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Age-related macular degeneration (AMD) causes worldwide vision loss, at a high social and economic cost.1–3 A disease of the photoreceptor support system,4 AMD's pathology is prominent in the retinal pigment epithelium (RPE) and underlying Bruch's membrane (BrM). The RPE is a monolayer of cuboidal epithelial cells of neuroectodermal origin, dually tasked with maintaining retina apically and choroid basally.5–7 In AMD, internal to the RPE basement membrane is basal laminar deposit (BLamD),8 a thickened layer of extracellular matrix proteins secreted by RPE and associated with disease progression.9 External to the RPE basement membrane are extracellular drusen and basal linear deposits10 that in vivo separate outer retinal cells from vasculature and promote neovascularization; these also are synthesized by RPE. Pigmentary and autofluorescence variations represent clinically detectable RPE decompensation and disease progression.11,12 The RPE is thus a key AMD participant, victim, and reporter of clinically inconspicuous events in BrM. High-resolution clinical imaging reveals the cellular basis of disease progression as never before.13 Clinically deployed and experimental technologies show the RPE en face14–19 and in cross section with other chorioretinal layers.20,21 A research priority is identifying novel anatomic biomarkers derived from spectral-domain optical coherence tomography (SDOCT),22 including components of the hyperreflective band attributed to RPE and BrM. The RPE is revealed in vivo by its abundant melanosomes, melanolipofuscin, and lipofuscin granules, all of lysosomal lineage23–25 and all potential subcellular contributors to SDOCT reflectivity.26,27 Yet RPE imaging relies on surprisingly few data about the number, size, shape, and disposition of individual RPE cells and their organelles of imaging significance. Previous morphological studies of RPE in AMD and Stargardt disease, an inherited disorder also featuring abundant RPE lipofuscin, collectively used low-resolution light microscopy, electron microscopy of small series, minimally characterized or insufficiently advanced pathology, and imprecisely specified retinal localizations.28–38 This knowledge gap impedes the full exploitation of RPE-centered imaging technologies. We hypothesize that the RPE exhibits stereotypic stress responses and death pathways, which if defined, quantified, and followed, provide windows into molecular pathology and points of therapeutic entry. Like others we used grading systems to discretize RPE morphology, compare across eyes and retinal regions, and facilitate quantification.31–33,39–43 Using this approach, we proposed two main pathways: apical (sloughing into subretinal space and intraretinal migration) versus basal (shedding of granules into subjacent BLamD).32 In this report, we describe, illustrate, and account for morphologies of RPE cells in geographic atrophy (GA) and choroidal neovascularization (CNV), the two AMD end stages, using melanosomes, lipofuscin, and BLamD as anatomical markers. A companion report44 focuses on RPE-derived cells, that is, out-of-RPE layer cells containing melanosomes and lacking contact with BLamD. We estimate the frequency of RPE morphologies, quantify RPE and BLamD thicknesses, determine if RPE morphologies are visible by SDOCT, and propose testable hypotheses about RPE fate in AMD, where fates include death, conversion to a cell type not meeting criteria for RPE, and emigration. Collectively, our data support multiple modes of RPE stress response; provide nomenclature, visualization targets, and metrics for clinical imaging and experimental systems; and motivate future molecular phenotyping studies. |