Sex Differences in the Clinical and Imaging Characteristics of Korean CADASIL Patients: Nationwide Retrospective Study

BackgroundCerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by NOTCH3 mutations. While CADASIL affects both sexes, differences in clinical presentation and brain magnetic resonance imaging (MRI) findings remain unclear. This study aims to investigate sex-specific variations in vascular risk factors, clinical manifestations, and brain MRI features among Korean CADASIL patients. MethodsA nationwide retrospective study analyzed 368 CADASIL patients (179 men, 189 women). Clinical characteristics, vascular risk factors, and NOTCH3 variants were compared between sexes. Brain MRI findings, including white matter hyperintensity, lacunes, cerebral microbleeds, atrophy, and enlarged perivascular spaces, were evaluated. Kaplan-Meier analysis assessed sex differences in the onset of ischemic stroke, intracerebral hemorrhage (ICH), and dementia, and recurrent headaches. ResultsMen exhibited a higher prevalence of ischemic stroke (70.9% vs. 44.4%, p<0.001), whereas women were more likely to report recurrent headaches (35.4% vs. 16.9%, p<0.001). Survival analysis showed that men had a significantly earlier onset of ischemic stroke (Hazard Ratio[HR]: 2.78, 95% CI: 1.92-4.03, p<0.001) while being male was associated with significantly later onset of recurrent headache (HR: 0.59, 95% CI: 0.38-0.90, p=0.016). No significant sex differences were observed for ICH (HR: 2.04, 95% CI: 0.80-5.18, p=0.136) or dementia (HR: 1.26, 95% CI: 0.56-2.84, p=0.579). On brain MRI, male sex was associated with significantly higher risk for lacune burden (Odds Ratio[OR] 3.03, 95% CI 1.70-5.38, p<0.001) along with age (OR 1.03, 95% CI 1.01-1.05, p=0.002) and hypertension (OR 1.86, 95% CI 1.15-3.03, p=0.002). ConclusionThis study highlights significant sex-based differences in CADASIL, with men experiencing earlier and higher risk of ischemic stroke, along with a greater burden of lacunes, while women showed an increased likelihood of recurrent headaches at an earlier age. These findings underscore the importance of integrating sex-specific considerations into CADASIL prognosis and treatment planning.