Abstract
Purpose :
Mitochondrial dysfunction in the retinal pigment epithelium (RPE) has been implicated in the pathogenesis of age-related macular degeneration (AMD). Here, we explored evidence of mitochondrial dysfunction in a nonhuman primate (NHP) model of aging and AMD using a combination of functional and structural imaging on aging rhesus macaques with and without spontaneous soft drusen.
Methods :
We characterized adult rhesus macaques with and without soft drusen by ophthalmic examination, color fundus photography, spectral-domain optical coherence tomography (OCT), blue-peak fundus autofluorescence (FAF), and flavoprotein fluorescence (FPF) imaging, which may serve to measure mitochondrial dysfunction in retinal tissues. FPF image intensity and heterogeneity were measured from the 4.8 mm-diameter macular region, normalized to age-related lens or media opacity. Eyes were collected from animals with drusen for transmission electron microscopy (TEM) to characterize mitochondrial morphology and structure as assessed by masked, trained graders.
Results :
We identified 37 rhesus macaques (mean age 19.74 ± 4.32 years), including 9 with soft drusen and 28 similarly-aged normal control animals. While FPF intensity was neither associated with age or presence of drusen, FPF heterogeneity was greater in eyes with drusen in comparison to controls (0.094 ± 0.016 vs. 0.083 ± 0.004, p<0.0001) and significantly associated with drusen volume (p=0.01). Eyes with medium to large drusen showed greater FPF heterogeneity than those with small or no drusen (0.97 ± 0.019 vs. 0.89 ± 0.003 or 0.83 ± 0.004, p=0.014), and larger drusen lesions appeared to demonstrate higher focal FPF. Ultrastructural analysis suggests morphological changes in RPE mitochondrial structure related to increased age and location over drusen lesions.
Conclusions :
Flavoprotein imaging and ultrastructural analyses suggest mitochondrial dysfunction in RPE of rhesus macaques with aging and age-related drusen. These NHP animal models may enable preclinical testing of novel therapies targeting mitochondrial dysfunction or oxidative stress to better predict their clinical efficacy in patients with AMD.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.