Elizabeth R Dellar, Iolanda Vendrell, Benazir Amein, David G Lester, Evan C Edmond, Katie Yoganathan, Thanuja Dharmadasa, Aitana Sogorb-Esteve, Roman Fischer, Kevin Talbot, Jonathan D Rohrer, Martin R Turner, Alexander G Thompson
{"title":"无症状的 C9orf72 六核苷酸重复扩增携带者脑脊液泛素羧基末端水解酶同工酶 L1 升高","authors":"Elizabeth R Dellar, Iolanda Vendrell, Benazir Amein, David G Lester, Evan C Edmond, Katie Yoganathan, Thanuja Dharmadasa, Aitana Sogorb-Esteve, Roman Fischer, Kevin Talbot, Jonathan D Rohrer, Martin R Turner, Alexander G Thompson","doi":"10.1002/ana.27133","DOIUrl":null,"url":null,"abstract":"<p><strong>Objective: </strong>To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.</p><p><strong>Methods: </strong>Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.</p><p><strong>Results: </strong>Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log<sub>2</sub>fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).</p><p><strong>Interpretation: </strong>Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.</p>","PeriodicalId":127,"journal":{"name":"Annals of Neurology","volume":" ","pages":""},"PeriodicalIF":8.1000,"publicationDate":"2024-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Elevated Cerebrospinal Fluid Ubiquitin Carboxyl-Terminal Hydrolase Isozyme L1 in Asymptomatic C9orf72 Hexanucleotide Repeat Expansion Carriers.\",\"authors\":\"Elizabeth R Dellar, Iolanda Vendrell, Benazir Amein, David G Lester, Evan C Edmond, Katie Yoganathan, Thanuja Dharmadasa, Aitana Sogorb-Esteve, Roman Fischer, Kevin Talbot, Jonathan D Rohrer, Martin R Turner, Alexander G Thompson\",\"doi\":\"10.1002/ana.27133\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Objective: </strong>To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.</p><p><strong>Methods: </strong>Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.</p><p><strong>Results: </strong>Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log<sub>2</sub>fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).</p><p><strong>Interpretation: </strong>Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.</p>\",\"PeriodicalId\":127,\"journal\":{\"name\":\"Annals of Neurology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":8.1000,\"publicationDate\":\"2024-11-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Annals of Neurology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1002/ana.27133\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annals of Neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/ana.27133","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0
摘要
目的通过C9orf72六核苷酸重复扩增（HRE）杂合子，确定肌萎缩侧索硬化症（ALS）或额颞叶痴呆症（FTD）高风险人群的生化变化：方法：对 48 名无症状的 C9orf72 HRE 携带者、39 名无症状的非携带者对照者、19 名散发性 ALS 患者、10 名 C9orf72 ALS 患者、14 名散发性 FTD 患者和 10 名 C9orf72 FTD 患者进行横断面观察研究。在无症状的 C9orf72 HRE 携带者和年龄匹配的非携带者对照组中，比较了 ALS 和 FTD 的 30 种预定义脑脊液生物标记物的相对丰度。采用数据独立采集质谱法或神经丝蛋白轻链电化学发光法对这些蛋白质的丰度差异进行量化。然后对整个脑脊液蛋白质组进行无偏分析：结果：无症状的 C9orf72 HRE 携带者与年龄匹配的非携带者相比，泛素羧基水解酶同工酶 L1 的水平更高（对数 2 倍变化 0.20，FDR 调整后的 p 值 = 0.034），而神经丝轻链的水平没有显著差异。根据神经丝水平对各组进行匹配（p = 0.011），并对年龄、性别和神经丝水平进行调整后，泛素羧基水解酶同工酶 L1 的水平仍然升高。将分析范围限制在较年轻的参与者时，也观察到了明显的差异（解释：脑脊液中脑蛋白酶 L1 水平升高可能与神经丝水平有关：C9orf72 HRE携带者脑脊液泛素羧基水解酶同工酶L1水平升高可能发生在神经丝水平未升高的情况下，这可能反映了神经元快速丧失之前的代偿或致病机制。这为了解与 C9orf72 HRE 携带者状态相关的变化提供了一个窗口，有可能为了解渗透性和预防方法提供信息。ann neurol 2024.
Objective: To identify biochemical changes in individuals at higher risk of developing amyotrophic lateral sclerosis (ALS) or frontotemporal dementia (FTD) via C9orf72 hexanucleotide repeat expansion (HRE) heterozygosity.
Methods: Cross-sectional observational study of 48 asymptomatic C9orf72 HRE carriers, 39 asymptomatic non-carrier controls, 19 people with sporadic ALS, 10 with C9orf72 ALS, 14 with sporadic FTD, and 10 with C9orf72 FTD. Relative abundance of 30 pre-defined cerebrospinal fluid biomarkers of ALS and FTD were compared in asymptomatic C9orf72 HRE carriers and age-matched non-carrier controls. Differential abundance of these proteins was quantified using data independent acquisition mass spectrometry or electro chemiluminescent assay for neurofilament light chain. Unbiased analysis of the entire cerebrospinal fluid proteome was then carried out.
Results: Ubiquitin carboxyl-hydrolase isozyme L1 levels were higher in asymptomatic C9orf72 HRE carriers compared with age-matched non-carriers (log2fold change 0.20, FDR-adjusted p-value = 0.034), whereas neurofilament light chain levels did not significantly differ. Ubiquitin carboxyl-hydrolase isozyme L1 levels remained elevated after matching of groups by neurofilament levels (p = 0.011), and after adjusting for age, sex, and neurofilament levels. A significant difference was also observed when restricting analysis to younger participants (<37) matched by neurofilament level (p = 0.007).
Interpretation: Elevated cerebrospinal fluid ubiquitin carboxyl-hydrolase isozyme L1 levels in C9orf72 HRE carriers can occur in the absence of increased neurofilament levels, potentially reflecting either compensatory or pathogenic mechanisms preceding rapid neuronal loss. This brings forward the window on changes associated with the C9orf72 HRE carrier state, with potential to inform understanding of penetrance and approaches to prevention. ANN NEUROL 2024.
期刊介绍：
Annals of Neurology publishes original articles with potential for high impact in understanding the pathogenesis, clinical and laboratory features, diagnosis, treatment, outcomes and science underlying diseases of the human nervous system. Articles should ideally be of broad interest to the academic neurological community rather than solely to subspecialists in a particular field. Studies involving experimental model system, including those in cell and organ cultures and animals, of direct translational relevance to the understanding of neurological disease are also encouraged.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
