Dominantly Inherited Early Onset Maculopathy in Japanese Macaques: Drusen Progression

Abstract

Purpose: Japanese macaques (Macaca fuscata) exhibit a syndrome of early onset, progressive, dominantly inherited drusenoid maculopathy. Subretinal drusen deposits in this species show the same morphological and immunohistochemical characteristics as drusen in human patients with age-related macular degeneration (AMD), and therefore they provide a particularly useful model for translational studies. We obtained repeated retinal fundus images of affected animals and developed a novel image analysis method to quantify drusen extent and estimate rates of progression.

Methods: Serial color retinal fundus photographs were obtained from 20 Japanese macaques with the dominant drusen phenotype at 3-month intervals over a 9- to 12-month period. The animals were 4-20 years old with a wide range of drusen severity; all were members of a troop resident at ONPRC since 1964. At each time, 5 images were analyzed to increase reliability. Images were segmented into the central 1 mm and a 1-6 mm annulus. A machine learning algorithm using advanced Weka segmentation (University of Waikato) was implemented to discriminate and quantify drusen, and rates of progression were determined.

Results: In the central macula, the initial extent of drusen ranged from <1% to 46% of the total area, with older animals showing more severe drusen loads. The rate of progression ranged from <1% to >20% (mean 5.4%) of the area of the central macula per year, largely depending on the initial area occupied by drusen. As a percentage of initial drusen area, rates of progression averaged 1.8% per year. In the 1-6 mm annulus, the initial percent area occupied by drusen ranged from 0.2-9% and increased at an average rate of 1.5% of area per year, or 1.2% of initial drusen area. A companion study is examining the relationship between these estimates of drusen load and cone densities measured by adaptive optics.

Conclusions: This maculopathy has close phenotypic similarity to human AMD. A similar syndrome was reported in cynomolgus macaques (Umeda et al., IOVS 46:683-691, 2005). Only higher nonhuman primates possess a macula, and macaques with naturally occurring macular disease syndromes provide a valuable resource for probing macular disease pathogenesis and for preclinical testing of AMD therapies.

Keywords: 412 age-related macular degeneration • 504 drusen • 550 imaging/image analysis: clinical