Effects of macular xanthophyll supplementation on brain-derived neurotrophic factor, pro-inflammatory cytokines, and cognitive performance.

PURPOSE: Oxidative and inflammatory processes play a major role in stress-induced neural atrophy. There is a wide body of literature linking oxidative and inflammatory stress with reductions in neurotrophic factors, stress resilience, and cognitive function. Based on their antioxidant and anti-inflammatory capacity, we investigated the effect of the dietary carotenoids lutein and zeaxanthin, along with the zeaxanthin isomer meso-zeaxanthin (collectively the "macular xanthophylls" [MXans]) on systemic brain-derived neurotrophic factor (BDNF) and anti-oxidant capacity (AOC), and the pro-inflammatory cytokines TNF-α, IL-6, and IL-1ß. To investigate higher-order effects, we assessed cognitive performance. METHODS: 59 young (18-25 yrs.), healthy subjects participated in a 6-month, double-blind, placebo-controlled trial to evaluate the effects of MXan supplementation on the aforementioned serum parameters and cognitive performance. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg/day total MXans; all measures were taken at baseline and 6 months. Blood was obtained via fasting blood draw, and MXan concentration in the retina (termed macular pigment optical density [MPOD]) was measured via customized heterochromatic flicker photometry. Serum BDNF and cytokines were assessed via ELISA. Serum antioxidant capacity (AOC) and serum MXan concentrations were quantified via colorimetric microplate assay, and high-performance liquid chromatography, respectively. Cognitive performance was measured via a computer-based assessment tool (CNS Vital Signs). RESULTS: BDNF, MPOD, serum MXans, and AOC all increased significantly versus placebo in both treatment groups over the 6-month study period (p < .05 for all). IL-1ß decreased significantly versus placebo in both treatment groups (p = .0036 and p = .006, respectively). For cognitive measures, scores for composite memory, verbal memory, sustained attention, psychomotor speed, and processing speed all improved significantly in treatment groups (p < .05 for all) and remained unchanged in the placebo group. Several measures were found to be significantly associated in terms of relational changes over the course of the study. Notably, change in BDNF was related to change in IL-1ß (r = -0.47; p < .001) and MPOD (r = 0.44; p = .0086). Additionally, changes in serum MXans were strongly related to AOC (r = 0.79 & 0.61 for lutein and zeaxanthin isomers respectively; p < .001). For cognitive scores, change in BDNF was correlated to change in composite memory (r = 0.32; p = .014) and verbal memory (r = 0.35; p = .007), whereas change in MPOD was correlated with change in both psychomotor speed (r = 0.38; p = .003), and processing speed (r = 0.35; p = .007). Change in serum lutein was found to be significantly correlated to change in verbal memory (r = 0.41; p < .001), composite memory (r = 0.31; p = .009), and sustained attention (r = 0.28; p = .036). Change in serum zeaxanthin isomers was significantly correlated with change in verbal memory (r = 0.33; p = .017). Lastly, change in AOC was significantly associated with verbal memory (r = 0.34; p = .021), composite memory (r = 0.29; p = .03), and sustained attention (r = 0.35; p = .016). No significant relational changes in any cognitive parameter were found for the placebo group. CONCLUSIONS: Six months of daily supplementation with at least 13 mg of MXans significantly reduces serum IL-1ß, significantly increases serum MXans, BDNF, MPOD, and AOC, and improves several parameters of cognitive performance. Findings suggest that increased systemic antioxidant/anti-inflammatory capacity (and not necessarily deposition of the carotenoids in neural tissues), may explain many of the effects determined in this study. The significant relationship between change in BDNF and IL-1ß over the course of the study suggests that regular consumption of MXans interrupts the inflammatory cascade that can lead to reduction of BDNF. Changes in MPOD and BDNF appear to account for enhancement in cognitive parameters that involve speed of processing and complex processing, respectively. ISRCTN Clinical Trial Registration: ISRCTN16156382.

Visual Performance in the "Real World": Contrast Sensitivity, Visual Acuity, and Effects of Macular Carotenoids.

Visual acuity (VA) is compared to contrast sensitivity (CS) testing in assessing "real-world" visual performance, and it is recommended that both should be measured routinely in the clinic. The role of nutritional intervention in improving visual performance is reviewed and emphasized. A brief history and illustration of both VA and CS, within the scope of visual performance, is presented. Parameters for effective CS testing in the clinic, and guidelines for interpretation of results, including a new model for understanding the visual impact of changes in CS, are also presented. Relevant research that supports the use of the macular carotenoids lutein, zeaxanthin, and meso-zeaxanthin to enhance visual performance is reviewed with suggested guidelines for supplementation. CS testing is easily performed at a single intermediate target size and is an excellent tool for the accurate assessment of a patient's overall visual experience. Research continues to uncover the strong link between nutrition and visual performance; the macular carotenoids appear to be especially effective in this regard, and their benefits to visual performance now importantly include contrast sensitivity. Clinicians can provide an improved level of care by incorporating into the examination protocol CS testing and, where appropriate, nutritional counseling and intervention.

Supplementation with macular carotenoids reduces psychological stress, serum cortisol, and sub-optimal symptoms of physical and emotional health in young adults.

PURPOSE: Oxidative stress and systemic inflammation are the root cause of several deleterious effects of chronic psychological stress. We hypothesize that the antioxidant and anti-inflammatory capabilities of the macular carotenoids (MCs) lutein, zeaxanthin, and meso-zeaxanthin could, via daily supplementation, provide a dietary means of benefit. METHODS: A total of 59 young healthy subjects participated in a 12-month, double-blind, placebo-controlled trial to evaluate the effects of MC supplementation on blood cortisol, psychological stress ratings, behavioural measures of mood, and symptoms of sub-optimal health. Subjects were randomly assigned to one of three groups: placebo, 13 mg, or 27 mg / day total MCs. All parameters were assessed at baseline, 6 months, and 12 months. Serum MCs were determined via HPLC, serum cortisol via ELISA, and macular pigment optical density (MPOD) via customized heterochromatic flicker photometry. Behavioural data were obtained via questionnaire. RESULTS: Significant baseline correlations were found between MPOD and Beck anxiety scores (r = -0.28; P = 0.032), MPOD and Brief Symptom Inventory scores (r = 0.27; P = 0.037), and serum cortisol and psychological stress scores (r = 0.46; P < 0.001). Supplementation for 6 months improved psychological stress, serum cortisol, and measures of emotional and physical health (P < 0.05 for all), versus placebo. These outcomes were either maintained or improved further at 12 months. CONCLUSIONS: Supplementation with the MCs significantly reduces stress, cortisol, and symptoms of sub-optimal emotional and physical health. Determining the basis for these effects, whether systemic or a more central (i.e. brain) is a question that warrants further study.

Macular Carotenoid Supplementation Improves Visual Performance, Sleep Quality, and Adverse Physical Symptoms in Those with High Screen Time Exposure.

The dramatic rise in the use of smartphones, tablets, and laptop computers over the past decade has raised concerns about potentially deleterious health effects of increased "screen time" (ST) and associated short-wavelength (blue) light exposure. We determined baseline associations and effects of 6 months' supplementation with the macular carotenoids (MC) lutein, zeaxanthin, and mesozeaxanthin on the blue-absorbing macular pigment (MP) and measures of sleep quality, visual performance, and physical indicators of excessive ST. Forty-eight healthy young adults with at least 6 h of daily near-field ST exposure participated in this placebo-controlled trial. Visual performance measures included contrast sensitivity, critical flicker fusion, disability glare, and photostress recovery. Physical indicators of excessive screen time and sleep quality were assessed via questionnaire. MP optical density (MPOD) was assessed via heterochromatic flicker photometry. At baseline, MPOD was correlated significantly with all visual performance measures (p < 0.05 for all). MC supplementation (24 mg daily) yielded significant improvement in MPOD, overall sleep quality, headache frequency, eye strain, eye fatigue, and all visual performance measures, versus placebo (p < 0.05 for all). Increased MPOD significantly improves visual performance and, in turn, improves several undesirable physical outcomes associated with excessive ST. The improvement in sleep quality was not directly related to increases in MPOD, and may be due to systemic reduction in oxidative stress and inflammation.

Contrast Sensitivity and Lateral Inhibition Are Enhanced With Macular Carotenoid Supplementation.

Purpose: Once deposited in the retina, the so-called macular carotenoids lutein (L), zeaxanthin (Z), and mesozeaxanthin (MZ) have been shown to enhance visual performance. The purpose of our study was to investigate whether increasing macular pigment optical density (MPOD) could enhance lateral inhibitory processes, and thereby improve contrast sensitivity (CS). Methods: A total of 59 young (18-25 years), healthy individuals participated in this 1-year, double-masked, placebo-controlled study. MPOD was assessed via heterochromatic flicker photometry. Lateral inhibition sensitivity (LIS) was determined with a computer-based, user-adjustable Hermann grid. CS (at 8 cycles/degree) was determined with a two-alternative, forced-choice procedure. Subjects received either the placebo (n = 10), 12 mg total macular carotenoids (n = 24), or 24 mg total macular carotenoids (n = 25). Results: MPOD, LIS, and CS increased significantly in treatment groups between baseline and 6 months, and between 6 and 12 months (P < 0.05 for all) versus placebo. The relationships between changes in MPOD and both LIS and CS were significant at 6 and 12 months (P < 0.05 for both). Changes in CS and LIS over the 12-month study period were found to be significantly related (r = 0.41; P = 0.0014). Conclusions: Increases in MPOD led to enhanced lateral inhibitory processes, which correspond to improved CS. Because optical filtering has the same net effect on dark versus light bars, it cannot explain these improvements. Improvement in CS with increases in MPOD therefore appears to involve enhancement of the fundamental physiological systems that give rise to edge detection.

Macular carotenoid supplementation improves disability glare performance and dynamics of photostress recovery.

BACKGROUND: The so-called macular carotenoids (MC) lutein (L), zeaxanthin (Z), and meso-zeaxanthin (MZ) comprise the diet-derived macular pigment (MP). The purpose of this study was to determine effects of MC supplementation on the optical density of MP (MPOD), repeated-exposure photostress recovery (PSR), and disability glare (DG) thresholds. METHODS: This was a double-blind, placebo-controlled trial. Fifty-nine young (mean age = 21.7), healthy volunteers participated in this study. Subjects supplemented their daily diet with either 10 mg L + 2 mg total Z (1 mg Z + 1 mg MZ; n = 24), 20 mg L + 4 mg total Z (2 mg Z + 2 mg MZ; n = 25), or placebo (n = 10) for 12 months. The primary outcome was a composite measure of visual performance in glare, defined by change in DG and PSR. Secondary outcomes included MPOD and visual fatigue. The primary endpoint for outcomes was 12 months. MPOD was assessed with customized heterochromatic flicker photometry. PSR times for an 8 cycle /degree, 15 % contrast Gabor patch target were determined after each of five successive exposures to intense LED lights. DG threshold was defined as the intensity of a ring of lights through which subjects were able to maintain visibility of the aforementioned target. Measures of all parameters were conducted at baseline, 6 months, and 12 months. Repeated-measures ANOVA, and Pearson product-moment correlations were used to determine statistically significant correlations, and changes within and between groups. RESULTS: MPOD for subjects in both supplementation groups increased significantly versus placebo at both 6- and 12-month visits (p < 0.001 for all). Additionally, PSR times and DG thresholds improved significantly from baseline compared to placebo at 6- and 12-month visits (p < 0.001 for all). At baseline, MPOD was significantly related to both DG thresholds (r = 0.444; p = 0.0021) and PSR times (r = -0.56; p < 0.001). As a function of MPOD, the repeated-exposure PSR curves became more asymptotic, as opposed to linear. The change in subjects' DG thresholds were significantly related to changes in PSR times across the study period (r = -0.534; p < 0.001). CONCLUSIONS: Increases in MPOD lead to significant improvements in PSR times and DG thresholds. The asymptotic shape of the repeated-exposure PSR curves suggests that increases in MPOD produce more consistent steady-state visual performance in bright light conditions. The mechanism for this effect may involve both the optical filtering and biochemical (antioxidant) properties of MP. TRIAL REGISTRATION: ISRCTN trial registration number: ISRCTN54990825. Data reported in this manuscript represent secondary outcome measures from the registered trial.

Serum and retinal responses to three different doses of macular carotenoids over 12 weeks of supplementation.

The macular carotenoids lutein (L), zeaxanthin (Z), and mesozeaxanthin (MZ) have been shown to have neuroprotective and visual performance benefits once deposited in retinal tissues. The purpose of this 12-week trial was to determine biweekly the absorption kinetics, efficiency of retinal deposition, and effects on the spatial profile of macular pigment for three levels of L + Z + MZ supplement. This study was a double-blind, placebo-controlled 12-week trial. Twenty-eight healthy subjects, aged 18-25 yrs participated. Subjects were randomly assigned to one of four daily supplementation groups: placebo (safflower oil; n = 5), 7.44 mg total macular carotenoid (n = 7), 13.13 mg total macular carotenoid (n = 8), and 27.03 (n = 8) mg total macular carotenoid. Ratios of the three carotenoids were virtually identical for the three levels of supplement (83% L, 10% Z, 7% MZ). At baseline and every two weeks thereafter over the 12-week study period, a fasting blood draw was conducted and, via heterochromatic flicker photometry, spatial profiles of macular pigment optical density (MPOD) were determined. Compared to placebo, serum concentrations of both L and total Z, for each of the supplement levels, were found to increase significantly from baseline after two weeks of daily ingestion (p < 0.001). Likewise, MPOD increased significantly in all treatment groups (p < 0.001) compared to placebo. Serum responses (L, Z, and L + Z) were linearly related to dose (p < 0.001 for all), but not to retinal response. L: Z serum response ratios decreased exponentially with increases in dose (p = 0.008). The ratio of MPOD change: total serum response was found to be highest for the 13.13 mg level of supplement (p = 0.021), followed by 27.03- and 7.44-mg doses. The very center of the spatial profile of MPOD increased in a fashion commensurate with dose level. Although L serum responses increased with dose, the slope of increase was shallower than for Z. Given the higher levels of L in the supplements, this is suggestive of a compressed response with relatively high doses of L. Although all three doses significantly augmented MPOD, the 13.13 mg/day L + Z supplement level was the most efficient in doing so. The data regarding efficiency may inform recommendations regarding macular carotenoid supplementation for age-related macular degeneration. Lastly (although not statistically significant), the shift toward a more pronounced central peak in the spatial profile of MPOD in all treatment groups suggests that central retinal deposition of Z and MZ was efficient and can be seen after a short period of supplementation, especially with higher (e.g. 27.03 mg) daily doses of macular carotenoids. ISRCTN trial registration number: ISRCTN54990825.

Macular pigment and visual performance under glare conditions.

PURPOSE: Many parameters of visual performance (e.g., contrast sensitivity) are compromised under glaring light conditions. Recent data indicate that macular pigment (MP) is strongly related to improvements in glare disability and photostress recovery based on a filtering mechanism. In this study, we assessed the causality of this relation by supplementing lutein and zeaxanthin for 6 months while measuring MP, glare disability, and photostress recovery. METHODS: Forty healthy subjects (mean age = 23.9) participated in the study. Subjects were followed for 6 months and assessed at baseline, 1, 2, 4, and 6 months. Spatial density profiles of MP were measured using heterochromatic flicker photometry. Disability glare was measured using a 1 degree-diameter circular grating surrounded by a broadband glare source (a xenon-white annulus). The intensity of the annulus (11 degree inner and 12 degree outer diameters) was adjusted by the subject until the grating target was no longer seen. For the photostress recovery experiment, the time required to detect a 1 degree-diameter grating stimulus after a 5-s exposure to a 2.5 muW/cm2, 5 degree-diameter disk was recorded. Subjects were tested under central viewing and eccentric viewing (10 degree temporal retina) conditions. RESULTS: At the baseline time point, MP optical density (OD) at 30' eccentricity ranged from 0.08 to 1.04, and was strongly correlated with improved visual performance in the two glare tasks. After 6 months of lutein (L) and zeaxanthin (Z) supplementation, average MPOD (at 30' eccentricity) had increased from 0.41 to 0.57, and was shown to significantly reduce the deleterious effects of glare for both the visual performance tasks assessed. CONCLUSIONS: MP is strongly related to improvements in glare disability and photostress recovery in a manner strongly consistent with its spectral absorption and spatial profile. Four to 6 months of 12 mg daily L + Z supplementation significantly increases MPOD and improves visual performance in glare for most subjects.

Macular pigment optical density at four retinal loci during 120 days of lutein supplementation.

BACKGROUND: Increased consumption of lutein and zeaxanthin has been shown to increase macular pigment optical density (MPOD) in some individuals. Most interventions either obtained infrequent measures of MPOD or measured MPOD at a single retinal locus. PURPOSE: The aim of this study was to measure acute changes in MPOD at four retinal loci during lutein intervention. METHODS: For 120 days, three subjects consumed 30 mg of lutein and 2.7 mg of zeaxanthin supplement per day. MPOD was measured with heterochromatic flicker photometry at 20', 30', 60' and 120' eccentricity three or four times per week. High-performance liquid chromatography was used to measure serum carotenoid concentrations in blood samples collected at baseline and at 30-day intervals. RESULTS: At the two most central loci, MPOD significantly increased in all three subjects with a mean change of approximately 0.09 log units at 20' eccentricity and 0.08 log units at 30' eccentricity. MPOD significantly increased in two subjects at 60' eccentricity, and in one subject at 120' eccentricity. The increases in MPOD appeared to be linear and continued after treatment was ended. In all three subjects, log sensitivity at the reference locus decreased linearly. Serum lutein and serum zeaxanthin increased from baseline, reaching peak concentrations after 30 days of supplementation. CONCLUSION: The changes in MPOD suggest that carotenoid deposition occurs linearly and may be biased towards the central retina. Further, carotenoid deposition may occur outside the central fovea in interventions with pharmacological doses of carotenoid, resulting in underestimations of psychophysical measures of MPOD.

Macular pigment optical density and photophobia light threshold.

Light absorption by macular pigment may attenuate visual discomfort, or photophobia, for targets composed of short-wavelength light. Macular pigment optical density (MPOD) and photophobia light thresholds were measured psychophysically in 10 subjects. The energy necessary to induce photophobia for a short-wavelength target relative to a long-wavelength target was linearly related to MPOD, as well as estimates of peak MPOD and integrated macular pigment. In four subjects who consumed lutein supplements, increases in MPOD corresponded to increases in photophobia light thresholds. Light absorption by macular pigment appears to influence the amount of short-wavelength light necessary to elicit photophobia.