Glaucoma, a leading cause of irreversible blindness in the world, is characterized by progressive degeneration of the retinal ganglion cells (RGCs), the retinal nerve fiber layer, and the optic nerve. Glaucoma is often associated with elevated intraocular pressure (IOP), and because the increased IOP exerts a compressing force on the blood vessels in the eye, it has long been hypothesized that the RGC damage is caused by mild, but chronic, reduction of basal blood flow and/or blood-flow dysregulation. For many patients, by the time glaucoma is detected in examinations or patients notice vision loss, more than half of the RGCs have already degenerated. The eventual outcome is often blindness. Thus, non-invasive imaging technologies capable of detecting depth-resolved blood flow, oxygenation, and stimulus-evoked hemodynamic changes to evaluate blood flow reduction and dysregulation in the retina and the optic nerve head could enable objective early detection, longitudinal disease staging, and monitoring of therapeutic interventions. Although optically based imaging techniques provide high spatial resolution, they are depth limited which precludes quantitative resolution of retinal, choroidal, and optic nerve blood flow. Our laboratory pioneered the application of multimodal MRI to image high-resolution lamina-specific anatomy, blood flow, oxygenation, and function of the retina without depth limitation. Here we propose: i) to develop a multimodal MRI approach to markedly improve contrast and spatial resolution (35x35x300 ?m) without MRI susceptibility artifact by using a 3D balanced Steady State Free Precession (bSSFP) data acquisition scheme, and ii) to apply this approach in an established genetic (DBA/2J) mouse glaucoma model to determine whether MRI can detect glaucomatous changes in early stage and examine a plausible mechanism of glaucoma pathogenesis. We hypothesize that: 1) MRI can provide high resolution, depth-resolved, laminar- specific anatomical, blood flow, and functional images free of susceptibility artifacts;and 2) the pathogenesis of glaucoma is mediated by reduced blood flow and/or blood-flow dysregulation in the early stage, resulting in eventual loss of RGCs by ischemic hypoxia, and, if this is the cause, hyperoxia treatment should halt glaucomatous damage.
This proposal outlines the development and novel application of MRI approaches to resolve structural, physiological and functional laminar specificity of the retina at very high spatial resolution in normal and glaucoma mice. It has strong clinical significance and potential impact to the field in that it can provide 1) an early marker of glaucoma and for monitoring therapeutic intervention and 2) powerful insights into how retinal and choroidal blood flow and oxygenation are regulated and how glaucoma affects the two vasculatures and the neural tissues they subserve. Data from these animal studies should advance these areas of research, open up new avenues for retinal research, and lay the foundation for future human studies.