Imaging Early-stage Damage to Individual Axons at An Early Stage of Glaucoma
Current clinical gold-standard methods for assessing the structural integrity of nerve fibers damaged by glaucoma are only able to detect complete loss of those fibers from the retinal layer within the eye. By the time such loss is detected, it is too late to rescue those fibers and the visual signals they had previously carried to the brain. In order to prevent loss of those fibers and their visual function, more sensitive techniques are needed to detect subtle abnormalities that occur at an earlier stage of injury from glaucoma. We seek in this proposal to determine whether a particular type of imaging is capable of assessing and reporting on the integrity of sub-microscopic structures within optic nerve fibers at an early stage of damage preceding their complete degeneration and loss from the eye.
We seek to determine whether a particular type of imaging, known as “polarization-sensitive” imaging, is capable of reporting on the integrity of sub-microscopic structures within optic nerve fibers at an early stage of damage from glaucoma, preceding their complete degeneration and loss from the eye.
The principle behind this type of imaging is that retinal ganglion cell axons exhibit an optical property known as birefringence. Structures with this property behave optically as though they are made of two different materials (each with a different refractive index), depending on the orientation of polarization of the light passing through them. When retinal ganglion cell (RGC) axons are injured, before completely degenerating, they exhibit a phase during which their internal “skeletal” structure (normally consisting of a highly organized arrangement of fibers) becomes disorganized. This disruption causes a change in the way light interacts with the tissue, such that the axon bundles exhibit less birefringence and also lower reflectance (back scatter). We have already shown that this type of imaging detects abnormalities of the axon bundles before any reduction of retinal nerve fiber layer (RNFL) thickness (the most common clinical standard metric of axon integrity) can be detected.
However, there remains an important gap in the evidence that needs to be addressed before this imaging approach can translate completely to influence clinical care. The resolution of current imaging techniques is insufficient to discern whether individual axons are dropping from bundles without bundle collapse (thus manifesting as reduced birefringence without bundle thinning) or whether cytoskeletal disruption occurs within axons that otherwise remain present within bundles. We aim to close this gap by implementing a novel assay to simultaneously assess the integrity of the axonal cytoskeletal structure (using electron microscopy) and a functional (physiological) correlate of healthy cytoskeletal structure, namely active axon transport, within individual RGC axons at an early stage of experimental glaucoma. This link is significant and necessary to close the existing evidence gap so that clinicians and their patients will know unequivocally that abnormalities of RNFL birefringence represent a sign of axonal stress rather than axonal loss. This should impact clinical care, making it clearer that new progressive RNFL retardance defects represent a “red flag” that can alert clinicians of the need to advance therapy before additional stages of axonal self destruction result in permanent axon and vision loss.
About the Researcher
I have been working in the field of glaucoma research, on pathophysiology and diagnostics, for the past 18 years, and have become increasingly interested in the use of advanced imaging techniques for characterization of glaucomatous changes within the retina and optic nerve head. During this time, I have been actively engaged in clinical studies of participants that have been diagnosed with glaucoma or high-risk ocular hypertension, as well as in laboratory-based studies on experimental glaucoma models in rodents and non-human primates. My research is focused on the pathophysiology of retinal ganglion cell (RGC) axon damage in glaucoma and detecting early-stage abnormalities by means of non-invasive imaging, psychophysical testing and electrophysiological measures such as electroretinography (ERG) and visually evoked cortical potentials (VEP). Specifically, the aims of recent projects were to determine whether axonal cytoskeletal disruption, transport abnormalities, and electrophysiological dysfunction occur prior to RGC death in experimental glaucoma (rodent and non-human primate models) and whether some of these phenomena are detectable by clinically-applicable means. Indeed, one important motivation for me is to facilitate the translation of laboratory findings to patient care. In this regard, I am always keen to determine how phenomena observed in the laboratory can be detected and monitored in a clinical setting. It is hoped that this project will provide clinicians with more useful tools to help decide which patients require the closest monitoring and earliest therapeutic intervention.
I am extremely grateful to the donors of the BrightFocus Foundation for this opportunity to advance our own investigations as well as contribute to the advancement of glaucoma research and clinical care more broadly. These are extraordinary times, with the pace of discovery and development of new techniques occurring so rapidly, yet budgets at Federal institutions supporting biomedical research (such as the NIH) are becoming ever more constrained. Without support from BrightFocus, there’s a risk our own investigations would be paused, indefinitely, at what we believe to be a most critical point.
First published on: August 24, 2017
Last modified on: August 28, 2019