Functionally validated imaging endpoints in the Alabama study on early age-related macular degeneration 2 (ALSTAR2): design and methods

Abstract

Background: Age-related macular degeneration (AMD), a leading cause of irreversible vision impairment in the United States and globally, is a disease of the photoreceptor support system involving the retinal pigment epithelium (RPE), Bruch's membrane, and the choriocapillaris in the setting of characteristic extracellular deposits between outer retinal cells and their blood supply. Research has clearly documented the selective vulnerability of rod photoreceptors and rod-mediated (scotopic) vision in early AMD, including delayed rod-mediated dark adaptation (RMDA) and impaired rod-mediated light and pattern sensitivity. The unifying hypothesis of the Alabama Study on Early Macular Degeneration (ALSTAR2) is that 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. Functionally this is manifest as delayed rod-mediated dark adaptation and eventually as rod-mediated visual dysfunction in general. Methods: A cohort of 480 older adults either in normal macular health or with early AMD will be enrolled and followed for 3 years to examine cross-sectional and longitudinal associations between structural and functional characteristics of AMD. Using spectral domain optical coherence tomography, the association between (1) subretinal drusenoid deposits and drusen, (2) RPE cell bodies, and (3) the choriocapillaris' vascular density and rodand cone-mediated vision will be examined. An accurate map and timeline of structure-function relationships in aging and early AMD gained from ALSTAR2, especially the critical transition from aging to disease, will identify major characteristics relevant to future treatments and preventative measures.

Local Abundance of Macular Xanthophyll Pigment Is Associated with Rod- and Cone-Mediated Vision in Aging and Age-Related Macular Degeneration

“…79 A recently articulated center-surround model of cone resilience and rod vulnerability in aging and AMD incorporates a barrier to retinoid transport in the choriocapillaris-Bruch's membrane-RPE complex. 10,80,81 In brief, the RPE constitutively secretes lipoproteins to the circulation to offload unneeded lipids. During aging, the exit route across Bruch's membrane and choriocapillaris endothelium gradually fails, resulting in lipid-rich drusen in many older eyes.…”

“…Many questions raised in this study will be addressed in a large prospective observational trial (ALSTAR2, NCT04112667) that is ongoing. 81…”

Resolution acuity across the visual field for mesopic and scotopic illumination

“…The stairstep model may also provide a mechanistic basis for the clinical use of scotopic acuity as a measure of low-luminance visual dysfunction for monitoring progression of retinal diseases such as age-related macular degeneration (AMD) (Sunness, Rubin, Broman, Applegate, Bressler, & Hawkins, 2008). In this disease, the selective vulnerability of rod photoreceptors is manifest as delayed, rod-mediated dark adaptation and visual dysfunction in general under scotopic conditions (Curcio et al, 2020). Assuming that compromised rods produce weak neural responses, AMD will have a similar effect as reduced retinal illumination; that is, the patient will be forced to depend on more eccentric retina to regain light sensitivity lost to disease.…”

Exploring a Structural Basis for Delayed Rod-Mediated Dark Adaptation in Age-Related Macular Degeneration Via Deep Learning

“…8 Rods are absent from this center. In young adults, rods outnumber cones 4:1 at 0.5-1.5 mm eccentricity 9 and crest in an elliptical ring at 3 to 5 mm, encircling the optic nerve head. In eyes of older adults like those included in our data, cones are stable in number and rods decline 30% in the 0.5 to 1.5 mm ring, exactly including the location of our biomarker.…”

“…8 Expressed in units of the widely used Early Treatment Diabetic Retinopathy Study (ETDRS) grid, the central subfield contains almost exclusively cone photoreceptors, the inner ring (0.5-1.5 mm from the foveal center) has a 4:1 rod:cone ratio, and the outer ring (1.5-3 mm) has a 10:1 ratio. 9 Eyes of aged donors exhibit loss of rods especially in the inner ring. 10 Third, RMDA was proposed by Bird and Fitzke as a dynamic measure of retinoid resupply to rods across the choriocapillaris-Bruch's membrane-retinal pigment epithelium (RPE) interface, 11 where AMD pathology is prominent, and given a strong neurophysiologic underpinning by Lamb and Pugh.…”