Project Summary / Abstract Glaucoma is a leading cause of blindness both in the US and worldwide, and is characterized by damage to and loss of retinal ganglion cells. It is known that blood flow within the optic nerve head and retina are altered in glaucomatous eyes. Flow may initially increase, but is eventually decreased in eyes with more severe glaucomatous damage. The capillary density gradually decreases as the disease progresses. There is also evidence of altered hemodynamics, in that the shape of the pulse waveform measured within the optic nerve head differs between glaucomatous and healthy eyes. However, it is not yet known whether these changes occur because axon loss has reduced the metabolic demand; or whether the changes contribute towards retinal ganglion cell damage and death; or both. This proposal will examine in detail the changes in blood flow and hemodynamics that occur at different stages of glaucoma. We will leverage new technologies to measure different aspect of the vasculature, and relate them to disease status and progression, both individually and in combination. In Aim 1, we will measure blood flow within the optic nerve head and as it passes through the peripapillary retina, both to quantify the amount of flow and to measure and quantify the pulse waveform. This will allow us to test whether the observed differences in flow in eyes that are considered glaucoma suspects are an early part of the disease process that could be measured diagnostically, and/or reflect longstanding differences that could be used to predict susceptibility to glaucoma. In Aim 2, we will also measure the systemic pulse waveform in the same individuals. This will allow us to determine whether differences in hemodynamics that could be measured diagnostically are localized to the eye due to pathophysiologic processes; and/or represent a systemic risk factor for glaucoma. In Aim 3, we will measure the area of perfused blood vessels, both in the optic nerve head and the peripapillary retina. This will allow us to determine whether flow is altered within the remaining vessels after some of the capillaries have been pruned, potentially causing further damage. Together, these aims will reveal multiple facets of the relation between vascular changes and glaucoma, and answer major questions that have remained unresolved. Overall, the project will provide substantial advances in both diagnostic tools and mechanistic understanding of glaucoma.

Project Narrative This project will provide important new information about the role of blood flow in glaucoma. It is known that blood flow in the retina is altered during the disease; this project will help determine whether that is the result of retinal ganglion cell loss, or a factor that contributes to cell loss, or both. It will reveal new targets both for diagnostic testing and for treatment, and elucidate the processes by which glaucoma progresses and ultimately leads to blindness.