Retinal Layer Changes With Aging and Cognitive Decline in Rhesus Macaques

Purpose: Nonhuman primates (NHPs) are powerful animal models of aging and neurodegeneration. We hypothesize that age-related retinal thinning measured by optical coherence tomography (OCT) may correlate with cognitive and behavioral decline. Here, we evaluate the relationship between neurocognitive function in rhesus macaques and retinal layer thickness on OCT. Methods: We evaluated 110 older rhesus macaques (mean age, 19.5 ± 3.3 years; range, 11-30 years) with an array of behavioral assessments, including visual acuity, decision-making, working memory, spatial memory, problem-solving, and social learning. We collected spectral domain OCT scans and measured retinal layer thicknesses in macular and peripapillary areas using custom segmentation software. Multivariate linear regression with generalized estimating equations was used to assess the association between retinal layer thicknesses and cognitive function. Results: OCT measurements of retinal layers were consistent with published data from humans and NHPs. Thinning of the macular nerve fiber layer (mNFL; P = 0.001) and photoreceptor segments (PSs; P = 0.014) were associated with slower decision-making, whereas thinner inner nuclear layer (INL) was linked to slower problem-solving and less problem-solving flexibility (P = 0.023). Thinner outer plexiform layer (OPL; P = 0.022) and PSs (P = 0.001) were associated with better visual prediction, and thinning of the mNFL (P = 0.038), OPL (P = 0.039), total retinal thickness (P = 0.015), and peripapillary NFL (P = 0.002) were associated with better social learning. Conclusions: Older rhesus macaques demonstrated measurable changes in behavior and retinal anatomy, but the relationship between retinal thinning and cognitive performance was modest, suggesting a unique relationship between retinal thinning and executive function, or a reflection of age-related decline and compensatory mechanisms. Translational Relevance: Identifying noninvasive measures of age-related cognitive and behavioral decline using OCT measurements of retinal anatomy in NHPs may help accelerate future preclinical testing of novel treatments for neurodegenerative diseases in these animal models.