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1.  The older people, omega-3, and cognitive health (EPOCH) trial design and methodology: A randomised, double-blind, controlled trial investigating the effect of long-chain omega-3 fatty acids on cognitive ageing and wellbeing in cognitively healthy older adults 
Nutrition Journal  2011;10:117.
Background
Some studies have suggested an association between omega-3 long-chain polyunsaturated fatty acids (n-3 LC PUFAs) and better cognitive outcomes in older adults. To date, only two randomised, controlled trials have assessed the effect of n-3 LC PUFA supplementation on cognitive function in older cognitively healthy populations. Of these trials only one found a benefit, in the subgroup carrying the ApoE-ε4 allele. The benefits of n-3 LC PUFA supplementation on cognitive function in older normal populations thus still remain unclear. The main objective of the current study was to provide a comprehensive assessment of the potential of n-3 LC PUFAs to slow cognitive decline in normal elderly people, and included ApoE-ε4 allele carriage as a potential moderating factor. The detailed methodology of the trial is reported herein.
Methods
The study was a parallel, 18-month, randomised, double-blind, placebo-controlled intervention with assessment at baseline and repeated 6-monthly. Participants (N = 391, 53.7% female) aged 65-90 years, English-speaking and with normal cognitive function, were recruited from metropolitan Adelaide, South Australia. Participants in the intervention arm received capsules containing fish-oil at a daily dosage of 1720 mg of docosahexaenoic acid and 600 mg of eicosapentaenoic acid while the placebo arm received the equivalent amount of olive oil in their capsules. The primary outcome is rate of change in cognitive performance, as measured by latent variables for the cognitive constructs (encompassing Reasoning, Working Memory, Short-term Memory, Retrieval Fluency, Inhibition, Simple and Choice-Reaction Time, Perceptual Speed, Odd-man-out Reaction Time, Speed of Memory Scanning, and Psychomotor Speed) and assessed by latent growth curve modeling. Secondary outcomes are change in the Mini-mental State Examination, functional capacity and well-being (including health status, depression, mood, and self-report cognitive functioning), blood pressure, and biomarkers of n-3 LC PUFA status, glucose, lipid metabolism, inflammation, oxidative stress, and DNA damage.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12607000278437
doi:10.1186/1475-2891-10-117
PMCID: PMC3210089  PMID: 22011460
2.  Visual evoked potentials and dietary long chain polyunsaturated fatty acids in preterm infants. 
The influence of dietary long chain polyunsaturated fatty acid (LCP) supply, and especially of docosahexaenoic acid (DHA), on evoked potential maturation, was studied in 58 healthy preterm infants using flash visual evoked potentials (VEPs), flash electroretinography (ERG), and brainstem acoustic evoked potentials (BAEPs) at 52 weeks of postconceptional age. At the same time, the fatty acid composition of red blood cell membranes was examined. The infants were fed on breast milk (n = 12), a preterm formula supplemented with LCP (PF-LCP) (n = 21), or a traditional preterm formula (PF) (n = 25). In the breast milk and PF-LCP groups the morphology and latencies of the waves that reflect the visual projecting system were similar; in the PF group the morphology was quite different and the wave latencies were significantly longer. This could mean that the maturation pattern of VEPs in preterm infants who did not receive LCP was slower. Moreover, a higher level of erythrocyte LCP, especially DHA, was found in breast milk and PF-LCP groups compared with the PF group. ERG and BAEP recordings were the same in all three groups. These results suggest that a well balanced LCP supplement in preterm formulas can positively influence the maturation of visual evoked potentials in preterm infants when breast milk is not available.
PMCID: PMC1061173  PMID: 8949693
3.  Feasibility of omega-3 fatty acid supplementation as an adjunct therapy for people with chronic obstructive pulmonary disease: study protocol for a randomized controlled trial 
Trials  2013;14:107.
Background
There is evidence to support the use of supplementation with long-chain omega-3 polyunsaturated fatty acids (LCn-3PUFA) from oily fish or fish oil for the treatment of various inflammatory diseases such as rheumatoid arthritis. Chronic obstructive pulmonary disease (COPD) is a progressive, terminal disease characterized by persistent airflow limitation, lung and systemic inflammation. To date, one randomized controlled trial has been published that assessed the efficacy of LCn-3PUFA in people with this condition. The aim of this article is to discuss the feasibility of conducting a trial to evaluate fish oil supplementation as adjunct therapy in people with COPD.
Methods/Design
A 16-week parallel, double-blind, randomized, placebo-controlled dietary supplementation trial will be evaluated. Forty participants meeting spirometric and clinical criteria for COPD will be recruited from metropolitan Adelaide, South Australia. Participants will be randomized by minimization, based on a score derived from the modified Medical Research Council Scale for breathlessness, to receive 6 g/day of fish oil (approximately 3.6 g/day of LCn-3PUFA), or placebo (6 g/day of corn oil) capsules. Feasibility outcomes (recruitment, retention, supplement adherence, and time lost to exacerbation) and scientific outcomes (effect size and estimates of variance for inflammatory biomarkers, incorporation of LCn-3PUFA into erythrocytes, small airways function, dyspnea and functional exercise capacity) will be assessed pre- and post-intervention. Key feasibility criteria include recruitment of 40 participants in 52 weeks, 75% participant retention rate, 2% increase in the proportion of long-chain omega-3 fatty acids in erythrocytes, and a positive moderate effect size in at least three efficacy measures.
Discussion
There are a number of challenges in designing supplementation intervention studies with this population. These include the lack of prior data from which to select appropriate primary outcomes or to estimate effect sizes, and the feasibility of continuous supplementation in a population characterized by multiple comorbidities and a high likelihood of exacerbations, potentially requiring hospitalization or change in medication. Upon completion of this protocol, feasibility outcomes will guide the direction of future multicentre dietary interventions in this population.
Trial registration
Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000158864
doi:10.1186/1745-6215-14-107
PMCID: PMC3748832  PMID: 23782589
4.  Effect of n-3 long chain polyunsaturated fatty acid supplementation in pregnancy on infants’ allergies in first year of life: randomised controlled trial 
Objective To determine whether dietary n-3 long chain polyunsaturated fatty acid (LCPUFA) supplementation of pregnant women with a fetus at high risk of allergic disease reduces immunoglobulin E associated eczema or food allergy at 1 year of age.
Design Follow-up of infants at high hereditary risk of allergic disease in the Docosahexaenoic Acid to Optimise Mother Infant Outcome (DOMInO) randomised controlled trial.
Setting Adelaide, South Australia.
Participants 706 infants at high hereditary risk of developing allergic disease whose mothers were participating in the DOMInO trial.
Interventions The intervention group (n=368) was randomly allocated to receive fish oil capsules (providing 900 mg of n-3 LCPUFA daily) from 21 weeks’ gestation until birth; the control group (n=338) received matched vegetable oil capsules without n-3 LCPUFA.
Main outcome measure Immunoglobulin E associated allergic disease (eczema or food allergy with sensitisation) at 1 year of age.
Results No differences were seen in the overall percentage of infants with immunoglobulin E associated allergic disease between the n-3 LCPUFA and control groups (32/368 (9%) v 43/338 (13%); unadjusted relative risk 0.68, 95% confidence interval 0.43 to 1.05, P=0.08; adjusted relative risk 0.70, 0.45 to 1.09, P=0.12), although the percentage of infants diagnosed as having atopic eczema (that is, eczema with associated sensitisation) was lower in the n-3 LCPUFA group (26/368 (7%) v 39/338 (12%); unadjusted relative risk 0.61, 0.38 to 0.98, P=0.04; adjusted relative risk 0.64, 0.40 to 1.02, P=0.06). Fewer infants were sensitised to egg in the n-3 LCPUFA group (34/368 (9%) v 52/338 (15%); unadjusted relative risk 0.61, 0.40 to 0.91, P=0.02; adjusted relative risk 0.62, 0.41 to 0.93, P=0.02), but no difference between groups in immunoglobulin E associated food allergy was seen.
Conclusion n-3 LCPUFA supplementation in pregnancy did not reduce the overall incidence of immunoglobulin E associated allergies in the first year of life, although atopic eczema and egg sensitisation were lower. Longer term follow-up is needed to determine if supplementation has an effect on respiratory allergic diseases and aeroallergen sensitisation in childhood.
Trial registration Australian New Zealand Clinical Trials Registry ACTRN12610000735055 (DOMInO trial: ACTRN12605000569606).
doi:10.1136/bmj.e184
PMCID: PMC3269207  PMID: 22294737
5.  Docosahexaenoic acid and cognitive function: Is the link mediated by the autonomic nervous system? 
Docosahexaenoic acid is a long-chain polyunsaturated fatty acid that is found in large quantity in the brain and which has repeatedly been observed to be related in positive ways to both cognitive function and cardiovascular health. The mechanisms through which docosahexaenoic acid affects cognition are not well understood, but in this article, we propose a hypothesis that integrates the positive effects of docosahexaenoic acid in the cognitive and cardiovascular realms through the autonomic nervous system. The autonomic nervous system is known to regulate vital functions such as heart rate and respiration, and has also been linked to basic cognitive components related to arousal and attention. We review the literature from this perspective, and delineate the predictions generated by the hypothesis. In addition, we provide new data showing a link between docosahexaenoic acid and fetal heart rate that is consistent with the hypothesis.
doi:10.1016/j.plefa.2008.09.014
PMCID: PMC3751406  PMID: 18930644
6.  Essential fatty acids in full term infants fed breast milk or formula. 
To determine the biochemical effects of the fatty acid composition of plasma lipids, two groups of 10 healthy full term infants who were either exclusively breast fed or received a formula with similar contents of linoleic and alpha linolenic acids, but without long chain polyunsaturated (LCP) fatty acids, were studied prospectively. Plasma phospholipid, triglyceride, and sterol ester fatty acids were determined at the age of 2, 4, and 8 weeks by high resolution capillary gas chromatography. Breast fed infants maintained stable LCP fatty acid concentrations throughout the study. Formula fed infants had significantly lower median values of arachidonic acid (AA) at the ages of 2 (6.9 v 9.5% wt/wt) and 4 weeks (5.9 v 7.9%) and docosahexaenoic acid (DHA) at the ages of 4 (1.1 v 1.7%) and 8 weeks (1.0 v 1.7%) in plasma phospholipids. Median AA values in triglycerides were also significantly lower in the infants receiving formula at the ages of 2 (0.4 v 0.6%) and 4 weeks (0.3 v 0.6%). It is concluded that formula fed full term infants are unable to match the omega-3 and omega-6 LCP status of breast fed full term infants until at least two months after birth.
PMCID: PMC2528425  PMID: 7743279
7.  A maternal erythrocyte DHA content of approximately 6 g% is the DHA status at which intrauterine DHA biomagnifications turns into bioattenuation and postnatal infant DHA equilibrium is reached 
European Journal of Nutrition  2011;51(6):665-675.
Purpose
Higher long-chain polyunsaturated fatty acids (LCP) in infant compared with maternal lipids at delivery is named biomagnification. The decline of infant and maternal docosahexaenoic acid (DHA) status during lactation in Western countries suggests maternal depletion. We investigated whether biomagnification persists at lifelong high fish intakes and whether the latter prevents a postpartum decline of infant and/or maternal DHA status.
Methods
We studied 3 Tanzanian tribes with low (Maasai: 0/week), intermediate (Pare: 2–3/week), and high (Sengerema: 4–5/week) fish intakes. DHA and arachidonic acid (AA) were determined in maternal (m) and infant (i) erythrocytes (RBC) during pregnancy (1st trimester n = 14, 2nd = 103, 3rd = 88), and in mother–infant pairs at delivery (n = 63) and at 3 months postpartum (n = 104).
Results
At delivery, infants of all tribes had similar iRBC-AA which was higher than, and unrelated to, mRBC-AA. Transplacental DHA biomagnification occurred up to 5.6 g% mRBC-DHA; higher mRBC-DHA was associated with “bioattenuation” (i.e., iRBC-DHA < mRBC-DHA). Compared to delivery, mRBC-AA after 3 months was higher, while iRBC-AA was lower. mRBC-DHA after 3 months was lower, while iRBC-DHA was lower (low fish intake), equal (intermediate fish intake), and higher (high fish intake) compared to delivery. We estimated that postpartum iRBC-DHA equilibrium is reached at 5.9 g%, which corresponds to a mRBC-DHA of 6.1 g% throughout pregnancy.
Conclusion
Uniform high iRBC-AA at delivery might indicate the importance of intrauterine infant AA status. Biomagnification reflects low maternal DHA status, and bioattenuation may prevent intrauterine competition of DHA with AA. A mRBC-DHA of about 6 g% during pregnancy predicts maternal–fetal equilibrium at delivery, postnatal iRBC-DHA equilibrium, but is unable to prevent a postnatal mRBC-DHA decline.
doi:10.1007/s00394-011-0245-9
PMCID: PMC3419349  PMID: 21952690
Biomagnification; Bioattenuation; Pregnancy; Long-chain polyunsaturated fatty acids; Docosahexaenoic acid; Arachidonic acid; Equilibrium
8.  Docosahexaenoic Acid Supplementation and Cognitive Decline in Alzheimer Disease 
Jama  2010;304(17):1903-1911.
Context
Docosahexaenoic acid (DHA) is the most abundant long-chain polyunsaturated fatty acid in the brain. Epidemiological studies suggest that consumption of DHA is associated with a reduced incidence of Alzheimer disease. Animal studies demonstrate that oral intake of DHA reduces Alzheimer-like brain pathology.
Objective
To determine if supplementation with DHA slows cognitive and functional decline in individuals with Alzheimer disease.
Design, Setting, and Patients
A randomized, double-blind, placebo-controlled trial of DHA supplementation in individuals with mild to moderate Alzheimer disease (Mini-Mental State Examination scores, 14–26) was conducted between November 2007 and May 2009 at 51 US clinical research sites of the Alzheimer’s Disease Cooperative Study.
Intervention
Participants were randomly assigned to algal DHA at a dose of 2 g/d or to identical placebo (60% were assigned to DHA and 40% were assigned to placebo). Duration of treatment was 18 months.
Main Outcome Measures
Change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and change in the Clinical Dementia Rating (CDR) sum of boxes. Rate of brain atrophy was also determined by volumetric magnetic resonance imaging in a subsample of participants (n = 102).
Results
A total of 402 individuals were randomized and a total of 295 participants completed the trial while taking study medication (DHA: 171; placebo: 124). Supplementation with DHA had no beneficial effect on rate of change on ADAS-cog score, which increased by a mean of 7.98 points (95% confidence interval [CI], 6.51–9.45 points) for the DHA group during 18 months vs 8.27 points (95% CI, 6.72–9.82 points) for the placebo group (linear mixed-effects model: P = .41). The CDR sum of boxes score increased by 2.87 points (95% CI, 2.44–3.30 points) for the DHA group during 18 months compared with 2.93 points (95% CI, 2.44–3.42 points) for the placebo group (linear mixed-effects model: P = .68). In the subpopulation of participants (DHA: 53; placebo: 49), the rate of brain atrophy was not affected by treatment with DHA. Individuals in the DHA group had a mean decline in total brain volume of 24.7 cm3 (95% CI, 21.4–28.0 cm3) during 18 months and a 1.32% (95% CI, 1.14%–1.50%) volume decline per year compared with 24.0 cm3 (95% CI, 20–28 cm3) for the placebo group during 18 months and a 1.29% (95% CI, 1.07%–1.51%) volume decline per year (P = .79).
Conclusion
Supplementation with DHA compared with placebo did not slow the rate of cognitive and functional decline in patients with mild to moderate Alzheimer disease.
doi:10.1001/jama.2010.1510
PMCID: PMC3259852  PMID: 21045096
9.  Alternative Sources of n-3 Long-Chain Polyunsaturated Fatty Acids in Marine Microalgae 
Marine Drugs  2013;11(7):2259-2281.
The main source of n-3 long-chain polyunsaturated fatty acids (LC-PUFA) in human nutrition is currently seafood, especially oily fish. Nonetheless, due to cultural or individual preferences, convenience, geographic location, or awareness of risks associated to fatty fish consumption, the intake of fatty fish is far from supplying the recommended dietary levels. The end result observed in most western countries is not only a low supply of n-3 LC-PUFA, but also an unbalance towards the intake of n-6 fatty acids, resulting mostly from the consumption of vegetable oils. Awareness of the benefits of LC-PUFA in human health has led to the use of fish oils as food supplements. However, there is a need to explore alternatives sources of LC-PUFA, especially those of microbial origin. Microalgae species with potential to accumulate lipids in high amounts and to present elevated levels of n-3 LC-PUFA are known in marine phytoplankton. This review focuses on sources of n-3 LC-PUFA, namely eicosapentaenoic and docosahexaenoic acids, in marine microalgae, as alternatives to fish oils. Based on current literature, examples of marketed products and potentially new species for commercial exploitation are presented.
doi:10.3390/md11072259
PMCID: PMC3736422  PMID: 23807546
marine microalgae; n-3 long-chain polyunsaturated fatty acids; EPA; DHA
10.  ELOVL2 gene polymorphisms are associated with increases in plasma eicosapentaenoic and docosahexaenoic acid proportions after fish oil supplement 
Genes & Nutrition  2013;9(1):362.
Fish oil supplementation provides an inconsistent degree of protection from cardiovascular disease (CVD), which may be attributed to genetic variation. Single nucleotide polymorphisms (SNPs) in the elongation-of-very-long-chain-fatty-acids-2 (ELOVL2) gene have been strongly associated with plasma proportions of n-3 long-chain polyunsaturated fatty acids (LC-PUFA). We investigated the effect of genotype interaction with fish oil dosage on plasma n-3 LC-PUFA proportions in a parallel double-blind controlled trial, involving 367 subjects randomised to treatment with 0.45, 0.9 and 1.8 g/day eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (1.51:1) or olive oil placebo for 6 months. We genotyped 310 subjects for ELOVL2 gene SNPs rs3734398, rs2236212 and rs953413. At baseline, carriers of all minor alleles had lower proportions of plasma DHA than non-carriers (P = 0.021–0.030). Interaction between genotype and treatment was a significant determinant of plasma EPA (P < 0.0001) and DHA (P = 0.004–0.032). After the 1.8 g/day dose, carriers of ELOVL2 SNP minor alleles had approximately 30 % higher proportions of EPA (P = 0.002–0.004) and 9 % higher DHA (P = 0.013–0.017) than non-carriers. Minor allele carriers could therefore particularly benefit from a high intake of EPA and DHA in maintaining high levels of plasma n-3 PUFA conducive to protection from CVD.
Electronic supplementary material
The online version of this article (doi:10.1007/s12263-013-0362-6) contains supplementary material, which is available to authorized users.
doi:10.1007/s12263-013-0362-6
PMCID: PMC3896629  PMID: 24292947
Docosahexaenoic acid; Eicosapentaenoic acid; Elongase; Fish oil; Single nucleotide polymorphism
11.  Plasma omega-3 PUFA and white matter mediated executive decline in older adults 
Introduction: Cross-sectional studies have identified long chain omega-3 polyunsaturated fatty acids (eicosapentaenoic acid 20:5n-3 and docosahexaenoic acid 22:6n-3 (O3PUFA) in association with fewer white matter lesions and better executive function in older adults. We hypothesized that O3PUFA are associated with less executive decline over time and that total white matter hyperintensity volume (WMH) mediates this association.
Methods: Eighty-six non-demented older adults were followed over 4 years after measurement of plasma O3PUFA with annual evaluations of cognitive function. A subset of these participants also had brain MRI of total WMH available to conduct a formal mediation analysis of a putative relationship between O3PUFA and cognitive function.
Results: Mean age at baseline was 86, 62% were female and 11% carried the APOE4 allele. Each 100 μg/ml increase in plasma O3PUFA associated with 4 s less change in executive decline per year of aging (p = 0.02, fully adjusted model). O3PUFA was not associated with verbal memory or global cognitive changes. The significance of the association between O3PUFA and better executive function was lost once WMH was added to the regression model.
Conclusion: Executive decline with age appears to be a cognitive domain particularly sensitive to plasma O3PUFA in longitudinal examination. O3PUFA may modulate executive functioning by mechanisms underlying the development of WMH, a biologically plausible hypothesis that warrants further investigation.
doi:10.3389/fnagi.2013.00092
PMCID: PMC3863786  PMID: 24379780
omega-3 fatty acids; white matter hyperintensity; cognitive decline; memory; hypertension
12.  Effects of supplementation with n-3 polyunsaturated fatty acids on cognitive performance and cardiometabolic risk markers in healthy 51 to 72 years old subjects: a randomized controlled cross-over study 
Nutrition Journal  2012;11:99.
Background
Higher plasma n-3 polyunsaturated fatty acids (PUFA) have been associated with a lower risk of age related cognitive decline, and to beneficially affect cardiometabolic risk factors. A relation exists between metabolic disorders such as diabetes type 2 and cognitive decline. Results regarding the potential effects of n-3 PUFA on risk factors in healthy subjects are divergent, and studies regarding the possible relation between cardiometabolic parameters and cognitive performance are scarce. The objective was to evaluate the effects of five weeks intake of long chain n-3 PUFA on cognitive performance in healthy individuals, and to exploit the possible relation between outcomes in cognitive tests to cardiometabolic risk parameters.
Methods
Fish oil n-3 PUFA (3g daily) were consumed during 5weeks separated by a 5 week washout period in a cross-over placebo controlled study, including 40 healthy middle aged to elderly subjects. Cognitive performance was determined by tests measuring working memory (WM) and selective attention.
Results
Supplementation with n-3 PUFA resulted in better performance in the WM-test compared with placebo (p < 0.05). In contrast to placebo, n-3 PUFA lowered plasma triacylglycerides (P < 0.05) and systolic blood pressure (p < 0.0001). Systolic blood pressure (p < 0.05), f-glucose (p = 0.05), and s-TNF-α (p = 0.05), were inversely related to the performance in cognitive tests.
Conclusions
Intake of n-3 PUFA improved cognitive performance in healthy subjects after five weeks compared with placebo. In addition, inverse relations were obtained between cardiometabolic risk factors and cognitive performance, indicating a potential of dietary prevention strategies to delay onset of metabolic disorders and associated cognitive decline.
doi:10.1186/1475-2891-11-99
PMCID: PMC3564898  PMID: 23173831
Omega-3 PUFA; DHA; EPA; Fish oil; Dietary prevention; Cognitive performance; Working memory; Metabolic disorders; Ageing
13.  Meta-analysis of Long-Chain Polyunsaturated Fatty Acid Supplementation of Formula and Infant Cognition 
Pediatrics  2012;129(6):1141-1149.
BACKGROUND AND OBJECTIVE:
Infant formula is supplemented with long-chain polyunsaturated fatty acids (LCPUFAs) because they are hypothesized to improve cognition. Several randomized controlled clinical trials have examined the effect of LCPUFA supplementation of infant formula on cognitive development. We conducted this meta-analysis to examine the efficacy of LCPUFA supplementation of infant formula on early cognitive development.
METHODS:
Two authors searched PubMed, PsychInfo, and Scopus for randomized controlled clinical trials assessing the efficacy of LCPUFA supplementation of infant formulas on cognition. Our analysis was restricted to randomized controlled clinical trials that examined the effect of LCPUFA supplementation on infant cognition using Bayley Scales of Infant Development. Our primary outcome was the weighted mean difference in Bayley Scales of Infant Development score between infants fed formula supplemented with LCPUFA compared with unsupplemented formula. We conducted secondary subgroup analyses and meta-regression to examine the effects of study sample, LCPUFA dose, and trial methodologic quality on measured efficacy of supplementation.
RESULTS:
Twelve trials involving 1802 infants met our inclusion criteria. Our meta-analysis demonstrated no significant effect of LCPUFA supplementation of formula on infant cognition. There was no significant heterogeneity or publication bias between trials. Secondary analysis failed to show any significant effect of LCPUFA dosing or prematurity status on supplementation efficacy.
CONCLUSIONS:
LCPUFA supplementation of infant formulas failed to show any significant effect on improving early infant cognition. Further research is needed to determine if LCPUFA supplementation of infant formula has benefits for later cognitive development or other measures of neurodevelopment.
doi:10.1542/peds.2011-2127
PMCID: PMC3362904  PMID: 22641753
infant formula; unsaturated fatty acids; infant cognition; long-chain polyunsaturated fatty acids; meta-analysis; Bayley Scales of Infant Development
14.  Omega-3 and omega-6 fatty acid intakes and endometrial cancer risk in a population-based case–control study 
European journal of nutrition  2012;52(3):1251-1260.
Purpose
Animal and laboratory studies suggest that long-chain omega-3 (n-3) fatty acids, a type of polyunsaturated fat found in fatty fish, may protect against carcinogenesis, but human studies on dietary intake of polyunsaturated fats and fish with endometrial cancer risk show mixed results.
Methods
We evaluated the associations between endometrial cancer risk and intake of fatty acids and fish in a population-based sample of 556 incident cancer cases and 533 age-matched controls using multivariate unconditional logistic regression methods.
Results
Although total n-3 fatty acid intake was not associated with endometrial cancer risk, higher intakes of eicosapentaenoic (EPA 20:5) and docosahexaenoic (DHA 22:6) fatty acids were significantly associated with lower risks (OR = 0.57, 95 % CI: 0.39–0.84; OR = 0.64, 95 % CI: 0.44–0.94; respectively) comparing extreme quartiles. The ratio of n-3:n-6 fatty acids was inversely associated with risk only on a continuous scale (OR = 0.84, 95 % CI: 0.71–0.99), while total fish intake was not associated with risk. Fish oil supplement use was significantly associated with reduced risk of endometrial cancer: OR = 0.63 (95 % CI: 0.45–0.88).
Conclusions
Our results suggest that dietary intake of the long-chain polyunsaturated fatty acids EPA and DHA in foods and supplements may have protective associations against the development of endometrial cancer.
doi:10.1007/s00394-012-0436-z
PMCID: PMC3548981  PMID: 22915050
Endometrial cancer; Fatty acids; Fish oil; Fish; Case–control study
15.  The influence of a formula supplemented with dairy lipids and plant oils on the erythrocyte membrane omega-3 fatty acid profile in healthy full-term infants: a double-blind randomized controlled trial 
BMC Pediatrics  2012;12:164.
Background
Human milk is the optimal nutrition for infants. When breastfeeding is not possible, supplementation of infant formula with long chain polyunsaturated fatty acids appears to promote neurodevelopmental outcome and visual function. Plant oils, that are the only source of fat in most of infant formulas, do not contain specific fatty acids that are present in human and cow milk and do not encounter milk fat triglyceride structure. Experimental data suggest that a mix of dairy lipids and plant oils can potentiate endogenous synthesis of n-3 long chain polyunsaturated fatty acids. This trial aims to determine the effect of an infant formula supplemented with a mixture of dairy lipids and plant oils on the erythrocyte membrane omega-3 fatty acid profile in full-term infants (primary outcome). Erythrocyte membrane long chain polyunsaturated fatty acids and fatty acids content, the plasma lipid profile and the insulin-growth factor 1 level, the gastrointestinal tolerance, the changes throughout the study in blood fatty acids content, in growth and body composition are evaluated as secondary outcomes.
Methods/Design
In a double-blind controlled randomized trial, 75 healthy full-term infants are randomly allocated to receive for four months a formula supplemented with a mixture of dairy lipids and plant oils or a formula containing only plant oils or a formula containing plant oils supplemented with arachidonic acid and docosahexaenoic acid. Twenty-five breast-fed infants constitute the reference group. Erythrocyte membrane omega-3 fatty acid profile, long chain polyunsaturated fatty acids and the other fatty acids content, the plasma lipid profile and the insulin-growth factor 1 level are measured after four months of intervention. Gastrointestinal tolerance, the changes in blood fatty acids content, in growth and body composition, assessed by means of an air displacement plethysmography system, are also evaluated throughout the study.
Discussion
The achievement of an appropriate long chain polyunsaturated fatty acids status represents an important goal in neonatal nutrition. Gaining further insight in the effects of the supplementation of a formula with dairy lipids and plant oils in healthy full-term infants could help to produce a formula whose fat content, composition and structure is more similar to human milk.
Trial registration
ClinicalTrials.gov Identifier NCT01611649
doi:10.1186/1471-2431-12-164
PMCID: PMC3480864  PMID: 23072617
Full-term infants; Formula supplementation; Dairy lipids; Erythrocyte membrane omega-3 fatty acid profile
16.  Fetal and Neonatal Levels of Omega-3: Effects on Neurodevelopment, Nutrition, and Growth 
The Scientific World Journal  2012;2012:202473.
Nutrition in pregnancy, during lactation, childhood, and later stages has a fundamental influence on overall development. There is a growing research interest on the role of key dietary nutrients in fetal health. Omega-3 polyunsaturated fatty acids (n-3 LCPUFAs) play an important role in brain development and function. Evidence from animal models of dietary n-3 LCPUFAs deficiency suggests that these fatty acids promote early brain development and regulate behavioral and neurochemical aspects related to mood disorders (stress responses, depression, and aggression and growth, memory, and cognitive functions). Preclinical and clinical studies suggest the role of n-3 LCPUFAs on neurodevelopment and growth. n-3 LCPUFAs may be an effective adjunctive factor for neural development, growth, and cognitive development, but further large-scale, well-controlled trials and preclinical studies are needed to examine its clinical mechanisms and possible benefits. The present paper discusses the use of n-3 LCPUFAs during different developmental stages and the investigation of different sources of consumption. The paper summarizes the role of n-3 LCPUFAs levels during critical periods and their effects on the children's neurodevelopment, nutrition, and growth.
doi:10.1100/2012/202473
PMCID: PMC3483668  PMID: 23125553
17.  The Home-Based Older People's Exercise (HOPE) trial: study protocol for a randomised controlled trial 
Trials  2011;12:143.
Background
Frailty is common in older age, and is associated with important adverse health outcomes including increased risk of disability and admission to hospital or long-term care. Exercise interventions for frail older people have the potential to reduce the risk of these adverse outcomes by increasing muscle strength and improving mobility.
Methods/Design
The Home-Based Older People's Exercise (HOPE) trial is a two arm, assessor blind pilot randomised controlled trial (RCT) to assess the effectiveness of a 12 week exercise intervention (the HOPE programme) designed to improve the mobility and functional abilities of frail older people living at home, compared with usual care. The primary outcome is the timed-up-and-go test (TUGT), measured at baseline and 14 weeks post-randomisation. Secondary outcomes include the Barthel Index of activities of daily living (ADL), EuroQol Group 5-Dimension Self-Report Questionnaire (EQ-5D) quality of life measure and the geriatric depression scale (GDS), measured at baseline and 14 weeks post-randomisation. We will record baseline frailty using the Edmonton Frail Scale (EFS), record falls and document muscle/joint pain. We will test the feasibility of collection of data to identify therapy resources required for delivery of the intervention.
Discussion
The HOPE trial will explore and evaluate a home-based exercise intervention for frail older people. Although previous RCTs have used operationalised, non-validated methods of measuring frailty, the HOPE trial is, to our knowledge, the first RCT of an exercise intervention for frail older people that includes a validated method of frailty assessment at baseline.
Trial registration
ISRCTN: ISRCTN57066881
doi:10.1186/1745-6215-12-143
PMCID: PMC3121609  PMID: 21651805
18.  The Relationship of Dietary ω-3 Long-Chain Polyunsaturated Fatty Acid Intake With Incident Age-Related Macular Degeneration AREDS Report No. 23 
Archives of ophthalmology  2008;126(9):1274-1279.
Objective
To examine the association of dietary ω-3 long-chain polyunsaturated fatty acid and fish intake with incident neovascular age-related macular degeneration (AMD) and central geographic atrophy (CGA).
Methods
Multicenter clinic-based prospective cohort study from a clinical trial including Age-Related Eye Disease Study (AREDS) participants with bilateral drusen at enrollment. Main outcome measures were incident neovascular AMD and CGA, ascertained from annual stereoscopic color fundus photographs (median follow-up, 6.3 years). We estimated nutrient and food intake from a validated food frequency questionnaire (FFQ) at baseline, with intake of docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), combined EPA and DHA, and fish as primary exposures.
Results
After controlling for known covariates, we observed a reduced likelihood of progression from bilateral drusen to CGA among people who reported the highest levels of EPA (odds ratio [OR], 0.44; 95% confidence interval [CI], 0.23-0.87) and EPA+DHA (OR, 0.45; 95% CI, 0.23-0.90) consumption. Levels of DHA were associated with CGA in age-, sex-, and calorie-adjusted models (OR, 0.51; 95% CI, 0.26-1.00); however, this statistical relationship did not persist in multivariable models.
Conclusions
Dietary lipid intake is a modifiable factor that may influence the likelihood of developing sight-threatening forms of AMD. Our findings suggest that dietary ω-3 long-chain polyunsaturated fatty acid intake is associated with a decreased risk of progression from bilateral drusen to CGA.
doi:10.1001/archopht.126.9.1274
PMCID: PMC2812063  PMID: 18779490
19.  Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial 
PLoS ONE  2010;5(9):e12244.
Background
An increased rate of brain atrophy is often observed in older subjects, in particular those who suffer from cognitive decline. Homocysteine is a risk factor for brain atrophy, cognitive impairment and dementia. Plasma concentrations of homocysteine can be lowered by dietary administration of B vitamins.
Objective
To determine whether supplementation with B vitamins that lower levels of plasma total homocysteine can slow the rate of brain atrophy in subjects with mild cognitive impairment in a randomised controlled trial (VITACOG, ISRCTN 94410159).
Methods and Findings
Single-center, randomized, double-blind controlled trial of high-dose folic acid, vitamins B6 and B12 in 271 individuals (of 646 screened) over 70 y old with mild cognitive impairment. A subset (187) volunteered to have cranial MRI scans at the start and finish of the study. Participants were randomly assigned to two groups of equal size, one treated with folic acid (0.8 mg/d), vitamin B12 (0.5 mg/d) and vitamin B6 (20 mg/d), the other with placebo; treatment was for 24 months. The main outcome measure was the change in the rate of atrophy of the whole brain assessed by serial volumetric MRI scans.
Results
A total of 168 participants (85 in active treatment group; 83 receiving placebo) completed the MRI section of the trial. The mean rate of brain atrophy per year was 0.76% [95% CI, 0.63–0.90] in the active treatment group and 1.08% [0.94–1.22] in the placebo group (P = 0.001). The treatment response was related to baseline homocysteine levels: the rate of atrophy in participants with homocysteine >13 µmol/L was 53% lower in the active treatment group (P = 0.001). A greater rate of atrophy was associated with a lower final cognitive test scores. There was no difference in serious adverse events according to treatment category.
Conclusions and Significance
The accelerated rate of brain atrophy in elderly with mild cognitive impairment can be slowed by treatment with homocysteine-lowering B vitamins. Sixteen percent of those over 70 y old have mild cognitive impairment and half of these develop Alzheimer's disease. Since accelerated brain atrophy is a characteristic of subjects with mild cognitive impairment who convert to Alzheimer's disease, trials are needed to see if the same treatment will delay the development of Alzheimer's disease.
Trial Registration
Controlled-Trials.com ISRCTN94410159
doi:10.1371/journal.pone.0012244
PMCID: PMC2935890  PMID: 20838622
20.  n-3 PUFA added to high-fat diets affect differently adiposity and inflammation when carried by phospholipids or triacylglycerols in mice 
Background
Dietary intake of n-3 polyunsaturated fatty acids (PUFA) is primarily recognized to protect against cardiovascular diseases, cognitive dysfunctions and the onset of obesity and associated metabolic disorders. However, some of their properties such as bioavailability can depend on their chemical carriers. The objective of our study was to test the hypothesis that the nature of n-3 PUFA carrier results in different metabolic effects related to adiposity, oxidative stress and inflammation.
Methods
4 groups of C57BL/6 mice were fed for 8 weeks low fat (LF) diet or high-fat (HF, 20%) diets. Two groups of high-fat diets were supplemented with long-chain n-3 PUFA either incorporated in the form of phospholipids (HF-ω3PL) or triacylglycerols (HF-ω3TG).
Results
Both HF-ω3PL and HF-ω3TG diets reduced the plasma concentrations of (i) inflammatory markers such as monocyte chemoattractant protein-1 (MCP-1) and interleukin 6 (IL-6), (ii) leptin and (iii) 4-hydroxy-2-nonenal (4-HNE), a marker of n-6 PUFA-derived oxidative stress compared with the control HF diet. Moreover, in both HF-ω3PL and HF-ω3TG groups, MCP-1 and IL-6 gene expressions were decreased in epididymal adipose tissue and the mRNA level of gastrointestinal glutathione peroxidase GPx2, an antioxidant enzyme, was decreased in the jejunum compared with the control HF diet. The type of n-3 PUFA carrier affected other outcomes. The phospholipid form of n-3 PUFA increased the level of tocopherols in epididymal adipose tissue compared with HF-ω3TG and resulted in smaller adipocytes than the two others HF groups. Adipocytes in the HF-ω3PL and LF groups were similar in size distribution.
Conclusion
Supplementation of mice diet with long-chain n-3 PUFA during long-term consumption of high-fat diets had the same lowering effects on inflammation regardless of triacyglycerol or phospholipid carrier, whereas the location of these fatty acids on a PL carrier had a major effect on decreasing the size of adipocytes that was not observed with the triacyglycerol carrier. Altogether, these results would support the development functional foods containing LC n-3 PUFA in the form of PL in order to prevent some deleterious outcomes associated with the development of obesity.
doi:10.1186/1743-7075-10-23
PMCID: PMC3585798  PMID: 23413782
n-3 PUFA; Phospholipid; Triacylglycerol; High-fat diet; Inflammation; Oxidative stress; Adipose tissue
21.  The ReSPonD trial - rivastigmine to stabilise gait in Parkinson’s disease a phase II, randomised, double blind, placebo controlled trial to evaluate the effect of rivastigmine on gait in patients with Parkinson’s disease who have fallen 
BMC Neurology  2013;13:188.
Background
Gait impairment is common in people with Parkinson’s disease. There is a lack of effective interventions to target this debilitating complication and therefore a need to identify new therapeutic options. An underlying cholinergic deficit contributes to both the gait and cognitive dysfunction seen in Parkinson’s disease. The combined impact of both impairments can be assessed in gait tasks performed with concomitant cognitive tasks. The aim of this trial is to evaluate the impact of a cholinesterase inhibitor on cognitive function and gait performance in people with established Parkinson’s disease.
Methods/design
This is a single centre, double-blind, randomised placebo-controlled trial in 130 people with Hoehn and Yahr stage 2–3 idiopathic Parkinson’s disease who have fallen in the past year. Participants will be randomised to two groups, receiving either rivastigmine capsules or identical placebo capsules for 8 months. Assessment will be undertaken at baseline and at the end of medication prescription (i.e. 8 months) with participants remaining enrolled in the trial for a further 4 months to monitor for falls and adverse events. The primary outcome is step time variability, assessed with and without the addition of concurrent cognitive tasks. Secondary outcomes will include other gait parameters, sensorimotor and balance performances, cognitive indices, falls and fall related injury, fear of falling, Parkinson’s symptoms and data pertaining to possible harms.
Discussion
This randomised controlled trial will examine the effect of cholinesterase inhibitor therapy on gait, balance and falls in Parkinson’s disease. If effective, it would offer a new therapeutic option to ameliorating gait and cognitive deficits in a population at high risk of falls.
Trial registration
ISRCTN19880883, UTN U1111-1124-0244.
doi:10.1186/1471-2377-13-188
PMCID: PMC3880104  PMID: 24299497
Randomised control trial; Parkinson’s disease; Accidental Falls; Freezing of gait; Intervention; Gait analysis; Acetylcholinesterase; Cognitive; Attention; Dual-tasking
22.  DHA Supplementation: Current Implications in Pregnancy and Childhood 
Dietary supplementation with (ω)-3 long chain fatty acids including docosahexaenoic acid (DHA) has increased in popularity in recent years and adequate DHA supplementation during pregnancy and early childhood is of clinical importance. Some evidence has been built for the neuro-cognitive benefits of supplementation with long chain polyunsaturated fatty acids (LCPUFA) such as DHA during pregnancy; however, recent data indicate that the anti-inflammatory properties may be of at least equal significance. Adequate DHA availability in the fetus/infant optimizes brain and retinal maturation in part by influencing neurotransmitter pathways. The anti-inflammatory properties of LCPUFA are largely mediated through modulation of signaling either directly through binding to receptors or through changes in lipid raft formation and receptor presentation. Our goal is to review the current findings on DHA supplementation, specifically in pregnancy and infant neurodevelopment, as a pharmacologic agent with both preventative and therapeutic value. Given the overall benefits of DHA, maternal and infant supplementation may improve neurological outcomes especially in vulernable populations. However, optimal composition of the supplement and dosing and treatment strategies still need to be determined to lend support for routine supplementation.
doi:10.1016/j.phrs.2012.12.003
PMCID: PMC3602397  PMID: 23266567
DHA; long chain fatty acids; natural products; lipids; omega-3
23.  Three Randomized Controlled Trials of Early Long-Chain Polyunsaturated Fatty Acid Supplementation on Means-End Problem Solving in Nine-Month Olds 
Child development  2009;80(5):1376-1384.
This study examines whether feeding infants formula supplemented with long-chain polyunsaturated fatty acids (LCPUFA) improves cognitive function of 9-month olds. Participants included 229 infants from 3, randomized controlled trials. Children received either formula supplemented with docosahexaenoic acid and arachidonic acid, or a control formula beginning at 1 to 5 d (12 month feeding study), or following 6 weeks (6-week weaning study) or 4 to 6 months of breastfeeding (4-to 6-month weaning study). Infants were assessed with a two-step problem solving task. In the 12-month feeding and 6-week weaning studies, supplemented children had more intentional solutions (successful task completions) and higher intention scores (goal-directed behaviors) than controls. These results suggest that LCPUFA-supplementation improves means-end problem solving.
doi:10.1111/j.1467-8624.2009.01339.x
PMCID: PMC2757317  PMID: 19765006
Docosahexaenoic acid; infant; cognitive development; means-end problem solving
24.  Low Blood Long Chain Omega-3 Fatty Acids in UK Children Are Associated with Poor Cognitive Performance and Behavior: A Cross-Sectional Analysis from the DOLAB Study 
PLoS ONE  2013;8(6):e66697.
Background
Omega-3 long-chain polyunsaturated fatty acids (LC-PUFA), especially DHA (docosahexaenonic acid) are essential for brain development and physical health. Low blood Omega-3 LC-PUFA have been reported in children with ADHD and related behavior/learning difficulties, as have benefits from dietary supplementation. Little is known, however, about blood fatty acid status in the general child population. We therefore investigated this in relation to age-standardized measures of behavior and cognition in a representative sample of children from mainstream schools.
Participants
493 schoolchildren aged 7–9 years from mainstream Oxfordshire schools, selected for below average reading performance in national assessments at age seven.
Method
Whole blood fatty acids were obtained via fingerstick samples. Reading and working memory were assessed using the British Ability Scales (II). Behaviour (ADHD-type symptoms) was rated using the revised Conners’ rating scales (long parent and teacher versions). Associations were examined and adjusted for relevant demographic variables.
Results
DHA and eicosapentaenoic acid (EPA), accounted for only 1.9% and 0.55% respectively of total blood fatty acids, with DHA showing more individual variation. Controlling for sex and socio-economic status, lower DHA concentrations were associated with poorer reading ability (std. OLS coeff. = 0.09, p = <.042) and working memory performance (0.14, p = <.001). Lower DHA was also associated with higher levels of parent rated oppositional behavior and emotional lability (−0.175, p = <.0001 and −0.178, p = <.0001).
Conclusions
In these healthy UK children with below average reading ability, concentrations of DHA and other Omega-3 LC-PUFA were low relative to adult cardiovascular health recommendations, and directly related to measures of cognition and behavior. These findings require confirmation, but suggest that the benefits from dietary supplementation with Omega-3 LC-PUFA found for ADHD, Dyspraxia, Dyslexia, and related conditions might extend to the general school population.
doi:10.1371/journal.pone.0066697
PMCID: PMC3691187  PMID: 23826114
25.  Long chain polyunsaturated fatty acid supplementation in infant formula and blood pressure in later childhood: follow up of a randomised controlled trial 
BMJ : British Medical Journal  2003;326(7396):953.
Objective
To determine whether supplementation of infant formula milk with long chain polyunsaturated fatty acids (LCPUFAs) influences blood pressure in later childhood.
Design
Follow up of a multicentre, randomised controlled trial.
Setting
Four study centres in Europe.
Participants
147 formula fed children, with a reference group of 88 breastfed children.
Intervention
In the original trial newborn infants were randomised to be fed with a formula supplemented with LCPUFAs (n=111) or a formula without LCPUFAs but otherwise nutritionally similar (n=126). In the present follow up study the blood pressure of the children at age 6 years was measured.
Main outcome measures
Systolic, diastolic, and mean blood pressure.
Results
71 children in the LCPUFA supplementation group (64% of the original group) and 76 children in the non-supplementation group (60%) were enrolled into the follow up study. The LCPUFA group had significantly lower mean blood pressure (mean difference −3.0 mm Hg (95% confidence interval −5.4 mm Hg to −0.5 mm Hg)) and diastolic blood pressure (mean difference −3.6 mm Hg (−6.5 mm Hg to −0.6 mm Hg)) than the non-supplementation group. The diastolic pressure of the breastfed children (n=88 (63%)) was significantly lower than that of the non-supplemented formula group but did not differ from the LCPUFA formula group.
Conclusions
Dietary supplementation with LCPUFAs during infancy is associated with lower blood pressure in later childhood. Blood pressure tends to track from childhood into adult life, so early exposure to dietary LCPUFAs may reduce cardiovascular risk in adulthood.
What is already known on this topicBreast milk contains long chain polyunsaturated fatty acids, and breastfed children have lower blood pressure than children fed with formula milkBlood pressure differences in childhood are known to carry through into adulthoodDietary omega 3 fatty acid supplementation can lower blood pressure in adults with hypertensionWhat this paper addsSupplementation with long chain polyunsaturated fatty acids in infancy results in lower blood pressure later in childhood
PMCID: PMC153849  PMID: 12727766

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