Correspondence to:

Samanta Maci

samanta.maci@kemin.com

Keywords: Lutein, Macular pigment optical density, Brain, Cognition

Abstract

Lutein selectively accumulates in the macula lutea and is a key component of the macular pigment. Recent research has indicated that lutein is also the predominant carotenoid in both the adult and the infant brain, and studies conducted in primates and humans have shown that lutein concentration in the retina is related to its concentrations in specific regions of the brain. A carotenoid-rich diet and high plasma levels of lutein are positively associated with cognitive status or function in healthy subjects, those with mild cognitive impairment, and subjects with Alzheimer’s disease.

Current research indicates that macular pigment optical density, a measure of dietary lutein (and zeaxanthin) deposited in the macula lutea, is positively associated with cognitive function. Additionally, interventional studies provide support that supplementation with lutein and/or zeaxanthin may enhance cognitive function and help maintain cognitive health. The beneficial effect of lutein is most likely linked to its antioxidant and anti-inflammatory properties, and its ability to integrate into cellular membranes, thereby influencing the structural properties and/or stability of those membranes, and possibly enhance gap junction communications. The aim of this review is to present the scientific evidence available to date.

Introduction

Lutein is well known for its role in eye health [1–4]. Three characteristics of lutein are reported to contribute to these health benefits, namely its antioxidant properties, anti-inflammatory benefits, and the nature of its interaction with lipid membranes [5–9]. New research shows that lutein crosses the blood–brain barrier and is the predominant carotenoid in the brain [5, 10], further suggesting that lutein has a critical role in overall brain health and cognitive function.

The eye and brain have a common developmental origin in the neural tube. Moreover, both organs are characterized by a high content of polyunsaturated fatty acids and high metabolic activity, making them particularly susceptible to oxidative stress and free radical damage [11]. Furthermore, carotenoids have been shown to enhance gap junction communication, which is proposed to be important for light processing in the retina and proper functioning of neural circuits in the visual system [5, 12], pointing to a joint role of lutein in both eye and brain health and function [13].

Cognition refers to the mental processes used to acquire knowledge and understanding. It is a multi-dimensional concept divided into domains of memory, attention, language, information processing, and executive function [14]. Each of these cognitive domains can be influenced by factors such as sleep, mood, stress and diet. As the brain ages, declines are observed in specific domains of cognition such as processing speed, episodic and working memory, and executive function. These changes are believed to be caused by physiological damage due to oxidative stress and inflammation, among other factors [15]. Molecules such as lutein with strong antioxidant and anti-inflammatory properties have great potential to play a beneficial role in cognitive health.

Lutein is the predominant carotenoid in the brain

In 2004, Craft et al. published a study that identified and measured a broad range of antioxidants in the adult brain [16]. Sixteen carotenoids, three tocopherols and retinol were identified in brain tissue. They found that xanthophylls (lutein, zeaxanthin and cryptoxanthin) account for 66–77% of the carotenoids in the brain regions studied, while data from previously published research reported that xanthophylls only account for about 40% of the total carotenoids in human blood [17, 18], prompting Craft et al. to suggest that there may be a ‘preferential accumulation of xanthophylls’ in the brain. Johnson et al. confirmed and extended these results in a 2013 study that measured carotenoid levels in both the serum and brain tissue of 42 centenarian decedents [5]. Carotenes (α-carotene, β-carotene and lycopene) were the predominant carotenoids in the serum, accounting for over half (57%) of total serum carotenoids. However, the ratio was reversed in the brain, with xanthophylls (lutein, zeaxanthin and cryptoxanthin) making up 72% of total carotenoids in the brain with lutein alone accounting for over one third (34%) of all brain carotenoids, a significantly greater proportion compared to other carotenoids (p<0.02), once again suggesting a selective uptake of lutein into the human brain. Data for carotene and xanthophyll concentrations in the serum and brain are given in Fig. 1 (data for α-carotene are not presented because it was detected in serum but not in brain tissue). The authors additionally assessed the relationship between brain carotenoid levels and 6-month premortem measures of cognitive function and found significant and positive correlations between several cognitive measures and lutein and zeaxanthin concentrations in the cortex. The mean concentration of all carotenoids progressively decreased with increased Global Deterioration Rating Scale (GDRS) scores from 1 (normal cognitive function) to 3 (mild cognitive impairment, MCI). Among all carotenoids, only the difference in brain lutein content between MCI and cognitively unimpaired subjects remained statistically significant (p<0.05) after adjusting for age, sex, education, diabetes and hypertension.

A similar result confirming the preferential uptake of lutein in the brain was observed in a study on infant brains published in 2014 by Vishwanathan et al. [10]. Lutein comprised almost two-thirds (58%) of the carotenoids in infant brains, while zeaxanthin made up 16% of the brain carotenoids, resulting in lutein and zeaxanthin together representing 74% of the total carotenoids (Fig. 2) (data for lycopene, detected in some of the tissue in only three infants, are not reported). This high concentration of lutein relative to other dietary carotenoids is noteworthy if we consider a study of dietary intake of carotenoids in infants aged 2–11 months (NHANES 1988-94) [19] which showed β-carotene as the major dietary carotenoid and lutein (assessed together with its dietary isomer zeaxanthin) representing only 17% of the total carotenoid intake (Fig. 2).

Scientific evidence

The importance of an adequate diet for maintaining general health and for sustaining optimal brain structure and function throughout life is well known [20]. Healthy subjects with high fruit and vegetable intake have higher blood antioxidant levels and better cognitive scores than healthy subjects with low fruit and vegetable intake [21]. Green and cruciferous vegetables are associated with a slower cognitive decline in ageing women [22]. These beneficial effects have been at least in part attributed to the nutritional compounds contained in these foods, including carotenoids [23]. For example, carotenoid-rich dietary patterns were positively associated with cognitive performance measured 13 years later [24]. Dietary intakes of lutein and zeaxanthin were found to be significantly lower in Alzheimer’s disease (AD) subjects compared to healthy controls [25]. However, other papers assessing the relationship between diet and brain health have provided confounding results [26, 27].

A search of third party literature was conducted on PubMed through August 2015 to identify articles that evaluated the effect of lutein (and its isomer zeaxanthin, commonly discussed together with lutein) on cognitive health and function or their relationship in healthy adult subjects, those with MCI or those with AD. The search terms were “lutein” OR “zeaxanthin” AND “cognition” OR “brain” OR “dementia”.

Only observational studies addressing the relationship between plasma lutein (and zeaxanthin) levels and/or their concentration in the macula expressed as macular pigment optical density (MPOD) and cognitive status/function, and interventional trials involving adult participants and published in English were selected. A total of 24 studies were identified that met the search criteria. So that the selection would be as comprehensive as possible, three known published papers not retrieved by the search [21, 28, 29] were additionally included for a total of 27 papers.

Observational studies

Twenty-three papers discussed the results of observational studies conducted to assess the relationship between plasma levels of lutein and zeaxanthin and/or MPOD levels and cognitive status/function (see flowchart in Fig. 3).



Thirteen of the 16 observational studies retrieved in the literature search assessing plasma lutein and zeaxanthin levels and cognitive status/function indicate that higher plasma levels of lutein and, to some extent zeaxanthin, are positively associated with cognitive status/function [5, 7, 23, 25, 30–38], while three papers reported no or a negative association [21, 39, 40].

Plasma levels of lutein and/or zeaxanthin were found to be significantly lower in subjects with MCI, AD or vascular dementia when compared to age-matched healthy control subjects [7, 25, 30–33, 35, 36]. Studies assessing levels of oxidative stress show that AD subjects have higher plasma levels of 8-hydroxyl-2’-deoxyguanosine (8-OHdG), a well-established biomarker of oxidative stress in DNA [30], or higher levels of phospholipid hydroperoxide (PLOOH) in red blood cells (RBC) [7] when compared to healthy subjects. Furthermore, lower plasma lutein levels were significantly correlated with higher plasma levels of 8-OHdG in AD subjects (p<0.05). A similar inverse correlation was observed with levels of PLOOH in RBC of both AD subjects and healthy controls (p<0.05 and p<0.01, respectively). Finally, in 2015 Feart et al. reported that in a population of 1,092 elderly subjects without dementia, higher plasma lutein levels were significantly associated with a decreased risk of dementia and AD over a 10-year follow-up period [23]. In the EVA (‘Etude du Vieillissement Artériel’) study [34] which included 589 participants, Akbaraly et al. showed that participants with the lowest cognitive performance, defined as a score below the 25th percentile in the neuropsychological tests, had a higher probability of having plasma zeaxanthin levels also below the 25th percentile. Data for the oldest old from the Georgia Centenarian Study [5] including 78 octogenarians (age between 80 and 89 years) and 220 centenarians (98 years or older) showed that serum lutein and zeaxanthin concentrations were more consistently associated with better performance in the different cognitive tests conducted than α-tocopherol, retinol or the majority of the other carotenoids assessed. In the octogenarian group, only serum lutein was significantly related to better cognition and executive function and lower dementia severity.

Additional support has been provided by the research conducted in the last decade and consolidated in the last 2 years that indicates that MPOD, a measure of lutein and zeaxanthin deposited in the macula lutea, is positively associated with cognitive function. All 10 observational studies measuring MPOD identified in the literature search confirmed this positive correlation [25, 28, 38, 40–46].

Studies conducted in healthy subjects across different age ranges have shown that MPOD is positively correlated with temporal processing speed and reaction time [28, 41, 43–45]. This indicates that subjects with higher MPOD have faster processing speeds and reaction times. It also supports the connection between eye and brain functionality.

In a study conducted in Ireland and enrolling 4,453 subjects 50 years of age or older [42], MPOD was found to be significantly and positively associated with two tests assessing global cognition – the Mini Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) – as well as other tests assessing specific cognitive domains. Subjects with lower MPOD had lower MMSE and MoCA scores and poorer performance in tests of prospective memory, executive function, mental processing speed and sustained attention. MMSE scores ranged on average from 28.6 to 28.2 by MPOD quintiles, while MoCA scores ranged from 25.2 to 24.6. The relationship between MPOD and different measures of cognitive performance in healthy subjects observed in this large study were additionally supported by two smaller studies published in 2014 [40] and 2015 [38] which were conducted in older and younger populations, respectively.

Research conducted in participants with MCI [46] has shown that MPOD is correlated with the composite MMSE score, the total score of the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and index scores of visuospatial and constructional abilities, language ability and attention. Finally, a study comparing AD patients and healthy controls [25] indicates that MPOD is significantly lower in AD subjects.

A summary of all the observational studies addressing the relationship between MPOD and cognitive function is reported in Table 1.

The relationship between MPOD and cognitive function is further supported by studies conducted in primates [47] and humans [48]. These studies have confirmed that lutein concentration in the retinal region is consistently related to its concentrations in the occipital cortex (the primary visual processing area of the brain). Additional macular–brain associations were found in primates for lutein and zeaxanthin and the cerebellum, lutein and pons, as well as for zeaxanthin and the frontal cortex. These findings suggest that MPOD has the potential to be used as a non-invasive biomarker for lutein and zeaxanthin concentration in the brain and potentially explain the observed relationship between MPOD and cognition.

Interventional studies

Interventional studies also provide support that supplementation with lutein and/or zeaxanthin may enhance cognitive function and help maintain cognitive health. A total of six randomized, double-blind, controlled interventional studies have been conducted to date to investigate the role of lutein and zeaxanthin in cognitive functions [29, 44, 45, 49–51]; five of these studies used FloraGLO® Lutein as the source of lutein at a dose ranging from 8 to 12 mg. A study by Johnson et al. [49] provided 4 months of supplementation with lutein, DHA or a combination of both to a group of healthy 60–80-year-old women.

The research found a statistically significant improvement in verbal fluency scores for both the lutein and the DHA groups as well as significant improvements in three other measures of cognition for the lutein plus DHA combination group. Serum lutein and DHA levels also increased significantly. This study represents the first of its kind conducted to determine the role of lutein on cognitive measures in older adults. It showed that lutein supplementation significantly improved verbal memory, a measure of executive function and frontal lobe capabilities.

In addition, Bovier et al. [44] conducted a 4-month supplementation regimen in healthy 18–32-year-old men and women. Subjects were supplemented with high-dose zeaxanthin, lutein plus high-dose zeaxanthin and omega-3 fatty acids, or placebo. Neural processing speed was assessed at the end of the supplementation period. The researchers found that critical flicker fusion thresholds and missed coincidence anticipation time, two measures of neural processing speed, were improved upon supplementation. A second publication by the same group in 2015 using the same formulations assessed the effects of supplementation on visual processing speed [45]. Significant improvements were seen in temporal processing speeds via increased temporal contrast sensitivity function scores after 4 months of supplementation. The researchers observed a 20% increase in visual processing speed in the young healthy subjects. The baseline data in these two studies were also considered in the observational studies pool discussed above.

Three interventional studies have observed mixed effects on cognition after supplementation with lutein or zeaxanthin [29, 50, 51]. These studies are similar in that they were all conducted in non-healthy subject populations diagnosed with either age-related macular degeneration (AMD) or AD, so it may not be appropriate to translate the results to a general healthy population. Only one of the studies used a true placebo-controlled design and all studies were conducted in an older subject demographic.

In 2015, Chew et al. [50] conducted a secondary analysis on the AREDS2 trial data and failed to find a statistically significant difference on a composite cognitive score between a lutein/zeaxanthin group and a non-lutein/zeaxanthin group following 5 years of supplementation. The study only included subjects with medically diagnosed AMD, a neurodegenerative disease with unknown consequences on cognition in a population with an average age of 72 years. In addition, as an ancillary evaluation, the authors state that this portion of the study was not sufficiently powered to assess the cognitive benefits of supplementation. In order to control for multiple comparisons, the researchers set the α level for the study at p<0.001. With those limitations, the researchers still observed trends in recall (p=0.06) and Wechsler logical memory (p=0.02) test scores in the lutein and zeaxanthin treated group.

A 1-year supplementation study with zeaxanthin, lutein and zeaxanthin, or lutein by itself by Hoffman et al. [29] was also conducted in an older population diagnosed with mild AMD. The researchers found a significant improvement from baseline in delayed memory in the zeaxanthin only group but failed to find any other statistically significant changes in cognitive performance among the other two groups. Also, a study by Nolan et al. [51] with AD subjects (MMSE scores between 14 and 24) and healthy controls utilized 6-month supplementation with meso-zeaxanthin, lutein and zeaxanthin or placebo. The researchers observed significant improvements in serum concentrations, macular pigment and contrast sensitivity but failed to find a significant change in the cognitive measures assessed. The lack of cognitive findings could be due to the start of treatment after the onset of AD. The authors concluded that the results were not surprising given the fact that for lutein to have a beneficial effect, the optimal conditions are to start treatment with lutein prior to the onset of a neurodegenerative disease state. In addition, the small samples sizes (average of n=13 per group) resulted in some of the cognitive tests not being evaluated due to statistical assumption violations.

A summary of the interventional studies is shown in Table 2. In order to keep the table concise, only lutein or zeaxanthin outcomes in the listed papers have been summarized.

Conclusions

The body of literature presented demonstrates that lutein crosses the blood–brain barrier and is the predominant carotenoid in the adult and infant human brain. This supports lutein’s role as an important nutrient for brain health and function throughout the lifespan. Observational data are consistent in suggesting that plasma lutein (and zeaxanthin) levels and MPOD are positively associated with cognitive function. Studies conducted in primates and humans indicate that macular pigment carotenoids in the retina are significantly correlated with lutein and zeaxanthin concentrations in the brain, further indicating that MPOD may serve as a non-invasive biomarker for lutein and zeaxanthin concentration in the brain and potentially for cognitive health. Furthermore, interventional studies investigating the effects of lutein and possibly zeaxanthin on cognitive function provide initial support that supplementation with these xanthophylls may enhance cognitive function and help maintain cognitive health. Although most of the data discussed were on older adults, there is evidence from observational and intervention studies in support of the benefit of lutein and zeaxanthin on processing speed and reaction time in a young adult population. Additional studies aiming to further elucidate these benefits are now being conducted. Little is currently known about the role of lutein in early life. Lutein is present in cord blood and is the predominant carotenoid in human colostrum and breast milk. Cheatham and co-authors [52] explored the relationship between lutein, choline and DHA levels in human milk and recognition memory in 5-month-old infants and showed that high levels of lutein and choline are associated with better recognition memory. The neuroprotective effect of lutein and zeaxanthin is most likely linked to its antioxidant and anti-inflammatory properties, its ability to integrate into cellular membranes thereby influencing the structural properties and/or stability of those membranes, and possibly to enhance gap junction communications. In an exploratory metabolomics analysis conducted on postmortem infant brain tissues, Lieblein-Boff and co-authors [53] indicated that lutein is concentrated in neural tissues important for learning and memory and is correlated with fatty acids, phospholipids, antioxidants and amino acid neurotransmitters in the brain. Additional work demonstrated significant correlations across the lifespan for brain concentrations of lutein and StARD3, a specific binding protein for lutein previously identified in retinal tissues, suggesting a possible mechanism for the selective accumulation of lutein in the brain [54]. As both lutein and StARD3 are found in membranes, future studies investigating lutein’s role in modulation of the functional properties of synaptic membranes could help to elucidate the specific mechanisms of action underlying the beneficial role of lutein in brain health and function.

Conflict of Interest

Samanta Maci, Brenda Fonseca and Yong Zhu are employees of Kemin Food L.C.

Human and Animal Rights

This article does not contain any studies with human or animal subjects performed by any of the authors.

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*Kemin Human Nutrition and Health, a division of Kemin Foods L.C., Campo Grande 35- 8ºD, 1700-087 Lisbon, Portugal.

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Nutrafoods (2016) 15:179-188

DOI 10.17470/NF-016-1014-3

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