Sex-related differences in clinical severity and neuroimaging burden in CADASIL: a systematic review

Abstract

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic cause of cerebral small vessel disease, resulting from mutations in the NOTCH3 gene and characterized by recurrent ischemic events, cognitive impairment, and a high burden of MRI lesions, including white matter hyperintensities, lacunes, and cerebral microbleeds (Chabriat et al., 2009; Tan & Markus, 2016). Despite advances in clinical and radiological characterization, the disease exhibits significant phenotypic heterogeneity that cannot be fully explained by genetic factors alone (Matsushima et al., 2017). Emerging evidence suggests that sex may influence disease severity, with males showing greater lesion burden, higher stroke risk, and more pronounced brain atrophy (Gunda et al., 2012; Jia et al., 2023). However, available data remain limited and heterogeneous, and the role of sex in CADASIL clinical and neuroimaging manifestations is not yet fully established. Objective: To evaluate sex-related differences in CADASIL, focusing on clinical burden and neuroimaging findings. Specifically, to assess the association between sex and stroke occurrence, as well as differences in structural lesion burden, including white matter hyperintensities, lacunes, cerebral microbleeds, and brain atrophy. Additionally, to investigate the impact of these differences on disease severity and phenotypic expression. Methods: A systematic review of the literature was conducted using PubMed, Scopus, and Embase databases, including studies published between 2010 and 2026. The search strategy combined terms related to CADASIL, sex differences, stroke, and neuroimaging markers. Observational studies with genetically confirmed CADASIL and sex-stratified analyses of clinical and/or MRI outcomes were included. Case reports, reviews, studies without sex stratification, and those lacking genetic confirmation were excluded. Study selection was performed through title, abstract, and full-text screening according to predefined eligibility criteria. Results: Six studies were included, comprising observational cohorts with genetically confirmed CADASIL. Across studies, males consistently exhibited a higher burden of small vessel disease markers, including greater white matter hyperintensities, more lacunes and microbleeds, and increased brain atrophy (Gunda et al., 2012; Jia et al., 2023). Male sex was also associated with higher stroke risk and more severe clinical presentation. Females showed lower lesion burden and milder phenotypes. Findings were consistent across studies despite methodological variability, with convergent evidence supporting a significant sex-related effect on disease severity and neuroimaging burden. Conclusion: Sex-related differences influence clinical severity and neuroimaging burden in CADASIL. Males show higher lesion load and stroke risk, while females have milder phenotypes, suggesting a modifier role, with implications for individualized risk stratification.