Spare the rods, save the cones in aging and age-related maculopathy.

Age-related maculopathy (ARM) is the leading cause of untreatable new vision loss among older adults in the United States and other industrialized countries. ARM is a heterogeneous disorder affecting the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris (the RPE/Bruch’s membrane complex). Early ARM is characterized by minor-to-moderate vision loss associated with focal or diffuse sub-RPE debris and changes in RPE pigmentation. Late ARM is characterized by severe vision loss associated with extensive RPE atrophy with or without the sequelae of choroidal neovascularization. Better understanding of early ARM will help guide development of better treatments or prevention for late ARM. As reviewed elsewhere, recent progress has been made in understanding the demographics and natural history of early ARM and identifying genetic mutations that produce degeneration of the macula in young adults. In this review we focus on recent studies of visual function in elderly persons and in patients with ARM that complement previous histopathologic studies of photoreceptor loss in these conditions. The RPE, Bruch’s membrane, and the choroid are vitally important for the well-being of photoreceptors. It is the dysfunction and death of photoreceptors, through an atrophic process or a neovascular event, that account for the vision loss associated with ARM. Therefore, photoreceptor health, assessed functionally in living patients, is the most direct bioassay of the significance of changes in the RPE/Bruch’s membrane complex, which may not be revealed by standard imaging techniques such as fundus photography and fluorescein angiography until late in ARM or not at all. The functional studies reviewed herein were facilitated by the development of standard fundus grading systems, which permit comparison of results from patients at similar stages of ARM across disciplines, and a better understanding of the mechanisms underlying normal human dark adaptation, which informs the interpretation of ageand diseaserelated changes. For the purposes of discussion, we consider the human macula an area 6 mm in diameter, or 21.5° of visual angle, centered on the fovea. The small cone-dominated fovea, only 0.8 mm (2.75°) in diameter, is surrounded by a rod-dominated parafovea. In young adults, rods outnumber cones in the macula by 9:1. In the entire eye, rods outnumber cones 20:1, so the macula can be considered cone-enriched but not conedominated. In maculas of older adults lacking grossly visible drusen and pigmentary change (i.e., they do not have ARM), the number of cones in the cone-dominated part of the macula is stable at approximately 32,000 through the ninth decade. In contrast the number of rods in the macula of the same eyes decreases by 30%. The greatest loss occurs in the parafovea (13 mm from the fovea or 3.5–10° from fixation), with loss at more peripheral locations uncertain. The location of age-related rod loss differs from the region where rod density is maximal (4–6 mm from the fovea) and from the region where the cell loss associated with retinitis pigmentosa typically begins (8–10 mm from the fovea). With respect to photoreceptor topography at different stages of ARM, the foveal cone mosaic of eyes with large drusen and thick basal deposits appeared surprisingly similar to that of age-matched controls, and the total number of foveal cones was normal. In contrast, in the parafovea, cones appeared large and misshapen, and few rods remained. Furthermore, in eyes with late ARM, virtually all surviving photoreceptors in the macula were cones, a reversal of the normal predominance of rods. Preferential loss of rods over cones was found in 3 of 4 of early and late ARM eyes examined (Medeiros NE, Curcio CA, unpublished results, April 2000). Psychophysical studies of photopic and scotopic sensitivity have identified functional correlates to the histopathologic findings that rods are at risk for degeneration in aging and ARM. Older adults with good macular health, as assessed by grading of fundus appearance, have reduced rod-mediated light sensitivity, and the magnitude of this scotopic sensitivity impairment is similar throughout the parafoveal region. Scotopic impairment is greater than photopic impairment in 80% of older adults evaluated, and, furthermore, scotopic sensitivity declines throughout adulthood faster than photopic sensitivity declines. With respect to ARM patients, mean scotopic sensitivity within 18° of fixation was significantly lower in early ARM patients as a group than in age-matched controls without ARM. The topography of sensitivity loss in the central 36° of the visual field varied considerably among individual patients with early ARM. Of the patients with reduced light sensitivity in this region, 59% showed reduced scotopic sensitivity, 27% showed both reduced scotopic and photopic sensitivity, and only 14% had reduced photopic sensitivity. Thus, in almost all (87%) of these patients, the magnitude of mean scotopic sensitivity loss exceeded the magnitude of mean photopic sensitivity loss. The ARM-related deficit in scotopic sensitivity was most severe within 9° of fixation, suggesting that the emergence of regional sensitivity impairments within the parafovea may be an early sign of ARM. In addition to the reduced sensitivity of the rod system, the kinetics of rod function also change with aging and From the Department of Ophthalmology, University of Alabama at Birmingham, Alabama. Supported by National Institutes of Health Grant R01 AG04212, Research to Prevent Blindness, Inc., and Alabama Eye Institute. Submitted for publication December 28, 1999; revised March 15, 2000; accepted March 15, 2000. Commercial relationships policy: N. Corresponding author: Christine A. Curcio, Department of Ophthalmology, University of Alabama at Birmingham, 700 South 18th Street, Birmingham AL 35294-0009. curcio@uab.edu