Enhancing children's cognitive function and achievement through carotenoid consumption: The Integrated Childhood Ocular Nutrition Study (iCONS) protocol.

Lutein and zeaxanthin (L + Z) are carotenoids that accumulate in neural tissue and potentially confer benefits to cognition. Whereas cross-sectional studies have revealed positive associations between macular carotenoids (MC) and cognition, no studies have investigated whether L + Z supplementation impacts MC and cognition in childhood. Accordingly, the Integrated Childhood Ocular Nutrition Study aims to investigate the impact of L + Z supplementation over 9-months on academic abilities, attentional control, memory, and MC among preadolescent children. Children 8-10 years (N = 288) will enroll in a 9-month double-blind, placebo-controlled, randomized trial. The study is registered and approved as a clinical trial on the U.S. National Library of Medicine http://ClinicalTrials.gov registry (NCT05177679). Participants will be randomized into an active (10 mg lutein+2 mg zeaxanthin) or waitlist placebo-controlled group. Primary outcomes include hippocampal-dependent memory, attentional inhibition, and academic achievement using a spatial reconstruction task, an Eriksen flanker task, and the Kaufman Test of Academic and Educational Achievement 3rd edition, respectively. Secondary outcomes include event-related brain potentials of attentional resource allocation and information processing speed (i.e., P3/P300 amplitude and latency) recorded during the flanker task. Macular pigment optical density (MPOD) will be assessed using heterochromatic flicker photometry. Cognitive assessments will be completed prior to and after completion of the supplementation period. MPOD will be quantified prior to, at the mid-point of (4-5 months), and after (9 months) the supplementation period. It is hypothesized that L + Z supplementation will improve cognition and academic achievement. Further, benefits for cognition and achievement are anticipated to be mediated by increases in MC among treatment group participants.

Macular pigment changes after cataract surgery with yellow-tinted intraocular lens implantation.

PURPOSE: We previously reported that macular pigment optical density (MPOD) levels decreased during a long follow-up period after clear intraocular lens (IOL) implant surgery presumably due to excessive light exposure. We examined changes in MPOD levels in the eyes that received yellow-tinted IOL implant surgery. SUBJECTS AND METHODS: This was a prospective, observational study. Fifty-five eyes of 35 patients were studied. MPOD levels were measured with a dual-wavelength autofluorescence technique on day 4; months 1, 3, and 6; and years 1 and 2 postoperatively. The average optical densities at 0°- 2° eccentricities (local MPODs) and total volumes of MPOD (MPOVs) in the area within 1.5° and 9° eccentricities were analyzed. RESULTS: The mean local MPOD at baseline (on day 4) was 0.79 at 0°, 0.71 at 0.5°, 0.68 at 0.9°, and 0.32 at 2°. The mean MPOV within 1.5° and 9° at baseline was 2950 and 18,897, respectively. Local MPOD at 0.9° and 2° and MPOVs were slightly decreased at month 1 and increased after that. The increase reached statistical significance in local MPOD at 0.5° and 2° and MPOVs (Tukey-Kramer test). The changes in MPOV within 9° at year 2 [(MPOV on year 2 - MPOV on day 4) / MPOV on day 4] were from -0.21 to 1.18 (mean and standard deviation: 1.14 ± 0.28). The MPOV of 15 eyes increased more than 10% from the initial value, was maintained within 10% in 21 eyes, and deteriorated more than 10% in only 3 eyes. CONCLUSIONS: Local MPOD and MPOV tended to slightly decrease month 1 postoperatively and gradually increased after that, but the rates of increases in MPOD levels were small. Yellow-tinted IOLs that have a lower transmittance of blue light might be preferable for preserving MPOD levels after surgery.

Macular pigment optical density and visual quality of life

PURPOSE: There is robust evidence that higher macular pigment concentrations help reduce both veiling and discomfort glare in patients with or without ocular disease. We investigated whether there was also a relationship between macular pigment optical density (MPOD) and patient surveys about glare or ocular discomfort. METHODS: We measured MPOD psychophysically in 23 healthy subjects and administered the National Eye Institute Visual Functioning Questionnaire (VFQ-25). Responses for each survey question were sorted from low (no limitation) to high (very severe limitation). The median response for each question was determined, and independent t-tests were performed on the mean MPOD values for survey responses above and below the median. We also performed a non-parametric correlation analysis between MPOD and survey responses. RESULTS: While the median response was "no limitation" for most (22 of 25) survey questions, responses were slightly higher for two questions concerning ocular discomfort and one question related to driving at night. MPOD levels were significantly higher in subjects that reported no discomfort in or around their eyes than in those that reported mild discomfort. There was also a trend toward higher MPOD levels in subjects who reported that pain in or around their eyes never limited their activity as well as in subjects who reported no difficulty driving at night. CONCLUSION: These preliminary findings are consistent with the well-established discomfort and glare hypotheses for MPOD. The current findings on subjective ocular discomfort in the absence of glare deserve further study

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Effects of lutein supplementation in age-related macular degeneration.

The purpose of this meta-analysis was to evaluate the effects of lutein supplementation on macular pigment optical density (MPOD) in randomized controlled trials involving patients with age-related macular degeneration (AMD). A comprehensive search of the literature was performed in PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, and Wan Fang database through December 2018. Nine randomized controlled trials involving 920 eyes (855 with AMD) were included. Meta-analysis suggested that lutein supplementation (10 or 20 mg per day) was associated with an increase in MPOD (mean difference (MD) 0.07; 95% confidence interval (CI) 0.03 to 0.10), visual acuity (MD 0.28; 95%CI 0.06 to 0.50) and contrast sensitivity (MD 0.26; 95%CI 0.22 to 0.30). Stratified analyses showed the increase in MPOD to be faster and greater with higher dose and longer treatment. The available evidence suggests that dietary lutein may be beneficial to AMD patients and the higher dose could make MPOD increase in a shorter time.

A review of the putative causal mechanisms associated with lower macular pigment in diabetes mellitus.

Macular pigment (MP) confers potent antioxidant and anti-inflammatory effects at the macula, and may therefore protect retinal tissue from the oxidative stress and inflammation associated with ocular disease and ageing. There is a body of evidence implicating oxidative damage and inflammation as underlying pathological processes in diabetic retinopathy. MP has therefore become a focus of research in diabetes, with recent evidence suggesting that individuals with diabetes, particularly type 2 diabetes, have lower MP relative to healthy controls. The present review explores the currently available evidence to illuminate the metabolic perturbations that may possibly be involved in MP's depletion. Metabolic co-morbidities commonly associated with type 2 diabetes, such as overweight/obesity, dyslipidaemia, hyperglycaemia and insulin resistance, may have related and independent relationships with MP. Increased adiposity and dyslipidaemia may adversely affect MP by compromising the availability, transport and assimilation of these dietary carotenoids in the retina. Furthermore, carotenoid intake may be compromised by the dietary deficiencies characteristic of type 2 diabetes, thereby further compromising redox homeostasis. Candidate causal mechanisms to explain the lower MP levels reported in diabetes include increased oxidative stress, inflammation, hyperglycaemia, insulin resistance, overweight/obesity and dyslipidaemia; factors that may negatively affect redox status, and the availability, transport and stabilisation of carotenoids in the retina. Further study in diabetic populations is warranted to fully elucidate these relationships.

Neural Activation During Visual Attention Differs in Individuals with High versus Low Macular Pigment Density.

SCOPE: The neural efficiency hypothesis for lutein (L) and zeaxanthin (Z) suggests that higher levels of L+Z in the central nervous system (CNS) are predictive of stronger stimulus-specific brain responses. Past research suggests that supplementing L+Z can improve neural processing speed and cognitive function across multiple domains, which supports this hypothesis. The purpose of this study is to determine the extent to which CNS L+Z levels predict brain responses using an attentionally taxing task. METHODS AND RESULTS: Macular pigment optical density (MPOD) is measured at baseline in 85 participants ranging in age from 18-92 years. Brain activation is measured using dense array electroencephalography. Stimuli evoking the signal include a grating array of vertical bars, oscillating at four driving frequencies. Significant stimulus-specific interactions are detected between attend condition, location, and age (p < .002) for unattended image locations, and between age and location (p < .008) for attended locations. Although no differences are found across age by MPOD, this measure is found to be predictive of neural power at parafoveal bar locations (R2 .080). CONCLUSION: CNS L+Z status is related to differences in brain activation in conditions designed to stress visual attention. These differences are strongest for older subjects.

An Investigation of the Role of Macular Pigment in Attenuating Photostress through Comparison between Blue and Green Photostress Recovery Times.

PURPOSE: Photostress recovery time (PSRT) is the time required for the macula to return to its normal functioning after the bleaching of cone photopigments due to light exposure, usually white. This work investigates the role of macular pigment (MP) as an optical filter that attenuates photostress by analyses of PSRT at different wavelengths. METHODS: Thirty-nine subjects (19-28 years) were exposed to blue/green photostress varying in irradiance. During photostress, pupil constriction (Cp) was measured. Twenty-seven subjects (20-27 years) were exposed to white photostress. After 25 s of photostress, the time (PSRT) required to read correctly a 0.2 logMAR letter was measured. Correlation was studied between PSRT, CP, and irradiance. Statistical significance of differences between PSRTs was evaluated at Log(irradiance(quanta s-1 cm-2)) = 14 by Student's t statistics. RESULTS: Cp and PSRT were found linearly correlated to Log(irradiance) for blue, green, and white. At Log(irradiance(quanta s-1 cm-2)) = 14, blue and green mean PSRTs resulted different (p < 0.001) with 3.8 ± 0.8 s and 6.7 ± 1.7 s, respectively. After correcting irradiance for the optical absorption of MP, mean blue PSRT became 6.6 ± 0.8 s, at the logarithm of MP-corrected irradiance in quanta s-1 cm-2 equal to 14 (p = 0.571 compared to green PSRT). For white light, at the logarithm of MP-corrected irradiance in quanta s-1 cm-2 equal to 14, mean PSRT was 7.5 ± 2.2 s, not significantly different from blue and green PSRT (p > 0.05). CONCLUSIONS: MP plays the role of an optical filter attenuating photostress. PSRT was substantially proportional to the number of incident photons corrected for the MP optical absorption, regardless of their wavelength.

Repeatability of the macular pigment spatial profile: A comparison of objective versus subjective classification.

PURPOSE: Classification of macular pigment (MP) spatial profile phenotypes varies and is often based on subjective visualisation. We investigated repeatability of MP optical density (MPOD) comparing an objective versus subjective profiling system. METHODS: The coefficient of repeatability (CoR) was calculated for point MPOD values (0-3.8°) obtained by dual-wavelength fundus autofluorescence (FAF) from two scans obtained in a single visit of 40 healthy individuals (39 ± 9 years). For each individual's dataset, the MP profile was classified as exponential, ring-like or central dip using an objective method (based on deviations away from an exponential fit), as well as by subjective visual profiling. Existing FAF images of 88 monozygotic (MZ) and 69 dizygotic (DZ) twin pairs were reanalysed using the objective profiling method and concordance and heritability of ring-like profiles determined. RESULTS: The CoR was 0.23 at 0° and 0.06 at 0.8°. Agreement of objective profiling between scans was excellent (κ = 0.85, 95% CI 0.69 to 1.00; p < 0.0005). Subjective profiling showed moderate agreement between scans (κ = 0.48, 95% CI 0.23 to 0.73; p < 0.0005). Agreement between objective and subjective classification was low (κ = 0.23, 95% CI 0.04 to 0.42; p = 0.02). Concordance for the ring-like profile using objective profiling was 0.74 for MZ compared to 0.36 for DZ twins. Heritability was calculated as 81.5% (95% confidence interval 61.1-93.1%). CONCLUSION: Compared to visual assessment, objective MP profiling is a more reliable method and should be considered in future observational and interventional studies. In addition, MP profile phenotypes showed high heritability.

Effect of Long-Term Xanthophyll and Anthocyanin Supplementation on Lutein and Zeaxanthin Serum Concentrations and Macular Pigment Optical Density in Postmenopausal Women.

Xanthophylls (lutein, L; zeaxanthin, Z) and anthocyanins are often included in food supplements to improve ocular health. There are no dietary reference intakes for them. The aim was to assess the effects of L, Z and anthocyanin supplementation on short and long-term lutein status markers (serum concentration and macular pigment optical density (MPOD)). Seventy-two postmenopausal women were randomized into a parallel study of 8 months: Group A-anthocyanines (60 mg/day); Group X-xanthophylls (6 mg L + 2 mg Z/day); Group X+A-anthocyanines (60 mg/day) + xanthophylls (6 mg L + 2 mg Z/day). At the beginning of the study, 4 and 8 month serum L and Z concentrations were determined (HPLC), as well as L, Z and anthocyanine dietary intake and MPOD (heterochromic flicker photometry). Baseline concentrations of L (0.35 ± 0.19 µmol/L), Z (0.11 ± 0.05 µmol/L), L+Z/cholesterol/triglycerides (0.07 ± 0.04 µmol/mmol) increased in Group X (2.8- and 1.6-fold in L and Z concentrations) and in group XA (2- and 1.4-fold in L and Z concentrations). MPOD (baseline: 0.32 ± 0.13 du) was not modified in any of the groups at the end of the study. There were no differences in the dietary intake of L+Z and anthocyanin at any point in time in any group. Supplementation of L and Z at a dietary level provoked an increase in their serum concentration that was not modified by simultaneous supplementation with anthocyanins.

Effect of intraocular scattering in macular pigment optical density measurements.

Fundus reflectometry is a common in-vivo, noninvasive method to estimate the macular pigment optical density (MPOD). The measured density, however, can be affected by the individual's intraocular scattering. Scattering causes a reduction in the contrast of the fundus image, which in turn leads to an underestimation of the measured density. Intraocular scattering was measured optically in a group of seven young, healthy subjects using the method of optical integration and was subsequently used to correctly estimate the MPOD from fundus images. It was shown that when scattering is not considered, the measured optical density using fundus reflectometry can be underestimated by as high as 16% for our group of subjects.

What do we know about the macular pigment in AMD: the past, the present, and the future.

Carotenoids are lipophilic isoprenoid pigments with a common C40H56 core chemical structure that are naturally synthesized by many plants, algae, bacteria, and fungi. Humans and animals cannot synthesize carotenoids de novo and must obtain them solely through dietary sources. Among the more than 750 carotenoids in nature, only lutein, zeaxanthin, meso-zeaxanthin, and their oxidative metabolites selectively accumulate in the foveal region of the retina where they are collectively referred to as the macular pigment (MP) of the macula lutea. MP serves an ocular protective role through its ability to filter phototoxic blue light radiation and also via its antioxidant activity. These properties have led to the hypothesis that carotenoids may protect against the development of age-related macular degeneration (AMD), the most common cause of blindness in the aged population >60 years old. Epidemiological studies have supported this by showing that patients with lower concentrations of serum carotenoids and macular pigment optical density (MPOD) measurements are at a higher risk of developing AMD. Conversely, nutritional supplementation and diets rich in lutein and zeaxanthin readily impact MP concentrations and reduce the risk of progression to advanced AMD, and the AREDS2 supplement formulation containing 10 mg of lutein and 2 mg of zeaxanthin is the standard-of-care recommendation for individuals at risk for visual loss from advanced AMD. This article reviews the rich history of research on the MP dating back to the 1700s and outlines their potential for further therapeutic improvements for AMD in the future.

The Macular Carotenoids are Associated with Cognitive Function in Preadolescent Children.

The macular carotenoids lutein (L) and zeaxanthin (Z) are obtained via diet and accumulate in the central retina where they are referred to as macular pigment. The density of this biomarker (macular pigment optical density; MPOD) has been positively correlated with cognitive functioning via measures of global cognition, processing speed, and visual-spatial abilities, among others. Although improvements in cognitive function have been found in adults, much less is known about how L and Z intake may support or improve cognitive functioning during periods of rapid developmental change, such as childhood and pre-adolescence. This study examined the relationship between MPOD and cognitive functioning in 51 7-13-year-old children (51% female). MPOD was measured using heterochromatic flicker photometry (HFP) optimized for this age group. Cognitive function was assessed using the Woodcock-Johnson III (composite standard scores were obtained for Brief Intellectual Ability, Verbal Ability, Cognitive Efficiency, Processing Speed, and Executive Processes). In this sample, MPOD was significantly related to Executive Processes, r(47) = 0.288, p < 0.05, and Brief Intellectual Ability, r(47) = 0.268, p < 0.05. The relationship to Cognitive Efficiency was positive and trending but not significant, r(49) = 0.206, p = 0.074. In general, these data are consistent with those of adults showing a link between higher carotenoid status and improved cognitive functioning.

Supplemental Retinal Carotenoids Enhance Memory in Healthy Individuals with Low Levels of Macular Pigment in A Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

BACKGROUND: There is a biologically plausible rationale whereby the dietary carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ), which are collectively referred to as macular pigment (MP) in the central retina (macula), support the maintenance of cognition via their antioxidant and anti-inflammatory properties. OBJECTIVE: To investigate the impact of supplemental L, Z, and MZ on memory, executive function, and verbal fluency among healthy individuals with low MP levels. METHODS: In this double-blind, placebo-controlled, randomized clinical trial, subjects (n = 91; mean±SD age = 45.42±12.40; % male = 51.6) consumed a daily formulation of 10 mg L, 10 mg MZ, and 2 mg Z (n = 45) or placebo (n = 46) for 12 months. Cognitive domains assessed included verbal and visual learning, immediate and delayed memory, executive function, and verbal fluency. MP and serum carotenoid concentrations of L, Z, and MZ were also measured. RESULTS: Following 12-month supplementation, individuals in the active group exhibited statistically significant improvements in memory when compared to the placebo group (paired associated learning [PAL] memory score [rANOVA, p = 0.009]; PAL errors [rANOVA, p = 0.017]). Furthermore, the observed reduction in the number of errors made in the PAL task among those in the intervention group was positively and significantly related to observed increases in MP volume (p = 0.005) and observed increases in serum concentrations of L (p = 0.009). CONCLUSION: This randomized, double-blind, placebo-controlled clinical trial demonstrates a memory-enhancing effect of daily supplementation with L, Z, and MZ in healthy subjects with low MP at baseline. The implications of these findings for intellectual performance throughout life, and for risk of cognitive decline in later life, warrant further study.

Relationship between macular pigment and visual function in subjects with early age-related macular degeneration.

PURPOSE: To investigate the relationship between macular pigment (MP) and visual function in subjects with early age-related macular degeneration (AMD). METHODS: 121 subjects with early AMD enrolled as part of the Central Retinal Enrichment Supplementation Trial (CREST; ISRCTN13894787) were assessed using a range of psychophysical measures of visual function, including best corrected visual acuity (BCVA), letter contrast sensitivity (CS), mesopic and photopic CS, mesopic and photopic glare disability (GD), photostress recovery time (PRT), reading performance and subjective visual function, using the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25). MP was measured using customised heterochromatic flicker photometry. RESULTS: Letter CS, mesopic and photopic CS, photopic GD and mean reading speed were each significantly (p<0.05) associated with MP across a range of retinal eccentricities, and these statistically significant relationships persisted after controlling for age, sex and cataract grade. BCVA, NEI VFQ-25 score, PRT and mesopic GD were unrelated to MP after controlling for age, sex and cataract grade (p>0.05, for all). CONCLUSIONS: MP relates positively to many measures of visual function in unsupplemented subjects with early AMD. The CREST trial will investigate whether enrichment of MP influences visual function among those afflicted with this condition. TRIAL REGISTRATION NUMBER: ISRCTN13894787.

Enrichment of Macular Pigment Enhances Contrast Sensitivity in Subjects Free of Retinal Disease: Central Retinal Enrichment Supplementation Trials - Report 1.

PURPOSE: The high-performance visual function associated with central vision is mediated by the macula (the central retina), which accumulates three diet-derived pigments (the carotenoids lutein [L], zeaxanthin [Z], and meso-zeaxanthin [MZ]). Our study sought to investigate the impact on visual function, including contrast sensitivity (CS), of supplementation with these naturally occurring carotenoids, in individuals with low retinal concentrations. METHODS: Subjects consumed daily a formulation containing 10 mg L, 2 mg Z, and 10 mg MZ (active group; n = 53) or placebo (n = 52) for a period of 12 months. Study visits were at baseline, 3, 6, and 12 months. Contrast sensitivity at 6 cycles per degree (cpd) was the primary outcome measure (POM). Secondary outcome measures included CS at other spatial frequencies, best-corrected visual acuity (BCVA), glare disability, photostress recovery, and light scatter. Macular pigment optical density (MPOD) was measured using dual-wavelength autofluorescence, and serum carotenoid concentrations were analyzed using high performance liquid chromatography (HPLC). RESULTS: Compared to placebo, statistically significant improvements from baseline CS were detected at 6 (P = 0.002) and 1.2 (P = 0.004) cpd in the active group. Additionally, improvements in CS were commensurate with the observed increases in retinal concentrations of these carotenoids (r = 0.342, P = 0.002 at 6 cpd). CONCLUSIONS: These results indicate that dietary fortification with the macular carotenoids can have meaningful effects on visual function.

Retinal Biochemistry, Physiology and Cell Biology.

The vitreous, the vasculature of the retina, macular pigments, phototransduction, retinal pigment epithelium, Bruch's membrane and the extracellular matrix, all play an important role in the normal function of the retina as well as in diseases. Understanding the pathophysiology allows us to target treatment. As ocular angiogenesis, immunity and inflammation are covered elsewhere, those subjects will not be discussed in this chapter.

Temporal Visual Mechanisms May Mediate Compensation for Macular Pigment.

Macular pigment (MP) is a pre-receptoral filter that is diet derived and deposited in relatively high optical density in the foveal region of the retina. Due to its yellow coloration, MP absorbs light of relatively short wavelengths, ranging from 400 nm to 520 nm. Despite the spectral and spatial nonuniformity imposed upon the sensory retina by MP, perception appears to be relatively uniform across the central visual field. MP therefore offers an opportunity to determine experimentally potential mechanisms responsible for mediating this uniformity. After assessing, in 14 subjects, MP's effects on the temporal sensitivity of both the short-wavelength- and middle-/long-wavelength-sensitive visual pathways, it appears that the visual system compensates for absorption of short-wavelength light by MP by slowing the sampling rate of short-wavelength cones and by increasing the processing speed of middle-/long-wavelength-sensitive cones. This mechanism could work via temporal summation or a temporal neural code, whereby slower response dynamics lead to amplification of relatively weak signals.

Visibility through atmospheric haze and its relation to macular pigment.

PURPOSE: A major factor limiting the visibility of distant targets is veiling attributed to atmospheric scattering, known commonly as haze. It has been suggested that yellow filters (in this case, the macular pigments, MPs) could selectively absorb this haze, thus extending visual range. This study is an empirical test of the visibility hypothesis. METHODS: Twelve subjects had their full contrast sensitivity function (CSF) (represented by six spatial frequencies) assessed in the presence of two background conditions: simulated blue haze and short wave-deficient light. Contrast sensitivity at the peak of the CSF (7.5 cycles per degree) was measured in the presence of the same two backgrounds as the full CSF, with the addition of a broadband xenon background condition in a separate sample of 25 subjects. RESULTS: Simulated blue haze was found to uniformly reduce the CSF in the 12 subjects for whom the full CSF was assessed. Therefore, only the peak was measured in the larger sample of 25 subjects. Macular pigment density was significantly related to energy at threshold for both the haze and xenon backgrounds but not the short wave-deficient background. Thus, subjects with higher levels of MP could withstand more light before losing sight of the target. CONCLUSIONS: This result is consistent with previous modeling of the visibility hypothesis as well as visual range improvements seen when using an artificial MP filter.