Abstract
Purpose :
Nonhuman primates (NHP) are an excellent animal model of age-related macular degeneration (AMD) because they possess a macula resembling humans and spontaneously develop drusen and drusen-like lesions with age. We previously characterized geriatric rhesus macaques with 1) soft drusen resembling AMD and 2) fine drusenoid punctate lesions resembling benign yellow dot maculopathy in humans using in vivo multimodal imaging. Here, we characterize the anatomy and ultrastructure of these lesions, and analyze the role of plasma lipids in these phenotypes.
Methods :
We evaluated adult rhesus macaques at the California National Primate Research Center with ophthalmic examination, color fundus photography (CFP), spectral-domain optical coherence tomography (OCT), and fundus autofluorescence (FAF). Drusen volumes were measured from OCT volumes using a machine learning-based segmentation algorithm. Severity of punctate lesions were graded from CFP and FAF images by 2 retinal specialists. Plasma samples were collected to measure fasting glucose, total cholesterol, HDL, LDL, triglycerides ApoA1, Apo B, ApoCIII and ApoE. Histological sections and transmission electron microscopy was performed on eyes from animals that undergo necropsy for natural causes.
Results :
Among 262 rhesus macaques (mean age 18.1 ± 5.0 years, prevalence of soft drusen was 13% and punctate lesions was 37%. NHP drusen presence or severity was associated with age, but not with any plasma lipid measures (P>0.05 for all groups). By contrast, presence and severity of punctate lesions were not associated with age, but with fasting glucose (P = 0.013), LDL (P = 0.022), and ApoB (P = 0.004). High-resolution methacrylate-embedded histological sections of macaque eyes with soft drusen revealed dysmorphic retinal pigment epithelial (RPE) cells overlying dome-shaped sub-RPE deposits with lipid pools. TEM revealed basal linear (BLinD) deposits and sub-RPE mounds of extracellular lipid particles in eyes with drusen, while eyes with punctate lesions showed large, lipid-filled vacuoles within individual RPE cells.
Conclusions :
Soft drusen in rhesus macaques are extracellular sub-RPE lipid deposits associated with aging similar to AMD, while punctate lesions are intracellular lipid accumulations that may be linked to systemic lipids or metabolic state, suggesting these two phenotypes in NHPs as distinct manifestations of defective lipid transport.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.