Lifelong trajectories of modifiable vascular risk factors and relation to cerebral small vessel disease in the Framingham Heart Study

BackgroundCerebral small vessel disease (CSVD) is strongly linked to stroke and dementia risk, frequently predating clinical events for years to decades. Preventive efforts focus on treatment of modifiable vascular risk factors (VRF), but the complex changes in VRF over long periods in relation to CSVD burden remain unclear. Thus, we aimed to characterize life-long VRF trajectories in community-dwelling individuals and relate them to CSVD burden. MethodsFramingham Heart Study participants from the Original and Offspring cohorts with six or more repeated VRF assessments over their lifetime were eligible for the present study. Among those who underwent MRI imaging, CSVD burden was quantified by assigning one point each for cerebral microbleeds, covert infarcts, extensive white matter hyperintensities, cortical superficial siderosis, and high perivascular space burden (range: 0-5). VRF trajectories and trajectory-based clusters were then examined in relation to CSVD burden using functional regression analysis. ResultsOf 7,961 participants with longitudinal VRF measurements (mean baseline age 39.8 {+/-} 10 years, 45% men), 1,625 underwent MRI imaging after exclusions for other neurological conditions. In models that used individual VRF trajectories as covariates, systolic and diastolic blood pressure, pulse pressure, cigarettes per day and triglycerides were significantly associated with CSVD burden later in life. In a complementary analysis, we clustered VRF trajectories and then used each participants cluster assignment (rather than the raw trajectories) as the covariate; cluster assignments diverged early in life for systolic blood pressure and pulse pressure and were significantly associated with CSVD burden. ConclusionsIndividuals following high risk lifetime patterns of vascular risk factors have higher CSVD burden later in life. These results highlight the importance of primordial and primary prevention with sustained risk factor management across the lifespan to mitigate CSVD burden, a strong determinant of stroke and dementia risk.