By optical coherence tomography (OCT) imaging, hyperreflective foci (HRF) indicate progression risk for advanced age-related macular degeneration (AMD) and are in part attributable to ectopic retinal pigment epithelium (RPE). We hypothesized that ectopic RPE are molecularly distinct from in-layer cells and that their cross-retinal course follows Müller glia.
In clinical OCT (61 eyes, 44 AMD patients, 79.4 ± 7.7 years; 29 female; follow-up = 4.7 ± 0.9 years) one HRF type, RPE plume, was reviewed. Twenty eyes of 20 donors characterized by
Trajectories of RPE plume and cellular debris paralleled Müller glia, whether ordered or subsident, near atrophy borders. RPE corresponding to HRF lost immunoreactivity for retinoid markers and gained immunoreactivity for immune markers. Aberrant immunoreactivity appeared in individual in-layer RPE cells and extended to all abnormal phenotypes. Müller glia remained CRALBP-positive. Plume cells approached and contacted retinal capillaries.
Gain- and loss-of-function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. Down-regulated RPE retinoid handling may impair rod vision while Müller glia sustain cone vision. Evidence for RPE transdifferentiation, possibly due to ischemia, supports a proposed process of epithelial-mesenchyme transition. Data can propel new biomarkers and therapeutic strategies for AMD.
Hyperreflective foci (HRF) are OCT progression risk indicators in age-related macular degeneration. Abnormal RPE cells including some that correspond to HRF lose immunoreactivity for retinoid markers and gain immunoreactivity for immune markers, indicating molecular transdifferentiation.