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DFA: EPA/DHA and Cognitive Health (2011)

Citation:
 
Study Design:
Class:
- Click here for explanation of classification scheme.
Quality Rating:
Research Purpose:

To investigate whether supplementation with n-3 (omega-3) long-chain polyunsaturated fatty acids (LC PUFAs) would improve cognitive function in cognitively healthy older adults. A 700mg n-3 LC PUFAs supplement was compared to an olive oil placebo over 24 months.

Inclusion Criteria:
  • Aged 70 to 79 years at baseline
  • Completed informed, written consent.
Exclusion Criteria:
  • Current diagnosis of diabetes or dementia
  • Recent bereavement
  • Terminal illness
  • Use of daily fish oil supplements
  • Mini-Mental State Examination (MMSE) score less than 24.
Description of Study Protocol:

Recruitment

Recruitment was from general practices across England and Wales from the Medical Research Council General Practice Research Framework. Individuals that were eligible were invited after being selected from lists in random blocks.

Design

Randomization was used to assign participants to one of two groups, fish oil or placebo. A central computerized randomization service was used to obtain treatment-allocation codes. To ensure balance across trial arms randomization was minimized by general practice and age group (70 to 74 and 75 to 79 years). Participants received daily capsules (EPA and DHA or olive oil) over 24 months. Cognitive function was assessed at baseline and 24 months by several tests.

Blinding Used

Group assignments were not disclosed to study staff until after completion of the trial and data analysis. Supplements were packaged by staff not involved in the study.

Intervention

Participants received two soft gel capsules daily (dark brown-colored, vanilla flavored, 650mg) consisting of either:

  • Avtive arm: 200mg eicosapentaenoic acid (EPA) and 500mg docosahexaenoic acid (DHA); 20:50 ethyl ester; Ocean Nutrition Canada Ltd., Canada
  • Placebo arm: Olive oil (rich in n-9 fatty acids).

 Statistical Analysis

  • 332 individuals in each group were required for 90% power and 1% significance (two-sided). Accounting for a 20% dropout rate, the total sample size needed for the study was calculated to be 798.
  • Intention-to-treat analysis included those participants who discontinued supplementation, but completed cognitive assessment tests at 24 months
  • Baseline cognitive function scores, age, sex, and age at leaving full-time education were covariates for the analysis of covariance model
  • Cognitive domains (global cognitive function, memory, processing speed, executive function and global delay score) were created by grouping Z scores from pooled secondary cognitive outcomes. 
Data Collection Summary:

Timing of Measurements

  • At baseline, demographic and medical information was collected (educational history, habitual fish consumption and five-year history of stroke and myocardial infarction. At baseline and 24 months, height, weight, blood pressure and a 30-item General Health Questionnaire (GHQ) were recorded. Several cognitive tests were performed both at baseline and 24 months. Tests were performed at general practice offices. These included:
    • Test of memory of a 16-item word list from the California Verbal Learning Test (sum of words recalled after three repeats of the list and number of words recalled after a 20-minute delay)
    • Short story recalls, delayed and immediate from the Wechsler Memory Scale
    • Spacial memory test
    • Processing speed tests (letter search and cancelation, symbol letter modality test and measure of simple and choice reaction time)
    • Executive function tests (digit span backward from the Weschsler adult intelligence scale and verbal fluency)
    • Prospective memory test
    • Digit span forward test
  • Three-month follow-up appointments were performed. At these appointments, adherence was measured by count of return capsules, minor adverse events were recorded and medical records were reviewed for deaths, hospital admissions, stroke or MI.

Dependent Variables

  • Changes within and between fish oil and olive oil groups in test scores between baseline and 24 months:
    • California Verbal Learning Test (CVT); total words correct in first three trials; words recalled at delayed recall
    • Global cognitive function Z scores
    • Memory Z score
    • Processing Z score
    • Executive function Z score
    • Global delay Z score
  • Changes within groups in secondary cognitive function tests between baseline and 24 months:
    • Memory:
      • Story recall: Immediate and delayed number of story items recalled
      • Spatial memory: Immediate and delayed number of correct images
    • Processing speed: Letter search/cancelation and symbol letter modality
    • Reaction time: Simple and choice
    • Executive function:
      • Digit span: Forward and backward number of correct sequences
      • Verbal fluency: Number of animals named.

Independent Variables

Fish oil  and placebo groups.

Control Variables

  •  Adherence to the supplementation intervention:
    • Measured by median proportion of capsules returned at follow-up visits
    • Serum fatty acid concentrations were measured at 24 months. Fatty acids measured were: 16:0, 16:1, 18:0, 18:1n-9, 18:2n-6, 18:3n-3, 20:3n-6, 20:4n-6, 20:5n-3, 22:4n-6, 22:5n-6, 22:5n-3, 22:6n-3
  • Baseline cognitive function scores, age, sex and age at leaving full-time education were covariates for the analysis of covariance model.
Description of Actual Data Sample:
  • Initial N:
    • 867
    • Fish oil: N=434 (53.4% men)
    • Placebo: N=433 (56.6% men)
  • Attrition (final N):
    • Fish oil: N=376 included in analysis (375 with cognitive function data)
    • Placebo: N=372 included in analysis (369 with cognitive function data)
    • Numbers for withdrawals and deaths were similar between trial arms
  • Age:
    • Mean age: Fish oil = 74.7±2.5 years; placebo = 74.6±2.7 years
    • Percentage 70 to 74 years: Fish oil = 56.5%; placebo = 58.3%
    • Percentage 75 to 79 years: Fish oil = 43.5 %; placebo = 41.7%
  • Ethnicity: Residents of England and Wales
  • Other relevant demographics:
    • Age at leaving full-time education: Fish oil = 16±3.0 years; placebo = 16±2.6 years
    • GHQ-30 score of five or more: Fish oil = 20.1%; placebo = 16.7% (GHQ-30 of five or more is cutoff for possible common mental disorders).
Frequency and Type of Fish Consumption (Percentage) Fish Oil Placebo
Once a month or less 8.6 7.9
Once a week per fortnight, mainly white 34.3 32.9
More than once a week, mainly white 28.9 30.8
Once a week per fortnight, mainly oily 12.0 11.3
More than once a week, mainly oily 16.2 17.1
  • Anthropometrics: BMI with fish oil = 26.5kg/m2; with placebo = 27.7kg/m2
  • Location: 20 general practices in England and Wales.
Summary of Results:

Key Findings

  • Baseline CVT scores:
    • Total words recalled immediately: Fish oil = 22.8±6.3; placebo = 24.0±6.3
    • Words for delayed recall: Fish oil = 6.9±3.0; placebo = 6.9±3.2
  • Changes in cognitive function domain Z scores were not observed in either group over 24 months
  • Significant differences in cognitive function were also not observed between the trial arms
  • Significant changes in secondary cognitive function tests over 24 months were not observed.

Other Findings

  • Minor adverse events were similar across treatment arms, fish oil vs. placebo, respectively:
    • Flatulence: 4.6% vs. 3.0%
    • Belching: 4.8% vs. 3.0%
    • Abdominal discomfort: 2.5% vs. 3.9%
    • Loose stools: 3.5% vs. 2.5%
    •  Other: 5.5% vs. 4.6%
  • Adherence to the supplementation intervention did not differ between groups as measured by returned capsules
  • Serum measurements:
    • At 24 months n-3 LC PUFAs EPA and DHA were significantly higher in fish oil group than in placebo group
    • Mean serum EPA: Fish oil = 49.9±2.7mg per L; placebo = 39.1±3.1mg per L (P=0.009) 
    • In the olive oil group, serum concentrations were higher in 16:1 (P=0.14); 18:1n-9 (P=0.62); 20:n3-6 (P=0.004); 20:4n-6 (P<0.001) than in the fish oil group. 
Author Conclusion:

The authors concluded that the trial did not show beneficial effects on cognitive function as a result of fish-oil supplementation. Cognitive function scores did not change and did not decline in either study arm over the intervention period. The authors suggest that future trials include longer treatment or follow-up periods, participants with mild cognitive impairments or populations with lower fish consumption.

Funding Source:
Government: UK Food Standards Agency; UK National Health Service Research and Development
Reviewer Comments:
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) Yes
  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) Yes
 
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? Yes
  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? Yes
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? 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? Yes
  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? N/A
  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? Yes
  6.2. In observational study, were interventions, study settings, and clinicians/provider described? N/A
  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? Yes
  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? Yes
  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)? Yes
  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