John M. Nolan

Lutein, zeaxanthin, and meso-zeaxanthin: The basic and clinical science underlying carotenoid-based nutritional interventions against ocular disease.

The human macula uniquely concentrates three carotenoids: lutein, zeaxanthin, and meso-zeaxanthin. Lutein and zeaxanthin must be obtained from dietary sources such as green leafy vegetables and orange and yellow fruits and vegetables, while meso-zeaxanthin is rarely found in diet and is believed to be formed at the macula by metabolic transformations of ingested carotenoids. Epidemiological studies and large-scale clinical trials such as AREDS2 have brought attention to the potential ocular health and functional benefits of these three xanthophyll carotenoids consumed through the diet or supplements, but the basic science and clinical research underlying recommendations for nutritional interventions against age-related macular degeneration and other eye diseases are underappreciated by clinicians and vision researchers alike. In this review article, we first examine the chemistry, biochemistry, biophysics, and physiology of these yellow pigments that are specifically concentrated in the macula lutea through the means of high-affinity binding proteins and specialized transport and metabolic proteins where they play important roles as short-wavelength (blue) light-absorbers and localized, efficient antioxidants in a region at high risk for light-induced oxidative stress. Next, we turn to clinical evidence supporting functional benefits of these carotenoids in normal eyes and for their potential protective actions against ocular disease from infancy to old age.

Augmentation of Macular Pigment Following Supplementation with All Three Macular Carotenoids: An Exploratory Study

Purpose: At the macula, the carotenoids meso-zeaxanthin (MZ), lutein (L), and zeaxanthin (Z) are collectively referred to as macular pigment (MP). This study was designed to measure serum and macular responses to a macular carotenoid formulation. Materials and Methods: Ten subjects were recruited into this study (five normal and five with early age-related macular degeneration [AMD]). Subjects were instructed to consume a formulation containing 7.3 mg of MZ, 3.7 mg of L, and 0.8 mg of Z everyday over an eight-week period. The spatial profile of MP optical density (i.e., MPOD at 0.25°, 0.5°, 1°, and 1.75°) was measured using customized heterochromatic flicker photometry, and a blood sample was collected at each study visit in order to analyze serum concentrations of MZ, L, and Z. Results: There was a significant increase in serum concentrations of MZ and L after two weeks of supplementation (p < 0.05). Baseline serum carotenoid analysis detected a small peak eluting at the same time as MZ in all subjects, with a mean ± SD of 0.02 ± 0.01 μmol/L. We report significant increases in MPOD at 0.25°, 0.5°, 1°, and average MPOD across its spatial profile after just two weeks of supplementation (p < 0.05, for all). Four subjects (one normal and three AMD) who had an atypical MPOD spatial profile (i.e., central dip) at baseline had the more typical MPOD spatial profile (i.e., highest MPOD at the center) after eight weeks of supplementation. Conclusion: We report significant increases in serum concentrations of MZ and L following supplementation with MZ, L, and Z and a significant increase in MPOD, including its spatial profile, after two weeks of supplementation. Also, this study has detected the possible presence of MZ in human serum pre-supplementation and the ability of the study carotenoid formulation to rebuild central MPOD in subjects who have atypical profiles at baseline.

The utility of using customized heterochromatic flicker photometry (cHFP) to measure macular pigment in patients with age-related macular degeneration

The purpose of this study was to assess the utility and validity of using customized heterochromatic flicker photometry (cHFP) to measure macular pigment optical density (MPOD) in patients with intermediate stages of age-related macular degeneration (AMD). The measurement procedure was optimized to accommodate individual differences in temporal vision related to age, disease, or other factors. The validity criteria were based on the similarity of the spectral absorption curves to ex vivo curves of lutein and zeaxanthin and the similarity of spatial density profiles to those measured in subjects without retinal disease. Macular pigment optical density (MPOD) spatial profiles were measured with an LED-based macular densitometer; spectral absorption curves were measured with a 3-channel Maxwellian view system including a monochromator. All patients were characterized via clinical exams and all but 2 subjects from whom data were obtained had masked grading of color fundus photographs using the Wisconsin Age-Related Maculopathy Grading System. Most of the patients were in AREDS category 2 (27%) or 3 (57%). Patients with visual acuity as poor as 20/80 were included, and could perform the task as long as they could see the stimulus. Eighty-one percent of the patients screened were able to perform the cHFP task, and data were obtained from 30 AMD patients. Spatial profiles of MPOD were measured in 19 subjects who could see the stimulus at all tested loci. These profiles were highly similar to those that have been measured with HFP in subjects without retinal disease. The average shape of the spectral absorption curves for the AMD subjects corresponded well to an ex vivo template. These data support both the utility and validity of the cHFP method for measuring MPOD in subjects with intermediate stages of AMD. The ability to measure the retinal response to nutritional intervention is of practical importance for monitoring patients being supplemented with lutein and zeaxanthin in hopes of retarding visual loss and/or disease progression.

Transport and Retinal Capture of Lutein and Zeaxanthin with Reference to Age-related Macular Degeneration

Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the elderly population in the western world. The etiology and pathogenesis of this disease remain unclear. However, there is an increasing body of evidence supporting the hypothesis that the macular pigment carotenoids, lutein and zeaxanthin, play an important role in protection against AMD, by filtering out blue light at a pre-receptoral level, or by quenching free radicals. Lutein and zeaxanthin are dietary xanthophyll carotenoids, which are delivered to the retina via plasma lipoproteins. The biological mechanisms governing retinal capture and accumulation of lutein and zeaxanthin, to the exclusion of other carotenoids, are still poorly understood. Although these mechanisms remain unclear, it is possible that selective capture of these carotenoids is related to lipoprotein, or apolipoprotein, function and profile. Xanthophyll-binding proteins appear to play an important role in the retinal capture of the xanthophyll carotenoids. The Pi isoform of GSTP1 has been isolated as a specific binding protein for zeaxanthin. The binding protein responsible for retinal uptake of lutein remains elusive. This article reviews the literature germane to the mechanisms involved in the capture, accumulation and stabilization of lutein and zeaxanthin by the retina, and the processes involved in their transport in serum.

The rationale and evidence base for a protective role of macular pigment in age-related maculopathy

Age-related maculopathy (ARM) remains the most common cause of blind registration in people aged 50 years or over in the developed world, and its prevalence continues to rise. Although effective new treatments have become available in the recent past, these are expensive and cumbersome to the healthcare provider and to the patient, and many cases remain resistant to such therapy. There is a biologically plausible rationale whereby macular pigment, which is entirely of dietary origin, may prevent or delay the onset, or ameliorate the clinical course, of ARM. In this article, we review this rationale, and critically appraise the current evidence base germane to the use of supplements containing the macular carotenoids in patients with, or at risk of developing, ARM.

Low macular pigment optical density is associated with lower cognitive performance in a large, population-based sample of older adults

Macular pigment (MP) is comprised of the carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which selectively accumulate at the macula (central retina) of the eye and are neuroprotective. These carotenoids are also present in the brain, and evidence suggests a close correlation between retinal and brain concentrations. We investigated the relationship between MP and cognitive function in 4453 adults aged ≥ 50 years as part of The Irish Longitudinal Study on Aging. Macular pigment optical density (MPOD) was determined using customized heterochromatic flicker photometry-a quick and noninvasive way of measuring the concentration of the pigment. Lower MPOD was associated with poorer performance on the mini-mental state examination (p = 0.026) and on the Montreal cognitive assessment (p = 0.016). Individuals with lower MPOD also had poorer prospective memory (p = 0.011), took longer time to complete a trail-making task (p = 0.003), and had slower and more variable reaction times on a choice reaction time task (p = 0.000 and 0.001). These associations were only slightly attenuated following adjustment for physical and mental health. There was no significant association between MPOD and verbal fluency, word recall, visual reasoning, or picture memory. Overall, the findings support the theory that xanthophyll carotenoids impact on cognitive function, underscoring the need for exploration of novel, noninvasive biomarkers for cognitive vulnerability and preventive strategies.

The impact of macular pigment augmentation on visual performance using different carotenoid formulations.

PURPOSE To investigate changes in macular pigment optical density (MPOD) and visual performance following supplementation with different macular carotenoid formulations. METHODS Thirty-six subjects (19 male, 17 female; mean SD, age 51 13 years) were recruited into this single-masked placebo-controlled study, and were randomly assigned to one of the following three intervention (supplementation) groups: (1) group 1 (20 mg lutein [L] and 2 mg zeaxanthin [Z]); (2) group 2 (10 mg L, 2 mg Z, and 10 mg meso-zeaxanthin [MZ]); and group 3 (placebo). Outcomes measures included visual performance and MPOD response. Data were collected at baseline, at 3 months, and at 6 months. RESULTS At 3 and 6 months, a statistically significant increase in MPOD was found at all eccentricities (other than the most peripheral 3° location) in group 2 (P < 0.05 for all), whereas no significant increase in MPOD was demonstrable at any eccentricity for subjects in groups 1 and 3. Statistically significant improvements in visual performance measures including visual acuity and contrast sensitivity with and without glare were observed for group 2 only. Only mesopic contrast sensitivity at one spatial frequency improved significantly by 6 months (P < 0.05) for group 1. No improvements in any parameters of visual performance were observed for subjects supplemented with placebo (P > 0.05 for all). CONCLUSIONS These results suggest that supplementation with all three macular carotenoids potentially offered advantages over preparations lacking MZ, both in terms of MPOD response and visual performance enhancement.

Psychophysical function in age-related maculopathy.

Age-related macular degeneration (AMD), the late stage of age-related maculopathy (ARM), is the leading cause of blind registration in developed countries. The visual loss in AMD occurs due to dysfunction and death of photoreceptors (rods and cones) secondary to an atrophic or a neovascular event. The psychophysical tests of vision, which depend on the functional status of the photoreceptors, may detect subtle alterations in the macula before morphological fundus changes are apparent ophthalmoscopically, and before traditional measures of visual acuity exhibit deterioration, and may be a useful tool for assessing and monitoring patients with ARM. Furthermore, worsening of these visual functions over time may reflect disease progression, and some of these, alone or in combination with other parameters, may act as a prognostic indicator for identifying eyes at risk for developing neovascular AMD. Lastly, psychophysical tests often correlate with subjective and relatively undefined symptoms in patients with early ARM, and may reflect limitation of daily activities for ARM patients. However, clinical studies investigating psychophysical function have largely been cross-sectional in nature, with small sample sizes, and lack consistency in terms of the grading and classification of ARM. This article aims to comprehensively review the literature germane to psychophysical tests in ARM, and to furnish the reader with an insight into this complex area of research.

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.

The Relationship Between Macular Pigment and Visual Performance

This study was designed to assess whether macular pigment optical density (MPOD) is associated with visual performance. One hundred and forty-two young healthy subjects were recruited. Macular pigment optical density and visual performance were assessed by psychophysical tests including best corrected visual acuity (BCVA), mesopic and photopic contrast sensitivity, glare sensitivity, photostress recovery time (PRT). Measures of central visual function, including BCVA and contrast sensitivity, were positively associated with MPOD (p<0.05, for all). Photostress recovery and glare sensitivity were unrelated to MPOD (p>0.05). A longitudinal, placebo-controlled and randomized supplementation trial will be required to ascertain whether augmentation of MPOD can influence visual performance.