Elizabeth J. Johnson

Cognitive findings of an exploratory trial of docosahexaenoic acid and lutein supplementation in older women

Abstract Introduction: Low dietary intake of docosahexaenoic acid (DHA) and/or foods rich in lutein may be associated with increased risk of cognitive decline in the elderly. Subjects and methods: The cognitive benefit of DHA and lutein in unimpaired elder women was explored in the context of a 4-month, double-blind, intervention trial of DHA and lutein supplementation for eye health. Forty-nine women (aged 60–80 years) were randomized to receive DHA (800 mg/day; n = 14), lutein (12 mg/day; n = 11), a combination of DHA and lutein (n = 14) or placebo (n = 10). Subjects underwent cognitive tests measuring verbal fluency, memory, processing speed and accuracy, and self-reports of mood at randomization and upon completion of the trial. Results: Following supplementation, verbal fluency scores improved significantly in the DHA, lutein, and combined treatment groups (P < 0.03). Memory scores and rate of learning improved significantly in the combined treatment group (P < 0.03), who also displayed a trend toward more efficient learning (P = 0.07). Measures of mental processing speed, accuracy and mood were not affected by supplementation. Conclusions: These exploratory findings suggest that DHA and lutein supplementation may have cognitive benefit for older adults.

Supplementation with β-carotene in vivo and in vitro does not inhibit low density lipoprotein oxidation

Abstract The inhibition of low density lipoprotein (LDL) oxidation has been postulated as one mechanism by which antioxidants may prevent the development of atherosclerosis. Available data on the ability of β-carotene to inhibit LDL oxidation are conflicting. We examined the role of in vivo and in vitro supplementation with β-carotene on metal ion-dependent (cupric ions, Cu 2+ ) and metal ion-independent (2,2′-azobis[2-amidinopropane]dihydrochloride, AAPH) oxidation of LDL as measured by the formation of conjugated dienes (absorbance at 234 nm). Sixteen subjects were supplemented with 50–100 mg of β-carotene on alternate days for 3 weeks following a week-long loading dose of 100 mg/day. Plasma β-carotene levels rose 5.5-fold, while LDL β-carotene levels rose 8.5-fold. Oxidation of LDL by Cu 2+ or AAPH was not significantly delayed after in vivo supplementation with β-carotene compared with baseline. For AAPH, the lag phase (in minutes) was 75 ± 8 at baseline and 83 ± 14 after supplementation ( P = 0.07). For Cu 2+ , the lag phase was 172 ± 41 at baseline and decreased to 130 ± 24 after supplementation ( P 2+ -induced oxidation was observed when β-carotene was added to LDL in vitro. Supplementation of plasma with β-carotene in vitro prior to LDL isolation also did not enhance LDLs resistance to Cu 2+ - or AAPH-induced oxidation, despite a 5-fold increase in LDL β-carotene levels over vehicle control. These data indicate that supplementation with β-carotene in vivo or in vitro does not enhance the protection of LDL against metal ion-dependent and -independent oxidation; rather, in vivo β-carotene supplementation may lead to a shortening of the lag phase of Cu 2+ -induced lipid peroxidation in LDL.

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 β-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 β-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.

Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A.

OBJECTIVE To determine whether lutein supplementation will slow visual function decline in patients with retinitis pigmentosa receiving vitamin A. DESIGN Randomized, controlled, double-masked trial of 225 nonsmoking patients, aged 18 to 60 years, evaluated over a 4-year interval. Patients received 12 mg of lutein or a control tablet daily. All were given 15,000 IU/d of vitamin A palmitate. Randomization took into account genetic type and baseline serum lutein level. MAIN OUTCOME MEASURES The primary outcome was the total point score for the Humphrey Field Analyzer (HFA) 30-2 program; prespecified secondary outcomes were the total point scores for the 60-4 program and for the 30-2 and 60-4 programs combined, 30-Hz electroretinogram amplitude, and Early Treatment Diabetic Retinopathy Study acuity. RESULTS No significant difference in rate of decline was found between the lutein plus vitamin A and control plus vitamin A groups over a 4-year interval for the HFA 30-2 program. For the HFA 60-4 program, a decrease in mean rate of sensitivity loss was observed in the lutein plus vitamin A group (P = .05). Mean decline with the 60-4 program was slower among those with the highest serum lutein level or with the highest increase in macular pigment optical density at follow-up (P = .01 and P = .006, respectively). Those with the highest increase in macular pigment optical density also had the slowest decline in HFA 30-2 and 60-4 combined field sensitivity (P = .005). No significant toxic effects of lutein supplementation were observed. CONCLUSION Lutein supplementation of 12 mg/d slowed loss of midperipheral visual field on average among nonsmoking adults with retinitis pigmentosa taking vitamin A. Application to Clinical Practice Data are presented that support use of 12 mg/d of lutein to slow visual field loss among nonsmoking adults with retinitis pigmentosa taking vitamin A. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT00346333.

Lutein and zeaxanthin supplementation reduces photooxidative damage and modulates the expression of inflammation-related genes in retinal pigment epithelial cells

Oxidative damage and inflammation are related to the pathogenesis of age-related macular degeneration (AMD). Epidemiologic studies suggest that insufficient dietary lutein and zeaxanthin intake or lower serum zeaxanthin levels are associated with increased risk for AMD. The objective of this work is to test the protective effects of lutein and zeaxanthin against photooxidative damage to retinal pigment epithelial cells (RPE) and oxidation-induced changes in expression of inflammation-related genes. To mimic lipofuscin-mediated photooxidation in vivo, we used ARPE-19 cells that accumulated A2E, a lipofuscin fluorophore and photosensitizer, as a model system to investigate the effects of lutein and zeaxanthin supplementation. The data show that supplementation with lutein or zeaxanthin in the medium resulted in accumulation of lutein or zeaxanthin in the RPE cells. The concentrations of lutein and zeaxanthin in the cells were 2- to 14-fold of that detected in the medium, indicating that ARPE-19 cells actively take up lutein or zeaxanthin. As compared with untreated cells, exposure of A2E-containing RPE to blue light resulted in a 40-60% decrease in proteasome activity, a 50-80% decrease in expression of CFH and MCP-1, and an~20-fold increase in expression of IL-8. The photooxidation-induced changes in expression of MCP-1, IL-8, and CFH were similar to those caused by chemical inhibition of the proteasome, suggesting that inactivation of the proteasome is involved in the photooxidation-induced alteration in expression of these inflammation-related genes. Incubation of the A2E-containing RPE with lutein or zeaxanthin prior to blue light exposure significantly attenuated the photooxidation-induced inactivation of the proteasome and photooxidation-induced changes in expression of MCP-1, IL-8, and CFH. Together, these data indicate that lutein or zeaxanthin modulates inflammatory responses in cultured RPE in response to photooxidation. Protecting the proteasome from oxidative inactivation appears to be one of the mechanisms by which lutein and zeaxanthin modulate the inflammatory response. Similar mechanisms may explain salutary effects of lutein and zeaxanthin in reducing the risk for AMD.

A possible role for lutein and zeaxanthin in cognitive function in the elderly

Epidemiologic studies suggest that dietary lutein and zeaxanthin may be of benefit in maintaining cognitive health. Among the carotenoids, lutein and zeaxanthin are the only two that cross the blood-retina barrier to form macular pigment (MP) in the eye. They also preferentially accumulate in the human brain. Lutein and zeaxanthin in macula from nonhuman primates were found to be significantly correlated with their concentrations in matched brain tissue. Therefore, MP can be used as a biomarker of lutein and zeaxanthin in primate brain tissue. This is of interest given that a significant correlation was found between MP density and global cognitive function in healthy older adults. An examination of a relation between cognition and lutein and zeaxanthin concentrations in the brain tissue of decedents from a population-based study in centenarians found that zeaxanthin concentrations in brain tissue were significantly related to antemortem measures of global cognitive function, memory retention, verbal fluency, and dementia severity after adjustment for age, sex, education, hypertension, and diabetes. In univariate analyses, lutein was related to recall and verbal fluency, but the strength of the associations was attenuated with adjustment for covariates. However, lutein concentrations in the brain were significantly lower in individuals with mild cognitive impairment than in those with normal cognitive function. Last, in a 4-mo, double-blinded, placebo-controlled trial in older women that involved lutein supplementation (12 mg/d), alone or in combination with DHA (800 mg/d), verbal fluency scores improved significantly in the DHA, lutein, and combined-treatment groups. Memory scores and rate of learning improved significantly in the combined-treatment group, who also showed a trend toward more efficient learning. When all of these observations are taken into consideration, the idea that lutein and zeaxanthin can influence cognitive function in older adults warrants further study.

Nutritional manipulation of primate retinas, V: effects of lutein, zeaxanthin, and n-3 fatty acids on retinal sensitivity to blue-light-induced damage.

PURPOSE Blue-light photooxidative damage has been implicated in the etiology of age-related macular degeneration (AMD). The macular pigment xanthophylls lutein (L) and zeaxanthin (Z) and n-3 fatty acids may reduce this damage and lower the risk of AMD. This study investigated the effects of the lifelong absence of xanthophylls followed by L or Z supplementation, combined with the effects of n-3 fatty acid deficiency, on acute blue-light photochemical damage. METHODS Subjects included eight rhesus monkeys with no lifelong intake of xanthophylls and no detectable macular pigment. Of these, four had low n-3 fatty acid intake and four had adequate intakes. Control subjects had typical L, Z, and n-3 fatty acid intake. Retinas received 150-μm-diameter exposures of low-power 476-nm laser light at 0.5 mm (∼2°) eccentricity, which is adjacent to the macular pigment peak, and parafoveally at 1.5 mm (∼6°). Exposures of xanthophyll-free animals were repeated after supplementation with pure L or Z for 22 to 28 weeks. Ophthalmoscopically visible lesion areas were plotted as a function of exposure energy, with greater slopes of the regression lines indicating greater sensitivity to damage. RESULTS In control animals, the fovea was less sensitive to blue-light-induced damage than the parafovea. Foveal protection was absent in xanthophyll-free animals but was evident after supplementation. In the parafovea, animals low in n-3 fatty acids showed greater sensitivity to damage than animals with adequate levels. CONCLUSIONS After long-term xanthophyll deficiency, L or Z supplementation protected the fovea from blue light-induced damage, whereas adequate n-3 fatty acid levels reduced the damage in the parafovea.

Role of lutein and zeaxanthin in visual and cognitive function throughout the lifespan

The relationship between lutein and zeaxanthin and visual and cognitive health throughout the lifespan is compelling. There is a variety of evidence to support a role for lutein and zeaxanthin in vision. Luteins role in cognition has only recently been considered. Lutein and its isomer, zeaxanthin, are taken up selectively into eye tissue. Lutein is the predominant carotenoid in human brain tissue. Lutein and zeaxanthin in neural tissue may have biological effects that include antioxidation, anti-inflammation, and structural actions. In addition, lutein and zeaxanthin may be protective against eye disease because they absorb damaging blue light that enters the eye. In pediatric brains, the relative contribution of lutein to the total carotenoids is twice that found in adults, accounting for more than half the concentration of total carotenoids. The greater proportion of lutein in the pediatric brain suggests a need for lutein during neural development as well. In adults, higher lutein status is related to better cognitive performance, and lutein supplementation improves cognition. The evidence to date warrants further investigation into the role of lutein and zeaxanthin in visual and cognitive health throughout the lifespan.

Associations Between Age-Related Nuclear Cataract and Lutein and Zeaxanthin in the Diet and Serum in the Carotenoids in the Age-Related Eye Disease Study (CAREDS), an Ancillary Study of the Women's Health Initiative

OBJECTIVE To evaluate associations between nuclear cataract (determined from slitlamp photographs between May 2001 and January 2004) and lutein and zeaxanthin in the diet and serum in patients between 1994 and 1998 and macula between 2001 and 2004. DESIGN A total of 1802 women aged 50 to 79 years in Iowa, Wisconsin, and Oregon with intakes of lutein and zeaxanthin above the 78th (high) and below the 28th (low) percentiles in the Womens Health Initiative Observational Study (1994-1998) were recruited 4 to 7 years later (2001-2004) into the Carotenoids in Age-Related Eye Disease Study. RESULTS Women in the group with high dietary levels of lutein and zeaxanthin had a 23% lower prevalence of nuclear cataract (age-adjusted odds ratio, 0.77; 95% confidence interval, 0.62-0.96) compared with those with low levels. Multivariable adjustment slightly attenuated the association (odds ratio, 0.81; 95% confidence interval, 0.65-1.01). Women in the highest quintile category of diet or serum levels of lutein and zeaxanthin as compared with those in the lowest quintile category were 32% less likely to have nuclear cataract (multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.48-0.97; P for trend = .04; and multivariable-adjusted odds ratio, 0.68; 95% confidence interval, 0.47-0.98; P for trend = .01, respectively). Cross-sectional associations with macular pigment density were inverse but not statistically significant. CONCLUSIONS Diets rich in lutein and zeaxanthin are moderately associated with decreased prevalence of nuclear cataract in older women. However, other protective aspects of such diets may in part explain these relationships.

Macular lutein and zeaxanthin are related to brain lutein and zeaxanthin in primates

Abstract 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.