Department of Clinical Genetics (R.J.H., M.N.C., G.G., S.T., F.B., J.W.R., S.A.J.L.O.), Leiden University Medical Center, the Netherlands.
Department of Radiology (A.H., J.v.d.G.), Leiden University Medical Center, the Netherlands.
Stroke. 2022 Oct;53(10):3133-3144. doi: 10.1161/STROKEAHA.122.039325. Epub 2022 Jul 13.
A retrospective study has shown that EGFr (epidermal growth factor-like repeat) group in the gene is an important cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) disease modifier of age at first stroke and white matter hyperintensity (WMH) volume. No study has yet assessed the effect of other known CADASIL modifiers, that is, cardiovascular risk factors and sex, in the context of EGFr group. In this study, we determined the relative disease-modifying effects of EGFr group, sex and cardiovascular risk factor on disease severity in the first genotype-driven, large prospective CADASIL cohort study, using a comprehensive battery of CADASIL clinical outcomes and neuroimaging markers.
Patients with CADASIL participated in a single-center, prospective cohort study (DiViNAS [Disease Variability in NOTCH3 Associated Small Vessel Disease]) between 2017 and 2020. The study protocol included a clinical assessment, neuropsychological test battery and brain magnetic resonance imaging on a single research day. Multivariable linear, logistic and Cox regression models were used to cross-sectionally assess the effect of CADASIL modifiers on clinical severity (stroke, disability, processing speed) and neuroimaging markers (WMH volume, peak width of skeletonized mean diffusivity, lacune volume, brain volume, cerebral microbleed count).
Two hundred patients with CADASIL participated, of which 103 harbored a EGFr 1-6 variant and 97 an EGFr 7-34 variant. EGFr 1-6 group was the most important modifier of age at first stroke (hazard ratio, 2.45 [95% CI, 1.39-4.31]; =0.002), lacune volume (odds ratio, 4.31 [95% CI, 2.31-8.04]; =4.0×10), WMH volume (B=0.81 [95% CI, 0.60-1.02]; =1.1×10), and peak width of skeletonized mean diffusivity (B=0.65 [95% CI, 0.44-0.87]; =1.6×10). EGFr 1-6 patients had a significantly higher WMH volume in the anterior temporal lobes and superior frontal gyri and a higher burden of enlarged perivascular spaces. After EGFr group, male sex and hypertension were the next most important modifiers of clinical outcomes and neuroimaging markers.
EGFr group is the most important CADASIL disease modifier not only for age at first stroke and WMH volume but also strikingly so for a whole battery of clinically relevant disease measures such as lacune volume and peak width of skeletonized mean diffusivity. EGFr group is followed in importance by sex, hypertension, diabetes, and smoking.
一项回顾性研究表明，基因中的 EGFr（表皮生长因子样重复）组是脑常染色体显性动脉病伴皮质下梗死和白质脑病（CADASIL）的重要疾病修饰因子，可影响首次中风的年龄和脑白质高信号（WMH）体积。尚无研究评估其他已知的 CADASIL 修饰因子，即心血管危险因素和性别，在 EGFr 组中的作用。在这项研究中，我们使用全面的 CADASIL 临床结局和神经影像学标志物，在首个基因型驱动的大型前瞻性 CADASIL 队列研究中，确定了 EGFr 组、性别和心血管危险因素对疾病严重程度的相对疾病修饰作用。
CADASIL 患者于 2017 年至 2020 年参加了一项单中心前瞻性队列研究（DiViNAS [NOTCH3 相关小血管病的疾病变异性]）。研究方案包括在一个研究日进行临床评估、神经心理学测试和脑磁共振成像。多变量线性、逻辑和 Cox 回归模型用于横断面评估 CADASIL 修饰因子对临床严重程度（中风、残疾、处理速度）和神经影像学标志物（WMH 体积、骨架化平均弥散峰宽、腔隙体积、脑体积、脑微出血计数）的影响。
200 名 CADASIL 患者参与了研究，其中 103 名患者携带 EGFr 1-6 变异，97 名患者携带 EGFr 7-34 变异。EGFr 1-6 组是首次中风年龄（危险比，2.45 [95%CI，1.39-4.31]；=0.002）、腔隙体积（比值比，4.31 [95%CI，2.31-8.04]；=4.0×10）、WMH 体积（B=0.81 [95%CI，0.60-1.02]；=1.1×10）和骨架化平均弥散峰宽（B=0.65 [95%CI，0.44-0.87]；=1.6×10）的最重要修饰因子。EGFr 1-6 患者在前颞叶和额上回的 WMH 体积明显较高，且腔隙和扩大的血管周围间隙的负担也较高。在 EGFr 组之后，男性和高血压是影响临床结局和神经影像学标志物的下一个最重要的修饰因子。
EGFr 组不仅是 CADASIL 疾病的最重要修饰因子，不仅影响首次中风的年龄和 WMH 体积，而且对一系列临床相关疾病指标（如腔隙体积和骨架化平均弥散峰宽）也有显著影响。其次重要的是性别、高血压、糖尿病和吸烟。
