Subretinal drusenoid deposits in non-neovascular age-related macular degeneration: morphology, prevalence, topography, and biogenesis model

Abstract

Purpose: To characterize the morphology, prevalence, and topography of subretinal drusenoid deposits, a candidate histological correlate of reticular pseudodrusen, with reference to basal linear deposit (BlinD), a specific lesion of age-related macular degeneration, and to propose a biogenesis model for both lesion.

Methods: Donor eyes with median death-to-preservation of 2:40 hours were postfixed in osmium tannic acid paraphenylenediamine and prepared for macula-wide high-resolution digital sections. Annotated thicknesses of 21 chorioretinal layers were determined at standard locations in sections through the fovea and the superior perifovea.

Results: In 22 eyes of 20 white donors (83.1 ± 7.7 years), SDD appeared as isolated or confluent drusenoid dollops punctuated by tufts of retinal pigment epithelium apical processes and associated with photoreceptor perturbation. Subretinal drusenoid deposits and BlinD were detected in 85 and 90% of non-neovascular age-related macular degeneration donors, respectively. Subretinal drusenoid deposit was thick (median, 9.4 μm) and more abundant in the perifovea than in the fovea (P < 0.0001). BlinD was thin (median, 2.1 μm) and more abundant in the fovea than in the perifovea (P < 0.0001).

Conclusion: Subretinal drusenoid deposits and BlinD prevalence in age-related macular degeneration eyes are high. Subretinal drusenoid deposits organized morphology, topography, and impact on surrounding photoreceptors imply specific processes of biogenesis. Contrasting topographies of subretinal drusenoid deposits and BlinD suggest relationships with differentiable aspects of rod and cone physiology, respectively. A 2-lesion 2-compartment biogenesis model incorporating outer retinal lipid homeostasis is presented.

Figure 1. Macula-wide, high-resolution section of an eye with non-neovascular AMD

Figure 2. Histological layer thicknesses in non-neovascular AMD

Figure 3. Basal linear deposits in atrophic AMD eyes

Figure 4. SDD morphology

Figure 5. SDD in superior-temporal perifovea

Figure 6. SDD is abundant in superior perifovea

Figure 7. Prevalence of SDD and BlinD

Figure 8. SDD and BlinD thicknesses and photoreceptor topography

Figure 9. Biogenesis of sub-RPE and sub-retinal AMD lesions: model

Normal at left-center, AMD at right. Details in ^, . OS, outer segment.. BlinD, current 1) Plasma lipoproteins delivering lipophilic nutrients enter RPE . 2) ApoB,E lipoproteins secreted basolaterally by RPE (gold circles) are assembled from multiple lipid sources. Fatty acids are dominated by linoleate, implicating internalized plasma lipoproteins as a major source. UC from all sources is esterified to EC. 3) Lipoproteins are retained by interacting with BrM extracellular matrix and accumulate throughout adulthood, creating a lipid wall on BrM's inner surface. 4) Reactive oxygen species from neighboring mitochondria promote appearance of pro-inflammatory and toxic moieties. Lipoproteins fuse and form lipid pools and UC-rich liposomes within BlinD/ soft drusen, rendering them biomechanically unstable. SDD, new 5) Disks in rod OS lose UC and gain docosahexaenoate in transit from OS base to tip (shown as loss of white). OS-derived DHA stored as triglycerides in RPE after phagocytosis return to OS . HDL particles cycling between RPE and photoreceptors could handle both transfers as part of a vectorial lipid flow retainable within interphotoreceptor matrix as UC-containing SDD, especially under rod-rich perifovea. BlinD, new 6) Cone OS maintain high UC content along their length, because their disks are comb-like projections of plasma membrane . Cone OS UC enters RPE via disk shedding, lysosomal uptake, and acid lipase activity . UC is released for intracellular transfer, esterification, and assembly into basolaterally-secreted lipoproteins, especially under cone-rich fovea.