MPOD has been reported by others to be related to serum lutein in healthy volunteers9–12
but not in a group of 48 patients with retinitis pigmentosa without CME, in whom the correlation was 0.14.12
After adjusting for age, sex, iris color, central foveal retinal thickness, loge
serum zeaxanthin, and serum total cholesterol and excluding eyes with CME, we found a higher correlation (0.37) between MPOD and loge
serum lutein in our patients with retinitis pigmentosa. This correlation was highly significant for the large sample size in this analysis (n
= 139) and would also have been statistically significant for the smaller sample size of the previous study.12
Although a simple correlation between MPOD and serum lutein in our patients was also significant and was higher (0.23) than what was obtained before,12
it would not have been statistically significant for the smaller sample size of the previous study. The present study, therefore, illustrates the value of reducing the unexplained MPOD variance by removing the influence of confounding factors in detecting a significant relationship between MPOD and serum lutein in retinitis pigmentosa.
Including serum total cholesterol in the multiple regression model revealed an inverse relationship between MPOD and serum cholesterol and strengthened the positive relationship between MPOD and serum lutein. The inference from these two observations is that a higher serum cholesterol level impedes the transport of lutein into the retina. Because these findings relating MPOD to serum lutein and to serum cholesterol were unchanged when we excluded patients with CME from the analysis, this conclusion does not appear to hinge on a partial breakdown of the distal blood-retinal barrier.
We also found that the relationship between MPOD and serum lutein tended to be stronger in men than in women, compatible with previous results in healthy subjects based on measurements of serum lutein11
or of plasma lutein plus zeaxanthin.26
The latter study hypothesized that hormonally controlled variations in lipid transport used by carotenoids in women might weaken the relationship between MPOD and plasma lutein plus zeaxanthin.
On the other hand, we did not find that MPOD was positively related to loge
serum zeaxanthin. The absence of a significant positive association between MPOD and serum zeaxanthin was reported previously for healthy volunteers.11
These negative results may be explained by the observations that lutein outweighs zeaxanthin in diet and serum,34–36
and, though zeaxanthin predominates in the center of the fovea,21,37
that approximately half of this zeaxanthin is derived from lutein.21
We did not find significant relationships between MPOD and age or sex in our patients with retinitis pigmentosa, although the trends were in the same direction as in some previous reports based on healthy volunteers.23–26
We did find that MPOD was significantly related to iris color. MPOD averaged 22% higher in patients with brown irides than in patients with lighter irides, slightly smaller than the 26% difference found in healthy volunteers27
and consistent with the observation that patients with retinitis pigmentosa and light irides were more likely to have a low MPOD than a high MPOD.12
We found that MPOD was nonmonotonically related to central foveal retinal thickness in our cohort, which included patients without CME and patients with CME in the study eye. MPOD initially increased with increasing retinal thickness in eyes without CME or with minimal swelling caused by CME and then decreased with further increasing retinal thickness in eyes primarily with moderate to marked CME. The initial increase is consistent with the idea that xanthophyll incorporation is proportional to the number of central foveal cone photoreceptors,12,28
and we confirmed a significant linear relationship between MPOD and central foveal retinal thickness when we excluded the data from patients with CME in the study eye. The subsequent decrease in MPOD based on our total cohort could mean that moderate to marked edema hinders the uptake of lutein into the macula or distorts the radial arrangement of the foveolar cone axons, whose macular pigment molecules are normally oriented perpendicularly to the fiber axes,6
reducing their effective absorbance of incident blue light. Part of the decline in MPOD also could reflect CME coexisting with central foveal photoreceptor cell loss, which would compound the deficiency of MPOD. Still, by comparing the two slopes in , photoreceptor cell loss clearly has a greater impact than CME on MPOD in retinitis pigmentosa.
It should be pointed out that the derivation of MPOD by heterochromatic flicker photometry assumes that the brightness match between the alternating blue and green test stimuli is mediated by the same proportion and relative sensitivities of long-wavelength–sensitive and middle-wavelength–sensitive cones at the test and reference locations within a given patient. The method also assumes that cone photopigment optical density is the same, or nearly the same, at the two locations.38
Although there is no evidence that long-wavelength–sensitive cones become more or less affected than middle-wavelength–sensitive cones as retinitis pigmentosa progresses, it is likely that cone photopigment optical density was reduced more in the parafovea than at the central fovea in most of our patients given that cone sensitivity39
and cone directionality40
are typically lost in the parafovea before the fovea in this disease. This difference in cone photopigment optical density would be expected to reduce the measured MPOD.38
On the other hand, the significant relationships we found between MPOD and serum lutein concentration, iris color, and central foveal retinal thickness are concordant with previous findings in healthy observers, suggesting, at least for these comparisons, that the validity of the MPOD measurements was not appreciably compromised in our patient cohort.
Although it was based on cross-sectional data, our finding that MPOD increased significantly with increasing serum lutein and not with increasing serum zeaxanthin raises the possibility that an increase in macular pigment in the axons of cone photoreceptors in patients with retinitis pigmentosa could be more easily achieved in the diet by increasing serum lutein than by increasing serum zeaxanthin. Of course, this hypothesis can only be verified by a longitudinal study involving supplementation. Because we also noted that the between-session reproducibility of our MPOD data was similar to that observed in healthy observers,29–33
we propose that an increase in MPOD could be used as a biomarker for lutein uptake by the retina in this disease. In this regard, an open-label pilot study in which 23 patients with retinitis pigmentosa were asked to take a 20-mg lutein supplement each day for 6 months found that mean MPOD increased significantly in the fovea over follow-up.12
Although that pilot study did not detect any significant improvement in visual acuity or in foveal sensitivity with lutein supplementation,12
it remains to be determined whether an increase in MPOD with lutein supplementation in retinitis pigmentosa might further shield cone photoreceptors from ambient light and reduce oxidative damage over the long term, possibly slowing the rate of cone photoreceptor degeneration.41,42