The term low luminance deficit
3 refers to the loss of visual acuity under mesopic conditions as compared with acuity under photopic conditions. Previously studied within the context of advanced AMD, low luminance deficit has been associated with an increased risk for visual acuity loss in GA
3 and also greater risk for GA progression.
6 Here, we report for eyes in presumably normal macular health (AREDS step 1
17) at baseline, low luminance deficit is not associated with early AMD 3 years later. However, we have found that the absolute level of mesopic acuity is a functional risk factor for early AMD. The point estimate of the mesopic acuity risk factor is slightly weaker than delayed rod-mediated dark adaptation, although the dark adaptation risk factor had a wider confidence interval (Fig.). That impaired mesopic acuity is associated with incident early AMD suggests that some older eyes in seemingly normal macular health have disturbed cone-mediated spatial resolution under low luminance conditions, which increases their risk for early AMD. The mechanisms underlying impaired mesopic acuity in AMD have not yet been identified. Cone density, including that in the fovea, remains remarkably stable during the aging process,
30 and the foveal cone photoreceptor matrix is well preserved in nonneovascular AMD.
31 While foveal acuity under mesopic conditions relies on cones, rod photoreceptors also have a role in mesopic acuity through rod–cone coupling. If rods around the cone-only foveola are abnormal because early AMD has already begun, then coupling to rods under mesopic lighting could result in poorly functioning cone-driven circuits, and in turn, a mesopic acuity deficit. In addition to changes in rod–cone coupling, disturbances in the operation of surround mechanisms maintained at the level of the two plexiform layers by horizontal and amacrine cells could contribute to decreased spatial resolution under mesopic conditions. There is previous evidence for reorganization of synaptic connectivity and degradation of inner retinal signal processing after photoreceptor degeneration in inherited retinopathies
32 and in AMD.
33 Thus, mesopic acuity loss in older adults in normal macular health who are at increased risk for early AMD might be attributable to changes in rod–cone coupling or foveal surround mechanisms under mesopic conditions, issues worthy of further investigation.
Although low luminance deficit has been found to be a functional risk factor for late stage AM (GA), our results suggest that it is not a risk factor for early AMD. The difference between a mesopic acuity measure and a low luminance deficit measure is that the former is not “anchored” against a photopic measure, whereas the latter is. Low luminance deficit is the difference between photopic and mesopic acuity, whereas mesopic acuity is simply the measurement of mesopic acuity. An obvious difference between GA and early AMD is that in GA significant photoreceptor degeneration has taken place, which could potentially lead to differential patterns of photopic and mesopic acuity impairment.
In evaluating whether mesopic acuity is a good candidate as a functional outcome measure in trials for treatments or prevention of early AMD, it is important to look at the natural history of the measure over time. We found that the mesopic acuity was remarkably stable over 3 years, in eyes that converted to early AMD 3 years later as well as those eyes that did not. Thus, while results suggest that mesopic acuity is a risk factor for early AMD, they do not suggest promise for mesopic acuity as an outcome measure for early AMD trials because it is relatively insensitive to AMD onset and early progression. Thus, mesopic acuity can be contrasted with rod-mediated dark adaptation, which has previously been shown in this same cohort to worsen over 3 years.
2
Not surprisingly, photopic visual acuity was not associated with incident early AMD. However, neither were photopic contrast sensitivity and macular light sensitivity. Yet cross-sectional studies have reported that those eyes with early AMD have worse contrast sensitivity and light sensitivity in the macula than eyes in normal macular health
9–11 (although not all agree
21). Cross-sectional studies suffer from ambiguities between the timing of disease onset and risk factor measurement. They also have selection biases, including survival bias, particularly if the risk factor and disease are also associated with mortality (which has been reported for both vision impairment
34,35 and AMD
36,37).
In the current study, light sensitivity testing was performed at a low photopic level (10 cd/m
2). However, scotopic conditions may be better at revealing light sensitivity impairments in older adults that enhance their risk for developing early AMD. Histopathologic studies have demonstrated a selective vulnerability of rods over cones in maculas of aged and AMD eyes.
30,31,38 Psychophysical studies have shown that scotopic sensitivity in aging and early AMD is typically more impaired than photopic sensitivity,
12,14,39,40 and that slowing of rod-mediated dark adaption is a functional marker for incident early AMD.
16,41–43 Thus, future prospective studies should address whether scotopic sensitivity impairment in eyes in normal macular health increases the risk for incident early AMD.
Strengths of this study include a very large sample of eyes in normal macular health at baseline (
N = 827). The study was prospective in design, and thus we could establish that the psychophysically measured deficit was present prior to the onset of early AMD. The study focus was on the transition from normal aging to early AMD, an understudied epoch in AMD pathogenesis. We selected psychophysical tests that prior research suggested might be good candidate risk factors for AMD. Many potential confounders were assessed before examining the relationship between visual dysfunction and incident early AMD. Participants were recruited from primary care ophthalmology practices where the general population seeks care. Limitations must also be acknowledged. Some visual function tests that have potential as functional outcomes based on previous research on AMD (e.g., flicker sensitivity, short wavelength light sensitivity, scotopic sensitivity, photopic multifocal electroretinogram)
12,40,44-47 were not included in the study protocol, but deserve further investigation. With respect to measuring the low luminance deficit, we used a 1.5–log unit filter as reported in the original paper describing the low luminance deficit in GA,
4 and not the 2.0–log unit neutral density filter, which was used in the more recent publications on GA.
3,6 Photopic light sensitivity in the macula was not assessed at follow-up so we could not compute how it may have changed over time. The study was not population-based with respect to the geographic region. Most participants were white of European descent, and thus the generalizability of our results to other subpopulations remains to be determined.
In conclusion, impaired mesopic visual acuity in older eyes in normal macular health is a risk factor for incident early AMD 3 years later. However, mesopic visual acuity does not grow worse over the subsequent 3 years, suggesting that it may not be a suitable outcome measure for evaluating interventions to prevent early AMD. Our study suggests that impaired photopic visual acuity, photopic contrast sensitivity, and light sensitivity under low photopic conditions, and the presence of the low luminance deficit, are not functional risk factors for early AMD.