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The X-linked intellectual disability gene CUL4B is critical for memory and synaptic function. x连锁的智力残疾基因CUL4B对记忆和突触功能至关重要。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-04 DOI: 10.1186/s40478-024-01903-y
Wei Jiang, Jian Zhang, Molin Wang, Yongxin Zou, Qiao Liu, Yu Song, Gongping Sun, Yaoqin Gong, Fan Zhang, Baichun Jiang

Cullin 4B (CUL4B) is the scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Loss-of-function mutations in the human CUL4B gene lead to syndromic X-linked intellectual disability (XLID). Till now, the mechanism of intellectual disability caused by CUL4B mutation still needs to be elucidated. In this study, we used single-nucleus RNA sequencing (snRNA-seq) to investigate the impact of CUL4B deficiency on the transcriptional programs of diverse cell types. The results revealed that depletion of CUL4B resulted in impaired intercellular communication and elicited cell type-specific transcriptional changes relevant to synapse dysfunction. Golgi-Cox staining of brain slices and immunostaining of in vitro cultured neurons revealed remarkable synapse loss in CUL4B-deficient mice. Ultrastructural analysis via transmission electron microscopy (TEM) showed that the width of the synaptic cleft was significantly greater in CUL4B-deficient mice. Electrophysiological experiments found a decrease in the amplitude of AMPA receptor-mediated EPSCs in the hippocampal CA1 pyramidal neurons of CUL4B-deficient mice. These results indicate that depletion of CUL4B in mice results in morphological and functional abnormalities in synapses. Furthermore, behavioral tests revealed that depletion of CUL4B in the mouse nervous system results in impaired spatial learning and memory. Taken together, the findings of this study reveal the pathogenesis of neurological disorders associated with CUL4B mutations and promote the identification of therapeutic targets that can halt synaptic abnormalities and preserve memory in individuals.

Cullin 4B (CUL4B)是CUL4B- ring E3泛素连接酶(CRL4B)复合物中的支架蛋白。人类CUL4B基因的功能缺失突变可导致综合征性x连锁智力残疾(XLID)。迄今为止,CUL4B突变导致智力残疾的机制仍有待阐明。在这项研究中,我们使用单核RNA测序(snRNA-seq)来研究CUL4B缺乏对不同细胞类型转录程序的影响。结果显示,CUL4B的缺失导致细胞间通讯受损,并引发与突触功能障碍相关的细胞类型特异性转录变化。脑切片高尔基-考克斯染色和体外培养神经元免疫染色显示,cul4b缺陷小鼠突触明显缺失。透射电镜(TEM)超微结构分析显示,cul4b缺陷小鼠突触间隙宽度明显增大。电生理实验发现cul4b缺陷小鼠海马CA1锥体神经元中AMPA受体介导的EPSCs振幅降低。这些结果表明,CUL4B在小鼠体内的缺失会导致突触的形态和功能异常。此外,行为测试显示,小鼠神经系统中CUL4B的消耗导致空间学习和记忆受损。综上所述,本研究的发现揭示了与CUL4B突变相关的神经系统疾病的发病机制,并促进了能够阻止突触异常和保持个体记忆的治疗靶点的鉴定。
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引用次数: 0
The neuropathological basis of elevated serum neurofilament light following experimental concussion. 实验性脑震荡后血清神经丝光升高的神经病理学基础。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-04 DOI: 10.1186/s40478-024-01883-z
John D Arena, Douglas H Smith, Ramon Diaz Arrastia, D Kacy Cullen, Rui Xiao, Jiaxin Fan, Danielle C Harris, Cillian E Lynch, Victoria E Johnson

Mild traumatic brain injury (mTBI) or concussion is a substantial health problem globally, with up to 15% of patients experiencing persisting symptoms that can significantly impact quality of life. Currently, the diagnosis of mTBI relies on clinical presentation with ancillary neuroimaging to exclude more severe forms of injury. However, identifying patients at risk for a poor outcome or protracted recovery is challenging, in part due to the lack of early objective tests that reflect the relevant underlying pathology. While the pathophysiology of mTBI is poorly understood, axonal damage caused by rotational forces is now recognized as an important consequence of injury. Moreover, serum measurement of the neurofilament light (NfL) protein has emerged as a potentially promising biomarker of injury. Understanding the pathological processes that determine serum NfL dynamics over time, and the ability of NfL to reflect underlying pathology will be critical for future clinical research aimed at reducing the burden of disability after mild TBI. Using a gyrencephalic model of head rotational acceleration scaled to human concussion, we demonstrate significant elevations in serum NfL, with a peak at 3 days post-injury. Moreover, increased serum NfL was detectable out to 2 weeks post-injury, with some evidence it follows a biphasic course. Subsequent quantitative histological examinations demonstrate that axonal pathology, including in the absence of neuronal somatic degeneration, was the likely source of elevated serum NfL. However, the extent of axonal pathology quantified via multiple markers did not correlate strongly with the extent of serum NfL. Interestingly, the extent of blood-brain barrier (BBB) permeability offered more robust correlations with serum NfL measured at multiple time points, suggesting BBB disruption is an important determinant of serum biomarker dynamics after mTBI. These data provide novel insights to the temporal course and pathological basis of serum NfL measurements that inform its utility as a biomarker in mTBI.

轻度创伤性脑损伤(mTBI)或脑震荡是全球性的重大健康问题,高达15%的患者会出现持续症状,严重影响生活质量。目前,mTBI的诊断依赖于临床表现和辅助神经影像学来排除更严重的损伤形式。然而,识别有不良预后或长期恢复风险的患者是具有挑战性的,部分原因是缺乏反映相关潜在病理的早期客观测试。虽然mTBI的病理生理机制尚不清楚,但旋转力引起的轴突损伤现在被认为是损伤的一个重要后果。此外,血清测量神经丝光(NfL)蛋白已成为一种潜在的有前途的损伤生物标志物。了解决定血清NfL动态随时间变化的病理过程,以及NfL反映潜在病理的能力,对于未来旨在减轻轻度TBI后残疾负担的临床研究至关重要。使用脑回模型的头部旋转加速度缩放到人类脑震荡,我们证明血清NfL显著升高,在损伤后3天达到峰值。此外,损伤后2周可检测到血清NfL升高,有证据表明它遵循双相病程。随后的定量组织学检查表明,轴突病理,包括在没有神经元体细胞变性的情况下,可能是血清NfL升高的原因。然而,通过多种标记量化的轴突病理程度与血清NfL的程度没有很强的相关性。有趣的是,血脑屏障(BBB)渗透性的程度与多个时间点测量的血清NfL具有更强的相关性,这表明血脑屏障破坏是mTBI后血清生物标志物动力学的重要决定因素。这些数据为血清NfL测量的时间过程和病理基础提供了新的见解,并告知其作为mTBI生物标志物的实用性。
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引用次数: 0
CK1δ/ε-mediated TDP-43 phosphorylation contributes to early motor neuron disease toxicity in amyotrophic lateral sclerosis. CK1δ/ε介导的TDP-43磷酸化有助于肌萎缩性侧索硬化症早期运动神经元疾病毒性。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-12-04 DOI: 10.1186/s40478-024-01902-z
Vivian I Ko, Kailee Ong, Deborah Y Kwon, Xueying Li, Alicia Pietrasiewicz, James S Harvey, Mukesh Lulla, Guruharsha Bhat, Don W Cleveland, John M Ravits

Hyperphosphorylated TDP-43 aggregates in the cytoplasm of motor neurons is a neuropathological signature of amyotrophic lateral sclerosis (ALS). These aggregates have been proposed to possess a toxic disease driving role in ALS pathogenesis and progression, however, the contribution of phosphorylation to TDP-43 aggregation and ALS disease mechanisms remains poorly understood. We've previously shown that CK1δ and CK1ε phosphorylate TDP-43 at disease relevant sites, and that genetic reduction and chemical inhibition could reduce phosphorylated TDP-43 (pTDP-43) levels in cellular models. In this study, we advanced our findings into the hTDP-43-ΔNLS in vivo mouse model of ALS and TDP-43 proteinopathy. This mouse model possesses robust disease-relevant features of ALS, including TDP-43 nuclear depletion, cytoplasmic pTDP-43 accumulation, motor behavior deficits, and shortened survival. We tested the effect of homozygous genetic deletion of Csnk1e in the hTDP-43-ΔNLS mouse model and observed a delay in the formation of pTDP-43 without significant ultimate rescue of TDP-43 proteinopathy or disease progression. Homozygous genetic deletion of Csnk1d is lethal in mice, and we were unable to test the role of CK1δ alone. We then targeted both CK1δ and CK1ε kinases by way of CK1δ/ε-selective PF-05236216 inhibitor in the hTDP-43-ΔNLS mouse model, reasoning that inhibiting CK1ε alone would be insufficient as shown by our Csnk1e knockout mouse model study. Treated mice demonstrated reduced TDP-43 phosphorylation, lowered Nf-L levels, and improved survival in the intermediate stages. The soluble TDP-43 may have been more amenable to the inhibitor treatment than insoluble TDP-43. However, the treatments did not result in improved functional measurements or in overall survival. Our results demonstrate that phosphorylation contributes to neuronal toxicity and suggest CK1δ/ε inhibition in combination with other therapies targeting TDP-43 pathology could potentially provide therapeutic benefit in ALS.

运动神经元细胞质中过度磷酸化的TDP-43聚集体是肌萎缩侧索硬化症(ALS)的神经病理学特征。这些聚集物被认为在ALS发病和进展中具有毒性疾病驱动作用,然而,磷酸化对TDP-43聚集和ALS疾病机制的贡献仍然知之甚少。我们之前已经证明CK1δ和CK1ε在疾病相关位点磷酸化TDP-43,并且遗传还原和化学抑制可以降低细胞模型中磷酸化的TDP-43 (pTDP-43)水平。在这项研究中,我们将我们的发现推进到hTDP-43-ΔNLS ALS和TDP-43蛋白病变的小鼠体内模型。该小鼠模型具有强大的ALS疾病相关特征,包括TDP-43核耗损、细胞质pTDP-43积累、运动行为缺陷和生存期缩短。我们在hTDP-43-ΔNLS小鼠模型中测试了Csnk1e纯合基因缺失的影响,并观察到pTDP-43的形成延迟,而没有明显的最终挽救TDP-43蛋白病变或疾病进展。Csnk1d的纯合子基因缺失在小鼠中是致命的,我们无法单独测试CK1δ的作用。然后,我们在hTDP-43-ΔNLS小鼠模型中通过CK1δ/ε选择性PF-05236216抑制剂靶向CK1δ和CK1ε激酶,原因是单独抑制CK1ε是不够的,正如我们的Csnk1e敲除小鼠模型研究所显示的那样。治疗小鼠表现出TDP-43磷酸化降低,Nf-L水平降低,中期生存率提高。可溶性TDP-43可能比不溶性TDP-43更适合抑制剂处理。然而,这些治疗并没有导致功能测量的改善或总生存率的提高。我们的研究结果表明,磷酸化有助于神经元毒性,并提示CK1δ/ε抑制与其他针对TDP-43病理的治疗联合可能提供治疗ALS的益处。
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引用次数: 0
Spatial transcriptomics in focal cortical dysplasia type IIb. 局灶性皮质发育不良IIb型的空间转录组学研究。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-30 DOI: 10.1186/s40478-024-01897-7
Yujiao Wang, Yihe Wang, Linai Guo, Chunhao Shen, Yongjuan Fu, Penghu Wei, Yongzhi Shan, Qian Wu, Yue-Shan Piao, Guoguang Zhao

Focal cortical dysplasia (FCD) type IIb (FCD IIb) is an epileptogenic malformation of the neocortex that is characterized by cortical dyslamination, dysmorphic neurons (DNs) and balloon cells (BCs). Approximately 30-60% of lesions are associated with brain somatic mutations in the mTOR pathway. Herein, we investigated the transcriptional changes around the DNs and BCs regions in freshly frozen brain samples from three patients with FCD IIb by using spatial transcriptomics. We demonstrated that the DNs region in a gene enrichment network enriched for the mTOR signalling pathway, autophagy and the ubiquitin‒proteasome system, additionally which are involved in regulating membrane potential, may contribute to epileptic discharge. Moreover, differential expression analysis further demonstrated stronger expression of components of the inflammatory response and complement activation in the BCs region. And the DNs and BCs regions exhibited common functional modules, including regulation of cell morphogenesis and developmental growth. Furthermore, the expression of representative proteins in the functional enrichment module mentioned above was increased in the lesions of FCD IIb, such as p62 in DNs and BCs, UCHL1 in DNs, and C3 and CLU in BCs, which was confirmed via immunohistochemistry. Collectively, we constructed a spatial map showing the potential effects and functions of the DNs and BCs regions at the transcriptomic level and generated publicly available data on human FCD IIb to facilitate future research on human epileptogenesis.

局灶性皮质发育不良(FCD) IIb型(FCD IIb)是一种癫痫致新皮质畸形,其特征是皮质层积异常、神经元(DNs)和球囊细胞(bc)畸形。大约30-60%的病变与mTOR通路中的脑体细胞突变有关。在此,我们利用空间转录组学研究了3例FCD IIb患者新鲜冷冻脑样本中DNs和BCs区域周围的转录变化。我们证明了mTOR信号通路、自噬和泛素-蛋白酶体系统富集的基因富集网络中的DNs区域,以及参与调节膜电位的基因富集网络,可能有助于癫痫放电。此外,差异表达分析进一步表明,炎症反应成分和补体激活在bc区表达更强。dn区和BCs区具有共同的功能模块,包括调控细胞形态发生和发育生长。此外,FCD IIb病变中上述功能富集模块的代表性蛋白如DNs和BCs中的p62、DNs中的UCHL1、BCs中的C3和CLU的表达均有所增加,免疫组织化学证实了这一点。总的来说,我们构建了一个空间图,显示了DNs和BCs区域在转录组水平上的潜在影响和功能,并生成了人类FCD IIb的公开数据,以促进未来人类癫痫发生的研究。
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引用次数: 0
Retinal cytoarchitecture is preserved in an organotypic perfused human and porcine eye model. 视网膜细胞结构在器官型灌注人眼和猪眼模型中得以保存。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-30 DOI: 10.1186/s40478-024-01892-y
Darren Chan, Jenny Wanyu Zhang, Gah-Jone Won, Jeremy M Sivak

Pathobiology of the intact human retina has been challenging to study due to its relative inaccessibility and limited sample availability. Thus, there is a great need for new translational models that can maintain human retinal integrity and cytoarchitecture. The role of physiologic intraocular pressure (IOP) and fluid flow on retinal tissue has not been well studied. Here, we present an ex vivo organotypic model to assess the impact of physiological intraocular perfusion on retinal cytoarchitecture and cell survival. We demonstrate that retinal cytoarchitecture is remarkably well preserved following re-establishment of physiological IOP and aqueous humor dynamics for up to 24 h in ex vivo whole globe porcine and human eyes, comparable to freshly preserved control eyes. Accordingly, cell death was minimized in the perfused retinas, which also displayed normal markers of cellular metabolism and astrogliosis. These results are in marked contrast to contralateral control eyes without active perfusion, which displayed excessive cell death and disrupted cytoarchitecture at the same time point. These experiments demonstrate the critical impact that physiological pressure and fluid flow have on retinal tissue, and introduce a new pre-clinical model to study human and porcine retinal health and degeneration in a relevant biomechanical setting.

完整人视网膜的病理生物学研究一直具有挑战性,由于其相对难以接近和有限的样本可用性。因此,有很大的需要新的翻译模型,可以维持人类视网膜的完整性和细胞结构。生理性眼内压(IOP)和液体流动对视网膜组织的作用尚未得到很好的研究。在这里,我们提出了一个体外器官型模型来评估生理眼内灌注对视网膜细胞结构和细胞存活的影响。我们证明,在离体猪和人的眼睛中,在生理IOP和房水动力学重建长达24小时后,视网膜细胞结构得到了非常好的保存,与新鲜保存的对照眼睛相当。因此,灌注视网膜的细胞死亡最小,细胞代谢和星形胶质细胞形成也显示正常。这些结果与没有主动灌注的对侧对照眼形成鲜明对比,后者在同一时间点表现出过度的细胞死亡和细胞结构破坏。这些实验证明了生理压力和流体流动对视网膜组织的重要影响,并在相关的生物力学环境下引入了一种新的临床前模型来研究人类和猪的视网膜健康和变性。
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引用次数: 0
ALS-linked mutant TDP-43 in oligodendrocytes induces oligodendrocyte damage and exacerbates motor dysfunction in mice. 少突胶质细胞中与 ALS 相关的突变体 TDP-43 会诱发少突胶质细胞损伤,并加剧小鼠的运动功能障碍。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-27 DOI: 10.1186/s40478-024-01893-x
Mai Horiuchi, Seiji Watanabe, Okiru Komine, Eiki Takahashi, Kumi Kaneko, Shigeyoshi Itohara, Mayuko Shimada, Tomoo Ogi, Koji Yamanaka

Nuclear clearance and cytoplasmic aggregation of TAR DNA-binding protein of 43 kDa (TDP-43) are pathological hallmarks of amyotrophic lateral sclerosis (ALS) and its pathogenic mechanism is mediated by both loss-of-function and gain-of-toxicity of TDP-43. However, the role of TDP-43 gain-of-toxicity in oligodendrocytes remains unclear. To investigate the impact of excess TDP-43 on oligodendrocytes, we established transgenic mice overexpressing the ALS-linked mutant TDP-43M337V in oligodendrocytes through crossbreeding with Mbp-Cre mice. Two-step crossbreeding of floxed TDP-43M337V and Mbp-Cre mice resulted in the heterozygous low-level systemic expression of TDP-43M337V with (Cre-positive) or without (Cre-negative) oligodendrocyte-specific overexpression of TDP-43M337V. Although Cre-negative mice also exhibit subtle motor dysfunction, TDP-43M337V overexpression in oligodendrocytes aggravated clasping signs and gait disturbance accompanied by myelin pallor in the corpus callosum and white matter of the lumbar spinal cord in Cre-positive mice. RNA sequencing analysis of oligodendrocyte lineage cells isolated from whole brains of 12-month-old transgenic mice revealed downregulation of myelinating oligodendrocyte marker genes and cholesterol-related genes crucial for myelination, along with marked upregulation of apoptotic pathway genes. Immunofluorescence staining showed cleaved caspase 3-positive apoptotic oligodendrocytes surrounded by activated microglia and astrocytes in aged transgenic mice. Collectively, our findings demonstrate that an excess amount of ALS-linked mutant TDP-43 expression in oligodendrocytes exacerbates motor dysfunction in mice, likely through oligodendrocyte dysfunction and neuroinflammation. Therefore, targeting oligodendrocyte protection, particularly through ameliorating TDP-43 pathology, could represent a potential therapeutic approach for ALS.

43 kDa TAR DNA 结合蛋白(TDP-43)的核清除和胞质聚集是肌萎缩侧索硬化症(ALS)的病理特征,其致病机制是由 TDP-43 的功能缺失和毒性增益介导的。然而,TDP-43毒性增益在少突胶质细胞中的作用仍不清楚。为了研究过量的 TDP-43 对少突胶质细胞的影响,我们通过与 Mbp-Cre 小鼠杂交,建立了在少突胶质细胞中过表达与 ALS 相关的突变体 TDP-43M337V 的转基因小鼠。浮性 TDP-43M337V 小鼠与 Mbp-Cre 小鼠两步杂交后,TDP-43M337V 在少突胶质细胞特异性过表达的同时(Cre 阳性)或不表达(Cre 阴性),形成杂合子低水平系统表达。虽然 Cre 阴性小鼠也表现出微弱的运动功能障碍,但在 Cre 阳性小鼠中,少突胶质细胞中 TDP-43M337V 的过表达加剧了胼胝体和腰部脊髓白质中髓鞘苍白的抓握征和步态障碍。从 12 个月大的转基因小鼠全脑中分离出的少突胶质细胞系细胞的 RNA 序列分析显示,髓鞘化少突胶质细胞标志基因和对髓鞘化至关重要的胆固醇相关基因下调,同时凋亡通路基因明显上调。免疫荧光染色显示,在老化的转基因小鼠中,被活化的小胶质细胞和星形胶质细胞包围的凋亡少突胶质细胞的caspase 3裂解酶呈阳性。总之,我们的研究结果表明,与 ALS 相关的突变型 TDP-43 在少突胶质细胞中的过量表达会加剧小鼠的运动功能障碍,这可能是通过少突胶质细胞功能障碍和神经炎症引起的。因此,针对少突胶质细胞的保护,特别是通过改善 TDP-43 的病理变化,可能是 ALS 的一种潜在治疗方法。
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引用次数: 0
Down syndrome frontal cortex layer III and layer V pyramidal neurons exhibit lamina specific degeneration in aged individuals. 唐氏综合征额叶皮层第 III 层和第 V 层锥体神经元在老年个体中表现出薄层特异性变性。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-27 DOI: 10.1186/s40478-024-01891-z
Melissa J Alldred, Kyrillos W Ibrahim, Harshitha Pidikiti, Gabriela Chiosis, Elliott J Mufson, Grace E Stutzmann, Stephen D Ginsberg

Selective vulnerability of neuronal populations occurs in both Down syndrome (DS) and Alzheimer's disease (AD), resulting in disproportional degeneration of pyramidal neurons (PNs) affecting memory and executive function. Elucidating the cellular mechanisms underlying the selective vulnerability of these populations will provide pivotal insights for disease progression in DS and AD. Single population RNA-sequencing analysis was performed on neurons critical for executive function, prefrontal cortex Brodmann area 9 (BA9) layer III (L3) and layer V (L5) excitatory PNs in postmortem human DS and age- and sex-matched control (CTR) brains. Data mining was performed on differentially expressed genes (DEGs) from PNs in each lamina with DEGs divergent between lamina identified and interrogated. Bioinformatic inquiry of L3 PNs revealed more unique/differentially expressed DEGs (uDEGs) than in L5 PNs in DS compared to CTR subjects, indicating gene dysregulation shows both spatial and cortical laminar projection neuron dependent dysregulation. DS triplicated human chromosome 21 (HSA21) comprised a subset of DEGs only dysregulated in L3 or L5 neurons, demonstrating partial cellular specificity in HSA21 expression. These HSA21 uDEGs had a disproportionally high number of noncoding RNAs, suggesting lamina specific dysfunctional gene regulation. L3 uDEGs revealed overall more dysregulation of cellular pathways and processes, many relevant to early AD pathogenesis, while L5 revealed processes suggestive of frank AD pathology. These findings indicate that trisomy differentially affects a subpopulation of uDEGs in L3 and L5 BA9 projection neurons in aged individuals with DS, which may inform circuit specific pathogenesis underlying DS and AD.

在唐氏综合征(DS)和阿尔茨海默病(AD)中,神经元群都会出现选择性易损性,导致锥体神经元(PNs)不成比例地退化,从而影响记忆和执行功能。阐明这些神经元群选择性易损性的细胞机制将为了解 DS 和 AD 的疾病进展提供关键信息。研究人员对死后人类 DS 和年龄与性别匹配的对照组(CTR)大脑中对执行功能至关重要的神经元、前额叶皮层布罗德曼第 9 区(BA9)第 III 层(L3)和第 V 层(L5)兴奋性 PNs 进行了单群 RNA 序列分析。对来自各层神经元的差异表达基因(DEGs)进行了数据挖掘,并对各层神经元之间的差异表达基因进行了识别和研究。与CTR受试者相比,DS患者L3 PNs的生物信息学调查显示,L5 PNs的独特/差异表达DEGs(uDEGs)比L3 PNs的多,这表明基因失调显示了空间和皮层板层投射神经元依赖性失调。DS的人类21号染色体三倍体(HSA21)组成了一个DEGs子集,该子集仅在L3或L5神经元中失调,这表明HSA21的表达具有部分细胞特异性。这些 HSA21 uDEGs 中的非编码 RNA 数量过多,这表明特定的薄层基因调控失调。L3 uDEGs总体上显示了更多的细胞通路和过程失调,其中许多与早期AD发病机制有关,而L5则显示了提示AD病理的过程。这些研究结果表明,三体综合征会对老年 DS 患者 L3 和 L5 BA9 投射神经元中的 uDEGs 亚群产生不同程度的影响,这可能会为 DS 和 AD 的电路特异性发病机制提供信息。
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引用次数: 0
Towards integrating imaging and immunology in glioblastoma: mapping blood immune system metrics to tumor magnetic resonance image data. 实现胶质母细胞瘤成像与免疫学的整合:将血液免疫系统指标映射到肿瘤磁共振成像数据。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-27 DOI: 10.1186/s40478-024-01888-8
Johanna Heugenhauser, Carmen Visus, Johanna Buchroithner, Christine Marosi, Karl Rössler, Thomas Felzmann, Georg Widhalm, Sarah Iglseder, Martha Nowosielski, Friedrich Erhart

Background: Glioblastoma is the most frequent and aggressive brain cancer. It is a highly immunology-driven disease as up to a third of its mass is composed of immune cells. Apart from immunology, imaging is a major research frontier. The VASARI (Visually AcceSAble Rembrandt Images) MRI feature set is a system designed to enable consistent description of gliomas using a set of defined visual features and controlled vocabulary. Even though imaging and immunology are both indispensable for glioblastoma phenotyping, a comprehensive integration of these two disciplines has not been performed so far.

Material and methods: 76 patients from a previous glioblastoma immunotherapy clinical trial were retrospectively screened for the availability of peripheral blood immunology and tumor imaging data at baseline, i.e. at the start of the study. For 41 patients both were available. MRI were then analyzed via volumetry and VASARI morphometry. The resulting 27 imaging variables were linked with 67 peripheral blood immunology variables from flow cytometry and PCR and all potential relations were mapped.

Results: In an initial broad screening, 94 imaging-immunology associations were discovered. Notably, features of the contrast-enhancing margin like its thickness and its shape were positively correlated with various T cell species including activated cytotoxic CD8+ T cells and central memory CD8+ T cells. The T2-volume was correlated with CD56+CD16- natural killer cells, and the necrosis volume was correlated with immunopolarizing mRNAs in the blood (IFN-γ, GATA3, ROR-gt). After multiple testing correction, two imaging-immunology associations were confirmed as significant: a thick contrast-enhancing margin was correlated with lower regulatory T cell markers in the blood and invasion of deep white matter was correlated with less T helper 17 factors.

Conclusion: We here provide first evidence that imaging and peripheral blood immunology features can go hand in hand and that imaging variables can correlate with systemic immunophenotypes. Especially a thick contrast-enhancing margin seems to indicate a pro-inflammatory immune state. Via pioneering the integration of imaging and immunology, we not only advance basic glioblastoma science but we also open up novel avenues for research. In the future, e.g. patient stratification for therapy development could be based on imaging-guided immunophenotyping.

背景:胶质母细胞瘤是最常见的侵袭性脑癌:胶质母细胞瘤是最常见的侵袭性脑癌。它是一种高度免疫学驱动的疾病,因为高达三分之一的癌块由免疫细胞组成。除了免疫学,成像也是一个重要的研究前沿。VASARI(Visually AcceSAble Rembrandt Images,可视伦勃朗图像)磁共振成像特征集是一个系统,旨在使用一组定义的视觉特征和受控词汇对胶质瘤进行一致的描述。尽管影像学和免疫学对于胶质母细胞瘤的表型分析都不可或缺,但迄今为止还没有对这两门学科进行过全面整合。材料与方法:我们对之前一项胶质母细胞瘤免疫疗法临床试验中的 76 名患者进行了回顾性筛选,以确定他们在基线(即研究开始时)是否有外周血免疫学和肿瘤影像学数据。41名患者的外周血免疫学数据和肿瘤成像数据均可用。然后通过容积测量法和 VASARI 形态测量法对核磁共振成像进行分析。由此得出的 27 个成像变量与来自流式细胞仪和 PCR 的 67 个外周血免疫学变量相关联,并绘制了所有潜在关系图:结果:在最初的广泛筛选中,发现了 94 个成像与免疫学的关联。值得注意的是,造影剂增强边缘的特征,如其厚度和形状,与各种 T 细胞物种(包括活化的细胞毒性 CD8+ T 细胞和中枢记忆 CD8+ T 细胞)呈正相关。T2- 体积与 CD56+CD16- 自然杀伤细胞相关,坏死体积与血液中的免疫极化 mRNA(IFN-γ、GATA3、ROR-gt)相关。经过多重检验校正后,有两个影像学与免疫学的关联被证实是显著的:厚的对比增强边缘与血液中较低的调节性T细胞标记物相关,深部白质的侵袭与较少的T辅助细胞17因子相关:我们在此首次证明,影像学和外周血免疫学特征可以同时存在,影像学变量可以与全身免疫表型相关。尤其是厚对比增强边缘似乎预示着一种促炎免疫状态。通过率先将成像与免疫学相结合,我们不仅推动了胶质母细胞瘤基础科学的发展,还开辟了新的研究途径。未来,患者分层治疗的开发可以基于成像引导的免疫分型。
{"title":"Towards integrating imaging and immunology in glioblastoma: mapping blood immune system metrics to tumor magnetic resonance image data.","authors":"Johanna Heugenhauser, Carmen Visus, Johanna Buchroithner, Christine Marosi, Karl Rössler, Thomas Felzmann, Georg Widhalm, Sarah Iglseder, Martha Nowosielski, Friedrich Erhart","doi":"10.1186/s40478-024-01888-8","DOIUrl":"10.1186/s40478-024-01888-8","url":null,"abstract":"<p><strong>Background: </strong>Glioblastoma is the most frequent and aggressive brain cancer. It is a highly immunology-driven disease as up to a third of its mass is composed of immune cells. Apart from immunology, imaging is a major research frontier. The VASARI (Visually AcceSAble Rembrandt Images) MRI feature set is a system designed to enable consistent description of gliomas using a set of defined visual features and controlled vocabulary. Even though imaging and immunology are both indispensable for glioblastoma phenotyping, a comprehensive integration of these two disciplines has not been performed so far.</p><p><strong>Material and methods: </strong>76 patients from a previous glioblastoma immunotherapy clinical trial were retrospectively screened for the availability of peripheral blood immunology and tumor imaging data at baseline, i.e. at the start of the study. For 41 patients both were available. MRI were then analyzed via volumetry and VASARI morphometry. The resulting 27 imaging variables were linked with 67 peripheral blood immunology variables from flow cytometry and PCR and all potential relations were mapped.</p><p><strong>Results: </strong>In an initial broad screening, 94 imaging-immunology associations were discovered. Notably, features of the contrast-enhancing margin like its thickness and its shape were positively correlated with various T cell species including activated cytotoxic CD8+ T cells and central memory CD8+ T cells. The T2-volume was correlated with CD56+CD16- natural killer cells, and the necrosis volume was correlated with immunopolarizing mRNAs in the blood (IFN-γ, GATA3, ROR-gt). After multiple testing correction, two imaging-immunology associations were confirmed as significant: a thick contrast-enhancing margin was correlated with lower regulatory T cell markers in the blood and invasion of deep white matter was correlated with less T helper 17 factors.</p><p><strong>Conclusion: </strong>We here provide first evidence that imaging and peripheral blood immunology features can go hand in hand and that imaging variables can correlate with systemic immunophenotypes. Especially a thick contrast-enhancing margin seems to indicate a pro-inflammatory immune state. Via pioneering the integration of imaging and immunology, we not only advance basic glioblastoma science but we also open up novel avenues for research. In the future, e.g. patient stratification for therapy development could be based on imaging-guided immunophenotyping.</p>","PeriodicalId":6914,"journal":{"name":"Acta Neuropathologica Communications","volume":"12 1","pages":"183"},"PeriodicalIF":6.2,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11603976/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
An immune scoring system predicts prognosis and immune characteristics in lung adenocarcinoma brain metastases by RNA sequencing. 通过RNA测序预测肺腺癌脑转移预后和免疫特征的免疫评分系统
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-26 DOI: 10.1186/s40478-024-01895-9
Gang Xiao, Guilong Tanzhu, Xuan Gao, Lifeng Li, Zhiyuan Liu, Xuefeng Xia, Rongrong Zhou

Background: Previous studies have reported that the tumor immune microenvironment (TIME) was associated with the prognosis of lung cancer patients and the efficacy of immunotherapy. However, given the significant challenges in obtaining specimens of brain metastases (BrMs), few studies explored the correlation between the TIME and the prognosis in patients with BrMs from lung adenocarcinoma (LUAD).

Methods: Transcript profiling of archival formalin-fixed and paraffin-embedded specimens of BrMs from 70 LUAD patients with surgically resected BrMs was carried out using RNA sequencing. An immune scoring system, the green-yellow module score (GYMS), was developed to predict prognosis and immune characteristics in both BrMs and primary LUAD using Weighted Correlation Network analysis (WGCNA) and GSVA analysis. We comprehensively evaluated the immunological role of GYMS based on gene expression profile of LUAD BrMs by systematically correlating GYMS with immunological characteristics and immunotherapy responsiveness in the BrMs. Immunohistochemistry was applied for validation.

Results: We found that the high-GYMS group had better clinical prognosis and inflamed immune landscape including high infiltrations of various immune cells, increased immunomodulatory expression, and enriched immune-related pathways by using RNA-seq and immunohistochemical analysis. Low-GYMS group presented a lacked immune infiltration characteristic. Besides, the high-GYMS group had lower TIDE score and higher T-cell inflamed score than low-GYMS group. The GYMS has been validated in independent BrMs cohorts and primary NSCLC cohort treated with anti-PD-1/PD-L1, showing strong reproducibility and stability in both primary LUAD and BrMs. In addition, we construct a GYMS-related risk signature for patients with LUAD BrMs to predict prognosis.

Conclusions: We identified two immune-related subtypes which used to estimate prognosis and immune characteristics and developed a reliable GYMS-related risk signature in LUAD BrMs. These results will enhance the understanding of the immune microenvironment in LUAD BrMs and lay the theoretical foundation for the development of personalized therapies for LUAD patients with BrMs.

研究背景以前的研究曾报道,肿瘤免疫微环境(TIME)与肺癌患者的预后和免疫疗法的疗效有关。然而,由于获取脑转移瘤(BrMs)标本面临巨大挑战,很少有研究探讨TIME与肺腺癌(LUAD)脑转移瘤患者预后的相关性:方法:利用 RNA 测序技术对 70 例经手术切除的肺腺癌(LUAD)患者的福尔马林固定和石蜡包埋的肺腺癌(BrMs)存档标本进行了转录本分析。利用加权相关网络分析(WGCNA)和GSVA分析,开发了一套免疫评分系统--绿黄模块评分(GYMS),用于预测BrMs和原发性LUAD的预后和免疫特征。我们基于LUAD BrMs的基因表达谱,通过系统地将GYMS与BrMs的免疫学特征和免疫治疗反应性相关联,全面评估了GYMS的免疫学作用。 结果:结果:通过RNA-seq和免疫组化分析,我们发现高GYMS组临床预后较好,并具有炎性免疫景观,包括各种免疫细胞的高浸润、免疫调节表达的增加以及免疫相关通路的丰富。低 GYMS 组缺乏免疫浸润特征。此外,与低GYMS组相比,高GYMS组的TIDE评分较低,T细胞炎症评分较高。GYMS已在独立的BrMs队列和接受抗PD-1/PD-L1治疗的原发性NSCLC队列中得到验证,在原发性LUAD和BrMs中均显示出很强的可重复性和稳定性。 此外,我们还为LUAD BrMs患者构建了GYMS相关风险特征,以预测预后:这些结果将加深人们对 LUAD BrMs 免疫微环境的了解,并为开发针对 LUAD BrMs 患者的个性化疗法奠定理论基础。
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引用次数: 0
Homozygous CDKN2A/B deletions in low- and high-grade glioma: a meta-analysis of individual patient data and predictive values of p16 immunohistochemistry testing. 低度和高度胶质瘤中的同基因CDKN2A/B缺失:个体患者数据和p16免疫组化检测预测值的荟萃分析。
IF 6.2 2区 医学 Q1 NEUROSCIENCES Pub Date : 2024-11-26 DOI: 10.1186/s40478-024-01889-7
Darius Noack, Johannes Wach, Alonso Barrantes-Freer, Nils H Nicolay, Erdem Güresir, Clemens Seidel

CDKN2A/B deletions are prognostically relevant in low- and high-grade gliomas. Data on this is derived from heterogeneous series, an accurate estimation of survival risk from homozygous CDKN2A/B deletion is missing. Besides genetic testing, p16-immunohistochemistry (IHC) as a less cost intensive means for indirect detection of CDKN2A/B alterations is possible but not validated in larger datasets. The present meta-analysis aimed to (1) reconstruct individual patient data (IPD) and estimate overall survival (OS) stratified by CDKN2A/B status from all literature and to (2) determine accuracy of p16 testing for CDKNA2/B detection from published studies. For survival analysis according to CDKN2A/B status 460 records were screened, four articles with 714 participants were included. In IDH-wildtype (IDH-wt) gliomas, 57.07% harbored the deletion compared to 9.76% in IDH-mutant (IDH-mut) gliomas. Median OS of patients with IDH-wt gliomas and homozygous CDKN2A/B deletion was 13.0 months compared to 18.0 months with non-deleted CDKN2A/B (p = 0.014, Log-Rank). With homozygous deletion of CDKN2A/B the risk of death was increased by 1.5 (95%-CI 1.1-2.1). Median OS in patients with IDH-mut gliomas without CDKN2A/B deletion was 92.0 months compared to 40.0 months with CDKN2A/B deletion (p < 0.001, Log-Rank). CDKN2A/B deletions were associated with a significantly shorter OS (HR = 3.2; 95%-CI 2.2-5.5). For p16 IHC analysis, 10 eligible studies with 1087 examined samples were included. The cut-off for retention differed between the studies. In 588/662 p16 retained cases CDKN2A/B deletions was not detected, implying a negative predictive value (NPV) of p16 staining of 88.8%. Conversely, 279/425 p16 absent cases showed a CDKN2A/B deletion resulting in a positive predictive value (PPV) of 65.6%. Sensitivity of p16 staining for CDKN2A/B detection was 79.0%, specificity 80.1%. Highest diagnostic accuracy of p16 IHC was reached with a cut-off of > 5% and within IDH-mut glioma.

CDKN2A/B缺失与低级别和高级别胶质瘤的预后相关。这方面的数据来自不同的系列,目前尚缺乏对同源 CDKN2A/B 缺失的生存风险的准确估计。除基因检测外,p16免疫组化(IHC)作为一种成本较低的间接检测CDKN2A/B改变的方法也是可行的,但尚未在更大的数据集中得到验证。本荟萃分析旨在:(1)重建患者个体数据(IPD),并根据所有文献中的 CDKN2A/B 状态分层估算总生存期(OS);(2)确定已发表研究中用于 CDKNA2/B 检测的 p16 检测的准确性。为了根据 CDKN2A/B 状态进行生存率分析,我们筛选了 460 条记录,纳入了 4 篇文章,共 714 名参与者。在IDH-野生型(IDH-wt)胶质瘤中,57.07%的患者存在缺失,而在IDH-突变型(IDH-mut)胶质瘤中,只有9.76%的患者存在缺失。IDH-wt胶质瘤和同源CDKN2A/B缺失患者的中位OS为13.0个月,而CDKN2A/B未缺失患者的中位OS为18.0个月(P = 0.014,Log-Rank)。CDKN2A/B 基因同源缺失患者的死亡风险增加了 1.5(95%-CI 1.1-2.1)。未发生CDKN2A/B缺失的IDH突变胶质瘤患者的中位生存期为92.0个月,而发生CDKN2A/B缺失的患者的中位生存期为40.0个月(P为5%,在IDH突变胶质瘤中为5%)。
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