Artificial intelligence in histopathological image analysis of central nervous system tumours: A systematic review

人工智能在中枢神经系统肿瘤组织病理学图像分析中的系统评价

The convergence of digital pathology and artificial intelligence could assist histopathology image analysis by providing tools for rapid, automated morphological analysis. This systematic review explores the use of artificial intelligence for histopathological image analysis of digitised central nervous system (CNS) tumour slides. Comprehensive searches were conducted across EMBASE, Medline and the Cochrane Library up to June 2023 using relevant keywords. Sixty-eight suitable studies were identified and qualitatively analysed. The risk of bias was evaluated using the Prediction model Risk of Bias Assessment Tool (PROBAST) criteria. All the studies were retrospective and preclinical. Gliomas were the most frequently analysed tumour type. The majority of studies used convolutional neural networks or support vector machines, and the most common goal of the model was for tumour classification and/or grading from haematoxylin and eosin-stained slides. The majority of studies were conducted when legacy World Health Organisation (WHO) classifications were in place, which at the time relied predominantly on histological (morphological) features but have since been superseded by molecular advances. Overall, there was a high risk of bias in all studies analysed. Persistent issues included inadequate transparency in reporting the number of patients and/or images within the model development and testing cohorts, absence of external validation, and insufficient recognition of batch effects in multi-institutional datasets. Based on these findings, we outline practical recommendations for future work including a framework for clinical implementation, in particular, better informing the artificial intelligence community of the needs of the neuropathologist.

数字病理学和人工智能的融合可以通过提供快速，自动化的形态分析工具来辅助组织病理学图像分析。本系统综述探讨了人工智能在数字化中枢神经系统 (CNS) 肿瘤载玻片的组织病理学图像分析中的应用。直到2023年6月，使用相关关键字在EMBASE，Medline和Cochrane图书馆进行了全面搜索。确定并定性分析了68项合适的研究。使用预测模型偏倚风险评估工具 (PROBAST) 标准评估偏倚风险。所有研究均为回顾性和临床前研究。神经胶质瘤是最常分析的肿瘤类型。大多数研究使用卷积神经网络或支持向量机，该模型最常见的目标是从苏木精和伊红染色的载玻片进行肿瘤分类和/或分级。大多数研究是在遗留的世界卫生组织 (WHO) 分类到位时进行的，当时主要依赖于组织学 (形态学) 特征，但此后已被分子进步所取代。总体而言，所有分析的研究都有很高的偏倚风险。持续存在的问题包括在模型开发和测试队列中报告患者和/或图像数量的透明度不足，缺乏外部验证以及对多机构数据集中的批次效应的认识不足。基于这些发现，我们概述了未来工作的实际建议，包括临床实施框架，特别是更好地向人工智能社区告知神经病理学家的需求。

REF: Jensen MP, Qiang Z, Khan DZ, et al. Artificial intelligence in histopathological image analysis of central nervous system tumours: A systematic review. Neuropathol Appl Neurobiol. 2024;50(3):e12981. doi:10.1111/nan.12981 PMID: 38738494

Interferon-gamma contributes to disease progression in the Ndufs4(−/−) model of Leigh syndrome

干扰素-γ 有助于Leigh综合征的Ndufs4 (-/-) 模型的疾病进展

The brainstems of diseased Ndufs4(−/−) mice—a mouse model of the genetic mitochondrial disease Leigh syndrome (LS)—have elevated levels of cytokines IP10 and IFNγ. To explore the role of these two factors in LS, we generated IFNγ and IP10 deficient Ndufs4(−/−) mice and evaluated survival and disease pathology. Loss of IP10 does not impact disease in Ndufs4(−/−) mice, but IFNγ loss prolongs survival and delays disease progression, indicating that IFNγ signaling contributes to disease onset and progression in LS.

患病的Ndufs4 (-/-) 小鼠的脑instems-遗传线粒体疾病Leigh综合征 (LS) 的小鼠模型-具有升高的细胞因子IP10和ifn γ 水平。为了探索这两个因素在LS中的作用，我们产生了ifn γ 和IP10缺陷的Ndufs4 (-/-) 小鼠，并评估了存活和疾病病理学。IP10的丧失不影响Ndufs4 (-/-) 小鼠的疾病，但ifn γ 的丧失延长了生存期并延迟了疾病进展，表明ifn γ 信号传导有助于LS的疾病发作和进展。

REF: Hanaford AR, Khanna A, James K, et al. Interferon-gamma contributes to disease progression in the Ndufs4(-/-) model of Leigh syndrome. Neuropathol Appl Neurobiol. 2024;50(3):e12977. doi:10.1111/nan.12977 PMID: 38680020

Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1G93A ALS mouse model

在SOD1G93A ALS小鼠模型中，表达小胶质细胞和星形胶质细胞的MMP-9吞噬了神经周神经网

Perineuronal nets (PNNs) surrounding motoneurons in ALS model mice are broken down by a process of MMP-9 release from and engulfment by microglia and astrocytes, during disease progression. (1) Activated microglia and astrocytes are recruited to motoneurons. (2) MMP-9 released by these microglia assist in the breakdown of PNNs around motoneurons and digest PNN fragments. (3) CX3CL1 released from motoneurons triggers microglia to phagocytose PNNs. (4) These motoneurons are then made vulnerable to stress as seen by the upregulation of 3-NT.

在疾病进展期间，ALS模型小鼠中运动神经元周围的神经网络 (pnn) 通过小胶质细胞和星形胶质细胞释放和吞噬MMP-9的过程而被分解。(1) 激活的小胶质细胞和星形胶质细胞被募集到运动神经元。(2) 这些小胶质细胞释放的MMP-9有助于分解运动神经元周围的PNN并消化PNN片段。(3) 运动神经元释放的CX3CL1触发小胶质细胞吞噬PNNs。(4) 从3-NT的上调可以看出，这些运动神经元容易受到压力的影响。

REF: Cheung SW, Bhavnani E, Simmons DG, Bellingham MC, Noakes PG. Perineuronal nets are phagocytosed by MMP-9 expressing microglia and astrocytes in the SOD1G93A ALS mouse model. Neuropathol Appl Neurobiol. 2024;50(3):e12982. doi:10.1111/nan.12982 PMID: 38742276

Accurate and comprehensive evaluation of O6-methylguanine-DNA methyltransferase promoter methylation by nanopore sequencing

纳米孔测序准确全面评价O6-methylguanine-DNA甲基转移酶启动子甲基化

We assessed the effectiveness of nanopore long-read sequencing for evaluatingmethylation levels across the MGMT CpG-island, crucial for prognosis in glioblastomapatients. Using 165 CNS tumour samples, nanopore sequencing was compared toestablished techniques, showing a strong correlation with pyrosequencing and effectivepatient stratification via hierarchical clustering. Nanopore sequencing provided rapid,high-confidence results and expanded analysis to all 98 CpGs of the MGMT CpG-island,suggesting its utility for clinically relevant patient subgroup identification and warranting further exploration in clinical settings.

我们评估了纳米孔长读测序评估MGMT CpG岛甲基化水平的有效性，这对胶质母细胞瘤患者的预后至关重要。使用165个CNS肿瘤样本，将纳米孔测序与已建立的技术进行比较，显示出与焦磷酸测序的强相关性以及通过分层聚类的有效患者分层。纳米孔测序提供了快速，高置信度的结果，并对MGMT CpG岛的所有98个CpG进行了扩展分析，表明其在临床相关患者亚组鉴定中的实用性，并保证了在临床环境中的进一步探索。

REF: Halldorsson S, Nagymihaly RM, Patel A, et al. Accurate and comprehensive evaluation of O6-methylguanine-DNA methyltransferase promoter methylation by nanopore sequencing. Neuropathol Appl Neurobiol. 2024;50(3):e12984. doi:10.1111/nan.12984 PMID: 38783575

Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains

氨基末端延长的a β 肽由分泌的金属蛋白酶ADAMTS4产生，并沉积在阿尔茨海默氏病的大脑中

The role of the metalloproteinase ADAMTS4 in the generation of N-terminally elongated Aβ peptide species has been characterized with cell-free and cell-based assays in combination with mass spectrometry. Immunohistochemical analysis revealed the deposition of N-terminally elongated Ab variants in the brains of a subset of AD patients.

金属蛋白酶ADAMTS4在产生N末端延长的a β 肽种类中的作用已通过无细胞和基于细胞的测定与质谱联用进行了表征。免疫组织化学分析揭示了N末端伸长的Ab变体在一部分AD患者的大脑中的沉积。

REF: Wirths O, Lehnen C, Fricke M, et al. Amino-terminally elongated Aβ peptides are generated by the secreted metalloprotease ADAMTS4 and deposit in a subset of Alzheimer's disease brains. Neuropathol Appl Neurobiol. 2024;50(3):e12991. doi:10.1111/nan.12991 PMID: 38867123

NLRP3 promotes radiation-induced brain injury by regulating microglial pyroptosis

NLRP3通过调控小胶质细胞焦亡促进放射性脑损伤

Radiation induced pyroptosis in microglia, promoting radiation-induced brain injury via the secretion of neurotoxic cytokines. NLRP3 was evaluated as an important mediator in radiation-induced pyroptosis and a promising therapeutic target of radiation-induced brain injury. The patients after irradiation with higher IL-6 were found to have a decreased MMSE score, indicating that the level of IL-6 could serve as a valuable biomarker for radiation-induced brain injury.

辐射诱导的小胶质细胞焦亡，通过神经毒性细胞因子的分泌促进放射性脑损伤。NLRP3被评估为辐射诱导的焦亡的重要介质，并且是辐射诱导的脑损伤的有希望的治疗靶标。发现接受较高IL-6照射后的患者的MMSE评分降低，表明IL-6水平可以作为放射性脑损伤的有价值的生物标志物。

REF: Zhang W, Wu Q, Zhang X, et al. NLRP3 promotes radiation-induced brain injury by regulating microglial pyroptosis. Neuropathol Appl Neurobiol. 2024;50(3):e12992. doi:10.1111/nan.12992 PMID: 38831600

Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle

与骨骼肌中glycogenin-1缺乏相关的聚葡聚糖体的蛋白质组学分析

Polyglucosan storage disorders represent an emerging field within neurodegenerative and neuromuscular conditions. We combined molecular genetic analyses, quantitative mass spectrometry of laser micro-dissected polyglucosan bodies, immunohistochemistry and western blot, and show that the absence of glycogenin-1 (GYG1), a protein important for glycogen synthesis initiation, causes storage of polyglucosan that displays accumulation of several proteins, including those essential for glycogen synthesis, sequestosome 1/p62 and desmin.

聚葡聚糖贮积症代表了神经退行性和神经肌肉疾病中的新兴领域。我们结合了分子遗传分析，激光显微解剖的聚葡聚糖体的定量质谱，免疫组织化学和蛋白质印迹，并显示glycogenin-1 (GYG1) 的缺失，一种对糖原合成起始重要的蛋白质，导致聚葡聚糖的储存，显示几种蛋白质的积累，包括糖原合成所必需的蛋白质，sequestosome 1/p62和结蛋白。

REF: Visuttijai K, Hedberg-Oldfors C, Costello DJ, Bermingham N, Oldfors A. Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle. Neuropathol Appl Neurobiol. 2024;50(3):e12995. doi:10.1111/nan.12995 PMID: 38923610

Diffuse infiltrating tumour with the molecular profile of an atypical teratoid rhabdoid tumour (AT/RT SHH-1B) in an adult patient

成人患者中具有非典型畸形性横纹肌样瘤 (AT/RT SHH-1B) 分子特征的弥漫性浸润性肿瘤

In this case report, we describe a 46-year-old patient with a brain lesion identified with imaging studies following a minor head injury. Initially suspected to be diffuse glioma, detailed histological, immunohistochemical and molecular investigations revealed characteristics consistent with an atypical teratoid/rhabdoid tumour (AT/RT), SHH-1B molecular subtype.

在此病例报告中，我们描述了一名46岁的患者，该患者在轻度头部受伤后通过影像学检查确定了脑部病变。最初怀疑是弥漫性神经胶质瘤，详细的组织学，免疫组织化学和分子研究显示，其特征与非典型畸形性/横纹肌样肿瘤 (AT/RT) SHH-1B分子亚型一致。

REF: Cordier F, Schouten JW, Geurts M, et al. Diffuse infiltrating tumour with the molecular profile of an atypical teratoid rhabdoid tumour (AT/RT SHH-1B) in an adult patient. Neuropathol Appl Neurobiol. 2024;50(3):e12983. doi:10.1111/nan.12983 PMID: 38708554