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Dietary carotenoids, plant pigments with anti-oxidant properties, accumulate in neural tissue and are often found in lower concentrations among individuals with obesity. Given previous evidence of negative associations between excess adiposity and memory, it is possible that greater carotenoid status may confer neuroprotective effects among persons with overweight or obesity. This study aimed to elucidate relationships between carotenoids assessed in diet, serum, and the macula (macular pigment optical density (MPOD)) and relational memory among adults who are overweight or obese. Adults aged 25–45 years (N = 94) completed a spatial reconstruction task. Task performance was evaluated for accuracy of item placement during reconstruction relative to the location of the item during the study phase. Dietary carotenoids were assessed using 7-day diet records. Serum carotenoids were measured using high-performance liquid chromatography. Hierarchical linear regression analyses were used to determine the relationship between carotenoids and task performance. Although initial correlations indicated that dietary lutein, beta-carotene, and serum beta-carotene were positively associated with memory performance, these relationships were not sustained following adjustment for age, sex, and BMI. Serum lutein remained positively associated with accuracy in object binding and inversely related to misplacement error after controlling for covariates. Macular carotenoids were not related to memory performance. Findings from this study indicate that among the carotenoids evaluated, lutein may play an important role in hippocampal function among adults who are overweight or obese.
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nutrients
Article
Serum Lutein is related to Relational
Memory Performance
Corinne N. Cannavale 1, Kelsey M. Hassevoort 2,3 , Caitlyn G. Edwards 4,
Sharon V. Thompson 4, Nicholas A. Burd 4,5 , Hannah D. Holscher 4,5,6 , John W. Erdman Jr. 4,6,
Neal J. Cohen 1,2,3,7 and Naiman A. Khan 1,4,5,*
1Neuroscience Program, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA;
cannava2@illinois.edu (C.N.C.); njc@illinois.edu (N.J.C.)
2Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign,
Champaign, IL 61801, USA; kelseyhassevoort@gmail.com
3Center for Brain Plasticity, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA
4Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA;
cgedwar2@illinois.edu (C.G.E.); svthomp2@illinois.edu (S.V.T.); naburd@illinois.edu (N.A.B.);
hholsche@illinois.edu (H.D.H.); jwerdman@illinois.edu (J.W.E.J.)
5Department of Kinesiology and Community Health, University of Illinois at Urbana-Champaign,
Champaign, IL 61801, USA
6Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign,
Champaign, IL 61801, USA
7Department of Psychology, University of Illinois at Urbana-Champaign, Champaign, IL 61801, USA
*Correspondence: nakhan2@illinois.edu; Tel.: +1-217-300-1667
Received: 28 February 2019; Accepted: 29 March 2019; Published: 2 April 2019


Abstract:
Dietary carotenoids, plant pigments with anti-oxidant properties, accumulate in neural
tissue and are often found in lower concentrations among individuals with obesity. Given previous
evidence of negative associations between excess adiposity and memory, it is possible that greater
carotenoid status may confer neuroprotective effects among persons with overweight or obesity.
This study aimed to elucidate relationships between carotenoids assessed in diet, serum, and the
macula (macular pigment optical density (MPOD)) and relational memory among adults who are
overweight or obese. Adults aged 25–45 years (N= 94) completed a spatial reconstruction task.
Task performance was evaluated for accuracy of item placement during reconstruction relative to
the location of the item during the study phase. Dietary carotenoids were assessed using 7-day
diet records. Serum carotenoids were measured using high-performance liquid chromatography.
Hierarchical linear regression analyses were used to determine the relationship between carotenoids
and task performance. Although initial correlations indicated that dietary lutein, beta-carotene, and
serum beta-carotene were positively associated with memory performance, these relationships were
not sustained following adjustment for age, sex, and BMI. Serum lutein remained positively associated
with accuracy in object binding and inversely related to misplacement error after controlling for
covariates. Macular carotenoids were not related to memory performance. Findings from this study
indicate that among the carotenoids evaluated, lutein may play an important role in hippocampal
function among adults who are overweight or obese.
Keywords: obesity; hippocampus; nutrition; overweight; carotenoids
1. Introduction
Overweight and obesity are conditions that increase metabolic risk and are characterized by
a body mass index (BMI) greater than 25 kg/m
2
[
1
]. Obesity can lead to a variety of metabolic and
Nutrients 2019,11, 768; doi:10.3390/nu11040768 www.mdpi.com/journal/nutrients
Nutrients 2019,11, 768 2 of 10
cardiovascular concerns such as type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular
disease [
1
]. According to the National Health and Nutrition Examination Survey (NHANES) data
from 2015–2016, approximately 40% of adults in the United States have obesity, with women having
a slightly higher prevalence than men (41.1% vs. 37.9%) [
1
]. In addition to the cardiometabolic concerns
that accompany obesity, excess fat mass or adiposity, as well as the associated metabolic complications,
have been associated with poorer cognitive function and brain structure [
2
]. One specific brain region
thought to be affected by obesity and other associated disorders is the hippocampus [
2
4
]. The
hippocampus is a highly plastic region of the brain, which may explain why hippocampal-dependent
memory function can be susceptible to behavior modulation through environmental factors [
5
,
6
].
Obesity, as well as a “western” diet characterized by high saturated fat and added sugar intake, has
been related to poorer hippocampal function [
3
,
4
]. However, research examining the influence of
specific dietary components on relational memory among individuals with overweight or obesity has
been limited.
Relational memory is a hippocampal-dependent process that involves the flexible binding of
arbitrary elements within an episode, and the subsequent reactivation of these relations [
7
]. In a
practical sense, relational memory allows us to put a name to a face or re-tell the story of a trip in any
order one chooses. One approach for assessing relational memory is to use a spatial reconstruction task.
Spatial reconstruction tasks require participants to return objects to locations they have previously
studied. This task design requires the participant to encode the arbitrary relationships between objects
and locations (or other objects) within each trial and subsequently use these bindings to reconstruct
the studied display successfully. Previous studies have shown that obesity and diet are associated with
relational memory performance; however, this has not yet been thoroughly investigated [4,8].
Carotenoids have been recently found to have relevance for hippocampal-dependent memory
performance [
7
]. Carotenoids are plant pigments that represent red, yellow, and orange color, and
can be found in egg yolks and a variety of fruits and vegetables such as avocados, carrots, sweet
potatoes, spinach, and other leafy green vegetables [
9
]. Previous studies have shown that, among the
numerous carotenoids in nature, only a handful accumulate in human neural tissue. These include
lutein, beta-carotene, beta-cryptoxanthin, and zeaxanthin, all of which accumulate in all cortices
and the hippocampus in humans and non-human primates [
10
12
]. However, lutein accumulation
in neural tissue is up to 5-fold greater than other carotenoids, inferring a potentially unique role
for this carotenoid in cognitive function and brain health [
10
]. Further, lutein, its stereoisomer,
zeaxanthin, and the lutein intermediate meso-zeaxanthin, collectively belonging to a group known
as xanthophylls, selectively accumulate in the macula of the human eye. The structural properties
of xanthophylls allow them to serve as blue light filters and antioxidants in the eye and protect
retinal tissue from photo-oxidative damage [
9
,
13
,
14
]. Opportunely, the macular concentration of
lutein, zeaxanthin, and meso-zeaxanthin can be non-invasively assessed as macular pigment optical
density (MPOD) [
15
]. Macular xanthophylls have previously been related to brain carotenoid
concentrations in non-human primates [
16
]. These macular carotenoids, assessed through MPOD, are
also positively associated with relational memory performance in children and with intellectual ability
and executive function in adults [
7
,
17
,
18
]. Additionally, higher MPOD scores have been associated
with better memory performance assessed using a delayed recall task [
11
,
19
]. However, given that
MPOD represents a composite metric of all three xanthophylls in the retina, it is incorrect to isolate
carotenoid-related cognitive benefits to lutein alone. Individual carotenoid quantification in serum
provides an opportunity to study the influence of lutein in a manner that would be separable from other
carotenoids
in vivo
. While serum does not provide a direct assessment of neuronal lutein, it provides us
with a more precise measure of individual carotenoids than what is determined using MPOD or dietary
assessment. In previous studies quantifying serum lutein rather than the composite MPOD measure,
it was shown that serum lutein mediated the relationship between the parahippocampal cortex and
crystallized intelligence [
20
]. Serum lutein is also associated with multiple domains of cognition,
including memory [
11
]. However, a potential limitation of relying on serum alone is that the content
Nutrients 2019,11, 768 3 of 10
in serum is transient and may not reflect xanthophyll status in neural tissue. Therefore, additional
studies that assess both MPOD and serum carotenoids are necessary to clarify the impact of lutein
and other carotenoids on relational memory. To our knowledge, there have been no previous studies
investigating associations between both MPOD and serum xanthophylls on relational memory abilities
among adults with overweight or obesity. Accordingly, this study aimed to understand whether dietary,
serum, or macular levels of carotenoids were associated with relational memory function in adults that
are overweight and obese. We hypothesized that macular carotenoids, assessed as MPOD, would be
positively associated with relational memory performance. Additionally, we anticipated that a greater
serum concentration of lutein would be associated with greater relational memory performance.
2. Materials and Methods
2.1. Participants
Eligible participants were adults aged 25–45 years who were overweight or obese (BMI
25 kg/m
2
) and no prior history of physician-diagnosed metabolic or gastrointestinal disease (e.g.,
Crohn’s Disease, Diabetes, CVD, etc.), or neurological or cognitive disorders. Participants were also
excluded if they were using any tobacco products.
2.2. Ethical Approval
At the first appointment, participants were informed of the overall procedure and written
informed consent was obtained before collection of any data. The University of Illinois Institutional
Review Board approved consent before recruitment, and the study was conducted following the
Declaration of Helsinki.
2.3. Procedure
Data were collected over the course of two appointments. At the first appointment, participants
were screened using medical history and demographic questionnaires. The second appointment
followed a 10-h overnight fast. The participants subsequently underwent adiposity assessment using
dual-energy X-ray absorptiometry (DXA) (Hologic, Bedford, MA, USA) and IQ was assessed using the
Kaufman brief intelligence test-2 (KBIT-2). A spatial reconstruction task was administered to assess
hippocampal-dependent relational memory ability. Fasted blood was collected at the conclusion of the
appointment and serum lutein levels were determined using high-performance liquid chromatography.
All participants were provided with a 7-day diet record to document their regular carotenoid intake,
which was completed within one week of relational memory assessment.
2.4. Relational Memory Assessment
Hippocampal-dependent relational memory ability was evaluated through a computerized spatial
reconstruction task (Figure 1). This task was completed using Presentation Software (Neurobehavioral
Systems, Berkeley, CA, USA). Participants were first shown 6 abstract shapes in the center of the screen
to introduce the shapes used for the reconstruction phase. After 6 s, the stimuli disappeared and
reappeared in a randomized array on the screen. The identities of the objects were then masked by
small squares and participants had 18 s to click the boxes and one-by-one learn the locations of each
shape. The boxes then disappeared and, after a 2 s fixation, they reappeared at the top of the screen.
Participants were instructed to reconstruct the array they previously studied. Reconstruction was
self-paced and, once the participant was satisfied with their reconstruction, they moved on to the
subsequent trial, for a total of 20 trials (4 blocks of 5). Each participant’s performance was assessed
using two error metrics: misplacement and object-location binding (Figure 2). Misplacement was
calculated as the average measure of distance (in pixels) between the objects’ studied and reconstructed
locations, with a higher score indicating poorer performance. Object-location binding was defined
as the number of times the participant correctly placed an item within a pre-defined radius around
Nutrients 2019,11, 768 4 of 10
its studied location. For each trial, a participant received a score of 0–6 for this metric, with a higher
score indicating better performance, and performance was averaged across trials. More detailed
explanations of these error metrics can be found in Horecka et al. (2018) [21].
Nutrients 2019, 11, x FOR PEER REVIEW 4 of 10
for this metric, with a higher score indicating better performance, and performance was averaged
across trials. More detailed explanations of these error metrics can be found in Horecka et al. (2018)
[21].
Figure 1. Spatial reconstruction task description.
Figure 2. Spatial reconstruction task error metrics.
2.5. Intelligence Assessment
The KBIT-2 was administered by a trained staff member to estimate IQ. The assessment is
comprised of 3 subtests: verbal knowledge, matrices, and riddles. Correct answers are given a score
of 1 and each subtest score is then transformed to a standardized score normed for ages 490 years
[22,23]. The verbal knowledge subtest includes 60 questions where the participant chooses which
of six images is most associated with a word or question spoken by the researcher. The matrices
subtest has 46 logic problems where the participant must choose an image that is most associated
with a single stimulus picture or which picture best completes the pattern of a 2 × 2, 2 × 3 or 3 × 3
matrix. The riddle subtest consists of 48 riddles spoken by the researcher where the participant
gives a single word response.
2.6. Dietary Assessment
All participants recorded regular dietary intake for 7 days in a provided food diary after
instruction by a trained staff member. Diet record data were recorded and analyzed using the
Nutrition Data System for Research (NDSR) 2015 (Minneapolis, MN, USA) by trained research staff.
There was not enough dietary information in the available nutrient databases to extract levels of
individual xanthophylls; therefore, dietary lutein and zeaxanthin were ascertained as an aggregate
measure (i.e., lutein + zeaxanthin). Consumption amounts of lutein + zeaxanthin, beta-carotene, and
beta-cryptoxanthin were extracted from NDSR.
Figure 1. Spatial reconstruction task description.
Nutrients 2019, 11, x FOR PEER REVIEW 4 of 10
for this metric, with a higher score indicating better performance, and performance was averaged
across trials. More detailed explanations of these error metrics can be found in Horecka et al. (2018)
[21].
Figure 1. Spatial reconstruction task description.
Figure 2. Spatial reconstruction task error metrics.
2.5. Intelligence Assessment
The KBIT-2 was administered by a trained staff member to estimate IQ. The assessment is
comprised of 3 subtests: verbal knowledge, matrices, and riddles. Correct answers are given a score
of 1 and each subtest score is then transformed to a standardized score normed for ages 490 years
[22,23]. The verbal knowledge subtest includes 60 questions where the participant chooses which
of six images is most associated with a word or question spoken by the researcher. The matrices
subtest has 46 logic problems where the participant must choose an image that is most associated
with a single stimulus picture or which picture best completes the pattern of a 2 × 2, 2 × 3 or 3 × 3
matrix. The riddle subtest consists of 48 riddles spoken by the researcher where the participant
gives a single word response.
2.6. Dietary Assessment
All participants recorded regular dietary intake for 7 days in a provided food diary after
instruction by a trained staff member. Diet record data were recorded and analyzed using the
Nutrition Data System for Research (NDSR) 2015 (Minneapolis, MN, USA) by trained research staff.
There was not enough dietary information in the available nutrient databases to extract levels of
individual xanthophylls; therefore, dietary lutein and zeaxanthin were ascertained as an aggregate
measure (i.e., lutein + zeaxanthin). Consumption amounts of lutein + zeaxanthin, beta-carotene, and
beta-cryptoxanthin were extracted from NDSR.
Figure 2. Spatial reconstruction task error metrics.
2.5. Intelligence Assessment
The KBIT-2 was administered by a trained staff member to estimate IQ. The assessment is
comprised of 3 subtests: verbal knowledge, matrices, and riddles. Correct answers are given a score of
1 and each subtest score is then transformed to a standardized score normed for ages 4–90 years [
22
,
23
].
The verbal knowledge subtest includes 60 questions where the participant chooses which of six images
is most associated with a word or question spoken by the researcher. The matrices subtest has 46 logic
problems where the participant must choose an image that is most associated with a single stimulus
picture or which picture best completes the pattern of a 2
×
2, 2
×
3 or 3
×
3 matrix. The riddle subtest
consists of 48 riddles spoken by the researcher where the participant gives a single word response.
2.6. Dietary Assessment
All participants recorded regular dietary intake for 7 days in a provided food diary after
instruction by a trained staff member. Diet record data were recorded and analyzed using the
Nutrition Data System for Research (NDSR) 2015 (Minneapolis, MN, USA) by trained research staff.
There was not enough dietary information in the available nutrient databases to extract levels of
individual xanthophylls; therefore, dietary lutein and zeaxanthin were ascertained as an aggregate
measure (i.e., lutein + zeaxanthin). Consumption amounts of lutein + zeaxanthin, beta-carotene, and
beta-cryptoxanthin were extracted from NDSR.
Nutrients 2019,11, 768 5 of 10
2.7. Serum Carotenoid Assessment
Serum carotenoid levels were assessed using high-performance liquid chromatography (HPLC).
Serum carotenoids were extracted using 3 consecutive hexane extraction processes using a previously
published protocol [
24
]. Briefly, the hexane layers were combined, dried under nitrogen, taken up
into 90% MTBE, 8% methanol, and 2% ammonium acetate in water solution (1.5% solution) and then
analyzed for carotenoid concentrations using the Alliance HPLC system (e2695 Separation Module)
equipped with 2998 photodiode array detector (Waters, Milford, MA, USA) and a reverse-phase
C30 column (4.6
×
150 nm, 3 micron, YMC, Wilmington, NC, USA). Serum levels of carotenoids
previously found in human neural tissue were assessed including lutein, zeaxanthin, beta-carotene,
and cryptoxanthin.
Carotenoid standards were obtained from Carotenature, Ostermundigen, Switzerland. For
quantification, standard curves were run for each carotenoid, and serum carotenoids were quantified
by use of the following extinction coefficients (all 1% solution): lutein 2550 in ethanol; zeaxanthin
2540 in ethanol; beta carotene 2592 in hexane; cryptoxanthin 2565 in hexane. The Erdman laboratory
routinely participates in the National Institutes for Standards and Testing micronutrient proficiency
testing program, and our serum carotenoid values for blinded serum samples consistently were within
1–2 SD of the medians.
2.8. Retinal Carotenoid Assessment
MPOD was assessed using a macular densitometer (Macular Metrics Corporation, Rehoboth,
MA, USA) via a customized hetero-flicker photometry (cHFP) technique). This two-step process
first required participants to focus on a flickering stimulus in their central line of vision, where the
macular pigment is at its highest concentration, and 7 degrees parafoveally, where the macular pigment
is at its lowest concentration. The stimulus flickered between 460 nm and 570 nm wavelengths at
a rate that has been optimized for the width of the null zone for the participant. Participants then
adjusted the radiance to identify the point at which they could not detect a flicker (the null flicker zone).
MPOD was calculated by subtracting the foveal from the parafoveal log sensitivity measurements
after normalizing at 570 nm. More detailed information on the principles behind this technique were
described in Wooten, et al. (1999) [25].
2.9. Weight Status and Adiposity
Height and weight were measured three times using a stadiometer (model 240; SECA, Hamburg,
Germany) and a digital scale (WB-300 Plus; Tanita, Tokyo, Japan) while participants were wearing
light clothing and no shoes. Mean height and weight values were used to calculate BMI. Whole body
adiposity (%Fat) was measured using a Hologic Horizon W bone densitometer (software version 13.4.2,
Bedford, MA, USA) DXA scanner.
2.10. Statistical Analysis
All statistical analyses were conducted using SPSS 2016 v24 (IBM Corp., Armonk, NY, USA).
Normality was assessed using the Shapiro-Wilk test and variables that did not display normal
distribution were log transformed. Pearson’s correlations were run to determine initial relationships
between hippocampal task performance, carotenoids, MPOD, Age, Sex, and %Fat. Hierarchical
linear regression modeling was used to further investigate the relationships between carotenoids with
statistically significant correlations to relational memory metrics. Step 1 of each regression model
included covariates that were found to be significantly related to the dependent, relational memory,
variable via bivariate correlations. Separate step 2
0
s were conducted for each carotenoid found to
be related to the respective dependent variable from bivariate correlations. A one-tailed approach
was used due to the positive directionality of our hypothesis and outcomes seen in the previous
literature [17,18,20,26].
Nutrients 2019,11, 768 6 of 10
3. Results
Descriptive statistics for participant demographics can be found in Table 1.
Table 1. Participant characteristics and memory performance.
Variable Mean ±SD
Sex, F/M 45, 54
Age, years 34.9 ±6.1
BMI, kg/m233.3 ±6.6
Fat, % 40.2 ±8.42
Intelligence Quotient 107 ±12.1
Macular Pigment Optical Density 0.438 ±0.20
Dietary Lutein + Zeaxanthin, mcg/day
2283 ±3382
Serum Lutein, µmol/L 0.129 ±0.06
Misplacement, pixels 219.3 ±77.0
Object-location binding 2.67 ±0.83
Bivariate correlations revealed that misplacement was positively related to age (r= 0.33, p= 0.001)
and %Fat (r= 0.19, p= 0.03), and inversely related to IQ (r=
0.37, p< 0.001). Further, misplacement
was negatively associated with dietary lutein + zeaxanthin (r=
0.22, p= 0.02) and serum lutein
(r=
0.25, p= 0.005) concentrations. Similarly, dietary and serum beta-carotene were negatively
associated with misplacement (r=
0.24, p= 0.01; r=
0.20, p= 0.03). Object-location binding
was negatively related to age (r=
0.25, p= 0.007) and positively related to IQ (r= 0.32, p= 0.001).
Object-location binding was not associated with %Fat (r=
0.11, p= 0.1), likely due to the decreased
range of performance. Additionally, object-location binding was positively associated with dietary
lutein + zeaxanthin (r= 0.21, p= 0.02), serum lutein (r= 0.22, p= 0.02), and dietary beta-carotene
(r= 0.20, p= 0.03). No other carotenoids were statistically significantly related to relational memory
measures in either diet or serum (all p’s > 0.09).
MPOD was not related to relational memory measures (all p’s > 0.4), nor was it related to dietary
lutein + zeaxanthin (p> 0.1). MPOD was, however, related to serum lutein (r= 0.30, p= 0.002), dietary
(r= 0.20, p= 0.03) and serum (r= 0.25, p= 0.007) beta-carotene, serum cryptoxanthin (r= 0.29, p= 0.007),
and serum zeaxanthin (r= 0.22, p= 0.017). Bivariate correlations are summarized in Table 2.
Table 2.
Bivariate correlations (Pearson’s r) between relational memory, participant characteristics,
and carotenoids.
Misplacement Object-Location Binding
Age 0.33 ** 0.25 **
Sex 0.17 0.10
%Fat 0.19 * 0.11
IQ 0.37 ** 0.32 **
Dietary L + Z 0.21 * 0.21 *
Dietary Beta-Carotene 0.24 ** 0.20 *
Dietary Beta-Cryptoxanthin 0.06 0.05
MPOD 0.110 0.083
Serum Lutein 0.266 ** 0.223 *
Serum Zeaxanthin 0.027 0.002
Serum Beta-Carotene 0.202 * 0.137
Serum Cryptoxanthin 0.103 0.076
*p< 0.05, ** p< 0.01.
Nutrients 2019,11, 768 7 of 10
Misplacement was modeled using hierarchical linear regression modeling with dietary lutein
+ zeaxanthin, serum lutein, and dietary and serum beta-carotene. Each carotenoid was modeled in
a separate step 2. Step 1 of each misplacement model controlled for covariates that were statistically
significantly related to misplacement in bivariate correlations (Age, %Fat, IQ).
Statistically significant regressions for misplacement can be found in Table 3. Serum lutein was the
only carotenoid significantly related to misplacement after covariate adjustment (
β
=
0.15, p= 0.05).
Dietary lutein + zeaxanthin (
β
=
0.07, p = 0.2), dietary beta-carotene (
β
=
0.07, p = 0.2), and serum
beta-carotene (β=0.05, p= 0.3) were no longer related after controlling for covariates in step 1.
Table 3. Hierarchical linear regression modeling of misplacement and carotenoids.
Step & Variable βR2
Step 1
Age 0.179 **
0.142 **
%Fat 0.019
IQ 0.363 **
Step 2 Serum Lutein 0.152 * 0.207 *
*p< 0.05, ** p< 0.01.
Object-location binding was modeled with serum lutein, dietary lutein + zeaxanthin, and dietary
beta-carotene. Similarly, serum lutein was the only carotenoid that was still statistically significantly
related to object-location binding after controlling for covariates in step 1 (
β
= 0.16, p= 0.05). Dietary
lutein + zeaxanthin (
β
= 0.10, p = 0.1), and dietary beta-carotene (
β
= 0.08, p = 0.2) were no longer
related to object-location binding after covariates were accounted for. This model is described in
Table 4.
Table 4. Hierarchical linear regression modeling of object-location binding and carotenoids.
Step & Variable βR2
Step 1 Age 0.290 ** 0.142 **
IQ 0.197 *
Step 2 Serum Lutein 0.159 * 0.166 *
*p< 0.05, ** p< 0.01.
4. Discussion
The present work examined the relationship between carotenoids in the macula, diet, and
serum, and their relationship with hippocampal-dependent relational memory performance. Given
previous literature indicating that lutein disproportionately accumulates in neural tissue, including the
hippocampus, we anticipated that serum and macular lutein concentrations, in particular, would be
related to relational memory. Herein, the results indicated that higher serum, but not macular, lutein
concentrations were positively associated with greater relational memory performance on a spatial
reconstruction task. Although dietary lutein + zeaxanthin and both dietary and serum beta-carotene
were correlated with performance, these relationships did not persist after covariate adjustment. Taken
together, these findings provide additional evidence that serum carotenoid status may impact memory
performance among adults who are overweight or obese.
There are many potential roles lutein may play in the brain. One proposed mechanism, which is
relevant in our sample, is that lutein can modulate inflammatory and oxidative stress pathways [
13
,
14
].
Participants with overweight or obesity are more susceptible to oxidative and inflammatory stress due
to the higher levels of chronic inflammation associated with excess adipose tissue [
27
,
28
]. Inflammation
and oxidative stress can be mitigated by fruit and vegetable intake, foods that are often rich in
Nutrients 2019,11, 768 8 of 10
carotenoids [
27
]. Inflammation is detrimental to hippocampal function, specifically by inhibiting
long term potentiation, the molecular mechanism for memory formation [
29
]. In the retina, lutein
is protective against age-related macular degeneration by reducing oxidative stress [
13
,
14
]. Thus,
we hypothesize that lutein may play a similar role in the hippocampus.
Previous studies have shown that elevated serum lutein concentrations are positively associated
with multiple realms of cognition, particularly in brain regions where lutein is known to deposit.
A recent MRI study found that the parahippocampal cortex mediates the relationships between serum
lutein concentrations and fluid intelligence [
20
]. Additionally, serum lutein concentrations were
positively related to delayed recall memory task performance, controlled oral word association tests,
and the Weshler adults intelligence scale-III similarities subtest [
11
]. Vishwanathan et al. did not
observe similar relationships with delayed recall and serum lutein + zeaxanthin in their sample [
19
].
Our results in comparison to these studies indicate that lutein, in particular, may impact cognition in
participants with overweight or obesity. When lutein is assessed as a combined metric (dietary, MPOD,
serum L + Z), significant associations have not been found. Our results, however, display a strong
association with lutein assessed independently of zeaxanthin.
Contrary to our a priori hypothesis, macular xanthophylls, assessed by MPOD, were not related to
relational memory performance. This was surprising given previous work linking MPOD to relational
memory in children, and in older adults which has shown positive associations between other memory
forms (e.g., delayed recall) and MPOD [
19
]. However, our finding may differ from the previous
literature due to the weight status of our participants. It is thought that increased adipose tissue,
owing to its capacity to store carotenoids, may limit carotenoid availability for other tissues (e.g.,
retina), which may contribute to this disparity. Though the current body of literature has displayed
positive relationships between MPOD and relational memory or executive function, these samples
were mainly healthy weight [
7
,
18
,
26
,
30
,
31
]. Nevertheless, our team has previously shown that MPOD
is associated with intellectual abilities among persons who are overweight or obese [
17
]. Therefore, it is
possible that the relationship between MPOD and cognitive function among persons with overweight
or obesity may be domain-dependent. While previous adult studies have displayed relationships
with memory function and MPOD, the memory assessments used primarily assessed item-memory
and therefore may not have depended on the hippocampus to the extent the spatial reconstruction
task does [18,26,30,31]. Additionally, we may have failed to observe the relationship between MPOD
and memory due to limitations in the technique we used to assess MPOD. Previous work has shown
that, while macular pigmentation is densest at the foveal pit at two sites, we were unable to assess
the complete spatial distribution of xanthophylls in the macula, thus, limiting our ability to link
macular lutein to memory performance. Additional research studies examining the impact of the
spatial profiles of the xanthophylls in the macula on memory function are necessary to characterize the
impact of macular lutein to hippocampal function comprehensively. Nevertheless, this work suggests
that serum lutein is unique among carotenoids in its relationship with memory. Future studies should
assess both blood and macular carotenoids to further elucidate this relationship in a larger and more
diverse population.
While we found significant correlations between memory performance and serum lutein
concentrations, there are some limitations worth considering. While spatial reconstruction tasks
have been shown to elicit the hippocampus, hippocampal-dependent cognition can also be assessed
via other tasks/paradigms that could inform the specific memory processes that benefit from lutein.
Second, relative to a previously studied Midwest sample, our serum lutein concentrations were
lower when compared to the population average (0.28
µ
mol/L
±
0.13 versus 0.129
µ
mol/L
±
0.06) [
32
]. This, however, may be explained by the higher BMI of our sample. Finally, this study
design was cross-sectional, providing no insights into the causal mechanisms that may underlie the
carotenoid and relational memory relationship. Intervention studies are necessary to understand
whether improvement in lutein status does, in fact, positively influence hippocampal-dependent
relational memory performance.
Nutrients 2019,11, 768 9 of 10
5. Conclusions
This study aimed to understand the relationship between dietary, serum, and macular carotenoids,
and relational memory. Our results revealed that serum lutein was significantly related to two metrics
of relational memory performance even after adjusting for significant covariates. While this study was
correlational, it lays the groundwork for subsequent research in this area. Further intervention studies
where carotenoids are assessed in the macula and serum must be conducted to better understand this
relationship, particularly in participants withoverweight or obesity.
Author Contributions:
N.A.K., C.N.C, and K.M.H analyzed the data. C.N.C., C.G.E., and S.V.T. were involved
in data collection. N.A.B., H.D.H., and N.A.K. conceived, designed, and acquired funding for the study. N.A.B
was responsible for blood sample collection. J.W.E.J. supervised serum carotenoid analyses. N.J.C. and K.M.H.
designed the spatial reconstruction task. All authors contributed to the writing of the manuscript draft.
Funding:
This work was supported by funds provided by the Department of Kinesiology and Community Health
at the University of Illinois and the USDA National Institute of Food and Agriculture, Hatch Project 1009249.
Partial support was also provided by the Hass Avocado Board.
Conflicts of Interest: The authors declare no conflict of interest.
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©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).
... Participants were provided with a diet record and instructed to record their dietary intake for 7 d by trained staff. Data were digitized and analyzed using the Nutrition Data System for Research (NDSR) 2015 (Minneapolis), identical to Cannavale et al. (35). ...
... Blood draws were collected in a fasted state, centrifuged for 5 minutes at 708 × g, serum removed and stored at −80 • C. Serum lutein and zeaxanthin were measured using HPLC, similar to Cannavale et al. (35). Three successive hexane extractions were utilized, similar to the methodology previously described by Jeon et al. (36). ...
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... For example, a higher dietary intake of lutein and/or zeaxanthin was associated with a lower risk of experiencing moderate-to-poor cognitive function in middle-aged women (12), better immediate and delayed word recall in older adults (13), and higher scores on several cognitivebased measures in adults over the age of 60 years (14). Moreover, higher plasma concentrations of lutein and/or zeaxanthin were associated with better cognitive function in older adults (15,16), visual-spatial functioning in older adults (17), and relational memory performance in young and middle-aged adults (18). Macular pigment optical density (MPOD), which provide a measure of lutein and zeaxanthin concentration in the brain (8,19), was also associated with better cognitive performance in older-age adults (16), adults with mild cognitive impairment (20), and in adults with age-related macular degeneration (21). ...
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... Lutein, as the antioxidant of the brain, is proposed to not only protect cognitive function but also improve cognitive performance [17][18][19][20][21]. Various observational studies have correlated MPOD to greater cognitive health [22][23][24][25][26], whereas others have examined the association between plasma lutein and better cognitive function [21,[27][28][29][30][31][32][33][34][35]. Clinical trials have expanded on these results and evaluated whether dietary lutein can improve brain health and cognitive function [18,[36][37][38][39][40][41][42][43][44][45][46]. ...
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... The shapes disappear, and after a short delay they appear at the top of the screen and the participant must drag each shape to the location in which it had appeared. In a recent study, performance on this task in overweight individuals was related to serum lutein (Cannavale et al., 2019). Because lutein is important for brain function and is reduced in individuals with obesity, these results suggest that this consequence of obesity may result in impaired hippocampal-dependent memory. ...
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Hippocampal involvement in learning and remembering relational information has an extensive history, often focusing specifically on spatial information. In humans, spatial reconstruction (SR) paradigms are a powerful tool for evaluating an individuals' spatial-relational memory. In SR tasks, participants study locations of items in space and subsequently reconstruct the studied display after a short delay. Previous work has revealed that patients with hippocampal damage are impaired both in overall placement accuracy as well as on a specific measure of relational memory efficacy, “swaps” (i.e. when the relative location of two items is reversed). However, the necessity of the hippocampus for other types of spatial-relational information involved in reconstruction behaviors (e.g. where in the environment and relative to which other items an item was located) have not yet been investigated systematically. In this work, three patients with hippocampal damage and nine healthy matched comparison participants performed an SR task. An analysis framework was developed to independently assess three first-order types of relations: 1) memory for the binding of specific item identities to locations, 2) memory for arrangement of items in relation to each other or the environment bounds, regardless of memory for the item identity, and 3) higher-order, compound relational errors (i.e. errors involving multiple pieces of relational information). Reconstruction errors were evaluated to determine the degree to which patients and comparisons differed (or not) on each type of spatial-relational information. Data revealed that the primary group difference in performance was for identity-location information. However, when the locations of items were evaluated without regarding the identities, no group difference was found in the number of item placements to studied locations. The present work provides a principled approach to analysis of SR data and clarifies our understanding of the types of spatial relations impaired in hippocampal damaged. This article is protected by copyright. All rights reserved.
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Background: Past studies have suggested that higher lutein (L) and zeaxanthin (Z) levels in serum and in the central nervous system (as quantified by measuring macular pigment optical density, MPOD) are related to improved cognitive function in older adults. Very few studies have addressed the issue of xanthophylls and cognitive function in younger adults, and no controlled trials have been conducted to date to determine whether or not supplementation with L + Z can change cognitive function in this population. Objective: The purpose of this study was to determine whether or not supplementation with L + Z could improve cognitive function in young (age 18–30), healthy adults. Design: A randomized, double-masked, placebo-controlled trial design was used. Fifty-one young, healthy subjects were recruited as part of a larger study on xanthophylls and cognitive function. Subjects were randomized into active supplement (n = 37) and placebo groups (n = 14). MPOD was measured psychophysically using customized heterochromatic flicker photometry. Cognitive function was measured using the CNS Vital Signs testing platform. MPOD and cognitive function were measured every four months for a full year of supplementation. Results: Supplementation increased MPOD significantly over the course of the year, vs. placebo (p < 0.001). Daily supplementation with L + Z and increases in MPOD resulted in significant improvements in spatial memory (p < 0.04), reasoning ability (p < 0.05) and complex attention (p < 0.04), above and beyond improvements due to practice effects. Conclusions: Supplementation with L + Z improves CNS xanthophyll levels and cognitive function in young, healthy adults. Magnitudes of effects are similar to previous work reporting correlations between MPOD and cognition in other populations.
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Introduction: Although diet has a substantial influence on the aging brain, the relationship between dietary nutrients and aspects of brain health remains unclear. This study examines the neural mechanisms that mediate the relationship between a carotenoid important for brain health across the lifespan, lutein, and crystallized intelligence in cognitively intact older adults. We hypothesized that higher serum levels of lutein are associated with better performance on a task of crystallized intelligence, and that this relationship is mediated by gray matter structure of regions within the temporal cortex. This investigation aims to contribute to a growing line of evidence, which suggests that particular nutrients may slow or prevent aspects of cognitive decline by targeting specific features of brain aging. Methods: We examined 75 cognitively intact adults between the ages of 65 and 75 to investigate the relationship between serum lutein, tests of crystallized intelligence (measured by the Wechsler Abbreviated Scale of Intelligence), and gray matter volume of regions within the temporal cortex. A three-step mediation analysis was implemented using multivariate linear regressions to control for age, sex, education, income, depression status, and body mass index. Results: The mediation analysis revealed that gray matter thickness of one region within the temporal cortex, the right parahippocampal cortex (Brodmann’s Area 34), partially mediates the relationship between serum lutein and crystallized intelligence. Conclusion: These results suggest that the parahippocampal cortex acts as a mediator of the relationship between serum lutein and crystallized intelligence in cognitively intact older adults. Prior findings substantiate the individual relationships reported within the mediation, specifically the links between (i) serum lutein and temporal cortex structure, (ii) serum lutein and crystallized intelligence, and (iii) parahippocampal cortex structure and crystallized intelligence. This report is the first to demonstrate a specific structural mediation between lutein status and crystallized intelligence, and therefore provides further evidence that specific nutrients may slow or prevent features of cognitive decline by hindering particular aspects of brain aging. Future work should examine the potential mechanisms underlying this mediation, including the antioxidant, anti-inflammatory, and membrane modulating properties of lutein.
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Lutein slows the progression of age-related macular degeneration (AMD), a leading cause of blindness in ageing societies. However, the underlying mechanisms remain elusive. Here, we evaluated lutein’s effects on light-induced AMD-related pathological events. Balb/c mice exposed to light (2000 lux, 3 h) showed tight junction disruption in the retinal pigment epithelium (RPE) at 12 h, as detected by zona occludens-1 immunostaining. Substantial disruption remained 48 h after light exposure in the vehicle-treated group; however, this was ameliorated in the mice treated with intraperitoneal lutein at 12 h, suggesting that lutein promoted tight junction repair. In the photo-stressed RPE and the neighbouring choroid tissue, lutein suppressed reactive oxygen species and increased superoxide dismutase (SOD) activity at 24 h, and produced sustained increases in sod1 and sod2 mRNA levels at 48 h. SOD activity was induced by lutein in an RPE cell line, ARPE19. We also found that lutein suppressed upregulation of macrophage-related markers, f4/80 and mcp-1, in the RPE-choroid tissue at 18 h. In ARPE19, lutein reduced mcp-1 mRNA levels. These findings indicated that lutein promoted tight junction repair and suppressed inflammation in photo-stressed mice, reducing local oxidative stress by direct scavenging and most likely by induction of endogenous antioxidant enzymes.