The utility of using customized heterochromatic flicker photometry (cHFP) to measure macular pigment in patients with age-related macular degeneration
Introduction
Age-related macular degeneration (AMD) is caused by slow degeneration of the retina and retinal pigment epithelium (RPE). Although a number of factors contribute to the progression of this degeneration, a central theme appears to be oxidative stress (e.g., Cai et al., 2000, Beatty et al., 2000). The role of oxidative stress is of particular interest because of its potential modifiability. By making healthy life style choices, oxidative stress to the retina and RPE may be lowered, and the probability that an individual will develop AMD could be reduced. One approach to combating oxidative stress, examined in the Age-Related Eye Disease Study (AREDS, 2001), is increasing the dietary intake of antioxidants. For subjects with intermediate stages of AMD, AREDS found that high-dose antioxidant supplementation (including zinc) reduced the risk of disease progression by 25% and the loss of visual acuity by 19%. However, the AREDS supplement did not include lutein (L) and zeaxanthin (Z), the components of the macular pigment, as part of their intervention. A growing body of evidence (e.g., Nolan et al., 2007, Whitehead et al., 2006) has suggested a role for retinal L and Z (L&Z) in protecting the retina and RPE from oxidative damage both by absorbing actinic short-wave light and through antioxidant mechanisms. Moreover, there is evidence that supplementing L&Z can improve visual performance for subjects with atrophic AMD (Richer, 1999, Richer et al., 2004). Based on current evidence, one arm of the follow-up AREDS II trial will test whether supplementation with L&Z, along with other nutrients, can retard vision loss and disease progression in subjects with intermediate stages of AMD.
Because subjects vary greatly in the ease with which L&Z is accumulated in the retina as macular pigment (e.g., Hammond et al., 1997a, Hammond et al., 1997b, Aleman et al., 2007, Bhosale et al., 2007, Richer et al., 2007) interpreting the outcome of supplementation trials in patients with AMD would be greatly facilitated by measuring the amount of the supplement that accumulates in the retina. If patients benefit from supplementation, one could gain insight into how much macular pigment is needed to derive a benefit. If patients fail to benefit from supplementation, it would be possible to distinguish whether (1) the lack of benefit was due to the failure of L&Z to be incorporated into the tissue, or (2) L&Z were incorporated into the retina but they were not effective in modifying the course of the disease at this stage. If supplementation did not increase macular pigment, it would be appropriate to study ways to improve L&Z uptake in the digestive system and L&Z accumulation in the retina, perhaps by modifying fat intake or lipoprotein profiles (e.g., Wang et al., 2007, Snodderly et al., 2004b). If outcome 2 occurred, effort could be concentrated on other stages of the disease or on evaluation of alternative therapies. Obviously, there could be individual differences, with some patients benefiting and others not. Knowing their macular pigment status might help to determine why individuals differed in their response to the intervention.
The study of L&Z as a potential nutritional therapy represents an unusual opportunity. Unlike most nutrients in tissues, L&Z can be measured as macular pigment using non-invasive in vivo methods. In this study, we evaluate whether heterochromatic flicker photometry (HFP), the most common non-invasive means of measuring macular pigment, is useful for patients with intermediate stages of AMD. For this method, the subject must judge the presence or absence of flicker when a properly configured stimulus alternates between a wavelength that is absorbed by MP and one that is not. An eccentric location outside the fovea, where MP levels are generally considered to be optically undetectable, serves as a reference (see Snodderly and Hammond, 1999). The validity of the HFP method in both young and older subjects has been the subject of several recent papers (Snodderly et al., 2004a, Hammond et al., 2005, Wooten and Hammond, 2005; Gallaher et al., 2007). These papers have provided strong evidence that the technique is both highly reliable and valid in normal subjects across the lifespan. Although HFP and a number of other methods have been used to measure MP in AMD patients, until now none of the MP measurement methods have been validated on patients, who have altered retinas and often have cloudy ocular media.
The advantages of HFP (when customized to provide optimal accuracy) include the following: (1) Pupil dilation is not required. (2) High light levels are not required. (3) The results are relatively insensitive to the state of the ocular media (e.g., Wooten et al., 1999, Ciulla et al., 2001, Gallaher et al., 2007, Ciulla and Hammond, 2004). (4) The results are not confounded by head movements (e.g., Wooten et al., 1999). (5) Testing can be optimized to control for individual differences in temporal vision. Optimization of temporal parameters is especially important in AMD patients, who tend to have decreased sensitivity to higher temporal frequencies (e.g., Falsini et al., 2000, Phipps et al., 2004). (6) Measurements can be integrated with other tasks in a single study visit. Elderly participants can complete a standard measurement at one eccentricity in 20–30 min (e.g., Snodderly et al., 2004a, Gallaher et al., 2007) and this location (0.5° eccentricity) captures most of the variance between subjects (e.g., Snodderly et al., 2004a, Mares et al., 2006).
The most serious limitation of HFP is that it requires the active participation of the subject, who must make accurate perceptual judgments of the presence or absence of flicker. For normal older subjects tested with optimized protocols, more than 80% of naïve subjects can perform the procedure (e.g., Snodderly et al., 2004b, Iannaccone et al., 2007). In the largest study on naïve subjects to date (n = 1158), comparison of data collected at two wavelengths confirmed that the values were consistent with the spectral absorption curve of MP (Snodderly et al., 2004b). In the present paper, we evaluate the utility of a particular implementation of HFP for measuring MP in patients with AMD. To distinguish our approach from other variants of HFP we refer to it as “customized HFP (cHFP)” because, among other refinements, the flicker frequency is individually customized to the visual capabilities of each subject. Using cHFP, we find that patients with AMD are about as proficient as normal elderly subjects in performing the flicker task, as long as the stimulus is clearly visible to them. Furthermore, their data are consistent with spectral and spatial criteria for a valid measurement of macular pigment (e.g., Snodderly et al., 2004a, Hammond et al., 2005).
Section snippets
Subjects
MPOD data were obtained from 28 subjects who were recruited in and around Augusta, GA, USA, and tested at the Medical College of Georgia. Two additional subjects were recruited at other sites, one at the Schepens Eye Research Institute in Boston, MA, and one at Brown University in Providence, RI, USA, making a total of 30 patients from whom data were obtained. The study followed the Tenets of the Declaration of Helsinki. All procedures were approved by the institutional review boards at the
Results
The personal characteristics for each subject are listed in Table 1. About half of the subjects were taking supplements that contained L and Z. The subjects that supplemented, however, did not have significantly higher MPOD levels as a result (p < 0.90). A short clinical description for each subject is provided in Table 2. Most subjects were well described by the age-related eye disease study (AREDS) categories 2 and 3 (category 1, no ARM with the exception of a few small drusen; category 2,
Discussion
The results from this study demonstrate that valid macular pigment measurements can be obtained in a reasonable time using carefully customized HFP (cHFP) in patients with intermediate AMD, as long as they have visual function sufficient to clearly see the stimulus. This conclusion is based on the similarity of the spectral curves to the ex vivo spectrum and the concordance of the MPOD spatial distributions of AMD patients with distributions measured in normal subjects (Table 3 and Fig. 1).
Acknowledgements
Supported by grants from Gustavus and Lousie Pfeiffer Research Foundation and Fight for Sight, Research to Prevent Blindness (PD04042). We thank Julian J. Nussbaum for access to patients with AMD, and the Fundus Photography Reading Center of the University of Wisconsin, Madison for grading fundus photographs of the patients.
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Proprietary interests. Dr Wooten is a principal of Macular Metrics Inc.