Joint Associations of Diet, Lifestyle, and Genes with Age-Related Macular Degeneration.

PURPOSE: Unhealthy lifestyles have been associated with increased odds for age-related macular degeneration (AMD). Whether this association is modified by genetic risk for AMD is unknown and was investigated. DESIGN: Interactions between healthy lifestyles AMD risk genotypes were studied in relation to the prevalence of AMD, assessed 6 years later. PARTICIPANTS: Women 50 to 79 years of age in the Carotenoids in Age-Related Eye Disease Study with exposure and AMD data (n=1663). METHODS: Healthy lifestyle scores (0-6 points) were assigned based on Healthy Eating Index scores, physical activity (metabolic equivalent of task hours/week), and smoking pack years assessed in 1994 and 1998. Genetic risk was based on Y402H in complement factor H (CFH) and A69S in age-related maculopathy susceptibility locus 2 (ARMS2). Additive and multiplicative interactions in odds ratios were assessed using the synergy index and a multiplicative interaction term, respectively. MAIN OUTCOME MEASURES: AMD presence and severity were assessed from grading of stereoscopic fundus photographs taken in 2001-2004. AMD was present in 337 women, 91% of whom had early AMD. RESULTS: The odds of AMD were 3.3 times greater (95% confidence interval [CI], 1.8-6.1) in women with both low healthy lifestyle score (0-2) and high-risk CFH genotype (CC), relative to those who had low genetic risk (TT) and high healthy lifestyle scores (4-6). There were no significant additive (synergy index [SI], 1.08; 95% CI, 0.70-1.67) or multiplicative (Pinteraction=0.94) interactions in the full sample. However, when limiting the sample to women with stable diets before AMD assessment (n=728) the odds for AMD associated with low healthy lifestyle scores and high-risk CFH genotype were strengthened (odds ratio, 4.6; 95% CI, 1.8-11.6) and the synergy index was significant (SI, 1.34; 95% CI, 1.05-1.70). Adjusting for dietary lutein and zeaxanthin attenuated, and therefore partially explained, the joint association. There were no significant additive or multiplicative interactions for ARMS2 and lifestyle score. CONCLUSIONS: Having unhealthy lifestyles and 2 CFH risk alleles increased AMD risk (primarily in the early stages), in an or additive or greater (synergistic) manner. However, unhealthy lifestyles increased AMD risk regardless of AMD risk genotype.

Macular lutein and zeaxanthin are related to brain lutein and zeaxanthin in primates.

OBJECTIVES: Xanthophyll pigments lutein and zeaxanthin cross the blood-retina barrier to preferentially accumulate in the macular region of the neural retina. There they form macular pigment, protecting the retina from blue light damage and oxidative stress. Lutein and zeaxanthin also accumulate in brain tissue. The objective of the study was to evaluate the relationship between retinal and brain levels of these xanthophylls in non-human primates. METHODS: Study animals included rhesus monkeys reared on diets devoid of xanthophylls that were subsequently fed pure lutein or pure zeaxanthin (both at 3.9 µmol/kg per day, n = 6/group) and normal rhesus monkeys fed a stock diet (0.26 µmol/kg per day lutein and 0.24 µmol/kg per day zeaxanthin, n = 5). Retina (4 mm macular punch, 4-8 mm annulus, and periphery) and brain tissue (cerebellum, frontal cortex, occipital cortex, and pons) from the same animals were analyzed by reverse-phase high-performance liquid chromatography. RESULTS: Lutein in the macula and annulus was significantly related to lutein levels in the cerebellum, occipital cortex, and pons, both in bivariate analysis and after adjusting for age, sex and n-3 fatty acid status. In the frontal cortex the relationship was marginally significant. Macular zeaxanthin was significantly related to zeaxanthin in the cerebellum and frontal cortex, while the relationship was marginally significant in the occipital cortex and pons in a bivariate model. DISCUSSION: An integrated measure of total macular pigment optical density, which can be measured non-invasively, has the potential to be used as a biomarker to assess brain lutein and zeaxanthin status.

Initiation of feeding by four sympatric Neotropical primates (Ateles belzebuth, Lagothrix lagotricha poeppigii, Plecturocebus (Callicebus) discolor, and Pithecia aequatorialis) in Amazonian Ecuador: Relationships to photic and ecological factors.

We examined photic and ecological factors related to initiation of feeding by four sympatric primates in the rain forest of Amazonian Ecuador. With rare exceptions, morning activities of all taxa began only after the onset of nautical twilight, which occurred 47-48 min before sunrise. The larger spider and woolly monkeys, Ateles belzebuth and Lagothrix lagotricha poeppigii, left their sleeping trees before sunrise about half the time, while the smaller sakis and titi monkeys, Pithecia aequatorialis and Plecturocebus (formerly Callicebus) discolor, did not emerge until sunrise or later. None of the four taxa routinely began feeding before sunrise. Pithecia began feeding a median 2.17 h after sunrise, at least 0.8 h later than the median feeding times of the other three taxa. The early movement of Ateles and Lagothrix, and late initiation of feeding by Pithecia are consistent with temporal niche partitioning. Among most New World primate species, all males and many females, have dichromatic color vision, with only two cone photopigments, while some females are trichromats with three cone photopigments. Current evidence indicates that the dichromats have a foraging advantage in dim light, which could facilitate utilization of twilight periods and contribute to temporal niche partitioning. However, in our study, dichromatic males did not differentially exploit the dim light of twilight, and times of first feeding bouts of female Ateles and Lagothrix were similar to those of males. First feeding bouts followed a seasonal pattern, occurring latest in May-August, when ripe fruit abundance and ambient temperature were both relatively low. The most frugivorous taxon, Ateles, exhibited the greatest seasonality, initiating feeding 1.4 h later in May-August than in January-April. This pattern may imply a strategy of conserving energy when ripe fruit is scarcer, but starting earlier to compete successfully when fruit is more abundant. Lower temperatures were associated with later feeding of Ateles (by 26 min / °C) and perhaps Pithecia, but not Lagothrix or Plecturocebus. The potential for modification of temporal activity patterns and temporal niche partitioning by relatively small changes in temperature should be considered when predicting the effects of climate change.

Physiological differences between neurons in layer 2 and layer 3 of primary visual cortex (V1) of alert macaque monkeys.

The physiological literature does not distinguish between the superficial layers 2 and 3 of the primary visual cortex even though these two layers differ in their cytoarchitecture and anatomical connections. To distinguish layer 2 from layer 3, we have analysed the response characteristics of neurons recorded during microelectrode penetrations perpendicular to the cortical surface. Extracellular responses of single neurons to sweeping bars were recorded while macaque monkeys performed a fixation task. Data were analysed from penetrations where cells could be localized to specific depths in the cortex. Although the most superficial cells (depth, 145-371 microm; presumably layer 2) responded preferentially to particular stimulus orientations, they were less selective than cells encountered immediately beneath them (depth, 386-696 microm; presumably layer 3). Layer 2 cells had smaller spikes, higher levels of ongoing activity, larger receptive field activating regions, and less finely tuned selectivity for stimulus orientation and length than layer 3 cells. Direction selectivity was found only in layer 3. These data suggest that layer 3 is involved in generating and transmitting precise, localized information about image features, while the lesser selectivity of layer 2 cells may participate in top-down influences from higher cortical areas, as well as modulatory influences from subcortical brain regions.

Spatial profile of macular pigment and its relationship to foveal architecture.

PURPOSE: Macular pigment (MP) is composed of two dietary carotenoids, lutein and zeaxanthin, and a carotenoid generated by the retina, meso-zeaxanthin. There is large intersubject variability in peak optical density, spatial profile, and lateral extent of macular pigment, and it has been suggested that foveal architecture may play a role in this variability. This study is an initial investigation of the relationship between the spatial profile of macular pigment and foveal architecture. METHODS: Sixty normal subjects were enrolled (one was eventually excluded). The spatial profile of macular pigment optical density (MPOD) was measured by customized heterochromatic flicker photometry (cHFP). High-resolution macular thickness maps were obtained by optical coherence tomography. Four parameters were analyzed: (1) minimum foveal thickness (MFT) at the intersection of six radial scans; (2) central foveal thickness (CFT) averaged over the central 1 mm of the fovea; (3) foveal width identified as the region lacking a nerve fiber layer; and (4) foveal width measured from crest to crest. Lifestyle and vision information were obtained by questionnaire. RESULTS: The mean +/- SD MPOD at 0.25 degrees eccentricity was 0.49 +/- 0.23 and at 0.5 degrees eccentricity, 0.41 +/- 0.21. A first-order decreasing exponential function accounted for most of the variance of the MP profile averaged across subjects (r(2) = 0.99). MPOD measured at 0.25 degrees was unrelated to both measures of foveal thickness for the entire study group (r = 0.03, P = 0.81, and r = -0.08, P = 0.57, respectively). Similarly, MPOD measured at 0.5 degrees was unrelated to foveal thickness in the entire study group (r = 0.12, P = 0.36 and r = -0.05, P = 0.71, respectively). However, when analyzed separately in the nonwhite subjects, the relationship between MPOD at 0.25 degrees and MFT was positive and significant (r = 0.59, P = 0.01), but remained unrelated to CFT (r = 0.20, P = 0.41). Similarly, in the nonwhite subjects, the relationship between MPOD at 0.5 degrees and MFT was positive and significant (r = 0.68, P < 0.01), but again was unrelated to CFT (r = 0.23, P = 0.32). There was no significant relationship between MPOD and either measure of foveal thickness in the white subjects. In the entire study group, there was a positive and significant relationship between foveal width and MPOD averaged across the fovea (r = 0.41, P < 0.01) and between foveal width and MP integrated across the fovea (r = 0.41, P < 0.01). CONCLUSIONS: Foveal MP was positively and significantly related to foveal width in the entire study group. This relationship may be determined by the greater length of the cone axons (Henle fibers) in wider foveas. MPOD was unrelated to foveal thickness in the white subjects. However, in the nonwhite subjects there was a positive association between MFT and MPOD at the 0.25 degrees and 0.5 degrees eccentricities, suggesting that other personal characteristics modulate the MPOD-retinal thickness relationship.

Macular pigment density and age-related maculopathy in the Carotenoids in Age-Related Eye Disease Study. An ancillary study of the women's health initiative.

PURPOSE: To examine the association between intermediate age-related macular degeneration (AMD) and the optical density of macular pigment (MPOD), which is composed of lutein and zeaxanthin from the diet. DESIGN: Cross-sectional cohort study. PARTICIPANTS: We included 1698 of 2005 women ages 54 to 86 years and participating in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative. METHODS: The MPOD was measured noninvasively by heterochromatic flicker photometry. Fundus photographs were taken to document prevalent AMD. MAIN OUTCOME MEASURES: Intermediate AMD (n = 305) and two subtypes-large drusen (n = 233) and pigmentary abnormalities (n = 157). RESULTS: After adjusting for covariates, the odds ratio (OR) and 95% confidence interval (CI) for AMD among women in quintile (Q) 5 (n = 339) versus 1 (n = 340) for MPOD was 1.4 (0.9, 2.1). However, after excluding women with possible unstable diets and recent supplement use due to chronic disease history, associations reversed (OR Q2-5 vs. 1, 0.8; 95% CI, 0.5-1.2), but remained nonsignificant. Associations also differed between middle-aged (54-69 years) and older (> or =70 years) women (P-interaction = 0.09), but less so, after excluding women who were likely to have unstable diets: adjusted ORs (95% CI) were 0.5 (0.3-1.0; P = 0.08) for intermediate AMD among middle-aged women (n = 516) with MPOD in Q2 to Q5 versus 1 and 1.0 (0.5-2.0; P = 0.90) for older women (n = 422). CONCLUSIONS: The MPOD is not cross-sectionally associated with AMD. The inconsistency of relationships across age groups and in subgroups of women who are likely to have more stable diets suggests that cross-sectional associations may be biased and highlights the need to study these relationships prospectively.

Associations between age-related nuclear cataract and lutein and zeaxanthin in the diet and serum in the Carotenoids in the Age-Related Eye Disease Study, an Ancillary Study of the Women's Health Initiative.

OBJECTIVE: To evaluate associations between nuclear cataract (determined from slitlamp photographs between May 2001 and January 2004) and lutein and zeaxanthin in the diet and serum in patients between 1994 and 1998 and macula between 2001 and 2004. DESIGN: A total of 1802 women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intakes of lutein and zeaxanthin above the 78th (high) and below the 28th (low) percentiles in the Women's Health Initiative Observational Study (1994-1998) were recruited 4 to 7 years later (2001-2004) into the Carotenoids in Age-Related Eye Disease Study. RESULTS: Women in the group with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio, 0.77; 95% confidence interval, 0.62-0.96) compared with those with low levels. Multivariable adjustment slightly attenuated the association (odds ratio, 0.81; 95% confidence interval, 0.65-1.01). Women in the highest quintile category of diet or serum levels of lutein and zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.97; P for trend = .04; and multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P for trend = .01, respectively). Cross-sectional associations with macular pigment density were inverse but not statistically significant. CONCLUSIONS: Diets rich in lutein and zeaxanthin are moderately associated with decreased prevalence of nuclear cataract in older women. However, other protective aspects of such diets may in part explain these relationships.

Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women.

INTRODUCTION: Low dietary intake of docosahexaenoic acid (DHA) and/or foods rich in lutein may be associated with increased risk of cognitive decline in the elderly. SUBJECTS AND METHODS: The cognitive benefit of DHA and lutein in unimpaired elder women was explored in the context of a 4-month, double-blind, intervention trial of DHA and lutein supplementation for eye health. Forty-nine women (aged 60-80 years) were randomized to receive DHA (800 mg/day; n = 14), lutein (12 mg/day; n = 11), a combination of DHA and lutein (n = 14) or placebo (n = 10). Subjects underwent cognitive tests measuring verbal fluency, memory, processing speed and accuracy, and self-reports of mood at randomization and upon completion of the trial. RESULTS: Following supplementation, verbal fluency scores improved significantly in the DHA, lutein, and combined treatment groups (P < 0.03). Memory scores and rate of learning improved significantly in the combined treatment group (P < 0.03), who also displayed a trend toward more efficient learning (P = 0.07). Measures of mental processing speed, accuracy and mood were not affected by supplementation. CONCLUSIONS: These exploratory findings suggest that DHA and lutein supplementation may have cognitive benefit for older adults.

Saccades and drifts differentially modulate neuronal activity in V1: effects of retinal image motion, position, and extraretinal influences.

In natural vision, continuously changing input is generated by fast saccadic eye movements and slow drifts. We analyzed effects of fixational saccades, voluntary saccades, and drifts on the activity of macaque V1 neurons. Effects of fixational saccades and small voluntary saccades were equivalent. In the presence of a near-optimal stimulus, separate populations of neurons fired transient bursts after saccades, sustained discharges during drifts, or both. Strength, time course, and selectivity of activation by fast and slow eye movements were strongly correlated with responses to flashed or to externally moved stimuli. These neuronal properties support complementary functions for post-saccadic bursts and drift responses. Local post-saccadic bursts signal rapid motion or abrupt change of potentially salient stimuli within the receptive field; widespread synchronized bursts signal occurrence of a saccade. Sustained firing during drifts conveys more specific information about location and contrast of small spatial features that contribute to perception of fine detail. In addition to stimulus-driven responses, biphasic extraretinal modulation accompanying saccades was identified in one third of the cells. Brief perisaccadic suppression was followed by stronger and longer-lasting enhancement that could bias perception in favor of saccade targets. These diverse patterns of neuronal activation underlie the dynamic encoding of our visual world.

Predictors of optical density of lutein and zeaxanthin in retinas of older women in the Carotenoids in Age-Related Eye Disease Study, an ancillary study of the Women's Health Initiative.

BACKGROUND: Lifestyle, diet, and physical and health predictors of xanthophyll carotenoids in the retina are poorly understood. OBJECTIVE: We aimed to investigate the predictors of the density of lutein and zeaxanthin in the macula of the retina. DESIGN: Macular pigment optical density (MPOD) was measured by heterochromatic flicker photometry. Relations to dietary lutein and zeaxanthin and to other predictors were measured in 1698 women aged 53-86 y. The women were members of observational study cohorts of the Women's Health Initiative at Iowa City, IA, Madison, WI, or Portland, OR, and participated in the Carotenoids in Age-Related Eye Disease Study (2001-2004). RESULTS: MPOD at 0.5 degrees from the foveal center was 30% higher in women in the highest quintile for lutein and zeaxanthin intake [x (+/-SD): 0.40 +/- 0.21] than in women in the lowest quintile (0.31 +/- 0.21) and 20% higher after adjustment for other predictors. Dietary intake of lutein, zeaxanthin, fiber, and polyunsaturated fatty acids (% of energy) together explained 3% of the variability in MPOD. Higher waist circumference and diabetes, which are related to lower MPOD, together with study site explained an additional 5% of variation. The total explained variability increased to 12% when lutein and zexanthin concentrations obtained from the serum, which were collected 4-7 y earlier, were added to the model. CONCLUSIONS: MPOD is directly related to dietary intake of lutein and zeaxanthin but even more strongly to serum concentrations, which may reflect unmeasured physical and medical factors that influence the uptake, distribution, and utilization of lutein and zeaxanthin. Higher abdominal body fat and diabetes are related to lower MPOD. Unknown predictors of retinal carotenoids remain.

A physiological perspective on fixational eye movements.

For a behavioral neuroscientist, fixational eye movements are a double-edged sword. On one edge, they make control of visual stimuli difficult, but on the other edge they provide insight into the ways the visual system acquires information from the environment. We have studied macaque monkeys as models for human visual systems. Fixational eye movements of monkeys are similar to those of humans but they are more often vertically biased and spatially more dispersed. Eye movements scatter stimuli from their intended retinal locations, increase variability of neuronal responses, inflate estimates of receptive field size, and decrease measures of response amplitude. They also bias against successful stimulation of extremely selective cells. Compensating for eye movements reduced these errors and revealed a fine-grained motion pathway from V1 feeding the cortical ventral stream. Compensation is a useful tool for the experimenter, but rather than compensating for eye movements, the brain utilizes them as part of its input. The saccades and drifts that occur during fixation selectively activate different types of V1 neurons. Cells that prefer slower speeds respond during the drift periods with maintained discharges and tend to have smaller receptive fields that are selective for sign of contrast. They are well suited to code small details of the image and to enable our fine detailed vision. Cells that prefer higher speeds fire transient bursts of spikes when the receptive field leaves, crosses, or lands on a stimulus, but only the most transient ones (about one-third of our sample) failed to respond during drifts. Voluntary and fixational saccades had very similar effects, including the presence of a biphasic extraretinal modulation that interacted with stimulus-driven responses. Saccades evoke synchronous bursts that can enhance visibility but these bursts may also participate in the visual masking that contributes to saccadic suppression. Study of the small eye movements of fixation may illuminate some of the big problems in vision.

Eye movements between saccades: Measuring ocular drift and tremor.

Intersaccadic periods of fixation are characterized by incessant retinal motion due to small eye movements. While these movements are often disregarded as noise, the temporal modulations they introduce to retinal receptors are significant. However, analysis of these input modulations is challenging because the intersaccadic eye motion is close to the resolution limits of most eyetrackers, including widespread pupil-based video systems. Here, we analyzed in depth the limits of two high-precision eyetrackers, the Dual-Purkinje Image and the scleral search coil, and compared the intersaccadic eye movements of humans to those of a non-human primate. By means of a model eye we determined that the resolution of both techniques is sufficient to reliably measure intersaccadic ocular activity up to approximately 80Hz. Our results show that the characteristics of ocular drift are remarkably similar in the two species; a clear deviation from a scale-invariant spectrum occurs in the range between 50 and 100Hz, generally attributed to ocular tremor, leading to intersaccadic retinal speeds as high as 1.5deg/s. The amplitude of this deviation differs on the two axes of motion. In addition to our experimental observations, we suggest basic guidelines to evaluate the performance of eyetrackers and to optimize experimental conditions for the measurement of ocular drift and tremor.

Nutritional manipulation of primate retinas, III: Effects of lutein or zeaxanthin supplementation on adipose tissue and retina of xanthophyll-free monkeys.

PURPOSE: Macular pigment (MP) is composed of the xanthophylls lutein (L) and zeaxanthin (Z) and may help to prevent age-related macular degeneration or retard its progression. In this study the effects of L or Z supplementation on carotenoid levels was examined in serum, adipose tissue, and retina in rhesus monkeys with no previous intake of xanthophylls. METHODS: From birth to 7 to 16 years of age, 18 rhesus monkeys were fed semipurified diets containing all essential nutrients but no xanthophylls. Six were supplemented with pure L and 6 with pure Z at 3.9 micromol/kg per day for 24 to 101 weeks. At baseline and at 4- to 12-week intervals, carotenoids in adipose tissue were measured by HPLC. At study completion, carotenoids in serum and retina (central 4 mm, 8-mm annulus, and the periphery) were determined. Results were compared with data from control monkeys fed a standard laboratory diet. RESULTS: Monkeys fed xanthophyll-free diets had no L or Z in serum or tissues. After L or Z supplementation, serum and adipose tissue concentrations significantly increased in the supplemented groups. Both L and 3R,3'S-Z (RSZ or meso-Z, not present in the diet) were incorporated into retinas of monkeys supplemented with L, with RSZ present only in the macula (central 4 mm). All-trans Z, but no RSZ, accumulated in retinas of monkeys supplemented with Z. CONCLUSIONS: L is the precursor of RSZ, a major component of macular pigment. Xanthophyll-free monkeys can accumulate retinal xanthophylls and provide a valuable model for examining their uptake and conversion.

Nutritional manipulation of primate retinas, I: effects of lutein or zeaxanthin supplements on serum and macular pigment in xanthophyll-free rhesus monkeys.

PURPOSE: The xanthophylls lutein (L) and zeaxanthin (Z) are the primary components of macular pigment (MP) and may protect the macula from age-related degeneration (AMD). In this study, L or Z was fed to rhesus monkeys reared on xanthophyll-free diets to follow the accumulation of serum carotenoids and MP over time. METHODS: Eighteen rhesus monkeys were fed xanthophyll-free semipurified diets from birth until 7 to 16 years. The diets of six were then supplemented with pure L and six with pure Z at 3.9 micromol/kg per day (2.2 mg/kg per day) for 24 to 56 weeks. At baseline and 4- to 12-week intervals during supplementation, serum carotenoids were measured by HPLC, and MP density was estimated by two-wavelength reflectometry. Serum carotenoids and MP were also measured in monkeys fed a stock diet. RESULTS: Monkeys fed xanthophyll-free diets had no L or Z in serum and no detectable MP. During supplementation, serum L or Z increased rapidly over the first 4 weeks and from 16 weeks onward maintained similar levels, both several times higher than in stock-diet-fed monkeys. The central peak of MP optical density increased to a relatively steady level by 24 to 32 weeks in both L- and Z-fed groups. Rhesus monkeys fed a stock diet had lower blood concentrations of L than those found in humans and other nonhuman primates. CONCLUSIONS: Rhesus monkeys respond to either dietary L or Z supplementation with increases in serum xanthophylls and MP, even after life-long xanthophyll deficiency. These animals provide a potential model to study mechanisms of protection from AMD.

Macular pigment density is reduced in obese subjects.

PURPOSE: Because of the potential protective function of lutein (L) and zeaxanthin (Z) within the retina and lens, a better understanding of factors influencing tissue deposition is needed. The largest fractions of L and Z are stored in adipose tissue. Thus, higher body fat content and body mass index (BMI) may be expected to influence the quantities of L and Z in the retina (measured as macular pigment optical density, MPOD). METHODS: Six hundred eighty subjects were tested. Information on MPOD, body mass index (BMI), body fat percentage (n = 400, using bioelectric impedance), dietary intake (n = 280, using a food frequency questionnaire), and serum carotenoid content (n = 280, using reversed phase high-performance liquid chromatography) was obtained. RESULTS: There was an inverse relationship between MPOD and BMI (n = 680, r = -0.12, P < 0.0008) and between MPOD and body fat percentage (n = 400, r = -0.12, P < 0.01). These relationships were largely driven by data from the subjects with higher BMI (more than 29, 21% less MP) and higher body fat percentage (more than 27%, 16% less MP). Dietary carotenoid intake and serum carotenoid levels were also lower in subjects with higher BMI (n = 280). CONCLUSIONS: Obese subjects tend to have lower retinal L and Z. This reduction may be due to decreased dietary intake of L and Z and/or competition between retina and adipose tissue for uptake of L and Z.

Macular pigment measurement by heterochromatic flicker photometry in older subjects: the carotenoids and age-related eye disease study.

PURPOSE: To develop a standardized protocol for measuring macular pigment optical density (MPOD) of experimentally naïve subjects by heterochromatic flicker photometry (HFP). METHODS: MPOD in eyes of 54 women, age 50 and 79 years (mean, 66), was studied. The spatial profile of MPOD was measured in the right eye, and two spatial points were also measured in the left eye. Forty-eight of these inexperienced subjects completed the protocol on two separate visits. For a subset of the group, the MPOD at two different wavelengths was measured. RESULTS: The test-retest correlation at 0.5 degrees eccentricity in the right eye was 0.9. On the second visit, more than 90% of the subjects were able to perform the HFP test with results that were consistent with the absorption spectrum of macular pigment. On the first visit, data from the inexperienced subjects deviated more from the expected relationships between the two wavelengths, presumably because they had less skill in performing the task. However, subjects with high or low macular pigment density were distinguished clearly. CONCLUSIONS: Reliable and meaningful measurements of macular pigment density in older subjects can be made using HFP, with a standardized protocol in the limited time available in large epidemiologic studies. This protocol will be made freely available to other researchers on request.

Nutritional manipulation of primate retinas, II: effects of age, n-3 fatty acids, lutein, and zeaxanthin on retinal pigment epithelium.

PURPOSE: To study the effects of age and of n-3 fatty acids, lutein, and zeaxanthin on the retinal pigment epithelium (RPE). METHODS: Rhesus monkeys (age range, 7-17 years; n = 18) were fed xanthophyll-free semipurified diets from birth. The diets had either low or adequate amounts of n-3 fatty acids. Six monkeys remained xanthophyll-free until death. Six received supplements of pure lutein and six of pure zeaxanthin for 6 to 24 months. The central retina was serially sectioned, and the number of RPE cells were counted in an 8-microm strip along the vertical meridian. Cell counts were compared with data from control monkeys (n = 15) fed a standard laboratory diet. RESULTS: Foveal and parafoveal RPE cell densities increased with age. Xanthophyll-free monkeys had a dip in the RPE cell density profile at the foveal center, rather than the normal peak. After supplementation with xanthophylls, the RPE profile of animals low in n-3 fatty acids no longer had a dip at the foveal center but became asymmetric, with higher densities in the inferior retina. In animals with adequate n-3 fatty acid levels, xanthophyll supplementation did not restore the foveal peak, and resulted in an asymmetric profile with higher densities in the superior retina. CONCLUSIONS: RPE cells are sensitive to the absence of macular pigment. Supplemental xanthophylls interact with n-3 fatty acid levels to produce asymmetries in the RPE profile. Xanthophylls and n-3 fatty acids are essential for the development and/or maintenance of a normal distribution of RPE cells.

Retinal pigment epithelial cell distribution in central retina of rhesus monkeys.

PURPOSE: To determine the cell density profile of the retinal pigment epithelium (RPE) in the central retina and relate it to the distribution of photoreceptors. METHODS: Wholemounts of rhesus monkey (Macaca mulatta) retinas with the choroid removed but the RPE attached were stained with the nuclear stain 4',6-diamidine-2-phenylindole dihydrochloride (DAPI) and imaged with a fluorescence microscope. RPE cell nuclei were counted at the foveal center and at 0.4-mm intervals along the vertical meridian. The number of photoreceptors per RPE cell at each location was estimated by using previously published data on the distribution of rhesus photoreceptors. RESULTS: Data were collected from eight retinas. Mean RPE cell density increased from a relatively stable baseline of approximately 4000 RPE cells/mm(2) beyond 2 mm (10 degrees ) eccentricity to more than 7000 cells/mm(2) at the center of the fovea. The number of cones per RPE cell in the rhesus retina was approximately 20:1 in the foveal center (similar to the human retina) and only approximately 1.5:1 in the parafovea. However, when the rods were included, and the total number of photoreceptors per RPE cell were considered, the ratio of photoreceptors to RPE cells was lower in the fovea than in the remainder of the central retina. CONCLUSIONS: In spite of the high cone density, there is a relatively low number of photoreceptors per RPE cell in the fovea. This may limit the metabolic demands on foveal RPE cells and help to preserve their functions in the face of aging and disease.

Primate area V1: largest response gain for receptive fields in the straight-ahead direction.

Although neuronal responses in behaving monkeys are typically studied while the monkey fixates straight ahead, it is known that eye position modulates responses of visual neurons. The modulation has been found to enhance neuronal responses when the receptive field is placed in the straight-ahead position for neurons receiving input from the peripheral but not the central retina. We studied the effect of eye position on the responses of V1 complex cells receiving input from the central retina (1.1-5.7° eccentricity) while minimizing the effect of fixational eye movements. Contrast response functions were obtained separately with drifting light and dark bars. Data were fit with the Naka-Rushton equation: r(c)=Rmax×c/(c+c50)+s, where r(c) is mean spike rate at contrast c, Rmax is the maximum response, c50 is the contrast that elicits half of Rmax, and s is the spontaneous activity. Contrast sensitivity as measured by c50 was not affected by eye position. For dark bars, there was a statistically significant decline in the normalized Rmax with increasing deviation from straight ahead. Data for bright bars showed a similar trend with a less rapid decline. Our results indicate that neurons representing the central retina show a bias for the straight-ahead position resulting from modulation of the response gain without an accompanying modulation of contrast sensitivity. The modulation is especially obvious for dark stimuli, which might be useful for directing attention to hazardous situations such as dark holes or shadows concealing important objects (Supplement 1: Video Abstract, Supplemental digital content 1, http://links.lww.com/WNR/A295).

Enhancing performance while avoiding damage: a contribution of macular pigment.

PURPOSE: To compare action spectra for visual discomfort in the fovea and the parafovea and to determine the effect of macular pigment (MP). METHODS: Visual discomfort thresholds to lights from 440 to 600 nm were obtained for six young (<35 y), visually normal subjects with a wide range of MP densities (0.10-0.71 at 30' eccentricity). Foveal and parafoveal conditions were assessed. Discomfort thresholds were also obtained for xenon-white light (partially absorbed by MP), and a broadband yellow (outside the absorption band of MP). MP was measured psychophysically using heterochromatic flicker photometry (HFP). RESULTS: For the parafovea, discomfort sensitivity (1/threshold) increased sharply with decreasing wavelength for all subjects. Commensurate with a subject's MP level, MP significantly reduced visual discomfort to short wavelengths (including xenon-white light) for central viewing. CONCLUSIONS: MP simultaneously reduces visual discomfort and protects from light damage at short wavelengths. As a result, MP increases the range of safe and comfortable light levels. Because higher light levels enable improved visual sensitivity for fine detail, these findings indicate that the spectral absorption properties and spatial distribution of MP combine to protect the retina while enhancing visual performance. The action spectrum for visual discomfort closely matches the risk for acute light damage to the retinal pigment epithelium, and it is consistent with a major influence from the intrinsically photosensitive retinal ganglion cells containing melanopsin. We suggest that MP interacts with nonimage-forming retinal input to achieve the dual outcomes of visual discomfort reduction and protection from light damage.