang, Naoki Nishida, Gabor G. Kovacs","doi":"10.1111/nan.12978","DOIUrl":"https://doi.org/10.1111/nan.12978","url":null,"abstract":"AimsHirano bodies (HBs) are eosinophilic pathological structures with two morphological phenotypes commonly found in the hippocampal CA1 region in Alzheimer's disease (AD). This study evaluated the prevalence and distribution of HBs in AD and other neurodegenerative diseases.MethodsThis cross‐sectional study systematically evaluated HBs in a cohort of 193 cases with major neurodegenerative diseases, including AD (<jats:italic>n</jats:italic> = 91), Lewy body disease (LBD, <jats:italic>n</jats:italic> = 87), progressive supranuclear palsy (PSP, <jats:italic>n</jats:italic> = 36), multiple system atrophy (MSA, <jats:italic>n</jats:italic> = 14) and controls (<jats:italic>n</jats:italic> = 26). The prevalence, number and morphology of HBs in the stratum lacunosum (HBL) and CA1 pyramidal cell layer were examined. In addition, we investigated the presence of HBs in five additional hippocampal subregions.ResultsThe morphological types of HBs in CA1 were divided into three, including a newly discovered type, and were evaluated separately, with their morphology confirmed in three dimensions: (1) classic rod‐shaped HB (CHB), (2) balloon‐shaped HB (BHB) and the newly described (3) string‐shaped HB (SHB). The prevalence of each HB type differed between disease groups: Compared with controls, for CHB in AD, AD + LBD, PSP and corticobasal degeneration, for BHB in AD + LBD and PSP, and SHB in AD + LBD and PSP were significantly increased. Regression analysis showed that CHBs were independently associated with higher Braak NFT stage, BHBs with LBD and TDP‐43 pathology, SHBs with higher Braak NFT stage, PSP and argyrophilic grain disease and HBLs with MSA.ConclusionsThis study demonstrates that HBs are associated with diverse neurodegenerative diseases and shows that morphological types appear distinctively in various conditions.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"19 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140630059","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":"Adult brain tumour research in 2024: Status, challenges and recommendations","authors":"Karin Purshouse, Helen J. Bulbeck, Alasdair G. Rooney, Karen E. Noble, Ross D. Carruthers, Gerard Thompson, Petra Hamerlik, Christina Yap, Kathreena M. Kurian, Sarah J. Jefferies, Juanita S. Lopez, Michael D. Jenkinson, C. Oliver Hanemann, Lucy F. Stead","doi":"10.1111/nan.12979","DOIUrl":"https://doi.org/10.1111/nan.12979","url":null,"abstract":"In 2015, a groundswell of brain tumour patient, carer and charity activism compelled the UK Minister for Life Sciences to form a brain tumour research task and finish group. This resulted, in 2018, with the UK government pledging £20m of funding, to be paralleled with £25m from Cancer Research UK, specifically for neuro‐oncology research over the subsequent 5 years. Herein, we review if and how the adult brain tumour research landscape in the United Kingdom has changed over that time and what challenges and bottlenecks remain. We have identified seven universal brain tumour research priorities and three cross‐cutting themes, which span the research spectrum from bench to bedside and back again. We discuss the status, challenges and recommendations for each one, specific to the United Kingdom.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"43 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570530","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":"Immune system involvement in neuronal intranuclear inclusion disease","authors":"Lei Bao, Dandan Zuo, Xiaoying Qu, Yingying Cui, Keke Li, Jing Dong, Renjin Chen, Zunsheng Zhang, Guiyun Cui, Hao Chen","doi":"10.1111/nan.12976","DOIUrl":"https://doi.org/10.1111/nan.12976","url":null,"abstract":"<h2> CONFLICT OF INTEREST STATEMENT</h2>\u0000<p>The authors declare that they have no competing interests.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"2000 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570443","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":"Response letter: Complexities in pericyte markers","authors":"Peter T. Nelson, Andras Sziraki, Junyue Cao","doi":"10.1111/nan.12975","DOIUrl":"https://doi.org/10.1111/nan.12975","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"2014 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140570357","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 the EGFR pathway: An alternative strategy for the treatment of tuberous sclerosis complex?","authors":"Julia Schachenhofer, Victoria-Elisabeth Gruber, Stefanie Valerie Fehrer, Carmen Haider, Sarah Glatter, Ewa Liszewska, Romana Höftberger, Eleonora Aronica, Karl Rössler, Jacek Jaworski, Theresa Scholl, Martha Feucht","doi":"10.1111/nan.12974","DOIUrl":"10.1111/nan.12974","url":null,"abstract":"<p><strong>Introduction: </strong>Tuberous sclerosis complex (TSC) is caused by variants in TSC1/TSC2, leading to constitutive activation of the mammalian target of rapamycin (mTOR) complex 1. Therapy with everolimus has been approved for TSC, but variations in success are frequent. Recently, caudal late interneuron progenitor (CLIP) cells were identified as a common origin of the TSC brain pathologies such as subependymal giant cell astrocytomas (SEGA) and cortical tubers (CT). Further, targeting the epidermal growth factor receptor (EGFR) with afatinib, which is expressed in CLIP cells, reduces cell growth in cerebral TSC organoids. However, investigation of clinical patient-derived data is lacking.</p><p><strong>Aims: </strong>Observation of EGFR expression in SEGA, CT and focal cortical dysplasia (FCD) 2B human brain specimen and investigation of whether its inhibition could be a potential therapeutic intervention for these patients.</p><p><strong>Methods: </strong>Brain specimens of 23 SEGAs, 6 CTs, 20 FCD2Bs and 17 controls were analysed via immunohistochemistry to characterise EGFR expression, cell proliferation (via Mib1) and mTOR signalling. In a cell-based assay using primary patient-derived cells (CT n = 1, FCD2B n = 1 and SEGA n = 4), the effects of afatinib and everolimus on cell proliferation and cell viability were observed.</p><p><strong>Results: </strong>EGFR overexpression was observed in histological sections of SEGA, CT and FCD2B patients. Both everolimus and afatinib decreased the proliferation and viability in primary SEGA, tuber and FCD2B cells.</p><p><strong>Conclusion: </strong>Our study demonstrates that EGFR suppression might be an effective alternative treatment option for SEGAs and tubers, as well as other mTOR-associated malformations of cortical development, including FCD2B.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 2","pages":"e12974"},"PeriodicalIF":5.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336324","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":"Mechanisms of COVID-19-associated olfactory dysfunction.","authors":"Koping Chang, Thomas Zaikos, Nicholas Kilner-Pontone, Cheng-Ying Ho","doi":"10.1111/nan.12960","DOIUrl":"10.1111/nan.12960","url":null,"abstract":"<p><p>Olfactory dysfunction is one of the most common symptoms of COVID-19. In the first 2 years of the pandemic, it was frequently reported, although its incidence has significantly decreased with the emergence of the Omicron variant, which has since become the dominant viral strain. Nevertheless, many patients continue to suffer from persistent dysosmia and dysgeusia, making COVID-19-associated olfactory dysfunction an ongoing health concern. The proposed pathogenic mechanisms of COVID-19-associated olfactory dysfunction are complex and likely multifactorial. While evidence suggests that infection of sustentacular cells and associated mucosal inflammation may be the culprit of acute, transient smell loss, alterations in other components of the olfactory system (e.g., olfactory receptor neuron dysfunction, olfactory bulb injury and alterations in the olfactory cortex) may lead to persistent, long-term olfactory dysfunction. This review aims to provide a comprehensive summary of the epidemiology, clinical manifestations and current understanding of the pathogenic mechanisms of COVID-19-associated olfactory dysfunction.</p>","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 2","pages":"e12960"},"PeriodicalIF":4.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10906737/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139990727","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":"Argyrophilic grain disease and co-pathologies in an older patient with a rapidly progressive neuropsychiatric syndrome.","authors":"Camilla N Clark, Norman Poole, Jeremy D Isaacs, Andrew D MacKinnon, Philip Rich, Leslie R Bridges, Zane Jaunmuktane, Elizabeth Caruana Galizia","doi":"10.1111/nan.12973","DOIUrl":"10.1111/nan.12973","url":null,"abstract":"","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"50 2","pages":"e12973"},"PeriodicalIF":5.0,"publicationDate":"2024-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140336323","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":"Chronic traumatic encephalopathy neuropathologic change in former Australian rugby players","authors":"Claire E. Shepherd, Heather McCann, Catriona A. McLean, Grant L. Iverson, Andrew J. Gardner","doi":"10.1111/nan.12972","DOIUrl":"https://doi.org/10.1111/nan.12972","url":null,"abstract":"AimsWe applied the 2021 consensus criteria for both chronic traumatic encephalopathy neuropathological change and traumatic encephalopathy syndrome in a small case series of six former elite‐level Australian rugby code players.MethodsNeuropathological assessment of these cases was carried out at the Sydney and Victorian Brain Banks. Clinical data were collected via clinical interviews and health questionnaires completed by the participants and/or their next of kin, and neuropsychological testing was conducted with participants who were capable of completing this testing.ResultsAll cases exhibited progressive cognitive impairment during life. Chronic traumatic encephalopathy neuropathological change was identified in four out of the six cases. However, coexisting neuropathologies were common, with limbic‐predominant age‐related TDP‐43 encephalopathy and ageing‐related tau astrogliopathy seen in all cases, intermediate or high Alzheimer's disease neuropathological change seen in four cases and hippocampal sclerosis seen in two of the six cases.ConclusionThe presence of multiple neuropathologies in these cases complicates clinical diagnostic efforts for traumatic encephalopathy syndrome. It will be important for further clinicopathological studies on larger groups to report all neuropathological comorbidities found in cases diagnosed with either chronic traumatic encephalopathy neuropathological change and/or traumatic encephalopathy syndrome.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"1152 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140169079","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":"Changes in the locus coeruleus during the course of Alzheimer's disease and their relationship to cortical pathology","authors":"Rebecca Beardmore, Matthew Durkin, Faizan Zayee-Mellick, Laurie C. Lau, James A. R. Nicoll, Clive Holmes, Delphine Boche","doi":"10.1111/nan.12965","DOIUrl":"https://doi.org/10.1111/nan.12965","url":null,"abstract":"In Alzheimer's disease (AD), the locus coeruleus (LC) undergoes early and extensive neuronal loss, preceded by abnormal intracellular tau aggregation, decades before the onset of clinical disease. Neuromelanin-sensitive MRI has been proposed as a method to image these changes during life. Surprisingly, human post-mortem studies have not examined how changes in LC during the course of the disease relate to cerebral pathology following the loss of the LC projection to the cortex.","PeriodicalId":19151,"journal":{"name":"Neuropathology and Applied Neurobiology","volume":"39 1","pages":""},"PeriodicalIF":5.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139767409","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}