Project Summary
Age-related macular degeneration (AMD), the leading cause of irreversible vision impairment in the US
and third globally, is a disease of the photoreceptor support system involving the retinal pigment
epithelium (RPE), Bruch's membrane, and the choriocapillaris, ultimately leading to photoreceptor
demise and eventual vision loss. Our research with that of others has clearly documented the selective
vulnerability of rod photoreceptors and rod-mediated (scotopic) vision, including delayed rod-mediated
dark adaptation (RMDA) and impaired rod-mediated light sensitivity, in aging and early AMD. RMDA is
not only more likely to be slower in eyes with early AMD compared to eyes in normal macular health, but
also delayed RMDA is a functional biomarker (i.e., risk factor) for incident early AMD. The next frontier
is to establish the structural basis of rod-mediated dysfunction in older adults at-risk for AMD and those
already converted to early AMD. Our unifying hypothesis across all aims is: Early AMD is a disease of
micronutrient deficiency and vascular insufficiency, due to detectable structural changes in the retinoid
re-supply route from the choriocapillaris to the photoreceptors, manifest functionally as delayed rod-
mediated dark adaptation. These structural disturbances will occur in specific chorioretinal layers and
regions reflecting the spatial distribution of disease in the photoreceptor support system. Our
multidisciplinary team has expertise in visual psychophysics, epidemiology, histopathology, digital image
analysis and interpretation for retinal disease, study design, and biostatistics. Toward our goals, we will
execute the 3 specific aims in an exceptionally well phenotyped cohort at aging-early AMD transition,
staged by the AREDS 9-step scale, with 3 years of longitudinal follow-up: (1) To examine the abundance
and extent of AMD's pathognomonic deposits (drusen and newly recognized subretinal drusenoid
deposits) in relationship to scotopic dysfunction via optical coherence tomography (OCT); (2) To
examine RPE cell bodies as structural correlates of scotopic dysfunction via quantitative fundus
autofluorescence and layer thicknesses via OCT; (3) To measure vascular density (coverage of macular
Bruch's membrane by choriocapillaris), a measure of exchange capacity for outer retinal cells, using OCT
angiography. An accurate map and timeline of structure-function relationships in aging and early AMD
gained from our research, especially the critical transition from aging to disease, will help define major
effects that can be developed into future treatments and preventative measures. Our data will help define
new endpoints for clinical trials for drugs to treat early AMD, the absence of which has impeded
translational research on this prevalent cause of legal blindness. Endpoints are needed more than ever,
because causal treatments targeting lipids in drusen and BrM can be pressed forward, thanks to clinical
and pre-clinical proof- of-concept studies.