Elevated intraocular pressure (IOP) has long been assumed to play a causative role in glaucomatous damage to the optic nerve head (ONH). Patient age is among the most important risk factors for the onset and progression of glaucomatous damage, regardless of the stage of glaucoma or the level of intraocular pressure (IOP) at which it has occurred. It is still unclear, however, how IOP triggers the cascade of events that lead to retinal ganglion cell death. We hypothesize that age-related alterations in ONH biomechanics contribute importantly to the increased susceptibility of the aged ONH in humans. Using three-dimensional (3D) reconstructions of the ONH, and principles of biomechanical engineering, we have studied the mechanical effects of elevated IOP in glaucoma. However, the relationship between patient age and the mechanical effects of elevated IOP is still unclear. How is the ONH altered as in the older patient that increases its susceptibility to IOP? Is the robustness of the ONH connective tissues the key to understanding individual susceptibility to glaucoma? What role does the structural stiffness of the lamina cribrosa and peripapillary sclera play in the increased age-related risk for glaucomatous progression? To answer these questions, we will use novel methods to elucidate the relationship between age and the IOP- induced deformation of ONH connective tissues are needed. By """"""""ONH biomechanics"""""""" we mean the interactions between IOP and connective tissue structural stiffness (the combination of tissue architecture and material properties) in the ONH and peripapillary sclera. The immediate goals of this project are to characterize age-related differences in ONH biomechanics and elucidate their effects on ONH susceptibility. Our long-term goal is to develop clinical diagnostics and interventions designed to manage each important biomechanical risk factor in the development and progression of glaucoma. To accomplish our immediate goals, we will build digital three-dimensional reconstructions of young and old human ONH tissues, quantify the ONH connective tissue architecture within each reconstruction, and build computational finite element models of the ONH connective tissues to estimate their biomechanical response to normal and elevated levels of IOP. We will also correlate the age-related variations in ONH architecture, tissue stiffness, and biomechanical behavior with the increased susceptibility and clinical behavior of the aged ONH.

Public Health Relevance

. Elevated intraocular pressure (IOP) has long been assumed to play a causative role in glaucomatous damage to the optic nerve head (ONH), and older patients have higher risk of development and progression of the disease. We propose to measure the age-related differences in ONH structure and IOP-induced biomechanical response. Then, using the principles of biomechanical engineering, we will use these data to create computational models of the age-related mechanical effects of elevated IOP on the ONH to elucidate the link between advancing age and glaucomatous susceptibility.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Anterior Eye Disease Study Section (AED)
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Agarwal, Neeraj
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Emanuel Hospital and Health Center
United States
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Downs, J Crawford; Girkin, Christopher A (2017) Lamina cribrosa in glaucoma. Curr Opin Ophthalmol 28:113-119
Girkin, Christopher A; Fazio, Massimo A; Yang, Hongli et al. (2017) Variation in the Three-Dimensional Histomorphometry of the Normal Human Optic Nerve Head With Age and Race: Lamina Cribrosa and Peripapillary Scleral Thickness and Position. Invest Ophthalmol Vis Sci 58:3759-3769
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Downs, J Crawford (2015) Optic nerve head biomechanics in aging and disease. Exp Eye Res 133:19-29
Qu, Jing; Chen, Huaping; Zhu, Lanyan et al. (2015) High-Magnitude and/or High-Frequency Mechanical Strain Promotes Peripapillary Scleral Myofibroblast Differentiation. Invest Ophthalmol Vis Sci 56:7821-30
Rhodes, Lindsay A; Huisingh, Carrie; Johnstone, John et al. (2015) Peripapillary choroidal thickness variation with age and race in normal eyes. Invest Ophthalmol Vis Sci 56:1872-9
Johnstone, John; Fazio, Massimo; Rojananuangnit, Kulawan et al. (2014) Variation of the axial location of Bruch's membrane opening with age, choroidal thickness, and race. Invest Ophthalmol Vis Sci 55:2004-9
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Rhodes, Lindsay A; Huisingh, Carrie; Johnstone, John et al. (2014) Variation of laminar depth in normal eyes with age and race. Invest Ophthalmol Vis Sci 55:8123-33

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