Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL.

IF 20.4 1区 医学 Q1 CLINICAL NEUROLOGY
Gido Gravesteijn, Julie W Rutten, Minne N Cerfontaine, Remco J Hack, Yi-Chu Liao, Amy A Jolly, Stéphanie Guey, Shao-Lun Hsu, Jae-Young Park, Yun Yuan, Anna Kopczak, Nicola Rifino, Sam J Neilson, Anna Poggesi, Md Manjurul Islam Shourav, Satoshi Saito, Hiroyuki Ishiyama, Ana Domínguez Mayoral, Renata Nogueira, Elena Muiño, Pia Andersen, Nicola De Stefano, Gustavo Santo, Nontapat Sukhonpanich, Francesco Mele, Ashley Park, Jung Seok Lee, Mar Rodríguez-Girondo, Sebastiaan J J Vonk, Amy Brodtmann, Anne Börjesson-Hanson, Leonardo Pantoni, Israel Fernández-Cadenas, Ana Rita Silva, Vinícus V A Montanaro, Rajesh N Kalaria, Diego Lopergolo, Masafumi Ihara, James F Meschia, Keith W Muir, Anna Bersano, Francesca Pescini, Marco Duering, Jay Chol Choi, Chen Ling, Hyunjin Kim, Hugh S Markus, Hugues Chabriat, Yi-Chung Lee, Saskia A J Lesnik Oberstein
{"title":"Disease Severity Staging System for NOTCH3-Associated Small Vessel Disease, Including CADASIL.","authors":"Gido Gravesteijn, Julie W Rutten, Minne N Cerfontaine, Remco J Hack, Yi-Chu Liao, Amy A Jolly, Stéphanie Guey, Shao-Lun Hsu, Jae-Young Park, Yun Yuan, Anna Kopczak, Nicola Rifino, Sam J Neilson, Anna Poggesi, Md Manjurul Islam Shourav, Satoshi Saito, Hiroyuki Ishiyama, Ana Domínguez Mayoral, Renata Nogueira, Elena Muiño, Pia Andersen, Nicola De Stefano, Gustavo Santo, Nontapat Sukhonpanich, Francesco Mele, Ashley Park, Jung Seok Lee, Mar Rodríguez-Girondo, Sebastiaan J J Vonk, Amy Brodtmann, Anne Börjesson-Hanson, Leonardo Pantoni, Israel Fernández-Cadenas, Ana Rita Silva, Vinícus V A Montanaro, Rajesh N Kalaria, Diego Lopergolo, Masafumi Ihara, James F Meschia, Keith W Muir, Anna Bersano, Francesca Pescini, Marco Duering, Jay Chol Choi, Chen Ling, Hyunjin Kim, Hugh S Markus, Hugues Chabriat, Yi-Chung Lee, Saskia A J Lesnik Oberstein","doi":"10.1001/jamaneurol.2024.4487","DOIUrl":null,"url":null,"abstract":"<p><strong>Importance: </strong>Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking.</p><p><strong>Objective: </strong>To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.</p><p><strong>Design, setting, and participants: </strong>A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024.</p><p><strong>Main outcomes and measures: </strong>Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level.</p><p><strong>Results: </strong>The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival.</p><p><strong>Conclusions and relevance: </strong>The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.</p>","PeriodicalId":14677,"journal":{"name":"JAMA neurology","volume":" ","pages":"49-60"},"PeriodicalIF":20.4000,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JAMA neurology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1001/jamaneurol.2024.4487","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

Abstract

Importance: Typical cysteine-altering NOTCH3 (NOTCH3cys) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3-SVD severity spectrum is needed and currently lacking.

Objective: To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.

Design, setting, and participants: A cohort study was performed in which the NOTCH3-SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3cys-positive cases from families with CADASIL; the validation set included 1713 NOTCH3cys-positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3cys-positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024.

Main outcomes and measures: Percentage of cases following the sequence of events of the NOTCH3-SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level.

Results: The NOTCH3-SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3-SVD staging system. The NOTCH3-SVD stages were associated with neuroimaging outcomes in the NOTCH3cys-positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3-SVD staging system captured disease progression and was associated with 18-year survival.

Conclusions and relevance: The NOTCH3-SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3cys variant to patients with end-stage disease. The NOTCH3-SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

notch3相关小血管疾病的疾病严重程度分期系统,包括CADASIL。
重要性:典型的半胱氨酸改变型NOTCH3 (NOTCH3cys)变异非常普遍(约1 / 300),并与广谱小血管疾病(SVD)相关,包括早发性卒中和痴呆(大脑常染色体显性动脉病变伴皮质下梗死和白质脑病[CADASIL])和非外显性。我们需要一种能够捕获NOTCH3-SVD完整严重性谱的分期系统,但目前还缺乏这种系统。目的:设计一个简单的疾病严重程度分期系统,以捕获临床放射学广泛的NOTCH3-SVD严重程度谱。设计、环境和参与者:进行了一项队列研究,其中使用发现队列(2019-2020)开发了NOTCH3-SVD严重程度分期系统,并在独立的国际CADASIL队列(1999-2023)和UK Biobank中进行了验证。临床和影像学数据来自23个国际CADASIL队列和UK Biobank的参与者。入选标准为NOTCH3cys变异的存在、脑磁共振成像的可用性和修改的Rankin量表评分。发现队列包括195例来自CADASIL家族的notch3cys阳性病例;验证集包括来自15个国家的1713例notch3cys阳性病例。英国生物银行队列包括101名notch3cys阳性个体。还分析了2年(2019-2023年)和18年(1999-2017年)随访研究的数据。数据分析时间为2023年7月至2024年8月。主要观察指标:NOTCH3-SVD分期按事件顺序发生的病例百分比,以及各分期与缺血性卒中、脑出血、整体认知、处理速度、脑容量、脑微结构损伤、血清神经丝轻链(NfL)水平的关系。结果:NOTCH3-SVD分期系统包括9个疾病分期或亚分期,从0期(前期)到4B期(终末期)。在所有1908例中,包括195例发现组(平均[SD]年龄52.4[12.2]岁)和1713例验证组(平均[SD]年龄53.1[13.0]岁),1789例(94%)遵循NOTCH3-SVD分期系统定义的事件顺序。在CADASIL队列和UK Biobank中,NOTCH3-SVD分期与notch3cs阳性病例的神经影像学结果相关,与CADASIL队列中患者的认知结果和血清NfL水平相关。NOTCH3-SVD分期系统捕获疾病进展并与18年生存率相关。结论和相关性:NOTCH3-SVD分期系统捕获了整个疾病谱系,从无症状的NOTCH3cys变体个体到终末期疾病患者。NOTCH3-SVD分期系统是临床上和研究中统一疾病分期的一种简单而有效的工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
JAMA neurology
JAMA neurology CLINICAL NEUROLOGY-
CiteScore
41.90
自引率
1.70%
发文量
250
期刊介绍: JAMA Neurology is an international peer-reviewed journal for physicians caring for people with neurologic disorders and those interested in the structure and function of the normal and diseased nervous system. The Archives of Neurology & Psychiatry began publication in 1919 and, in 1959, became 2 separate journals: Archives of Neurology and Archives of General Psychiatry. In 2013, their names changed to JAMA Neurology and JAMA Psychiatry, respectively. JAMA Neurology is a member of the JAMA Network, a consortium of peer-reviewed, general medical and specialty publications.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
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
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
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 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信