Myocardial sympathetic distal axon loss in subjects with Lewy pathology in three autopsy cohorts

三个尸检队列中存在路易体病理改变的受试者的心肌交感神经远端轴突丢失

Cardiac manifestations are associated with Lewy body disease, but studies addressing the underlying histopathological mechanisms at the myocardial level are sparse. Here, we generated an artificial intelligence-based algorithm to quantify tyrosine hydroxylase (TH)-immunoreactive sympathetic distal axons at the myocardial level. In conclusion, our results show that Lewy pathology in the central nervous system, and particularly its caudo-rostral subtype, is strongly associated with loss of sympathetic distal axons at the myocardial level. We also provide evidence that the caudo-rostral subtype is one of the strongest predictors of myocardial sympathetic denervation/dysfunction in the oldest-old population.

心脏表现与路易体病相关，但针对心肌层面潜在组织病理学机制的研究较少。在此，我们开发了一种基于人工智能的算法，用于量化心肌层面酪氨酸羟化酶（TH）免疫反应性交感神经末梢轴突。总之，我们的研究结果表明，中枢神经系统中的路易体病理改变，尤其是尾 - 头亚型，与心肌层面交感神经末梢轴突的丢失密切相关。我们还证实，尾 - 头亚型是高龄人群心肌交感神经去神经支配/功能障碍的最强预测因素之一。

REF: Kivistö V, Englert B, Tuimala J, et al. Myocardial sympathetic distal axon loss in subjects with Lewy pathology in three autopsy cohorts. Acta Neuropathol. 2025;150(1):11. Published 2025 Aug 1. doi:10.1007/s00401-025-02918-y PMID: 40748411 PMCID: PMC12316836

PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration

PLAG1融合定义了具有PLAG家族基因改变的中枢神经系统胚胎性肿瘤的第三种亚型

CNS embryonal tumors with PLAGL amplification (ET, PLAGL) are a recently described tumor type marked by amplification of one of the PLAG family genes, PLAGL1 or PLAGL2. Separately, a supratentorial, ependymoma-like CNS tumor type with PLAG family alteration, namely PLAGL1 fusion, was also reported (NET_PLAGL1). Here, we use DNA methylation profiling in combination with copy number, RNA-seq, and histological analysis to characterize and classify a novel group of CNS embryonal tumors harboring PLAG1 gene fusions (n=12). In summary, we describe a third subtype of PLAG family-altered pediatric CNS embryonal tumor characterized by PLAG1 gene fusion, which leads to upregulation of PLAG1 and downstream genes. We therefore propose to rename ET, PLAGL to ET, PLAG (CNS embryonal tumor with PLAG family gene alteration) together with a specification of the respective subtype.

伴有PLAGL扩增的中枢神经系统胚胎性肿瘤（ET, PLAGL）是最近报道的一种肿瘤类型，其特征是PLAG家族基因之一PLAGL1或PLAGL2发生扩增。此外，也有报道称存在一种幕上、类似室管膜瘤的伴有PLAG家族改变（即PLAGL1融合）的中枢神经系统肿瘤类型（NET_PLAGL1）。在此，我们结合DNA甲基化谱分析、拷贝数分析、RNA测序和组织学分析，对一组携带PLAG1基因融合的新型中枢神经系统胚胎性肿瘤（n = 12）进行了特征描述和分类。总之，我们描述了第三种伴有PLAG家族改变的儿童中枢神经系统胚胎性肿瘤亚型，其特征为PLAG1基因融合，这会导致PLAG1及其下游基因表达上调。因此，我们建议将ET, PLAGL重命名为ET, PLAG（伴有PLAG家族基因改变的中枢神经系统胚胎性肿瘤），并明确各自的亚型。

REF: Keck MK, Al-Hussaini M, Amayiri N, et al. PLAG1 fusions define a third subtype of CNS embryonal tumor with PLAG family gene alteration. Acta Neuropathol. 2025;150(1):12. Published 2025 Aug 2. doi:10.1007/s00401-025-02917-z PMID: 40751809 PMCID: PMC12317869

Estradiol rescues male hydroxyl radical-mediated Charcot-Marie-Tooth 2Z by Morc2a stabilization through autophagy inhibition in a murine model

在小鼠模型中，雌二醇通过抑制自噬稳定Morc2a，挽救由羟自由基介导的雄性2Z型夏科 - 马里 - 图思病

Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an inherited axonal neuropathy caused by haploinsufficiency of microrchidia CW-type zinc finger protein 2 (MORC2), which leads to elevated hydroxyl radical levels, reduced ATPase activity, and apoptosis-mediated neuromuscular degeneration. CMT2Z presents with severe clinical manifestations, yet no widely applicable and affordable treatment has been developed. While gene therapy presents a theoretical solution, its feasibility remains constrained by prohibitive costs and delivery challenges. This study highlights the pivotal role of oxidative stress in the pathophysiology of CMT2Z and identifies MORC2 stabilization as a promising intervention. Moreover, the findings advocate for repurposing existing therapeutics to address rare genetic disorders, broadening treatment paradigms for neuromuscular diseases beyond CMT2Z.

2Z型夏科 - 马里 - 图思病（CMT2Z）是一种遗传性轴索性神经病，由微睾症CW型锌指蛋白2（MORC2）单倍剂量不足所致，这会导致羟基自由基水平升高、ATP酶活性降低以及凋亡介导的神经肌肉变性。CMT2Z临床表现严重，但目前尚未研发出广泛适用且经济实惠的治疗方法。虽然基因疗法从理论上提供了解决方案，但其可行性仍受高昂成本和递送难题的限制。本研究强调了氧化应激在CMT2Z病理生理过程中的关键作用，并指出稳定MORC2是一种有前景的干预措施。此外，研究结果支持将现有疗法重新用于治疗罕见遗传病，拓展了除CMT2Z之外的神经肌肉疾病的治疗模式。

REF: Kim JW, Nam SH, Lee GS, et al. Estradiol rescues male hydroxyl radical-mediated Charcot-Marie-Tooth 2Z by Morc2a stabilization through autophagy inhibition in a murine model. Acta Neuropathol. 2025;150(1):13. Published 2025 Aug 4. doi:10.1007/s00401-025-02922-2 PMID: 40760337 PMCID: PMC12321673

A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression

聚焦多发性硬化症患者大脑中外观正常的白质和灰质：与隐匿性进展的关联

Multiple sclerosis is a chronic neuro-inflammatory and neurodegenerative disease, traditionally characterized by the presence of focal demyelinating lesions in the CNS. However, accumulating evidence suggests that multiple sclerosis pathophysiology extends beyond such classical lesions, affecting also 'normal' appearing tissue in both white and gray matter, referred to as 'normal-appearing white matter' and 'normal-appearing gray matter', respectively. Here, we provide a comprehensive overview of the widespread biochemical, cellular, and microstructural alterations occurring in these 'normal-appearing' CNS regions. Additionally, we discuss the evidence derived from human post-mortem studies that support that normal-appearing white and gray matter could be the drivers of smoldering-associated pathological worsening once repair mechanisms are exhausted. Comprehensive understanding of multiple sclerosis pathology beyond classical lesions not only provides a more complete picture of disease progression, but also provides further insights into potential novel therapeutic avenues in order to slow or halt disability accumulation.

多发性硬化症是一种慢性神经炎症性和神经退行性疾病，传统上以中枢神经系统中存在局灶性脱髓鞘病变为特征。然而，越来越多的证据表明，多发性硬化症的病理生理过程超出了此类经典病变的范畴，还会影响外观“正常”的白质和灰质组织，分别称为“外观正常的白质”和“外观正常的灰质”。在此，我们全面概述了这些中枢神经系统“外观正常”区域发生的广泛的生化、细胞和微观结构改变。此外，我们讨论了来自人体尸检研究的证据，这些证据支持在修复机制耗尽后，外观正常的白质和灰质可能是隐匿性病理恶化的驱动因素。全面了解经典病变之外的多发性硬化症病理，不仅能更完整地呈现疾病进展情况，还能为探索潜在的新型治疗途径提供进一步的见解，以减缓或阻止残疾的累积。

REF: Muñoz González G, T Hart BA, Bugiani M, et al. A focus on the normal-appearing white and gray matter within the multiple sclerosis brain: a link to smoldering progression. Acta Neuropathol. 2025;150(1):16. Published 2025 Aug 10. doi:10.1007/s00401-025-02923-1 PMID: 40783892 PMCID: PMC12336099

Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U

大脑转录组学研究凸显了泛素阳性的额颞叶变性（aFTLD - U）中非神经元细胞存在大量的基因表达和剪接改变

Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is a rare cause of frontotemporal lobar degeneration (FTLD), characterized postmortem by neuronal inclusions of the FET family of proteins (FTLD-FET). The recent discovery of TAF15 amyloid filaments in aFTLD-U brains represents a significant step toward improved diagnostic and therapeutic strategies. However, our understanding of the etiology of this FTLD subtype remains limited, which severely hampers translational research efforts. To explore the transcriptomic changes in aFTLD-U, we performed bulk RNA sequencing on the frontal cortex tissue of 21 aFTLD-U patients and 20 control individuals. Together, these findings highlight a central role for glial cells, particularly astrocytes and oligodendrocytes, in the pathogenesis of aFTLD-U, with disruptions in mitochondrial activity, RNA metabolism, Shh signaling, and myelination as possible disease mechanisms. This study offers the first transcriptomic insight into aFTLD-U and presents new avenues for research into FTLD-FET.

伴泛素阳性包涵体的非典型额颞叶变性（aFTLD - U）是额颞叶变性（FTLD）的一种罕见病因，尸检时其特征为FET家族蛋白的神经元包涵体（FTLD - FET）。近期在aFTLD - U患者大脑中发现TAF15淀粉样细丝，这是迈向改进诊断和治疗策略的重要一步。然而，我们对这种FTLD亚型病因的了解仍然有限，这严重阻碍了转化研究工作。为了探究aFTLD - U的转录组变化，我们对21例aFTLD - U患者和20例对照个体的额叶皮质组织进行了批量RNA测序。总之，这些发现凸显了神经胶质细胞，尤其是星形胶质细胞和少突胶质细胞，在aFTLD - U发病机制中的核心作用，线粒体活性、RNA代谢、Shh信号传导和髓鞘形成的紊乱可能是其发病机制。本研究首次对aFTLD - U进行了转录组分析，为FTLD - FET的研究开辟了新途径。

REF: Alidadiani S, Faura J, Wynants S, et al. Brain transcriptomics highlight abundant gene expression and splicing alterations in non-neuronal cells in aFTLD-U. Acta Neuropathol. 2025;150(1):17. Published 2025 Aug 10. doi:10.1007/s00401-025-02919-x PMID: 40783910 PMCID: PMC12336083

Diffuse leptomeningeal glioneuronal tumor (DLGNT): a comprehensive clinical and molecular analysis

弥漫性软脑膜胶质神经元肿瘤（DLGNT）：一项全面的临床与分子分析

Diffuse leptomeningeal glioneuronal tumors (DLGNTs) are rare, and optimal treatment remains undefined. We aim to comprehensively characterize their clinical and molecular features, offering granular insights into presentations and therapies to elucidate prognostic factors and therapeutic targets. Histologic, molecular, and clinical data of 30 patients with DLGNT were analyzed. Multi-omic analysis revealed simultaneous activation of multiple signaling pathways, which may serve as potential therapeutic targets. DLGNT remains challenging to treat, with poor outcomes across modalities. Further investigation of treatment, including targeted therapies addressing activated pathways, is needed to improve patient survival.

弥漫性软脑膜神经胶质神经元肿瘤（DLGNTs）较为罕见，最佳治疗方案尚未明确。我们旨在全面描述其临床和分子特征，深入了解其临床表现和治疗方法，以阐明预后因素和治疗靶点。对30例DLGNT患者的组织学、分子和临床数据进行了分析。多组学分析显示多个信号通路同时激活，这些通路可能成为潜在的治疗靶点。DLGNT的治疗仍具挑战性，各种治疗方式的预后均不佳。需要进一步研究治疗方法，包括针对激活通路的靶向治疗，以提高患者生存率。

REF: Mikkelsen MK, Li X, Yu K, et al. Diffuse leptomeningeal glioneuronal tumor (DLGNT): a comprehensive clinical and molecular analysis. Acta Neuropathol. 2025;150(1):18. Published 2025 Aug 11. doi:10.1007/s00401-025-02924-0 PMID: 40788548 PMCID: PMC12339613

Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology

DNAJC7 基因的双等位基因变异导致伴有 TDP - 43 病理改变的家族性肌萎缩侧索硬化症

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the progressive degeneration of motor neurons. ALS pathology primarily involves the failure of protein quality control mechanisms, leading to the accumulation of misfolded proteins, particularly TAR DNA-binding protein 43 (TDP-43). TDP-43 aggregation is a central pathological feature of ALS. Maintaining protein homeostasis is critical and facilitated by heat shock proteins (HSPs), particularly the HSP40 family, which includes co-chaperones such as DNAJC7. Here, we report a family with three siblings affected by ALS who carry a homozygous c.518dupC frameshift variant in DNAJC7, a member of the HSP40 family. To the best of our knowledge, this study provides the first evidence linking biallelic loss-of-function variants in DNAJC7 to familial ALS with TDP-43 pathology.

肌萎缩侧索硬化症（ALS）是一种致命的神经退行性疾病，其特征是运动神经元进行性退化。ALS的病理机制主要涉及蛋白质质量控制机制失效，导致错误折叠的蛋白质（尤其是TAR DNA结合蛋白43，即TDP - 43）积累。TDP - 43聚集是ALS的核心病理特征。维持蛋白质稳态至关重要，热休克蛋白（HSPs）尤其是HSP40家族有助于维持这一稳态，HSP40家族包括如DNAJC7等辅助伴侣蛋白。在此，我们报道了一个有三名患ALS兄弟姐妹的家族，他们均携带HSP40家族成员DNAJC7基因的纯合c.518dupC移码变异。据我们所知，本研究首次提供了证据，将DNAJC7双等位基因功能丧失变异与伴有TDP - 43病理的家族性ALS联系起来。

REF: Yamashita T, Yokota O, Ousaka D, et al. Biallelic variants in DNAJC7 cause familial amyotrophic lateral sclerosis with the TDP-43 pathology. Acta Neuropathol. 2025;150(1):19. Published 2025 Aug 13. doi:10.1007/s00401-025-02899-y PMID: 40802071 PMCID: PMC12350594

DNA methylation analysis reveals an epigenetic signature distinctive of high-grade oligodendroglioma

DNA甲基化分析揭示了高级别少突胶质细胞瘤特有的表观遗传学特征

IDH-mutant gliomas represent a subtype of diffuse gliomas that primarily affect patients in early to mid-adolescence. These tumors are classified into three distinct CNS WHO grades of malignancy. Accurate grading is essential for selecting an appropriate treatment maximizing anti-tumor efficacy while minimizing adverse effects. However, grading of oligodendrogliomas with 1p/19q codeletion currently relies on qualitative tumor characteristics that may be influenced by observer subjectivity, sampling bias, and tumor heterogeneity. This study aimed to explore DNA methylation-based tumor deconvolution into latent methylation components (LMCs) to evaluate their potential as objective grading tools in a cohort of 137 IDH-mutant gliomas. LMCs were analyzed in relation to malignancy markers, cellular composition, and underlying methylation signatures of the chromatin landscape. Glioma subtypes were associated with distinct LMCs. Two LMCs correlated with higher cellular density and advanced epigenetic age as well as with microvascular proliferation, necrosis, and epigenetically defined high-grade astrocytoma. The epigenetic patterns defining high-grade astrocytoma or oligodendroglioma, respectively, were similar. Higher-grade oligodendrogliomas, identified by LMC-based grading, were associated with more copy number alterations. Among patients of an external cohort who died during the assessment period, higher LMC1 proportions were associated with poorer overall survival. Therefore, LMCs hold the potential to support IDH-mutant glioma grading by incorporating objective epigenetic markers.

异柠檬酸脱氢酶（IDH）突变型胶质瘤是弥漫性胶质瘤的一种亚型，主要影响青春期早期至中期的患者。这些肿瘤被分为三个不同的中枢神经系统（CNS）世界卫生组织（WHO）恶性等级。准确分级对于选择合适的治疗方案至关重要，这样能在最大限度提高抗肿瘤疗效的同时，将不良反应降至最低。然而，目前伴有1p/19q共缺失的少突胶质细胞瘤的分级依赖于定性的肿瘤特征，而这些特征可能会受到观察者主观因素、取样偏差和肿瘤异质性的影响。本研究旨在探索基于DNA甲基化的肿瘤反卷积为潜在甲基化成分（LMCs），以评估其在137例IDH突变型胶质瘤队列中作为客观分级工具的潜力。研究分析了LMCs与恶性标志物、细胞组成以及染色质景观的潜在甲基化特征之间的关系。胶质瘤亚型与不同的LMCs相关。两种LMCs与较高的细胞密度、较高的表观遗传年龄以及微血管增生、坏死和表观遗传学定义的高级别星形细胞瘤相关。分别定义高级别星形细胞瘤或少突胶质细胞瘤的表观遗传模式相似。基于LMC分级确定的高级别少突胶质细胞瘤与更多的拷贝数改变相关。在评估期间死亡的外部队列患者中，LMC1比例较高与较差的总体生存率相关。因此，LMCs有可能通过纳入客观的表观遗传标志物来辅助IDH突变型胶质瘤的分级。

REF: Weber KJ, Dettki M, Münzberg M, et al. DNA methylation analysis reveals an epigenetic signature distinctive of high-grade oligodendroglioma. Acta Neuropathol. 2025;150(1):21. Published 2025 Aug 23. doi:10.1007/s00401-025-02926-y PMID: 40849395 PMCID: PMC12374884