Structure-function associations in eyes with Early Atrophic Age-related Macular Degeneration

To characterize baseline structure-function relationships in eyes with early atrophic age-related macular degeneration (AMD) and to identify functional outcomes that best reflect structural disease burden.

Cross-sectional study PARTICIPANTS: A total of 87 eyes from 87 participants enrolled in the ongoing prospective observational study of early atrophic AMD (ClinicalTrials.gov NCT05959005), with incomplete or complete retinal pigment epithelium and outer retinal atrophy and total atrophic lesion size ≤ 1.27 mm² METHODS: Structural metrics derived from multimodal imaging included fundus autofluorescence (FAF)-defined geographic atrophy (GA) lesion size (total and targeted), targeted hypertransmission size, and distance to the fovea (DTF) from the lesion border. Structure-function relationships were evaluated using correlations and univariable linear regressions with multiple-comparison adjustment.

Best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), Moorfields Acuity Test (MAT), reading acuity and reading speed, and mesopic and dark-adapted (DA) cyan fundus-controlled perimetry (FCP) using fixed and lesion-targeted macular patterns.

Lesion size-based structural metrics showed the strongest associations with FCP outcomes. In eyes with FAF-defined GA (n = 38), each doubling of targeted GA lesion size was associated with a 3.55 dB decrease in mean targeted mesopic sensitivity and 3.65 dB in mean targeted DA sensitivity (all P < 0.001). Similarly, doubling of targeted hypertransmission size (n = 81) was associated with decreases of 1.65 dB and 1.97 dB in mean targeted mesopic and DA sensitivities, respectively (both P < 0.001; correlations up to ρ = -0.66). In contrast, central visual and reading outcomes were primarily associated with lesion topography. Greater DTF was associated with better BCVA, LLVA, and MAT (approximately 4 to 5 letters per mm) and improved reading acuity (-0.11 logRAD per mm; all adjusted P < 0.05), whereas lesion size-based metrics showed no consistent significant association with these outcomes.

In early atrophic AMD, lesion size and hypertransmission extent are closely linked to localized FCP sensitivity loss, whereas central visual acuity and reading outcomes are determined by lesion proximity to the fovea. This domain-specific separation supports targeted FCP as a sensitive endpoint for detecting structure-related functional change in early atrophic AMD.