ImportanceTypical 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.ObjectiveTo design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3-SVD severity spectrum.Design, Setting, and ParticipantsA 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 MeasuresPercentage 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.ResultsThe 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 RelevanceThe 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.

中文翻译：

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NOTCH3 相关小血管疾病的疾病严重程度分期系统，包括 CADASIL


重要性典型的改变半胱氨酸的 NOTCH3 （NOTCH3cys） 变异非常普遍（约 1/300 个体），与广谱小血管病 （SVD） 相关，范围从早发性卒中和痴呆（脑常染色体显性遗传性动脉病伴皮质下梗死和白质脑病 [CADASIL]）到非外显性。需要一个能够捕获完整 NOTCH3-SVD 严重程度谱的分期系统，但目前缺乏。目的设计一个简单的疾病严重程度分期系统，以捕获广泛的临床放射学 NOTCH3-SVD 严重程度谱。设计、设置和参与者进行了一项队列研究，其中 NOTCH3-SVD 严重程度分期系统是使用发现队列 （2019-2020） 开发的，并在独立的国际 CADASIL 队列 （1999-2023） 和英国生物库中进行了验证。从来自 23 个国际 CADASIL 队列和英国生物样本库的参与者那里收集了临床和影像学数据。资格标准是存在 NOTCH3cys 变体、脑磁共振成像的可用性和改良的 Rankin 量表评分。发现队列由来自 CADASIL 家庭的 195 例 NOTCH3cys 阳性病例组成;验证集包括来自 1713 个国家/地区的 15 例 NOTCH3cys 阳性病例。英国生物样本库队列由 101 名 NOTCH3cys 阳性个体组成。还分析了 2 年 （2019-2023） 和 18 年 （1999-2017） 随访研究的数据。数据分析于 2023 年 7 月至 2024 年 8 月进行。主要结局和测量遵循 NOTCH3-SVD 分期事件顺序的病例百分比，以及分期与缺血性卒中、脑出血、整体认知、处理速度、脑容量、脑微结构损伤和血清神经丝轻链 （NfL） 水平之间的关联。结果NOTCH3-SVD 分期系统包括 9 个疾病分期或亚期，范围从 0 期（显现前阶段）到 4B 期（终末期）。在所有 1908 例病例中，包括 195 例发现队列 （平均 [SD] 年龄，52.4 [12.2] 岁） 和 1713 例验证队列 （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。NOTCH3-SVD 分期与 CADASIL 队列和英国生物样本库中 NOTCH3cys 阳性病例的神经影像学结果相关，与 CADASIL 队列病例的认知结果和血清 NfL 水平相关。NOTCH3-SVD 分期系统捕捉疾病进展并与 18 年生存率相关。结论和相关性NOTCH3-SVD 分期系统捕捉了完整的疾病谱，从具有 NOTCH3cys 变异的无症状个体到终末期疾病患者。NOTCH3-SVD 分期系统是一种简单但有效的工具，可在临床和研究中进行统一的疾病分期。