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Rapid brain lymphoma diagnostics through nanopore sequencing of cytology-negative cerebrospinal fluid 通过对细胞学阴性脑脊液进行纳米孔测序快速诊断脑淋巴瘤。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00401-024-02793-z
J. Hench, C. Hultschig, I. Bratic Hench, H. Sadasivan, Ö Yaldizli, G. Hutter, S. Dirnhofer, A. Tzankov, S. Frank
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引用次数: 0
Glioblastoma, IDH-wildtype with primarily leptomeningeal localization diagnosed by nanopore sequencing of cell-free DNA from cerebrospinal fluid 通过对脑脊液中的无细胞DNA进行纳米孔测序,诊断出主要位于脑膜外的IDH-野生型胶质母细胞瘤。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00401-024-02792-0
Nik Sol, Evert-Jan Kooi, Marc Pagès-Gallego, Dieta Brandsma, Marianna Bugiani, Jeroen de Ridder, Pieter Wesseling, Carlo Vermeulen
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引用次数: 0
Association of quantitative histopathology measurements with antemortem medial temporal lobe cortical thickness in the Alzheimer’s disease continuum 定量组织病理学测量与阿尔茨海默氏症连续症中死前颞叶内侧皮质厚度的关联。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-09-03 DOI: 10.1007/s00401-024-02789-9
Amanda E. Denning, Ranjit Ittyerah, Lisa M. Levorse, Niyousha Sadeghpour, Chinmayee Athalye, Eunice Chung, Sadhana Ravikumar, Mengjin Dong, Michael Tran Duong, Yue Li, Ademola Ilesanmi, Lasya P. Sreepada, Philip Sabatini, MaKayla Lowe, Alejandra Bahena, Jamila Zablah, Barbara E. Spencer, Ryohei Watanabe, Boram Kim, Maja Højvang Sørensen, Pulkit Khandelwal, Christopher Brown, Stanislau Hrybouski, Sharon X. Xie, Robin de Flores, John L. Robinson, Theresa Schuck, Daniel T. Ohm, Sanaz Arezoumandan, Sílvia Porta, John A. Detre, Ricardo Insausti, Laura E. M. Wisse, Sandhitsu R. Das, David J. Irwin, Edward B. Lee, David A. Wolk, Paul A. Yushkevich

The medial temporal lobe (MTL) is a hotspot for neuropathology, and measurements of MTL atrophy are often used as a biomarker for cognitive decline associated with neurodegenerative disease. Due to the aggregation of multiple proteinopathies in this region, the specific relationship of MTL atrophy to distinct neuropathologies is not well understood. Here, we develop two quantitative algorithms using deep learning to measure phosphorylated tau (p-tau) and TDP-43 (pTDP-43) pathology, which are both known to accumulate in the MTL and are associated with MTL neurodegeneration. We focus on these pathologies in the context of Alzheimer’s disease (AD) and limbic predominant age-related TDP-43 encephalopathy (LATE) and apply our deep learning algorithms to distinct histology sections, on which MTL subregions were digitally annotated. We demonstrate that both quantitative pathology measures show high agreement with expert visual ratings of pathology and discriminate well between pathology stages. In 140 cases with antemortem MR imaging, we compare the association of semi-quantitative and quantitative postmortem measures of these pathologies in the hippocampus with in vivo structural measures of the MTL and its subregions. We find widespread associations of p-tau pathology with MTL subregional structural measures, whereas pTDP-43 pathology had more limited associations with the hippocampus and entorhinal cortex. Quantitative measurements of p-tau pathology resulted in a significantly better model of antemortem structural measures than semi-quantitative ratings and showed strong associations with cortical thickness and volume. By providing a more granular measure of pathology, the quantitative p-tau measures also showed a significant negative association with structure in a severe AD subgroup where semi-quantitative ratings displayed a ceiling effect. Our findings demonstrate the advantages of using quantitative neuropathology to understand the relationship of pathology to structure, particularly for p-tau, and motivate the use of quantitative pathology measurements in future studies.

内侧颞叶(MTL)是神经病理学的热点区域,对MTL萎缩的测量通常被用作与神经退行性疾病相关的认知能力下降的生物标志物。由于该区域聚集了多种蛋白病,MTL萎缩与不同神经病理学的具体关系还不十分清楚。在这里,我们利用深度学习开发了两种定量算法来测量磷酸化 tau(p-tau)和 TDP-43(pTDP-43)的病理变化,已知这两种病理变化都会在 MTL 中聚集,并与 MTL 神经变性有关。我们重点研究了阿尔茨海默病(AD)和肢端占优势的年龄相关 TDP-43 脑病(LATE)的病理变化,并将深度学习算法应用于不同的组织学切片,在这些切片上对 MTL 亚区进行了数字注释。我们证明,这两种定量病理学测量方法与专家的病理学目测评级具有很高的一致性,并能很好地区分不同的病理学阶段。在 140 个有死前磁共振成像的病例中,我们比较了海马中这些病理变化的半定量和定量死后测量值与 MTL 及其亚区的活体结构测量值之间的关联。我们发现p-tau病变与MTL亚区域结构测量结果存在广泛关联,而pTDP-43病变与海马和内侧皮层的关联则较为有限。与半定量评分相比,p-tau病理的定量测量能更好地建立死前结构测量模型,并显示出与皮质厚度和体积的密切联系。通过提供更精细的病理测量结果,定量p-tau测量结果还显示,在半定量评分显示出天花板效应的严重AD亚组中,p-tau测量结果与结构呈显著负相关。我们的研究结果证明了使用定量神经病理学方法来了解病理学与结构之间关系的优势,尤其是p-tau,这也促使我们在未来的研究中使用定量病理学测量方法。
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引用次数: 0
Histopathologic correlates of opioid-associated injury in CHANTER syndrome: first report of a post-mortem examination 陈特综合征中阿片相关损伤的组织病理学相关性:首次尸检报告
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-31 DOI: 10.1007/s00401-024-02797-9
Katherine E. Schwetye, Lakshmi Ramachandran Nair, Joseph Boyle, Jed A. Barash

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.

阿片类药物相关脑损伤可能涉及选择性区域,包括单纯海马、苍白球和小脑半球。例如,阿片相关失忆综合征就是海马损伤的一种临床表现,表现为核磁共振成像异常。当这三个区域都受累时,可能是一种更严重的损伤,这种综合征被称为 "小脑、海马和基底核一过性水肿伴弥散受限(CHANTER)",最初是在 2019 年描述的。据我们所知,迄今为止,CHANTER 综合征的影像学发现还没有组织病理学相关性。在此,我们首次展示了一名因芬太尼中毒后并发 CHANTER 综合征而死亡的患者的尸检脑组织病理学结果。这些观察结果包括微出血、反应性和坏死性血管、嗜酸性粒细胞性神经元坏死、轴突肿胀和球形体以及明显的梗死。这些研究结果支持以前的实验模型,即缺氧缺血和细胞毒性机制都与陈氏综合征的组织损伤有关,但还需要进一步研究,以更好地确定所涉及的确切细胞通路,从而开发出有针对性的治疗方法。
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引用次数: 0
Disability independent of cerebral white matter demyelination in progressive multiple sclerosis 进行性多发性硬化症患者的残疾与脑白质脱髓鞘无关
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-31 DOI: 10.1007/s00401-024-02796-w
Vikas Singh, Yufan Zheng, Daniel Ontaneda, Kedar R Mahajan, Jameson Holloman, Robert J Fox, Kunio Nakamura, Bruce D Trapp

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 in situ 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.

人们对导致进行性多发性硬化症(PMS)神经系统残疾的致病机制知之甚少。脊髓皮质多发性硬化症(MCMS)中独立于大脑白质(WM)脱髓鞘的皮质神经元缺失,以及具有广泛皮质萎缩和独立于复发活动(PIRA)的残疾进展的多发性硬化症患者的鉴定,都支持大脑WM脱髓鞘以外的致病机制。研究人员对多发性硬化症死后大脑中髓鞘化 T2 病变的三维分布和潜在病理进行了调查。对先前定性的 MCMS(10 例)和典型 MS(TMS)病例(12 例)的死后脑切片与原位死后 T2 高密度和 T1 低密度进行了共同登记。利用 T1 强度阈值建立了区分 MCMS 和 TMS 的分类器。该分类器在 36 个未定性的死后大脑中进行了验证,并应用于参加 SPRINT-MS 的 255 名在世 PMS 患者的基线 MRI。MCMS死后大脑中的髓质T2高密度呈连续的脑室周围分布,并在侧脑室枕极扩展,在该处观察到髓质轴突变性的由表及里梯度。核磁共振成像分类器能区分经病理证实的尸检MCMS和TMS病例,准确率高达94%。对于 SPRINT-MS 患者,核磁共振成像分类器将 78% 识别为 TMS,10% 识别为 MCMS,12% 识别为大脑 T1 和 T2 强度不足。在 SPRINT-MS 中,MCMS 和 TMS 组群的扩展残疾状况量表和脑萎缩测量结果相似。22%的在世多发性硬化症患者存在大脑WM脱髓鞘现象,这让人怀疑大脑WM脱髓鞘在所有多发性硬化症患者的残疾进展中是否起主要作用,并对多发性硬化症患者的临床管理和多发性硬化症的临床试验结果产生了影响。脑室周围髓鞘纤维变性为多发性硬化症神经退行性变的表里梯度提供了更多支持。
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引用次数: 0
PRDM16-DT is a novel lncRNA that regulates astrocyte function in Alzheimer’s disease PRDM16-DT 是一种新型 lncRNA,可调控阿尔茨海默病的星形胶质细胞功能
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-29 DOI: 10.1007/s00401-024-02787-x
Sophie Schröder, Ulrike Fuchs, Verena Gisa, Tonatiuh Pena, Dennis M. Krüger, Nina Hempel, Susanne Burkhardt, Gabriela Salinas, Anna-Lena Schütz, Ivana Delalle, Farahnaz Sananbenesi, Andre Fischer

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 PRDM16-DT as highly enriched in the human brain, where it is almost exclusively expressed in astrocytes. PRDM16-DT and its murine homolog, Prdm16os, are downregulated in the brains of AD patients and in AD models. In line with this, knockdown of PRDM16-DT and Prdm16os 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 Prdm16os mitigated functional deficits in astrocytes induced by stimuli linked to AD pathogenesis. These findings underscore the importance of PRDM16-DT in astrocyte function and its potential as a novel therapeutic target for neurodegenerative disorders characterized by astrocyte dysfunction.

星形胶质细胞为神经元提供重要支持,有助于突触生成、突触维持和神经递质循环。在病理条件下,星形胶质细胞的失调会导致神经退行性疾病,如阿尔茨海默病(AD)。虽然这一领域的大部分研究都集中在蛋白编码基因上,但非编码 RNA,尤其是长非编码 RNA(lncRNA),已成为重要的调控分子。在这项研究中,我们发现了在人脑中高度富集的 lncRNA PRDM16-DT,它几乎只在星形胶质细胞中表达。PRDM16-DT及其鼠类同源物Prdm16os在AD患者和AD模型的大脑中下调。与此相一致,PRDM16-DT 和 Prdm16os 的敲除揭示了它在维持星形胶质细胞平衡和支持神经元功能方面的关键作用,它通过与 RE1-Silencing Transcription factor (Rest) 和 Polycomb Repressive Complex 2 (PRC2) 相互作用,调节谷氨酸摄取、乳酸释放和神经元脊柱密度所必需的基因。值得注意的是,CRISPR介导的Prdm16os过表达减轻了与AD发病机制相关的刺激诱导的星形胶质细胞的功能缺陷。这些发现强调了PRDM16-DT在星形胶质细胞功能中的重要性,以及其作为以星形胶质细胞功能障碍为特征的神经退行性疾病的新型治疗靶点的潜力。
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引用次数: 0
Inflammatory aspects of Alzheimer’s disease 阿尔茨海默病的炎症方面。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-28 DOI: 10.1007/s00401-024-02790-2
Pablo Botella Lucena, Michael T. Heneka

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.

阿尔茨海默病(AD)是最常见的慢性神经退行性疾病。阿尔茨海默病的主要病理特征是进行性认知能力下降和记忆力减退,神经变性是其主要病理特征。神经炎症在发病过程中的作用已成为研究的热点。虽然小胶质细胞--大脑中的常驻巨噬细胞--在研究中枢免疫炎症中起着关键作用,但最近的证据强调了其他细胞实体对神经炎症过程的贡献。在本文中,我们回顾了小胶质细胞和星形胶质细胞的炎症作用,重点探讨了它们与 AD 核心病理、淀粉样蛋白 beta 沉积和 tau 纠结形成之间的相互作用。此外,我们还讨论了 AD 中不同的细胞死亡调控模式如何影响慢性神经炎症环境。这篇综述旨在突出 AD 神经炎症研究不断发展的现状,并强调在开发新的治疗策略时考虑多种细胞因素的重要性。
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引用次数: 0
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 NF2相关分裂瘤病脑膜瘤的自然史与多组学分析之间的相关性表明甲基化组和免疫微环境在肿瘤生长速度中的作用。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-27 DOI: 10.1007/s00401-024-02791-1
Yu Teranishi, Andrey Yurchenko, Suzanne Tran, Philipp Sievers, Fatemeh Rajabi, Singhabahu Ruchith, Samiya Abi-Jaoude, Antoine Blouin, Franck Bielle, Dominique Cazals-Hatem, Felix Sahm, Sergey Nikolaev, Michel Kalamarides, Matthieu Peyre
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引用次数: 0
Methylation profiling of plasma cell-free DNA in pediatric brain tumor patients 小儿脑肿瘤患者血浆无细胞DNA甲基化图谱。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-26 DOI: 10.1007/s00401-024-02795-x
Shejuan An, Kathleen McCortney, Jordain Walshon, Kaethe Leonard, Brian Wray, Matthew McCord, Michael DeCuypere, Craig Horbinski
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引用次数: 0
The RNA-binding protein IGF2BP1 regulates stability of mRNA transcribed from FOXM1 target genes in hypermitotic meningiomas 核糖核酸结合蛋白 IGF2BP1 可调控高发脑膜瘤中 FOXM1 靶基因转录的 mRNA 的稳定性
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-08-23 DOI: 10.1007/s00401-024-02788-w
Nathan K. Leclair, Calixto-Hope G. Lucas, Kanish Mirchia, Kathleen McCortney, Craig M. Horbinski, David R. Raleigh, Olga Anczukow
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引用次数: 0
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Acta Neuropathologica
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