In vivo Ultrastructure of Chorioretinal Disease

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Project Summary This renewal will address crucial knowledge gaps in the pathway that subretinal drusenoid deposits (SDD) lead to Type 3 macular neovascularization (T3MNV, also known as retinal angiomatous proliferation) in age-related macular degeneration (AMD). SDD are extracellular lesions present between photoreceptors and their supportive retinal pigment epithelium (RPE) cells. Thus they’re on the opposite side of the physiologic blood-retina-barrier to classical drusen, which are AMD’s hallmark lesions. Drusen accumulate on the inner surface of Bruch’s membrane posterior to the RPE. T3MNV is an important by less recognized form of neovascular AMD that has an intraretinal origin and can result in severe vision loss. SDD have a strikingly high occurrence in eyes with T3MNV. The distribution of T3MNV has a large overlap with that of SDD. T3MNV’s etiology is recently appreciated by advanced retinal imaging including optical coherence tomography (OCT) structure and angiography (OCTA). It’s been suggested that T3MNV originates from the deep capillary plexus (DCP) of the retina after precursory RPE cells migrate anteriorly. How SDD lead to T3MNV, and how retinal capillaries interact with precursor migratory RPE cells to initiate T3MNV is not completely understood. Nor is why and when RPE cells begin migration. We hypothesize that reduced or impaired metabolic supply due to dysfunction of the choriocapillaris or accumulation of extracellular lesions on both sides of the RPE are inciting events that promote RPE cells to leave their monolayer and migrate to the DCP, thereby eliciting neovascularization in the retina; this process can be significantly exacerbated by SDD. We thus propose to evaluate the health status of the retinal capillary system through in vivo characterization of the retinal capillary hemodynamics in relation to the developmental stage of SDD and drusen, the health of the RPE, and the structure of the choriocapillaris and the choroid, in patients with AMD. We’ve developed an adaptive optics (AO) enhanced high speed near confocal ophthalmoscope (AONCO), which can image the retina with cellular resolution and measure the high-order hemodynamics in retinal capillaries. We've developed novel method to estimate the choriocapillaris structure using OCTA. We obtained fluorescence lifetime imaging ophthalmoscopy (FLIO), which can assess RPE health. Our objectives are two-fold: understanding the pathway by which SDD lead to T3MNV and developing AO imaging based biomarkers for early detection of T3MNV. We predict: 1. High-order hemodynamic characteristics that measure the acceleration (and its change) of the blood flow within retinal capillaries may provide sensitive detection of abnormalities of the retinal microcirculation induced by early neovascular events that lead to T3MNV. 2. FLIO may provide an objective quantification of RPE health that correlates with the stages of SDD and drusen, and the health of the choriocapillaris. Success of this research will provide improved markers and endpoint for monitoring and treating T3MNV by objective measurements of RPE health and retinal vascular health, thereby, represents a significant stride toward our long-term goal that dedicates to improve the basis of assessing risk for AMD progression and clinical endpoints for evaluating treatments.