Wang, Yalin

Objectives: This study aims to identify retinal biomarkers of NOTCH3 mutation carriers using optical coherence tomography (OCT) data from the UK Biobank. Methods: We conducted a cross-sectional, matched case-control study of individuals with or without NOTCH3 mutation from the UK Biobank between 2006 and 2010. All participants had macular OCT scan and cognitive assessment. Cases were identified based on pathogenic/likely pathogenic NOTCH3 mutations and 1:1 matched with controls based on age, sex, hypertension, diabetes mellitus, and cigarette smoking status. Baseline characteristics and cognitive test scores were compared using χ 2 or Mann-Whitney U test appropriately. Macular thickness at central, inner, and outer subfields and at each retinal layer was compared using Wilcoxon signed-rank test. Results: Our analysis included 134 participants (67 cases, 67 controls) with a mean age of 54 ± 9 years. NOCTH3 mutation carriers performed worse in prospective memory ( P =0.043), verbal and numerical reasoning ( P =0.178), visual memory ( P =0.227), and processing speed ( P =0.101) than matched controls. There were no differences in visual acuity between the 2 groups. NOTCH3 mutation carriers had significantly thinner macular inner subfield at the superior ( P =0.006), temporal ( P =0.008), and nasal ( P =0.034) quadrants, and significantly thinner macular RNFL ( P =0.008) compared with age-, sex-, and vascular risk factor-matched controls. Conclusion: The presence of NOTCH3 mutation is associated with reduced thickness in the inner macular subfield and macular RFNL. These retinal changes may reflect early pericyte dysfunction and microvascular ischemia. Longitudinal studies are needed to assess the temporal relationship between these retinal changes, cerebrovascular disease progression, and clinical severity of disease.

Objective: To assess the link between retinal vascular health and cognitive performance in a diverse population, using a novel mobile laboratory platform and portable color fundus photography. Background: The retina is an accessible window into brain health. Studies that had highlighted the link between retinal vasculature and cognition included clinical populations or narrowly defined research cohorts, with limited generalizability. To address the need to expand this research to demographic and geographic diverse communities, we launched a mobile laboratory platform across rural and urban Arizona zip codes. Methods: 240 subjects were recruited in our prospective community-based study. We assessed cognition using the MindCrowd web-based testing platform and analyzed verbal paired associates (VPA) task, a validated measure of verbal associative memory sensitive to age-related cognitive decline. Non-mydriatic color fundus photographs were obtained using the portable hand-held Aurora camera (Optomed), two images per eye (disc- and macula-centered). Image processing and vascular feature quantification were automatically conducted using Automorph software. Linear regression models examined the associations between retinal vascular metrics and VPA, adjusting for age, sex, education attainment, and risk factors. Results: Our cohort’s mean age was 45 +/-16.7 years, 32.9% were male and 39.5% had a college degree. In disc-centered fundus images, fractal dimension strongly associated with chronological age (p = 1.04E-10). Greater artery tortuosity in the retinal zones B and C was associated with lower VPA (p = 0.02 and p = 0.004, respectively). In macula-centered images, fractal dimension showed the strongest association with age (p = 4.31E-11), reinforcing its utility as a robust biomarker of vascular aging. Males had wider average artery caliber in zone B (p=0.02). Zone B vein fractal dimension (p=0.002) and vein vessel density (p=0.006) were the strongest predictors of VPA. Conclusions: This study demonstrates the safety, feasibility, and utility of a mobile laboratory to collect high-quality non-mydriatic color photos and cognitive data across a geographically diverse cohort. Arterial tortuosity and venous fractal dimension and density, particularly in retinal zone B, were predictive of cognitive performance, after adjusting for vascular health covariates. Retina may become a scalable and accessible platform for studying brain aging in the general population.