BACKGROUND AND OBJECTIVES Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most frequent small artery brain disease caused by pathogenic variants of the NOTCH3 gene. During the disease, we still do not know how the various deficits progress and develop with each other at different stages of the disease. We aim to model disease progression and identify possible progressive subgroups and the effects of different covariates on clinical worsening. METHODS Data were obtained from patients followed in the French CADASIL referral center, who were aged 25-80 years and had completed at least 2 visits and one of 14 clinical scores. Progression and variability were assessed using a disease course model (Leaspy). A Gaussian mixture model was used to identify different progression subgroups. Logistic regressions were used to compare the characteristics between groups. RESULTS In 395 patients along 2,007 visits, the follow-up ranged from 6 months to 19 years, with a mean of 7.5 years. They were 45% men with a mean age of 52.2 years. The evolution curves of the different scores showed that clinical manifestations develop heterogeneously and can vary considerably depending on the disease stage. We identified an early-onset, rapidly progressing subgroup of patients with earlier motor symptoms and focal neurologic deficits (median time shift 59 [Q1-Q3 48.9-66.3], median acceleration rate 0.84 [0.07-1.31]) and a late-onset slowly progressing group with earlier cognitive symptoms (median time shift 69.2 [63.4-75.1], median acceleration rate -0.18 [-0.48 to 0.14]). Male sex, lower education level, hypertension, and NOTCH3 pathogenic variant location within epidermal growth factor-like repeat (EGFr) 1-6 were found to be associated with this group difference. DISCUSSION Our results suggest a gradual and heterogeneous decline in different clinical and cognitive performances over the lifetime of patients with CADASIL. Two progression profiles-one rapid and early and the other, more delayed and slower-are possible after the onset of symptoms. A major limitation of our study is that the clusters were assessed post hoc, which may induce some bias. Overall, male sex, low level of education, pathogenic variant location in EGFr 1 to 6 domains, smoking, and/or arterial hypertension may affect the clinical progression of the disease.

中文翻译：

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确定有症状的 CADASIL 患者的临床疾病进展。


背景和目的 常染色体显性遗传性脑动脉病伴皮质下梗死和白质脑病 （CADASIL） 是由 NOTCH3 基因的致病性变异引起的最常见的小动脉脑病。在疾病期间，我们仍然不知道各种缺陷在疾病的不同阶段是如何相互发展和发展的。我们旨在模拟疾病进展并确定可能的进行性亚组以及不同协变量对临床恶化的影响。方法 数据来自法国 CADASIL 转诊中心随访的患者，患者年龄在 25-80 岁之间，至少完成了 2 次就诊和 14 次临床评分中的 1 次。使用病程模型 （Leaspy） 评估进展和变异性。使用高斯混合模型来识别不同的进展亚组。采用 Logistic 回归比较组间特征。结果 在 395 名患者中，共 2,007 次就诊，随访时间从 6 个月到 19 年不等，平均为 7.5 年。他们是 45% 的男性，平均年龄为 52.2 岁。不同评分的演变曲线显示，临床表现发展异质性，并且根据疾病阶段的不同可能会有很大差异。我们确定了一个早发性、进展迅速的患者亚组，这些患者具有早期运动症状和局灶性神经功能缺损 （中位时间偏移 59 [Q1-Q3 48.9-66.3]，中位加速率 0.84 [0.07-1.31]） 和一个具有早期认知症状的迟发性缓慢进展组 （中位时间偏移 69.2 [63.4-75.1]，中位加速率 -0.18 [-0.48 至 0.14]）。 发现男性、较低教育水平、高血压和 NOTCH3 致病性变异在表皮生长因子样重复序列 （EGFr） 1-6 内的位置与该组差异相关。讨论 我们的结果表明，在 CADASIL 患者的一生中，不同的临床和认知表现会逐渐和异质性地下降。症状出现后可能有两种进展特征——一种是快速和早期的，另一种是更延迟和更慢的。我们研究的一个主要局限性是集群是事后评估的，这可能会引起一些偏倚。总体而言，男性、低教育水平、EGFr 1 至 6 域中的致病变异位置、吸烟和/或动脉高血压可能会影响疾病的临床进展。