Abstract
Nonhuman primates are the only mammals to possess a true macula similar to humans, and spontaneously develop drusenoid lesions which are hallmarks of age-related macular degeneration (AMD). Prior studies demonstrated similarities between human and nonhuman primate drusen based on clinical appearance and histopathology. Here, we employed fundus photography, spectral domain optical coherence tomography (SD-OCT), fundus autofluorescence (FAF), and infrared reflectance (IR) to characterize drusenoid lesions in aged rhesus macaques. Of 65 animals evaluated, we identified lesions in 20 animals (30.7%). Using the Age-Related Eye Disease Study 2 (AREDS2) grading system and multimodal imaging, we identified two distinct drusen phenotypes – 1) soft drusen that are larger and appear as hyperreflective deposits between the retinal pigment epithelium (RPE) and Bruch’s membrane on SD-OCT, and 2) hard, punctate lesions that are smaller and undetectable on SD-OCT. Both exhibit variable FAF intensities and are poorly visualized on IR. Eyes with drusen exhibited a slightly thicker RPE compared with control eyes (+3.4 μm, P=0.012). Genetic polymorphisms associated with drusenoid lesions in rhesus monkeys in ARMS2 and HTRA1 were similar in frequency between the two phenotypes. These results refine our understanding of drusen development, and provide insight into the absence of advanced AMD in nonhuman primates.
Highlights
Nonhuman primates are the only mammals to possess a true macula similar to humans, and spontaneously develop drusenoid lesions which are hallmarks of age-related macular degeneration (AMD)
Genetic polymorphisms associated with drusenoid lesions in rhesus monkeys in ARMS2 and HTRA1 were similar in frequency between the two phenotypes
We identified two morphologic phenotypes of drusenoid deposits, which can be distinguished by different imaging features, and investigated potential associations between drusen phenotype with single-nucleotide polymorphisms in ARMS2 and HTRA1 which are known to be associated with macular drusen in rhesus monkeys
Summary
Nonhuman primates are the only mammals to possess a true macula similar to humans, and spontaneously develop drusenoid lesions which are hallmarks of age-related macular degeneration (AMD). Reticular pseudodrusen are located in the subretinal space above the RPE9,10, and may be distinguished by their location on histology and optical coherence tomography (OCT)[11] These different drusen phenotypes are associated with certain genotypic variants such as those in the complement factor H (CFH) and age-related maculopathy susceptibility (ARMS2) loci, and may have differential propensity for progression to RPE atrophy and late-stage AMD12,13. Rhesus monkeys and humans were found to share genetic polymorphisms in genes such as ARMS2 and HTRA1 (high temperature-requirement factor A1) that are associated with drusen formation[23,24,25] These studies suggest that the drusenoid deposits in nonhuman primates may offer significant insight into drusen formation in humans, but more refined, quantitative methods are necessary to characterize these lesions in monkeys for translational research
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