The Relationship of Macular Pigment Optical Density to
Serum Lutein in Retinitis Pigmentosa
Michael A. Sandberg,1Elizabeth J. Johnson,2and Eliot L. Berson1
PURPOSE. To determine whether macular pigment optical den-
sity (MPOD) is related to serum lutein or serum zeaxanthin in
patients with retinitis pigmentosa.
METHODS. The authors measured MPOD with heterochromatic
flicker photometry, serum lutein and serum zeaxanthin by high
performance liquid chromatography, and central foveal retinal
thickness by optical coherence tomography (OCT) in 176
patients (age range, 18–68 years) with typical forms of retinitis
pigmentosa; 37 (21%) of these patients had cystoid macular
edema (CME) by OCT. The authors performed multiple regres-
sion analysis with MPOD as the dependent variable and with
logeserum lutein and logeserum zeaxanthin as independent
variables adjusting for age, sex, iris color, central foveal retinal
thickness, and, in some analyses, serum total cholesterol.
RESULTS. MPOD increased with increasing serum lutein (P ?
0.0017) and decreased with increasing serum total cholesterol
(P ? 0.0025) but was unrelated to serum zeaxanthin. MPOD
was higher in patients with brown irides than in patients with
lighter irides (P ? 0.014) and was nonmonotonically related to
central foveal retinal thickness (P ? 0.0001), being lower in
eyes with more photoreceptor cell loss and in eyes with mod-
erate to marked CME.
CONCLUSIONS. MPOD is independently related to serum lutein,
serum total cholesterol, iris color, and central foveal retinal thick-
ness in patients with retinitis pigmentosa. (Invest Ophthalmol Vis
Sci. 2010;51:1086–1091) DOI:10.1167/iovs.09-3396
by lipoproteins.1–4Both are concentrated in and around the
foveal depression in cone axons as yellow macular pigment,5,6
which partially screens the photoreceptors from short-wave-
length light and thereby minimizes the effect of chromatic
aberration on visual acuity and perhaps protects these cells
from oxidative light damage.7,8
Although macular pigment optical density (MPOD) has
been found to be directly related to serum lutein in healthy
volunteers,9–12it was reported to be unrelated to serum lutein
utein and zeaxanthin, carotenoids found in dark green,
leafy vegetables, are transported in the plasma exclusively
in patients with the typical forms of retinitis pigmentosa.12We
hypothesized that the absence of a significant association be-
tween MPOD and serum lutein in patients with retinitis pig-
mentosa was due, at least in part, to variable incorporation of
lutein as macular pigment in cone axons as a result of photo-
receptor degeneration. In the present study, we compared
MPOD to serum lutein and to serum zeaxanthin in a large
cohort of patients with typical retinitis pigmentosa, adjusting
for the relationships of MPOD to central foveal retinal thick-
ness and to other potentially confounding factors (age, sex, iris
color, and serum total cholesterol). This afforded us an oppor-
tunity also to test the hypothesis that cystoid macular edema
(CME), which occurs in more than 25% of patients with this
disease,13–15reduces MPOD; this hypothesis was raised but not
answered by a previous study.12
PATIENTS AND METHODS
The protocol was approved by the institutional review boards of the
Massachusetts Eye and Ear Infirmary and Harvard Medical School and
conformed to the tenets of the Declaration of Helsinki and to HIPAA
regulations. Informed consent was obtained from all patients. This
population included 176 unrelated adults with typical forms of retinitis
pigmentosa (58% male; age range, 18–68 years), best-corrected visual
acuities of 20/80 or better, and sufficiently large central visual fields for
measurement of MPOD. These patients with typical retinitis pigmen-
tosa had elevated dark-adapted thresholds, retinal arteriolar attenua-
tion, and reduced and delayed full-field electroretinograms; most had
intraretinal bone spicule pigmentation in the peripheral retina. Our
cohort included only patients who denied smoking, which removed
one potential source of variability with respect to MPOD.16In addition,
all denied taking a separate lutein supplement over the past year based
on their answers to a food-frequency questionnaire.17There were 41
dominant cases (23.3%), 23 recessive cases (13.1%), 8 X-linked cases
(4.5%), 97 simplex cases (55.1%), and 7 cases with undetermined
inheritance (4.0%). Thirty-seven (21%) of the patients had CME in the
study eye by optical coherence tomography (OCT), as defined by one
or more intraretinal cysts measuring at least 50 ?m.15
MPOD was measured by heterochromatic flicker photometry using a
commercial tabletop instrument (Macular Metrics Corp., Rehoboth,
MA)18in the eye with better visual acuity (or the right eye, if the two
eyes were equal) after pupillary dilation to maximize sensitivity. Before
testing, the patients watched a training video provided by the instru-
showed how a subject should make the manual adjustments. After the
patients were optically corrected and aligned with the instrument, the
examiner had them look at the red fixation LED with the 2° stimulus
flickering at a 5° eccentricity, the reference location. This eccentricity
was chosen as a reference because the retina there should have had
sufficiently low macular pigment absorbance in our patients with
retinitis pigmentosa to serve as a reference location yet should have
From the1The Berman-Gund Laboratory for the Study of Retinal
Degenerations, Harvard Medical School, Massachusetts Eye and Ear
Infirmary, Boston, Massachusetts; and the2Jean Mayer USDA Human
Nutrition Research Center on Aging at Tufts University, Boston, Mas-
Supported by National Eye Institute Grant EY00169, the United
States Department of Agriculture under agreement number 58–1950-
7–707, and The Foundation Fighting Blindness.
Submitted for publication January 12, 2009; revised June 17 and
August 11, 2009; accepted September 10, 2009.
Disclosure: M.A. Sandberg, None; E.J. Johnson, None; E.L.
Corresponding author: Michael A. Sandberg, Berman-Gund Labo-
ratory for the Study of Retinal Degenerations, Harvard Medical School,
Massachusetts Eye and Ear Infirmary, 243 Charles Street, Boston, MA
Investigative Ophthalmology & Visual Science, February 2010, Vol. 51, No. 2
Copyright © Association for Research in Vision and Ophthalmology
retained adequate light sensitivity for the patients to perform the task.
Furthermore, this reference eccentricity was compatible with methods
used previously to measure MPOD in patients with retinitis pigmen-
tosa.12All patients included in this report confirmed that they could
visualize the entire flickering stimulus at the 5° eccentricity, indicating
that their central fields were sufficiently large to measure MPOD.
The task was for the patient to adjust the radiances of a 460-nm
stimulus and an alternating 570-nm stimulus to achieve a brightness
match by eliminating flicker. These stimuli were centered on a 6°
background of 475 nm to desensitize rods and short-wavelength–
sensitive cones so that they would not contribute to the patient’s
judgment. After a practice session during which the examiner set the
frequency of flicker to elicit a small “no flicker zone,” the patients
adjusted the radiances to eliminate flicker within the central 1°, where
macular pigment absorbance is maximal, and at the reference location.
During testing, the examiner continually reinforced the principles of
converging on the “no flicker zone” and of periodic blinking to reduce
stimulus fading, particularly when the stimulus was at the reference
location. The adjusted log10radiance of the 460-nm stimulus minus the
adjusted log10radiance of the 570 nm stimulus for the central fovea
minus the same difference for the reference location provided a psy-
chophysical estimate of MPOD.
We assessed the intervisit variability of MPOD measurements in the
first 66 patients who were invited and able to return for follow-up
within 2 months of their original visits. These patients appeared to be
a representative sample because at their first visit they did not differ
significantly from the remaining 110 patients with respect to mean age
(P ? 0.10), sex distribution (P ? 0.31), mean Snellen acuity in the
study eye (P ? 0.79), likelihood of having CME in the study eye (P ?
0.67), or mean MPOD in the study eye (P ? 0.17).
We used a high-resolution optical coherence tomographer (Stratus,
model 3000; Zeiss Meditec, Dublin, CA) to assess retinal structure and
to measure retinal thickness after pupillary dilation, as described pre-
viously.15,19Central foveal retinal thickness was routinely measured by
the automated OCT software as the distance between the high-reflec-
tance vitreoretinal interface and the retinal pigment epithelium (RPE)/
choriocapillaris complex at the intersection of six radial scans oriented
at 30° intervals. Every tomogram in this study was inspected to verify
that the algorithm correctly defined these two high-reflective bound-
aries at the foveal center. In only one instance—an eye with 20/80
visual acuity without CME—was an interface (the vitreoretinal border)
incorrectly designated, and one of us (MAS) used the manual software
calipers to redo the thickness measurement.
Serum Lutein and Zeaxanthin Measurements
Fasting blood was drawn, and serum was stored in the dark under
nitrogen at ?80°C. Serum was analyzed by high-performance liquid
chromatography (HPLC) for lutein and zeaxanthin (Alliance 2695;
Waters, Milford, MA), as described previously with echinenone as the
internal standard.20Using this method, cis lutein, all-trans lutein, cis
zeaxanthin, all-trans zeaxanthin, cryptoxanthin, ?-carotene, 13-cis
?-carotene, all-trans ?-carotene, 9-cis ?-carotene, cis lycopene, and
trans lycopene were separated. Lutein and zeaxanthin were quantified
by determining peak areas in the HPLC chromatograms calibrated
against known amounts of standards. Lutein and zeaxanthin standards,
provided by DSM Nutritional Products (Basel, Switzerland), were dis-
solved in ethanol and used as references to quantify the peak areas for
these carotenoids in the HPLC chromatograms. Data were collected
and analyzed (Millenium32, version 3.05.01, Windows NT; Waters)
with the lower limit of detection for carotenoids at 0.2 pmol.
We performed multiple regression analysis with MPOD as the depen-
dent variable and serum trans lutein, serum trans zeaxanthin, age, sex,
iris color, and central foveal retinal thickness as independent variables.
Because MPOD was not normally distributed in this population (see
Results), the analysis was repeated after density values were converted
to ranks and then to the standard normal distribution with the Van Der
Waerden approximation to test the validity of the original model’s
findings. Given that both analyses led to substantially the same con-
clusions, only the model based on actual density values is considered
Analysis was performed using the trans isomers of serum lutein and
serum zeaxanthin because only very small amounts of the cis isomers
have been detected in macular pigment.21Because their distributions
showed moderate positive skew (see Results), we converted serum
lutein and serum zeaxanthin values to natural logarithms to minimize
the effect of high leverage values, as performed in earlier studies with
We included age in the model because of its possible association
with MPOD in healthy volunteers,23–25and we included sex because
MPOD has been found to be higher in men than in women.23,26We
included an indicator variable for iris color (brown versus blue/green/
hazel) because higher MPOD has been associated with darker irises in
healthy volunteers.27Central foveal retinal thickness was included
because previous studies found MPOD to be directly related to foveal
retinal thickness in healthy volunteers28and in patients with retinitis
pigmentosa without CME.12Central foveal retinal thickness was given
the attribute of a spline with three knots so that we could fit MPOD to
this variable by a nonmonotonic function, if needed, given that our
cohort included patients with CME who might have had low MPOD
values associated with marked retinal swelling.
We also performed an analysis including serum total cholesterol in
the model, as in one previous study,11because serum carotenoids are
exclusively transported on lipoproteins and, therefore, variation in
serum total cholesterol could confound the relationships of MPOD to
serum lutein and serum zeaxanthin. Fasting serum cholesterol was
measured by the clinical laboratory of the Massachusetts Eye and Ear
Lastly, we performed three subset analyses. In the first two analy-
ses, we removed sex from the model and evaluated the relationship of
MPOD to logeserum lutein separately in men and in women because
a study of healthy volunteers found a stronger relationship in men than
in women.11In the third subset analysis, we excluded the 37 patients
with CME and assumed a linear relationship between MPOD and
central foveal retinal thickness to better relate our findings to an earlier
study of patients with retinitis pigmentosa that excluded those with
CME and failed to find a significant relationship between MPOD and
serum lutein.12We even performed a bivariate analysis correlating
MPOD with serum lutein to match what had been done previously.12
Analyses were performed with JMP, version 6 (SAS Institute, Cary, NC).
Distribution and Reproducibility of Macular
Pigment Optical Density
The frequency distribution of MPOD in the 176 patients with
retinitis pigmentosa is shown in Figure 1. The distribution had
a mean ? SEM of 0.32 ? 0.02 log10-unit, only slightly higher
than the mean (0.29 log10-unit) found in a previous study of
patients with retinitis pigmentosa.12The distribution also had
a small skewness coefficient (0.83) that did not affect the
conclusions from the regression analyses reported here (see
Patients and Methods).
MPOD test-retest data based on the subset of 66 patients
who returned within 2 months yielded a standard deviation for
the absolute value of the between-visit differences (SD) of 0.06.
Compared with other measurements done with heterochro-
matic flicker photometry, our SD was higher than that (0.04)
reported by a previous study of patients with retinitis pigmen-
tosa12but within the range (0.02–0.10) based on five studies of
IOVS, February 2010, Vol. 51, No. 2
Macular Pigment in Retinitis Pigmentosa1087
Distributions of Serum Lutein and
Figure 2 illustrates the frequency distributions for serum trans
lutein and for serum trans zeaxanthin based on the 176 pa-
tients. The distribution of serum lutein had a mean ? SEM of
11.5 ? 0.4 ?g/dL, the distribution of serum zeaxanthin had a
mean ? SEM of 3.1 ? 0.1 ?g/dL, and both distributions had
moderate positive skew (1.3 and 1.6, respectively). When con-
verted to a log scale to minimize the effect of high leverage
values in the regression analyses, neither distribution differed
significantly from normal (Shapiro-Wilk W test for goodness-of-
fit, P ? 0.82 for serum lutein and P ? 0.62 for serum zeaxan-
Relationships of MPOD to Age, Sex, Iris Color,
and Central Foveal Retinal Thickness
Mean MPOD fell by 0.0022 log10-unit (0.5%) for each increas-
ing year of age and was 0.04 log10-unit (10%) higher in males
than females, values that were not significantly different from
zero (Table 1). On the other hand, MPOD was significantly
related to iris color, averaging 0.08 log10-unit (22%) higher in
eyes with brown irides than in eyes with lighter irides, and to
central foveal retinal thickness (Table 1). Figure 3 illustrates
the spline regression of MPOD on central foveal retinal thick-
ness. Based on the fitted curve, MPOD first increased with
increasing retinal thickness and then declined for greater reti-
nal thicknesses. The data show that the increase primarily
reflected eyes without CME and that the decrease primarily
reflected eyes with moderate to marked CME.
Relationship of MPOD to Serum Lutein and to
With the model adjusted for age, sex, iris color, central foveal
retinal thickness, and logeserum zeaxanthin, MPOD increased
significantly with increasing logeserum lutein (Table 1), and
the partial correlation between the two variables was 0.24.
When added to the model, serum total cholesterol was a
negative predictor of MPOD (P ? 0.0025). Because serum
cholesterol was positively correlated with logeserum lutein in
our patients (r ? 0.21, P ? 0.0046) and because MPOD was
inversely related to serum cholesterol, adding serum choles-
terol to the model strengthened the relationship of MPOD to
based on 176 patients with retinitis pigmentosa. In 10 patients, re-
corded density values between ?0.2 and 0 were recoded as 0.
Frequency distribution of macular pigment optical density
on 176 patients with retinitis pigmentosa.
Distributions of serum lutein and serum zeaxanthin based
TABLE 1. Multiple Regression of Macular Pigment Optical Density on
Age, Sex, Iris Color, Central Foveal Retinal Thickness, Serum Lutein,
and Serum Zeaxanthin in Patients with Retinitis Pigmentosa
Characteristic Estimate SE
Iris color (brown–not brown)
Central foveal retinal thickness, ?m*
Serum lutein, loge?g/dL
Serum zeaxanthin, loge?g/dL
* Spline function with three knots.
thickness for 176 patients with retinitis pigmentosa, 37 of whom had
CME in the study eye. Solid curve: fitted spline function with three
Macular pigment optical density by central foveal retinal
1088 Sandberg et al.
IOVS, February 2010, Vol. 51, No. 2
serum lutein (rpartial? 0.27, P ? 0.0003). Figure 4 illustrates
the relationship of MPOD to serum lutein adjusted for the other
terms in the model, including serum cholesterol. The fitted line
indicates that a 10-fold increase in serum lutein was associated
with an average MPOD increase of ?0.4 log10-unit. In contrast
to logeserum lutein, MPOD was not significantly related to loge
serum zeaxanthin (Table 1). This was also true after serum total
cholesterol was included in the model (data not shown).
We also tested whether the relationship between MPOD and
logeserum lutein was stronger in men than in women, as found
in a previous study of healthy observers.11When we removed
sex from the multiple regression model (but included serum
cholesterol11), we found that the relationship of MPOD to loge
serum lutein was significant for the 102 men (P ? 0.0048) and
borderline for the 74 women (P ? 0.0504) and that the slope
for men (0.188 ? 0.065 MPOD/logeserum lutein in ?g/dL) was
steeper than the slope for women (0.137 ? 0.069 MPOD/loge
serum lutein in ?g/dL), albeit not significantly different.
A previous study of 48 patients with retinitis pigmentosa
that excluded those with CME found a nonsignificant relation-
ship between MPOD and serum lutein (r ? 0.14, P ? 0.44).12
In our third subset analysis we regressed MPOD on age, sex,
iris color, central foveal retinal thickness, logeserum lutein,
logeserum zeaxanthin, and serum total cholesterol, excluding
the patients with CME in the study eye. For the remaining 139
patients, MPOD increased linearly with increasing central fo-
veal retinal thickness (P ? 0.0001), and we again found that
MPOD increased with increasing logeserum lutein (P ?
0.0001); the partial correlation between MPOD and logeserum
lutein was 0.33 without serum cholesterol and 0.37 with serum
cholesterol in the model. Even for a simple bivariate relation-
ship, MPOD was significantly correlated with serum lutein in
this patient subset (r ? 0.23, P ? 0.0068).
MPOD has been reported by others to be related to serum
lutein in healthy volunteers9–12but not in a group of 48
patients with retinitis pigmentosa without CME, in whom the
correlation was 0.14.12After adjusting for age, sex, iris color,
central foveal retinal thickness, logeserum 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 lu-
tein in our patients was also significant and was higher (0.23)
than what was obtained before,12it would not have been
statistically significant for the smaller sample size of the previ-
ous 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 pig-
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 im-
pedes the transport of lutein into the retina. Because these
findings relating MPOD to serum lutein and to serum choles-
terol 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 lutein11or of plasma lutein plus zeax-
anthin.26The latter study hypothesized that hormonally con-
trolled 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 posi-
tively related to logeserum zeaxanthin. The absence of a
significant positive association between MPOD and serum ze-
axanthin was reported previously for healthy volunteers.11
These negative results may be explained by the observations
that lutein outweighs zeaxanthin in diet and serum,34–36and,
though zeaxanthin predominates in the center of the fo-
vea,21,37that approximately half of this zeaxanthin is derived
We did not find significant relationships between MPOD
and age or sex in our patients with retinitis pigmentosa, al-
though the trends were in the same direction as in some
previous reports based on healthy volunteers.23–26We did find
that MPOD was significantly related to iris color. MPOD aver-
aged 22% higher in patients with brown irides than in patients
with lighter irides, slightly smaller than the 26% difference
found in healthy volunteers27and consistent with the obser-
vation 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 in-
crease is consistent with the idea that xanthophyll incorpora-
tion is proportional to the number of central foveal cone
on serum lutein for 176 patients with retinitis pigmentosa. Serum
lutein is displayed on a log scale because logeserum lutein was used in
the regression analysis. Both the x-coordinates and the y-coordinates
have been adjusted for the relationships of macular pigment optical
density to age, sex, iris color, a spline function of central foveal retinal
thickness, logeserum zeaxanthin, and serum total cholesterol. As a
result of adjusting for these variables, for example, eight macular
pigment optical density values ranging from 0 to 0.08 have shifted in
this plot to negative values ranging from ?0.01 to ?0.17.
Partial regression plot of macular pigment optical density
IOVS, February 2010, Vol. 51, No. 2
Macular Pigment in Retinitis Pigmentosa 1089
photoreceptors,12,28and we confirmed a significant linear re-
lationship 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 hin-
ders the uptake of lutein into the macula or distorts the radial
arrangement of the foveolar cone axons, whose macular pig-
ment molecules are normally oriented perpendicularly to the
fiber axes,6reducing 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 Figure 3, 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 bright-
ness 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 sensitivity39and cone directionality40are typ-
ically 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.38On 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 com-
promised 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 hypoth-
esis 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,29–33we propose that an in-
crease 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.12Although that pilot study did not detect any
significant improvement in visual acuity or in foveal sensitivity
with lutein supplementation,12it 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 degen-
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