PROJECT SUMMARY Diabetic retinopathy is the most serious ocular complication of diabetes mellitus and is the leading cause of new cases of legal blindness among working age adults in the United States There is evidence that diabetes affects retinal neurons before abnormalities of the retinal vasculature can be seen on clinical examination. However, relatively little is known about these neural deficits and how they affect visual function in diabetic patients who have mild or no clinically-apparent diabetic retinopathy (M/N DR). The objective of this proposal is to develop and apply novel approaches for characterizing the nature and extent of visual dysfunction and its relationship to neural processes in M/N DR patients. Achieving this objective will provide important new insight into neural dysfunction in these individuals and will establish new tests that are capable of classifying patients who have not yet developed clinically-apparent retinopathy, a group that cannot be staged or subtyped according to existing scales. This new insight and the ability to subtype these patients would be of great use in clinical trials that aim to slow or prevent neurodegeneration in early-stage disease. Three complementary aims are proposed that use electrophysiological, psychophysical, and pupillometric techniques to provide new views of retinal function in M/N DR patients and to address important questions generated by our preliminary investigations: Aim 1 will characterize and understand the effects of M/N DR on rod activation, inactivation, and post-receptor function. A comprehensive battery of electrophysiological tests will be used to challenge common assumptions regarding the sites of disease action that underlie ERG abnormalities. Aim 2 will develop and apply advanced psychophysical techniques for rapid characterization of rod pathway function in M/N DR subjects. Aim 3 will evaluate functional abnormalities in M/N DR subjects using novel pupillometric techniques. After accomplishing these aims, we will have: 1) established clinically-applicable approaches to vision assessment that can quantify neural abnormalities in diabetic patients who have M/N DR; 2) gained new insight into the sites and mechanisms that underlie impaired visual function in these patients. This line of study is particularly important and timely as new therapeutic approaches for treating early-stage retinopathy are being investigated, but the tools that are currently available to subtype patients and evaluate therapeutic efficacy lag behind.