Midlife Retinal Microvascular Signs and Late-Life Neuroimaging Features of Cerebral Small Vessel Disease in the ARIC Study

Cerebral small vessel disease (CSVD) is a leading cause of cognitive and functional deficits. Retinal vasculature abnormalities may be an early indicator of CSVD. The aim of this study was to investigate the associations between retinal signs in midlife and imaging markers of CSVD 18 years later. This study included participants from the Atherosclerosis Risk in Communities Study, a prospective community-based cohort, who had retinal imaging at visit 3 (1993-1995) and 3T brain MRI at visit 5 (2011-2013). MRI scans were reviewed centrally and rated for white matter hyperintensities (WMHs), lacunes (present vs absent), cerebral microbleeds (present vs absent), brain volumes (total, lobar, temporoparietal meta region of interest, deep gray subcortical structure), global fractional anisotropy (FA) and mean diffusivity (MD) obtained from diffusion tensor imaging. Retinal imaging was evaluated centrally for 4 retinal signs: (1) central retinal arteriolar equivalent-lowest (worst) quartile vs top 3 quartiles; (2) arteriovenous nicking (present vs absent); (3) focal arteriolar narrowing (present vs absent); (4) retinopathy (mild, moderate, severe vs none). We used multivariable-adjusted Poisson regression with robust SEs for lacunes and cerebral microbleeds and linear regression for other MRI measures. Models were adjusted for age, sex, race-center, education, APOE ε4 allele, smoking, drinking, body mass index, hypertension, diabetes, and low-density lipoprotein cholesterol. We also adjusted for intracranial volume when WMHs and brain volumes were analyzed. Among 1,809 participants (mean visit 3 age = 59 years, mean visit 5 age = 77 years, 60% female, 27% Black), comparing participants with focal arteriolar narrowing present vs absent, worse white matter integrity (FA: difference = -0.006, 95% CI -0.010 to -0.001; MD: difference = 0.141 × 10-4 mm2/s, 95% CI 0.047-0.235) and higher WMH burden (difference = 5.119 cm3, 95% CI 1.352-8.885) were found, after adjusting for demographic and cardiovascular factors. Retinopathy was associated with cerebral microbleeds (prevalence ratio = 1.597, 95% CI 1.052-2.426). We did not find other significant associations between retinal microvascular signs and brain MRI measures. Midlife retinal microvascular abnormalities may be a valuable risk indicator of late-life CSVD neuroimaging markers. Retinal fundus photography might be a promising tool for early identification of CSVD.