Monday, May 6, 2024
5/6/2024
Currently, diagnosis of glaucoma and patient management decisions are often informed by thinning of the optic nerve head (ONH) neuro-retinal rim, peripapillary retinal nerve fiber layer (RNFL), and macular inner retinal layers, as detected using optical coherence tomography (OCT). These measurements are useful because they are predictive of subsequent visual field decline, and of faster rates of subsequent thinning. However, by the time thinning can be detected with current OCT systems, retinal ganglion cells (RGCs) and their axons have already been lost, and therefore some impairment of visual function is unavoidable. Thus, a key gap in the current approach to glaucoma care is the lack of reliable biomarkers that alert the clinician to early-stage glaucomatous damage of RGCs/axons before they are permanently lost. We propose that such information is present within OCT scans from commercially available instruments, but that additional approaches for testing and analysis are required to reveal this information. Our overarching hypothesis is that cues of eye-specific sensitivity to intraocular pressure (IOP) and early RGC/axon distress and damage are present in OCT scans, and that exploiting them will provide meaningful clinical benefits. We will use a well-established non-human primate (NHP) model of experimental glaucoma to test three independent, but mutually supportive, hypotheses, each with its own strong potential to advance clinical care and patient management. In Aim 1, we will test the hypothesis that larger magnitude deformations within the ONH rim and peripapillary RNFL tissues will predict earlier and more severe loss of RGCs/axons across eyes and locations (sectors). Specifically, in Aim 1.1, we test this prediction using the deformations resulting from acute IOP elevation (i.e., elastic deformations or strains), and in Aim 1.2, using the deformations measured after exposure to chronic IOP elevation (plastic deformations and remodeling). In Aim 2, we will test the hypothesis that autoregulation dysfunction within the ONH and peripapillary RNFL tissues precedes capillary dropout (Aim 2.1) and precedes RGCs/axon loss (Aim 2.2). In Aim 3, we will test the hypothesis that an early stage of RGC pathology, characterized by disruption of axonal cytoskeletal ultrastructure and dendritic atrophy, is detectable by OCT (Aim 3.1); that its onset and location are predicted by the acute and chronic deformations determined by strain mapping (Aim 3.2); and that it represents a sign of imminent loss of RGCs/axons (Aim 3.3). Success of any one Aim would represent an important step forward in the determination of risk for glaucoma progression in individual eyes; success of all three Aims would represent a major step forward in this area as each biomarker could enhance the predictive capacity of the others. Moreover, because we are conducting these studies in a species with anatomy and physiology so similar to human beings and with standard, commercially available clinical instrumentation (OCT/OCT-angiography devices), the results could rapidly translate to clinical testing and provide beneficial analysis tools for use by clinicians and researchers.
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