To investigate whether the spatial distribution of photoreceptor density governs the rate and directionality of geographic atrophy (GA) progression and to propose a photoreceptor density–based metric for biologically informed assessment of GA progression. A retrospective longitudinal analysis of untreated fellow eyes from a multicenter, randomized, sham-controlled clinical trial (MAHALO). A total of 103 untreated fellow eyes from 143 eyes enrolled in the MAHALO study, all with GA secondary to age-related macular degeneration. Fundus autofluorescence images obtained at baseline and 18 months were analyzed. Geographic atrophy lesion area and boundary progression distance (“front”) were quantified using rigidly registered images. The retina was divided into concentric eccentricity rings centered on the fovea. Theoretical cone and rod density models derived from histologic data were applied to generate photoreceptor density maps. Photoreceptor loss within GA lesions was estimated, and a photoreceptor-adjusted front was calculated by weighting boundary progression by local photoreceptor density. Directional progression was further evaluated using clock-hour–based analysis and a cosine-based directional metric (cosθ). Geographic atrophy area enlargement, front progression distance, photoreceptor-adjusted front, ring-wise photoreceptor loss, and directional variability of lesion expansion. Geographic atrophy enlargement differed significantly across eccentricity rings (P < 0.001), demonstrating relatively slower expansion in regions with higher modeled photoreceptor density and greater expansion in lower-density regions. Total photoreceptor loss showed a moderate positive correlation with GA area enlargement (r = 0.48; P = 0.001). Directional variability of progression was significantly reduced when using the photoreceptor-adjusted front compared with the geometric front (coefficient of variation: 0.769 vs. 1.145; P < 0.01). In extrafoveal lesions, conventional front measurements demonstrated more rapid peripheral versus foveal progression, whereas this directional asymmetry was attenuated after photoreceptor density adjustment. Geographic atrophy progression may be partly explained by the spatial distribution of photoreceptor density, among other contributing biological factors. Apparent directional and regional differences in GA expansion may reflect underlying gradients in photoreceptor density in addition to geometric and other biological influences. Photoreceptor density–based metrics provide a biologically informed framework for interpreting GA progression and may serve as complementary measures for natural history studies and clinical trials. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

To characterize the prevalence of some critical optical coherence tomography (OCT) biomarkers-including cuticular drusen and acquired vitelliform lesions (AVLs)-and to identify their relative risk for progression to late age-related macular degeneration (AMD) over two years in subjects with early or intermediate AMD in the Amish Eye Study. Prospective, observational, longitudinal, population-based cohort study. This study included 276 eyes from 171 subjects with early or intermediate AMD at baseline who completed the two-year follow-up. Baseline OCT scans were evaluated for the presence of: cuticular drusen, AVLs, subretinal drusenoid deposits (SDD), high drusen volume (defined as ≥0.2mm³ within the central 5mm), intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDC), thick/thin double-layer sign, and incomplete retinal pigment epithelium and outer retinal atrophy (iRORA). Subfoveal choroidal thickness (SFCT) was also measured. Incidence of late AMD (geographic atrophy or macular neovascularization) at two years as determined by multimodal imaging (OCT, color fundus photography (CFP), and confocal fundus autofluorescence (FAF)). By 2-years of follow-up, 26 eyes (10.7%) progressed to late AMD. The most prevalent baseline features in this cohort, in descending order, were cuticular drusen (52.3%), IHRF (17.3%), hDC (16.0%), thin DLS (11.9%), SDD (8.2%), iRORA (7.8%), AVL (7.0%), and high drusen volume (2.5%). The mean SFCT was 243.23 ± 75.45 μm. Univariate analysis demonstrated that the presence of thick DLS, iRORA, AVL, SDD, IHRF, hDC, and SFCT were associated with increased risk of progression. In multivariate regression, however, only the presence of iRORA (OR: 29.60; 95% CI: 6.86-127.84; p < 0.001) and AVL (OR: 15.90; 95% CI: 3.24-78.00; p < 0.001) remained significant, while the presence of IHRF showed borderline significance (OR: 4.71; 95% CI: 1.00-22.16; p = 0.050). In this cohort, the presence of iRORA and AVL was independently associated with progression to late AMD over 2 years. Although cuticular drusen were highly prevalent, their presence, as assessed in this study, was not significantly associated with an increased risk of progression to late AMD.

Purpose: To characterise regional and topographic choroidal thickness (CT) profiles using ultra-widefield swept-source optical coherence tomography (UWF SS-OCT) and to compare topographic CT between normal eyes and eyes with pachychoroid disease. Methods: All participants underwent UWF SS-OCT using an approximately 26 mm × 21 mm field of view with fixation centred on the fovea. CT was quantified within concentric rings centred on the optic nerve head and stratified by sector. Linear mixed-effects models were performed separately for each sector, adjusting for age, sex and spherical equivalent (SE). Main outcome measures were regional CT differences between normal and pachychoroid eyes. Results: 60 subjects were included in the study. 37 participants (61.7%) were males and 23 (38.3%) were females. 24 participants (40%) were classified as pachychoroid and 36 (60.0%) as normal. Across all sectors and eccentricities, pachychoroid eyes demonstrated significantly greater CT compared with normal eyes (p<0.001). The largest differences were observed in the temporal sector. In mixed-effects models, pachychoroid status remained a significant independent predictor of increased CT in all sectors (p<0.05) after adjusting for age, SE and sex. SE was independently associated with CT in the inferior, superior and temporal sectors, whereas age and sex were not consistently associated. Conclusions: UWF SS-OCT shows that pachychoroid disease is associated with diffuse, sectorally heterogeneous choroidal thickening extending beyond the fovea. These findings support the concept of pachychoroid disorders as conditions of global choroidal remodelling and highlight the value of regional, distance-based choroidal assessment as a potential imaging biomarker.

Background: Age-related macular degeneration is a major cause of vision loss, and improved visualization of macular neovascularization (MNV) on OCT angiography (OCTA) could enhance clinical assessment. This study aimed to establish a simple and accessible image enhancement method. Methods: We retrospectively analyzed 24 eyes from 22 patients with MNV at the Doheny UCLA Eye Centers. Grayscale-inverted OCTA images were generated using the basic “Invert” function in ImageJ 1.51 23. Each original and inverted image pair was assessed for seven MNV-related features: structure and area within 3 × 3 mm, 6 × 6 mm and 12 × 12 mm scans, and presence of polypoidal lesions. Twenty-one ophthalmologists graded visibility using a standardized five-point scale. Paired comparisons were performed using the Wilcoxon signed-rank test. Results: Grayscale inversion significantly improved the visualization of MNV structure in 6 × 6 mm scans (mean difference: +0.67 ± 1.02; p = 0.008), 12 × 12 mm scans (+0.62 ± 1.07; p = 0.013), and detection of polypoidal lesions (+0.43 ± 0.98; p = 0.030). No significant differences were found for 3 × 3 mm structure (p = 0.793) or area-related features (all p > 0.3). Conclusions: Grayscale inversion may enhance MNV visibility and polypoidal lesion detection on OCTA. As this study relied solely on subjective assessments, future work should incorporate quantitative image analysis.