Lutein is one of the most prevalent carotenoids in nature and in the human diet. Together with zeaxanthin, it is highly concentrated as macular pigment in the foveal retina of primates, attenuating blue light exposure, providing protection from photo-oxidation and enhancing visual performance. Recently, interest in lutein has expanded beyond the retina to its possible contributions to brain development and function. Only primates accumulate lutein within the brain, but little is known about its distribution or physiological role. Our team has begun to utilize the rhesus macaque (Macaca mulatta) model to study the uptake and bio-localization of lutein in the brain. Our overall goal has been to assess the association of lutein localization with brain function. In this review, we will first cover the evolution of the non-human primate model for lutein and brain studies, discuss prior association studies of lutein with retina and brain function, and review approaches that can be used to localize brain lutein. We also describe our approach to the biosynthesis of ¹³C-lutein, which will allow investigation of lutein flux, localization, metabolism and pharmacokinetics. Lastly, we describe potential future research opportunities.

Lutein is the predominant carotenoid in the developing primate brain and retina, and may have important functional roles. However, its bioaccumulation pattern during early development is not understood. In this pilot study, we investigated whether carotenoid supplementation of infant formula enhanced lutein tissue deposition in infant rhesus macaques. Monkeys were initially breastfed; from 1 to 3 months of age they were fed either a formula supplemented with lutein, zeaxanthin, β-carotene and lycopene, or a control formula with low levels of these carotenoids, for 4 months (n = 2/group). All samples were analyzed by high pressure liquid chromatography (HPLC). Final serum lutein in the supplemented group was 5 times higher than in the unsupplemented group. All brain regions examined showed a selective increase in lutein deposition in the supplemented infants. Lutein differentially accumulated across brain regions, with highest amounts in occipital cortex in both groups. β-carotene accumulated, but zeaxanthin and lycopene were undetectable in any brain region. Supplemented infants had higher lutein concentrations in peripheral retina but not in macular retina. Among adipose sites, abdominal subcutaneous adipose tissue exhibited the highest lutein level and was 3-fold higher in the supplemented infants. The supplemented formula enhanced carotenoid deposition in several other tissues. In rhesus infants, increased intake of carotenoids from formula enhanced their deposition in serum and numerous tissues and selectively increased lutein in multiple brain regions.

Maternal nutrition is an important factor for infant neurodevelopment. However, prior magnetic resonance imaging (MRI) studies on maternal nutrients and infant brain have focused mostly on preterm infants or on few specific nutrients and few specific brain regions. We present a first study in term-born infants, comprehensively correlating 73 maternal nutrients with infant brain morphometry at the regional (61 regions) and voxel (over 300 000 voxel) levels. Both maternal nutrition intake diaries and infant MRI were collected at 1 month of life (0.9 ± 0.5 months) for 92 term-born infants (among them, 54 infants were purely breastfed and 19 were breastfed most of the time). Intake of nutrients was assessed via standardized food frequency questionnaire. No nutrient was significantly correlated with any of the volumes of the 61 autosegmented brain regions. However, increased volumes within subregions of the frontal cortex and corpus callosum at the voxel level were positively correlated with maternal intake of omega-3 fatty acids, retinol (vitamin A) and vitamin B12, both with and without correction for postmenstrual age and sex (P < 0.05, q < 0.05 after false discovery rate correction). Omega-3 fatty acids remained significantly correlated with infant brain volumes after subsetting to the 54 infants who were exclusively breastfed, but retinol and vitamin B12 did not. This provides an impetus for future larger studies to better characterize the effect size of dietary variation and correlation with neurodevelopmental outcomes, which can lead to improved nutritional guidance during pregnancy and lactation.

Objectives: While others have reported that milk from coastal Chinese women contains high levels of lutein and zeaxanthin, no research has determined the corresponding infant plasma response. Whether infant plasma levels increase commensurately provides important guidance for supplementation of these increasingly intriguing carotenoids in breast-feeding mothers and formula-fed infants. Methods: Fifty-six mother–infant pairs with a maternal diet rich in eggs, green leafy vegetables, and fruit were enrolled between 6 and 16 weeks of lactation. Milk samples and blood samples from both the mother and infant were collected at entry. Maternal 3-day dietary records and a second milk sample were collected 1 to 3 weeks later. Results: Mean milk lutein concentrations in samples 1 and 2 were 6.5 and 7.7 μg/dL (range 1–22.5 μg/dL), and for zeaxanthin, 1.6 and 1.7 μg/dL (range 1–5.9 μg/dL). Lutein concentrations in infant plasma (18.2 μg/dL) were similar to those in maternal plasma (21.6 μg/dL); zeaxanthin was lower than lutein in both maternal (3.1 μg/dL) and infant (2.9 μg/dL) plasma. Infant and maternal mean plasma lutein and zeaxanthin concentrations were higher than those in both milk samples 1 and 2 (lutein, 6.9 and 8.2 μg/dL; zeaxanthin, 1.9 and 2.0 μg/dL). Infant plasma lutein and zeaxanthin concentrations positively correlated with those in milk sample 1 (lutein, r² = 0.15, p = 0.004; zeaxanthin, r² = 0.21, p < 0.001). Conclusions: Together, these results reveal that high milk concentrations of lutein and zeaxanthin driven by healthy maternal intakes of xanthophyll rich foods are associated with high infant plasma concentrations. These findings will be useful for determining appropriate lutein fortification strategies. Clinical Study.gov registration number: NCT01669655.

α-Tocopherol is the principal source of vitamin E, an essential nutrient that plays a crucial role in maintaining healthy brain function. Infant formula is routinely supplemented with syntheticα-tocopherol, a racaemic mixture of eight stereoisomers with less bioactivity than the natural stereoisomerRRR-α-tocopherol.α-Tocopherol stereoisomer profiles have not been previously reported in the human brain. In the present study, we analysed totalα-tocopherol andα-tocopherol stereoisomers in the frontal cortex (FC), hippocampus (HPC) and visual cortex (VC) of infants (n36) who died of sudden infant death syndrome or other conditions.RRR-α-tocopherol was the predominant stereoisomer in all brain regions (P<0·0001) and samples, despite a large intra-decedent range in totalα-tocopherol (5–17 μg/g). MeanRRR-α-tocopherol concentrations in FC, HPC and VC were 10·5, 6·8 and 5·5 μg/g, respectively. In contrast, mean levels of the synthetic stereoisomers wereRRS, 1–1·5;RSR, 0·8–1·0;RSS, 0·7–0·9; and Σ2S0·2–0·3 μg/g. Samples from all but two decedents contained measurable levels of the synthetic stereoisomers, but the intra-decedent variation was large. The ratio ofRRR:the sum of the synthetic 2Rstereoisomers (RRS+RSR+RSS) averaged 2·5, 2·3 and 2·4 in FC, HPC and VC, respectively, and ranged from 1 to at least 4·7, indicating that infant brain discriminates against synthetic 2Rstereoisomers in favour ofRRR. These findings reveal thatRRR-α-tocopherol is the predominant stereoisomer in infant brain. These data also indicate that the infant brain discriminates against the synthetic 2Rstereoisomers, but is unable to do so completely. On the basis of these findings, investigation into the impact ofα-tocopherol stereoisomers on neurodevelopment is warranted.

Two previous studies have shown that the addition of nucleotides to single feedings of formula is associated with increased 90-minute postprandial superior mesenteric artery (SMA) blood flow velocity (BFV). To assess the effect of chronic feeding of nucleotide-supplemented formula, we measured pre- and postprandial SMA BFV in term infants fed formula with or without added nucleotides for 4 weeks. At 1 week of age, healthy, term infants were randomized to receive formula with added nucleotides (NT+), or formula without added nucleotides (NT−) from age 1 to 5 weeks. When the infants were 5 weeks of age, SMA BFV was measured by Doppler ultrasound 15 minutes before the assigned feeding (baseline) and 30, 60, and 90 minutes after the start of feeding. A reference group of human milk-fed infants was studied before and after breast feeding. Thirty formula-fed (NT+ = 17; NT− = 13) and 10 human milk-fed infants were studied. Baseline BFV was similar among the three groups. BFV increased in each group from baseline to 30 minutes after initiation of feeding and progressively declined from 30 to 90 minutes in infants fed NT− formula or human milk. In infants fed NT+ formula, BFV decreased between 30 and 60 minutes. However, from 60 to 90 minutes, velocity was unchanged or increased. At 90 minutes, mean and peak systolic velocities were significantly greater in the NT+ group than the NT− group (P < 0.001). These data agree with those of previous studies showing increased 90-minute postprandial SMA BFV after a feeding with nucleotide-supplemented formula. The clinical significance of these findings is unknown.