Choriocapillaris Impairment, Visual Function, and Distance to Fovea in Aging and Age-Related Macular Degeneration: ALSTAR2 Baseline

Abstract

Purpose: In aging and early-intermediate age-related macular degeneration (AMD), rod-mediated dark adaptation (RMDA) slows more at 5° superior than at 12°. Using optical coherence tomography angiography (OCTA), we asked whether choriocapillaris flow deficits are related to distance from the fovea.

Methods: Persons ≥60 years stratified for AMD via the Age-Related Eye Disease Study's nine-step system underwent RMDA testing. Two adjacent 4.4° × 4.4° choriocapillaris OCTA slabs were centered on the fovea and 12° superior. Flow signal deficits (FD%) in concentric arcs (outer radii in mm, 0.5, 1.5, 2.2, 4.0, and 5.0 superior) were correlated with rod intercept time (RIT) and best-corrected visual acuity (BCVA).

Results: In 366 eyes (170 normal, 111 early AMD, 85 intermediate AMD), FD% was significantly worse with greater AMD severity in all regions (overall P < 0.05) and poorest under the fovea (P < 0.0001). In pairwise comparisons, FD% worsened with greater AMD severity (P < 0.05) at distances <2.2 mm. At greater distances, eyes with intermediate, but not early AMD differed from normal eyes. Foveal FD% was more strongly associated with longer RIT at 5° (r = 0.52) than RIT at 12° (r = 0.39) and BCVA (r = 0.21; all P < 0.0001). Choroidal thickness was weakly associated with longer RIT at 5° and 12° (r = 0.10-0.20, P < 0.05) and not associated with AMD severity.

Conclusions: Reduced transport across the choriocapillaris-Bruch's membrane-retinal pigment epithelium complex, which contributes to drusen formation under the macula lutea (and fovea), may also reduce retinoid resupply to rods encircling the high-risk area. FD% has potential as a functionally validated imaging biomarker for AMD emergence.

Figure 1.

Retinal landmarks and regions of interest used for choriocapillaris flow signal deficit quantification. Two en face choriocapillaris OCTA scans centered on 0° and 12° eccentricities overlaid on confocal fundus photograph. Arrowhead denotes the superior edge of the 0° centered OCTA scan (see Methods). Gray circles indicate the 5° and 12° dark adaptation test locations used in the study.

Figure 2.

Regional choriocapillaris flow signal deficits by AMD severity. Dot-and-whisker plot demonstrates choriocapillaris FD% (mean and standard deviation) in eccentricity regions 1–5 of Figure 1. Region 1 includes the fovea. AMD severity groups are assigned based on AREDS 9-step grading system. Asterisks indicate the level of significance. n.s.; non-significant (P > 0.05).

Figure 3.

Heatmaps of choriocapillaris demonstrate regional flow signal deficits (FD%) by AMD severity. (A–C) Heatmaps demonstrate greater choriocapillaris FD% in foveal and perifoveal regions, and these worsen with disease severity. Gray circles indicate the 5° and 12° RMDA test locations. (B) In early AMD, worse FD% is roughly confined to the parafoveal regions, near the 5° dark adaptation test target location. (C) In intermediate AMD, there is significant worsening of FD% extending to the perifoveal regions. White reference outlines show the regions of interest defined in Figure 1. AMD severity groups are assigned based on AREDS nine-step grading system.

Figure 4.

Structure-function correlations between regional choriocapillaris flow signal deficits (FD%) and rod- versus cone-mediated visual function. Age-adjusted Spearman correlations between regional choriocapillaris FD% with RIT at 5° and 12°, and BCVA in 366 eyes of 366 participants. In all regions, delayed RMDA at 5° was more strongly associated with worse FD%, than RMDA at 12° and BCVA. Correlations decreased with increasing eccentricity across all visual function tests. Asterisks indicate the level of significance. n.s., nonsignificant (P > 0.05). NSTI graphic shows retinal directions (Nasal, Superior, Temporal, Inferior). Gray spots indicate test target locations for RMDA at 5° and 12° (lower and upper, respectively).

Figure 5.

Why rod vision is influenced by FD% near the fovea. Cone resilience and rod vulnerability in aging and AMD can be modeled as difference of 2-dimensional Gaussian surfaces, a mathematical relationship familiar to vision science.^, In the top row is an en face view of help, epitomized by macular xanthophyll pigment (orange) and harm via soft drusen/basal linear deposit and sequelae. 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 Figure 2, is a focused center of help in the macula lutea. (B) The distribution of soft druse material and sequela is shown as a broad circular area of harm. (C) Together, help and harm make a narrow center of foveal cone resilience on top of a broad surround of parafoveal and perifoveal rod vulnerability. Reprinted from under Creative Commons No Derivatives License.