Characterisation of the tumour microenvironment in primary and recurrent glioblastomas

原发性和复发性胶质母细胞瘤中肿瘤微环境的表征

Glioblastoma patients have a dismal prognosis, due to inevitable tumour recurrence and respond poorly to immunotherapy. Tumour-associated microglia/macrophages (TAMs) dominate the glioblastoma tumour microenvironment and have been implicated in tumour progression and immune evasion. Early recurrent glioblastomas contain focal reactive regions with occasional fibrosis, chronic inflammation, TAMs and tumour cells. Surgical specimens from these tumours are rare and provide crucial insights into glioblastoma recurrence biology. This study aimed to characterise TAM- and lymphocyte phenotypes in primary vs early- and late-recurrent glioblastomas. Early recurrent glioblastomas showed enrichment for TAMs, expressing both pro- and anti-inflammatory markers and B-lymphocytes. This may indicate a time-dependent response to immunotherapy explained by time-dependent alterations in the immune-microenvironment in recurrent glioblastomas.

由于不可避免的肿瘤复发，胶质母细胞瘤患者的预后很差，并且对免疫疗法的反应很差。肿瘤相关的小胶质细胞/巨噬细胞 (tam) 在胶质母细胞瘤肿瘤微环境中占主导地位，并与肿瘤进展和免疫逃避有关。早期复发性胶质母细胞瘤包含局灶性反应区域，偶尔伴有纤维化，慢性炎症，tam和肿瘤细胞。来自这些肿瘤的手术标本很少见，并且提供了对胶质母细胞瘤复发生物学的重要见解。这项研究旨在表征原发性与早期和晚期复发性胶质母细胞瘤的TAM和淋巴细胞表型。早期复发性胶质母细胞瘤显示tam富集，表达促炎和抗炎标志物以及B淋巴细胞。这可能表明对免疫疗法的时间依赖性反应可以通过复发性胶质母细胞瘤中免疫微环境的时间依赖性改变来解释。

REF: Knudsen AM, Ewald JD, Pedersen V, Haupt-Jorgensen M, Hansen EVR, Kristensen BW. Characterisation of the tumour microenvironment in primary and recurrent glioblastomas. Neuropathol Appl Neurobiol. 2024;50(5):e13012. doi:10.1111/nan.13012 PMID: 39449228

A reassessment of spinal cord pathology in severe infantile spinal muscular atrophy: Reassessment of spinal cord pathology

严重婴儿型脊髓性肌萎缩症脊髓病理学的重新评估: 脊髓病理学的重新评估

Spinal muscular atrophy (SMA) is a life-limiting paediatric motor neuron disease characterised by lower motor neuron loss, skeletal muscle atrophy and respiratory failure, if untreated. Revolutionary treatments now extend patient survival. However, a limited understanding of the foundational neuropathology challenges the evaluation of therapeutic success. As opportunities to study treatment-naïve tissue decrease, we have characterised spinal cord pathology in severe infantile SMA using gold-standard techniques, providing a baseline to measure treatment success and therapeutic limitations. We provide robust quantification of the neuronal deficit found at the end of life in SMA spinal cord. We question long-accepted dogmas of SMA pathogenesis and shed new light on SMA neuropathology out with the ventral horn, which must be considered in future therapeutic design.

脊髓性肌萎缩症 (SMA) 是一种限制生命的儿童运动神经元疾病，如果不治疗，其特征是下运动神经元丢失，骨骼肌萎缩和呼吸衰竭。革命性的治疗方法现在延长了患者的生存期。然而，对基础神经病理学的有限理解挑战了对治疗成功的评估。随着研究治疗幼稚组织减少的机会，我们使用黄金标准技术表征了严重婴儿SMA的脊髓病理学，提供了衡量治疗成功和治疗局限性的基线。我们提供了在SMA脊髓中生命末期发现的神经元缺陷的有力量化。我们质疑长期以来接受的SMA发病机理的教条，并通过腹角为SMA神经病理学提供了新的思路，在未来的治疗设计中必须考虑这一点。

REF: Allardyce H, Lawrence BD, Crawford TO, Sumner CJ, Parson SH. A reassessment of spinal cord pathology in severe infantile spinal muscular atrophy: Reassessment of spinal cord pathology. Neuropathol Appl Neurobiol. 2024;50(5):e13013. doi:10.1111/nan.13013 PMID: 39449271

DNA methylation-array interlaboratory comparison trial demonstrates highly reproducible paediatric CNS tumour classification across 13 international centres

DNA甲基化阵列实验室间比较试验在13个国际中心展示了高度可重复的儿科CNS肿瘤分类

DNA methylation profiling, recently endorsed by the World Health Organisation (WHO) as a pivotal diagnostic tool for brain tumours, most commonly relies on bead arrays. Despite its widespread use, limited data exist on the technical reproducibility and potential cross-institutional differences. The LOGGIC Core BioClinical Data Bank registry conducted a prospective laboratory comparison trial with 12 international laboratories to enhance diagnostic accuracy for paediatric low-grade gliomas, focusing on technical aspects of DNA methylation data generation and profile interpretation under clinical real-time conditions. Our study demonstrates remarkable concordance in DNA methylation profiling and profile interpretation across 12 international centres. These findings underscore the potential contribution of DNA methylation analysis to the harmonisation of brain tumour diagnostics.

DNA甲基化分析最近被世界卫生组织 (WHO) 认可为脑肿瘤的关键诊断工具，最常见的是依赖于珠子阵列。尽管它被广泛使用，但有关技术可重复性和潜在的跨机构差异的数据有限。LOGGIC Core BioClinical Data Bank registry与12个国际实验室进行了一项前瞻性实验室比较试验，以提高儿科低级别神经胶质瘤的诊断准确性，重点关注临床实时条件下DNA甲基化数据生成和谱图解释的技术方面。我们的研究表明，在12个国际中心的DNA甲基化图谱和图谱解释中存在显着的一致性。这些发现强调了DNA甲基化分析对协调脑肿瘤诊断的潜在贡献。

REF: Chirica M, Jurmeister P, Teichmann D, et al. DNA methylation-array interlaboratory comparison trial demonstrates highly reproducible paediatric CNS tumour classification across 13 international centres. Neuropathol Appl Neurobiol. 2024;50(5):e13010. doi:10.1111/nan.13010 PMID: 39410806

Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology

阿尔茨海默氏病临床变异表现出明显的神经炎症特征与神经病理学

Although the neuroanatomical distribution of tau and amyloid-β is well studied in Alzheimer's disease (AD) (non)-amnestic clinical variants, that of neuroinflammation remains unexplored. We investigate the neuroanatomical distribution of activated myeloid cells, astrocytes, and complement alongside amyloid-β and phosphorylated tau in a clinically well-defined prospectively collected AD cohort. Our data suggests that different involvement of neuroinflammation may add to clinical heterogeneity in AD, which has implications for neuroinflammation-based biomarkers and future therapeutics.

尽管在阿尔茨海默氏病 (AD) (非) 遗忘性临床变体中对tau和淀粉样蛋白 β 的神经解剖学分布进行了充分研究，但神经炎症的分布仍未得到探索。我们在临床上明确定义的前瞻性收集的AD队列中研究了活化的髓样细胞，星形胶质细胞和补体以及淀粉样 β 和磷酸化tau的神经解剖学分布。我们的数据表明，神经炎症的不同参与可能会增加AD的临床异质性，这对基于神经炎症的生物标志物和未来的治疗方法具有影响。

REF: Boon BDC, Frigerio I, de Gooijer D, et al. Alzheimer's disease clinical variants show distinct neuroinflammatory profiles with neuropathology. Neuropathol Appl Neurobiol. 2024;50(5):e13009. doi:10.1111/nan.13009 PMID: 39400356

Hippocampal dentate granule cells in temporal lobe epilepsy: A morphometry and transcriptomic study

颞叶癫痫中的海马齿状颗粒细胞: 形态计量学和转录组学研究

The dentate gyrus (DG) plays a critical role in hippocampal circuitry, providing a "gate-like" function to the downstream cornu ammonis (CA) sectors. Despite this critical role, pathologies in DG are less commonly described than those in the CA sectors in the diagnosis of mesial temporal lobe epilepsy (mTLE). To elucidate the role of the DG in mTLE, we analysed hippocampal sclerosis (HS), no-HS, non-TLE epilepsy control, and non-epilepsy control cohorts using morphometry and gene expression profiling techniques. The dentate gyrus (DG) plays a critical role in hippocampal circuitry, providing a "gate-like" function to the downstream cornu ammonis (CA) sectors. Despite this critical role, pathologies in DG are less commonly described than those in the CA sectors in the diagnosis of mesial temporal lobe epilepsy (mTLE). To elucidate the role of the DG in mTLE, we analysed hippocampal sclerosis (HS), no-HS, non-TLE epilepsy control, and non-epilepsy control cohorts using morphometry and gene expression profiling techniques.

齿状回 (DG) 在海马回路中起着至关重要的作用，为下游的cornu ammonis (CA) 部分提供了 “门状” 功能。尽管有此关键作用，但在诊断内侧颞叶癫痫 (mTLE) 时，DG的病理描述不如CA部门。为了阐明DG在mTLE中的作用，我们使用形态计量学和基因表达谱技术分析了海马硬化 (HS)，non-hs，非TLE癫痫对照和非癫痫对照队列。齿状回 (DG) 在海马回路中起着至关重要的作用，为下游的cornu ammonis (CA) 部分提供了 “门状” 功能。尽管有此关键作用，但在诊断内侧颞叶癫痫 (mTLE) 时，DG的病理描述不如CA部门。为了阐明DG在mTLE中的作用，我们使用形态计量学和基因表达谱技术分析了海马硬化 (HS)，non-hs，非TLE癫痫对照和非癫痫对照队列。

REF: Twible C, Abdo R, Zhao C, Zhang Q. Hippocampal dentate granule cells in temporal lobe epilepsy: A morphometry and transcriptomic study. Neuropathol Appl Neurobiol. 2024;50(5):e13008. doi:10.1111/nan.13008 PMID: 39375854

GFAP expression in the brain during human postnatal development

人类出生后发育过程中大脑GFAP的表达

Glial fibrillary acidic protein (GFAP) immunohistochemistry was investigated in the developing human brain using two measures; the number of GFAP-positive cells (density, GFAP+/mm2), and a reactivity score (R-score), which we recently introduced to indicate astrogliosis, with scores ≥120 indicative of pathological processes. The primary aim was to report on GFAP expression and cell soma size in 26 microscopically defined regions of the amygdala, basal ganglia, cerebellum, hippocampus and medulla, and to determine whether they are affected by postconceptional age (PCA) from 40 to 83 weeks. The findings indicate that the density of GFAP decreases in specific regions of the brain within the first year of postnatal development, and that reactive astrocytes are common, particularly within the early postnatal months.

使用两种方法在发育中的人脑中研究了神经胶质纤维酸性蛋白 (GFAP) 免疫组织化学; GFAP阳性细胞的数量 (密度，GFAP /mm2) 和反应性评分 (R评分)，我们最近引入该评分来指示星形胶质细胞增生，评分 ≥ 120指示病理过程。主要目的是报告杏仁核，基底神经节，小脑，海马和髓质的26个显微镜定义区域中的GFAP表达和细胞体大小，并确定它们是否受40至83周的受孕后年龄 (PCA) 的影响。研究结果表明，在出生后的第一年内，GFAP的密度在大脑的特定区域降低，并且反应性星形胶质细胞很常见，尤其是在出生后的早期。

REF: Luijerink L, Waters K, Rodriguez M, Machaalani R. GFAP expression in the BRAIN during human postnatal development. Neuropathol Appl Neurobiol. 2024;50(5):e13007. doi:10.1111/nan.13007 PMID: 39297350