Evidence we and others have published unequivocally demonstrates that retinal nerve fiber layer (RNFL) retardance measured by scanning laser polarimetry (SLP) declines prior to and faster than RNFL thickness measured by optical coherence tomography (OCT) following experimental retinal ganglion cell (RGC) axonal injury, including non-human primate (NHP) unilateral experimental glaucoma (EG). SLP detects the relative degree of phase retardance manifest by a scanning beam after it passes through the birefringent RNFL tissue. Normal RNFL tissue inherently exhibits strong birefringence primarily because its axons are enriched with a dense, orderly array of axonal cytoskeletal elements, microtubules in particular. SLP measurements of RNFL retardance thus provide a clinical assay of RNFL axonal cytoskeletal integrity. We have shown that these early RNFL retardance abnormalities are accompanied by loss of RGC function and that by the time RNFL thickness changes are detected by spectral domain OCT (SDOCT), 10-15% of the orbital optic nerve axons are lost. The current proposal will extend this line of investigation in two ways that are critical to translating our findings to the clinical management of human glaucoma patients. First, we will test the hypothesis that early-stage RNFL retardance abnormalities are associated with axonal transport deficits. Second, we will test the hypothesis that early RNFL retardance abnormalities are reversible by lowering intraocular pressure (IOP), that reversal is enhanced by calcium channel regulation, and that reversal will be protective against subsequent RGC functional loss, RNFL thinning, axonal transport disruption and optic nerve axon loss.
The Specific Aims of the project are:
Specific Aim 1 : To test the prediction that sectoral abnormalitie of RNFL retardance (measured by SLP) are predictive of subsequent sectoral RNFL thinning (measured by SDOCT) and of subsequent sectoral retinal dysfunction (measured by multifocal electroretinography).
Specific Aim 2 : To test the hypothesis that axonal transport deficits exist a the onset of RNFL retardance changes measured by SLP.
Specific Aim 3 : To test the hypothesis that RNFL retardance changes measured by SLP are reversible upon topical therapeutic intervention and that reversal will be protective against subsequent progressive RGC functional loss and RNFL thinning measured in vivo, as well as axonal transport disruption and optic nerve axon loss (assessed by post mortem histopathological studies). Proving that early-stage RNFL retardance abnormalities are associated with axonal transport disruption and that their reversal by common topical therapeutic intervention is protective against subsequent progressive RGC functional changes and optic nerve axon loss will have direct, translational relevance to the clinical care of human glaucoma patients and provide insight into the pathophysiological sequence of glaucomatous axonal degeneration.

Public Health Relevance

Glaucoma is the second most common cause of visual impairment worldwide and is the leading cause of irreversible blindness affecting more than 66 million people and causing bilateral blindness in nearly 7 million. It is a chronic disease with no known cure. Prospective clinical trials support the rationale for the only current treatment, which is to lower intraocular pressure (IOP), yet progressive vision loss still occurs even in some patients whose treatment has successfully lowered their IOP. Thus our knowledge about the pathophysiology of this disease remains incomplete and continued investigations into IOP-independent avenues of therapy are imperative. This project evaluates and advances clinical tools for detecting early-stage glaucomatous abnormalities within axons of the retina and optic nerve that are thought to precede permanent axon degeneration, a novel area of research that could lead to new avenues of treatment.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
2R01EY019327-05A1
Application #
8762356
Study Section
Special Emphasis Panel (ZRG1-BDCN-H (02))
Program Officer
Chin, Hemin R
Project Start
2008-12-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
5
Fiscal Year
2014
Total Cost
$371,250
Indirect Cost
$146,250
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
Morrison, John C; Cepurna, William O; Tehrani, Shandiz et al. (2016) A Period of Controlled Elevation of IOP (CEI) Produces the Specific Gene Expression Responses and Focal Injury Pattern of Experimental Rat Glaucoma. Invest Ophthalmol Vis Sci 57:6700-6711
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
Gardiner, Stuart K; Fortune, Brad; Demirel, Shaban (2016) Localized Changes in Retinal Nerve Fiber Layer Thickness as a Predictor of Localized Functional Change in Glaucoma. Am J Ophthalmol 170:75-82
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
Wilsey, Laura J; Fortune, Brad (2016) Electroretinography in glaucoma diagnosis. Curr Opin Ophthalmol 27:118-24
Gardiner, Stuart K; Demirel, Shaban; Reynaud, Juan et al. (2016) Changes in Retinal Nerve Fiber Layer Reflectance Intensity as a Predictor of Functional Progression in Glaucoma. Invest Ophthalmol Vis Sci 57:1221-7
Hood, Donald C; De Cuir, Nicole; Mavrommatis, Maria A et al. (2016) Defects Along Blood Vessels in Glaucoma Suspects and Patients. Invest Ophthalmol Vis Sci 57:1680-6
Fortune, Brad (2015) In vivo imaging methods to assess glaucomatous optic neuropathy. Exp Eye Res 141:139-53
Wang, Lin; Cull, Grant A; Fortune, Brad (2015) Optic nerve head blood flow response to reduced ocular perfusion pressure by alteration of either the blood pressure or intraocular pressure. Curr Eye Res 40:359-67

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