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IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-10-16 DOI: 10.1111/bpa.13308

引用次数: 0

40-Year-old man with two asynchronous spinal cord tumors 40 岁男子患有两个不同步脊髓肿瘤。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-10-06 DOI: 10.1111/bpa.13309

Maximilian Bschorer, Matthias Dottermusch, Jakob Matschke, Jens Gempt, Ulrich Schüller, Malte Mohme

A 38-year-old individual presented with intermittent bladder dysfunction, radicular pain, and mild foot elevator paresis. After an emergency lumbar MRI revealed a vertebral disc herniation at the L5/S1 level, an emergency sequestrectomy was performed. Although the radicular pain resolved postoperatively, the patient's bladder voiding dysfunction worsened. Further MRI imaging revealed a contrast-enhancing intramedullary lesion at the TH11/TH12 spinal levels (Figure 1A).The patient was transferred to the neurosurgical department for further treatment, and urgent surgery was performed with continuous intraoperative neurophysiological monitoring. Histopathological analysis was conducted and subsequent DNA methylation analysis confirmed the histological diagnosis. The patient did not undergo genetic testing for neurofibromatosis (NF), as he did not exhibit any other typical features or tumors associated with NF.Postoperative paraparesis and bladder dysfunction were promptly resolved in neurological rehabilitation, resulting in a McCormick score of one. Three years later, the patient presented with new radiculopathy in both legs accompanied and hypesthesia. MRI showed a new contrast-enhancing lesion at L2/L3, which was located at a distance from the previous lesion (Figure 1B). The patient underwent surgery for this symptomatic lesion. The histopathological and methylation analysis revealed a distinct diagnosis, when compared to the histological examination of the initial tumor. Postoperative imaging showed no residual tumor, and there were no other central nervous system (CNS) manifestations of the tumor. The patient's rapid recovery from neurological symptoms allowed for discharge to ambulatory service.Histological comparison of the first and second tumor revealed distinctive features. The first tumor was characterized by isomorphic glial cells with round nuclei within a delicate fibrillary matrix, as observed in H&E staining (Figure 2, Box 1). The tumor cells showed clear expression of glial fibrillary acidic protein (GFAP), but not OLIG2 or NMYC. The Ki67 labeling index was below 5% of the tumor cell nuclei. Zones without nuclei around blood vessels, known as perivascular pseudorosettes, were also present.The second tumor was characterized by more spindled tumor cells within a coarse myxoid glial matrix, indicative of a divergent histological diagnosis. The cell nuclei were oval to elongated with slightly loosened nuclear chromatin. Similar to the first tumor, strong GFAP immunostaining was observed. The second tumor was distinctively marked by nuclear expression of HOXB1, absent in the first tumor.For both samples, DNA methylation data were obtained using the Illumina Human MethylationEPIC (850 k) array bead chips. The classification of brain tumors based on DNA methylation was performed using the publicly available “classifier” tool, version v12.8 (www.molecularneuropathology.org/mnp). The epigenetic anal

因此，在手术方案有限的情况下，放疗经常被推荐使用，但其疗效仍在不断评估中[2]。鉴于脊柱上皮瘤组织学表现的异质性，本病例加强了对分子诊断的依赖，以指导治疗决策。MD准备了切片并进行了组织学和免疫组织学分析。MM和US修改了手稿。MM、US、JM和JG参与了研究设计，并为手稿的起草和提交提供了支持。U.S.还得到了汉堡儿童疾病中心的资助。作者声明没有利益冲突。

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引用次数: 0

A 55-year-old man with a cerebral mass 一名 55 岁男子，脑部肿块。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-10-03 DOI: 10.1111/bpa.13310

Serena Ammendola, Giuseppe Kenneth Ricciardi, Valeria Barresi

A 55-year-old man presented with recent onset of dizziness and left lower limb weakness. Magnetic resonance imaging revealed a relatively circumscribed mass in the left frontal lobe extending to the corpus callosum and contralateral hemisphere, with conspicuous perilesional edema and contrast enhancement (Figure 1). A whole-body computerized tomography (CT) scan did not reveal any other lesions. The patient underwent partial excision of the mass. F-18 fluorodeoxyglucose–positron emission tomography (PET) imaging demonstrated hypermetabolism in the residual brain mass, but no evidence of any lesion outside the central nervous system.Microscopic examination revealed a hypercellular neoplasm mainly composed of large cells exhibiting irregular or indented, frequently nucleolated, nuclei, and eosinophilic cytoplasm, and characterized by brisk mitotic activity (Figure 2A; Box 1) and necrosis. Additionally, scattered binucleated or multinucleated cells were observed (Figure 2A). Some neoplastic cells exhibited hemophagocytic activity, consisting of engulfment of fragmented neutrophils or red blood cells in the cytoplasm (Figure 2B), whereas others displayed a brown cytoplasmic pigment (Figure 2C). Perl's staining revealed the presence of iron deposits in these cells (Figure 2D). Immunohistochemistry showed that the tumor cells were diffusely positive for CD68 (Figure 2E), CD163 (Figure 2F), and CD45, and negative for CD3, CD20, CD30, ALK, Langerin (CD207), CD21, myeloperoxidase, CD34, CD117, HMB45, Melan-A, CKAE1-AE3, GFAP, and OLIG2. CD4 (Figure 2G) and S100 positivity was observed in some neoplastic cells (Figure 2). Ki-67 labeling index was 40%. Immuno-expression of BRAF p. V600E was absent. CD3 immunostaining revealed abundant infiltration of small lymphocytes (Figure 2H).Histiocytic sarcoma (HS).HS is an exceedingly rare and aggressive hematopoietic tumor that primarily affects the lymph nodes, skin, gastrointestinal tract, or soft tissues, and can occur in individuals of varying ages, ranging from infancy to older adulthood. Primary HS of the central nervous system (CNS) is extremely uncommon, with fewer than 40 cases reported in the English literature [1]. Herein we present an additional case, which was considered as primary HS of the CNS owing to the lack of localization outside the CNS on CT and PET scans. According to the World Health Organization classification of CNS tumors, HS is defined as a malignant proliferation of cells showing morphological and immunophenotypic features of histiocytes and no other lines of differentiation. Histologically, HS is characterized by large cells with irregular nucleolated nuclei and eosinophilic cytoplasm, and brisk mitotic activity. An infiltrate of lymphocytes surrounding tumor cells, along with the presence of large pleomorphic cells and CD45 positivity may suggest anaplastic large-cell lymphoma or diffuse large B-cell lymphoma. However, the absence of immunostaining

BRAF激活突变（包括BRAF p. V600E突变）和BRAF重排均已在HS中发现，可作为潜在的治疗靶点[1, 3]。G.K.R.和 V.B.审阅并编辑了稿件。Valeria Barresi由意大利维罗纳大学（FUR 2023）资助。作者声明无利益冲突。

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引用次数: 0

hnRNP A1, hnRNP A2B1, and hnRNP K are dysregulated in tauopathies, but do not colocalize with tau pathology. hnRNP A1、hnRNP A2B1 和 hnRNP K 在牛头蛋白病中失调，但并不与牛头蛋白病理共聚焦。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-10-01 DOI: 10.1111/bpa.13305

Tomas Kavanagh, Kaleah Balcomb, Diba Ahmadi Rastegar, Guinevere F Lourenco, Thomas Wisniewski, Glenda Halliday, Eleanor Drummond

Tau interacts with multiple heterogeneous nuclear ribonucleoproteins (hnRNPs)-a family of RNA binding proteins that regulate multiple known cellular functions, including mRNA splicing, mRNA transport, and translation regulation. We have previously demonstrated particularly significant interactions between phosphorylated tau and three hnRNPs (hnRNP A1, hnRNP A2B1, and hnRNP K). Although multiple hnRNPs have been previously implicated in tauopathies, knowledge of whether these hnRNPs colocalize with tau aggregates or show cellular mislocalization in disease is limited. Here, we performed a neuropathological study examining the colocalization between hnRNP A1, hnRNP A2B1, hnRNP K, and phosphorylated tau in two brain regions (hippocampus and frontal cortex) in six disease groups (Alzheimer's disease, mild cognitive impairment, progressive supranuclear palsy, corticobasal degeneration, Pick's disease, and controls). Contrary to expectations, hnRNP A1, hnRNP A2B1, and hnRNP K did not colocalize with AT8-immunoreactive phosphorylated tau pathology in any of the tauopathies examined. However, we did observe significant cellular mislocalization of hnRNP A1, hnRNP A2B1 and hnRNP K in tauopathies, with unique patterns of mislocalization observed for each hnRNP. These data point to broad dysregulation of hnRNP A1, A2B1 and K across tauopathies with implications for disease processes and RNA regulation.

Tau 与多种异质性核核糖核蛋白（hnRNPs）相互作用--这是一个 RNA 结合蛋白家族，可调控多种已知的细胞功能，包括 mRNA 剪接、mRNA 运输和翻译调控。我们之前已经证明了磷酸化 tau 与三种 hnRNPs（hnRNP A1、hnRNP A2B1 和 hnRNP K）之间特别重要的相互作用。虽然多种 hnRNPs 以前与 tau 病有牵连，但关于这些 hnRNPs 是否与 tau 聚集体共定位或在疾病中表现出细胞错定位的知识还很有限。在这里，我们进行了一项神经病理学研究，在六个疾病组（阿尔茨海默病、轻度认知障碍、进行性核上性麻痹、皮质基底变性、皮克氏病和对照组）的两个脑区（海马和额叶皮层）检测了 hnRNP A1、hnRNP A2B1、hnRNP K 和磷酸化 tau 之间的共定位。与预期相反，在所研究的任何一种牛磺酸病中，hnRNP A1、hnRNP A2B1 和 hnRNP K 均未与 AT8 免疫反应性磷酸化牛磺酸病理共聚焦。不过，我们确实观察到，在牛磺酸脑病中，hnRNP A1、hnRNP A2B1 和 hnRNP K 出现了明显的细胞错定位，每种 hnRNP 的错定位模式都各不相同。这些数据表明，在各种au病中，hnRNP A1、A2B1和K都出现了广泛的失调，对疾病过程和RNA调控产生了影响。

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引用次数: 0

Posterior pituitary tumors and other rare entities involving the pituitary gland. 垂体后叶肿瘤及其他涉及垂体的罕见病变。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-09-30 DOI: 10.1111/bpa.13307

Federico Roncaroli, Caterina Giannini

Non-neuroendocrine tumors account for around 10% of all primary neoplasms of the sella. If meningiomas, craniopharyngiomas, and germ cell tumors are excluded, the remaining lesions include a broad spectrum of uncommon, benign, and aggressive, often diagnostically challenging lesions. This review aims to summarize the essential clinicopathological features of tumors of the posterior pituitary gland, infundibulum spectrum expressing thyroid transcription factor 1, and primary sellar atypical rhabdoid teratoid tumor, and provide the criteria for their diagnosis and management.

非神经内分泌肿瘤约占蝶鞍原发性肿瘤的 10%。如果排除脑膜瘤、颅咽管瘤和生殖细胞瘤，剩下的病变包括不常见的、良性的和侵袭性的广泛病变，通常在诊断上具有挑战性。本综述旨在总结垂体后叶肿瘤、表达甲状腺转录因子1的基底膜谱肿瘤和原发性蝶鞍非典型横纹肌畸胎瘤的基本临床病理特征，并提供其诊断和处理标准。

引用次数: 0

A 53-year-old woman with a 16-year history of epilepsy 一名 53 岁女性，有 16 年癫痫病史

IF 6.4 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-09-24 DOI: 10.1111/bpa.13311

Rong Ge, Chenning Shao, Lixia Lu, Li Wang, Can Peng

BOX 1. Virtual glass slide

https://isn-slidearchive.org/?col=ISN&fol=Archive&file=BPA-24-04-CI-091.svs

BOX 1. 虚拟玻璃幻灯片https://isn-slidearchive.org/?col=ISN&fol=Archive&file=BPA-24-04-CI-091.svs

引用次数: 0

DCC in the cerebral cortex is required for cognitive functions in mouse 小鼠的认知功能需要大脑皮层中的 DCC

IF 6.4 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-09-18 DOI: 10.1111/bpa.13306

Yun-Qing Hu, Wei-Tang Liu, Yong Wu, Zhi-Bin Hu, Yun-Chao Tao, Qiong Zhang, Jia-Yin Chen, Ming Li, Ling Hu, Yu-Qiang Ding

Schizophrenia (SZ) is a highly heritable mental disorder, and genome-wide association studies have identified the association between deleted in colorectal cancer (DCC) and SZ. Previous study has shown a lowered expression of DCC in the cerebral cortex of SZ patient. In this study, we identified novel single nucleotide polymorphisms (SNPs) of DCC statistically correlated with SZ. Based on these, we generated DCC conditional knockout (CKO) mice and explored behavioral phenotypes in these mice. We observed that deletion of DCC in cortical layer VI but not layer V led to deficits in fear and spatial memory, as well as defective sensorimotor gating revealed by the prepulse inhibition test (PPI). Critically, the defective sensorimotor gating could be restored by olanzapine, an antipsychotic drug. Furthermore, we found that the levels of p-AKT and p-GSK3α/β were decreased, which was responsible for impaired PPI in the DCC-deficient mice. Finally, the DCC-deficient mice also displayed reduced spine density of pyramidal neurons and disturbed delta-oscillations. Our data, for the first time, identified and explored downstream substrates and signaling pathway of DCC which supports the hypothesis that DCC is a SZ-related risky gene and when defective, may promote SZ-like pathogenesis and behavioral phenotypes in mice.

精神分裂症（SZ）是一种高度遗传性精神疾病，全基因组关联研究发现，大肠癌中的删除基因（DCC）与精神分裂症之间存在关联。先前的研究表明，DCC 在 SZ 患者大脑皮层中的表达量降低。在本研究中，我们发现了与 SZ 统计相关的 DCC 的新型单核苷酸多态性（SNPs）。在此基础上，我们产生了DCC条件性基因敲除（CKO）小鼠，并研究了这些小鼠的行为表型。我们观察到，在大脑皮层第 VI 层而非第 V 层缺失 DCC 会导致恐惧和空间记忆缺陷，以及通过前脉冲抑制测试（PPI）发现的感觉运动门控缺陷。重要的是，奥氮平（一种抗精神病药物）可以恢复感觉运动门控缺陷。此外，我们还发现p-AKT和p-GSK3α/β的水平降低，这是导致DCC缺陷小鼠PPI受损的原因。最后，DCC缺陷小鼠还表现出锥体神经元棘密度降低和δ振荡紊乱。我们的数据首次发现并探索了DCC的下游底物和信号传导途径，这支持了DCC是SZ相关风险基因的假设，当DCC缺陷时，可能会促进小鼠的SZ样发病机制和行为表型。

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引用次数: 0

Perivascular phosphorylated TDP-43 inclusions are associated with Alzheimer's disease pathology and loss of CD146 and Aquaporin-4 血管周围磷酸化 TDP-43 包涵体与阿尔茨海默病的病理以及 CD146 和 Aquaporin-4 的缺失有关

IF 6.4 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-09-09 DOI: 10.1111/bpa.13304

Jessica Santiago, Dovilė Pocevičiūtė, , Malin Wennström

The majority of patients with Alzheimer's disease (AD) exhibit aggregates of Trans-active response DNA binding protein 43 (TDP-43) in their hippocampus, which is associated with a more aggressive disease progression. The TDP-43 inclusions are commonly found in neurons, but also in astrocytes. The impact of the inclusions in astrocytes is less known. In the current study, we investigate the presence of phosphorylated TDP-43 (pTDP-43) inclusions in astrocytic endfeet and their potential association with blood–brain barrier (BBB) damage, glymphatic system dysfunction, and AD pathology. By staining postmortem hippocampal sections from AD patients and non-demented controls against TDP-43 and pTDP-43 together with the astrocytic markers glial fibrillary acidic protein (GFAP), astrocytic endfeet marker Aquaporin-4 (AQP4), and markers for BBB alterations (CD146) and leakiness (Immunoglobulin A), we demonstrate a close association between perivascular pTDP-43 or TDP-43 inclusions and GFAP or AQP4. These perivascular inclusions were more prominent in AD and correlated with the disease severity and loss of CD146 and AQP4. The findings indicate a relationship between pTDP-43 accumulation in astrocytic endfeet and BBB and glymphatic system dysfunction, which may contribute to the downstream pathological events seen in AD patients and the aggressive disease progression.

大多数阿尔茨海默氏症（AD）患者的海马体中都有跨活性反应 DNA 结合蛋白 43（TDP-43）的聚集体，这与疾病的恶化有关。TDP-43 包涵体通常存在于神经元中，但也存在于星形胶质细胞中。星形胶质细胞中的 TDP-43 包涵体的影响尚不清楚。在本研究中，我们调查了星形胶质细胞内膜中磷酸化 TDP-43 （pTDP-43）包涵体的存在及其与血脑屏障（BBB）损伤、淋巴系统功能障碍和 AD 病理学的潜在联系。通过用 TDP-43 和 pTDP-43 以及星形胶质细胞标记物胶质纤维酸性蛋白（GFAP）对阿氏痴呆症患者和非痴呆症对照组的死后海马切片进行染色、通过将 TDP-43 和 pTDP-43 与星形胶质细胞标记物胶质纤维酸性蛋白（GFAP）、星形胶质细胞内膜标记物 Aquaporin-4 (AQP4)、BBB 改变标记物（CD146）和渗漏标记物（免疫球蛋白 A）进行对比，我们发现血管周围 pTDP-43 或 TDP-43 包涵体与 GFAP 或 AQP4 密切相关。这些血管周围包涵物在 AD 中更为突出，并与疾病的严重程度以及 CD146 和 AQP4 的丧失相关。研究结果表明，pTDP-43在星形胶质细胞内膜的积聚与BBB和淋巴系统功能障碍之间存在关系，这可能是导致AD患者出现下游病理事件和病情恶化的原因之一。

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引用次数: 0

Lack of classical astroblastoma features in pediatric MN1::BEND2-fused brain tumors. 小儿MN1::BEND2融合脑肿瘤缺乏经典星形母细胞瘤特征。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-09-05 DOI: 10.1111/bpa.13297

Nicholas Chapman, Mohammed Iqbal, Adam D Walker, Debra Hawes, Tom Belle Davidson, Nathan Robison, Benita Tamrazi, Jianling Ji, Mark D Krieger, Jennifer A Cotter

Three distinct MN1::BEND2 fusion-positive tumors in pediatric patients. (A) Clinical course for each patient was variable in part due to differences in initial diagnosis. Each patient responded favorably to gross total resection and is stable at last follow-up. (B) Histologic diversity, lack of prominent classical astroblastoma features, and variable immunoexpression of key markers makes microscopic diagnosis challenging.

儿科患者中三种不同的 MN1::BEND2 融合阳性肿瘤。(A）每位患者的临床病程各不相同，部分原因是初始诊断不同。每位患者均对全切除术反应良好，最近一次随访时病情稳定。(B）组织学上的多样性、典型星形母细胞瘤特征的缺乏以及关键标志物免疫表达的不同使得显微诊断具有挑战性。

引用次数: 0

Comparing GBA1-Parkinson's disease and idiopathic Parkinson's disease: α-Synuclein oligomers and synaptic density as biomarkers in the skin biopsy 比较 GBA1-帕金森病和特发性帕金森病：皮肤生物标记物中的α-突触核蛋白寡聚体和突触密度。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2024-09-01 DOI: 10.1111/bpa.13284

Samanta Mazzetti, Elena Contaldi, Milo Jarno Basellini, Claudia Novello, Alessandra Maria Calogero, Letizia Straniero, Federica Garrì, Valentina Ferri, Daniela Calandrella, Francesca Del Sorbo, Rosanna Asselta, Emanuele Cereda, Graziella Cappelletti, Ioannis Ugo Isaias, Gianni Pezzoli

The main genetic risk factors for Parkinson's disease (PD) are presently represented by variants in GBA1 gene encoding for the β-glucocerebrosidase (GCase). Searching for a peripheral biomarker that can be used for selecting and monitoring patients in clinical trials targeting GBA1-associated PD (GBA1-PD) is a current challenge. We previously demonstrated that α-synuclein oligomers expressed as proximity ligation assay (PLA) score in synaptic terminals of skin biopsy are a reliable biomarker for distinguishing idiopathic PD (iPD) from healthy controls (HC). This cross-sectional study investigates an unexplored cohort of GBA1-PD (n = 27) compared to 28 HC, and 36 iPD cases to (i) analyze α-synuclein oligomers and quantify them throughout PLA score, (ii) investigate GCase expression in brain and synaptic terminals targeting the sweat gland, (iii) unravel indicators that could differentiate patients with specific GBA1 mutations. PLA score discriminates GBA1-PD from HC with sensitivity = 88.9% (95% CI 70.84–97.65), specificity = 88.5% (95% CI 69.85–97.55), and PPV = 88.9% (95% CI 73.24–95.90), AUC value = 0.927 (95% CI 0.859–0.996). No difference was found between GBA1-PD patients and iPD, suggesting a common pathological pathway based on α-synuclein oligomers. GCase score did not differ in GBA1-PD, iPD, and HC in the synaptic terminals, whereas a positive correlation was found between PLA score and GCase score. Moreover, a significant increase in synaptic density was observed in GBA1-PD compared to iPD and HC (P < 0.0001). Employing ROC curve to discriminate GBA1-PD from iPD, we found an AUC value for synaptic density = 0.855 (95% CI 0.749–0.961) with sensitivity = 85.2% (95% CI 66.27%–95.81%), specificity = 77.1% (95% CI 59.86%–89.58%), and PPV = 74.19% (60.53%–84.35%). The highest synaptic density values were observed in p.N409S patients. This work points out to the value of both PLA score and synaptic density in distinguishing GBA1-PD from iPD and to their potential to stratify and monitor patients in the context of new pathway-specific therapeutic options.

帕金森病（PD）的主要遗传风险因素目前以编码β-葡糖脑苷脂（GCase）的GBA1基因变异为代表。在针对 GBA1 相关帕金森病（GBA1-PD）的临床试验中，寻找一种可用于选择和监测患者的外周生物标记物是目前面临的一项挑战。我们以前曾证实，在皮肤活检的突触末端中以邻近结扎法（PLA）评分表达的α-突触核蛋白寡聚体是区分特发性帕金森病（iPD）和健康对照组（HC）的可靠生物标记物。这项横断面研究调查了一组尚未研究过的GBA1-PD患者（n = 27），与28例HC患者和36例iPD病例进行了比较，目的是：(i) 分析α-突触核蛋白寡聚体，并通过PLA评分对其进行量化；(ii) 调查GCase在大脑和以汗腺为目标的突触末端的表达；(iii) 揭示可区分特定GBA1突变患者的指标。PLA 评分能将 GBA1-PD 与 HC 区分开来，灵敏度 = 88.9% (95% CI 70.84-97.65)，特异度 = 88.5% (95% CI 69.85-97.55)，PPV = 88.9% (95% CI 73.24-95.90)，AUC 值 = 0.927 (95% CI 0.859-0.996)。GBA1-PD患者和iPD患者之间没有发现差异，这表明基于α-突触核蛋白寡聚体的病理途径是相同的。在突触末端，GBA1-PD、iPD 和 HC 的 GCase 评分没有差异，而 PLA 评分与 GCase 评分呈正相关。此外，与 iPD 和 HC 相比，GBA1-PD 的突触密度明显增加（P

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引用次数: 0