The primary goal of this project is to test three hypotheses regarding glaucomatous damage to the visual system. First, that clinically detectable neural, glial and connective tissue alterations occur deep in the optic nerve head (ONH) at a very early stage in the pathophysiology of glaucomatous damage to the visual system. Second, that the location and magnitude of the earliest of these ONH changes, detectable in vivo by spectral domain optical coherence tomography (SDOCT), predict the specific locations of subsequent alterations of the peripapillary retinal nerve fiber layer (RNFL) and orbital optic nerve axon loss. Third, that ONH connective tissue structural stiffness is altered both by age and glaucomatous damage and that it underlies the clinical appearance of the glaucomatous optic disc, specifically by influencing the "depth" of glaucomatous ONH structural change or "cupping". Until now, all animal models of glaucoma have been studied in isolation from human glaucoma. A second goal is to demonstrate that our hypotheses and techniques have evolved to a point where both can be simultaneously tested in monkeys (Specific Aim 1) and humans (Specific Aim 2).
Aim 1 is to characterize the onset and progression of SDOCT ONH structural change within pre- and post- laser SDOCT ONH data sets from both eyes of 70 unilateral experimental glaucoma (EG) monkeys.
Aim 2 is to characterize the onset and progression of ONH structural change within longitudinal SDOCT ONH data sets from 250 human ocular hypertensive and early glaucoma patients. The methodology includes: longitudinal Heidelberg Spectralis 870 and 1060 nm SDOCT ONH image acquisition in monkeys (870 nm only in humans); their visualization, delineation and quantification within custom Multiview software;and in monkeys only, post- mortem 3D histomorphometric ONH reconstruction and quantification, co-localized, eye-specific comparison of SDOCT ONH and 3D histomorphometric reconstructions and regionally-aligned orbital optic nerve axon damage map generation using our custom Axonmaster axon counting software. The expected outcomes are: 1) deep ONH structural change will occur before and predict subsequent ONH surface and RNFL change during the onset and progression of glaucomatous damage in both monkey and human eyes;2) early ONH structural change will co-localize to orbital optic nerve axon loss in monkey eyes and precede RNFL alterations in both monkey and human hypertensive eyes;3) in monkeys, younger ONHs will be "more compliant" and older ONHs will be "stiffer" when normal, and both will demonstrate transient hypercompliance followed by progressive stiffening as glaucomatous damage progresses;4) younger monkey and human ONHs will demonstrate a "deeper" form of "cupping" than older ONHs;5) in younger compared to older eyes, the onset and progression of structural change ("cupping") will include a larger connective tissue component;and 6) 1060 nm SDOCT imaging will improve visualization of deep monkey ONH imaging targets compared to the existing clinical standard (870 nm imaging).

Public Health Relevance

The clinical detection of the onset and progression of glaucomatous damage to the optic nerve head (ONH) is central to the care of every glaucoma patient. We propose to use 870 nm and 1060 nm Heidelberg Spectralis Spectral Domain Optical Coherence Tomography (SDOCT) to characterize the onset and progression of ONH structural change within pre and post- laser SDOCT ONH data sets from both eyes of 70 unilateral experimental glaucoma (EG) monkeys and 250 ocular hypertensive and early glaucoma patients. In this project we will translate 11 years of NIH-funded, post-mortem monkey work to an in-vivo imaging modality that will be shown to have important and novel clinical care applications in humans.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY021281-04
Application #
8585070
Study Section
Special Emphasis Panel (ZRG1-AED-W (02))
Program Officer
Chin, Hemin R
Project Start
2010-12-01
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$344,250
Indirect Cost
$119,250
Name
Emanuel Hospital and Health Center
Department
Type
DUNS #
050973098
City
Portland
State
OR
Country
United States
Zip Code
97232
Wilsey, Laura J; Reynaud, Juan; Cull, Grant et al. (2016) Macular Structure and Function in Nonhuman Primate Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:1892-900
Fortune, Brad; Reynaud, Juan; Hardin, Christy et al. (2016) Experimental Glaucoma Causes Optic Nerve Head Neural Rim Tissue Compression: A Potentially Important Mechanism of Axon Injury. Invest Ophthalmol Vis Sci 57:4403-11
Ivers, Kevin M; Yang, Hongli; Gardiner, Stuart K et al. (2016) In Vivo Detection of Laminar and Peripapillary Scleral Hypercompliance in Early Monkey Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:OCT388-403
Fortune, Brad; Hardin, Christy; Reynaud, Juan et al. (2016) Comparing Optic Nerve Head Rim Width, Rim Area, and Peripapillary Retinal Nerve Fiber Layer Thickness to Axon Count in Experimental Glaucoma. Invest Ophthalmol Vis Sci 57:OCT404-12
Ing, Eliesa; Ivers, Kevin M; Yang, Hongli et al. (2016) Cupping in the Monkey Optic Nerve Transection Model Consists of Prelaminar Tissue Thinning in the Absence of Posterior Laminar Deformation. Invest Ophthalmol Vis Sci 57:2598-611
Gardiner, Stuart K; Boey, Pui Yi; Yang, Hongli et al. (2015) Structural Measurements for Monitoring Change in Glaucoma: Comparing Retinal Nerve Fiber Layer Thickness With Minimum Rim Width and Area. Invest Ophthalmol Vis Sci 56:6886-91
Burgoyne, Claude (2015) The morphological difference between glaucoma and other optic neuropathies. J Neuroophthalmol 35 Suppl 1:S8-S21
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Chauhan, Balwantray C; Danthurebandara, Vishva M; Sharpe, Glen P et al. (2015) Bruch's Membrane Opening Minimum Rim Width and Retinal Nerve Fiber Layer Thickness in a Normal White Population: A Multicenter Study. Ophthalmology 122:1786-94
Fortune, Brad; Cull, Grant; Reynaud, Juan et al. (2015) Relating Retinal Ganglion Cell Function and Retinal Nerve Fiber Layer (RNFL) Retardance to Progressive Loss of RNFL Thickness and Optic Nerve Axons in Experimental Glaucoma. Invest Ophthalmol Vis Sci 56:3936-44

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