Epidemiology of Biomarkers of AMD Progression

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Project Abstract There are currently no effective treatments for atrophic age-related macular degeneration (AMD), in part because we may be intervening too late in the disease course after geographic atrophy (GA) has developed. A far preferable strategy would be to intervene at an earlier phase of the disease, but there is uncertainty with regards to disease biomarkers to select the most appropriate patients as well as endpoints which could be used to conduct an interventional trial in a clinically-practical time-frame. This is in large part because of the lack of a sufficiently granular staging system describing the progression from early to late stage AMD. The best currently available data comes from studies such as the Age-Related Eye Diseases Study and the Beaver Dam Eye Study, but these studies were largely based on color fundus photographs with AMD disease features assessed using historical protocols developed in the film-based imaging era. The AMD disease severity scales and staging systems built from these studies are insufficiently granular and fail to take advantage of modern, pervasive digital imaging technologies such as optical coherence tomography (OCT) and OCT angiography (OCT-A) which readily lend themselves to quantification. Extensive research over the past decade has identified a number of structural OCT features of AMD, such as intraretinal hyper-reflective foci and subretinal drusenoid deposits, which appear to increase the risk for developing late AMD (atrophy and/or neovascularization). More recently, choriocapillaris (CC) flow deficits have been shown to increase with age and in AMD. The relationship between CC flow deficits and the onset and stage of AMD still remains to be defined. In addition, although a number of genetic risk factors for AMD have been identified, the genetics of AMD progression are not yet elucidated. This research application proposes to address these critical knowledge gaps by evaluating elderly subjects with AMD who have previously been recruited as part of the NEI-funded Amish Eye Study. The Amish represent a homogenous population with regards to environmental and social exposures which reduces variability and makes this group ideally suited for epidemiologic studies of AMD progression. Through that previous study, baseline (and some 2-year follow up) clinical, multimodal imaging (including OCT), and genetic data have already been collected. However, long-term (7 year) data, which will be a focus of our proposed research, is critical to actually establish which individuals go on to progress to late AMD, which is vital in order to determine which baseline features are associated with a higher risk of progression, and to develop a granular and quantitative staging system for AMD. The development of this novel AMD staging system will provide points of intervention and outcome assessment to enable early intervention clinical trials and provide new insights into the genetics and pathophysiology of AMD.