Brain Pathology最新文献_第7页

Correspondence to: Clinico-sero-pathological characteristics of anti-Ha antisynthetase syndrome 对应于：抗ha抗合成酶综合征的临床-血清-病理特征。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-05-12 DOI: 10.1111/bpa.70015

Marie-Therese Holzer, Robert Biesen, Sarah Tansley, Carsten Dittmayer, Werner Stenzel, Udo Schneider

With great interest, we read the article on the clinico-sero-pathological characteristics of anti-Ha antisynthetase syndrome by Zhao et al. [1].The authors describe 12 patients with anti-Ha as a single myositis-specific antibody [1]. In light of this manuscript, we would like to add a report and discuss an anti-Ha-positive patient (a 39-years-old female), who was diagnosed and treated at the university hospital Charité Berlin with severe antisynthetase syndrome (ASyS).The patient initially presented in 2023 with arthralgia and scaly skin on her palms (see Figure 1A) and was diagnosed with psoriatic arthritis. In the following months, she developed a dry cough and myalgia, and subsequently, in early 2024, progressive dyspnoea and night sweats. Because of the existing prednisolone and TNF-inhibitor treatment for supposed psoriatic arthritis, an infection with pneumocystis jirovecii was suspected. Following a thorough and negative infection screen, the patient was ultimately transferred to the intensive care unit of the Charité with acute respiratory distress syndrome (ARDS) and evaluated for possible lung transplantation (see Figure 1D). Because of progressive respiratory insufficiency, high-dose glucocorticosteroids as well as cyclophosphamide were initiated. The suspected diagnosis was revised to idiopathic inflammatory myopathy (IIM) based on the clinical presentation with arthritis, myalgia with elevated creatine kinase (CK, 939 U/L), scaly exanthema (retrospectively identified as mechanic hands) and rapidly progressive interstitial lung disease (RP-ILD). Immunofluorescence on HEp2 cells revealed a speckled cytoplasmic pattern with a titre of 1:640 (see Figure 1B). Despite repetitive testing of myositis-specific and myositis-associated antibodies with commercial line blots, only anti-Ro52 antibodies were identified. Therefore, after muscle MRI showing patchy oedema and fasciitis, a muscle biopsy of the M. quadriceps was performed. This revealed a histopathological pattern consistent with ASyS: A mild but typical pattern of perifascicular necrosis and atrophy, as well as positive MHC class I and II staining with a perifascicular pattern (particularly for MHC class II) (see Figure 2).Combined, the clinical symptoms with a complete clinical triad (Arthritis, Myositis, ILD [2, 3]) and the muscle biopsy consistent with ASyS led to the diagnosis of ASyS [4]. Hence, treatment was expanded to include rituximab (RTX), as a good response to RTX in ASyS had been reported [4, 5]. To search thoroughly for possible autoantibodies in this apparent myositis-specific antibody-negative case, radioimmunoprecipitation was performed at the University of Bath [6] and anti-Ha-antibodies were identified (see Figure 1C). Following RTX therapy, the patient experienced significant improvement of her ILD (see early follow-up CT, Figure 1D). On subsequent outpatient

我们饶有兴趣地阅读了Zhao等人关于抗ha抗合成酶综合征的临床-血清-病理特征的文章[10]。作者将12例患者的抗ha描述为单一肌炎特异性抗体[1]。鉴于这篇手稿，我们想增加一篇报告并讨论一名抗ha阳性患者（39岁女性），她在柏林慈善大学医院诊断并治疗了严重的抗合成酶综合征（ASyS）。患者最初于2023年表现为关节痛和手掌皮肤鳞状（见图1A），并被诊断为银屑病关节炎。在接下来的几个月里，她出现干咳和肌痛，随后在2024年初出现进行性呼吸困难和盗汗。由于现有的强的松龙和tnf抑制剂治疗疑似银屑病关节炎，怀疑感染了肺囊虫。经过彻底且阴性的感染筛查后，患者最终因急性呼吸窘迫综合征（ARDS）被转移到慈善医院的重症监护病房，并评估是否可能进行肺移植（见图1D）。由于进行性呼吸功能不全，开始使用大剂量糖皮质激素和环磷酰胺。根据临床表现（关节炎、肌痛伴肌酸激酶升高（CK, 939 U/L）、甲状疹（回顾性鉴定为机械性手）和快速进行性间质性肺病（RP-ILD）），疑似诊断修改为特发性炎性肌病（IIM）。HEp2细胞的免疫荧光显示滴度为1:640的斑点细胞质模式（见图1B）。尽管反复检测肌炎特异性抗体和肌炎相关抗体，但只有抗ro52抗体被鉴定出来。因此，在肌肉MRI显示斑片状水肿和筋膜炎后，对股四头肌进行肌肉活检。这显示了与ASyS一致的组织病理学模式：轻度但典型的囊周坏死和萎缩模式，以及阳性的MHC I和II类染色囊周模式（特别是MHC II类）（见图2）。结合具有完整临床三联征（关节炎、肌炎、ILD[2,3]）的临床症状以及与ASyS相符的肌肉活检结果，诊断为ASyS bb0。因此，治疗扩大到包括利妥昔单抗（RTX），因为有报道称RTX在ASyS中有良好的反应[4,5]。为了在这个明显肌炎特异性抗体阴性的病例中彻底搜索可能的自身抗体，在巴斯大学[6]进行了放射免疫沉淀，并鉴定了抗ha抗体（见图1C）。RTX治疗后，患者的ILD明显改善（见早期随访CT，图1D）。在3个月和6个月后的后续门诊访问中，她不需要任何动态氧气，并且接受RTX作为维持治疗的肌肉骨骼缓解。本病例显示了ASyS的诊断是多么具有挑战性，特别是在与罕见抗体相关的情况下，因此详细的形态学检查结合彻底的临床检查对于精确诊断是多么有价值。在我们的患者中，组织病理学分析突出了明显的血管周围坏死和萎缩模式，以及MHC I类阳性和更明显的血管周围MHC II类梯度。碱性磷酸酶在肌束周围呈阳性，补体在肌束周围呈阳性。这种清晰的囊泡周围模式不同于Zhao等人报道的大多数非囊泡周围模式。除了定义ASyS中与频繁发生的自身抗体（如Jo-1、PL-7和PL-12[7]）相关的肌肉病理的典型组织病理学特征外，超微结构检查还描述了肌动蛋白包涵体（见图2）[7]。总之，肌肉活检中ASyS的清晰组织病理学图像导致了治疗方案的调整和对疾病特异性自身抗体的进一步研究。常规的肌炎筛查试验，如系免疫分析法，并不总能检测到抗ha或抗oj等罕见的自身抗体[4,8]。在临床怀疑程度较高的情况下，免疫沉淀等附加技术可能会有所帮助。对于原因不明的ILD患者，ASyS应被视为一种可能的诊断，因为典型肺部受累的呼吸系统症状可能是唯一的初始症状[9,10]。总之，本病例表明，对肌肉进行组织病理学检查，即使是轻度影响或临床淀粉样病变患者，也可能是关键，增加了诊断价值，并对潜在的器官和危及生命的疾病（如抗合成酶综合征）具有直接的治疗效果。 th， WS， US：概念化，调查，资源，写作-初稿，写作-审查&；编辑。RB， ST， CD：调查，资源，写作-审查& &；编辑。维尔纳·斯坦泽尔和乌多·施耐德贡献相同。作者声明无利益冲突。病人书面同意发表这篇文章。

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引用次数: 0

Comparative pathology boards facilitate the translation of knowledge between canine and human cancer patients 比较病理学委员会促进犬和人类癌症患者之间的知识翻译。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-05-05 DOI: 10.1111/bpa.70013

Jessica A. Beck, Christina Mazcko, Sara Belluco, Mireille Bitar, Daniel Brat, Jonathan W. Bush, Rati Chkheidze, Kara N. Corps, Chad Frank, Caterina Giannini, Craig Horbinski, Jason T. Huse, Jennifer W. Koehler, Andrew D. Miller, C. Ryan Miller, M. Gerard O'Sullivan, Joanna J. Phillips, Daniel R. Rissi, Courtney R. Schott, Anat Stemmer-Rachamimov, Stephen Yip, Amy K. LeBlanc

Comparative pathology boards bring together anatomic pathologists with expertise in canine and human histology to identify shared features, including immune or TME components, tumor subtypes, or prognostic tissue biomarkers. This article summarizes feedback to improve future initiatives and enhance the translational relevance of comparative oncology for human patients.

比较病理学委员会汇集了具有犬类和人类组织学专业知识的解剖病理学家，以确定共同的特征，包括免疫或TME成分，肿瘤亚型或预后组织生物标志物。这篇文章总结了反馈，以改善未来的举措和提高比较肿瘤学对人类患者的翻译相关性。

引用次数: 0

A pineal mass in a 39-year-old woman 一名39岁女性的松果体肿块。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-05-05 DOI: 10.1111/bpa.70012

Charlotte Paoli, Thibault Fabas, Lydiane Mondot, Catherine Godfraind, Bérengère Dadone-Montaudié, Fanny Burel-Vandenbos

A 39-year-old woman, with no significant medical history, presented progressively worsening behavioral problems. Brain MRI revealed a nodular lesion in the pineal region, with a necrotic center, heterogeneous peripheral enhancement, and an ependymal spread to the floor of the third ventricle and posterior part of the bulb (Figure 1). Germ cell markers (HCG, AFP) in CSF were negative. Because of the development of obstructive hydrocephalus, a ventriculocisternostomy with endoscopic ventricular biopsy (three biopsies from 1 to 5 mm) was performed, followed by a resection 1 month later. The surgical specimen was composed of fragments with a total weight of 3 g (Box 1).

Histologically, the lesion had a predominantly piloid morphology with some radial perivascular arrangements on an abundant myxoid background. Most cells showed an eosinophilic cytoplasm and bi- or multipolar extensions as well as round to angular nuclei with homogeneous chromatin. Floret-like multinucleated cells were present. In certain places, the glial cells were arranged in cords, giving the tumor a chordoid morphology. Cytonuclear atypia ranged from mild to pronounced. Mitotic index was 4 mitoses per 10 fields. Endothelial vascular proliferation and necrotic areas were present. No Rosenthal fibers or granular bodies were found. Tumor cells were immunopositive for GFAP and OLIG2 as well as focally for synaptophysin, but were negative for CD34, TTF1, EMA, NeuN, and Chromogranin A. ATRX, H3K27me3, INI1, and BRG1 expression was retained (Figure 2).

No mutation or gene rearrangement was detected by next-generation sequencing (NGS), RNA sequencing, or droplet digital PCR (FGFR1) in panel genes, including MAPK pathway genes (BRAF, KRAS, HRAS, and FGFR1-3). The DNA methylation array data, obtained using EPICv2 Beadchips, was analyzed using the DKFZ brain classifier v12.8 (https://www.molecularneuropathology.org/) and the resulting methylation profiles matched (calibrated score 0.99) with the methylation class of high-grade astrocytoma with piloid features (HGAP). The profiles were then clustered within the HGAP class using Uniform Manifold Approximation and Projection (UMAP). Copy number analysis showed homozygous deletion of the CDKN2A/CDKN2B loci (Figure 2).

High-grade astrocytoma with piloid features (HGAP).

Gliomas account for about 14%–22% of all pineal region tumors. They are mainly circumscribed low-grade astrocytomas, especially in children, and diffuse high-grade gliomas. The 2021 WHO classification has expanded the scope of circumscribed gliomas to include HGAP. This novel and rare glioma, mainly occurring in the adult cerebellum, has not been previously reported in the pineal region. This particular tumor, with a distinctive DNA methylation profile essential to the diagnosis, without specific histological or molecular hallmarks, may mimic other malignant or benign gliomas developing in the pineal region [1].

Before DN

39岁女性，无明显病史，行为问题逐渐恶化。脑MRI显示松果体区结节状病变，中心坏死，外周不均匀强化，室管膜扩散至第三脑室底和脑球后部（图1）。脑脊液生殖细胞标志物（HCG、AFP）均为阴性。由于梗阻性脑积水的发展，我们进行了脑室脑池造口术和内窥镜下的脑室活检（3个活检从1到5毫米），然后在1个月后切除。手术标本由总重量为3g的碎片组成（框1）。组织学上，病变主要呈毛样形态，在丰富的黏液背景上有一些放射状血管周围排列。大多数细胞呈嗜酸性细胞质，双极或多极延伸，细胞核呈圆形至角状，染色质均匀。可见小花样多核细胞。在某些地方，神经胶质细胞呈索状排列，使肿瘤呈索样形态。细胞核异型性从轻微到明显不等。有丝分裂指数为每10个野4个。可见内皮血管增生及坏死区。没有发现罗森塔尔纤维或颗粒体。肿瘤细胞GFAP和OLIG2呈免疫阳性，synaptophysin呈局部阳性，但CD34、TTF1、EMA、NeuN和Chromogranin a呈阴性。ATRX、H3K27me3、INI1和BRG1的表达保留（图2）。通过下一代测序（NGS）、RNA测序或微滴数字PCR （FGFR1）在包括MAPK通路基因（BRAF、KRAS、HRAS和FGFR1-3）在内的各组基因中未检测到突变或基因重排。使用EPICv2 Beadchips获得的DNA甲基化阵列数据，使用DKFZ脑分类器v12.8 （https://www.molecularneuropathology.org/）进行分析，得到的甲基化谱（校准评分0.99）与具有核样特征的高级星形细胞瘤（HGAP）的甲基化分类相匹配。然后使用均匀流形近似和投影（UMAP）将这些配置文件聚类到HGAP类中。拷贝数分析显示CDKN2A/CDKN2B基因座纯合缺失（图2）。高级别星形细胞瘤伴核样特征（HGAP）。胶质瘤约占松果体区肿瘤的14%-22%。它们主要是局限的低级别星形细胞瘤，尤其是在儿童中，以及弥漫性高级别胶质瘤。世卫组织2021年分类扩大了限定胶质瘤的范围，将HGAP纳入其中。这种新的和罕见的胶质瘤，主要发生在成人小脑，以前没有报道在松果体区域。这种特殊的肿瘤具有独特的DNA甲基化特征，对诊断至关重要，没有特定的组织学或分子特征，可能与松果体区域[1]中发生的其他恶性或良性胶质瘤相似。在DNA甲基化分析之前，我们的病例只能归类为神经胶质瘤，NOS，在粘液样背景下以脊髓样和局灶性脊索样为主。胶质瘤通常描述在松果体区域被考虑。其中弥漫性中线胶质瘤由于存在H3K27三甲基化而不存在H3K27M突变而被迅速排除。脊索样胶质瘤，一种界限清楚的胶质肿瘤，通常发生在第三脑室前部，也被排除在TTF1免疫阴性的基础上。还考虑了松果体区SMARCB1突变体[2]的结缔组织增生黏液样瘤（DMT）的形态学诊断。DMT是最近在2021年世卫组织分类中加入松果体肿瘤类别的一个新实体。DMT是由黏液和胶原背景下的小细胞束形成的。有丝分裂计数通常较低。这种gfap阴性肿瘤的特征是SMARCB1/INI1的表达缺失，并且典型地表达CD34和EMA。在我们的病例中没有这些免疫组织化学标准，允许我们排除这种诊断。本病例的组织学和免疫表型与毛细胞星形细胞瘤保持一致，特别是毛粘液样形态。只有通过研究甲基化谱才能对HGAP进行诊断。虽然HGAP主要发生在小脑，但理论上它可以发生在整个中枢神经系统。此外，HGAP的组织学特征可能从低级别到高级别胶质瘤样变化，因此，没有进一步的分子检测，没有明确的肿瘤定义。从分子上看，MAPK通路的改变、CDKN2A/CDKN2B位点的纯合缺失和ATRX的改变在[1]中很常见，可能指向HGAP的诊断，但并不恒定。除了NF1和ATRX突变状态外，本病例中主要的分子改变已被研究。我们的病例极具挑战性，因为免疫组织化学中ATRX的保守性和MAPK通路中未检测到的改变。适当识别HGAP是至关重要的，因为尽管存在潜在的低级别外观，但该实体与不良临床结果相关。总之，我们所描述的这个病例扩大了松果体区域胶质瘤的范围。表观遗传学表征是关键在这种情况下，以达到HGAP的明确诊断。该病例强调了包括全基因组甲基化谱在内的先进分子研究在脑肿瘤评估中的重要性。夏洛特·保利：原稿（相等）。Thibault Fabas：数据管理（equal）；形式分析（相等）。Lydiane Mondot：数据管理（equal）；形式分析（相等）；写作—评审与编辑（同等）。凯瑟琳·戈德弗里德：数据管理（平等）；形式分析（相等）；写作—评审与编辑（同等）。breng<e:1> - dadone - montaudi<e:1>：数据管理（平等）；形式分析（相等）；写作—评审与编辑（同等）。Fanny Burel-Vandenbos：概念化（领导）；监督(领导);写作-审查和编辑（主导）。作者声明无利益冲突。在法国国家RENOCLIP-LOC网络中接受审查的每个患者都被告知并表示同意。

{"title":"A pineal mass in a 39-year-old woman","authors":"Charlotte Paoli, Thibault Fabas, Lydiane Mondot, Catherine Godfraind, Bérengère Dadone-Montaudié, Fanny Burel-Vandenbos","doi":"10.1111/bpa.70012","DOIUrl":"10.1111/bpa.70012","url":null,"abstract":"A 39-year-old woman, with no significant medical history, presented progressively worsening behavioral problems. Brain MRI revealed a nodular lesion in the pineal region, with a necrotic center, heterogeneous peripheral enhancement, and an ependymal spread to the floor of the third ventricle and posterior part of the bulb (Figure 1). Germ cell markers (HCG, AFP) in CSF were negative. Because of the development of obstructive hydrocephalus, a ventriculocisternostomy with endoscopic ventricular biopsy (three biopsies from 1 to 5 mm) was performed, followed by a resection 1 month later. The surgical specimen was composed of fragments with a total weight of 3 g (Box 1).Histologically, the lesion had a predominantly piloid morphology with some radial perivascular arrangements on an abundant myxoid background. Most cells showed an eosinophilic cytoplasm and bi- or multipolar extensions as well as round to angular nuclei with homogeneous chromatin. Floret-like multinucleated cells were present. In certain places, the glial cells were arranged in cords, giving the tumor a chordoid morphology. Cytonuclear atypia ranged from mild to pronounced. Mitotic index was 4 mitoses per 10 fields. Endothelial vascular proliferation and necrotic areas were present. No Rosenthal fibers or granular bodies were found. Tumor cells were immunopositive for GFAP and OLIG2 as well as focally for synaptophysin, but were negative for CD34, TTF1, EMA, NeuN, and Chromogranin A. ATRX, H3K27me3, INI1, and BRG1 expression was retained (Figure 2).No mutation or gene rearrangement was detected by next-generation sequencing (NGS), RNA sequencing, or droplet digital PCR (FGFR1) in panel genes, including MAPK pathway genes (BRAF, KRAS, HRAS, and FGFR1-3). The DNA methylation array data, obtained using EPICv2 Beadchips, was analyzed using the DKFZ brain classifier v12.8 (https://www.molecularneuropathology.org/) and the resulting methylation profiles matched (calibrated score 0.99) with the methylation class of high-grade astrocytoma with piloid features (HGAP). The profiles were then clustered within the HGAP class using Uniform Manifold Approximation and Projection (UMAP). Copy number analysis showed homozygous deletion of the CDKN2A/CDKN2B loci (Figure 2).High-grade astrocytoma with piloid features (HGAP).Gliomas account for about 14%–22% of all pineal region tumors. They are mainly circumscribed low-grade astrocytomas, especially in children, and diffuse high-grade gliomas. The 2021 WHO classification has expanded the scope of circumscribed gliomas to include HGAP. This novel and rare glioma, mainly occurring in the adult cerebellum, has not been previously reported in the pineal region. This particular tumor, with a distinctive DNA methylation profile essential to the diagnosis, without specific histological or molecular hallmarks, may mimic other malignant or benign gliomas developing in the pineal region [1].Before DN","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"35 5","pages":""},"PeriodicalIF":6.2,"publicationDate":"2025-05-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961698","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

Stereological analysis of cholinergic neurons within bilateral pedunculopontine nuclei in health and when affected by Parkinson's disease 健康及帕金森病患者双侧桥脚核内胆碱能神经元的体视学分析。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-04-15 DOI: 10.1111/bpa.70011

Puneet Kumar Sharma, Steve Gentleman, David Trevor Dexter, Ilse Sanet Pienaar

During Parkinson's disease (PD), loss of brainstem-based pedunculopontine nucleus' (PPN) cholinergic neurons induces progressive postural-gait disability (PGD). PPN-deep brain stimulation inconsistently alleviates PGD, due to stereotactic targeting inaccuracies resulting from insufficiently detailed human PPN anatomical descriptions. Relatedly, rodent studies show rostro-caudal clustering of PPN-cholinergic neurons, reflecting functional sub-territories. We applied unbiased cerebro-bilateral 3-dimensional (3-D) stereology to post-mortem PPNs from PD versus neurological-control cases, to estimate total numbers of cholinergic neurons and describe their rostro-caudal distribution. Given ambiguous descriptions of the PPN's confines, we utilized two complimentary definitions of the PPN's anatomical boundaries. The first was based on the structure's gross anatomy, by considering the nucleus as a recognizable “channel” enclosed by distinct white matter fiber tracts (WMFT) encompassing the medial lemniscus, central tegmental tract and decussation of the superior cerebellar peduncle. Second, the PPN was recognized by its histological architecture, as a dense collection of cholinergic neurons (the “Ch5” group) that were immunoreactive for choline acetyltransferase (ChAT), the enzyme responsible for biosynthesis of the neurotransmitter acetylcholine. Many such ChAT-immunoreactive neurons were dispersed within the traversing tracks and hence the PPN's Ch5-based outlining method permitted their stereological capture while also allowing distinction between the PPN's two subnuclei, namely the pars compacta (PPNc) and pars dissipata (PPNd), based on subnuclei-specific cholinergic cytoarchitectural organization. We further reconstructed template data as 3-D renders, revealing gross morphological differences between control and PD-affected PPNs. PD brains revealed significant PPN cholinergic neuronal loss, particularly affecting the PPNd. Control cases showed bimodal clustering of cholinergic neurons, prominently affecting left-sided PPNs. Most PD cases revealed more severe cholinergic neuronal loss in right-sided PPNs, potentially driving symptom lateralization. Our study provides a comprehensive cholinergic cytoarchitectural atlas of the human PPN in health versus during PD.

在帕金森病（PD）期间，脑干基础的桥脚核（PPN）胆碱能神经元的丧失可诱导进行性姿势-步态残疾（PGD）。由于人体PPN解剖描述不够详细，导致立体定向靶向不准确，因此PPN-深部脑刺激不一致地缓解了PGD。与此相关，啮齿动物研究显示ppn -胆碱能神经元的尾部聚集，反映了功能亚区。我们应用无偏倚脑-双侧三维立体技术对PD与神经控制病例的死后ppn进行了分析，以估计胆碱能神经元的总数并描述它们的直立-尾侧分布。鉴于对PPN范围的模糊描述，我们使用了PPN解剖边界的两个互补定义。第一种是基于结构的大体解剖，将核视为一个可识别的“通道”，由不同的白质纤维束（WMFT）包围，包括内侧小网膜、中央被盖束和小脑上脚的讨论。其次，PPN通过其组织学结构被识别为胆碱能神经元（“Ch5”组）的密集集合，这些神经元对胆碱乙酰转移酶（ChAT）具有免疫反应，胆碱乙酰转移酶负责神经递质乙酰胆碱的生物合成。许多这样的chat免疫反应性神经元分散在穿越轨道内，因此PPN基于ch5的概述方法允许它们的立体捕获，同时也允许区分PPN的两个亚核，即紧核部（PPNc）和散核部（PPNd），基于亚核特异性胆碱能细胞结构组织。我们进一步将模板数据重建为3d渲染，揭示了对照和pd影响的ppn之间的大体形态学差异。PD脑显示显著的PPN胆碱能神经元损失，特别是影响PPNd。对照病例胆碱能神经元呈双峰聚集，左侧ppn明显受损。大多数PD病例在右侧ppn中显示更严重的胆碱能神经元丧失，可能导致症状偏侧。我们的研究提供了健康与PD期间人类PPN的全面胆碱能细胞结构图谱。

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引用次数: 0

Quantitative T1 is sensitive to cortical remyelination in multiple sclerosis: A postmortem MRI study 定量T1对多发性硬化症的皮质再髓鞘形成敏感：一项死后MRI研究。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-04-14 DOI: 10.1111/bpa.70010

Riccardo Galbusera, Matthias Weigel, Erik Bahn, Sabine Schaedelin, Alessandro Cagol, Po-Jui Lu, Muhamed Barakovic, Lester Melie-Garcia, Jonas Franz, Peter Dechent, Govind Nair, Ludwig Kappos, Wolfgang Brück, Christine Stadelmann, Cristina Granziera

Remyelination of cortical lesions in people with multiple sclerosis (pwMS) has been shown to be extensive. In this work, we aimed to assess whether postmortem quantitative MRI (qMRI) can help detect those areas. We imaged six fixed whole brains of deceased pwMS by 3T-MRI using magnetization transfer ratio (MTR, 570 μm isotropic), myelin water fraction (MWF, 1000 μm isotropic), quantitative T1 (qT1, 670 μm isotropic), quantitative susceptibility mapping (QSM, 330 μm isotropic) and radial diffusivity (RD, 1300 or 1400 μm isotropic) maps. Immunohistochemistry for myelin proteins was performed in 129 tissue blocks including the cortex and enabled the detection of cortical demyelination (DM), cortical remyelination (RM), and normal-appearing cortex (NAC). We identified 25 DM, 25 RM, and for each of these areas, a corresponding NAC near the lesion. Wilcoxon paired tests showed that: (a) qT1 and RD were higher and QSM lower in DM versus NAC (all p < 0.001), whereas RD was higher and QSM lower in RM versus NAC (p = 0.048 and p < 0.01 respectively); (b) mean qT1 in RM did not differ from mean qT1 in NAC (p = 0.074); (c) MWF and MTR were not different between DM and RM. We compared the delta between DM versus NAC (∆DM) and the delta between RM versus NAC (∆RM) using a Mann–Whitney test, in which RM showed a partial recovery of qT1 only (∆qT1 DM > ∆qT1 RM, p = 0.045). Mixed-effect models confirmed the findings obtained using univariate analyses. qT1 and QSM, but not RD, correlated with MBP intensity (r = −0.28, p < 0.01 and r = 0.29, p < 0.01 respectively). A Bonferroni correction was performed for multiple testing. Our data show that qT1 is altered in demyelinated but not in remyelinated cortical areas, while QSM and RD are affected by any cortical abnormalities. Accordingly, qT1 might be considered a potential imaging biomarker of cortical RM.

多发性硬化症（pwMS）患者皮质病变的再髓鞘化已被证明是广泛的。在这项工作中，我们旨在评估死后定量MRI （qMRI）是否可以帮助检测这些区域。采用3T-MRI对6例固定的pwMS全脑进行磁化传递比（MTR， 570 μm各向同性）、髓鞘水分数（MWF， 1000 μm各向同性）、定量T1 （qT1, 670 μm各向同性）、定量敏感性作图（QSM， 330 μm各向同性）和径向扩散率（RD， 1300或1400 μm各向同性）作图。在包括皮质在内的129个组织块中对髓鞘蛋白进行免疫组化，并检测皮质脱髓鞘（DM）、皮质再髓鞘（RM）和正常皮质（NAC）。我们确定了25个DM， 25个RM，对于每个这些区域，在病变附近有一个相应的NAC。Wilcoxon配对检验显示：(a)与NAC相比，DM的qT1和RD更高，QSM更低（均p∆qT1 RM， p = 0.045）。混合效应模型证实了使用单变量分析获得的结果。qT1和QSM与MBP强度相关，但RD无关(r = -0.28, p

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引用次数: 0

A 23-year-old woman with a headache and imbalance 一个23岁的女人，头痛，身体不平衡。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-03-30 DOI: 10.1111/bpa.70008

Lukas Marcelis, Andrew Folpe, Sounak Gupta, Cinthya J Zepeda Mendoza

A 23-year-old woman presented to the emergency department with headaches and imbalance. Computer tomography imaging was obtained first and showed the presence of a hemorrhagic lesion in the left cerebellum (not shown). Subsequent magnetic resonance imaging showed a heterogeneously enhancing mass in the left cerebellum measuring 3.4 × 2.1 × 2.4 cm with peripheral blood products (Figure 1). There was associated vasogenic edema in the left cerebellum with mass effect on the posterior lateral brainstem and encroachment upon the 4th ventricle without hydrocephalus. An operative resection of the lesion was then pursued.H&E-stained section revealed a highly cellular spindle cell neoplasm with a prominently fascicular growth pattern and no readily identifiable stroma (Figure 2A and Box 1). The tumor had very high mitotic activity (up to 10 mitotic figures in a single high-powered field) (Figure 2B). The spindle cells were monomorphic with oval to elongated nuclei and inapparent nucleoli (Figure 2B).The immunophenotype of the tumor did not reveal a clear line of origin, with negative staining for GFAP, OLIG2, S100 protein, SOX10, desmin (Figure 2C), pankeratin, synaptophysin, and only focally positive vimentin. Delicate pericellular reticulin deposition was noted, supporting the hypothesis of a sarcomatous neoplasm. The proliferation index (Ki-67) was over 80% in accordance with the high mitotic activity. Subsequent staining for H3K27me3 showed loss of nuclear expression (Figure 2D); beta-catenin staining was exclusively cytoplasmic, and SS18-SSX fusion antibody staining was negative (Figure 2E), but SSX-C terminus antibody staining was strongly and diffusely positive (Figure 2F).DNA next-generation sequencing (NGS) mutation analysis with a neuro-oncology gene panel was performed and showed three clinically relevant mutations, one in TP53 (c.493C > T (Exon 5)) and two mutations in DICER1 (c.4405_4406del (Exon 23) and c.5425G > A (Exon 25)). RNA NGS gene fusion analysis with a sarcoma gene panel did not reveal any gene fusions. Chromosome microarray (CMA) analysis was performed (Applied Biosystems (Affymetrix) OncoScan) and was consistent with a clonal neoplastic process with chromosomal complexity including heterozygous deletion of 9p (encompassing CDKN2A/B) and chromosome Xq chromothripsis, among others (Figure 2G).Primary intracranial sarcoma, DICER1-mutant.This was a difficult to diagnose as a high-grade spindle cell neoplasm without specific morphological or immunohistochemical features. The initial differential diagnosis based on imaging included medulloblastoma given the anatomical location and the patient's age. The morphologic presentation of a sarcomatous, monomorphic spindle cell proliferation raised a broad differential diagnosis including malignant peripheral nerve sheath tumor (MPNST), primary intracranial sarcoma, DICER1-mutant, and synovial sarcoma (SS). Subsequent targete

一名23岁女性因头痛和身体失衡就诊于急诊科。首先获得计算机断层成像，显示左侧小脑出现出血性病变（未示出）。随后的磁共振成像显示左侧小脑有一个3.4 × 2.1 × 2.4 cm的非均匀强化肿块，周围有血液制品（图1）。左小脑伴血管源性水肿，脑干后外侧占位，侵犯第四脑室，无脑积水。h&； e染色切片显示高细胞梭形细胞肿瘤，具有明显的束状生长模式，没有容易识别的间质（图2A和框1）。肿瘤具有非常高的有丝分裂活性（在单个高倍视场中可达10个有丝分裂象）（图2B）。梭形细胞单形，细胞核卵形至细长，核仁不明显（图2B）。肿瘤的免疫表型没有明确的起源线，GFAP、OLIG2、S100蛋白、SOX10、desmin（图2C）、pankeratin、synaptophysin染色为阴性，只有vimentin局部阳性。可见细胞周围网状蛋白沉积，支持肉瘤性肿瘤的假设。增殖指数（Ki-67）达80%以上，具有较高的有丝分裂活性。H3K27me3的后续染色显示细胞核表达缺失（图2D）；β -连环蛋白染色仅为细胞质，SS18-SSX融合抗体染色为阴性（图2E），但SSX-C端抗体染色强烈且弥漫性阳性（图2F）。使用神经肿瘤基因面板进行DNA下一代测序（NGS）突变分析，发现三个临床相关突变，一个在TP53 （c.493C >； T（外显子5）），两个突变在DICER1 （c.4405_4406del（外显子23）和c.5425G > a（外显子25））。RNA NGS基因融合分析与肉瘤基因面板没有发现任何基因融合。进行染色体微阵列（CMA）分析（Applied Biosystems (Affymetrix) OncoScan），结果与染色体复杂性的克隆性肿瘤过程一致，包括9p的杂合缺失（包括CDKN2A/B）和Xq染色体的断染色体等（图2G）。原发性颅内肉瘤，dicer1突变体。这是一种难以诊断的高级别梭形细胞肿瘤，没有特定的形态学或免疫组织化学特征。最初的鉴别诊断基于影像学包括髓母细胞瘤鉴于解剖位置和患者的年龄。肉瘤的形态学表现，单形梭形细胞增殖引起了广泛的鉴别诊断，包括恶性周围神经鞘瘤（MPNST），原发性颅内肉瘤，dicer1突变体和滑膜肉瘤（SS）。随后的靶向免疫组织化学染色显示核H3K27me3染色缺失，如MPNST所示，SSX-SS18融合蛋白染色为阴性，而SSX-C蛋白染色为阳性。虽然SSX- ss18抗体是一种基因融合位点特异性抗体，对SS具有高度特异性，但SSX- c抗体靶向SSX蛋白的c端，并且在SS的组织学模拟亚群（包括MPNST[1]）中也可能呈阳性。核H3K27me3缺失在MPNST和原发性颅内肉瘤dicer1突变体[2]中都有报道，而据我们所知，目前还没有关于后者的SSX-C染色的数据。虽然该肿瘤中存在Xq染色体断裂，但在SSX1所在的Xp处未发现明显的拷贝数变化。包含SS18的肉瘤基因组的RNA NGS未显示任何基因融合。DNA NGS显示DICER1外显子23和25发生突变。外显子25编码RNase IIIb结构域，是原发性颅内肉瘤dicer1突变[3]中高度复发的突变热点。Koelche等人于2018年首次描述了该实体，由于其罕见性，难以确定预后，但怀疑其临床病程具有侵袭性。本病例具有挑战性，因为它缺乏更具体的组织学特征，如软骨或肌源性分化、粘液样基质和嗜酸性细胞质球。尽管dicer1突变的原发性颅内肉瘤通常累及硬脑膜，但大多数病例也发生在幕上，而该病变位于小脑。卢卡斯·马塞利斯（Lukas Marcelis）撰写了手稿，并参与了诊断讨论。Dr. Andrew Folpe以软组织肿瘤专家的身份参与了诊断，并对草案进行了评审和编辑。Sounak Gupta博士和Cinthya Zepeda Mendoza博士对分子结果进行了解读，参与了图2的制作，并对草稿进行了审阅和编辑。作者声明无利益冲突。

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引用次数: 0

Herpes simplex virus-1 infection alters microtubule-associated protein Tau splicing and promotes Tau pathology in neural models of Alzheimer's disease 单纯疱疹病毒-1感染改变微管相关蛋白Tau剪接并促进阿尔茨海默病神经模型中的Tau病理。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-03-26 DOI: 10.1111/bpa.70006

Emmanuel C. Ijezie, Michael J. Miller, Celine Hardy, Ava R. Jarvis, Timothy F. Czajka, Lianna D'Brant, Natasha Rugenstein, Adam Waickman, Eain Murphy, David C. Butler

Herpes simplex virus 1 (HSV-1) infection alters critical markers of Alzheimer's disease (AD) in neurons. One key marker of AD is the hyperphosphorylation of Tau, accompanied by altered levels of Tau isoforms. However, an imbalance in these Tau splice variants, specifically resulting from altered 3R to 4R MAPT splicing of exon 10, has yet to be directly associated with HSV-1 infection. To this end, we infected 2D and 3D human neural models with HSV-1 and monitored MAPT splicing and Tau phosphorylation. Further, we transduced SH-SY5Y neurons with HSV-1 ICP27, which alters RNA splicing, to analyze if ICP27 alone is sufficient to induce altered MAPT exon 10 splicing. We show that HSV-1 infection induces altered splicing of MAPT exon 10, increasing 4R-Tau protein levels, Tau hyperphosphorylation, and Tau oligomerization. Our experiments reveal a novel link between HSV-1 infection and the development of cytopathic phenotypes linked with AD progression.

单纯疱疹病毒1型（HSV-1）感染改变了神经元中阿尔茨海默病（AD）的关键标志物。AD的一个关键标志是Tau的过度磷酸化，伴随着Tau亚型水平的改变。然而，这些Tau剪接变体的不平衡，特别是由外显子10的3R到4R MAPT剪接改变引起的，尚未与HSV-1感染直接相关。为此，我们用HSV-1感染2D和3D人类神经模型，并监测MAPT剪接和Tau磷酸化。此外，我们用改变RNA剪接的HSV-1 ICP27转导SH-SY5Y神经元，分析ICP27是否足以诱导MAPT外显子10剪接的改变。我们发现HSV-1感染诱导MAPT外显子10剪接改变，增加4R-Tau蛋白水平，Tau过度磷酸化和Tau寡聚化。我们的实验揭示了HSV-1感染与与AD进展相关的细胞病变表型之间的新联系。

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引用次数: 0

Multiple intracranial hemorrhages in a postmenopausal female 绝经后女性多发颅内出血。

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-03-24 DOI: 10.1111/bpa.70007

Xinhua Lu, Xinya Xu, Xiaopeng Zhang

A 53-year-old postmenopausal female presented to the neurology clinic with acute onset of right arm weakness for 1 week. Neurologic examination was notable for 4/5 strength in the right upper extremity. Computed tomography revealed multiple hematomas with mass effect in the left frontal lobe and basal ganglia (Figure 1A; Box 1). Magnetic resonance imaging with gadolinium showed multiple heterogeneously enhancing lesions associated with surrounding edema, mass effect, and midline shift (Figure 1B). Given the absence of an overt primary source for the hemorrhagic mass with elevated intracranial pressure and neurologic deficits, surgical excision of the left frontal lobe lesion was performed. Intraoperatively, the mass showed evidence of prior hemorrhage and was noted to encase a relatively large vessel. Postoperative CT imaging showed gross total resection of the frontal lesion and found a new lesion adjacent to the left lateral ventricle (Figure 1A inset). Of notice in the past medical history, the patient had undergone hysterectomy 3 years earlier. After a final diagnosis was reached, adjuvant treatment was performed with stereotactic radiosurgery (SRS) and chemotherapy. At 10 months of follow-up, the patient's symptoms have resolved.Hematoxylin–eosin stain showed that several pieces of tissue mingled together with a lot of blood. There was no normal brain parenchyma found. Small clusters of atypical cells made up of uninucleate and multinucleated cells were embedded in the hemorrhagic material. These were big cells with clumped chromatin, noticeable nucleoli, uneven nuclear outlines and nuclear-cytoplasmic ratios, and a modest proportion of amphophilic cytoplasm. Eosinophilic hyaline globules were seen in a large number of the cells. Mitoses were present (Figure 2A,B). Moreover, we saw atypical cells infiltrating relatively large vessels (Figure 2A) and some small vessels. Looking carefully into the previous history of hysterectomy, we found the diagnosis of complete hydatidiform mole, which led us to consider the possibility of metastatic gestational trophoblastic neoplasia (GTN). The atypical cells were strongly and diffusely positive for CK7 (Figure 2C) and β-HCG (Figure 2D), slightly immunopositive for SALL-4 (Figure 2E) on immunohistochemical examination. Ki-67 displayed a high proliferative index (approximately 60%, Figure 2F).Metastatic gestational choriocarcinoma following complete hydatidiform mole.Multiple intracranial hemorrhages can be due to a variety of causes, including hypertension, cerebral amyloid angiopathy (CAA), primary or secondary CNS vasculitis, hematologic disorders, anticoagulant use, sinus thrombosis, and brain tumors, most frequently metastatic. In this patient, normotensive, young for CAA, and overall only apparently without a significant past medical history, multiple hemorrhagic lesions on MRI led to the suspicion of brain metastases. Once discovered, the previous diagnosis of complete hydat

该病例在治疗技术和预后方面都是独特的。对于伴有脑转移的绒毛膜癌，目前还没有针对这些个体的治疗技术指南。在我们的病例中，患者随后接受了开颅手术、SRS和化疗。随访10个月，患者症状缓解，β-hCG水平从31,289下降到0.25 mIU / ml（参考值，<2.9）。吕新华起草了手稿。徐新亚、张小鹏对初稿进行了审阅和编辑。所有作者都认可了手稿的最终定稿。作者声明无利益冲突。

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引用次数: 0

SOCIETY NEWS 社会新闻

IF 5.8 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-03-23 DOI: 10.1111/bpa.70009

Audrey Rousseau

The ISN is looking for a group of young motivated neuropathologists to promote the specialty via the ISN website. If you are interested in participating, please contact Audrey Rousseau ([email protected]) or Monika Hofer ([email protected]).

The International Congress of Neuropathology (ICN) will be held in Edinburgh, Scotland, in 2027 (ICN27). The Congress President will be Prof Colin Smith and the ICN27 will be hosted by the British Neuropathological Society (BNS).

“On behalf of the British Neuropathological Society I am delighted to extend a warm invitation to all our colleagues across the world to join us in Edinburgh for the International Congress of Neuropathology 2027. Edinburgh is an easily accessible centre, surrounded by 1000 years of living history. We will develop a strong academic programme covering all aspects of neuropathology with world leading plenary speakers, supported by a social programme highlighting some of Edinburgh's historic charms. For those wishing to explore further, Edinburgh offers access to many of Scotland's highlights, be it touring the Highlands, sampling our famous whisky or golfing on some of our picturesque courses. I do hope you will be able to join us for what I am sure will be a memorable meeting showcasing the best in international neuropathology.

Colin Smith

Congress President ISN 2027”

Summary report for ICN23 Berlin (our most recent International Congress of Neuropathology, September 2023) now available in the Society's journal Brain Pathology (see link: https://doi.org/10.1111/bpa.13249).

We are delighted to start the bidding process for holding the 2031 XXII International Congress of Neuropathology (ICN). As you know, the 2027 XXI ICN Congress will be in Edinburgh and we now need to think ahead to 2031 and find a new home for our much-loved congress.

The Invitation Letter calling for bids and outlining the process can be found on the ISN website (www.intsocneuropathol.com). Please note that the deadline is the 31st August 2025.

The 7th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies will be held in conjunction with the 30th Annual Meeting & Education Day of the Society for Neuro-Oncology November 19-23, 2025 in Honolulu, Hawaii.

Brain Pathology has joined Wiley's Open Access portfolio as of January 2021. As a result, all submissions are subject to an Article Publication Charge (APC) if accepted and published in the journal. ISN members are eligible for a 10% discount off the Open Access APC. For more information on the fees, please click here.

Free resource: digital microscopy platform for neurodegenerative diseases curated in Munich. Prof Jochen Herms and his team have been setting up a digital microscopy platform for neurodegenerative diseases in their department in Munich. Registration is free. ISN members and interested

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{"title":"SOCIETY NEWS","authors":"Audrey Rousseau","doi":"10.1111/bpa.70009","DOIUrl":"https://doi.org/10.1111/bpa.70009","url":null,"abstract":"The ISN is looking for a group of young motivated neuropathologists to promote the specialty via the ISN website. If you are interested in participating, please contact Audrey Rousseau ([email protected]) or Monika Hofer ([email protected]).The International Congress of Neuropathology (ICN) will be held in Edinburgh, Scotland, in 2027 (ICN27). The Congress President will be Prof Colin Smith and the ICN27 will be hosted by the British Neuropathological Society (BNS).“On behalf of the British Neuropathological Society I am delighted to extend a warm invitation to all our colleagues across the world to join us in Edinburgh for the International Congress of Neuropathology 2027. Edinburgh is an easily accessible centre, surrounded by 1000 years of living history. We will develop a strong academic programme covering all aspects of neuropathology with world leading plenary speakers, supported by a social programme highlighting some of Edinburgh's historic charms. For those wishing to explore further, Edinburgh offers access to many of Scotland's highlights, be it touring the Highlands, sampling our famous whisky or golfing on some of our picturesque courses. I do hope you will be able to join us for what I am sure will be a memorable meeting showcasing the best in international neuropathology.Colin SmithCongress President ISN 2027”Summary report for ICN23 Berlin (our most recent International Congress of Neuropathology, September 2023) now available in the Society's journal Brain Pathology (see link: https://doi.org/10.1111/bpa.13249).We are delighted to start the bidding process for holding the 2031 XXII International Congress of Neuropathology (ICN). As you know, the 2027 XXI ICN Congress will be in Edinburgh and we now need to think ahead to 2031 and find a new home for our much-loved congress.The Invitation Letter calling for bids and outlining the process can be found on the ISN website (www.intsocneuropathol.com). Please note that the deadline is the 31st August 2025.The 7th Quadrennial Meeting of the World Federation of Neuro-Oncology Societies will be held in conjunction with the 30th Annual Meeting & Education Day of the Society for Neuro-Oncology November 19-23, 2025 in Honolulu, Hawaii.Brain Pathology has joined Wiley's Open Access portfolio as of January 2021. As a result, all submissions are subject to an Article Publication Charge (APC) if accepted and published in the journal. ISN members are eligible for a 10% discount off the Open Access APC. For more information on the fees, please click here.Free resource: digital microscopy platform for neurodegenerative diseases curated in Munich. Prof Jochen Herms and his team have been setting up a digital microscopy platform for neurodegenerative diseases in their department in Munich. Registration is free. ISN members and interested","PeriodicalId":9290,"journal":{"name":"Brain Pathology","volume":"35 3","pages":""},"PeriodicalIF":5.8,"publicationDate":"2025-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/bpa.70009","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143750004","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

Spliceosome protein alterations differentiate hubs of the default mode connectome during the progression of Alzheimer's disease 在阿尔茨海默病的进展过程中，剪接体蛋白改变区分了默认模式连接组的枢纽。

IF 6.2 2区医学 Q1 CLINICAL NEUROLOGY

Brain Pathology

Pub Date : 2025-03-23 DOI: 10.1111/bpa.70004

Sylvia E. Perez, Muhammad Nadeem, Bin He, Jennifer C. Miguel, David G. Moreno, Marta Moreno-Rodriguez, Michael Malek-Ahmadi, Chadwick M. Hales, Elliott J. Mufson

Default mode network (DMN) is comprised in part of the frontal (FC), precuneus (PreC), and posterior cingulate (PCC) cortex and displays amyloid and tau pathology in Alzheimer's disease (AD). The PreC hub appears the most resilient to AD pathology, suggesting differential vulnerability within the DMN. However, the mechanisms that underlie this differential pathobiology remain obscure. Here, we investigated changes in RNA polymerase II (RNA pol II) and splicing proteins U1-70K, U1A, SRSF2, and hnRNPA2B1, phosphorylated AT8 tau, 3R and 4Rtau isoforms containing neurons and amyloid plaques in layers III and V–VI in FC, PreC, and PCC obtained from individuals with a preclinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), and mild/moderate mAD. We found a significant increase in pS5-RNA pol II levels in FC NCI, U1-70K in PreC MCI and mAD, and hnRNPA2B1 and SRSF2 levels in PCC mAD. 1N3Rtau levels were significantly increased in FC, decreased in PreC in mAD, and unchanged in PCC, whereas 1N4Rtau increased in mAD across the hubs. SRSF2, U1-70K, U1A, and hnRNPA2B1 nuclear optical density (OD), size, and number were unchanged across groups in FC and PCC, while PreC OD hnRNPA2B1 was significantly greater in mAD. Mislocalized U1A and U1-70K tangle-like structures were found in a few PCC cases and colocalized with AT8-bearing neurofibrillary tangles (NFTs). FC pS5-RNA pol II, PreC U1-70K, Pre pS5,2-RNA pol II, and PCC hnRNPA2B1 and SRSF2 protein levels were associated with cognitive decline but not neuropathology across clinical groups. By contrast, splicing protein nuclear OD measures, size, counts, and mislocalized U1-70K and U1A NFT-like structures were not correlated with NFT or plaque density, cognitive domains, and neuropathological criteria in DMN hubs. Findings suggest that RNA splicing protein alterations and U1 mislocalization contribute differentially to DMN pathogenesis and cognitive deterioration in AD.

默认模式网络（DMN）由额叶（FC）、楔前叶（PreC）和后扣带（PCC）皮层组成，在阿尔茨海默病（AD）中表现出淀粉样蛋白和tau蛋白病理。PreC中心似乎对AD病理最具弹性，这表明DMN内部存在不同的脆弱性。然而，这种差异病理生物学背后的机制仍然不清楚。在这里，我们研究了RNA聚合酶II （RNA pol II）和剪接蛋白U1-70K、U1A、SRSF2和hnRNPA2B1的变化，磷酸化了FC、PreC和PCC中含有神经元和III层和V-VI层淀粉样斑块的AT8 tau、3R和4Rtau亚型，这些亚型来自临床前诊断为无认知障碍（NCI）、轻度认知障碍（MCI）和轻度/中度mAD的个体。我们发现FC NCI中pS5-RNA pol II水平显著升高，PreC MCI和mAD中U1-70K水平显著升高，PCC mAD中hnRNPA2B1和SRSF2水平显著升高。1N3Rtau水平在FC中显著升高，在mAD的PreC中显著降低，在PCC中保持不变，而1N4Rtau水平在所有枢纽中均升高。SRSF2、U1-70K、U1A和hnRNPA2B1核光密度（OD）、大小和数量在FC和PCC各组间没有变化，而PreC OD hnRNPA2B1在mAD组中显著增加。在少数PCC病例中发现错误定位的U1A和U1-70K缠结样结构，并与含at8的神经原纤维缠结（nft）共定位。FC pS5- rna pol II、PreC U1-70K、Pre pS5、2-RNA pol II和PCC hnRNPA2B1和SRSF2蛋白水平与认知能力下降有关，但与神经病理学无关。相比之下，剪接蛋白核OD测量、大小、计数和错误定位的U1-70K和U1A NFT样结构与DMN中心的NFT或斑块密度、认知域和神经病理标准无关。研究结果表明，RNA剪接蛋白改变和U1错定位在AD患者DMN发病和认知功能恶化中起着不同的作用。

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