Pulsatility in the retina in glaucoma

The National Eye Institute awarded Legacy Emanuel Hospital & Health Center $702,487 on September 1, 2026, under the Vision Research program (CFDA 93.867) to investigate pulsatility in retinal and optic nerve head blood flow in glaucomatous disease. The research develops diagnostic tools using scanning laser ophthalmoscopy and laser speckle flowgraphy to measure changes in vessel diameter and blood flow across the cardiac pulse cycle. The project tests two competing hypotheses: whether elevated pulsatility results from biomechanical stiffening of vessels induced by elevated intraocular pressure, or from transient vasoconstriction due to aberrant pericytes and upregulated endothelin receptors. Specific Aim 1 will create mechanical strain maps and compare them against flow pulsatility, disease stage, and progression rate. Specific Aim 2 will quantify blood flow changes in response to suspected vasoconstriction. Work is performed in Portland, Oregon, with a period of performance through April 30, 2030. The research supports NEI's mission to drive innovative research to understand vision diseases and prevent blindness, with the ultimate goal of developing potential new diagnostic tests for clinical use in glaucoma management.

Abstract

Glaucoma is the leading cause of irreversible blindness worldwide. IT is known that blood flow within the retina and optic nerve head is reduced in eyes with glaucoma. However, there are also hemodynamic changes in the pulse cycle, which extend beyond a simple reduction of time-averaged flow. We have developed new tools to measure pulsatility (the change across the pulse cycle as a proportion of the average) and its effects, using clinically-approved instruments: scanning laser ophthalmoscopy for changes in vessel diameter and resulting strains, and laser speckle flowgraphy for changes in blood flow. Using these tools we have recently shown that eyes with progressing glaucoma have higher pulsatility of flow in the arteries surrounding the optic nerve head. This implies that vessels are less able to dilate to accommodate high flow during the pulse cycle, either at the point of measurement or further downstream in the retina. There are competing hypotheses about what may cause this change in pulsatility, and this project will provide significant progress towards resolving that question; while simultaneously developing potential new diagnostic tests for clinical use. IT is possible that there is a decrease in pulsatility of diameter, and consequent increase in pulsatility of flow, due to biomechanical stiffening, induced by the intraocular pressure being too high for that specific eye. We will test this in specific aim 1, by creating maps of the mechanical strains impacting vessels and their surrounding tissues, and comparing these against pulsatility of flow, disease stage, and rate of disease progression. IT is also possible that the increase in pulsatility of flow is due to transient vasoconstriction in affected regions of the retina, due to aberrant pericytes and/or upregulated endothelin receptors. We will test this in specific aim 2, by quantifying the change in blood flow that occurs in response to visual stimulation; a normal or elevated response in the presence of decreased pulsatility of diameter would suggest that vasoconstriction is temporary and reversible, and hence unlikely to be due to long-term biomechanical stiffening. In specific aim 3, we will analyze these measurements longitudinally, testing participants every six months for five years. We will use advanced statistical methods to determine whether changes in pulsatility precede glaucomatous progression (suggesting a potential causative link), or occur after disease progression (suggesting that they are a consequence of damage). All of these analyses will be performed at different stages of the disease, since the mechanisms may vary with glaucoma severity. Our results will provide vital new information towards the development of novel therapeutic approaches that could complement intraocular pressure lowering. All testing will be performed using novel methods but in human subjects on clinical instruments, so informative results will be easily translatable to new diagnostic tools that will help refine predictions of progression risk for individual patients. Overall, this project will provide substantial advances in our understanding of changes in retinal hemodynamics as the disease progresses, leading towards new diagnostic and therapeutic approaches for patients with glaucoma.