Intraretinal Correlates of Reticular Pseudodrusen Revealed by Autofluorescence and En Face OCT

Paavo, Maarjaliis; Lee, Winston; Merriam, John C.; Bearelly, Srilaxmi; Tsang, Stephen H.; Chang, Stanley; Sparrow, Janet R.

doi:10.1167/iovs.17-22338

Cited by 27 publications

(22 citation statements)

References 51 publications

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“…Strengths of this study include the robust sample of 29,323 human RPE cells in 25 AMD eyes preserved ≤4.2 hours after death, unbiased sampling for improved RPE demographic description, virtual 0.4-μm-step z-stack scrolling to visualize L/ML within individual cells, discrete phenotype categories, and good intraobserver repeatability. Limitations include lack of clinical information for eye donors, loss of some RPE apical processes and subretinal drusenoid deposits93 during tissue preparation, lack of cell height data, inability to account for out-of-layer factors and other in vivo AF-influencers, not separately analyzing macular subregions, lack of molecular identification techniques, and lack of specific visualizations for non-AF nuclei and melanosomes. Nevertheless, this is the first quantitative study of RPE morphology and subcellular AF patterns in donor eyes with AMD.…”

Section: Discussionmentioning

confidence: 99%

Quantifying Retinal Pigment Epithelium Dysmorphia and Loss of Histologic Autofluorescence in Age-Related Macular Degeneration

Gambril

Sloan

Swain

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Lipofuscin and melanolipofuscin organelles in retinal pigment epithelium (RPE) cells are signal sources for clinical fundus autofluorescence (AF). To elucidate the subcellular basis of AF imaging, we identified, characterized, and quantified the frequency of RPE morphology and AF phenotypes in donor eyes with age-related macular degeneration (AMD). METHODS. In 25 RPE-Bruch's membrane flat mounts from 25 eyes, we analyzed 0.4-lm z-stack epifluorescence images of RPE stained with phalloidin for actin cytoskeleton. Using a custom ImageJ plugin, we classified cells selected in a systematic unbiased fashion in six phenotypes representing increasing degrees of pathology. For each cell, area, AF intensity, and number of Voronoi neighbors were compared with phenotype 1 (uniform AF, polygonal morphology) via generalized estimating equations. We also analyzed each cell's neighborhood. RESULTS. In 29,323 cells, compared with phenotype 1, all other phenotypes, in order of increasing pathology, had significantly larger area, reduced AF, and more variable number of neighbors. Neighborhood area and AF showed similar, but subtler, trends. Cells with highly autofluorescent granule aggregates are no more autofluorescent than others and are in fact lower overall in AF. Pre-aggregates were found in phenotype 1. Phenotype 2, which exhibited degranulation despite normal cytoskeleton, was the most numerous nonhealthy phenotype (16.23%). CONCLUSIONS. Despite aggregation of granules that created hyperAF aggregates within cells, overall AF on a per cell basis decreased with increasing severity of dysmorphia (abnormal shape). Data motivate further development of subcellular resolution in clinical fundus AF imaging and inform an ongoing reexamination of the role of lipofuscin in AMD.

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Section: Discussionmentioning

confidence: 99%

Quantifying Retinal Pigment Epithelium Dysmorphia and Loss of Histologic Autofluorescence in Age-Related Macular Degeneration

Gambril

Sloan

Swain

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…Reticular pseudodrusen also present as hyperreflective lesions in photoreceptor-attributable OCT bands (Paavo et al 2017). Indeed the appearance of RPD in OCT images is quite similar to flecks and in both cases the hyperreflective foci can extend through the EZ and ELM and into a thinning ONL.…”

Section: Discussionmentioning

confidence: 99%

Photoreceptor cells as a source of fundus autofluorescence in recessive Stargardt disease

Paavo

Lee

Allikmets

et al. 2018

J of Neuroscience Research

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Bisretinoid fluorophores form in photoreceptor outer segments from nonenzymatic reactions of vitamin A aldehyde. The short-wavelength autofluorescence (SW-AF) of fundus flecks in recessive Stargardt disease (STGD1) suggests a connection to these fluorophores. Through multimodal imaging, we sought to elucidate this link. Flecks observed in SW-AF images often colocalized with foci exhibiting reduced or absent near-infrared autofluorescence signal, the source of which is melanin in retinal pigment epithelial (RPE) cells. With serial imaging, changes in near-infrared autofluorescence (NIR-AF) preceded the onset of fleck hyperautofluorescence in SW-AF images and fleck profiles in NIR-AF images tended to be larger. Flecks in SW-AF and NIR-AF images also corresponded to hyperreflective lesions traversing photoreceptor-attributable bands in horizontal SD-OCT scans. The hyperreflective lesions interrupted adjacent OCT reflectivity bands and were associated with thinning of the outer nuclear layer. These SD-OCT findings are attributable to photoreceptor cell degeneration. Progressive increases and decreases in the SW-AF intensity of flecks were evident in color-coded quantitative fundus autofluorescence maps. In some cases, flecks appeared to spread radially from the fovea to approximately 8° of eccentricity, beyond which a circumferential spread characterized the distribution. Since the NIR-AF signal is derived from melanin and loss of this autofluorescence is indicative of RPE atrophy, the SW-AF of flecks cannot be accounted for by bisretinoid lipofuscin in RPE. Instead, we suggest that the bisretinoid serving as the source of the SW-AF signal, resides in photoreceptors, the cell that is also the site of bisretinoid synthesis.

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“…RPD are distinctly discernible using this modality and on the ellipsoid zone slab appear as small round lesions with bright hyper‐reflective centres and darker edges . At corresponding locations on a retinal pigment epithelium slab, darker areas of reduced reflectivity can be seen . Comparison between using en face optical coherence tomography imaging alone and conventional multimodal imaging for identification of RPD, demonstrated no difference in detection rates …”

Section: Appearance On Imagingmentioning

confidence: 97%

“…En face optical coherence tomography produces transverse views of the retina and choroid at specified depths . RPD are distinctly discernible using this modality and on the ellipsoid zone slab appear as small round lesions with bright hyper‐reflective centres and darker edges . At corresponding locations on a retinal pigment epithelium slab, darker areas of reduced reflectivity can be seen .…”

Section: Appearance On Imagingmentioning

confidence: 99%

Reticular pseudodrusen: current understanding

Wightman

Guymer

2019

Clinical and Experimental Optometry

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Reticular pseudodrusen (RPD), also known as subretinal drusenoid deposits, represent a morphological change to the retina distinct from other subtypes of drusen by being located above the level of the retinal pigment epithelium. Although they can infrequently appear in individuals with no other apparent pathology, their highest rates of occurrence are in association with age-related macular degeneration (AMD), for which they hold clinical significance by being highly correlated with end-stage disease sub-types, choroidal neovascularisation and geographic atrophy. Reticular pseudodrusen are also found in other diseases, most notably Sorsby's fundus dystrophy, pseudoxanthoma elasticum and acquired vitelliform lesions. They are found more frequently in females, with increased age and more commonly bilaterally than unilaterally. Increased risk of RPD formation is conveyed by genetic variants known to increase risk of AMD development, including complement factor H, age-related maculopathy susceptibility 2, and high-temperature requirement A serine peptidase 1; however, to date, no genetic factor has been found to predispose to RPD independent of those that carry risks for AMD. They have typical features visible on multimodal imaging, identifiable either as single lesions or more commonly in yellowishwhite net-like patterns on colour fundus photography and are particularly distinguishable using spectral domain optical coherence tomography, fundus auto-fluorescence, and near infrared reflectance imaging. On histological examination, RPD have been shown to have distinct compositions in comparison to typical drusen, suggesting different pathways of pathogenesis. Although their aetiology remains unclear, presence of opsin within lesions, a high topographic association with areas of highest rod-photoreceptor concentration and functional deficits most pronounced within the scotopic range, has implicated rod photoreceptor dysfunction as a component of RPD.

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Intraretinal Correlates of Reticular Pseudodrusen Revealed by Autofluorescence and En Face OCT

Cited by 27 publications

References 51 publications

Quantifying Retinal Pigment Epithelium Dysmorphia and Loss of Histologic Autofluorescence in Age-Related Macular Degeneration

Quantifying Retinal Pigment Epithelium Dysmorphia and Loss of Histologic Autofluorescence in Age-Related Macular Degeneration

Photoreceptor cells as a source of fundus autofluorescence in recessive Stargardt disease

Reticular pseudodrusen: current understanding

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