Abstract
Brain damage caused by small vessel disease (SVD) differs between males and females. We aimed to examine the pure sex-specific neuroanatomical mechanisms of SVD adjusted for voxel-based expected effects of age and sex on healthy brain volume. Thirty-one female and 32 male genetic SVD (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy, CADASIL) patients and 55 sex- and age-matched healthy controls (HCs) underwent 7-Tesla MRI examinations. Voxel-based W-score maps were calculated from volumes and deformations of brain tissues, controlling for the expected effects of age and sex in HCs. Significant cognitive declines in working memory and executive function were identified in male CADASIL patients compared to female patients. Greater gray matter (GM) atrophy was found in the bilateral orbitofrontal cortex (OFC), left anterior cingulate cortex (ACC), left entorhinal cortex (EC), and right temporooccipital cortex in male CADASIL patients than in females. Working memory was associated with volumes in the right OFC specific to female CADASIL patients, whereas visuospatial ability was associated with the right hOcl (primary visual area, BA 17) volume specific to males. The current findings indicate that sex affects the pathogenesis of CADASIL, ranging from differences in neuroanatomy to those in behavioral performance, which may facilitate the development of more effective sex-specific therapeutic strategies for CADASIL and SVD.