首页 > 最新文献

Acta Neuropathologica最新文献

英文 中文
Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer 天然朊病毒的冷冻电子显微镜结构:来自鹿的慢性消耗性疾病纤维蛋白
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-24 DOI: 10.1007/s00401-024-02813-y
Parvez Alam, Forrest Hoyt, Efrosini Artikis, Jakub Soukup, Andrew G. Hughson, Cindi L. Schwartz, Kent Barbian, Michael W. Miller, Brent Race, Byron Caughey

Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular β-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics.

慢性消耗性疾病(CWD)是一种广泛分布的颈鹿朊病毒疾病,对野生动物保护以及人类和牲畜健康都有影响。人们对导致 CWD 和哺乳动物宿主其他天然朊病毒疾病的传染性朊病毒的结构知之甚少。在此,我们报告了一种基于 2.8 Å 分辨率低温电子显微镜的 CWD 朊病毒纤维结构,该结构来自表达最常见野生型 PrP 序列的自然感染白尾鹿的大脑。与最近解决的啮齿动物适应性豚鼠瘙痒症朊病毒纤维一样,我们的CWD纤维原子模型也包含单堆PrP分子,这些分子形成了平行的套内分子间β片和由纤维横截面内主要N端和C端叶组成的间隔环。然而,来自天然鹿宿主的 CWD 纤维在许多其他特征上与啮齿类动物的结构明显不同,其中包括裂片相对方向的约 180° 扭转。这种 CWD 结构揭示了 CWD 向人类传播的明显障碍的内在机制,并有助于采用更合理的方法来开发 CWD 疫苗和疗法。
{"title":"Cryo-EM structure of a natural prion: chronic wasting disease fibrils from deer","authors":"Parvez Alam,&nbsp;Forrest Hoyt,&nbsp;Efrosini Artikis,&nbsp;Jakub Soukup,&nbsp;Andrew G. Hughson,&nbsp;Cindi L. Schwartz,&nbsp;Kent Barbian,&nbsp;Michael W. Miller,&nbsp;Brent Race,&nbsp;Byron Caughey","doi":"10.1007/s00401-024-02813-y","DOIUrl":"10.1007/s00401-024-02813-y","url":null,"abstract":"<div><p>Chronic wasting disease (CWD) is a widely distributed prion disease of cervids with implications for wildlife conservation and also for human and livestock health. The structures of infectious prions that cause CWD and other natural prion diseases of mammalian hosts have been poorly understood. Here we report a 2.8 Å resolution cryogenic electron microscopy-based structure of CWD prion fibrils from the brain of a naturally infected white-tailed deer expressing the most common wild-type PrP sequence. Like recently solved rodent-adapted scrapie prion fibrils, our atomic model of CWD fibrils contains single stacks of PrP molecules forming parallel in-register intermolecular <i>β</i>-sheets and intervening loops comprising major N- and C-terminal lobes within the fibril cross-section. However, CWD fibrils from a natural cervid host differ markedly from the rodent structures in many other features, including a ~ 180° twist in the relative orientation of the lobes. This CWD structure suggests mechanisms underlying the apparent CWD transmission barrier to humans and should facilitate more rational approaches to the development of CWD vaccines and therapeutics.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02813-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489363","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer’s disease BACE1 自身抗体促进阿尔茨海默病的 Aβ 积累和神经退行性变
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-24 DOI: 10.1007/s00401-024-02814-x
Ye-Ran Wang, Xiao-Qin Zeng, Jun Wang, Christopher J. Fowler, Qiao-Xin Li, Xian-Le Bu, James Doecke, Paul Maruff, Ralph N. Martins, Christopher C. Rowe, Colin L. Masters, Yan-Jiang Wang, Yu-Hui Liu

The profile of autoantibodies is dysregulated in patients with Alzheimer’s disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET CN, 169 Aβ-PET+ cognitively normal subjects (preclinical AD), and 31 Aβ-PET+ cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.

阿尔茨海默氏症(AD)患者体内的自身抗体谱出现失调。人体血液中存在β位点淀粉样前体蛋白(APP)清除酶1(BACE1)的自身抗体。本研究旨在探讨BACE1自身抗体在AD中的临床意义和病理生理学作用。临床研究在两个独立队列(重庆队列和澳大利亚影像、生物标记和生活方式队列)中进行。重庆队列包括 55 名 AD 患者、28 名非 AD 痴呆症患者和 70 名认知能力正常的受试者(CN)。AIBL队列包括162名Aβ-PET- CN患者、169名Aβ-PET+认知功能正常者(临床前AD)和31名Aβ-PET+认知功能受损者(临床AD)。血浆中的BACE1自身抗体通过单点Elisa法测定。研究了血浆中的BACE1自身抗体与大脑Aβ负荷和认知轨迹之间的关系。在APP/PS1小鼠和SH/APPswe/PS1wt细胞系中研究了BACE1自身抗体对AD型病变的影响及其内在机制。在重庆队列中,AD患者的血浆BACE1自身抗体高于CN和非AD痴呆患者。在AIBL队列中,血浆BACE1自身抗体在临床AD患者中最高,其次是临床前AD和CN受试者。BACE1自身抗体越高,随访期间脑淀粉样蛋白阳性转换的发生率越高。BACE1自身抗体会加剧APP/PS1小鼠的脑淀粉样蛋白沉积和随后的AD型病变,包括Tau高磷酸化、神经炎症和神经退行性变。BACE1自身抗体通过抑制PPARγ信号传导来促进BACE1的表达,从而增加了Aβ的产生。这些发现表明,BACE1自身抗体是AD的致病因子,这些自身抗体的上调可能会促进疾病的发展。这项研究从自身免疫的角度对AD的发病机制提出了新的见解。
{"title":"Autoantibodies to BACE1 promote Aβ accumulation and neurodegeneration in Alzheimer’s disease","authors":"Ye-Ran Wang,&nbsp;Xiao-Qin Zeng,&nbsp;Jun Wang,&nbsp;Christopher J. Fowler,&nbsp;Qiao-Xin Li,&nbsp;Xian-Le Bu,&nbsp;James Doecke,&nbsp;Paul Maruff,&nbsp;Ralph N. Martins,&nbsp;Christopher C. Rowe,&nbsp;Colin L. Masters,&nbsp;Yan-Jiang Wang,&nbsp;Yu-Hui Liu","doi":"10.1007/s00401-024-02814-x","DOIUrl":"10.1007/s00401-024-02814-x","url":null,"abstract":"<div><p>The profile of autoantibodies is dysregulated in patients with Alzheimer’s disease (AD). Autoantibodies to beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) are present in human blood. This study aims to investigate the clinical relevance and pathophysiological roles of autoantibodies to BACE1 in AD. Clinical investigations were conducted in two independent cohorts, the Chongqing cohort, and the Australian Imaging, Biomarkers, and Lifestyle (AIBL) cohort. The Chongqing cohort included 55 AD patients, 28 patients with non-AD dementia, and 70 cognitively normal subjects (CN). The AIBL cohort included 162 Aβ-PET<sup>−</sup> CN, 169 Aβ-PET<sup>+</sup> cognitively normal subjects (preclinical AD), and 31 Aβ-PET<sup>+</sup> cognitively impaired subjects (Clinical AD). Plasma autoantibodies to BACE1 were determined by one-site Elisa. The associations of plasma autoantibodies to BACE1 with brain Aβ load and cognitive trajectory were investigated. The effects of autoantibodies to BACE1 on AD-type pathologies and underlying mechanisms were investigated in APP/PS1 mice and SH/APPswe/PS1wt cell lines. In the Chongqing cohort, plasma autoantibodies to BACE1 were higher in AD patients, in comparison with CN and non-AD dementia patients. In the AIBL cohort, plasma autoantibodies to BACE1 were highest in clinical AD patients, followed by preclinical AD and CN subjects. Higher autoantibodies to BACE1 were associated with an increased incidence of brain amyloid positivity conversion during follow-up. Autoantibodies to BACE1 exacerbated brain amyloid deposition and subsequent AD-type pathologies, including Tau hyperphosphorylation, neuroinflammation, and neurodegeneration in APP/PS1 mice. Autoantibodies to BACE1 increased Aβ production by promoting BACE1 expression through inhibiting PPARγ signaling. These findings suggest that autoantibodies to BACE1 are pathogenic in AD and the upregulation of these autoantibodies may promote the development of the disease. This study offers new insights into the mechanism of AD from an autoimmune perspective.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489364","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes MYB/MYBL1基因改变的神经胶质瘤经常携带MYB和MYBL1基因的截断和非生产性融合
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-18 DOI: 10.1007/s00401-024-02803-0
Hye-Jung Chung, Sharika Rajan, Zhichao Wu, Christina K. Ferrone, Mark Raffeld, Ina Lee, Jeffrey Gagan, Christopher Dampier, Zied Abdullaev, Manoj Tyagi, Patrick. J. Cimino, Martha Quezado, Kenneth Aldape

Astrocytomas that harbor recurrent genomic alterations in MYB or MYBL1 are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in MYB or MYBL1. In this report, we examine 14 consecutive cases in which a MYB or MYBL1 alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, MYB- or MYBL1-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the MYB or MYBL1 genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the MYB(L1) genes, regardless of the presence of a productive fusion. In addition, QKI, a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising >1000 CNS tumors of various types, regardless of whether a genomic alteration in QKI was present. Overall, the results show that truncations, in the absence of a productive fusion, of the MYB(L1) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, MYB- or MYBL1-altered, especially for cases that are tested on panels designed to focus on fusion detection.

携带MYB或MYBL1复发性基因组改变的星形细胞瘤是2021年《世界卫生组织中枢神经系统肿瘤分类》中新认定的一类儿科型弥漫低级别胶质瘤。这些肿瘤在WHO分类中被描述为携带MYB或MYBL1融合。在本报告中,我们研究了14例连续发现MYB或MYBL1改变的病例(6例血管中心型胶质瘤和8例弥漫型星形细胞瘤,MYB或MYBL1改变),每个病例都通过全基因组DNA甲基化图谱进行了诊断确认,并研究了这些基因的特定基因组改变。通过 RNA 测序,我们发现仅有 5/14 个病例的 MYB 或 MYBL1 基因发生了有成效的框架内融合。其余 9 个病例的基因组发生了改变,导致基因截断,但没有证据表明存在框架内融合的伴侣。基因表达分析表明,无论是否存在生产性融合,MYB(L1)基因都会过度表达。此外,QKI是血管中心性胶质瘤中常见的公认融合伙伴,与由1000个不同类型的中枢神经系统肿瘤组成的队列相比,无论QKI是否存在基因组改变,这14个病例中的QKI都普遍上调。总之,研究结果表明,在没有产生融合的情况下,MYB(L1)基因的截短很可能会驱动肿瘤的发生,这对分析和诊断血管中心型胶质瘤和弥漫性星形细胞瘤、MYB或MYBL1基因改变的病例具有重要意义,尤其是对那些通过旨在重点检测融合的检测板进行检测的病例。
{"title":"MYB/MYBL1-altered gliomas frequently harbor truncations and non-productive fusions in the MYB and MYBL1 genes","authors":"Hye-Jung Chung,&nbsp;Sharika Rajan,&nbsp;Zhichao Wu,&nbsp;Christina K. Ferrone,&nbsp;Mark Raffeld,&nbsp;Ina Lee,&nbsp;Jeffrey Gagan,&nbsp;Christopher Dampier,&nbsp;Zied Abdullaev,&nbsp;Manoj Tyagi,&nbsp;Patrick. J. Cimino,&nbsp;Martha Quezado,&nbsp;Kenneth Aldape","doi":"10.1007/s00401-024-02803-0","DOIUrl":"10.1007/s00401-024-02803-0","url":null,"abstract":"<div><p>Astrocytomas that harbor recurrent genomic alterations in <i>MYB</i> or <i>MYBL1</i> are a group of Pediatric-type diffuse low-grade gliomas that were newly recognized in the 2021 WHO Classification of Tumors of the Central Nervous System. These tumors are described in the WHO classification as harboring fusions in <i>MYB</i> or <i>MYBL1</i>. In this report, we examine 14 consecutive cases in which a <i>MYB</i> or <i>MYBL1</i> alteration was identified, each with diagnostic confirmation by genome-wide DNA methylation profiling (6 Angiocentric gliomas and 8 Diffuse astrocytomas, <i>MYB-</i> or <i>MYBL1</i>-altered), for their specific genomic alterations in these genes. Using RNA sequencing, we find productive in-frame fusions of the <i>MYB</i> or <i>MYBL1</i> genes in only 5/14 cases. The remaining 9 cases show genomic alterations that result in truncation of the gene, without evidence of an in-frame fusion partner. Gene expression analysis showed overexpression of the <i>MYB</i>(<i>L1</i>) genes, regardless of the presence of a productive fusion. In addition, <i>QKI,</i> a recognized fusion partner common in angiocentric glioma, was generally up-regulated in these 14 cases, compared to a cohort comprising &gt;1000 CNS tumors of various types, regardless of whether a genomic alteration in <i>QKI</i> was present. Overall, the results show that truncations, in the absence of a productive fusion, of the <i>MYB</i>(<i>L1</i>) genes can likely drive the tumors and have implications for the analysis and diagnosis of Angiocentric glioma and Diffuse astrocytoma, <i>MYB-</i> or <i>MYBL1</i>-altered, especially for cases that are tested on panels designed to focus on fusion detection.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02803-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142447317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia 基于假设的已知阿尔茨海默病风险变异调查揭示了阿尔茨海默型痴呆症神经病理学病变的遗传基础
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-18 DOI: 10.1007/s00401-024-02815-w
Celeste Laureyssen, Fahri Küçükali, Jasper Van Dongen, Klara Gawor, Sandra O. Tomé, Alicja Ronisz, Markus Otto, Christine A. F. von Arnim, Philip Van Damme, Rik Vandenberghe, Dietmar Rudolf Thal, Kristel Sleegers

Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (Aβ) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of APH1B, with tau-related pathology. Second, a relation between APOE and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of APOE with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, α-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between TPCN1 (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of ANK3. We found association between BIN1 (rs6733839) and α-synuclein pathology, and replicated a prior association between USP6NL (rs7912495) and Lewy body pathology. Additionally, we also found that UMAD1 (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.

阿尔茨海默病(AD)是全球痴呆症的主要病因。除了神经纤维缠结和淀粉样β(Aβ)斑块外,在阿尔茨海默病大脑中还可观察到多种共病神经病理学特征。由于注意力缺失症具有很强的遗传背景,并表现出广泛的表型异质性,本研究旨在调查共病和标志性神经病理学病变的遗传基础。为此,研究人员从鲁汶脑库 325 个个体的低覆盖率全基因组测序数据中获得了 75 个老年痴呆症风险变体的基因型。与深度神经病理学病变的关联测试表明,APH1B 第 1 外显子中的 SNP rs117618017 与 tau 相关病理有很强的直接影响。其次,APOE 与粒细胞变性(代表坏死)之间的关系也被发现,此外,众所周知的 APOE 与 AD 标志性神经病理学病变之间的关系也被证实。此外,在 pTDP 病理学、α-突触核蛋白病变和 pTau 相关病理学方面,还发现了一些与 AD 风险基因的名义关联。这些发现在三组独立队列的荟萃分析中得到了证实。例如,我们重复了之前发现的 TPCN1(rs6489896)与 LATE-NC 风险之间的关联。此外,我们还发现了新的可能与 LATE-NC 相关的 SNPs,包括位于 ANK3 上游的 rs7068231。我们发现了 BIN1(rs6733839)与α-突触核蛋白病理学之间的关联,并复制了之前 USP6NL(rs7912495)与路易体病理学之间的关联。此外,我们还发现 UMAD1(rs6943429)与路易体病理学有名义上的关联。总之,这些结果有助于人们更广泛地了解在大规模临床全基因组关联研究中发现的AD风险变体是如何参与AD病理机制的,并表明了从下游消除这些研究中引入的表型异质性的重要性。
{"title":"Hypothesis-based investigation of known AD risk variants reveals the genetic underpinnings of neuropathological lesions observed in Alzheimer’s-type dementia","authors":"Celeste Laureyssen,&nbsp;Fahri Küçükali,&nbsp;Jasper Van Dongen,&nbsp;Klara Gawor,&nbsp;Sandra O. Tomé,&nbsp;Alicja Ronisz,&nbsp;Markus Otto,&nbsp;Christine A. F. von Arnim,&nbsp;Philip Van Damme,&nbsp;Rik Vandenberghe,&nbsp;Dietmar Rudolf Thal,&nbsp;Kristel Sleegers","doi":"10.1007/s00401-024-02815-w","DOIUrl":"10.1007/s00401-024-02815-w","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is the leading cause of dementia worldwide. Besides neurofibrillary tangles and amyloid beta (A<i>β</i>) plaques, a wide range of co-morbid neuropathological features can be observed in AD brains. Since AD has a very strong genetic background and displays a wide phenotypic heterogeneity, this study aims at investigating the genetic underpinnings of co-morbid and hallmark neuropathological lesions. This was realized by obtaining the genotypes for 75 AD risk variants from low-coverage whole-genome sequencing data for 325 individuals from the Leuven Brain Collection. Association testing with deeply characterized neuropathological lesions revealed a strong and likely direct effect of rs117618017, a SNP in exon 1 of <i>APH1B</i>, with tau-related pathology. Second, a relation between <i>APOE</i> and granulovacuolar degeneration, a proxy for necroptosis, was also discovered in addition to replication of the well-known association of <i>APOE</i> with AD hallmark neuropathological lesions. Additionally, several nominal associations with AD risk genes were detected for pTDP pathology, <i>α</i>-synuclein lesions and pTau-related pathology. These findings were confirmed in a meta-analysis with three independent cohorts. For example, we replicated a prior association between <i>TPCN1</i> (rs6489896) and LATE-NC risk. Furthermore, we identified new putative LATE-NC-linked SNPs, including rs7068231, located upstream of <i>ANK3</i>. We found association between <i>BIN1</i> (rs6733839) and α-synuclein pathology, and replicated a prior association between <i>USP6NL</i> (rs7912495) and Lewy body pathology. Additionally, we also found that <i>UMAD1</i> (rs6943429) was nominally associated with Lewy body pathology. Overall, these results contribute to a broader general understanding of how AD risk variants discovered in large-scale clinical genome-wide association studies are involved in the pathological mechanisms of AD and indicate the importance of downstream elimination of phenotypic heterogeneity introduced in these studies.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02815-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy 抗IgLON5疾病的神经病理学谱系和脑干tau病理学阶段:疾病相关tau病的最新神经病理学研究标准
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-14 DOI: 10.1007/s00401-024-02805-y
Ellen Gelpi, Raphael Reinecke, Carles Gaig, Alex Iranzo, Lidia Sabater, Laura Molina-Porcel, Iban Aldecoa, Verena Endmayr, Birgit Högl, Erich Schmutzhard, Werner Poewe, Bettina Pfausler, Mara Popovic, Janja Pretnar-Oblak, Frank Leypoldt, Jakob Matschke, Markus Glatzel, Elena Maria Erro, Ivonne Jerico, Maria Cristina Caballero, Maria Victoria Zelaya, Sara Mariotto, Anna Heidbreder, Ognian Kalev, Serge Weis, Stefan Macher, Evelyn Berger-Sieczkowski, Julia Ferrari, Christoph Reisinger, Nikolaus Klupp, Pentti Tienari, Osma Rautila, Marja Niemelä, Deniz Yilmazer-Hanke, Mar Guasp, Bas Bloem, Judith Van Gaalen, Benno Kusters, Maarten Titulaer, Nina L. Fransen, Joan Santamaria, Thimoty Dawson, Janice L. Holton, Helen Ling, Tamas Revesz, Liisa Myllykangas, Herbert Budka, Gabor G. Kovacs, Jan Lewerenz, Josep Dalmau, Francesc Graus, Inga Koneczny, Romana Höftberger

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.

抗 IgLON5 病是一种独特的疾病,它连接着自身免疫和神经变性。自 10 年前首次描述该病以来,越来越多的尸检结果表明,在特定的临床症状群中,神经病理学的范围越来越广。在本研究中,我们描述了来自欧洲 9 个不同中心的 22 名抗 IgLON5 患者的神经病理学发现。在 15 名患者(68%)中,我们观察到了严重程度不等的下丘脑和脑干为主的 tau 病变,其中原始研究的神经病理学标准很容易适用。年轻患者(发病年龄中位数为 61 岁)和病程较长(病程中位数为 9 年)的患者都出现了这种病理现象。与此相反,在 7 例(32%)患者中,尽管具有轻度至中度神经退行性病变特征,临床症状一致,脑脊液和血清中存在抗 IgLON5 抗体,但最初描述的脑干 tauopathy 几乎不存在,或仅以细线的形式存在。这些患者发病时年龄较大(中位数为 79 岁),病程较短(中位数为 1 年)。总体而言,约三分之一的患者在受 tau 病变和/或神经变性影响的区域内同时出现 TDP-43 病变。基于这些观察结果,并考虑到疾病核心区域的 tau 负荷范围,我们提出了一个简单的分期系统:1 期轻度神经变性,无明显或仅有轻微 tau 病变;2 期中度神经变性和轻度/中度 tau 病变;3 期突出神经变性和 tau 病变。这一分期旨在反映tau病理学的潜在(年龄和时间依赖性)进展,支持目前的观点,即tau积累是与中枢神经系统中存在抗IgLON5抗体有关的继发现象。最后,我们调整了与抗IgLON5疾病相关的tau病的原始研究标准,以纳入在这一更大规模的尸检系列中观察到的病理范围。
{"title":"Neuropathological spectrum of anti-IgLON5 disease and stages of brainstem tau pathology: updated neuropathological research criteria of the disease-related tauopathy","authors":"Ellen Gelpi,&nbsp;Raphael Reinecke,&nbsp;Carles Gaig,&nbsp;Alex Iranzo,&nbsp;Lidia Sabater,&nbsp;Laura Molina-Porcel,&nbsp;Iban Aldecoa,&nbsp;Verena Endmayr,&nbsp;Birgit Högl,&nbsp;Erich Schmutzhard,&nbsp;Werner Poewe,&nbsp;Bettina Pfausler,&nbsp;Mara Popovic,&nbsp;Janja Pretnar-Oblak,&nbsp;Frank Leypoldt,&nbsp;Jakob Matschke,&nbsp;Markus Glatzel,&nbsp;Elena Maria Erro,&nbsp;Ivonne Jerico,&nbsp;Maria Cristina Caballero,&nbsp;Maria Victoria Zelaya,&nbsp;Sara Mariotto,&nbsp;Anna Heidbreder,&nbsp;Ognian Kalev,&nbsp;Serge Weis,&nbsp;Stefan Macher,&nbsp;Evelyn Berger-Sieczkowski,&nbsp;Julia Ferrari,&nbsp;Christoph Reisinger,&nbsp;Nikolaus Klupp,&nbsp;Pentti Tienari,&nbsp;Osma Rautila,&nbsp;Marja Niemelä,&nbsp;Deniz Yilmazer-Hanke,&nbsp;Mar Guasp,&nbsp;Bas Bloem,&nbsp;Judith Van Gaalen,&nbsp;Benno Kusters,&nbsp;Maarten Titulaer,&nbsp;Nina L. Fransen,&nbsp;Joan Santamaria,&nbsp;Thimoty Dawson,&nbsp;Janice L. Holton,&nbsp;Helen Ling,&nbsp;Tamas Revesz,&nbsp;Liisa Myllykangas,&nbsp;Herbert Budka,&nbsp;Gabor G. Kovacs,&nbsp;Jan Lewerenz,&nbsp;Josep Dalmau,&nbsp;Francesc Graus,&nbsp;Inga Koneczny,&nbsp;Romana Höftberger","doi":"10.1007/s00401-024-02805-y","DOIUrl":"10.1007/s00401-024-02805-y","url":null,"abstract":"<div><p>Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median &lt; 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: <i>stage 1</i> mild neurodegeneration without overt or only minimal tau pathology,<i> stage 2</i> moderate neurodegeneration and mild/ moderate tauopathy and <i>stage 3</i> prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02805-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142434932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway 神经元BAG3通过调节自噬-溶酶体途径减轻创伤性脑损伤引起的tau高磷酸化、突触功能障碍和认知缺陷。
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-11 DOI: 10.1007/s00401-024-02810-1
Nicholas Sweeney, Tae Yeon Kim, Cody T. Morrison, Liangping Li, Diana Acosta, Jiawen Liang, Nithin V. Datla, Julie A. Fitzgerald, Haoran Huang, Xianglan Liu, Gregory Huang Tan, Min Wu, Kate Karelina, Chelsea E. Bray, Zachary M. Weil, Douglas W. Scharre, Geidy E. Serrano, Takashi Saito, Takaomi C. Saido, Thomas G. Beach, Olga N. Kokiko-Cochran, Jonathan P. Godbout, Gail V. W. Johnson, Hongjun Fu

Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer’s disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.

越来越多的证据表明,早年或中年创伤性脑损伤(TBI)是罹患阿尔茨海默病(AD)和 AD 相关痴呆症(ADRD)的风险因素。然而,创伤性脑损伤诱发 AD 类病理和认知障碍的分子机制仍不清楚。在这项研究中,我们发现单次创伤性脑损伤(由受控皮质冲击诱发)会降低神经元和少突胶质细胞中 BCL2 相关的阿坦基因 3(BAG3)的表达、这与自噬-溶酶体途径(ALP)相关蛋白的减少、兴奋性神经元和少突胶质细胞中高磷酸化 tau(ptau)积累的增加、胶质细胞病变、突触功能障碍以及野生型(WT)和人类 tau 敲入(hTKI)小鼠的认知缺陷有关。在有创伤性脑损伤病史的人类病例中也发现了这些病理变化,而在有创伤性脑损伤的人类注意力缺失症病例中,这些病理变化更为严重。在体外,敲除 BAG3 能显著抑制自噬通量,而过表达 BAG3 则能显著增加自噬通量。在海马中特异性过表达神经元 BAG3 可减轻 hTKI 小鼠因 TBI 引起的 AD 类病理和认知障碍,这与 ALP 相关蛋白的增加有关。我们的数据表明,以神经元 BAG3 为靶点可能是预防或减轻 TBI 诱发的 AD 类病理变化和认知障碍的一种治疗策略。
{"title":"Neuronal BAG3 attenuates tau hyperphosphorylation, synaptic dysfunction, and cognitive deficits induced by traumatic brain injury via the regulation of autophagy-lysosome pathway","authors":"Nicholas Sweeney,&nbsp;Tae Yeon Kim,&nbsp;Cody T. Morrison,&nbsp;Liangping Li,&nbsp;Diana Acosta,&nbsp;Jiawen Liang,&nbsp;Nithin V. Datla,&nbsp;Julie A. Fitzgerald,&nbsp;Haoran Huang,&nbsp;Xianglan Liu,&nbsp;Gregory Huang Tan,&nbsp;Min Wu,&nbsp;Kate Karelina,&nbsp;Chelsea E. Bray,&nbsp;Zachary M. Weil,&nbsp;Douglas W. Scharre,&nbsp;Geidy E. Serrano,&nbsp;Takashi Saito,&nbsp;Takaomi C. Saido,&nbsp;Thomas G. Beach,&nbsp;Olga N. Kokiko-Cochran,&nbsp;Jonathan P. Godbout,&nbsp;Gail V. W. Johnson,&nbsp;Hongjun Fu","doi":"10.1007/s00401-024-02810-1","DOIUrl":"10.1007/s00401-024-02810-1","url":null,"abstract":"<div><p>Growing evidence supports that early- or middle-life traumatic brain injury (TBI) is a risk factor for developing Alzheimer’s disease (AD) and AD-related dementia (ADRD). Nevertheless, the molecular mechanisms underlying TBI-induced AD-like pathology and cognitive deficits remain unclear. In this study, we found that a single TBI (induced by controlled cortical impact) reduced the expression of BCL2-associated athanogene 3 (BAG3) in neurons and oligodendrocytes, which is associated with decreased proteins related to the autophagy-lysosome pathway (ALP) and increased hyperphosphorylated tau (ptau) accumulation in excitatory neurons and oligodendrocytes, gliosis, synaptic dysfunction, and cognitive deficits in wild-type (WT) and human tau knock-in (hTKI) mice. These pathological changes were also found in human cases with a TBI history and exaggerated in human AD cases with TBI. The knockdown of BAG3 significantly inhibited autophagic flux, while overexpression of BAG3 significantly increased it in vitro. Specific overexpression of neuronal BAG3 in the hippocampus attenuated AD-like pathology and cognitive deficits induced by TBI in hTKI mice, which is associated with increased ALP-related proteins. Our data suggest that targeting neuronal BAG3 may be a therapeutic strategy for preventing or reducing AD-like pathology and cognitive deficits induced by TBI.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02810-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded neuropathology specimens 从福尔马林固定石蜡包埋的神经病理标本中进行靶向全病毒基因组测序
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-09 DOI: 10.1007/s00401-024-02812-z
Charlotte Gorißen, Anne Albers, Viktoria Ruf, Emil Chteinberg, Reiner Siebert, Leonille Schweizer, Lukas Kaufmann, Joachim E. Kühn, Dennis Tappe, Tanja Kuhlmann, Christian Thomas
{"title":"Targeted whole-viral genome sequencing from formalin-fixed paraffin-embedded neuropathology specimens","authors":"Charlotte Gorißen,&nbsp;Anne Albers,&nbsp;Viktoria Ruf,&nbsp;Emil Chteinberg,&nbsp;Reiner Siebert,&nbsp;Leonille Schweizer,&nbsp;Lukas Kaufmann,&nbsp;Joachim E. Kühn,&nbsp;Dennis Tappe,&nbsp;Tanja Kuhlmann,&nbsp;Christian Thomas","doi":"10.1007/s00401-024-02812-z","DOIUrl":"10.1007/s00401-024-02812-z","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02812-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma 表观遗传景观重组和胚胎发育基因的重新激活与 IDH 突变星形细胞瘤的恶性程度有关
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-09 DOI: 10.1007/s00401-024-02811-0
Santoesha A. Ghisai, Levi van Hijfte, Wies R. Vallentgoed, C. Mircea S. Tesileanu, Iris de Heer, Johan M. Kros, Marc Sanson, Thierry Gorlia, Wolfgang Wick, Michael A. Vogelbaum, Alba A. Brandes, Enrico Franceschi, Paul M. Clement, Anna K. Nowak, Vassilis Golfinopoulos, Martin J. van den Bent, Pim J. French, Youri Hoogstrate

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. HOX, PAX, and TBX) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.

IDH突变胶质瘤的准确分级可确定患者的预后并指导治疗方案。组织学分级具有挑战性,除了 IDH 突变星形细胞瘤中的 CDKN2A/B 基因同源缺失外,目前还没有其他用于分级的客观分子标记物。我们对前瞻性CATNON试验中的原发性IDH突变星形细胞瘤(n = 138)进行了RNA测序,该试验旨在评估替莫唑胺辅助治疗和同期治疗对预后的影响。我们将 RNA 序列数据与匹配的 DNA 甲基化和 NGS 数据进行了整合。我们还使用了TCGA数据集中IDH突变星形细胞瘤的多组学数据,并验证了GLASS-NL研究中匹配的原发样本和复发样本的结果。由于离散分级不能充分捕捉这些肿瘤的分级,我们利用DNA甲基化图谱,根据中枢神经系统肿瘤分类器的分类分数生成连续分级系数(CGC)。CGC 是生存率的独立预测指标,优于目前的 WHO-CNS5 和基于甲基化的分类。我们的 RNA 序列分析发现了四个不同的转录集群,它们分别与:(i) 细胞周期基因的上调;(ii) 神经胶质分化基因的下调;(iii) 胚胎发育基因(如 HOX、PAX 和 TBX)的上调和 (iv) 细胞外基质基因的上调有关。胚胎发育基因的上调与这些基因附近 CpG 岛甲基化的特定增加有关。高级别 IDH 突变星形细胞瘤的 DNA 甲基化特征在 RNA 水平上与细胞周期、肿瘤细胞去分化和细胞外基质重塑的增加有关。这些综合分子特征可作为 IDH 突变星形细胞瘤分级的客观标记。
{"title":"Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma","authors":"Santoesha A. Ghisai,&nbsp;Levi van Hijfte,&nbsp;Wies R. Vallentgoed,&nbsp;C. Mircea S. Tesileanu,&nbsp;Iris de Heer,&nbsp;Johan M. Kros,&nbsp;Marc Sanson,&nbsp;Thierry Gorlia,&nbsp;Wolfgang Wick,&nbsp;Michael A. Vogelbaum,&nbsp;Alba A. Brandes,&nbsp;Enrico Franceschi,&nbsp;Paul M. Clement,&nbsp;Anna K. Nowak,&nbsp;Vassilis Golfinopoulos,&nbsp;Martin J. van den Bent,&nbsp;Pim J. French,&nbsp;Youri Hoogstrate","doi":"10.1007/s00401-024-02811-0","DOIUrl":"10.1007/s00401-024-02811-0","url":null,"abstract":"<div><p>Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from <i>CDKN2A/B</i> homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (<i>n</i> = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. <i>HOX</i>, <i>PAX,</i> and <i>TBX</i>) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02811-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline 颞叶癫痫微血管病变伴弥散核磁共振成像改变和认知能力下降
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-08 DOI: 10.1007/s00401-024-02809-8
Joan Liu, Lawrence Binding, Isha Puntambekar, Smriti Patodia, Yau Mun Lim, Alicja Mryzyglod, Fenglai Xiao, Shengning Pan, Remika Mito, Jane de Tisi, John S. Duncan, Sallie Baxendale, Matthias Koepp, Maria Thom

White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, p < 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, p < 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, p < 0.01) which was more marked the longer the duration of epilepsy (p < 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (p < 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.

颞叶癫痫(TLE)的白质微血管改变可能与后天神经退行性过程和认知障碍有关。我们对 44 例伴有或不伴有海马硬化的 TLE 患者手术切除的回旋核心和颞叶深部白质区域的微血管变化、髓鞘、轴突、胶质和细胞外基质标记进行了量化。我们将这些病理数据与术前共存区域的活体磁共振成像弥散测量结果以及认知障碍和认知能力下降的神经心理学测量结果进行了比较。在切除术中,与非癫痫对照组相比,我们观察到TLE患者的动脉硬化程度增加(硬化指数增大,p <0.001),这与年龄无关。微血管变化包括某些区域的血管密度增加,但平均血管大小却一致减小(用胶原蛋白-4定量,p< 0.05-0.0001),小血管和毛细血管的周细胞覆盖率增加,尤其是在深部白质中(用血小板衍生生长因子受体β和平滑肌肌动蛋白定量,p< 0.01),癫痫持续时间越长,这种变化越明显(p< 0.05)。我们注意到,与对照组相比,TLE 中胶质细胞数量(Olig2、Iba1)增加,但髓鞘(MAG、PLP)减少,在深部白质中尤为突出。基因表达分析表明,与非HS病例相比,HS病例中的髓鞘化基因减少得更多,并且随着年龄的增长而减少,这与弥散磁共振成像的改变有关。神经胶质密度和血管大小随磁共振成像弥散度的增加而增加,血管密度随白质异常的增加而增加。血管周围空间的增加与分数各向异性降低以及手术前年龄加速认知能力下降有关(p <0.05)。总之,TLE 可能存在获得性微血管病理改变,包括血管硬化、包膜覆盖增加和小血管尺寸缩小,这可能表明小血管收缩力和血液动力学发生了功能性改变,从而影响组织灌注。这些形态学特征与白质弥散核磁共振成像改变相关,可能解释了TLE认知能力下降的原因。
{"title":"Microangiopathy in temporal lobe epilepsy with diffusion MRI alterations and cognitive decline","authors":"Joan Liu,&nbsp;Lawrence Binding,&nbsp;Isha Puntambekar,&nbsp;Smriti Patodia,&nbsp;Yau Mun Lim,&nbsp;Alicja Mryzyglod,&nbsp;Fenglai Xiao,&nbsp;Shengning Pan,&nbsp;Remika Mito,&nbsp;Jane de Tisi,&nbsp;John S. Duncan,&nbsp;Sallie Baxendale,&nbsp;Matthias Koepp,&nbsp;Maria Thom","doi":"10.1007/s00401-024-02809-8","DOIUrl":"10.1007/s00401-024-02809-8","url":null,"abstract":"<div><p>White matter microvascular alterations in temporal lobe epilepsy (TLE) may be relevant to acquired neurodegenerative processes and cognitive impairments associated with this condition. We quantified microvascular changes, myelin, axonal, glial and extracellular-matrix labelling in the gyral core and deep temporal lobe white matter regions in surgical resections from 44 TLE patients with or without hippocampal sclerosis. We compared this pathology data with in vivo pre-operative MRI diffusion measurements in co-registered regions and neuropsychological measures of cognitive impairment and decline. In resections, increased arteriolosclerosis was observed in TLE compared to non-epilepsy controls (greater sclerotic index, <i>p</i> &lt; 0.001), independent of age. Microvascular changes included increased vascular densities in some regions but uniformly reduced mean vascular size (quantified with collagen-4, <i>p</i> &lt; 0.05–0.0001), and increased pericyte coverage of small vessels and capillaries particularly in deep white matter (quantified with platelet-derived growth factor receptorβ and smooth muscle actin, <i>p</i> &lt; 0.01) which was more marked the longer the duration of epilepsy (<i>p</i> &lt; 0.05). We noted increased glial numbers (Olig2, Iba1) but reduced myelin (MAG, PLP) in TLE compared to controls, particularly prominent in deep white matter. Gene expression analysis showed a greater reduction of myelination genes in HS than non-HS cases and with age and correlation with diffusion MRI alterations. Glial densities and vascular size were increased with increased MRI diffusivity and vascular density with white matter abnormality quantified using fixel-based analysis. Increased perivascular space was associated with reduced fractional anisotropy as well as age-accelerated cognitive decline prior to surgery (<i>p</i> &lt; 0.05). In summary, likely acquired microangiopathic changes in TLE, including vascular sclerosis, increased pericyte coverage and reduced small vessel size, may indicate a functional alteration in contractility of small vessels and haemodynamics that could impact on tissue perfusion. These morphological features correlate with white matter diffusion MRI alterations and might explain cognitive decline in TLE.</p></div>","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s00401-024-02809-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384485","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"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
Correction to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins 更正为扩增的 C9orf72 六核苷酸重复序列的双向转录本被翻译成聚集二肽重复序列蛋白
IF 9.3 1区 医学 Q1 CLINICAL NEUROLOGY Pub Date : 2024-10-05 DOI: 10.1007/s00401-024-02806-x
Kohji Mori, Thomas Arzberger, Friedrich A. Grässer, Ilse Gijselinck, Stephanie May, Kristin Rentzsch, Shih‑Ming Weng, Martin H. Schludi, Julie van der Zee, Marc Cruts, Christine Van Broeckhoven, Elisabeth Kremmer, Hans A. Kretzschmar, Christian Haass, Dieter Edbauer
{"title":"Correction to: Bidirectional transcripts of the expanded C9orf72 hexanucleotide repeat are translated into aggregating dipeptide repeat proteins","authors":"Kohji Mori,&nbsp;Thomas Arzberger,&nbsp;Friedrich A. Grässer,&nbsp;Ilse Gijselinck,&nbsp;Stephanie May,&nbsp;Kristin Rentzsch,&nbsp;Shih‑Ming Weng,&nbsp;Martin H. Schludi,&nbsp;Julie van der Zee,&nbsp;Marc Cruts,&nbsp;Christine Van Broeckhoven,&nbsp;Elisabeth Kremmer,&nbsp;Hans A. Kretzschmar,&nbsp;Christian Haass,&nbsp;Dieter Edbauer","doi":"10.1007/s00401-024-02806-x","DOIUrl":"10.1007/s00401-024-02806-x","url":null,"abstract":"","PeriodicalId":7012,"journal":{"name":"Acta Neuropathologica","volume":"148 1","pages":""},"PeriodicalIF":9.3,"publicationDate":"2024-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377702","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Acta Neuropathologica
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1