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.

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.

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.

Nitric Oxide and Lutein: Function, Performance, and Protection of Neural Tissue.

The soluble gas neurotransmitter nitric oxide (NO) serves many important metabolic and neuroregulatory functions in the retina and brain. Although it is necessary for normal neural function, NO can play a significant role in neurotoxicity. This is often seen in disease states that involve oxidative stress and inflammation of neural tissues, such as age-related macular degeneration and Alzheimer's disease. The dietary xanthophyll carotenoid lutein (L) is a potent antioxidant and anti-inflammatory agent that, if consumed in sufficient amounts, is deposited in neural tissues that require substantial metabolic demand. Some of these specific tissues, such as the central retina and frontal lobes of the brain, are impacted by age-related diseases such as those noted above. The conspicuous correspondence between metabolic demand, NO, and L is suggestive of a homeostatic relationship that serves to facilitate normal function, enhance performance, and protect vulnerable neural tissues. The purpose of this paper is to review the literature on these points.

A potential mechanism for compensation in the blue-yellow visual channel.

Due to their unique contribution to human vision, the short (S)-wavelength sensitive cones, their anatomical projections and, more recently, the cortical representation of their function, have motivated intense scientific interest. The principal study of the visual channel associated with S-cone projections has been conducted using psychophysical, neurophysiological, and ex vivo anatomical techniques, whereas more recent research on the pathway has employed functional magnetic resonance imaging (fMRI). The purpose of this manuscript is to present a perspective regarding the means by which color signals within this visual channel are processed in the brain, namely how differences in short-wavelength light transmission caused by intraocular, pre-receptoral filtration are compensated for. Recent results from fMRI and psychophysical studies indicate the existence of a frequency-dependent signal amplification mechanism, whereby lower frequencies result in an amplification of S-cone signals. This finding could motivate a future research direction for determining the localization of blue-yellow color processing and neural compensation in the blue-yellow visual channel.