Choriocapillaris Impairment Is Associated With Delayed Rod-Mediated Dark Adaptation in Age-Related Macular Degeneration

Abstract

Purpose: Progress toward treatment and prevention of age-related macular degeneration (AMD) requires imaging end points that relate to vision. We investigated choriocapillaris flow signal deficits (FD%) and visual function in eyes of individuals aged ≥60 years, with and without AMD.

Methods: One eye of each participant in the baseline visit of the Alabama Study on Early Age-Related Macular Degeneration 2 (ALSTAR2; NCT04112667) was studied. AMD presence and severity was determined using the Age-Related Eye Disease Study (AREDS) grading system. FD% was quantified using macular spectral domain optical coherence tomography angiography (OCTA) scans. Vision tests included rod-mediated dark adaptation (RMDA), best-corrected visual acuity, and contrast sensitivity (photopic and mesopic), and microperimetric light sensitivity (scotopic, mesopic, and photopic). Presence of subretinal drusenoid deposits (SDD) was determined using multimodal imaging.

Results: In 410 study eyes of 410 participants (mean [SD] age = 71.7 years [5.9]), FD% was higher in early AMD (mean [SD] = 54.0% [5.5], N = 122) and intermediate AMD (59.8% [7.4], N = 92), compared to normal (52.1% [5.3], N = 196) eyes. Among visual functions evaluated, RMDA showed the strongest association with FD% (r = 0.35, P < 0.0001), followed by contrast sensitivity (r = -0.22, P < 0.0001). Eyes with SDD had worse FD% (58.3% [7.4], N = 87), compared to eyes without SDD (53.4% [6.0], N = 323, P = < 0.0001).

Conclusions: Choriocapillaris FD% were associated with AMD severity and with impaired vision, especially RMDA. Reduced metabolic transport and exchange across the choriocapillaris-Bruch's membrane retinal pigment epithelium (RPE) complex, a causal factor for high-risk soft drusen formation, also may impair photoreceptor sustenance from the circulation. This includes retinoid resupply, essential to dynamic rod function.

Figure 1.

Boxplot comparison of choriocapillaris flow signal deficits by AMD severity. Box plots indicate the median and interquartile ranges. Whiskers indicate the 5th and 95th percentiles. Notches indicate the 95% confidence interval of the median. AMD severity groups are assigned based on color fundus photography grading (AREDS 9-step).

Figure 2.

Representative case examples of choriocapillaris flow signal deficits in normal versus intermediate AMD. (A1) Confocal color fundus photographs showing the unremarkable macula of a 69-year-old, White woman graded as normal (AREDS1). Dotted circle shows the location of the rod-mediated dark adaptation test spot at 5 degrees superior. (A2) En face structural optical coherence tomography (OCT) slab segmented from the external limiting membrane (ELM) and interdigitation zone (IZ) boundaries. (A3) En face structural choriocapillaris slab located 10 to 30 µm below Bruch's membrane (identical slab boundaries as that of A4). (A4) En face OCT angiography (OCTA) of the choriocapillaris flow slab located 10 to 30 µm below Bruch's membrane (red lines in A5). Dark pixels denote flow signal deficits. (A5) Unremarkable foveal OCT B-scan with flow signal overlay. (B1) Confocal color fundus photographs show drusen in the left eye of a 73-year-old, White man graded as intermediate AMD (AREDS7). (B2) En face structural OCT slab show numerous drusen identified as small hyper-reflective regions each surrounded by a hyporeflective annulus. (B3) En face structural choriocapillaris slab located 10 to 30 µm below Bruch's membrane (identical slab boundaries as that of B4). (B4) En face OCTA shows generalized loss of choriocapillaris flow signal within the 3 mm submacular region, with deficits extending beyond the areas of drusen (yellow overlay in B5) labeled using OCTA B-scans (B6). Scale bars = panels A1-A3, and B1-B4 = 1 mm; panels A4, B5 = 200 µm.

Figure 3.

Association of choriocapillaris flow signal deficits with visual acuity, contrast sensitivity, and rod intercept time stratified by AMD severity. Scatterplot shows AMD severity groups in different colors. Spearman correlations (r) between choriocapillaris flow signal deficits with rod intercept time, contrast sensitivity, and best-corrected visual acuity are 0.35 (P < 0.0001), -0.22 (P < 0.0001), and 0.11 (P = 0.0277), respectively. Dotted lines represent the regression line, and shaded gray areas represent the 95% confidence intervals of the fit of the overall sample (N = 410). Ellipses show the 95% confidence level for the t-distribution of each AMD severity group.

Figure 4.

Vascular basis of rod- versus cone-mediated visual dysfunction in age-related macular degeneration. We hypothesize that choriocapillaris dysfunction is a causal factor for visual deficits in AMD, due to impaired retinoid and metabolic exchange to the photoreceptors. (1) In normal eyes, the choriocapillaris meshwork supplies retinoids to both rod (R) and cone (C) photoreceptors via the retinal pigment epithelium-Bruch's membrane interface. (2) Cones additionally receive retinoids from an alternate supply route from Müller glia (M) and the retinal circulation (cone-specific second visual cycle). By contrast, rods are solely dependent on the choroid for retinoid resupply. In AMD, choriocapillaris degeneration (3) and/or accumulation of drusen and other age-related extracellular deposits (4) lead to impaired retinoid exchange to photoreceptors, compromising the efficiency of classic visual cycle. (5) Thus, rod-mediated visual deficits in the parafovea occur earlier in disease because they are solely dependent on the choroidal circulation for retinoid resupply. Cone-mediated visual function in the fovea is generally preserved until later stages of disease due to the additional retinoid resupply route from Müller glia (M).