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

Abstract

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 Müller cells in the human fovea, through RPE, is one strong candidate, because Müller 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.

Figure 1

Neurobiology and aging of macula. Top: (A) Cross-section of a human eye. Green bracket shows area in (B), including optic nerve head and macula. (B) Swept-source optical coherence tomography of a living human neurosensory retina (black bar) and choroid (white bar), showing the 6-mm-diameter macula and adjacent optic nerve. The retina contains multiple bands of alternating high and low reflectivity that coincide in part with the anatomic layers. Blue bar delimits layers occupied by photoreceptors and interleaved Müller glia (M). Arrows indicate the fovea. The choroidal vasculature contains lumens of large vessels and is bounded externally by the sclera. (C) High-resolution histology of the fovea, in the center of macula and responsible for high acuity vision. The retina, photoreceptor layers, and choroid are indicated by black, blue, and white arrows, respectively. A foveal pit is created by inner retinal neurons, Müller cells, and accompanying retinal vasculature being swept to the side of the visual axis. The RPE is a simple cuboidal epithelium that sits on Bruch's membrane, the inner wall of the choroidal vasculature. Osmium postfixation, epoxy embedding, 1-μm-thick section, toluidine blue stain. Lower left: Photoreceptor mosaic and topography of outer retinal cells. (A) Foveal cone inner and outer segments, longitudinal section. (B) Foveal cone inner segments in a flat-mounted retina of a 34-year-old donor, Nomarski differential interference contrast optics and video. (C) Nonfoveal cone and rod inner segments, longitudinal section. (D) Cone inner segments (large) and rod inner segments (small) in the same eye. (E) Number of cones (C), rods (R), and RPE per square millimeter of retinal surface in nasal and temporal retina, in young adults, as a function of eccentricity from the foveal center in mm. Peak densities of cones, rods, and RPE in young adults are 200,000/mm², 150,000/mm², and 10,000/mm², respectively. With increasing eccentricity, cone density decreases, and rod density increases, becoming equal at ∼0.55 mm. The RPE exhibits central peak with a shallow gradient. Scale bars: 10 μm. Hatched rectangle, optic nerve head. Dashed lines, limits of macula. Lower right: Topography of cones and rods in aging human retina, shown as a fundus of a left eye. Black oval, optic nerve; ring, limits of macula. In (C) and (F), warm colors mean that older group has higher mean density than younger group and cool colors mean that older group has lower mean density than younger group. A yellow-green map means that differences between groups are small. (A) Cones, 27- to 36-year-old donors. (B) Cones, 82- to 90-year-old donors. (C) Log mean difference in cone density between younger adults and older adults is small and inconsistent. (D) Rods, 27- to 36-year-old donors. (E) Rods, 82- to 90-year-old donors. (F) Log mean difference in rod density between younger adults and older adults is greatest at 0.5 mm to 3 mm from fovea. Purple signifies that the log mean difference (aged-young) was < −0.16 log units, that is, that aged eyes had 31% fewer cells than young eyes. G, globule; GCL, ganglion cell layer; HFL, Henle fiber layer; INL, inner nuclear layer; IPL, inner plexiform layer; IS, inner segments; NFL, nerve fiber layer; ONL, outer nuclear layer; OPL, outer plexiform layer; OS, outer segments. Top: reprinted with permission from Tian L, Kazmierkiewicz KL, Bowman AS, Li M, Curcio CA, Stambolian DE. Transcriptome of the human retina, retinal pigmented epithelium and choroid. Genomics. 2015;105:253–264. © 2015 Elsevier Inc. Bottom: reprinted with permission from Jackson GR, Curcio CA, Sloan KR, Owsley C. Photoreceptor degeneration in aging and age-related maculopathy. In: Penfold PL, Provis JM, eds. Macular Degeneration. Berlin: Springer-Verlag; 2005:45–62.

Figure 2

Topography of human macular photoreceptors, retinal pigment epithelium, XP, and BLinD/soft drusen. Dotted lines indicate the limits of the 6-mm-diameter macula. Stippled rectangles indicate the optic nerve head. Green downward arrows indicate the annulus of deepest rod loss in aging (Fig. 1, bottom right, deep blue). The lateral extents of XP and BLinD/soft drusen are drawn to scale on the eccentricity axis and not-to-scale on the y-axis. Data come from different eyes of younger adults: photoreceptors/mm² (Ref. 18); RPE/mm² (Ref. 18); XP; thickness of BLinD/soft drusen in AMD eyes.

Figure 3

Outer retinal lipid recycling pathways potentially involved in XP transport. Lutein and zeaxanthin, vitamin A, and some unesterified cholesterol (UC) enter RPE via receptor-mediated uptake of plasma lipoproteins, especially at the LDL and SRB-I receptors. These are transferred to photoreceptors by poorly understood mechanisms that may involve interphotoreceptor retinol-binding protein (IRBP, center), an apoE-based small HDL particle (right), or diffusion (not shown). Because lipids in Bruch membrane lipoproteins are rich in the fatty acid (FA) linoleate (and not docosahexaenoate [DHA]), soft drusen are proposed as a downstream consequence to constitutive dietary delivery of lipophilic essentials to macular cells, and the RPE-mediated recycling of unneeded lipids from these sources and from outer segments, to the circulation via large lipoprotein particles containing apoB and apoE. Lipoproteins accumulate in the sub–RPE-basal lamina largely because of impaired egress through the Bruch's membrane-choriocapillary complex. This is part of a larger system thought to include physiologic release of molecules contributing to subretinal drusenoid deposit (not shown)., Reproduced with permission from Spaide RF, Ooto S, Curcio CA. Subretinal drusenoid deposits AKA pseudodrusen [published online ahead of print May 30, 2018]. Surv Ophthalmol. doi:10.1016/j.survophthal.2018.05.005. © 2018 Published by Elsevier Inc.