Purpose: In this study, we evaluated the presence of tau deposition and protein expression of Reelin/GSK-3(3/p-Tau signaling pathway in the hippocampus of patients with temporal lobe epilepsy (TLE). Methods: A total of 37 cases of TLE with and without hippocampal sclerosis (HS) were selected histopathologically for our study with 5 autopsy cases as the control group. Immunohistochemistry and the histelide assay, a novel technique quantifying antigens in paraffin section, were used to confirm the distribution of protein within Reelin/GSK-3(3/p-Tau signaling pathway and validate the expression of GSK-3(3 and AT8 (hyperphosphorylated tau) in this study. Results: Immunohistochemical staining for AT8 revealed punctate and filamentous positive expression in the CA1, CA2 and CA3 regions of the hippocampus with TLE under the ependyma, distributed in a band-like pattern. By contrast, the control group did not exhibit any immunopositivity. GSK-3(3 was strongly positive in the neuronal bodies, apical dendrites and axons in both groups of TLE, while all controls were negative. In addition, there was no significant difference in the immunohistochemical labelling of Reelin among all cases. The histelide assay indicated that the amounts of AT8 and GSK-3(3 were significantly increased in the two TLE groups (P < 0.05). Notably, there was a positive correlation between AT8 and GSK-3(3 in TLE without HS (P < 0.05). Conclusion: The present data indicates that phosphorylated tau protein and GSK-3(3 are activated in the hippocampus of patients with TLE, and this is the first study to examine relevant proteins with the histelide assay in paraffin samples of human tissue. We consider that the regulatory network of tau protein between the two groups may be similar but not identical. Significance: This study emphasized the Reelin/GSK-3(3/p-Tau signaling pathway in TLE with a quantitative data of human tissues innovatively, revealing inspiration for mechanism exploration.

Objective: To investigate the clinical, radiological, and pathological features of anaplastic gangliogliomas (AGGs) and to determine whether these tumors represent a distinct entity. Methods: Consecutive 667 cases of ganglioglioma (GG) diagnosed at the Xuanwu Hospital, Capital Medical University, Beijing, China between January 2015 and July 2023 were screened. Among these cases, 9 pathologically confirmed AGG cases were identified. Their clinical, radiological, treatment, and outcome data were analyzed retrospectively. Most of the tumor samples were subject to next-generation sequencing, while a subset of them were subject to DNA methylation profiling. Results: Among the 9 patients, there were five males and four females, with a median age of 8 years. Epileptic seizures (5/9) were the most frequently presented symptom. Radiological examinations showed three types of radiological manifestations: four cases showed abnormal MRI signals with no significant mass effects and mild enhancement; two cases demonstrated a mixed solid-cystic density lesion with peritumoral edema, which showed significant heterogeneous enhancement and obvious mass effects, and one case displayed cystic cavity formation with nodules on MRI, which showed evident enhancements. All cases exhibited mutations that were predicted to activate the MAP kinase signaling pathway, including seven with BRAF p.V600E mutation and two with NF1 mutation. Five AGGs with mutations involving the MAP kinase signaling pathway also had concurrent mutations, including three with CDKN2A homozygous deletion, one with a TERT promoter mutation, one with a H3F3A mutation, and one with a PTEN mutation. Conclusions: AGG exhibits a distinct spectrum of pathology, genetic mutations and clinical behaviors, differing from GG. Given these characteristics suggest that AGG may be a distinct tumor type, further expansion of the case series is needed. Therefore, a comprehensive integration of clinical, histological, and molecular analyses is required to correctly diagnose AGG. It will also help guide treatments and prognostication.

With rapid development of genetic testing techniques, neuroimaging and neuroelectrophysiological technologies, our understanding of malformations of cortical development continues to be deepened and updated. In particular, mutations in genes related to the mammalian target of rapamycin (mTOR) signaling pathway have been successively discovered in focal cortical dysplasia (FCD). At the same time, the classification consensus on FCD issued by the International League Against Epilepsy (ILAE) in 2011 has encountered problems and challenges in diagnostic practice. Therefore, in 2022, ILAE proposed an updated version of the FCD classification based on the progress in molecular genetics over the past decade. The main addition to the classification system is "white matter lesions, " and it is also suggested to integrate histopathological, neuroimaging, and molecular testing results for multi-level integrated diagnosis to achieve reliable, clinically relevant, and therapeutic targeted final diagnosis.

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

Focal cortical dysplasia (FCD) is a major cause of drug‐resistant paediatric epilepsy and is amenable to successful neurosurgical resection. FCD ILAE Type IIb is the most common FCD subtype, and brain somatic mutations affecting the mTOR pathway play a major pathogenic role. The aim of this study was to comprehensively describe the genotype–phenotype association of 20 patients with histopathologically confirmed FCDIIb using next generation sequencing (NGS) of paired blood–brain samples.

Juan Lin,1,2,&ast; Xinyu Lin,1,&ast; Yong-Juan Fu,1 Xuran Li,3 Xin Li,3 Yujiao Wang,1,4 Lihong Zhao,1 Shun Yu,3 Yue-Shan Piao1,5,6 1Department of Pathology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China; 2Department of Pathology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, People’s Republic of China; 3Department of Neurobiology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, People’s Republic of China; 4Department of Pathology, Shanxi Provincial People’s Hospital, Affiliated People’s Hospital of Shanxi Medical University, Taiyuan, 030012, People’s Republic of China; 5Clinical Research Center for Epilepsy, Capital Medical University, Beijing, 100053, People’s Republic of China; 6National Center for Neurological Disorders, Beijing, 100053, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yue-Shan Piao, Email yueshanpiao@126.com; Shun Yu, Email yushun103@163.comPurpose: In this study, we evaluated the presence of tau deposition and protein expression of Reelin/GSK-3β/p-Tau signaling pathway in the hippocampus of patients with temporal lobe epilepsy (TLE).Methods: A total of 37 cases of TLE with and without hippocampal sclerosis (HS) were selected histopathologically for our study with 5 autopsy cases as the control group. Immunohistochemistry and the histelide assay, a novel technique quantifying antigens in paraffin section, were used to confirm the distribution of protein within Reelin/GSK-3β/p-Tau signaling pathway and validate the expression of GSK-3β and AT8 (hyperphosphorylated tau) in this study.Results: Immunohistochemical staining for AT8 revealed punctate and filamentous positive expression in the CA1, CA2 and CA3 regions of the hippocampus with TLE under the ependyma, distributed in a band-like pattern. By contrast, the control group did not exhibit any immunopositivity. GSK-3β was strongly positive in the neuronal bodies, apical dendrites and axons in both groups of TLE, while all controls were negative. In addition, there was no significant difference in the immunohistochemical labelling of Reelin among all cases. The histelide assay indicated that the amounts of AT8 and GSK-3β were significantly increased in the two TLE groups (P < 0.05). Notably, there was a positive correlation between AT8 and GSK-3β in TLE without HS (P < 0.05).Conclusion: The present data indicates that phosphorylated tau protein and GSK-3β are activated in the hippocampus of patients with TLE, and this is the first study to examine relevant proteins with the histelide assay in paraffin samples of human tissue. We consider that the regulatory network of tau protein between the two groups may be similar but not identical.Significance: This study emphasized the Reelin/GSK-3β/p-Tau signaling pathway in TLE with a quantitative data of human tissues innovatively, revealing inspiration for mechanism exploration.Keywords: epilepsy, temporal lobe epilepsy, hippocampal sclerosis, Reelin, GSK-3β, p-Tau

目的 探讨脉络丛癌(CPC)的临床病理及免疫组化特征.方法 收集首都医科大学宣武医院诊断的CPC共10例,总结临床病例资料、组织学以及免疫组化特征,并进行文献复习.结果 10例CPC发病部位以脑室居多,侧脑室及四脑室总占比60％;其次散发在枕叶、顶叶、脑干及鞍区,占比40％.年龄0.7～14岁,中位年龄为3.0岁;男性4例,女性5例;均有不同程度的中枢神经系统疾病表现,常见为嗜睡、哭闹、头痛及脑积水等症状.影像学表现为孤立性实性肿物,镜下符合2021版CNS WHO CPC诊断标准.免疫组化表型中EMA均表现为灶状阳性,GFAP、CK、CK7和CK20均有各自比例的阳性值和阳性结果,Ki-67增殖指数为15％～50％,INI-1未见缺失.特异性较强的两个指标:Kir7.1细胞膜及细胞质表达,阳性细胞数为80％,其中1例阳性细胞数低于50％;TTR在细胞质中表达,阳性细胞数为60％.结论 CPC是一种罕见的、生长迅速的、好发于婴幼儿的恶性肿瘤,EMA、GFAP、CK、CK7及CK20表达有一定的规律,Kir7.1和TTR诊断CPC特异性较强,鉴别诊断婴幼儿中枢神经系统恶性肿瘤具有一定的临床价值.

中枢神经系统结核是肺外结核病的一种少见形式，具有较高的病死率，包括结核性脑膜炎、颅内结核瘤和结核性蛛网膜炎。颅内结核瘤是结核病危害最大的一种类型，它的临床及影像学表现多样，极易误诊，早期正确诊断对于疾病的治疗和预后有非常重要的意义。本文报道了一例青年男性结核瘤患者的诊治过程，其临床表现及实验室检查等结果不典型，最终通过脑组织活检确诊，为临床对该类疾病的诊断带来一定的启示。

Over decades, nearly all attempts to translate the benefits of therapeutic hypothermia in stroke models of lower-order species to stroke patients have failed. Potentially overlooked reasons may be biological gaps between different species and the mismatched initiation of therapeutic hypothermia in translational studies. Here, we introduce a novel strategy of selective therapeutic hypothermia in a non-human primate ischemia-reperfusion model, in which autologous blood was cooled ex vivo and the cool blood transfusion was administered at the middle cerebral artery just after the onset of reperfusion. Cold autologous blood cooled the targeted brain rapidly to below 34 °C while the rectal temperature remained around 36 °C with the assistance of a heat blanket during a 2-h hypothermic process. Therapeutic hypothermia or extracorporeal-circulation related complications were not observed. Cold autologous blood treatment reduced infarct sizes, preserved white matter integrity, and improved functional outcomes. Together, our results suggest that therapeutic hypothermia, induced by cold autologous blood transfusion, was achieved in a feasible, swift, and safe way in a non-human primate model of stroke. More importantly, this novel hypothermic approach conferred neuroprotection in a clinically relevant model of ischemic stroke due to reduced brain damage and improved neurofunction. This study reveals an underappreciated potential for this novel hypothermic modality for acute ischemic stroke in the era of effective reperfusion.

Vertebrobasilar dolichoectasia (VBD) is a rare type of cerebrovascular disorder with high rates of morbidity and mortality. Due to the distinct pathological characteristics that fragmented internal elastic lamina and multiple dissections, VBD is difficult to treat and cured. Stent-assisted coil embolization is one of the main treatment modalities for such lesions. However, the duration of healing remained questionable, and there were no effective measures for evaluating endothelial coverage. Before complete endothelial coverage, the discontinuation of antiplatelet therapy may lead to fatal in-stent thrombosis; however, continued antiplatelet therapy could also result in bleeding complications. Thus, we present an autopsy case of late in-stent thrombosis due to the discontinuation of antiplatelet therapy and systematically review the literature to provide a reference for endovascular treatment and antiplatelet regimen of VBD.

目的 探讨大脑淋巴瘤病(lymphomatosis cerebri,LC)的临床病理学特点,以期为临床诊治提供思路.方法 选取2020年1月至2022年1月首都医科大学宣武医院确诊的LC患者4例,对其临床资料、影像学及病理学特点进行回顾性分析.结果 4例患者中男3例,女1例,年龄49～63岁,平均59岁.临床表现为进行性进展的认知功能障碍、行为改变和行走不稳等,影像学检查均表现为大脑弥漫性及多发性病变,以白质受累为主,CT呈低密度影,T1WI等或低信号,T2WI及FLAIR高信号,无明显强化.3例为立体定向穿刺活检标本,1例为开颅手术切除标本.组织学诊断均为弥漫性大B细胞淋巴瘤,结合临床及影像学表现,符合原发性中枢神经系统淋巴瘤、LC.结论 LC为累及中枢神经系统的弥漫性病变,以白质受累为主,亚急性或快速进展的认知功能障碍为其显著临床特征,涉及的鉴别诊断复杂多样,立体定向穿刺活检为获得确定诊断提供了可能性,尽早明确病理诊断是确保临床进行精准治疗的关键.

Over decades of research into the treatment of stroke, nearly all attempts to translate experimental treatments from discovery in cells and rodents to use in humans have failed. The prevailing belief is that it might be necessary to pretest pharmacological neuroprotection in higher-order brains, especially those of nonhuman primates (NHPs). Over the past few years, chemical thrombolysis and mechanical thrombectomy have been established as the standard of care for ischemic stroke in patients. The spotlight is now shifting towards emphasizing both focal ischemia and subsequent reperfusion in developing a clinically relevant stroke model in NHPs. This protocol describes an embolic model of middle cerebral artery occlusion in adult rhesus monkeys. An autologous clot is combined with a microcatheter or microwire through endovascular procedures, and reperfusion is achieved through local intra-artery thrombolysis with tissue plasminogen activator. These NHP models formed relatively stable infarct sizes, delivered predictable reperfusion and survival outcomes, and recapitulated key characteristics of patients with ischemic stroke as observed on MRI images and behavioral assays. Importantly, treated animals could survive 30 d after the surgery for post-stroke neurologic deficit analyses. Thus far, this model has been used in several translational studies. Here we describe in detail the teamwork necessary for developing stroke models of NHPs, including the preoperation preparations, endovascular surgery, postoperation management and histopathological analysis. The model can be established by the following procedures over a 45-d period, including preparation steps (14 d), endovascular operation (1 d) and evaluation steps (30 d).

Background and Objectives:Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebrovascular disease caused by homozygous or compound heterozygous variations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. However, several studies in recent years have found that some heterozygous HTRA1 mutations also cause cerebral small vessel disease (CSVD). The current study aims to report the novel genotypes, phenotypes, and histopathologic results of 3 pedigrees of CSVD with heterozygous HTRA1 mutation.Methods:Three pedigrees of familiar CSVD, including 11 symptomatic patients and 3 asymptomatic carriers, were enrolled. Whole-exome sequencing was conducted in the probands for identifying rare variants, which were then evaluated for pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was performed for validation of mutations in the probands and other family members. The protease activity was assayed for the novel mutations. All the participants received detailed clinical and imaging examinations and the corresponding results were concluded. Hematoma evacuation was performed for an intracerebral hemorrhage patient with the p.Q318H mutation, and the postoperative pathology including hematoma and cerebral small vessels were examined.Results:Three novel heterozygous HTRA1 mutations (p.Q318H, p.V279M, and p.R274W) were detected in the 3 pedigrees. The protease activity was largely lost for all the mutations, confirming that they were loss-of-function mutations. The patients in each pedigree presented with typical clinical and imaging features of CVSD, and some of them displayed several new phenotypes including color blindness, hydrocephalus, and multiple arachnoid cysts. In addition, family 1 is the largest pedigree with heterozygous HTRA1 mutation so far and includes homozygous twins, displaying some variation in clinical phenotypes. More importantly, pathologic study of a patient with p.Q318H mutation showed hyalinization, luminal stenosis, loss of smooth muscle cells, splitting of the internal elastic lamina, and intramural hemorrhage/dissection-like structures.Discussion:These findings broaden the mutational and clinical spectrum of heterozygous HTRA1-related CSVD. Pathologic features were similar with the previous heterozygous and homozygous cases. Moreover, clinical heterogeneity was revealed within the largest single family, and the mechanisms of the phenotypic heterogenetic remain unclear. Overall, heterozygous HTRA1-related CSVD should not be simply taken as a mild type of CARASIL as previously considered.

Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a rare hereditary cerebrovascular disease caused by homozygous or compound heterozygous variations in the high-temperature requirement A serine peptidase 1 (HTRA1) gene. However, several studies in recent years have found that some heterozygous HTRA1 mutations also cause cerebral small vessel disease (CSVD). The current study aims to report the novel genotypes, phenotypes, and histopathologic results of 3 pedigrees of CSVD with heterozygous HTRA1 mutation.Three pedigrees of familiar CSVD, including 11 symptomatic patients and 3 asymptomatic carriers, were enrolled. Whole-exome sequencing was conducted in the probands for identifying rare variants, which were then evaluated for pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Sanger sequencing was performed for validation of mutations in the probands and other family members. The protease activity was assayed for the novel mutations. All the participants received detailed clinical and imaging examinations and the corresponding results were concluded. Hematoma evacuation was performed for an intracerebral hemorrhage patient with the p.Q318H mutation, and the postoperative pathology including hematoma and cerebral small vessels were examined.Three novel heterozygous HTRA1 mutations (p.Q318H, p.V279M, and p.R274W) were detected in the 3 pedigrees. The protease activity was largely lost for all the mutations, confirming that they were loss-of-function mutations. The patients in each pedigree presented with typical clinical and imaging features of CVSD, and some of them displayed several new phenotypes including color blindness, hydrocephalus, and multiple arachnoid cysts. In addition, family 1 is the largest pedigree with heterozygous HTRA1 mutation so far and includes homozygous twins, displaying some variation in clinical phenotypes. More importantly, pathologic study of a patient with p.Q318H mutation showed hyalinization, luminal stenosis, loss of smooth muscle cells, splitting of the internal elastic lamina, and intramural hemorrhage/dissection-like structures.These findings broaden the mutational and clinical spectrum of heterozygous HTRA1-related CSVD. Pathologic features were similar with the previous heterozygous and homozygous cases. Moreover, clinical heterogeneity was revealed within the largest single family, and the mechanisms of the phenotypic heterogenetic remain unclear. Overall, heterozygous HTRA1-related CSVD should not be simply taken as a mild type of CARASIL as previously considered.

The BRAF p.V600E mutation is the most common genetic alteration in ganglioglioma (GG). Herein, we collected a consecutive series of 30 GG specimens from Xuanwu Hospital in order to corroborate the genetic landscape and genotype–phenotype correlation of this enigmatic and often difficult‐to‐classify epilepsy‐associated brain tumor entity. All specimens with histopathologically confirmed lesions were submitted to targeted next‐generation sequencing using a panel of 131 genes. Genetic alterations in three cases with histologically distinct tumor components, that is, GG plus pleomorphic xanthoastrocytoma (PXA), dysembryoplastic neuroepithelial tumor (DNT), or an oligodendroglioma (ODG)‐like tumor component, were separately studied. A mean post‐surgical follow‐up time‐period of 23 months was available in 24 patients. Seventy seven percent of GG in our series can be explained by genetic alterations, with BRAF p.V600E mutations being most prevalent (n = 20). Three additional cases showed KRAS p.Q22R and KRAS p.G13R , IRS2 copy number gain (CNG) and a KIAA1549‐BRAF fusion. When genetically studying different histopathology patterns from the same tumor we identified composite features with BRAF p.V600E plus CDKN2A/B homozygous deletion in a GG with PXA features, IRS2 CNG in a GG with DNT features, and a BRAF p.V600E plus CNG of chromosome 7 in a GG with ODG‐like features. Follow‐up revealed no malignant tumor progression but nine patients had seizure recurrence. Eight of these nine GG were immunoreactive for CD34, six patients were male, five were BRAF wildtype, and atypical histopathology features were encountered in four patients, that is, ki‐67 proliferation index above 5% or with PXA component. Our results strongly point to activation of the MAP kinase pathway in the vast majority of GG and their molecular‐genetic differentiation from the cohort of low‐grade pediatric type diffuse glioma remains, however, to be further clarified. In addition, histopathologically distinct tumor components accumulated different genetic alterations suggesting collision or composite glio‐neuronal GG variants.

Objective: To explore the disease manifestations and radiological characteristics of patients with meningeal carcinomatosis (MC) combined with myelopathy. Patients and Methods: The detailed medical information of patients who suffered from MC with myelopathy in record system were collected and reviewed. Results: In these patients, five cases were male and two cases were female. The age was from fifteen to fifty-seven years. In the course of disease, tumor cells were discovered in cerebrospinal fluid of three patients and in biopsy samples of four patients. Cerebrospinal fluid (CSF) test results showed white blood cell counts increased in seven patients, protein increased in six patients and glucose reduced in five patients. In addition, MRI revealed that the white matter abnormalities showed in all cases and pia mater was enhanced in four patients, meningeal enhanced was observed in three patients. All patients were given appropriate therapy during hospitalization. Follow-up result showed that all patients passed away two to five months after diagnosis. Conclusion: MC causes spinal membrane, spinal nerve root to be involved besides, also can produce the matter of myelopathy. Early detection of intramedullary lesion is conducive to strengthening the awareness of the diagnosis of MC.

随着神经影像学技术和神经外科技术尤其是外科手术机器人的发展和应用，立体定向活检手术逐渐成为神经系统疑难病例精确诊断的有力手段。病理科将接收越来越多的活检小标本，并面对各种各样的非肿瘤性病变以及处于早期的病变。病理医师如何迎接挑战，突破瓶颈？该文从神经病理基本病变的识别，紧密结合临床、影像及实验室检查以及密切关注分子生物学新进展三方面介绍作者在神经病理诊断实践中的体会。

临床神经病理学作为神经病学和病理学的桥梁学科，其亚专科建设是临床病理医师规范化培训和继续教育的重要组成部分，也在神经内科、神经外科及神经影像等相关专业医师的培训中起着重要的作用。本文从神经病理基本功的训练、病理与临床的结合、病理与影像的结合以及专业知识的更新四个方面阐述了临床神经病理学亚专科建设的重点。临床神经病理诊断水平的高低直接关系着神经系统疾病的临床诊疗效果，以及神经系统疾病相关科学研究的客观性和可信度。做好临床神经病理学亚专科的建设才能从根本上提升临床神经病理诊断的水平，助力我国脑科学的进步。.