Mechanisms of Early Functional Loss in Diabetic Eye Disease

University Of Illinois At Chicago, Chicago IL

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Abstract

PROJECT SUMMARY Although there is growing consensus that diabetic retinal neurodegeneration (DRN) can precede clinically-apparent vascular abnormalities and may eventually be useful for staging diabetic retinopathy (DR), there is no agreement regarding how DRN is defined, staged, or which measures best reflect neural dysfunction in these individuals. Work completed during prior funding cycles, supported by other researchers, has shown that electrophysiological, psychophysical, and pupillometric approaches can provide sensitive, non-invasive, and quantifiable measures of DRN. However, prior studies that have measured functional consequences of DRN have generally been cross-sectional and performed under typical light- adapted clinical conditions. These studies provide little insight into important challenges reported by individuals with DR, including functioning under dim illumination and adjusting to changing illumination conditions. To address these limitations, we propose to develop and apply novel tools and approaches capable of characterizing the nature and extent of visual dysfunction and its relationship to DRN in individuals with mild or no DR (M/N DR). These approaches will evaluate visual function across a wide range of lighting conditions typical of daily life, assess the ability to adjust to changing illumination conditions, and will be performed longitudinally. Three complementary aims are proposed that use non-invasive tools to provide new views of retinal function under broad and varying levels of illumination: Aim 1 will define key pathophysiological changes in rod, cone, and post-receptor function in M/N DR; Aim 2 will develop and apply a battery of electrophysiological techniques to identify photoreceptor and downstream post-receptor dysfunction; Aim 3 will determine how M/N DR affects non-image- forming pathways. We will determine whether functional measures targeting the inner- or outer- retina show greater DRN progression and if either predicts ETDRS stage advancement. Completing these Aims will: 1) provide a novel framework using complementary approaches for assessing visual dysfunction and the underlying mechanisms in M/N DR, 2) introduce new tools and functional assays that can provide clinically-relevant indices of DRN that address common visual complaints of DR subjects, 3) permit comparisons among measures to define optimal tests of DRN with high diagnostic power. We expect these studies to drive significant advances in clinical DR staging and understanding of early neural deficits.