Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Geographic Atrophy in Age-Related Macular Degeneration

Abstract

Purpose To inform the interpretation of clinical optical coherence tomography and fundus autofluorescence?imaging in geographic atrophy (GA) of age-related macular degeneration (AMD) by determining the distribution of retinal pigment epithelium (RPE) phenotypes in the transition from health to atrophy (GA) in donor eyes. Method In RPE-Bruch’s membrane flat mounts of 2 GA eyes the terminations of organized RPE cytoskeleton and autofluorescent material were compared. In high-resolution histological sections of 13 GA eyes, RPE phenotypes were assessed at ±500 and ±100 µm from the descent of the external limiting membrane (ELM) towards Bruch’s membrane. The ELM descent was defined as curved, reflected, or oblique in shape. Thicknesses of RPE, basal laminar deposit (BLamD), and RPE+BLamD were measured. Results A border of atrophy that can be precisely delimited is the ELM descent, as opposed to the termination of the RPE layer itself, because of dissociated RPE in the atrophic area. Approaching the ELM descent, the percentage of abnormal RPE morphologies increases, the percentage of age-normal cells decreases, overall RPE thickens, and BLamD does not thin. The combination of RPE plus BLamD is 19.7% thicker at −100 µm from the ELM descent than at −500 µm (23.1 ± 10.7 vs 19.3 ± 8.2 µm; p=0.05). Conclusion The distribution of RPE phenotypes at the GA transition support the idea that these morphologies represent defined stages of a degeneration sequence. The idea RPE dysmorphia including rounding and stacking helps explain variable autofluorescence patterns in GA 14 is reinforced. The ELM descent and RPE+BLamD thickness profile may have utility as SDOCT metrics in clinical trials.

Visualizing Retinal Pigment Epithelium Phenotypes in the Transition to Atrophy in Neovascular Age-Related Macular Degeneration

“…Using high-resolution histology, we recently developed a system of RPE morphologic phenotypes and determined that many are visible by SDOCT 28, 29 . In eyes with GA 30 , we found that the RPE layer thickens near the border of atrophy, due to a progressive dysmorphia that also helps explain variable FAF at the margin of atrophy 31 . Here we use these same methods to investigate RPE morphology and thickness in the transition to atrophy in eyes with nvAMD.…”

“…The border of atrophy was defined as the descent of the external limiting membrane (ELM) towards Bruch’s membrane. 30 As described 30, 39 , the descent of the ELM is comprised of reactive Müller cell processes extending outward to approach Bruch’s membrane in areas of photoreceptor loss. An ELM descent was analyzed if it was at least 500 µm from the termination of subretinal fibrovascular scar.…”

“…RPE flat mounts of nvAMD eyes were studied to assess the relationship of histological autofluorescence (AF) and cytoskeleton at the termination of the intact RPE layer, as done for GA. 30, 32 In other nvAMD eyes, sub-micrometer histological cross-sections through the fovea and superior perifovea were studied to assess phenotypes of RPE morphology, as done for GA. 28–30 Tissues came from a bio-repository of short post-mortem (<6 hr) eyes assembled for AMD research from donors to the Alabama Eye Bank 1995–2009. More information on all eyes is available (Supplementary material 28 ).…”

“…As recently done for eyes with GA 30 , we annotated RPE morphology and measured RPE and BLamD thickness at atrophy borders in two sections, one through the foveal center and another at 2 mm superior to the foveal center. The border of atrophy was defined as the descent of the external limiting membrane (ELM) towards Bruch’s membrane.…”

Retinal Pigment Epithelium Degeneration Associated With Subretinal Drusenoid Deposits in Age-Related Macular Degeneration

“…Eyes with geographic atrophy exhibit features suggestive of motile non-epithelioid RPE, as revealed by AO-assisted IR imaging. 50 Recent imaging-histology correlations have demonstrated cells with a full complement of reflective RPE organelles within the subretinal space and retina, 46,51,52 consistent with anterior migration. Thus the range of RPE cellular activities observable in vivo has expanded in step with new visualization technologies.…”