EAL

FNOA: Antioxidants (2011-2012)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

To examine the sex-specific associations of plasma concentrations of iron, copper, and zinc with cognitive function in older community-dwelling adults.

Inclusion Criteria:

Men and women who were community-dwelling and not clinically demented
Residents of the predominantly white, middle-class Southern California community of Rancho Bernardo
Aged 60 years and older.

Exclusion Criteria:

Subjects who declined all cognitive function tests or had missing plasma mineral assays
Subjects with extreme plasma mineral values.

Description of Study Protocol:

Recruitment

Between 1972 and 1974, 82% of all residents of the predominantly white, middle-class Southern California community of Rancho Bernardo were surveyed for heart disease risk factors
In 1988 and 1992, a follow-up clinic visit included blood collection and assessment of cognitive function.

Design

Cross-sectional study

Blinding used

Implied with measurements

Intervention

Not applicable

Statistical Analysis

Means and standard deviations were calculated for continuous variables including trace elements, which were approximately normally distributed
Rates were calculated for categorical variables
Comparisons between men and women were made using T-tests for continuous data and chi-square tests for categorical data
Because of known sex differences in cognitive function, analyses were sex-specific; potential confounders were included only if their inclusion changed beta estimates by >10% for at least one mineral
Linear and quadratic terms for trace elements were examined; quadratic terms were included in models only if they were statistically significant
Trace element variables were also categorized into low, medium and high levels using classification and regression tree (CART) analysis to determine optimal cut-offs.

Data Collection Summary:

Timing of Measurements

In 1988 and 1992, a follow-up clinic visit included blood collection and assessment of cognitive function.

Dependent Variables

Cognitive function tests with established reliability and validity:
- Buschke-Fuld Selective Reminding Test
- Heaton Visual Reproduction Tests
- Mini-Mental State Examination
- Blessed Information-Memory-Concentration Test
- Trails B from the Halstead-Reitan Neuropsychological Test Battery
- Category Fluency.

Independent Variables

Plasma trace elements (iron, copper and zinc) measured through analysis of blood samples

Control Variables

The following were assessed through self-administered questionnaire:

Age
Education
Alcohol consumption
Smoking
Exercise
Estrogen use in women.

Description of Actual Data Sample:

Initial N: 909 women and 629 men, representing 80% of the surviving cohort
Attrition (final N): 1,451 participants in the analysis
- 602 men
- 849 women
Age: Mean age 75±8 years
Ethnicity: Predominantly White
Other relevant demographics:
- 78% of men and 63% of women had attended some college or more (P<0.001)
Anthropometrics: Not reported
Location: Southern California.

Summary of Results:

Key Findings

Men and women differed significantly in education, exercise and alcohol intake (all P<0.001), concentrations of plasma iron, copper and zinc (all P<0.001), and scores on 11 of 12 cognitive function tests (P values ranging from 0.04 to<0.001)
Regression analyses showed significant inverted U-shaped associations in men—both low and high iron levels were associated with poor performance on total and long-term recall and Serial 7's (P=0.018, 0.042 and 0.004, respectively) compared to intermediate concentrations
In women, iron and copper concentrations had inverse linear associations with Buschke total, long and short-term recall and Blessed scores (P<0.05)
Zinc was positively associated with performance on Blessed items in women (P=0.008) but not any cognitive function scores in men
Analyses comparing cognitive function using categorically defined mineral concentrations yielded similar sex-specific results.

	Cognitive Function Score	Categorical Trace Mineral Concentration	β	P-value
Men	Total Recall	Low iron vs. intermediate	-1.05	<0.001
		High iron vs. intermediate	-0.53	0.072
	Long-term Recall	Low iron vs. intermediate	-0.94	<0.001
		High iron vs. intermediate	-0.69	0.020
	Serial 7's	Low iron vs. intermediate	-1.05	0.001
		High iron vs. intermediate	-0.51	0.133
	Trials B	Intermediate copper vs. low	-0.05	0.489
Women	Total Recall	Intermediate iron vs. low	0.02	0.953
		High iron vs. low	-0.55	0.228
	Long-term Recall	Intermediate iron vs. low	0.07	0.826
		High iron vs. low	-0.51	0.266
	Blessed Items	Intermediate iron vs. low	-0.60	0.097
		High iron vs. low	-0.77	0.118
	Total Recall	Intermediat copper vs. low	-0.01	0.915
		High copper vs. low	-0.63	0.076
	Long-term Recall	Intermediate copper vs. low	-0.04	0.756
		High copper vs. low	-0.77	0.031
	Short-term Recall	Intermediate copper vs. low	0.01	0.979
		High copper vs. low	-0.80	0.032
	Blessed Items	Low zinc vs. high	-0.31	0.313
		Intermediate zinc vs. high	-0.10	0.578

Author Conclusion:

Both deficiencies and excesses of trace elements may be potentially preventable causes of cognitive impairment. This study found significant associations between trace elements and cognitive function; it is the first study to demonstrate sex-specific differences in associations, possibly due to sex differences in mineral concentrations and nutritional requirements. Other studies longitudinally examining sex-specific associations are needed to confirm these results.

Funding Source:

Government:

National Institute on Aging

Reviewer Comments:

Subjects were predominantly white, relatively well-educated and middle-class, not necessarily representative of all older adults. Authors note the following:

Homogeneous nature of the cohort reduces confounding effects of education and socioeconomic status on cognitive function and nutritional status
Higher iron and zinc concentrations in men are consistent with their higher meat consumption; the difference in association between iron and cognition for men and women may indicate that men require more iron than women, and the lower iron concentrations may reflect deficient levels for men but not for women
Cross-sectional design.

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?		???
	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?	Yes
	2.2.	Were criteria applied equally to all study groups?	Yes
	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?	???
3.	Were study groups comparable?		Yes
	3.1.	Was the method of assigning subjects/patients to groups described and unbiased? (Method of randomization identified if RCT)	Yes
	3.2.	Were distribution of disease status, prognostic factors, and other factors (e.g., demographics) similar across study groups at baseline?	Yes
	3.3.	Were concurrent controls or comparisons used? (Concurrent preferred over historical control or comparison groups.)	Yes
	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?	Yes
	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.)	Yes
	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?	N/A
	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?	Yes
	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?	Yes
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?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes