EAL

DFA: EPA/DHA and Cognitive Health (2011)

Citation:

Study Design:

Class:

- Click here for explanation of classification scheme.

Quality Rating:

Research Purpose:

The purpose of this study was to assess the effects of ω3 supplementation on behavioral and psychiatric symptoms and daily functions in Alzheimer's disease (AD) patients. The relationship between the ApoE4 genotype and supplementation was also examined.

Inclusion Criteria:

Alzheimer's disease diagnosis
Mini-Mental State Exam (MMSE) between 15-30
Living in own homes
Taking stable dose of acetylcholine esterase inhibitors for at least three months
Both patients and caregivers completed written informed consent.

Exclusion Criteria:

Those treated with NSAID (low-dose acetlysalicylic acid was accepted), omega-3 fatty acids or anti-coagulants
Alcohol abusers
Those suffering from another serious disease
No caregiver.

Description of Study Protocol:

Recruitment

Not described

Design

Double blind randomized placebo-controlled study
Randomization was via sealed envelopes in blocks of four
Participants were assigned to receive either a DHA/EPA supplement or a placebo oil. This treatment continued for six months and was followed by a six month treatment of the DHA/EPA supplement in all participants.
Neuropsychiatric symptoms, depressive symptoms, caregiver burden, and activities of daily living were assessed at baseline, six and 12 months
APOE genotype was determined using standard methods. Serum fatty acids were analyzed.

Blinding used

Double blind

Intervention

For six months, participants received four one-gram capsules each day containing either:
- 430mg DHA and 150mg EPA (EPAX1050TG, Pronova Biocare A/S, Lysaker, Norway); ω3 group
- Isocaloric placebo oil (one gram of corn oil, including 0.6g of linoleic acid); placebo group
After the first six months of supplementation, all participants received another six months of treatment with the DHA/EPA supplement
The study groups are noted as ω3/ω3 and placebo/ω3
EPAX1050TG: 60% ω3 concentrate in triglyceride form
4mg vitamin E added to both placebo and EPAX1050TG capsules.

Statistical Analysis

Repeated measures ANOVA were used to assess longitudinal changes in Neuropsychiatric Inventory (NPI), Montgomery Åsberg Depression rating scale (MADRS), caregiver burden, and Disability Assessment for Dementia scale (DAD)
Mann-Whitney U test were used for inter-group analyses of skewed variables
Treatment effect was controlled for gender and APOE frequency using general regression models, when analyzing changes over time.

Data Collection Summary:

Timing of Measurements

Study occurred between December 2000 and March 2004
Psychiatric and behavioral symptoms, activities of daily living and caregiver burden were assessed at baseline, six and 12 months.

Dependent Variables

Neuropsychatric Inventory (NPI): Used to assess neuropsychiatric symptoms; total score is sum of 12 behavioral domains. High symptoms correspond to a high number of points; completed by caregivers. NPI domains: Delusions, hallucinations, agitation, depression, anxiety, euphoria, apathy, disinhibition, irritability, aberrant motor behaviors, night time behavior, appetite.
Montgomery Åsberg Depression rating scale (MADRS): Scored zero to 30 points; higher points indicate more symptoms
Caregivers burden scale (CGB): Used to evaluate caregiver burden with three items from scale (emotional overload, economic overload, caregiver feels himself captured in role)
Activities of daily living: rated by Disability Assessment for Dementia Scale (DAD)
An experienced geriatrician and psychiatrist performed the assessments.

Independent Variables

ω3/ω3 vs. placebo/ω3 group

Control Variables

Age
Gender
APOE genotype.

Description of Actual Data Sample:

Initial N: 204
- ω3 group: N=103
- Placebo group: N=101
Attrition (final N): 174
- ω3/ω3: N=89; 57% female
- placebo/ω3: N=85; 46% female
Age:
- ω3/ω3: 72.6±9.0
- Placebo/ω3: 72.9±8.6
Ethnicity: Not described

Other relevant demographics:

	ω3/ω3	placebo/ω3
MMSE score	23.6 (22.8-24.4)	23.2 (22.4-24.0)
ApoEε4 (N, percent)
0 allele	21 (23)	28 (33)
1 allele	46 (52)	39 (46)
2 alleles	22 (25)	18 (21)
Anti-depressant use	45%	38% (P=0.36)
Neuroleptic use	10%	6 % (P=0.31)
Smoking	10%	9%

Most participants had AD at the mild stage
Stable dosages of AChEIs were maintained in all patients throughout the study
Anthropometrics: Not described
Location: Not described.

Summary of Results:

Key Findings

NPI scores (0-144 points):

Low total scores were observed in both groups at baseline:
- ω3/ω3: Mean=15.6, 95% CI=12.9-18.2
- Placebo/ω3: Mean=14.9, 95% CI=12.1-17.7
No significant difference in NPI were observed between the two groups over six and 12 months (P=0.52)
The 12 different NPI domains were examined
- Score changes in hallucination in favor of treatment were observed at zero to six months (P=0.04); this effect normalized over six to 12 months when both groups were receiving ω3 supplements (P=0.11)
- Score changes in irritation were shown in favor of the placebo at zero to six months (P=0.008); this effect normalized over six to 12 months when both groups received the ω3 supplement (P=0.94)
When age, APOE genotype and gender were controlled for, the only effect on neuropsychiatric symptoms observed was in the agitation domain. A significant positive treatment effect was observed in subjects with the APOEω4 allele (N=57) compared to the placebo/ω3 group (N=68); P=0.0006
A correlation was not observed between DHA and EPA serum levels and total NPI scores at baseline, six and 12 months.

Depressive symptoms:

No significant differences were observed in MADRS scores in either group at zero to six and six to 12 months (P=0.49)
No significant differences were observed in NPI depressive domain scores in either group at zero to six months and six to 12 months (P=0.84)
An interaction effect between treatment and APOE on MADRS was observed; non-APOEω4 carriers in the ω3/ω3 group (N=27) showed significant decrease in MADRS scores between zero to six months compared to non-carriers (N=18) receiving placebo (P=0.005)

DAD scores: No significant differences were observed between the two groups in DAD score change at zero to six months.

Caregiver burden: No significant differences were observed between the two groups in the three items of care givers burden at zero to six months.

Author Conclusion:

In participants with mild to moderate AD, EPA/DHA supplementation over six months did not impact neuropsychiatric symptoms, behavior or functional ability. Possible positive effects on depressive symptoms in non-APOEω4 carriers and agitation symptoms in APOEω4 carriers were observed. Based on this study the authors conclude that "no recommendations on ω3 treatment on neuropsychiatric symptoms in AD can be advised." The authors recommend future studies, including patients with moderate to severe AD that express prominent neuropsychiatric symptoms and future exploration of relation of ω3 fatty acids to APOE status.

Funding Source:

Not-for-profit

Funds of Capio, Demensforbundet, Gamla Tjanorinnor, Swedish Alzheimer Foundation, Odd Fellow, Swedish Society of Physicians and Lion's Sweden

Other:

Pronova Biocare A/S, Lysaker, Norway

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
	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
	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
	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
	4.	Is the intervention or procedure feasible? (NA for some epidemiological studies)	Yes

Validity Questions
	1.	Was the research question clearly stated?	Yes
1.	Was the research question clearly stated?		Yes
	1.1.	Was (were) the specific intervention(s) or procedure(s) [independent variable(s)] identified?	Yes
	1.1.	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
	1.2.	Was (were) the outcome(s) [dependent variable(s)] clearly indicated?	Yes
	1.3.	Were the target population and setting specified?	Yes
	1.3.	Were the target population and setting specified?	Yes
	2.	Was the selection of study subjects/patients free from bias?	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
	2.1.	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
	2.2.	Were criteria applied equally to all study groups?	Yes
	2.3.	Were health, demographics, and other characteristics of subjects described?	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
	2.4.	Were the subjects/patients a representative sample of the relevant population?	Yes
	3.	Were study groups comparable?	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
	3.1.	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
	3.2.	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
	3.3.	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
	3.4.	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
	3.5.	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
	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.	Was method of handling withdrawals described?		Yes
	4.1.	Were follow-up methods described and the same for all groups?	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
	4.2.	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
	4.3.	Were all enrolled subjects/patients (in the original sample) accounted for?	Yes
	4.4.	Were reasons for withdrawals similar across groups?	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
	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.	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
	5.1.	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
	5.2.	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
	5.3.	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
	5.4.	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
	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.	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
	6.1.	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
	6.2.	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
	6.3.	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
	6.4.	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?	Yes
	6.5.	Were co-interventions (e.g., ancillary treatments, other therapies) described?	Yes
	6.6.	Were extra or unplanned treatments 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
	6.7.	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
	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.	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
	7.1.	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
	7.2.	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
	7.3.	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
	7.4.	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
	7.5.	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
	7.6.	Were other factors accounted for (measured) that could affect outcomes?	Yes
	7.7.	Were the measurements conducted consistently across groups?	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.	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
	8.1.	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
	8.2.	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
	8.3.	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
	8.4.	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
	8.5.	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
	8.6.	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
	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.	Are conclusions supported by results with biases and limitations taken into consideration?		Yes
	9.1.	Is there a discussion of findings?	Yes
	9.1.	Is there a discussion of findings?	Yes
	9.2.	Are biases and study limitations identified and discussed?	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.	Is bias due to study's funding or sponsorship unlikely?		Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.1.	Were sources of funding and investigators' affiliations described?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes
	10.2.	Was the study free from apparent conflict of interest?	Yes