Retinal Ganglion Cell Changes in Glaucomatous Monkeys

Glaucoma is the second leading cause of blindness in the United States, and the leading cause of blindne.ss among Black Americans. Of the different types of glaucoma, primary open-angle glaucoma (POAG) is the most common form, affecting approximately 3 million people. An additional one million Americans are considered to be at risk of developing glaucoma because they have at least one or more of the risk factors commonly associated with the disease. These include, but are not limited to, a family history of glaucoma, high intraocular pressure (IOP), myopia, and diabetes. Age also is a critical factor. The incidence of glaucoma increases approximately 10-fold between 50 and 70 years of age, ranging from about 0.2% of the population between the ages of 50 and 54 to 2.0% of the population aged 70-74 . The identification of patients at risk of developing POAG is complicated by both the lack of a reliable predictor of the disease and a method sensitive enough to detect structural and functional changes indicative of the very earliest stages of the disease. Elevated intraocular pressure, which for years was considered to be synonymous with glaucoma, no longer is considered to be a reliable predictor of the disease. Some eyes with above normal intraocular pressure show no signs of optic neuropathy, while other eyes with normal or lower than normal pressure show significant signs of neuronal degeneration as well as visual field defects. Nevertheless, elevated intraocular pressure is considered to be an important causative factor. Patients with unilateral elevation of intraocular pressure that is secondary to other eye disorders often develop glaucoma in the eye with elevated pressure. In addition, patients over the age of 30 that are diagnosed as ocular hypertensives, because they have above normal intraocular pressure but no degenerative signs of the disease, have been shown to have a higher incidence of developing glaucoma over a five year period than patients of similar age that are classified as normal. The primary treatment for patients with, or suspected of developing glaucoma., remains the reduction of intraocular pressure. At present, however, the degree of functional recovery that can be expected by reducing IOP is unclear. Some studies report no recovery, or even a further progression of visual dysfunction, while other studies indicate varied levels of structural and functional improvement. It is reasonable to hypothesize that these different results might reflect differences in the amount of neuronal damage present at the time that IOP is reduced. This possibility is supported by the fact that ocular hypertensives typically show a greater degree of recovery than patients with clinically-diagnosed POAG. At present, however, no comprehensive data are available concerning the relation between duration and level of increased intraocular pressure, damage to the optic nerve head (based on standard clinical evaluation of the optic disc), and the degeneration of nerve cells in the retina. A major focus of the proposed work is to compare systematically the structural changes that occur at the optic nerve head of glaucomatous eyes with nerve cell atrophy in the retina. In particular, these studies will focus on the effect that chronic elevation of intraocular pressure has on individual ganglion cells in the retina. These neurons play an important role in the processing of visual signals within the retina, and they represent the only means by which visual information is conveyed to higher centers of the brain. A Second specific aim of the proposed work is to determine whether different levels and durations of elevated intraocular pressure have a differential effect on the various types of ganglion cells in the retina. These data could be useful in the design and refinement of psychophysical tests used to detect and evaluate POAG patients, and those at risk of developing the disease. Most psychophysical tests are based on the premise that the primate visual system can be divided anatomically and physiologically into at least two primary, parallel pathways. The M pathway originates from parasol cells, which represent about 10 of the ganglion cells in the retina. At all locations in the retina, parasol cells are among the largest neurons in the ganglion cell layer, and they have large, sparsely branched processes. The P pathway originates from midget ganglion cells in the retina. These cells represent about 80% of the ganglion cells in the primate retina. They are characterized by their medium-small cell bodies and small and densely branched processes. Recent studies in humans with primary open-angle glaucoma and monkeys with experimentally-induced glaucoma have suggested, based on cell body measurements, that large ganglion cells, and therefore presumably the M pathway, may be most vulnerable during the early stages. of glaucoma.. However, since retinal ganglion cell loss in glaucoma is not restricted to only the largest cells, and since most ganglion cells in the primate retina cannot be classified based on cell body size alone, one cannot rule out the possibility that glaucoma affects both the M and P pathways. Similarly, studies of higher visual centers also indicate that both visual pathways might be affected. Using the technique of intracellular labeling, the proposed research will address directly the issue of whether prolonged periods of increased intraocular pressure affect specific visual channels differentially. By labeling single ganglion cells completely (cell body and processes), it should be possible to detect whether different classes of retinal ganglion cells are affected preferentially during the different clinical. stages of glaucoma. In addition, we will be able to determine whether ganglion cells located in different regions of the retina are more susceptible to damage from elevated IOP than ganglion cells located in other regions (i.e. central vs peripheral retina). We believe that the proposed studies will provide much needed information concerning the onset and progression of glaucoma-related neuronal damage in the primate visual system. In particular, the data will define the temporal relation between the clinical stages of the disease, based on standard ophthalmologic evaluation of the optic nerve head, and the degeneration of ganglion cells in the retina. Further, intracellular labeling of single ganglion cells will establish directly whether different classes of ganglion cells, and therefore specific visual channels, differ in their vulnerability to increased elevation of intraocular pressure. These data will aid in the development of more sensitive psychophysical tests to detect the earliest visual defects associated with glaucoma, and they also will provide a foundation for future studies aimed at the development of better treatment strategies for patients with glaucoma.