Long-term Evolution and Remodeling of Soft Drusen in Rhesus Macaques

Abstract

PURPOSE.To characterize the evolution and structure of soft drusen in aged rhesus macaques using in vivo multimodal retinal imaging and ex vivo histologic and ultrastructural analyses as a nonhuman primate model of early age-related macular degeneration (AMD). METHODS.Multimodal imaging including fundus photography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF) were used to characterize and track individual drusen lesions in 20 aged rhesus macaques (mean age 23.3 ± 2.7 years) with drusenoid lesions over 2 years, followed by semithin histologic analysis and transmission electron microscopy (TEM). RESULTS.Although most drusen gradually increased in size, a portion spontaneously regressed or collapsed over 2 years. Histologic analyses showed that soft drusen exhibit hypertrophy and dysmorphia of overlying retinal pigment epithelium (RPE), as seen in early and intermediate AMD, but do not exhibit RPE atrophy, RPE migration, or photoreceptor degeneration characteristic of advanced AMD. Ultrastructure of soft drusen showed abundant lipid particles within Bruch's membrane and AMD-related basal linear deposits (BlinD) resembling those in human drusen. CONCLUSIONS.The dynamic remodeling, histologic findings, and ultrastructural features of soft drusen in aged rhesus macaques support nonhuman primates as an animal model of early AMD and reveal important insights into drusen biogenesis and AMD development.

Measuring the Contributions of Basal Laminar Deposit and Bruch's Membrane in Age-Related Macular Degeneration

“…45,54,76 Some mouse strains exhibit thin BLamD, and, to date, only models involving the genes listed above have thick BLamD. 66,77 Aged monkeys may naturally exhibit soft drusen, but lack BLamD and do not progress to atrophy or NV, 78 suggesting that BLamD is required for drusen that progress. Indeed, BLamD may share some of the pathophysiology postulated for drusen, with important differences.…”

Quantitative Fundus Autofluorescence in Rhesus Macaques in Aging and Age-Related Drusen

“…Our findings are also consistent with studies using SD-OCT imaging, in which soft drusen in macaques demonstrate homogenous internal reflectivity, whereas those in humans exhibit greater heterogeneity in reflectivity with variable internal substructures. 8,58,59 Thus our data suggests both localized and global impact on lipofuscin distribution in eyes with drusen and AMD in primate species. As the pathogenesis of AMD is complex and multifactorial, including oxidative stress, 60 lipid accumulation, 61,62 immune dysregulation, 63,64 and vascular changes, 65,66 the role of lipofuscin accumulation among these factors remains unclear.…”

“…In our study, we found a subset of eyes with these punctate lesions, which exhibited similar qAF8 levels to age-matched eyes without fundus findings, and supports our hypothesis that lipoidal degeneration is not related to soft drusen or AMD. 8 NHPs are potentially important animal models of AMD because they possess a true macula similar to humans and spontaneously develop soft drusen that has similar components and ultrastructure 67 and share similar genetic susceptibility loci. [68][69][70] However, despite reported drusen prevalence of up to 47% in some colonies, [5][6][7]71 macaques do not develop advanced, atrophic AMD, or risk features for atrophy, such as reticular pseudodrusen.…”

“…NHPs, such as rhesus macaques, exhibit some forms of inherited retinal degenerations, 2 – 4 and spontaneously develop age-related soft drusen similar to those in human AMD. 5 – 8 Soft drusen are subretinal deposits that form between the retinal pigment epithelium (RPE) and basal lamina, appearing clinically as yellow-white elevations with indistinct borders ranging from 30 to 1000 µm. 9 Preclinical testing in NHPs can accelerate the translation of novel interventions to human trials, including pharmacologic agents or gene therapies.…”

Evolution of ocular defects in infant macaques following in utero Zika virus infection

“…SD-OCT was performed using a 20 º x 20º volume scan and a 30 º x 5º raster scan protocol, centered on the fovea and in areas of chorioretinal colobomas, with progression mode using retinal vessel tracking enabled where possible to reliably image the same area for longitudinal imaging sessions. All retinal measurements were made using the Heidelberg Explorer software (version 1.9.13.0, Heidelberg Engineering, Heidelberg, Germany), which has been used in prior studies and calibrated for both humans (54)(55)(56) and macaques (57)(58)(59).…”