Exploring the dynamics of pigment in dry AMD through clinical and histological characterization of the RPE

Abstract

Purpose : Dry AMD (dAMD) is a frequent and disabling condition affecting the elderly. Mechanisms underlying the progression of atrophy remain largely unknown. Several studies have shown that pigment (melanin) mottling accompanies progression of dAMD. We recently observed that dynamic remodelling of pigment spots in margins moves in synchrony with atrophy progression. Our aim is to understand those dynamics at work in dAMD.

Methods : We analyzed time-lapse sequences from various imaging technologies in 6 patients with dAMD: reflectance and autofluorescence infrared scanning laser ophthalmoscopy, en face scleral slab OCT and flood illumination adaptive optics ophthalmoscopy, with or without transscleral illumination. Confocal microscopy of RPE flat-mounts of 7 eyes from 4 donors with dAMD was performed to characterize the mosaic of RPE.

Results : Pigment mottling was present in all patients and showed different aspects by these different modalities. We hypothesize that the appearance of melanin varies by modality due to light- tissue interaction including specular reflectance, scattering, absorption and shadowing (i.e. retroillumination). ). In time-lapse sequences, motility of pigment mottling was seen across all modality. Most pigmented spots moved simultaneously to atrophy progression. Interestingly, two different dynamic patterns were visualized: pigment mottling located at the level of the RPE moved with the atrophy bordure whereas the so-called "hyperreflective foci" located in the neurosensory retina did not show lateral motion. Additionally, intermittent foci of hypertransmission were identified by scleral slab. By confocal microscopy, the mosaic of the diseased RPE was clearly defined and allowed us to map the RPE cell morphology. Transmitted light enabled to document the redistribution of melanin and provided evidence of depigmented RPE cells in every donor eye.

Conclusions : By comparing RPE flat-mounts to in vivo en face imaging, a fine characterization of pigment mottling can be obtained. Pigmentary changes may have a variety of origins, and does not necessarily involve RPE cell death. We hypothesize that RPE associated pigment mottling (that we propose to term subretinal HRF) might be a previous state of HRF before it migrates to the inner retina. Those two entities show different dynamic behavior. This approach may help to decipher cellular mechanisms involved in atrophy progression.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.