Adaptive optics imaging of the human retina.

Purpose To summarize and contextualize recent histology and clinical imaging publications on retinal pigment epithelium (RPE) fate in advanced age-related macular degeneration (AMD); to support RPE activation and migration as important precursors to atrophy, manifest as intraretinal hyperreflective foci in spectral-domain optical coherence tomography (SDOCT) Methods The Project MACULA online resource for AMD histopathology was surveyed systematically to form a catalog of 15 phenotypes of RPE and RPE-derived cells and layer thicknesses in advanced disease Phenotypes were also sought in correlations with clinical longitudinal eye-tracked SDOCT and with ex vivo imaging-histopathology correlations in geographic atrophy (GA) and pigment epithelium detachments (PED) Results The morphology catalog suggested two main pathways of RPE fate: basolateral shedding of intracellular organelles (apparent apoptosis in situ) and activation with anterior migration Acquired vitelliform lesions may represent a third pathway Migrated cells are packed with RPE organelles and confirmed as hyperreflective on SDOCT RPE layer thickening due to cellular dysmorphia and thick basal laminar deposit is observed near the border of GA Drusenoid PED show a life cycle of slow growth and rapid collapse preceded by RPE layer disruption and anterior migration Conclusions RPE activation and migration comprise an important precursor to atrophy that can be observed at the cellular level in vivo via validated SDOCT Collapse of large drusen and drusenoid PED appears to occur when RPE death and migration prevent continued production of druse components Data implicate excessive diffusion distance from choriocapillaris in RPE death as well as support a potential benefit in targeting drusen in GA

Activated Retinal Pigment Epithelium, an Optical Coherence Tomography Biomarker for Progression in Age-Related Macular Degeneration

https://escholarship.org/content/qt43k6z8gp/qt43k6z8gp.pdf?t=onkgvd

Vision science and adaptive optics, the state of the field.

Purpose To evaluate how metrics used to describe the cone mosaic change in response to simulated photoreceptor undersampling (i.e., cell loss or misidentification). Methods Using an adaptive optics ophthalmoscope, we acquired images of the cone mosaic from the center of fixation to 10° along the temporal, superior, inferior, and nasal meridians in 20 healthy subjects. Regions of interest (n = 1780) were extracted at regular intervals along each meridian. Cone mosaic geometry was assessed using a variety of metrics - density, density recovery profile distance (DRPD), nearest neighbor distance (NND), intercell distance (ICD), farthest neighbor distance (FND), percentage of six-sided Voronoi cells, nearest neighbor regularity (NNR), number of neighbors regularity (NoNR), and Voronoi cell area regularity (VCAR). The "performance" of each metric was evaluated by determining the level of simulated loss necessary to obtain 80% statistical power. Results Of the metrics assessed, NND and DRPD were the least sensitive to undersampling, classifying mosaics that lost 50% of their coordinates as indistinguishable from normal. The NoNR was the most sensitive, detecting a significant deviation from normal with only a 10% cell loss. Conclusions The robustness of cone spacing metrics makes them unsuitable for reliably detecting small deviations from normal or for tracking small changes in the mosaic over time. In contrast, regularity metrics are more sensitive to diffuse loss and, therefore, better suited for detecting such changes, provided the fraction of misidentified cells is minimal. Combining metrics with a variety of sensitivities may provide a more complete picture of the integrity of the photoreceptor mosaic.

/pdf/evaluating-descriptive-metrics-of-the-human-cone-mosaic-2135fvbady.pdf

Evaluating Descriptive Metrics of the Human Cone Mosaic.

AMD pathobiology was irreversibly changed by the recent discovery of extracellular cholesterol-containing deposits in the subretinal space, between the photoreceptors and retinal pigment epithelium (RPE), called subretinal drusenoid deposits (SDDs). SDDs strikingly mirror the topography of rod photoreceptors in human macula, raising the question of whether an equivalent process results in a deposition related to foveal cones. Herein we propose that AMD's pathognomonic lesion-soft drusen and basal linear deposit (BLinD, same material, diffusely distributed)-is the leading candidate. Epidemiologic, clinical, and histologic data suggest that these deposits are most abundant in the central macula, under the fovea. Strong evidence presented in a companion article supports the idea that the dominant ultrastructural component is large apolipoprotein B,E-containing lipoproteins, constitutively secreted by RPE. Lipoprotein fatty acids are dominated by linoleate (implicating diet) rather than docosahexaenoate (implicating photoreceptors); we seek within the retina cellular relationships and dietary drivers to explain soft druse topography. The delivery of xanthophyll pigments to highly evolved and numerous Muller cells in the human fovea, through RPE, is one strong candidate, because Muller cells are the main reservoir of these pigments, which replenish from diet. We propose that the evolution of neuroglial relations and xanthophyll delivery that underlie exquisite human foveal vision came with a price, that is, soft drusen and sequela, long after our reproductive years.

Antecedents of Soft Drusen, the Specific Deposits of Age-Related Macular Degeneration, in the Biology of Human Macula.

Variability in Human Cone Topography Assessed by Adaptive Optics Scanning Laser Ophthalmoscopy.

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Variability in Human Cone Topography Assessed by Adaptive Optics Scanning Laser Ophthalmoscopy.