Association of Lacunes with Risk Factors, Cognition, and Atrophy: The Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract Background: Lacunes are 3-15 mm cavities originating from small perforating artery disease and are a hallmark of cerebral small vessel disease (cSVD). Prior prevalence studies relied on manual rating, which is prone to inter-rater variability and cannot quantify volume. We applied deep learning to quantify lacunes in a diverse community-based cohort. Methods: In this cross-sectional analysis of 1,038 Multi-Ethnic Study of Atherosclerosis (MESA) participants, with longitudinal cognitive follow-up, we quantified lacunes, confirmed them with a trained rater, and classified them as deep or lobar. Regression models examined associations of lacunes with cardiovascular risk factors, other small vessel disease lesions, brain atrophy, and cognition. Structural equation modeling evaluated whether deep lacune burden mediated associations of age or Framingham All-Cardiovascular Disease (CVD) Risk Score with atrophy and cognition. Results: Overall, 182 participants (17.5%) had at least one lacune (deep: 9.2%; lobar: 9.6%). Hispanic participants had lower lacune burden than White participants. Age, Framingham All-CVD Risk Score, PREVENT 10-year Total CVD Risk Score, and hypertension were associated with overall and deep lacunes, while lobar lacunes showed no associations. Deep lacunes were associated with white matter hyperintensities, enlarged perivascular spaces, and cerebral microbleeds, as well as SPARE-BA, SPARE-AD, and cortical and hippocampal atrophy. Deep lacunes were cross-sectionally associated with decreased global cognition and language/semantic performance, and longitudinally with accelerated executive function decline independent of count. Deep lacune burden significantly mediated associations of age and Framingham All-CVD Risk Score with SPARE-AD, SPARE-BA, and global cognition. Conclusions: In this multi-ethnic community-based cohort, deep lacune burden demonstrated stronger associations with vascular risk, other cerebral small vessel disease markers, brain atrophy, and longitudinal executive function decline than lobar burden. By providing a continuous measure of lesion volume, automated quantification captured information beyond lacune count.