Hyperreflective Foci, Optical Coherence Tomography Progression Indicators in Age-Related Macular Degeneration, Include Transdifferentiated Retinal Pigment Epithelium

Abstract

Purpose 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. Methods In clinical OCT (61 eyes, 44 patients with AMD, 79.4 ± 7.7 years; 29 female; follow-up = 4.7 ± 0.9 years), one HRF type, RPE plume (n = 129 in 4 morphologies), was reviewed. Twenty eyes of 20 donors characterized by ex vivo OCT were analyzed by histology (normal, 4; early/intermediate AMD, 7; geographic atrophy, 6; neovascular AMD, 3). Cryosections were stained with antibodies to retinoid (RPE65, CRALPB) and immune (CD68, CD163) markers. In published RPE cellular phenotypes, red immunoreactivity was assessed semiquantitatively by one observer (none, some cells, all cells). Results Plume morphology evolved over time and many resolved (40%). Trajectories of RPE plume and cellular debris paralleled Müller glia, including 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. Conclusions HRF are indicators not predictors of overall disease activity. Gain and loss of function starts with individual in-layer RPE cells and extends to all abnormal phenotypes. 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.

Optical coherence tomography as retinal imaging biomarker of neuroinflammation/neurodegeneration in systemic disorders in adults and children

“…1 ) as well as in CNS disease such as multiple sclerosis (MS) an increase in the number of HRS has been documented [ 24 , 29 – 31 ]. Histologic evidence from human donor eyes with AMD and acquired vitelliform lesions demonstrated that HRS visualized on SD-OCT may originate from both anteriorly migrated retinal pigment epithelium cells and lipid-filled cells (thought to correspond to activated microglia) [ 32 – 34 ]. In patients with diabetic macular oedema, a positive correlation between the number of HRS and aqueous humour concentration of soluble CD14 (a cytokine associated with immune response, expressed in microglia, monocytes and macrophages) was reported [ 35 ].…”

Long Term Time-Lapse Imaging of Geographic Atrophy: A Pilot Study

“…This contrasted with our observation of a HRF which remained static during follow-up. In the literature, migration of a HRF toward the inner retina was previously reported (23) as well as stability over several years (19) but not centrifugal migration. Hence, taken collectively, these data suggests that subretinal hyperreflective spots and HRFs may behave differentially.…”

“…Along margins of atrophy, duplication of the RPE layer has also been described ( 16 ), which may account for short wavelength hyperautofluorescence seen clinically ( 17 ). Whether this pigment mottling corresponds to detached RPE cells ( 14 , 15 ) transdifferentiated RPE cells ( 18 , 19 ) or macrophages that have phagocytozed RPE cells ( 20 , 21 ) is still a matter of debate.…”

Ilex paraguariensis Extracts Prevent Oxidative Damage in a Mouse Model of Age‐Related Macular Degeneration

“…Intraretinal migration of injured RPE cells is well known in AMD, where they appear as hyper-reflective foci in optical coherence tomography (OCT) studies. [31,32] Under these conditions, RPE cells can transdifferentiate into mesenchymal phenotypes, [32,33] including macrophage-like cells. [34] RPE transdifferentiated cells are key players in the development of human and experimental proliferative vitreoretinopathy membranes.…”