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Original Articles: Hepatology and Nutrition

Lutein and Preterm Infants With Decreased Concentrations of Brain Carotenoids

Vishwanathan, Rohini*; Kuchan, Matthew J.; Sen, Sarbattama; Johnson, Elizabeth J.*

Author Information
Journal of Pediatric Gastroenterology and Nutrition: November 2014 - Volume 59 - Issue 5 - p 659-665
doi: 10.1097/MPG.0000000000000389
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See “Importance of Carotenoids in Optimizing Eye and Brain Development” by Henriksen and Chan on page 552.

Carotenoids are plant pigments that cannot be synthesized de novo and are obtained from the diet. Of the 600 carotenoids identified in nature, only approximately 40 or so are present in the fruits and vegetables commonly consumed in the United States, and only approximately 25 are found in human serum and milk (1). Only lutein and its isomer zeaxanthin, which are oxygenated carotenoids or xanthophylls, preferentially accumulate in the macular region of the retina to form macular pigment (2). The macula is a yellowish region 5 to 6 mm in diameter in the posterior pole of the retina (3). It is unique to humans and other higher primates, and is responsible for their highly developed central visual acuity. Lutein and zeaxanthin protect the macula from short-wavelength blue light and oxidative stress (4–6). In infants, lutein and zeaxanthin may also play a role in the maturation of cells in the developing macula (7). Other biologically significant carotenoids include cryptoxanthin, α-carotene, and β-carotene, which have provitamin A activity, and lycopene, suggested to protect against prostate cancer. All of these carotenoids are also potent antioxidants (8).

Lutein has been reported to be the predominant carotenoid in the brain of older adults, accounting for 30% of total brain carotenoids (9,10). This observation suggests that a preferential uptake of lutein into brain tissue as intake is typically low compared with other carotenoids in the US diet (2,9). Nonhuman primate and human studies indicate that both macular and brain concentrations of lutein and zeaxanthin are related to serum concentrations, an indirect measure of dietary intake, and that macular pigment optical density may be predictive of brain concentrations (9,11,12). A possible role for lutein and zeaxanthin in cognitive function was supported by the finding that macular pigment optical density was positively correlated with measures of cognitive function in older adults (13,14). Subsequent research revealed significant associations between brain lutein concentration and premortem measures of cognitive function in older adults (9). Finally, lutein supplementation was shown to significantly improve measures of cognitive function in older women (15). These findings support lutein's role in cognitive function.

Available evidence indicates that infant intake of lutein is highly variable and tends to be low in formula-fed infants and in children from ages 1 to 3 years (16). In breast milk–feeding infants this variability can be explained by differences in maternal intake and several factors that affect maternal carotenoid status, such as alcohol intake and smoking (17,18). Furthermore, mothers with obesity were found to have decreased concentration of carotenoids in breast milk compared with lean mothers (ongoing study at Tufts Medical Center), resulting in variable intake in infants. Consistent with these observations, Bone et al (19) have shown that macular pigment density is highly variable in the infant retina. Because the developing infant brain is known to be sensitive to a wide range of nutritional deficiencies, it is important to describe the range of infant brain lutein concentrations. Premature infants are nutritionally unique given differences in feeding practices. They may be particularly vulnerable to lutein insufficiency, increasing the susceptibility of the immature retina and brain to oxidative stress. As a first step in the understanding of a possible role of lutein in early neural development, the objective of this study was to determine the distribution of carotenoids in the brain tissue of infant decedents during the first 1.5 years of life and to assess the differences in brain carotenoids between preterm and full-term infants.



Voluntarily donated brain tissue samples of otherwise healthy infants (without any brain and/or other systemic pathologies) who died during the first 18 months of life were obtained from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Brain and Tissue Bank for Developmental Disorders, University of Maryland ( Tissues were identified using a unique numerical identifier, which obscured the identity of the decedent. Tissues were obtained from different regions of the brain, which included hippocampus (Hipp) and prefrontal (PFC), frontal (FC), auditory (AC), and occipital (OC) cortices. It is noteworthy that these regions of the brain are associated with memory (Hipp), executive function (PFC and FC), hearing (AC), and vision (OC). Decedents included both preterm (infants whose gestational age was <37 weeks at birth, n = 8) and term infants (infants whose gestational age was ≥37 weeks at birth, n = 22). Nine decedents had tissues from all 5 regions of the brain. A total of 108 tissues were obtained. Tissues (∼0.5 g) were stored at −70°C until analysis for carotenoids. The average interval in hours between death and brain tissue collection was 15.9 (± 5.8, standard deviation [SD]) hours and ranged from 2 to 23 hours.

Brain Carotenoid Extraction

Carotenoids were extracted from brain tissue by a method adapted from Park et al (20). The detailed extraction procedure has been described in a report by Vishwanathan et al (12). Extracts were analyzed by means of reverse-phase high-performance liquid chromatography using a method described by Yeum et al (21), with a C30 carotenoid column (3 μm, 150 mm × 4.6 mm; YMC, Wilmington, NC). Concentrations are corrected for extraction and handling losses by monitoring the recovery of the internal standards. The lower limit of detection is 0.2 pmol for carotenoids. In our laboratory, the interassay coefficient of variation is 4%; the intraassay coefficient of variation is 4%. Recovery of the internal standard averages 97%. Tissues from the Hipp, FC, AC, and OC were analyzed at the same time. PFC tissues were obtained at a later date and analyzed separately for 9 decedents. Data were expressed per wet weight of tissue.

Statistical Analysis

Given the novelty of this work, no sample size calculations were feasible. Data are expressed as mean ± standard error of mean. Total lutein (sum of cis and trans isomers) was used for the data analysis. β-Carotene represents the sum of trans and 9-cis isomers. Differences in characteristics of preterm and term infants were assessed using the t test for continuous variables and the χ2 test for categorical variables. Differences in concentration of carotenoids within each region of the brain and between regions of the brain (for 9 decedents who had all 5 brain regions) were evaluated using repeated measures analysis of variance with significance level set at 0.05. Pearson correlations were performed to determine whether carotenoid concentrations were related to date of tissue collection and interval between time of death and tissue storage. Differences in brain carotenoid concentrations between infants who died of sudden infant death syndrome (SIDS) and those who died of other causes, between preterm and term infants, between breast milk–fed and formula-fed term infants, between formula-fed term and preterm infants, and between term infants with no brain cryptoxanthin and term infants with measurable brain cryptoxanthin were evaluated using 1-way analysis of variance. Data were analyzed using SPSS version 19.0 (IBM SPSS Statistics, Armonk, NY).


Characteristics of the infant decedents whose brain tissues were analyzed are described in Table 1. The postmenstrual age (PMA = gestational age at birth + chronologic age) of preterm and term infants was not different. There were also no significant differences in age, distribution of boys and girls, cause of death, and race between preterm and term infants. Two infant decedents were >1 year old at the time of death. One was a 443-day-old preterm infant and the other was a 488-day-old term infant. Fifty percent of the infants died of SIDS, whereas the remaining 50% died of various other conditions that are listed in Table 1. Brain carotenoid concentrations were not significantly different between infants who died of SIDS and other causes (data not shown); hence, data for these groups of decedents were combined. There were no significant relations between carotenoid concentrations and either postmortem interval (time of death to storage) or date of collection.

Subject characteristics

The major carotenoids detected in the infant brain were lutein (range 0–181.7 pmol/g), zeaxanthin (range 0–33.94 pmol/g), cryptoxanthin (range 0–35.29 pmol/g), and β-carotene range 0–88.19 pmol/g). The mean concentration of lutein was significantly greater than that of the other carotenoids (P < 0.05) in all the brain regions analyzed (Fig. 1). In the AC, lutein was marginally greater than β-carotene (P = 0.074, n = 11). In each brain region analyzed, the mean concentration of lutein was >40 pmol/g, whereas the mean combined concentration of zeaxanthin, cryptoxanthin, and β-carotene was ≤40 pmol/g. cis isomers were only detected for lutein and β-carotene. Although 17 decedents had detectable levels of cis lutein in at least 1 brain region analyzed, 13 decedents had no cis lutein isomer in any of the brain regions analyzed. It is noteworthy that the average ratio of trans to cis lutein of 18.6 to 1. 9-cis-β-carotene was detected in the brain regions of only 4 decedents. Lycopene was detected in only 3 decedents at concentrations of 39.19 pmol/g in the FC and 45.85 pmol/g in the Hipp for 1 decedent, 8.67 pmol/g in the FC and 16.07 pmol/g in the OC for the second decedent, and 13.04 pmol/g in the PFC for the third decedent. No α-carotene was detected in any tissue.

Distribution of carotenoids in the 5 brain regions analyzed. The difference between lutein and all other carotenoids (mean ± standard error of mean) was statistically significant in all regions (P < 0.05), except in the auditory cortex where the difference between lutein and β-carotene was marginally significant (P = 0.074, repeated measures analysis of variance).

Carotenoid concentrations generally fit this same lutein-predominant pattern for the 9 decedents who had tissue from all 5 regions of the brain (data not shown). Among these 9 decedents, zeaxanthin concentration was significantly higher in the AC than in the PFC (P < 0.05), and β-carotene in the AC and OC was significantly higher than in the Hipp and PFC, respectively (P ≤ 0.05).

Infants born preterm (n = 8) had significantly lower concentrations of lutein and zeaxanthin compared with term infants (n = 22) in most of the brain regions analyzed (Fig. 2). In contrast, cryptoxanthin was significantly lower only in the Hipp, and β-carotene was not different in any of the brain regions. All of the preterm infants, except 1, had no cryptoxanthin in their brain tissues. It is noteworthy that compared with term infants there were significantly more preterm infants with undetectable levels of carotenoids in at least 1 cortex (Table 1). All of the term decedents had detectable levels of lutein and zeaxanthin in the brain regions analyzed, but multiple infants were devoid of other carotenoids (Table 1). One preterm infant had no carotenoids, including lutein, in the FC and OC. Samples from other cortices were not available for this decedent who was a boy, white, 136 days old, and had died of SIDS. Another preterm infant had no lutein and zeaxanthin in the PFC, whereas the concentrations of lutein and zeaxanthin were extremely low (≤5 pmol/g) in the FC, Hipp, AC, and OC. This decedent was a girl, white, 95 days old, and had died of SIDS. The time interval for tissue collection for these 2 decedents was similar to that for the rest of the decedents (15 and 11 hours, respectively). Additionally, handling and analysis of tissues from these 2 decedents were identical to the other decedents. Among the remaining 6 preterm infants, brain lutein concentration was ≤12 pmol/g in 3 preterm infants, 1 of whom died of SIDS; the second died of respiratory distress syndrome, and the third infant died of acute bronchopneumonia. Other than the 2 decedents, 1 with no carotenoids in the brain and 1 with no lutein and zeaxanthin in the PFC, 3 preterm infants had undetectable amounts of zeaxanthin in the PFC.

The concentrations (picomoles per gram) of lutein, zeaxanthin, and cryptoxanthin in the preterm infant brain were lower (* P < 0.05 in the regions indicated), compared with term infants. Shown here are the concentrations of (A) lutein, (B) zeaxanthin, (C) cryptoxanthin, and (D) β-carotene in the prefrontal cortex (PFC), frontal cortex (FC), hippocampus (Hipp), auditory cortex (AC), and occipital cortex (OC) of preterm (n = 8, light gray bars) and term (n = 22, dark gray bars) infants.

Feeding data were available for 12 of the 30 decedents, of whom 3 were preterm and 9 were term. All of the 3 preterm infants were formula-fed. Among the term infants, 2 were fed breast milk, 2 were fed breast milk for 6 weeks, 1 was fed breast milk for 1 week, and 4 were fed infant formula. These 12 infants were divided into 2 groups, as shown in Table 2, to evaluate differences in brain carotenoids between breast milk–fed and formula-fed decedents. One 9-week-old infant who was fed breast milk for 6 weeks was included in the breast milk–fed group because this infant received breast milk for majority of their life. Another 14-week-old infant was fed breast milk for only 1 week and thus was included in the formula-fed group. One 17-week-old infant was fed breast milk for the first 6 weeks and subsequently fed formula. Although this infant was fed formula for majority of its life, the influence of the first 6 weeks of breast milk feeding on brain carotenoids cannot be completely eliminated, and hence this infant was excluded from the feeding analysis. There were no significant differences in brain carotenoid concentrations between the breast milk–fed and formula-fed term infants (Table 3). Preterm infants were not included in the analysis as there were no breast milk–fed preterm infants. Among the formula-fed infants, brain lutein (P = 0.067) and zeaxanthin (P < 0.05, in PFC and OC) concentrations were lower in preterm infants compared with term infants (Table 4). PMA was not different between the 2 groups.

Preterm and full-term infants with known feeding history (n = 12) were categorized as shown below into breast milk–fed and formula-fed groups
Mean (± SEM) concentration of carotenoids in the brain (average of the 5 regions analyzed) of full-term infants who were fed breast milk and formula
Mean (± SEM) concentrations of carotenoids in the brain (average of the 5 regions analyzed) of formula-fed preterm and full-term infants

Mean concentrations of lutein and cryptoxanthin in the brain were positively correlated (r = 0.407, P = 0.06) in term decedents (n = 22), indicating that infants with high cryptoxanthin also had high lutein in the brain. Additionally, mean lutein concentration in the brain of term infants with no cryptoxanthin (n = 6) was significantly lower (P = 0.006) compared with term infants who had measurable amounts of brain cryptoxanthin (n = 16, Fig. 3). There was only 1 outlier, a decedent with moderate cryptoxanthin and a low level of lutein.

Mean (± standard error of mean) lutein concentration (picomoles per gram) was significantly lower (P < 0.05) in term infants with no brain cryptoxanthin (26.21 ± 3.82, n = 6) compared with term infants with measurable amounts of brain cryptoxanthin (78.12 ± 10.12, n = 16). Mean lutein concentrations shown here represent average of the 5 brain regions analyzed (hippocampus, prefrontal, frontal, auditory, and occipital cortices).


This is the first report to describe the distribution of carotenoids in infant brain tissue. A variety of carotenoids were detected in regions of the infant brain that are associated with memory, executive function, vision, and hearing. Consistent with previous findings in older adult brain (9), the concentration of lutein was higher than that of the other detected carotenoids in all of these brain regions. Surprisingly, the extent of lutein predominance observed here exceeded that previously observed in older adult brain despite the brief duration of exposure of the infant decedents to a diet typically low in lutein (16). Lutein accounted for more than half of total brain carotenoids. For some decedents brain lutein concentration was ≥3 times the mean value of 49.054 pmol/g (n = 30), supporting the finding of lutein predominance. Another important finding was that preterm infants had significantly lower concentrations of lutein and zeaxanthin compared with term infants in a majority of the brain regions analyzed. In addition, although there were no term infants with undetectable levels of lutein, there were preterm infants who had undetectable levels of carotenoids in their brains. This finding is of particular importance to the infant because lutein and zeaxanthin are not synthesized de novo, and research in older adult brain has suggested that lutein may have a role in cognitive function (9,13,14).

There is substantial evidence to support the role of lutein and zeaxanthin in early visual and cognitive development. Lutein and zeaxanthin are actively transported into breast milk, indicating that they may have a specific role early in life (22–24). Both of these xanthophylls have a unique role as macular pigment in the neural retina (25). Lutein is predominant in the macula of infants ages 0 to 2 years, and zeaxanthin is predominant thereafter (26). In nonhuman primates (macaques) on a lifelong diet devoid of xanthophylls, distinct morphological changes in the retinal pigment cells were observed that were largely reversed with lutein and zeaxanthin supplementation, supporting the role of lutein and zeaxanthin in retinal development (27). Furthermore, lutein and zeaxanthin appear to influence neural functions within the visual system as macular pigment density is positively related to measures of neural visual processing function (28). Other literature on neural functions of lutein and zeaxanthin include their ability to enhance gap junction communication (29). Gap junctions increase intracellular communications between glial and neuronal cells and are important for light processing within the retina. These findings together with the predominance of lutein in the brain tissue and an established role in the neural retina suggest that lutein may have an important role in the developing brain and eye.

One of the possible reasons for decreased concentration of lutein and zeaxanthin in the preterm infant brain despite the similarity in PMA to term infants could be inadequate intake/supplementation of these carotenoids. Plasma carotenoid concentrations were shown to increase in preterm infants who received a formula supplemented with a mixture of lutein/zeaxanthin, lycopene, and β-carotene (30). Additionally, premature birth may have also resulted in limited in utero accretion of lutein and zeaxanthin, because nutrient accretion is dramatic during the third trimester. This hypothesis is further substantiated by the finding that lutein and zeaxanthin as macular pigment are undetectable in the retina of premature infants accompanied by unusually low concentrations of serum and skin carotenoids (31). Alternately, there is a possibility that premature birth resulted in deficits in cortical structure or mechanisms required for carotenoid uptake in the brain.

Dietary data were not available for these infants nor were plasma samples, carotenoid concentrations of which can be used as a biomarker of intake (32). Survey data, however, indicate that lutein accounts for approximately 12% of total carotenoids consumed in the US infant's diet during the first year of life, whereas β-carotene and lycopene together account for approximately 70% (National Health and Nutrition Examination Survey III 1988–1994). Breast milk is a major source of carotenoids in the first year of life, and levels of carotenoids in breast milk are greatly dependent on maternal intake. National Health and Nutrition Examination Survey 2009–2010 data showed mean intake of lutein and zeaxanthin in women ages 20 to 44 years (including pregnant and breast-feeding women), with a reliable dietary recall to be only 1329 ± 141 μg. Additionally, infant foods that are introduced in the first year of life mainly consist of apples, pears, carrots, sweet potatoes, and peas, which are not high in lutein. In contrast to its minimal dietary prevalence in the first year of life, lutein accounted for 59% of the total carotenoids in the infant brain, whereas β-carotene and lycopene for only 20%, thereby strengthening the hypothesis of preferential uptake and/or maintenance of lutein in the infant brain. An alternate explanation for the observed preferential concentration of lutein in the brain could be that breast-feeding was predominant among decedents who did not have a reported feeding history. This explanation is based on the relatively higher concentration (22–24) and bioavailability (33) of lutein in breast milk compared with infant formula.

An important question is whether a higher intake of lutein is associated with a higher concentration of lutein in the brain. We applied 2 approaches to address the influence of intake on brain lutein levels: feeding history and use of cryptoxanthin as an internal marker for breast-feeding. Feeding history showed no differences in brain lutein concentrations between term infants reported to have been breast milk–fed and term infants that were formula-fed. Because the majority of these infants were approximately 3 months old, brain lutein levels should not have been greatly influenced by introductory foods, which tend to be extremely low in lutein. Although feeding history was known for only 12 of the 30 decedents studied, cryptoxanthin values were available for each decedent. Breast milk contains meaningful concentrations of both cryptoxanthin and lutein, whereas infant formulas contained extremely low levels of both (34–36). We found that detectable levels of brain cryptoxanthin were associated with higher brain lutein concentrations in term decedents. Owing to the dramatic difference in breast milk and formula cryptoxanthin levels, this finding suggests that the higher levels of lutein from breast milk were associated with higher levels of lutein in the infant brain. This, together with the wide range of brain lutein concentrations observed, suggests that type of feeding is a determinant of brain lutein concentration as is observed for the macula.

It is noteworthy that lutein was the predominant carotenoid in the formula-fed term infant brain despite the fact that infant formulas were not supplemented with lutein when these decedent samples were collected. This observation suggests that the brain of term infants was able to maintain measurable amounts of lutein despite limited lutein intake. Also, of importance is the finding that formula-fed preterm infants had significantly lower amounts of lutein and zeaxanthin in their brain compared with formula-fed term infants, suggesting that factors surrounding prematurity may be linked to lower levels of lutein and zeaxanthin in the preterm brain. Taken together, these findings indicate that dietary intake, stage of development (preterm/term), and feeding practices influence brain lutein concentrations. Owing to differences in dietary practices, breast milk from Western countries has significantly lower concentrations of lutein than that from China and Japan (36). In addition, most infant formulas are not supplemented with lutein, and when it is supplemented the lutein is known to be less bioavailable than that in breast milk (33). These factors are likely to increase the risk of low lutein status in early life, when the brain is rapidly developing. Low lutein/carotenoid status at birth is particularly relevant to preterm infants who are exposed to the high oxidative stress environment of the neonatal intensive care unit. Because lutein is emerging as an important dietary factor in visual and cognitive development, the present study findings provide a rationale to further investigate the impact of lutein intake early in life on neural development in infants.


The authors thank the parents of the decedents for donating the brain tissues.


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brain; carotenoids; cognition; lutein; neural development; preterm infants

© 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology,