Project Summary Glaucoma damage to the optic nerve and impairment of vision are progressive and irreversible. Understanding mechanisms of glaucomatous injury will help to develop new approaches for treatments that can be used along with traditional therapies that lower intraocular pressure (IOP). Recent developments in optical coherence tomography (OCT) angiography have brought increased attention to the role of the inner retinal circulation in glaucoma. To improve our understanding of retinal vascular alterations in glaucoma, we can take advantage of recent developments in visible-light OCT (vis-OCT) to characterize simultaneously tissue structure, vessel density, blood flow and oxygenation. The goal of this project is to further advance vis-OCT by attaining capillary-level measurements, test the value of measuring their local alterations as early indicators of glaucoma and glaucomatous progression and use this to evaluate impaired retinal autoregulation from retinal ganglion cell (RGC) loss as a potential cause of increased susceptibility in advanced glaucoma. In Specific Aim 1 we will develop high-speed, high-sensitivity, high-resolution vis-OCT. The speed will be double that of the current system. A more stable supercontinuum laser will be used to improve system sensitivity, and a tighter focus will be used to improve lateral resolution. This will enable complete detection of capillaries that may be vulnerable to vascular dysfunction. Specific Aim 2 will develop quantitative OCT angiography, velocimetry and oximetry in capillaries as well as arteries and veins. Building on the high-resolution, high-contrast scans acquired in Aim 1, we will use machine learning to segment capillary plexuses, and advanced image processing to extract capillary architecture. Aided by this capillary architecture, we will automatically measure blood flow and oxygenation in capillary segments and incorporate them into a real-time platform. Specific Aim 3 will use this system to demonstrate that acute loss of RGCs, produced by optic nerve transection, alters retinal capillary plexus density, oximetry and velocimetry over time and that these changes precede altered oximetry and flow in larger retinal vessels. We will also show that loss of RGCs impairs the autoregulatory response to acute IOP challenge. In Specific Aim 4, we will demonstrate that optic nerve injury in a model of controlled, elevated IOP produces early alterations in capillary velocimetry, oximetry and autoregulation, show that they are more persistent with advanced injury, and demonstrate the pathophysiologic consequences of these observations. Successful development of this new technology will improve methods of early glaucoma diagnosis and detection of progression. Better understanding of retinal vascular factors that lead to increased susceptibility in advanced glaucoma will lead to improved treatments for these highly vulnerable patients.

Project Narrative This project will develop advanced technology to image retinal capillaries and measure capillary blood flow and oxygen content. This may provide an early indicator of glaucoma progression and help study a potential cause of increased susceptibility to intraocular pressure in glaucoma patients.