Journal of Neuropathology and Experimental Neurology最新文献_第2页

Neuropathological findings of very low-density lipoprotein receptor-related cerebellar hypoplasia in a full-term fetus. 足月胎儿极低密度脂蛋白受体相关小脑发育不全的神经病理学表现。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-09-11 DOI: 10.1093/jnen/nlaf110

John Michael Newman, Hannes Vogel

引用次数: 0

3D spatial sampling to quantify morphologic heterogeneity in isocitrate dehydrogenase-wildtype glioblastoma. 三维空间采样量化异柠檬酸脱氢酶野生型胶质母细胞瘤的形态异质性。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-09-03 DOI: 10.1093/jnen/nlaf101

Viva Voong, Sol Beccari, Elaheh Hashemi, Birgit Kriener, Radhika Mathur, Marisa Lafontaine, Anny Shai, Janine M Lupo, Edward F Chang, Shawn L Hervey-Jumper, Mitchel S Berger, Sebastian M Waszak, Joseph F Costello, Joanna J Phillips

{"title":"3D spatial sampling to quantify morphologic heterogeneity in isocitrate dehydrogenase-wildtype glioblastoma.","authors":"Viva Voong, Sol Beccari, Elaheh Hashemi, Birgit Kriener, Radhika Mathur, Marisa Lafontaine, Anny Shai, Janine M Lupo, Edward F Chang, Shawn L Hervey-Jumper, Mitchel S Berger, Sebastian M Waszak, Joseph F Costello, Joanna J Phillips","doi":"10.1093/jnen/nlaf101","DOIUrl":"https://doi.org/10.1093/jnen/nlaf101","url":null,"abstract":"Advances in digital pathology and machine learning have the potential to revolutionize diagnostic neuropathology. Current brain tumor models are typically trained and validated using morphologic features from a single hematoxylin and eosin (H&E)-stained slide per patient. Yet, brain tumors such as diffuse glioma are known for their epigenetic, genetic, and transcriptional heterogeneity within an individual patient. The impact of this heterogeneity on model accuracy and development is unknown. To quantitatively investigate morphologic intratumoral heterogeneity in glioblastoma (GBM), we acquired 92 regionally distinct samples representing maximal tumor sampling across 10 patients with isocitrate dehydrogenase-wildtype GBM and quantified cell density, nucleus area, and nucleus circularity from whole-slide scanned images of H&E-stained slides. All 3 parameters exhibited significant morphologic variation between tumors from different patients and within a given tumor. To identify potential drivers of this variation, tumor-level and sample-level mutation profiling was performed. Mutations in tumor protein 53 both at the tumor level and the sample level had larger nuclear area and decreased nuclear circularity. Morphological features were not associated with regional location within the tumor. Accurate and robust H&E-based models to improve diagnosis and disease prognostication may require training sets that incorporate multiple spatially distinct samples per patient.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A fixed brain seeded amplification assay to complement neuropathological prion disease diagnosis. 固定脑种子扩增试验补充神经病理朊病毒病的诊断。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-09-03 DOI: 10.1093/jnen/nlaf105

Victoria Lewis, Laura Ellett, Enie Lei, Christiane Stehmann, Ian Birchall, Matteo Senesi, Catriona McLean, Steven J Collins

{"title":"A fixed brain seeded amplification assay to complement neuropathological prion disease diagnosis.","authors":"Victoria Lewis, Laura Ellett, Enie Lei, Christiane Stehmann, Ian Birchall, Matteo Senesi, Catriona McLean, Steven J Collins","doi":"10.1093/jnen/nlaf105","DOIUrl":"https://doi.org/10.1093/jnen/nlaf105","url":null,"abstract":"Prion diseases are rare neurodegenerative disorders that share misfolding of the normal cellular prion protein into disease-causing isoforms known as \"prions\" as the critical pathophysiological event. Definite diagnosis can only be achieved through neuropathological confirmation. The neuropathological features of prion disease are well described; however, some molecular subtypes are typified by characteristic neuropathological features that are subtle or absent. Prion seeding assays have excellent specificity and have considerably improved premortem diagnostic accuracy but they have reduced sensitivity for some uncommon prion disease molecular subtypes. We developed a formalin-fixed, paraffin-embedded tissue-based prion seeding assay to serve as a complementary diagnostic tool for prion diseases. Fixed brain tissue was prepared through an optimized process involving careful defacing of tissue blocks prior to sampling and then stepwise deparaffinization and homogenization. Fixed tissue homogenates are then tested in an adapted version of a diagnostic cerebrospinal fluid (CSF) prion seeding assay, which utilizes full-length recombinant hamster prion protein as substrate. Two examples illustrate the utility of the assay by confirming prion seeding in fixed brain tissue from previously neuropathologically misdiagnosed obligate carriers of 2 different prion protein gene mutations. The importance of careful tissue sampling to rigorously maintain the diagnostic specificity of this assay is also highlighted.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neuropathologic findings in a community-based autopsy cohort of older, virally suppressed, people with HIV. 基于社区的老年、病毒抑制的HIV感染者尸检队列的神经病理学发现。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-29 DOI: 10.1093/jnen/nlaf102

Thomas D Zaikos, Haidan Guo, Alex Barrett, Raha Dastgheyb, Leah H Rubin, Juan Troncoso, Meaghan Morris

{"title":"Neuropathologic findings in a community-based autopsy cohort of older, virally suppressed, people with HIV.","authors":"Thomas D Zaikos, Haidan Guo, Alex Barrett, Raha Dastgheyb, Leah H Rubin, Juan Troncoso, Meaghan Morris","doi":"10.1093/jnen/nlaf102","DOIUrl":"10.1093/jnen/nlaf102","url":null,"abstract":"Combination antiretroviral therapy (cART) has reduced the incidence of HIV-related mortality, leading to a growing population of older virally suppressed people with HIV (PWH). cART has also decreased the prevalence of HIV-associated dementia; however, many virally suppressed PWH still experience milder forms of cognitive impairment. It remains unclear whether aging virally suppressed PWH demonstrate distinct risks or patterns of neurodegenerative pathology. We examined brain tissue of 13 virally suppressed PWH and 13 matched HIV-negative controls from a community-based cohort and characterized β-amyloid (Aβ), tau, α-synuclein, and TDP-43 pathology. Both groups had similar demographics, medical comorbidities, and routine histologic brain findings. PWH demonstrated trends toward an increased prevalence of both Alzheimer disease (AD) and non-AD neurodegenerative pathologies, including Aβ pathology, higher stage tau pathology, aging-related tau astrogliopathy, and α-synuclein pathology. They showed similar trends toward increased severity of Aβ and tau pathology. We also identified a negative correlation between the burden of entorhinal cortical neurofibrillary tangles and end-of-life body mass index in PWH. Thus, PWH may have a greater burden of neurodegenerative pathology, including both AD and non-AD neurodegenerative pathologies; there is a need for the assessment of neurodegenerative pathology in community-based cohort studies to understand mechanisms of HIV-associated neuropathology and cognitive impairment in aging virally suppressed PWH.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144958022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Desmoplastic myxoid tumor of the pineal region presenting with Parinaud syndrome. 以Parinaud综合征为表现的松果体区结缔组织增生黏液样瘤。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-20 DOI: 10.1093/jnen/nlaf096

Tal Jonatan Koren, Michael Back, Jason Chen, Kate Ahmad

引用次数: 0

Downregulating Cdk5 reverses hippocampal neuron ferroptosis by regulating the AMP-activated protein kinase pathway and "M1" polarized microglia. 下调Cdk5通过调节amp激活的蛋白激酶途径和“M1”极化小胶质细胞逆转海马神经元铁下垂。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-19 DOI: 10.1093/jnen/nlaf092

Na Liu, Aini Peng, Bo Peng, Haiping Xia, Zhenzhen Zhang, Dandan Zhang, Shoucheng Xu, Hang Xu

{"title":"Downregulating Cdk5 reverses hippocampal neuron ferroptosis by regulating the AMP-activated protein kinase pathway and \"M1\" polarized microglia.","authors":"Na Liu, Aini Peng, Bo Peng, Haiping Xia, Zhenzhen Zhang, Dandan Zhang, Shoucheng Xu, Hang Xu","doi":"10.1093/jnen/nlaf092","DOIUrl":"10.1093/jnen/nlaf092","url":null,"abstract":"Aberrant activation of microglia plays a crucial role in neuronal injury after ischemic stroke. Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine-directed kinase that plays a significant role in neuronal damage. We investigated the role of Cdk5 in microglial activation and neuronal ferroptosis in cellular and animal models of hypoxic-ischemic neuronal injury. Treatment with the Cdk5 inhibitor (S)-roscovitine (Ros) and/or an AMPK pathway activator metformin (Met) were investigated in a middle cerebral artery occlusion/reperfusion (MCAO/R) model in C57BL/6J mice. The results showed that Ros and Met improved neurological functions, brain edema, mitigated \"M1\" polarization of microglia, and inhibited neuronal ferroptosis. The combination of Ros and Met had additive effects on the MCAO/R mice. Ros and Met suppressed the expression of Cdk5 and inhibited NF-κB pathway activation, whereas the AMPK inhibitor Compound C (CC) reversed the neuroprotective and anti-inflammatory effects of Ros and Met. In vitro assays revealed that Ros and Met inhibited the proinflammatory reactions of BV2 microglia and the damage and ferroptosis of HT22 cells after OGD/R stimulation; these effects were also reversed by CC. These results indicate that targeting Cdk5 and AMPK mitigated microglia-mediated neuroinflammation and reduced neuronal ferroptosis in ischemic stroke models.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

METTL14/IGF2BP2-mediated m6A modification of PD-L1 promotes proliferation, metastasis, and immune escape in high-grade gliomas. METTL14/ igf2bp2介导的m6A修饰PD-L1促进高级别胶质瘤的增殖、转移和免疫逃逸。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-11 DOI: 10.1093/jnen/nlaf090

Zexiang Zhang, Xiaoyu Guo, Tengfei Qi, Chongcheng Wang, Xiaodong Zhai, Min Wang

{"title":"METTL14/IGF2BP2-mediated m6A modification of PD-L1 promotes proliferation, metastasis, and immune escape in high-grade gliomas.","authors":"Zexiang Zhang, Xiaoyu Guo, Tengfei Qi, Chongcheng Wang, Xiaodong Zhai, Min Wang","doi":"10.1093/jnen/nlaf090","DOIUrl":"https://doi.org/10.1093/jnen/nlaf090","url":null,"abstract":"N6-methyladenosine (m6A) RNA modification is involved in regulating the malignant progression and immune escape of glioblastoma multiforme (GBM). This study investigated the role of methyltransferase-like protein 14 (METTL14), the central component of the m6A methylated transferase complex, in GBM progression and immune escape. METTL14 and programmed death ligand 1 (PD-L1) levels were analyzed by qRT-PCR and Western blot in human GBM samples. Effects of METTL14 knockdown on GBM tumorigenesis were investigated in mouse tumor xenografts. GBM cell proliferation and metastasis were examined by colony formation assay and transwell assay; immune escape was assessed by detecting cytotoxicity, immune-related markers, and exhaustion markers. The interaction between PD-L1 and METTL14 or the m6A reader IGF2BP2 was confirmed by MeRIP assay and RIP assay. METTL14 was upregulated in GBM tissues and cells and its knockdown reduced GBM tumor growth in the xenografts. Downregulation of METTL14 could suppress GBM cell proliferation, metastasis, and immune escape. METTL14 stabilized PD-L1 mRNA; this modification could be recognized by IGF2BP2. Moreover, PD-L1 overexpression eliminated the inhibitory effect of METTL14 knockdown on GBM cell proliferation, metastasis, and immune escape. In conclusion, METTL14-mediated m6A modification of PD-L1 contributed to GBM cell proliferation, metastasis, and immune escape in an IGF2BP2-dependent manner.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis. 小鼠前脑蛋白酶体功能障碍诱导线粒体DNA释放、cGAS-STING信号激活和坏死下垂。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-01 DOI: 10.1093/jnen/nlaf093

Abena Dwamena, Yasin Asadi, Erin Gilstrap, Hongmin Wang

{"title":"Proteasomal dysfunction in the mouse forebrain induces mitochondrial DNA release, cGAS-STING signaling activation, and necroptosis.","authors":"Abena Dwamena, Yasin Asadi, Erin Gilstrap, Hongmin Wang","doi":"10.1093/jnen/nlaf093","DOIUrl":"https://doi.org/10.1093/jnen/nlaf093","url":null,"abstract":"Impaired proteasome function is associated with various neurodegenerative disorders that are hallmarked by neuroinflammation and neurodegeneration, including Alzheimer disease (AD); however, the relationships between these phenomena remain unclear. By utilizing a neuron-specific Psmc1 conditional knockout (cKO) mouse model in which one of the 19S proteasome is disrupted, we studied the effect of impaired proteasome function on neuroinflammation and neuronal death in the brain. We discovered that disrupting the 19S proteasome led to increased release of mitochondrial double-stranded DNA into the cytosol, upregulated levels of cyclic GMP-AMP synthase (cGAS), stimulator of interferon gene (STING), phosphorylated TBK1, and IRF3, and the downstream pro-inflammatory mediators, including STAT1, NF-κB, IL-1β, IL-6, and TNFα in the cKO mouse brains as compared to control brains. Importantly, we also observed reduced brain weight and elevation in levels of factors involved in necroptosis, ie the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interacting protein kinases (RIPK) 1 and 3 in the cKO mouse brains. Together, our data suggest that proteasome dysfunction activates the cGAS-STING pathway and induces neuroinflammation and necroptotic neuronal death.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reliability and modeling of digital histological measurements in Alzheimer's disease neuropathologic change and Lewy body disease. 阿尔茨海默病、神经病理改变和路易体病的数字化组织学测量的可靠性和建模。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-01 DOI: 10.1093/jnen/nlaf047

Yongya Kim, Thea Andreasson, Namitha Vishupad, Avani Benegal, Donald Pizzo, Lawrence Hansen, Annie Hiniker, David Coughlin

{"title":"Reliability and modeling of digital histological measurements in Alzheimer's disease neuropathologic change and Lewy body disease.","authors":"Yongya Kim, Thea Andreasson, Namitha Vishupad, Avani Benegal, Donald Pizzo, Lawrence Hansen, Annie Hiniker, David Coughlin","doi":"10.1093/jnen/nlaf047","DOIUrl":"10.1093/jnen/nlaf047","url":null,"abstract":"Digital histology offers a more objective, continuous definition of neuropathological severity than traditional staging systems, but its reliability remains underexplored. We calculated regional percentage areas occupied by phosphorylated tau (p-Tau, AT8), amyloid-β (Aβ, NAB228), and phosphorylated α-synuclein (p-αSyn, 81A) pathology in 24 autopsied cases with varying degrees of Alzheimer disease neuropathological change and Lewy body disease (LBD) using manual and automated immunostaining methods to investigate variability across protocols. We then compared natural log-transformed percent area occupied values (ln%AO) to blinded ordinal severity scores, Braak stages, Thal phases, and McKeith LBD stages. p-Tau ln%AO from methodologically similar runs had the highest correlations (R2 = 0.91-0.95, β = 0.95-0.97 for manual and automated methods, respectively); p-αSyn ln%AO from disparate immunostaining methods had the lowest (R2 = 0.16-0.34 β = 0.40-0.59). p-Tau and Aβ ln%AO increased regionally with higher Braak and Thal stages (p-Tau: z = 2.06 P = .04. Aβ: z = 3.70 P < .001). Regional p-αSyn ln%AO increased from limbic to neocortical stages (z = 5.86 P < .001); amygdala-predominant type LBD cases peaked in the amygdala and dropped in other limbic regions. These findings show the potential to quantify differences in p-Tau, Aβ, and p-αSyn pathologies using digital histological methods in single-center studies.","PeriodicalId":16682,"journal":{"name":"Journal of Neuropathology and Experimental Neurology","volume":" ","pages":"725-733"},"PeriodicalIF":3.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12277698/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144018852","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CAPNON: A rare entity with long-term follow-up. CAPNON：罕见的长期随访病例。

IF 3 3区医学

Journal of Neuropathology and Experimental Neurology Pub Date : 2025-08-01 DOI: 10.1093/jnen/nlaf097

Thomas Auen, Jerrold Boxerman, Christine Z Yu, Deus Cielo, John E Donahue, Douglas Anthony

引用次数: 0