African Descent and Glaucoma Evaluation (ADAGES) IV: Alterations of the lamina cribrosa in progression

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Project Abstract Overall Objective: This proposal is focused on morphological changes in the lamina cribrosa with glaucoma onset and progression, and how those changes impact visual function, with a focus on racial disparities. This project leverages on the longitudinal monitoring of a subset of glaucoma patients in the existing ADAGES cohort of which 3.7 years(average) of enhanced depth imaging optical coherence tomography (EDIOCT) and visual field standard perimetry (VF) is available. The overall objective of the ADAGES studies is to identify what ocular, systemic and genetic factors account for the differences in the glaucoma prevalence, severity, and rates of disease progression in individuals of African Descent (AD) compared to those of European Descent (ED). The specific aims are: 1) To determine if the progressive changes in lamina cribrosa observed longitudinally in glaucomatous ADAGES patients will be associated with greater VF progression in a 8(at least) year of EDOCT and VF follow-up imaging, and if this association differs across race. 2) To determine what baseline morphologic characteristics of the optic nerve head (ONH) are associated with progression-dependent remodeling of the lamina cribrosa and ONH. 3) To determine if mechanical compliance of the ONH as measured in-vivo and longitudinally is associated with remodeling of the lamina cribrosa and progressive neural tissue (structure) and VF damage (function). Design: Participants are 148 AD and 144 ED individuals with glaucoma who have 3.7 years(average) of ONH EDIOCT imaging and VF longitudinal data from the ADAGES cohort. Demographic variables, ophthalmological examination including stereo-photographs, visual function with standard perimetry, intraocular and systemic pressures, and other risk factors will be documented longitudinally. The morphology and compliance of the lamina cribrosa and ONH will be quantified on 60 newly enrolled ED and 60 AD glaucoma patients by EDIOCT and VF imaging over a follow-up of 5 or more years. Impact: Glaucoma is 4 to 5 times more likely to occur and progress to severe visual impairment in persons of AD compared to persons of ED. Our group has identified several racial differences in the morphology and mechanical behavior of the lamina cribrosa and peripapillary sclera that suggest these differences will meaningfully impact or possibly be causative of the load bearing connective tissue remodeling seen in both natural aging and in the onset and progression of glaucoma. The race-specific and extensive longitudinal data of this study will provide a detailed insight of the pathophysiologic relationship between remodeling of the ONH load bearing tissues with the rate of structural damage of the retinal neural tissue and the resulting progressive visual impairment. This study, through the inclusion of an innovative biomechanical compliance testing protocol, will inform the development of mechanistically relevant biomarkers for glaucoma necessary for the development of non-IOP lowering glaucoma therapies targeted at altering mechanical strain-driven pathophysiology of the ONH.!