EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To determine if carotenoids have a role in preventing cognitive impairment due to their antioxidant properties.

Inclusion Criteria:

Participants from the Etude du Vieillissement Artériel (EVA) longitudinal study wave 6.

Exclusion Criteria:

Participants of EVA wave 6 that did not provide a blood sample and a cognitive evaluation.

Description of Study Protocol:

Recruitment

EVA is a nine-year longitudinal study with six waves of follow-up. Participants born between 1922 and 1932 residing in the town of Nantes, Eastern France, were recruited from electoral rolls and via information campaigns.

Design

Cross-sectional analysis of a cohort study.

Blinding Used

Implied with measurements.

Statistical Analysis

The characteristics of the participants included in the analysis were described compared to the participants in EVA who had the blood sampling, but not the cognitive evaluation at EVA6. These results were expressed as percentages and means with their standard deviation (SD). To test the differences between the two groups, the Chi-square test and the Student T-test were used.
To calculate the correlation between carotenoids, Pearson correlation coefficients on log-transformed carotenoids were used.
Because the graphic representation of the percentage of participants with low cognitive functioning for the different carotenoid levels showed the relationship between cognition and biological variables was not linear, they were considered categorical variables
The characteristics of participants in the different levels of carotenoids (less than 25th percentile vs. 25th or more percentile) were compared by using the Student T-test or the Chi-square test for both continuous and categorical variables
Two cutoffs were used to define participants with the lowest cognitive performance in this well-educated cohort (participants with scores below the 25th percentile and participants who had cognitive scores below the 10th percentile)
Classical multivariate logistic regressions were performed to test associations between probability of participants to have the lowest cognitive functioning and levels of plasma carotenoids (less than 25th percentile vs. more than 25th percentile), adjusting for all potential confounding factors
Results were expressed as odds ratios (OR) with their 95% confidence intervals (CI).

Data Collection Summary:

Timing of Measurements

June 2000 to December 2001.

Dependent Variables

Mini-Mental State Examination (MMSE)
Digit Symbol Substitution (DSS)
Trail Making Test Part A (TMTA)
Trail Making Test Part B (TMTB)
Word Fluency Test (WFT)
Finger Tapping Test (FTT).

Independent Variables

Plasma carotenoid levels:

Lutein
Zeaxanthin
β-cryptoxanthin
Lycopene
α-carotene
trans-β-carotene
cis-β-carotene
Total carotenoids.

Control Variables

Sex
Age
Education
Smoking status
Alcohol consumption
Medicine consumption
Body mass index (BMI)
Diabetes
Dyslipidemia
Hypertension
Cardiovascular disease
APOE ε4 carrier
Depressive symptomatology.

Description of Actual Data Sample:

Initial N: 1,389
Attrition (final N): 589
Age: 73.55±2.93
Ethnicity: French.

Other Relevant Demographics

Women	61%
Well-educated	52.1%
Smokers or ex-smokers	39%
Consumed alcohol regularly	24%
Depressive symptomatology	8.3%
Diabetic	8.1%
Dyslipidemic	65%
Hypertension	78.8%
History of cardiovascular disease	19.7%
At least one allele ε4	20.5%

Anthropometrics

Underweight	13.8%
Overweight	34%
Obese	8.5%

Location

Nantes, France.

Summary of Results:

Key Findings

Plasma carotene were highly and significantly intercorrelated. The highest correlations were found among the following carotenes:

*α-carotene/trans-ß-carotene*	R=0.78
trans-β-carotene/cis-ß-carotene	R=0.61
α-carotene/lycopene	R=0.6
lutein/zeaxanthin	R=0.58

Various relationships were found between carotene and profile factors:

The profile factors associated with α-carotene, trans-β-carotene and cis-β-carotene were identical
Gender was associated with all carotene with the exception of zeaxanthin, which reached higher levels in women
Smoking status and alcohol consumption were significantly associated with lower levels of total plasma carotene, β-cryptoxanthin, α-carotene and trans- and cis-β-carotene
Diabetes was associated with low levels of all carotene and hypertension was significantly associated with low levels of lutein, α-carotene and trans- and cis-β-carotene
Being obese or overweight was associated with low levels of all carotene except for zeaxanthin and β-cryptoxanthin
Age, education, depressive symptomatology, dyslipidemia, history of cardiovascular disease and apolipoprotein E genotype were not associated with any plasma carotene.

Association Between Cognition and Carotenoids

Participants with the lowest cognitive performance had a higher probability of having low levels of some carotene. Significant associations were observed between zeaxanthin and all cognitive tests except the MMSE:

	OR	CI
TMTA	1.66	1.08 to 2.55
TMTB	1.60	0.04 to 2.44
DSS	1.87	1.21 to 2.89
FTT	1.7	1.1 to 2.62
WFT	1.87	1.16 to 3.0

Low levels of lycopene were associated with low performance on the TMTB (OR=1.76; CI=1.16 to 2.67) and on the DSS (OR=2.02; CI=1.32 to 3.11)
A significant association was found between low performance on the TMTB and low levels of total plasma carotene and trans-β-carotene (OR=1.57; CI=1.03 to 2.40] and OR=1.58; CI=1.04 to 2.41)
After taking into consideration sociodemographic factors (sex, age, education) and consumption habits (tobacco, alcohol), diabetes, hypertension and BMI, class associations between zeaxanthin and cognitive tests remained statistically significant for the following:

	OR	CI
TMTA	1.67	1.06 to 2.66
DSS	1.92	1.18 to 3.14
FTT	1.69	1.05 to 2.72
WFT	1.8	1.07 to 3.05

Lycopene remained associated with the TMTB (OR=1.54; CI=0.97 to 2.43] and the DSS (OR=1.85; CI=1.14 to 2.98).

Sensitivity Analysis

When the analyses between cognitive performance and carotenoid levels were repeated using only those subjects with scores below the 10th percentile only the following associations were found:
- Zeaxanthin and FTT (P=0.003) and TMTB (P=0.06)
- Lycopene and DSS (P=0.07)
When Spearmen correlation coefficients between cognitive variables and log-transformed carotene were completed the following significant associations were found:
- Zeaxanthin and lycopene and DSS (R=0.08, P=0.01 and R=0.11, P=0.006)
- TMTA (R=-0.11, P=0.01 and R=-0.08, P=0.05)
- TMTB (R=-0.08, P=0.05 and R=-0.12 and P=0.004)
- FTT (R=0.09, P=0.04 and R=0.09, P=0.04).

Author Conclusion:

The EVA study included volunteers with higher educational status, higher incomes and greater cognitive function than the average elderly French population. Despite this selection, plasma carotenoid concentrations in the EVA study population were in the same ranges as those in different European or American populations. In this present study, low levels of specific plasma carotenoids, lycopene and zeaxanthin were associated with poor cognitive functioning in a highly educated, community dwelling population. It is impossible to know if the association between carotenoids and cognitive function is the result of a specific effect of carotenoids or if it is the result of the combined effects of the different fruit and vegetable compounds.
Although there were important correlations among all carotenoids, significant associations were found between low cognitive performances and some (but not all) carotenoids. More specifically, there were no associations between β-carotenes (trans or cis) or α-carotene, which are the most studied carotenoids in epidemiological literature on cognitive impairment. These studies show conflicting results. These discrepancies can be explained by methodological differences. Many epidemiological studies have associated high carotenoid status with a decrease in the incidence of chronic diseases (heart and cancer); the biological mechanism for such protection is currently unclear.
The biological significance of these findings need further research by biological studies, longitudinal epidemiological studies and by specific clinical trials with carotenoid supplements.

Funding Source:

Government:

INSERM

Industry:

Merck, Sharp and Dohme-Chibret Laboratories, EISAI Laboratory

Pharmaceutical/Dietary Supplement Company:

Not-for-profit

French Alzheimer's Disease Asssociation

Foundation associated with industry:

Reviewer Comments:

The authors note the following limitation:

The results on the relationship between carotenoids and cognitive performance were not modified when the participants with BMI less than 21, for which the hypothesis of undernutrition was probable were excluded. This finding suggests that this relationship could not be limited by the influence of undernourished participants. In this cross-sectional framework, it is not possible to affirm whether these low levels of carotenoids preceded or were the consequence of cognitive impairment in a context where poor cognitive status may be a risk factor for poor nutrition.
The full inclusion and exclusion criteria for the EVA study was not provided in this article. The participants in the EVA study had a higher education, higher incomes and greater cognitive function than the average elderly French population.

Quality Criteria Checklist: Primary Research
Relevance Questions
	1.	Would implementing the studied intervention or procedure (if found successful) result in improved outcomes for the patients/clients/population group? (Not Applicable for some epidemiological studies)	N/A
	2.	Did the authors study an outcome (dependent variable) or topic that the patients/clients/population group would care about?	Yes
	3.	Is the focus of the intervention or procedure (independent variable) or topic of study a common issue of concern to dieteticspractice?	Yes
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	N/A

Validity Questions
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
2.	Was the selection of study subjects/patients free from bias?		No
	2.1.	Were inclusion/exclusion criteria specified (e.g., risk, point in disease progression, diagnostic or prognosis criteria), and with sufficient detail and without omitting criteria critical to the study?	No
	2.2.	Were criteria applied equally to all study groups?	N/A
	2.3.	Were health, demographics, and other characteristics of subjects described?	Yes
	2.4.	Were the subjects/patients a representative sample of the relevant population?	No
3.	Were study groups comparable?		N/A
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	N/A
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	N/A
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	N/A
	3.4.	If cohort study or cross-sectional study, were groups comparable on important confounding factors and/or were preexisting differences accounted for by using appropriate adjustments in statistical analysis?	N/A
	3.5.	If case control study, were potential confounding factors comparable for cases and controls? (If case series or trial with subjects serving as own control, this criterion is not applicable.)	N/A
	3.6.	If diagnostic test, was there an independent blind comparison with an appropriate reference standard (e.g., "gold standard")?	N/A
4.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	Yes
	4.2.	Was the number, characteristics of withdrawals (i.e., dropouts, lost to follow up, attrition rate) and/or response rate (cross-sectional studies) described for each group? (Follow up goal for a strong study is 80%.)	Yes
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	Yes
	4.5.	If diagnostic test, was decision to perform reference test not dependent on results of test under study?	N/A
5.	Was blinding used to prevent introduction of bias?		Yes
	5.1.	In intervention study, were subjects, clinicians/practitioners, and investigators blinded to treatment group, as appropriate?	N/A
	5.2.	Were data collectors blinded for outcomes assessment? (If outcome is measured using an objective test, such as a lab value, this criterion is assumed to be met.)	Yes
	5.3.	In cohort study or cross-sectional study, were measurements of outcomes and risk factors blinded?	Yes
	5.4.	In case control study, was case definition explicit and case ascertainment not influenced by exposure status?	N/A
	5.5.	In diagnostic study, were test results blinded to patient history and other test results?	N/A
6.	Were intervention/therapeutic regimens/exposure factor or procedure and any comparison(s) described in detail? Were interveningfactors described?		Yes
	6.1.	In RCT or other intervention trial, were protocols described for all regimens studied?	N/A
	6.2.	In observational study, were interventions, study settings, and clinicians/provider described?	Yes
	6.3.	Was the intensity and duration of the intervention or exposure factor sufficient to produce a meaningful effect?	Yes
	6.4.	Was the amount of exposure and, if relevant, subject/patient compliance measured?	N/A
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	N/A
	6.6.	Were extra or unplanned treatments described?	N/A
	6.7.	Was the information for 6.4, 6.5, and 6.6 assessed the same way for all groups?	N/A
	6.8.	In diagnostic study, were details of test administration and replication sufficient?	N/A
7.	Were outcomes clearly defined and the measurements valid and reliable?		Yes
	7.1.	Were primary and secondary endpoints described and relevant to the question?	Yes
	7.2.	Were nutrition measures appropriate to question and outcomes of concern?	Yes
	7.3.	Was the period of follow-up long enough for important outcome(s) to occur?	N/A
	7.4.	Were the observations and measurements based on standard, valid, and reliable data collection instruments/tests/procedures?	Yes
	7.5.	Was the measurement of effect at an appropriate level of precision?	Yes
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	N/A
8.	Was the statistical analysis appropriate for the study design and type of outcome indicators?		Yes
	8.1.	Were statistical analyses adequately described and the results reported appropriately?	Yes
	8.2.	Were correct statistical tests used and assumptions of test not violated?	Yes
	8.3.	Were statistics reported with levels of significance and/or confidence intervals?	Yes
	8.4.	Was "intent to treat" analysis of outcomes done (and as appropriate, was there an analysis of outcomes for those maximally exposed or a dose-response analysis)?	N/A
	8.5.	Were adequate adjustments made for effects of confounding factors that might have affected the outcomes (e.g., multivariate analyses)?	Yes
	8.6.	Was clinical significance as well as statistical significance reported?	Yes
	8.7.	If negative findings, was a power calculation reported to address type 2 error?	N/A
9.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	Yes
10.	Is bias due to study's funding or sponsorship unlikely?		???
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	???