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OPHTHALMOLOGY Researchers Eye Earliest Triggers of Age-related Macular DegenerationOld age can extract a heartless toll on those affected by age-related macular degeneration. This blinding disease claims exactly that region of the eye that is responsible for the most valuable type of sight--precise straight-ahead vision. As it progresses, the disease blots out a person's ability to distinguish what might have made old age most pleasurable--words on a page, the colors of the world, and, most of all, people's faces.
In the healthy eye, cones are neatly lined up to maximize their exposure to light. During age-related macular degeneration, the cones become disoriented. In addition, fatty deposits accumulate in the underlying retinal pigment epithelium (RPE), and the membrane below the RPE thickens. These changes in the RPE, which is responsible for regenerating pigment, were thought to impair the cones' ability to collect light. But Ann Elsner and her colleagues found that the cones begin to malfunction even when their ability to regenerate pigment is about normal. They believe the problem may lie in the cones themselves or in their dense extracellular matrix. Illustration adapted from original by Steven Burns, Ann Elsner, and Francois Delori Age-related macular degeneration is the leading cause of blindness for Americans over 60 years of age, affecting more than 14 million people. Yet how it cuts its swathe through the macula, the cone-rich center of the retina, is a controversial question. A leading camp says the disease begins when nearby cells that help replenish the vital pigment found in the cones become clogged with fatty deposits. Unable to renew their store of light-absorbing pigment by the usual route, the cones' ability to process light becomes extinguished. It now appears that the cones' demise may begin long before their stores of pigment are cut off. Schepens Eye Research Institute's Ann Elsner, Stephen Burns, and John Weiter have been studying people with early stages of disease and found that the cones' ability to collect light is impaired even when their ability to regenerate pigment is about normal. The researchers, whose report appears in the January Journal of the Optical Society of America, suggest that the initial problem lies not in the cones' ability to recycle their light-processing pigment but in their ability to physically capture light in the first place. The Cones Have ItNormally, cones are aligned in the retina in a way that affords them the maximum exposure to light. They are supported by a dense matrix of proteins, lipids, and chemicals. The Schepens researchers believe that there may be changes in this complex matrix that cause the cones to become physically disoriented, or changes inside the cones themselves, impairing their ability to catch and conduct light. "To guide the light, everything has to be lined up properly," said Elsner, HMS assistant professor of ophthalmology. "Somehow these cones, which are like tiny antennae, are not tuned correctly any more," said Burns, HMS associate professor of ophthalmology. Weiter is an HMS associate clinical professor of ophthalmology.
"People are moving down to Florida thinking they're going to be playing golf," said Ann Elsner (right), shown here with John Weiter (left) and Stephen Burns. "At age 71, which is only a few years after retirement, they're losing their sight. It's heartbreaking." Photo by Steve Gilbert The findings cannot help the millions of affected Americans--including the one in three people over 80 years of age who have the disease--but they could be used to prevent future generations from suffering its damage. For example, people might be screened for early signs that their pigment-rich cones are not doing an adequate job of collecting and conducting light, using the criteria discovered by the Schepens group. People with this deficiency might consider increasing their intake of antioxidants, which were found to slow the course of disease in 20 percent of patients in a recent National Eye Institute study. The research grew out of Elsner's desire to allow people with the disease to prepare for what might lie ahead. Clinicians long ago noticed two distinctive features in the retinas of patients with age-related macular degeneration--white fatty deposits, or drusen, and a thickening of the membrane separating the retina from nutrient-carrying blood vessels. The prevailing view when Elsner set out on her study was that the drusen and the membrane thickening were damaging the cones by clogging up the flow of nutrients. It was also thought that they might be interfering with the cones' ability to regenerate pigment. In the healthy eye, cones collect light and guide it back to stacks of pigment, which are activated, allowing a response to be generated. The pigment is generally thought to be recycled by traveling outside the cell to a layer of retinal pigment epithelial cells. There it is rebuilt and sent back to the cones, where it awaits the next burst of light. As it turns out, the retinal pigment epithelial cells are the same ones that become clogged in people with age-related macular degeneration, supporting the notion that changes in these cells' ability to recycle pigment were responsible for the cone's demise. Theoretical BlindspotsBut Elsner and her colleagues saw gaps in this scenario. If traffic of nutrients and pigment was blocked, then the cones should die off relatively quickly. Yet the cones hang on for remarkably long periods of time after a person develops the disease.To find out what was happening to the cones, and specifically to see if their pigment regeneration was impaired, the researchers tested the color vision of 53 adults, average age 71, who were at a relatively early stage of disease. Elsner and her colleagues were able to assess their baseline level of pigment. As expected, many subjects had low levels of pigment, but some had near-normal reserves. The next step was to measure the rate at which their pigment was being regenerated. To do this, the researchers asked the subjects to perform a color-matching test at different light levels. At low light, little pigment is activated because cones are absorbing less light. But the more light the cones receive, the more pigment is used and the more that needs to be recycled. At some point, the rate of pigment use surpasses the rate of regeneration, leading to almost complete depletion, or bleaching, of pigment. If regeneration were slowed in age-related macular degeneration patients, as was supposed, bleaching should occur at fairly low levels of light. Yet Elsner and her colleagues found that bleaching required high levels of luminance in patients with normal as well as low levels of pigment. One possibility is that the age-related macular degeneration patients are regenerating pigment faster than normal--a prospect the researchers find unlikely. Far more likely is that the cones are having trouble netting the light coming into the back of the eye. Elsner and her colleagues believe that a fuller exploration of this idea could lead to new treatments for age-related macular degeneration. For example, if changes in the matrix cause the cones to lose their proper alignment, then finding a way to bolster the cones could help stop the disease. "If you really want to arrest the disease and maximize the vision, there is an opportunity waiting at this very early stage, if we could just figure out why the cones are being damaged and how," she said. --Misia Landau |
