AXON: Axonal biomechaniX to unveil injury mechanisms in glaucomatous Optic Neuropathy

Emory University, Atlanta GA

Investigators

Abstract

PROJECT SUMMARY/ABSTRACT Glaucoma, a major cause of irreversible blindness, damages the retinal ganglion cell axons that carry visual signals to the brain. The exact mechanisms and primary sites of axonal injury remain debated, challenging clinicians to predict disease progression. Research suggests the lamina cribrosa of the optic nerve head (ONH), where axons exit the eye, as a key injury site, though theories also consider the neuro-retinal rim and peripapillary retina. This complexity underscores the need for deeper insights into glaucoma's pathophysiology. Our recent work has highlighted the critical role of biomechanics in glaucoma pathophysiology. Changes in intraocular pressure (IOP) cause distortion of the neural tissues within the ONH. The tissue-level distortions represent an insult to the axons with several components, including stretch, compression, bending, and torsion. These insults, when excessive, prolonged, or combined with other risk factors may lead to axonal injury. Given that each ONH is unique and subjected to a distinct biomechanical environment, the variability could explain why injury sites differ among individuals. However, these phenomena have never been directly observed in vivo in humans. Our proposal aims to leverage innovative tools from Engineering, AI, and advanced imaging (optical coherence tomography or OCT) to make these observations possible. By monitoring patients longitudinally, we intend to unveil which mechanical insults to axons are most likely to influence vision loss progression, identify where these insults occur, and explore variations across glaucoma subtypes and demographics. For this grant, we hypothesize that the deformations of individual ONH axon-bundles following an acute but gentle IOP insult reflects axonal health and could serve as diagnostic/prognostic biomarkers for glaucoma; further the axon-level deformations will help identify the most likely primary site of axonal injury across different glaucoma subgroups and demographics and point to the mechanisms underlying axonal damage and vision loss. The following three aims are proposed. Aim 1. To map the human ONH axonal paths in 3D from a single OCT scan of the ONH. Aim 2. To leverage AI to assess whether axonal deformations could serve as diagnostic and prognostic biomarkers for glaucoma. Aim 3. To leverage explainable AI to provide insights into axonal injury mechanisms by identifying the types of axon-bundle deformations and their locations that putatively influence visual field loss patterns and progression; and by assessing how age, glaucoma severity, and sub-types influence the patterns of these insults. Our project aims to apply Engineering and AI tools to precisely characterize, for the first time, insults at the axon- bundle level. This initiative not only holds the potential to enhance clinical practices for diagnosing and prognosing glaucoma but also deploys explainable AI to pinpoint potential injury sites across various glaucoma subtypes and demographics. Such advancements could significantly refine our understanding and management of glaucoma, ultimately paving the way for innovative therapeutic approaches tailored to individual patient needs.