Care of the suddenly bereaved.

Abstract

<h3>Abstract</h3> Age-related macular degeneration (AMD) is a common sight-threatening disease of older adults and treatment options are needed. Abnormalities of retinal pigment epithelium (RPE), supporting cells to photoreceptors and capillaries, are a hallmark. Clinical optical coherence tomography (OCT) imaging reveals hyperreflective foci (HRF) that confer risk for end-stage disease and are attributed to ectopic out-of-layer RPE. Using longitudinal OCT imaging of AMD patients, we demonstrate that the trajectory of one HRF form, RPE plume, parallels the retinal Henle fiber layer. Histology shows fully pigmented cells approaching and contacting retinal capillaries with RPE organelles dispersing along Müller glia columns. We used immunohistochemistry and a system of morphologic phenotypes to assess RPE functional repertoire in AMD. RPE corresponding to HRF loses immunoreactivity for retinoid processing proteins RPE65 and CRALBP, and gains immunoreactivity for immune cell markers CD68 and CD163. Müller glia retain CRALBP immunoreactivity. Gain- and loss-of-function for RPE starts with individual in-layer cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may contribute to slowed rod vision while Müller glia sustain cone vision. Ectopic RPE corresponding to HRF are emblematic of widespread transdifferentiation, motivating treatments targeting AMD pathology earlier than the initiation of atrophy. Data can propel new biomarkers and therapeutic strategies for AMD. <h3>One Sentence Summary</h3> In age-related macular degeneration retinal pigment epithelial cells transdifferentiate and migrate into the retina where they are clinically visible progression risk indicators.