Carotenoid-Rich Brain Nutrient Pattern Is Positively Correlated With Higher Cognition and Lower Depression in the Oldest Old With No Dementia.

Background: Healthy dietary patterns are related to better cognitive health in aging populations. While levels of individual nutrients in neural tissues are individually associated with cognitive function, the investigation of nutrient patterns in human brain tissue has not been conducted. Methods: Brain tissues were acquired from frontal and temporal cortices of 47 centenarians from the Georgia Centenarian Study. Fat-soluble nutrients (carotenoids, vitamins A, E, K, and fatty acids [FA]) were measured and averaged from the two brain regions. Nutrient patterns were constructed using principal component analysis. Cognitive composite scores were constructed from cognitive assessment from the time point closest to death. Dementia status was rated by Global Deterioration Scale (GDS). Pearson's correlation coefficients between NP scores and cognitive composite scores were calculated controlling for sex, education, hypertension, diabetes, and APOE ε4 allele. Result: Among non-demented subjects (GDS = 1-3, n = 23), a nutrient pattern higher in carotenoids was consistently associated with better performance on global cognition (r = 0.38, p = 0.070), memory (r = 0.38, p = 0.073), language (r = 0.42, p = 0.046), and lower depression (r = -0.40, p = 0.090). The findings were confirmed with univariate analysis. Conclusion: Both multivariate and univariate analyses demonstrate that brain nutrient pattern explained mainly by carotenoid concentrations is correlated with cognitive function among subjects who had no dementia. Investigation of their synergistic roles on the prevention of age-related cognitive impairment remains to be performed.

Serum Carotenoids, Tocopherols, Total n-3 Polyunsaturated Fatty Acids, and n-6/n-3 Polyunsaturated Fatty Acid Ratio Reflect Brain Concentrations in a Cohort of Centenarians.

Investigating the role of nutrition on cognitive health is challenging. Human brain tissue is inaccessible in living humans and is often limited in deceased individuals. Therefore, biomarkers of brain nutrient levels are of interest. The objective of this study was to characterize the relationships between levels of fat-soluble nutrients in serum and matched brain tissues from the frontal and temporal cortices of participants in the Georgia Centenarian Study (n = 47). After adjusting for sex, race, cognitive status (Global Deterioration Scale), body mass index, and presence of hypertension and/or diabetes, there was a significant relationship (p < 0.05) between serum and brain levels of carotenoids (lutein, zeaxanthin, cryptoxanthin, ß-carotene), α-, γ-tocopherols, total n-3 polyunsaturated fatty acids (PUFAs), and n-6/n-3 PUFA ratio. The relationship between serum and brain total n-6 PUFAs was inconsistent among the two brain regions. No significant relationship was identified between serum and brain retinol, total saturated fatty acid, total monounsaturated fatty acid, and trans-fatty acid levels. These findings suggest that serum carotenoids, tocopherols, total n-3 PUFAs, and n-6/n-3 PUFA ratio reflect levels in brain and can be used as surrogate biomarkers in older population.

Correction: Relationship between Concentrations of Lutein and StARD3 among Pediatric and Geriatric Human Brain Tissue.

[This corrects the article DOI: 10.1371/journal.pone.0155488.].

Relationship between Concentrations of Lutein and StARD3 among Pediatric and Geriatric Human Brain Tissue.

Lutein, a dietary carotenoid, selectively accumulates in human retina and brain. While many epidemiological studies show evidence of a relationship between lutein status and cognitive health, lutein's selective uptake in human brain tissue and its potential function in early neural development and cognitive health have been poorly evaluated at a molecular level. The objective of this study was to evaluate the cross-sectional relationship between concentrations of brain lutein and StARD3 (identified as its binding protein in retinal tissue) among three age groups: infants (1-4 months, n = 10), older adults (55-86 years, n = 8), and centenarians (98-105 years, n = 10). Brain lutein concentrations were analyzed by high-performance liquid chromatography and StARD3 levels were analyzed by Western Blot analysis. The strong relationship in infant brains (r = 0.75, P < 0.001) suggests that lutein has a role in neural development. The relationship remained significant but weaker in older adults (r = 0.51, P < 0.05) and insignificant in centenarians (r = 0.08, P > 0.05), seven of whom had mild cognitive impairment (MCI) or dementia. These exploratory findings suggest an age-related decrease or abnormality of StARD3 activity in human brain. Given that StARD3 is also involved in cholesterol transportation, a process that is aberrant in neurodegenerative diseases, the potential protective function of lutein against these diseases remains to be explored.

Macular pigment carotenoids in the retina and occipital cortex are related in humans.

OBJECTIVES: Lutein and zeaxanthin are dietary carotenoids that preferentially accumulate in the macular region of the retina. Together with meso-zeaxanthin, a conversion product of lutein in the macula, they form the macular pigment. Lutein is also the predominant carotenoid in human brain tissue and lutein status is associated with cognitive function in adults. The study objective was to evaluate the relationship between retinal and brain lutein and zeaxanthin in humans. METHODS: Donated brain tissue (occipital cortex and hippocampus) and matched retina were obtained from the National Disease Research Interchange, a national human tissue resource center which adheres to strict consent and confidentiality procedures. Decedents were men and women aged >50 years who either had normal cognitive function or Alzheimer's disease. Tissues were analyzed using standard lipid extractions followed by analysis on reverse-phase high performance liquid chromatography (HPLC) and normal-phase HPLC (for meso-zeaxanthin). RESULTS: Macular pigment carotenoids (lutein, meso-zeaxanthin, and zeaxanthin combined) in the retina were significantly related to the combined concentrations of lutein and zeaxanthin in the occipital cortex. When analyzed separately, only retinal lutein (plus meso-zeaxanthin), not zeaxanthin, was significantly related to lutein in the occipital cortex. No correlations were observed with lutein and zeaxanthin in the hippocampus. DISCUSSION: Total macular pigment density measured via non-invasive, psychophysical techniques can be used as a biomarker to ascertain brain lutein and zeaxanthin status in clinical studies.

Dietary cholesterol and cardiovascular disease: a systematic review and meta-analysis.

BACKGROUND: Dietary cholesterol has been suggested to increase the risk of cardiovascular disease (CVD), which has led to US recommendations to reduce cholesterol intake. OBJECTIVE: The authors examine the effects of dietary cholesterol on CVD risk in healthy adults by using systematic review and meta-analysis. DESIGN: MEDLINE, Cochrane Central, and Commonwealth Agricultural Bureau Abstracts databases were searched through December 2013 for prospective studies that quantified dietary cholesterol. Investigators independently screened citations and verified extracted data on study and participant characteristics, outcomes, and quality. Random-effect models meta-analysis was used when at least 3 studies reported the same CVD outcome. RESULTS: Forty studies (17 cohorts in 19 publications with 361,923 subjects and 19 trials in 21 publications with 632 subjects) published between 1979 and 2013 were eligible for review. Dietary cholesterol was not statistically significantly associated with any coronary artery disease (4 cohorts; no summary RR), ischemic stroke (4 cohorts; summary RR: 1.13; 95% CI: 0.99, 1.28), or hemorrhagic stroke (3 cohorts; summary RR: 1.09; 95% CI: 0.79, 1.50). Dietary cholesterol statistically significantly increased both serum total cholesterol (17 trials; net change: 11.2 mg/dL; 95% CI: 6.4, 15.9) and low-density lipoprotein (LDL) cholesterol (14 trials; net change: 6.7 mg/dL; 95% CI: 1.7, 11.7 mg/dL). Increases in LDL cholesterol were no longer statistically significant when intervention doses exceeded 900 mg/d. Dietary cholesterol also statistically significantly increased serum high-density lipoprotein cholesterol (13 trials; net change: 3.2 mg/dL; 95% CI: 0.9, 9.7 mg/dL) and the LDL to high-density lipoprotein ratio (5 trials; net change: 0.2; 95% CI: 0.0, 0.3). Dietary cholesterol did not statistically significantly change serum triglycerides or very-low-density lipoprotein concentrations. CONCLUSION: Reviewed studies were heterogeneous and lacked the methodologic rigor to draw any conclusions regarding the effects of dietary cholesterol on CVD risk. Carefully adjusted and well-conducted cohort studies would be useful to identify the relative effects of dietary cholesterol on CVD risk.

Bioavailability of AREDS1 micronutrients from softgel capsules and tablets: a pilot study.

PURPOSE: The benefits of antioxidant micronutrients in slowing progression to advanced stages of age-related macular degeneration (AMD) was supported by the 4/day tablet form investigated in the Age-related Eye Disease Study 1 (AREDS1) and the 2/day softgel form in the Age-related Eye Disease Study 2 (AREDS2). However, the choices of excipient, dosage form, and ingredient chemistry as well as the patient physiologies and pathologies can influence bioavailability and efficacy. The objective of the study was to explore the influence of dosage form on the bioavailability of the five primary AREDS1 and Tier-2 AREDS2 micronutrients: the metals zinc and copper, ß-carotene, and vitamins E and C. The intent was to establish by chemical analysis the relative bioavailabilities of these five micronutrients in plasma, or serum for the metals, as well as to identify any opportunities for improvements. METHODS: A total of 15 healthy men (5) and women (10) were recruited for a controlled, randomized, three-arm, crossover trial of the AREDS1 micronutrients. The study investigated responses in bioabsorption to a single dose of either four tablets or two softgels at the full dose level, or one softgel at the half-dose level. The bioavailability of each micronutrient was based on the pharmacokinetic profiles established through 15 samplings for each ingredient/dosage form in plasma/serum over the course of one week. RESULTS: Bioavailability was estimated using model-independent and model-dependent procedures. A statistical advantage of the dosage form was observed in only two cases from the exaggerated effects using the half-dose softgel and for the tablet dosage form for ß-carotene and vitamin E. An unanticipated complexity was suggested by the bimodal absorption of zinc. For these micronutrients, no disadvantage (though potential advantage) was inferred for the water-soluble components presented in a softgel formulation. Increased fractional absorption was observed for the smaller dose (one capsule versus two), but it was not sufficient to reach the level achieved by the full dose of either four tablets or two softgels. A model-dependent analysis permitted an estimation of the percentage of micronutrients absorbed, with zinc, the single most important ingredient, absorbed at about a 10% level. CONCLUSIONS: The results suggest modestly contradictory requirements in the dosage form for water-soluble and lipid-soluble ingredients, as based on a goal of improved bioavailability. Comparative consistency in bioavailability was observed across dosage forms, and most nutrients between AREDS1 and AREDS2 (full dose) formulations relative to the significant variations observed within this controlled population. The results emphasize the importance of defining the requisite bioavailability of each micronutrient and the influence of the dosage form that provides it. With the recognition of global and population-specific micronutrient deficiencies, notably in the elderly populations afflicted with AMD and their significant metabolic and health consequences, establishing efficient means of supplementation are of continuing epidemiologic interest.

Lutein and preterm infants with decreased concentrations of brain carotenoids.

OBJECTIVES: Lutein and zeaxanthin are dietary carotenoids that may influence visual and cognitive development. The objective of this study was to provide the first data on distribution of carotenoids in the infant brain and compare concentrations in preterm and term infants. METHODS: Voluntarily donated brain tissues from 30 infants who died during the first 1.5 years of life were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank. Tissues (hippocampus and prefrontal, frontal, auditory, and occipital cortices) were extracted using standard lipid extraction procedures and analyzed using reverse-phase high-pressure liquid chromatography. RESULTS: Lutein, zeaxanthin, cryptoxanthin, and ß-carotene were the major carotenoids found in the infant brain tissues. Lutein was the predominant carotenoid accounting for 59% of total carotenoids. Preterm infants (n = 8) had significantly lower concentrations of lutein, zeaxanthin, and cryptoxanthin in their brain compared with term infants (n = 22) despite similarity in postmenstrual age. Among formula-fed infants, preterm infants (n = 3) had lower concentrations of lutein and zeaxanthin compared with term infants (n = 5). Brain lutein concentrations were not different between breast milk-fed (n = 3) and formula-fed (n = 5) term decedents. In contrast, term decedents with measurable brain cryptoxanthin, a carotenoid that is inherently low in formula, had higher brain lutein, suggesting that the type of feeding is an important determinant of brain lutein concentrations. CONCLUSIONS: These data reveal preferential accumulation and maintenance of lutein in the infant brain despite underrepresentation in the typical infant diet. Further investigation on the impact of lutein on neural development in preterm infants is warranted.

Macular pigment optical density is related to cognitive function in older people.

BACKGROUND: the xanthophylls lutein (L) and zeaxanthin (Z) exist in relatively high concentration in multiple central nervous tissues (e.g. cortex and neural retina). L + Z in macula (i.e. macular pigment, MP) are thought to serve multiple functions, including protection and improvement of visual performance. Also, L + Z in the macula are related to L + Z in the cortex. OBJECTIVE: to determine whether macular pigment optical density (MPOD, L + Z in the macula) is related to cognitive function in older adults. METHODS: participants were older adults (n = 108, 77.6 ± 2.7 years) sampled from the age-related maculopathy ancillary study of the Health Aging and Body Composition Study (Memphis, TN, USA). Serum carotenoids were measured using high performance liquid chromatography. MPOD was assessed using heterochromatic flicker photometry. Eight cognitive tests designed to evaluate several cognitive domains including memory and processing speed were administered. Partial correlation coefficients were computed to determine whether cognitive measures were related to serum L + Z and MPOD. RESULTS: MPOD levels were significantly associated with better global cognition, verbal learning and fluency, recall, processing speed and perceptual speed, whereas serum L + Z was significantly related to only verbal fluency. CONCLUSION: MPOD is related to cognitive function in older people. Its role as a potential biomarker of cognitive function deserves further study.

Relationship between Serum and Brain Carotenoids, α-Tocopherol, and Retinol Concentrations and Cognitive Performance in the Oldest Old from the Georgia Centenarian Study.

Oxidative stress is involved in age-related cognitive decline. The dietary antioxidants, carotenoids, tocopherols, and vitamin A may play a role in the prevention or delay in cognitive decline. In this study, sera were obtained from 78 octogenarians and 220 centenarians from the Georgia Centenarian Study. Brain tissues were obtained from 47 centenarian decedents. Samples were analyzed for carotenoids, α-tocopherol, and retinol using HPLC. Analyte concentrations were compared with cognitive tests designed to evaluate global cognition, dementia, depression and cognitive domains (memory, processing speed, attention, and executive functioning). Serum lutein, zeaxanthin, and ß-carotene concentrations were most consistently related to better cognition (P < 0.05) in the whole population and in the centenarians. Only serum lutein was significantly related to better cognition in the octogenarians. In brain, lutein and ß-carotene were related to cognition with lutein being consistently associated with a range of measures. There were fewer significant relationships for α-tocopherol and a negative relationship between brain retinol concentrations and delayed recognition. These findings suggest that the status of certain carotenoids in the old may reflect their cognitive function. The protective effect may not be related to an antioxidant effect given that α-tocopherol was less related to cognition than these carotenoids.

A systematic review on zinc for the prevention and treatment of age-related macular degeneration.

PURPOSE: The objective of this systematic review was to examine the evidence on zinc intake from foods and supplements in the primary prevention and treatment of AMD. METHODS: Randomized controlled trials (RCTs), prospective cohort, retrospective cohort, and case-control studies that investigated zinc intake from foods and/or supplements, and AMD in men and women with a mean age of 50 years or older were included. Medline and Cochrane Central were searched from inception to February 2012 and November 2012, respectively. Data extraction and quality appraisal were done on all eligible studies. RESULTS: TEN STUDIES WERE INCLUDED: four RCTs, four prospective cohort, and two retrospective cohort studies. Age-related Eye Disease Study (AREDS) showed zinc treatment to significantly reduce the risk of progression to advanced AMD. The risk of visual acuity loss was of similar magnitude, but not statistically significant. Two RCTs reported statistically significant increases in visual acuity in early AMD patients and one RCT showed no effect of zinc treatment on visual acuity in advanced AMD patients. Results from six cohort studies on associations between zinc intake and incidence of AMD were inconsistent. CONCLUSIONS: Current evidence on zinc intake for the prevention of AMD is inconclusive. Based on the strength of AREDS, we can conclude that zinc treatment may be effective in preventing progression to advanced AMD. Zinc supplementation alone may not be sufficient to produce clinically meaningful changes in visual acuity.

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.

Increased consumption of dietary cholesterol, lutein, and zeaxanthin as egg yolks does not decrease serum concentrations and lipoprotein distribution of other carotenoids, retinol, and tocopherols.

We have previously reported that consumption of lutein and zeaxanthin as 2 and 4 egg yolks per day for 5 weeks significantly increased serum lutein and zeaxanthin concentrations in older adults taking cholesterol-lowering statins. We hypothesized that increased consumption of eggs, lutein, and zeaxanthin may correlate with decreased absorption of other carotenoids and increased absorption of vitamins A and E, thus affecting their serum concentrations and lipoprotein distribution. Fifty-two subjects aged at least 60 years consumed 2 egg yolks per day followed by 4 egg yolks per day for 5 weeks each with a 4-week egg-free period at baseline and between the 2 interventions. Mean serum ß-cryptoxanthin, lycopene, α-carotene, ß-carotene, α-tocopherol, and retinol concentrations did not change during the 2 and 4 egg yolk phases. Mean serum α-cryptoxanthin and γ-tocopherol concentrations did not change after the 2 egg yolk phase, but increased by 47% (P < .001) and 19% (P < .05), respectively, after the 4 egg yolk phase. The percentage distribution of carotenoids and tocopherols between the high-density lipoprotein (HDL) and non-HDL fractions was not significantly different during the egg yolk phases compared with baseline despite the significant increases in lutein and zeaxanthin carried on HDL and non-HDL fractions. In conclusion, increased dietary cholesterol, lutein, and zeaxanthin consumed as egg yolks did not decrease the absorption of other carotenoids, and increased γ-tocopherol but not retinol as evidenced by their serum and lipoprotein concentrations. Two and 4 egg yolk consumption increases serum and retinal lutein and zeaxanthin without altering the serum status of the other carotenoids, tocopherol, and retinol.

Consumption of 2 and 4 egg yolks/d for 5 wk increases macular pigment concentrations in older adults with low macular pigment taking cholesterol-lowering statins.

BACKGROUND: Lutein and zeaxanthin may reduce the risk of dry, age-related macular degeneration because of their photo-oxidative role as macular pigment. OBJECTIVE: The present study evaluated serum lutein, zeaxanthin, and macular pigment optical density (MPOD) responses at 0.25 degrees , 0.5 degrees , and 1 degree retinal eccentricities to the consumption of 2 and 4 egg yolks/d by older adults taking cholesterol-lowering medications. DESIGN: Subjects consumed foods containing 2 followed by 4 egg yolks/d for 5 wk each with a 4-wk egg-free period at baseline and between the 2 interventions. RESULTS: Changes in MPOD (n = 37) with egg yolk consumption were inversely associated (P < 0.05) with baseline MPOD. Subjects with low-baseline MPOD (defined as MPOD < or =0.5 at 0.25 degrees , < or =0.4 at 0.5 degrees , and < or =0.35 at 1 degrees ) showed increases of < or =50% (P < 0.05) with 4 egg yolks at the 3 retinal eccentricities. MPOD increased by 31% (P = 0.059) at 0.5 degrees with 2 egg yolks. Serum lutein increased by only 16% and 24% (P < 0.05) compared with increases of 36% and 82% (P < 0.001) in serum zeaxanthin (n = 52) after consumption of 2 and 4 egg yolks, respectively. Serum HDL cholesterol increased by 5% (P < 0.05) after consumption of 2 and 4 egg yolks. Serum LDL cholesterol did not change with either egg yolk treatment. CONCLUSIONS: Consumption of 4 egg yolks/d, and possibly of 2 egg yolks/d, for 5 wk benefited macular health in older adults with low MPOD. Serum HDL cholesterol increased without an increase in LDL cholesterol in this study population, most of whom were taking cholesterol-lowering statins.

Consumption of one egg per day increases serum lutein and zeaxanthin concentrations in older adults without altering serum lipid and lipoprotein cholesterol concentrations.

Lutein and zeaxanthin accumulate in the macular pigment of the retina, and are reported to be associated with a reduced incidence of age-related macular degeneration. A rich source of lutein and zeaxanthin in the American diet is the yolk of chicken eggs. Thus, the objective of the study was to investigate the effect of consuming 1 egg/d for 5 wk on the serum concentrations of lutein, zeaxanthin, lipids, and lipoprotein cholesterol in individuals >60 y of age. In a randomized cross-over design, 33 men and women participated in the 18-wk study, which included one run-in and one washout period of no eggs prior to and between two 5-wk interventions of either consuming 1 egg or egg substitute/d. Serum lutein 26% (P < 0.001) and zeaxanthin 38% (P < 0.001) concentrations increased after 5-wk of 1 egg/d compared with the phase prior to consuming eggs. Serum concentrations of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides were not affected. These findings indicate that in older adults, 5 wk of consuming 1 egg/d significantly increases serum lutein and zeaxanthin concentrations without elevating serum lipids and lipoprotein cholesterol concentrations.