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

Christine A Curcio, Gerald McGwin Jr, Srinivas R Sadda, Zhihong Hu, Mark E Clark, Kenneth R Sloan, Thomas Swain, Jason N Crosson, Cynthia Owsley, Christine A Curcio, Gerald McGwin Jr, Srinivas R Sadda, Zhihong Hu, Mark E Clark, Kenneth R Sloan, Thomas Swain, Jason N Crosson, Cynthia Owsley

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 rod- and 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.

Discussion: A major barrier to developing treatments and prevention strategies for early AMD is a limited understanding of the temporal interrelationships among structural and functional characteristics while transitioning from aging to early AMD. ALSTAR2 will enable the development of functionally valid, structural biomarkers for early AMD, suitable for use in forthcoming clinical trials as endpoint/outcome measures. The comprehensive dataset will also allow hypothesis-testing for mechanisms that underlie the transition from aging to AMD, one of which is a newly developed Center-Surround model of cone resilience and rod vulnerability.

Trial registration: ClinicalTrials.gov Identifier NCT04112667, October 7, 2019.

Keywords: Age-related macular degeneration; Aging; Cones; Dark adaptation; Light sensitivity; Macula; Quantitative autofluorescence; Retina; Rods; Spectral domain optical coherence tomography.

Conflict of interest statement

CO declares that she is an inventor on the dark adaptometer used in this study. The other authors have identified no competing interests.

Figures

Fig. 1
Fig. 1
Aging of the human photoreceptor mosaic and the outer retinal neurovascular unit. A-C Rod vulnerability and cone resilience in healthy aging [34, 35]. Topography of rods and cones determined from computer-assisted cell counts in flat-mounts of human retina [3]. Maps are shown as a fundus of a left eye. Black oval, optic nerve; black ring, outer limit of Early Treatment of Diabetic Retinopathy Study grading grid. A1, A2. Rods and cones in 27–37-year-old donors. B1, B2. Rods and cones in 82–90-year-old donors. C1, C2. Log mean difference in cell density between younger and older adults. C1. Difference in rod density between younger and older adults is greatest at 0.5 mm to 3 mm from fovea (parafovea and perifovea). Purple signifies that aged eyes had 31% fewer cells than young eyes. C2. Log mean difference in cone density between younger and older adults is small and inconsistent, indicated by the yellow-green map. D Outer retinal neurovascular unit and retinoid re-supply to cone and rod photoreceptors. Shown are rods (R), cones (C), Müller glia (M), RPE, and vascular endothelium of the choriocapillaris (ChC) and capillary plexuses of the retinal circulation. We hypothesize that to the photoreceptors, AMD is a disease of the retinoid re-supply route. Vitamin A delivered from plasma is rate-limiting for recovery of sensitivity by rods. Rods need choriocapillaris, Bruch’s membrane, and RPE, whereas the cones have these, plus an additional second delivery route, via Müller glia and the retinal circulation. RMDA assesses how pathology in the choriocapillaris, Bruch’s membrane, and RPE complex impacts rods. It is expected that cone-mediated vision will be resilient. Retinal layers: ILM, inner limiting membrane; NFL, nerve fiber layer; GCL, ganglion cell layer; IPL, inner plexiform layer; INL, inner nuclear layer; OPL, outer plexiform layer; ONL, outer nuclear layer; ELM, external limiting membrane; RPE, retinal pigment epithelium; BrM, Bruch’s membrane; ChC, choriocapillaris
Fig. 2
Fig. 2
Visual neuroscience of human retinal aging and age-related macular degeneration.Schematic shows log cone and rod density [30], choriocapillaris and retinal vessels, and helpful/ harmful factors for photoreceptor function and survival in the human macula. Soft drusen and basal linear deposits (gray) accumulate between choriocapillaris and retinal cells. They are thickest and confer highest risk for progression in central macula. Xanthophyll carotenoid pigment (orange) is highest in the foveal center (shown) with lateral extensions into the plexiform layers (not shown), plausibly attributable to the distribution of protective Müller glia [34]. The retinal capillaries and choriocapillaris are shown
Fig. 3
Fig. 3
Conceptual framework of visual impairment across retinal layers and time. Outer retinal neurovascular is at the bottom of the framework. Inner retina is at the top
Fig. 4
Fig. 4
Test locations for perimetry. The same 21 locations will be used for 3 test paradigms, the Humphrey Field Analyzer (for photopic sensitivity) and two-color dark-adapted microperimetry (cyan 505 nm, red 627 nm) using the MAIA-S. Perimetry will be tested in one eye only (the eye undergoing testing for RMDA tested at 5° and 12°). Targets are 0.43° in diameter (Goldmann III). Locations were chosen to sample closely near the fovea, where cell densities change rapidly with eccentricity and an effect of Bruch’s membrane lipidization is expected. In addition, targets in perifoveal and paramacular locations are included where rod density is high and subretinal drusenoid deposit is expected
Fig. 5
Fig. 5
Center-surround model of cone resilience and rod vulnerability in aging and AMD. In the top row is an en face view of help via xanthophyll carotenoid pigment (orange) and harm via soft drusen/ basal linear deposit, as shown in Fig. 1. In the bottom row help and harm are plotted on one vertical axis, positive and negative directions, respectively. a. The distribution of xanthophyll carotenoids, as shown in Fig. 1, is a focused center of help in the central macula. b The distribution of soft druse material is shown as a broad circular area of harm (see Fig. 1). c Together, help and harm make a center of foveal cone resilience on top of a surround of para- and perifoveal rod vulnerability. The resemblance of this map to the maps of photoreceptor loss in human retinal aging in Fig. 1 are striking. See text for further details. Figure prepared with assistance of Deepayan Kar MS.

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