PROJECT SUMMARY Age-related macular degeneration (AMD) is an eye disease leading to permanent central vision loss. Our prior work focused on using optical coherence tomographic angiography (OCTA) in the diagnosis and management of choroidal neovascularization (CNV), the characteristic feature of exudative AMD. Our clinical studies have shown OCTA has high sensitivity and specificity for CNV detection when evaluated by clinicians and artificial intelligence; we have developed novel CNV quantitative metrics to monitor treatment response; and, have shown OCTA can identify non-exudative CNV that carries a high risk for developing exudation. Though exudative AMD is treatable, many eyes under treatment will lose vision due to developing advanced dry AMD, characterized by geographic atrophy (GA). There is great interest in using OCTA to detect perfusion defects in the choriocapillaris and retinal DCP that could serve as biomarkers for eyes at risk for developing advanced AMD prior to vision loss. We will accomplish these goals with the following aims and evaluations: Aim 1: Improve imaging of the choriocapillaris and deep capillary plexus (DCP). Our high-speed swept-source (SS)-OCT prototype has shown superior resolution compared to other OCTA devices. However, several issues currently still prevent clean visualization of deep vascular layers on 9×9-mm scans at the central macula. We will address these issues by optimizing scan sampling density, improving the OCTA computation algorithm, and developing a new projection resolution algorithm that is effective in these layers. Aim 2: Develop quantitative analysis of choriocapillaris and deep capillary plexus perfusion defects. Imaging capillaries in deeper anatomic layers is difficult due to signal attenuation and background noise. To compensate for these effects, we will improve avascular area measurements by including a capillary reconstruction strategy in the pre-processing steps. We will also develop a novel flow defect measurement by combining the structural OCT and OCTA signals that will be able to identify non-perfused capillary segments. Aim 3: Evaluate advanced OCTA for AMD in clinical studies. Three clinical studies will test three advanced OCTA-derived biomarkers: choriocapillaris avascular area, DCP avascular areas, and non-perfused capillary length in the DCP. (1) Conduct a cross-sectional study to determine if the advanced OCTA biomarkers are associated with increasingly advanced stages of AMD. (2) Conduct a longitudinal study that evaluates eyes with intermediate AMD to determine if advanced OCTA biomarkers can identify eyes at risk factors for developing advanced AMD. (3) Conduct a longitudinal study of eyes with exudative AMD under treatment, to determine if the advanced OCTA biomarkers will predict eyes at risk for developing GA. If successful, OCTA will enable a better understanding of the role of choriocapillaris and DCP in AMD pathogenesis and will help predict eyes at risk for developi...