PUFA NEWSLETTER. August 2012 Contents. Volume 17 Issue 2. Editorial In Honor of Ralph Holman PUFA Newsletter Staff ISSFAL

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1 PUFA NEWSLETTER Volume 17 Issue 2 August 2012 Contents Editorial In Honor of Ralph Holman... 2 Report ISSFAL CARDIOVASCULAR HEALTH Differential Effects of Omega-3 PUFAs on Lipoprotein Profiles in Alaska Natives Atrial Fibrillation More Mixed Findings on Omega-3s and Risk of Incident Atrial Fibrillation... 7 MATERNAL AND INFANT HEALTH No Less Gestational Diabetes or Preeclampsia with DHA Supplementation in Pregnancy Is Preterm Infant Development Undermined by High Linoleic Acid and Low DHA? DHA-Supplemented Healthy Term Infants Score Higher in Gesture Communication MENTAL HEALTH & COGNITION Depressive Symptoms EPA + DHA Associated with 25% Lower Risk of Depressive Symptoms in US Adults Neither Folate Nor Long-Chain Omega-3s Affect Depressive Symptoms in Heart Patients Supplemental EPA or DHA May Be Linked to Improved Depression Scores in Older Adults Alzheimer s Disease Omega-3 Intakes and Plasma Amyloid-Beta Peptides in Non-Demented Older Adults EPA and DHA Intakes Linked to Better Cognition and Gray Matter Volume in Older Adults FRONTIERS Stepping Stones to Treating Alzheimer s Disease: Is Insulin the Key? PUFA Newsletter Staff Editor Joyce A. Nettleton, DSc Communications Manager Angela Dansby Sponsor DSM Nutritional Products, Columbia, MD, USA Science Advisory Board J. Thomas Brenna, PhD Cornell University Ithaca, NY, USA Berthold Koletzko, MD, PhD University of Munich Marlene P. Freeman, MD Massachusetts General Hospital Boston, MA, USA Adina Michael-Titus, DSc Barts, London School of Medicine London, UK Trevor Mori, PhD University of Western Australia Perth, WA, Australia Letters and editorial comments should be submitted to sciencevoice@q.com and technical comments to angela@fatsoflife.com. Subscribe to the PUFA Newsletter at

2 n Editorial In Honor of Ralph Holman This issue of the PUFA Newsletter is dedicated to the achievements of the man who first coined the term omega-3, Ralph Theodore Holman. He died on August 15th. His studies on essential fatty acids in 1958 described the accumulation of trienoic fatty acids (those with three double bonds) in animals fed lard as the only source of fat and led to the suggestion that the trienoic acid content of heart tissue is a criterion of essential fatty acid status. This work eventually resulted in Holman s suggestion in 1960 that the ratio of trienoic:tetraenoic acids (later interpreted as Mead acid/arachidonic acid or 20:3n-9/20:4n-6) in tissue lipids reflects the requirement for essential fatty acids. Today, this ratio is called the Holman index and it is still used as an indicator of linoleic acid deficiency. His proposal for the omega nomenclature based on the location of the first double bond nearest the methyl end of the fatty acid chain was proposed in Holman and colleagues studied the effects of linoleic and alpha-linolenic acids (ALA) on each other, proposed essential fatty acid requirements for the rat and human infant, and were the first to report a case of human ALA deficiency. Holman was the first to report that linoleic acid was the precursor of arachidonic acid and that ALA could be converted to EPA and DHA in the rat. Expressing concern about the deficiency of essential fatty acids in pregnancy, he warned 20 years ago that, oils rich in linoleic but poor in ALA may be raising the proportion of linoleic acid in our diet so high that it suppresses the utilization of the small proportion of ALA present. In one of his last published papers, Holman lamented the slow discovery of the importance of omega-3 (n-3) essential fatty acids in humans. The freely accessible article reveals how much the study of n-3 PUFAs owes to this remarkable and prescient scientist. The August issue of the PUFA Newsletter includes selected highlights from the biennial meeting of the International Society for the Study of Fatty Acids and Lipids held in May 2012 and presents three articles on the importance of long-chain (LC) n-3 PUFAs in the diets of pregnant women, preterm infants and healthy term babies. Three articles report the associations of n-3 LC-PUFAs on the symptoms of depressive illness, documenting the relationship between higher intakes of EPA and DHA and lower risk of these symptoms in US adults and older adults. There are also noteworthy developments on the relationship between n-3 LC-PUFAs and markers of preclinical Alzheimer s disease described in three articles. The final article describes potentially groundbreaking work in understanding and possibly treating the symptoms of early Alzheimer s disease. We hope you enjoy this issue and some of the recent changes to the Fats of Life web site. Let us know what you think! Joyce A. Nettleton, DSc Editor, PUFA Newsletter and Fats of Life sciencevoice@q.com 2

3 n Report ISSFAL 2012 The 10 th Congress of the International Society for the Study of Fatty Acids and Lipids (ISSFAL) convened May 26-30, in Vancouver, Canada, overlooking the North Shore Mountains, Coal Harbor and Stanley Park. Three days packed with meetings, breakfast workshops, plenary and poster sessions, exhibits and a gala dinner brought together scientists and others from 33 countries. All share an interest in current research on the biochemistry, health effects and genomics of fatty acids and lipids. The conference program and abstracts can be downloaded here. Selected highlights from the meeting include: Several papers described research with resolvins and protectins regarding the resolution of inflammation; reduction in the time to resolve inflammatory responses; enhanced immune responses to airway inflammation from injury, infection and allergens; and their increased production with n-3 LC-PUFA supplementation in patients with chronic kidney disease. John Paul SanGiovanni described the activity of 4-HDHA, a metabolite generated by 5-lipoxygenase, and the complement system in the antiangiogenic properties of DHA in retinal neovascularization, which occurs in the advanced stages of age-related macular degeneration (AMD). Martha Neuringer detailed the effects of deficiencies in xanthophylls or n-3 LC-PUFAs or both on retinal structure and function in rhesus monkeys. Deficient animals developed premature signs of AMD and those deficient in n-3 LC-PUFAs also developed reduced rod sensitivity and selective losses in the central retina. Results suggest that both types of nutrients may help prevent AMD. Cécilia Samieri assessed plasma EPA and DHA levels and their relationship to MRI images of brain in 65-year-old adults at baseline and after 4 years to evaluate changes in gray matter volume in the right hippocampus and right amygdala, semantic memory and depressive symptoms. Higher plasma EPA, but not DHA, was associated with less atrophy of gray matter in both brain regions and with less decline in semantic memory and less severe symptoms of depressive illness. Hiroshi Kawashima reported that among more than 1,100 Japanese adults aged 60 to 88 years, low serum levels of ARA and EPA were associated with a significantly higher risk of cognitive decline compared with participants in the third or fourth quintiles of these fatty acids. Bert Koletzko reported that for 1- to 11-year-old children with phenylketonuria (PKU), an inborn error of metabolism, who have very low protein intakes and no food sources of n-3 LC-PUFAs, supplementation with fish oil containing 15 mg DHA/ kg body weight for 3 months was associated with significantly improved visual evoked potential latencies, motor function and coordination. An ongoing multi-center study aims to determine the quantitative requirements for DHA in PKU children. David Ma presented details of a study in delta-6-desaturase knock-out mice and wild-type mice comparing the effects of a low or high ALA diet compared with a fish oil or lard diet on the development of hepatic steatosis and inflammation. They hoped to identify potential effects attributable solely to ALA. At 8 weeks, the hepatic inflammation scores for the ALA groups were intermediate between those of the lard and fish oil groups in both strains of mice. Hepatic steatosis scores were higher in the knock-out mice on the ALA diets compared with the wild-type mice. However, knock-out mice fed the high ALA or fish oil diets had less liver lipid compared with the lard-fed knock-out animals. The results suggested that ALA had direct effects on inflammation independent of conversion to long-chain forms, but that lack of conversion was associated with the development of fatty liver. Maria Makrides described findings from a supplementation study of 800 mg of DHA or vegetable oil in the last half of pregnancy on the risk of developing gestational diabetes or preeclampsia. There was no difference between the DHA-supplemented and control mothers in either outcome, but perinatal death and neonatal convulsions were significantly lower in the DHA group. Christopher Ramsden presented a detailed analysis of data from the Sydney Diet Heart Study in which linoleic acid intakes in middle-aged men with coronary 3

4 n report heart disease increased from 8% to 15% of energy at the expense of saturated fat consumption. In a follow-up of 2 to 7 years, all cause mortality increased by 62%, CVD mortality by 70% and CHD mortality by 74% in the intervention group compared with the no-intervention control group. This analysis provides additional evidence that high intakes of linoleic acid are associated with increased risk of mortality, especially from heart disease. Richard Bazinet discussed the uptake and metabolism of PUFAs into the brain using radiolabelled fatty acids. Some PUFAs, such as ARA and DHA, are highly conserved and recycled, whereas others, such as EPA, are rapidly removed from the brain largely by betaoxidation. These observations would explain why EPA levels are very low in the brain. Gunter Eckert reported that the brains of aged animals or those with neurodegenerative diseases exhibit reduced mitochondrial function, increased oxidative stress and greater synaptic dysfunction. Brain cells and mitochondria from aged brains have lower ATP levels, reduced respiration and less DHA. The provision of fish oil to young or old animals increased DHA concentrations in the brain, improved mitochondrial respiration and promoted the production of ATP. James Ntambi described the activity of stearoyl-coa desaturase (SCD) enzyme in skin and its function in the synthesis of oleate and palmitoleate. Animals lacking this enzyme develop sebaceous gland hypoplasia and progressive hair loss with decreased levels of monounsaturated fatty acids and increased skin levels of retinol and retinoic acid. Feeding these animals diets high in oleate fails to increase skin levels of oleate or restore sebaceous gland lipids and normal hair growth. These observations suggest that SCD is important for normal skin function and retinol homeostasis, with implications for several human skin disorders, such as acne and seborrheic dermatitis. Alex Richardson and Paul Montgomery presented data from the DHA Oxford Learning and Behavior Study. Behavior, working memory and reading ability correlated with blood DHA levels in a large sample of 7-9 year old children from Oxfordshire who read at the 33rd percentile or lower. As part of a subsequent intervention with 600 mg of DHA per day for 16 weeks, they found that normal school children with reading difficulties, (test scores at the 20th percentile) showed significant improvement in reading performance after the intervention compared with the placebo group. Improvement in Parent-rated behavior also improved, but there was no benefit on memory. Susan Carlson reported that healthy pregnant women supplemented with 600 mg of DHA per day from 14 weeks gestation until delivery had a significantly increased gestation time from 272 to 276 days and their infants were significantly heavier, longer and had greater head circumferences compared with infants of mothers consuming a placebo supplement. DHA levels in the mothers and offspring were also increased. 4

5 n CARDIOVASCULAR HEALTH Differential Effects of Omega-3 PUFAs on Lipoprotein Profiles in Alaska Natives Relationships between the pattern and size of circulating lipoproteins and cardiovascular disease have been extensively Patterns of plasma lipoproteins in Alaska Natives whose diet has undergone rapid change were evaluated to better understand the high cardiovascular risk in a population that once had almost no heart disease. studied, with high concentrations of low-density lipoprotein-cholesterol (LDL-C) and highdensity lipoproteincholesterol (HDL-C) particles associated with higher and lower disease risk, respectively. Recently, the effectiveness of various interventions to raise HDL-cholesterol levels has been questioned as a result of disappointing trial results. Dietary intakes of different fatty acid classes, PUFAs and carbohydrates affect the amounts, size and distribution of lipoprotein particles and contribute to changes in the risk of cardiovascular disease. For example, high intakes of omega-6 PUFAs are associated with reductions in LDL-C, while consumption of the long-chain omega-3 PUFAs (n-3 LC-PUFAs) DHA and EPA associates with lower triglycerides and sometimes higher HDL-C, with modest increases in LDL-C. A recent review discussed the effects of EPA and DHA together or separately on LDL-C and other lipids. It is also established that high intakes of carbohydrates are linked to smaller LDL particle size or increased particle density, as also observed in type 2 diabetes. This article describes findings from the ongoing study of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study. The population is unique in several ways because it has undergone rapid and dramatic dietary and lifestyle changes and experienced soaring rates of cardiovascular disease and diabetes. Formerly, these diseases were infrequent, in spite of high intakes of n-3 LC-PUFAs, high HDL-C and normal LDL-C levels. This report examines the lipoprotein dis tributions and particle sizes in residents of 8 villages in the Norton Sound Region of Alaska who were 17 to 91 years of age at enrolment. The sample of 977 participants comprised 74% of all age-eligible residents. Those with diabetes or taking hypolipidemic agents were excluded. Dietary intakes were assessed by a food frequency questionnaire previously developed and validated for the region. Assessment included all major traditional and key Figure. Relative size of the major lipoprotein subfractions measured in Angstroms. 1 Angstrom = 0.1 nm. Source: Lipoprotein Subfractions; Clinical Chemistry and Toxicology Advisory Committee Meeting December 2006, Center for Devices and Radiological Health. D.O. Wood. foods available in small village stores. Fasting blood samples were obtained at baseline for lipid analysis and lipoprotein subclassification in plasma. Lipoprotein subfractions were analyzed by NMR spectroscopy as described in detail in the paper. Nomenclature for different lipoprotein subfractions differs with the analytical methodology, as illustrated and compared in a presentation by Wood (Figure). The distribution of lipoprotein fractions differed between sexes with women having lower total VLDL and LDL particles and higher concentrations of total and large HDL. For LDL, women had significantly fewer small particles, but higher concentrations of larger ones. The values are summarized in Table 1. Table 1. Mean ± SD lipoprotein particle distribution in 977 adult Alaska natives Lipoproteins* (nmol/l) Women Men P VLDL Total 58.3 ± ± LDL Total 1025 ± ± 349 <0.001 Large 554 ± ± 172 <0.001 Small 450 ± ± 349 <0.001 HDL Total 29.6 ± ± 5.8 <0.001 Large 7.2 ± ± 3.7 <0.001 * Particle sizes: large LDL, nm; small LDL, nm; large HDL, nm. 5 PUFA Newsletter August 2011

6 The median total n-3 PUFA consumption, primarily from n-3 LC-PUFAs, was 2.6 g/day (0.8% energy) for women and 3.0 g/day (0.7% energy) for men, intakes that approximate the highest intakes of n-3 PUFAs in middleaged Japanese adults. In women, Women had lower total VLDL and LDL particles and higher concentrations of total and large HDL compared with men. Both sexes consumed large amounts of n-3 LC-PUFAs with median intakes of 2.6 and 3.0 g/day for women and men, respectively. higher intakes of n-3 LC-PUFAs were significantly associated with smaller VLDL size. Women with higher n-3 LC-PUFA intakes also had larger HDL particles and lower triglyceride levels (Table 2). There were no significant associations between n-3 LC-PUFAs and the number or size of LDL particles or total LDL-C concentrations. In men, higher intakes of n-3 LC-PUFAs were associated with slightly but significantly increased LDL particle size and larger HDL particles, but triglycerides were not significantly reduced. These results are summarized in Table 2. Individuals with higher n-3 LC-PUFA intakes also had lower intakes of carbohydrates and sugars. Higher intakes of total carbohydrates were associated with higher concentrations of large VLDL particles and chylomicrons in both sexes. However, the carbohydrate and sugar intakes did not affect the associations between n-3 LC-PUFA consumption and lipoproteins except for small VLDL particles in men. The authors suggested that the decrease in the number of large VLDL particles and smaller average VLDL particle size with increasing n-3 LC-PUFA intakes might reflect greater catabolism of VLDL and thus, lower triglyceride concentrations. Increased availability of triglycerides, which exchange with HDL, would contribute to the increase in Table 2. Plasma lipoprotein particle concentration and size by quartile of dietary n-3 LC-PUFAs in 242 to 246 men and women in the GOCADAN study Lipoprotein concentration n-3 LC-PUFA intake and size Q1 Q2 Q3 Q4 P* Women Total VLDL particles, nmol/l 59.5 ± ± ± ± VLDL size, nm 46.3 ± ± ± ± Total LDL particles, nmol/l 1031 ± ± ± ± LDL size, nm ± ± ± ± Total HDL particles, nmol/l ± ± ± ± HDL size, nm 9.08 ± ± ± ± Triglycerides, mg/dl ± ± ± ± Men Total VLDL particles, nmol/l 58.3 ± ± ± ± VLDL size, nm ± ± ± ± Total LDL particles, nmol/l 1089 ± ± ± ± LDL size, nm ± ± ± ± Total HDL particles, nmol/l ± ± ± ± HDL size, nm 8.79 ± ± ± ± Triglycerides, mg/dl ± ± ± ± *Multivariate analysis adjusted for age, BMI, total energy intake and percent energy from fat. 6

7 large HDL particles observed in men and the increase in average HDL particle size seen in both sexes. Large HDL particles are considered less atherogenic than small ones. However, several investigators have emphasized the importance of HDL functionality, i.e., its In both sexes, higher intakes of n-3 LC-PUFAs were associated with larger HDL particle size, but only women had significantly smaller VLDLs and lower triglycerides as intake of n-3 LC-PUFAs increased. ability to promote reverse cholesterol transport from the periphery and its anti-inflammatory effects, in addition to the levels of HDL-C. A further caution about efforts to raise HDL-C levels as a way to reduce the risk of cardiovascular disease is the premature cessation of a recent clinical trial due to futility. The interpretation of the association between higher n-3 LC-PUFA intakes and larger average LDL particle size in men warrants care. Higher LDL-C and total LDL particle concentration were linked to greater carotid intima media thickness in an earlier report from this study. That study also reported a significant association between larger LDL size and plaque. The complex interactions among lipoprotein classes and subclasses make it difficult to interpret the true effects of high intakes of n-3 LC-PUFAs in this and other populations. In these Alaska natives, the protective associations usually observed with high intakes of n-3 LC-PUFAs and cardiovascular disease appear to be undermined by the adoption of an unhealthy diet. Annuzzi G, Rivellese AA, Wang H, Patti L, Vaccaro O, Riccardi G, Ebbesson SO, Comuzzie AG, Umans JG, Howard BV. Lipoprotein subfractions and dietary intake of n-3 fatty acid: the Genetics of Coronary Artery Disease in Alaska Natives study. Am J Clin Nutr 2012;95: [PubMed] Worth Noting Jacobson TA, Glickstein SB, Rowe JD, Soni PN. Effects of eicosapentaenoic acid and docosahexaenoic acid on lowdensity lipoprotein cholesterol and other lipids: a review. J Clin Lipidol 2012;6:5-18. [PubMed] Atrial Fibrillation More Mixed Findings on Omega-3s and Risk of Incident Atrial Fibrillation Data on the relationship between long-chain omega-3 PUFAs (n-3 LC-PUFAs) and the risk of developing atrial Data on the risk of incident, postsurgical or recurrent atrial fibrillation are notoriously inconsistent. Most reports found no association or a reduced risk. Do n-3 LC-PUFAs have any effect on the risk of atrial fibrillation? fibrillation are notoriously inconsistent. Whether examining the risk of incident atrial fibrillation in individuals with no history of the condition, risk following coronary surgery or the odds of recurrent atrial fibrillation, reports vary from reduced risk to no association or, in a rare instance, an adverse association. Finding ways to lower the risk of atrial fibrillation is important because the condition is associated with an increased risk of stroke, myocardial infarction ventricular arrhythmia and mortality (Figure). Current risk reduction strategies focus on restoring normal sinus rhythm, controlling symptoms and preventing strokes. There would be considerable patient benefit if one could reduce the risk of developing the condition or reduce or prevent subsequent episodes. Mixed findings have been reported for the consumption or status of n-3 LC-PUFAs and the risk of incident atrial fibrillation. In a recent study among older US adults without atrial fibrillation, those with higher total n-3 LC-PUFA or DHA levels in blood had a significant 29% Figure. Disordered blood flow in the atria of the heart as a result of atrial fibrillation. lower risk of the condition compared with those having lower levels. Similar results were reported in a Finnish study among men. Another study of older US adults observed that those who consumed tuna or other broiled or baked fish 1 to 4 times/week had a significant 28% lower risk of incident atrial fibrillation. A study among patients hospitalized for myocardial infarction reported a significant reduction in 1-year atrial fibrillation in patients with n-3 LC-PUFA supplementation. In contrast, the Rotterdam Study of 67-year-old adults without atrial fibrillation observed no association between fish or EPA and DHA consumption with subsequent risk of the condition. Similarly, data from the Women s Health Initiative indicated no association 7

8 between fish or n-3 intakes and risk of the condition among older women. A large cohort study among Danes found no association between fish consumption and incident atrial fibrillation. In the Framingham Study, fish consumption was not associated with risk, except in a small number of participants (5 of 21 at risk) who ate more than 4 servings of dark fish per week. These individuals experienced a significantly higher risk of the condition. Two meta-analyses of randomized controlled trials on the prevention of atrial fibrillation with n-3 LC-PUFAs concluded that these fatty acids were not associated with a reduced risk of developing the condition. Two new studies have reported findings about the consumption of fish or blood levels of n-3 LC-PUFAs and the risk of incident atrial fibrillation in older adults. Jason Wu and colleagues analyzed plasma phospholipid fatty acid data from 3,326 men and women, 74 years of age on average, who were free of atrial fibrillation or heart failure at baseline. Participants were enrolled in the Cardiovascular Health Study, a community-based sample of older adults. The investigators had previously reported a significant reduction in incident atrial fibrillation among those participants who consumed tuna or other baked fish 1 to 4 times/week. However, analysis Using biomarkers to assess n-3 LC-PUFA status, a large study in older adults reported a significantly lower risk of incident atrial fibrillation over 3 years as n-3 LC-PUFA or DHA status increased. of biomarkers avoids the errors associated with dietary intake data. The investigators measured plasma phospholipid fatty acids approximately 3 years after baseline. In a subset of samples, they evaluated the change in dietary exposure over time using blood samples obtained 13 years after baseline. With these data, they were able to adjust the regression data for regression dilution bias and estimate how usual n-3 LC-PUFA levels relate to atrial fibrillation. Consistent with their previous dietary associations, the investigators observed a significant reduction in the relative risk of incident atrial fibrillation with higher concentrations of total n-3 LC-PUFAs and DHA in plasma phospholipids in multivariate analysis (Table). After correction for regression dilution bias, the relative risk associated with the highest quartile of total n-3 LC-PUFAs was 0.57 (95% CI, ). A similar correction for DHA led to a relative risk of 0.65 (95% CI, ). In additional multivariate analysis, adjustment for plasma phospholipid total n-3 LC-PUFAs attenuated the previous association between fish consumption and atrial fibrillation by 82% for those consuming 1 to 4 fish servings a week. These results support data from the Finnish study noted above. In the second study, researchers led by Noelle Gronroos evaluated data from the Atherosclerosis Risk in Communities Study to determine whether the consumption of fish or plasma phospholipid levels of DHA and EPA were related to the risk of incident atrial fibrillation. There were 14,222 participants recruited from 4 US communities who averaged 54 years of age. Fish consumption was estimated from food frequency questionnaires. The investigators analyzed plasma phospholipid fatty acid concentrations in samples from 3,757 Minnesota participants. Those who had prevalent atrial fibrillation or whose race was neither white nor black or had implausible energy intakes were excluded from the analysis. The average followup time was 17.6 years. Table. Relative risk (95% CI)* of incident atrial fibrillation by quartiles of plasma phospholipid n-3 LC-PUFA concentration in 3,326 US adults with an average age of 74 years n-3 LC-PUFA Quartiles of Plasma Phospholipid Fatty Acid Concentrations Q1 Q2 Q3 Q4 P for trend Total n LC-PUFAs ( ) ( ) ( ) DHA ( ) ( ) ( ) 0.01 DPA ( ) ( ) ( ) 0.24 EPA ( ) ( ) ( ) 0.30 *Expressed as hazard ratios. 8

9 The consumption of all fish, canned tuna, oily fish or other fish and of DHA plus EPA was not associated with risk of incident atrial fibrillation in multivariate analysis, regardless of the amount or type of fish consumed. Furthermore, plasma phospholipid A second large study of fish consumption and the risk of incident atrial fibrillation reported no significant association with fish, type of fish or DHA + EPA intakes over nearly 18 years. DHA + EPA were not associated with risk for incident atrial fibrillation. For DHA alone, the association was U-shaped among the quartiles of DHA, with the greatest risk observed in the first and fourth quartiles. EPA was not associated with risk. Thus, this large cohort study supports four other prospective studies that failed to show an association between n-3 LC-PUFAs and incident atrial fibrillation. It is noteworthy that the highest quartile of tuna or baked fish consumption in the Wu study reflected more than double the amount consumed in the Gronroos et al. study, suggesting that the amount of n-3 LC-PUFAs consumed could be important. Dose might also explain the differences observed in this study and those reported in the Finnish and Cardiovascular Health Studies for plasma phospholipid DHA concentrations. Two additional reports are also inconsistent, but measured different characteristics. One observed a significantly greater risk of atrial fibrillation with higher plasma total free fatty acids in 75-year-old adults monitored for 10 years. Individual free fatty acids were not reported. Two additional reports bear on the relationship between n-3 LC-PUFAs or other fatty acids and incident atrial fibrillation. The first is an additional analysis from the Cardiovascular Health Study by Khawaja and colleagues who examined the relationship between total plasma free fatty acids and the risk of incident atrial fibrillation in 75-yearold US adults. The rationale for examining the association between free fatty acids and atrial fibrillation is that free fatty acids are elevated in individuals with type 2 diabetes, hypertension, obesity and inflammation who also face a higher risk of the condition. There is no previous report describing a relationship between plasma free fatty acids and atrial fibrillation risk. The sample included 4,175 participants without prevalent atrial fibrillation who had baseline fatty acid data. Atrial fibrillation risk was examined against quartiles of free fatty acids and in regression models using free fatty acids as a continuous variable, adjusting for age, gender, race and other confounding variables. After an average of 10 years follow-up, there was a statis tically significant 29% greater risk of atrial fibrillation between the highest and lowest quartiles of free fatty acid concentrations. Analysis of the data after 5 years of follow-up, estimated the risk as 39% higher. Participants in the highest quartile of free fatty acids were older, more likely to be women and had higher adiposity, triglycerides, C-reactive protein, hypertension, type 2 diabetes and other cardiovascular risk factors. Thus, the positive association between high free fatty acid levels and risk of incident atrial fibrillation is consistent with other reports linking higher plasma free fatty acids with different cardiac arrhythmias. Individual free fatty acids were not reported. The fourth paper in this discussion examined the differences in n-3 and n-6 PUFA content in the serum of 110 patients with atrial fibrillation, of whom 36 also had a history of ischemic heart disease. The mean age of the participants was 66 years. Two control groups were included, 46 individuals with ischemic heart disease and no atrial fibrillation and 36 healthy volunteers without atrial fibrillation or cardiac disease. Participants with atrial fibrillation in each group were further stratified by whether they had paroxysmal or persistent types. Participants with ischemic heart disease were more likely to have hypertension, dyslipidemia and diabetes. Those with ischemic heart disease and atrial fibrillation also had significantly larger left atria compared with healthy controls. In a small study in Japan, serum EPA was higher in patients with persistent or permanent atrial fibrillation compared with all other participants. Risk of atrial fibrillation was higher with greater levels of EPA, but not DHA. Patients who experienced atrial fibrillation, but did not have ischemic heart disease, had significantly higher plasma phospholipid EPA and DHA concentrations than all other groups. Although EPA concentrations were higher in the patients with both heart disease and atrial fibrillation compared with those having only ischemic heart disease, DHA concentrations did not differ among heart disease groups or controls. Patients with 9

10 persistent or permanent atrial fibrillation also had higher EPA concentrations compared with controls or patients with paroxysmal atrial fibrillation. DHA concentrations were higher than controls only in patients with paroxysmal atrial fibrillation. In multivariate analysis of the risk of atrial fibrillation according to patient clinical characteristics, only EPA was statistically significant, but the risk was just 2% greater. The small numbers of patients in the groups most likely limited the strength of this analysis. The four recent papers investigating the relationship of n-3 LC-PUFAs to incident atrial fibrillation have not resolved the inconsistencies among observational studies on this topic. However, they have raised the possibility that factors such as dose of n-3 LC-PUFAs consumed, plasma free fatty acids and high plasma EPA, all might be relevant. These findings need confirmation before they can be made into nutrition recommendations. Finally, two recent meta-analyses of n-3 LC-PUFAs and atrial fibrillation suggest that cohort and randomized trials do not support a major effect of fish or n-3 LC-PUFA consumption on reducing risk. However, n-3 LC-PUFAs reduce risk of postoperative atrial fibrillation, but not recurrence of the condition. Wu JH, Lemaitre RN, King IB, Song X, Sacks FM, Rimm EB, Heckbert SR, Siscovick DS, Mozaffarian D. Association of plasma phospholipid long-chain omega-3 fatty acids with incident atrial fibrillation in older adults: The Cardiovascular Health Study. Circulation 2012;125: [PubMed] Gronroos NN, Chamberlain AM, Folsom AR, Soliman EZ, Agarwal SK, Nettleton JA, Alonso A. Fish, fish-derived n-3 fatty acids, and risk of incident atrial fibrillation in the Atherosclerosis Risk in Communities (ARIC) study. PLoS One 2012;7:e [PubMed] Khawaja O, Bartz TM, Ix JH, Heckbert SR, Kizer JR, Zieman SJ, Mukamal KJ, Tracy RP, Siscovick DS, Djoussé L. Plasma free fatty acids and risk of atrial fibrillation (from the Cardiovascular Health Study). Am J Cardiol 2012;110: [PubMed] Tomita T, Hata T, Takeuchi T, Oguchi Y, Okada A, Aizawa K, Koshikawa M, Otagiri K, Motoki H, Kasai H, Izawa A, Koyama J, Hongo M, Ikeda U. High concentrations of omega- 3 fatty acids are associated with the development of atrial fibrillation in the Japanese population. Heart Vessels 2012; Jun 14. [PubMed] Worth noting He Z, Yang L, Tian J, Yang K, Wu J, Yao Y. Efficacy and safety of omega-3 fatty acids for the prevention of atrial fibrillation: A meta-analysis. Can J Cardiol 2012; June 6. [PubMed] Khawaja O, Gaziano JM, Djoussé L. A meta-analysis of omega-3 fatty acids and incidence of atrial fibrillation. J Am Coll Nutr 2012;31:4-13. [PubMed] n MATERNAL AND INFANT HEALTH No Less Gestational Diabetes or Preeclampsia with DHA Supplementation in Pregnancy Preeclampsia, a condition of hypertension and proteinuria that may develop late in pregnancy, and gestational diabetes mellitus are two of the most common medical complications of pregnancy. Women with hypertension prior to Preeclampsia and gestational diabetes are among the most frequent complications in pregnancy. A recent study examined whether high-dose DHA might reduce the risk of these conditions in healthy pregnant women. pregnancy are more likely to develop preeclampsia, which then increases the risk of preterm delivery. Preeclampsia and eclampsia together are among the top 3 causes of maternal morbidity and mortality worldwide. Preeclampsia affects 3% to 5% of all US pregnancies, but the prevalence is higher in developing countries with limited access to prenatal care. The risk of developing preeclampsia is greater in women with higher body mass index and excess weight gain during pregnancy. Gestational diabetes mellitus is abnormal glucose tolerance that is first detected in pregnancy. Its prevalence, according to a recent literature review, was estimated between 1.7% and 11.6% for advanced economies, with ethnicity a contributing factor. However, the Hyperglycemia and Adverse Pregnancy Outcome Study reported a frequency of 17.8% (range 9.3 to 25.5%), in a multi-center study conducted in the U.S. using a 75-g oral glucose tolerance test in mid to late gestation. The higher prevalence estimate might reflect the rapidly increasing incidence of type 2 diabetes worldwide. 10

11 Factors that increase the likelihood of developing gestational diabetes include excessive weight gain in early pregnancy (15 to 18 weeks gestation), overweight or obesity prior to pregnancy, high blood pressure before and during early pregnancy, older maternal age (>30 y in white Caucasians, >25 y in African Americans), high-risk ethnicity (Hispanic, Asian, African American, Native American), family history of diabetes, glucosuria or impaired glucose tolerance and previous birth of an infant over 4,100 grams (9 lb). Gestational diabetes increases both the mother s and child s risk of developing type 2 diabetes and obesity. It is also associated with relatively small, but significantly greater, risks for fetal macrosomia (excessive birthweight), large for gestational age birthweight, perinatal mortality, preeclampsia and cesarean delivery. Gestational diabetes may also put the offspring at risk of adverse growth, and affects attention span and motor functions. Changes in maternal phospholipid PUFAs in the third trimester occur that are not observed in women without gestational diabetes. Gestational diabetes is also associated with higher serum concentrations of insulin, homeostasis model assessment and glycerol compared with control pregnancies. The same study reported increased concentrations of glucose and free fatty acids in the cord blood of affected women, with free fatty acids correlated with neonatal weight and fat mass. Others have reported higher triglyceride concentrations in gestational diabetes, which have been linked to large for gestational age infants. Women with gestational diabetes were reported to have higher plasma phospholipid DHA concentrations compared with control women, but concentrations of ARA did not differ between the two groups. Others reported that women newly diagnosed with gestational diabetes had higher levels of ARA in their plasma phospholipids and DHA in plasma triglycerides compared with non-diabetic pregnant women. These investigators noted that DHA levels in phospholipids and cholesteryl esters did not differ between the two groups. Evidence suggests that lipid metabolism is altered in gestational diabetes, but the effects on LC-PUFAs are inconsistent. Infants of mothers with gestational diabetes have lower LC-PUFA concentrations, especially of DHA. In contrast to the mothers, fetal and neonatal erythrocyte concentrations of ARA and DHA were lower in the offspring of mothers with gestational diabetes compared with controls, suggesting impaired LC-PUFA transport or fetal accretion in gestational diabetes. A different study reported significantly lower DHA concentrations in the plasma phospholipids of neonates born to mothers with gestational diabetes, with reductions in ARA not reaching statistical significance. These differences were not attributable to different dietary intakes between the two groups of mothers, as the diabetic mothers consumed significantly more DHA than the controls. Epidemiological data are inconsistent on the association between the intake of n-3 LC-PUFAs and the risk of developing type 2 diabetes, but there are no data from randomized trials on the effect of n-3 LC-PUFA supplementation and the risk of gestational diabetes. Some studies suggest that women with higher intakes of n-3 LC-PUFAs are less likely to develop preeclampsia, but a systematic review concluded that there was no clear difference in the risk of this condition with marine oil supplementation. These questions were addressed in a multi-center, randomized, controlled study of 2,399 healthy pregnant women who were supplemented with 800 mg per day of DHA from DHA-rich fish oil from approximately the 21st week of gestation through delivery. Control group women consumed the equivalent amount of blended vegetable oil. The primary outcomes were incident preeclampsia defined as pregnancy-induced hyper tension and proteinuria, and gestational diabetes defined as mid-pregnancy fasting glucose >5.5 mmol/l and/or a 2-hr glucose concentration >8.0 mmol/l after a 75-g glucose load. The investigators also included pregnancy and birth outcomes and perinatal complications. The overall Maternal DHA incidence of supplementation was p r e e c l a m p s i a was 5% according to measures not associated with the occurrence of preeclampsia of hypertension or gestational diabetes. a n d c l i n i c a l However, the infants of diagnosis, while supplemented mothers had the incidence higher birthweights and of gestational lengths and fewer were diabetes was 6% born at < 2,500 g or before 34 weeks gestation. based on oral glucose-tolerance tests and 8% by clinical diagnosis. The incidence of either condition and of pregnancyinduced hypertension did not differ between the two groups. Infants of mothers consuming the DHA oil had significantly higher birthweights and lengths, but the 11

12 z scores (standard deviations from the mean) did not differ between the groups. There was a significantly lower rate of birthweight <2,500 g in the DHA group (P = 0.03) and significantly fewer births before 34 weeks gestation, as previously reported. The occurrence of macrosomia, defined as birthweight >4,000 g, was significantly higher in the fish oil group (16.3%) compared with the controls (12.8%), but there was no difference between groups in the number of large for gestational age infants. Mothers consuming supplemental DHA had significantly fewer perinatal complications and deaths compared with the control group. Perinatal complications and deaths were significantly higher in the controls than DHA group. Five control group infants experienced neonatal convulsion or brain injury at birth, whereas none in the DHA group did (P = 0.03 for each complication). There were 12 perinatal deaths (stillbirth or death in the first 28 days) in the control group and 3 in the DHA group (P = 0.03). The absence of effect on the incidence of gestational diabetes is in accord with studies of fish oil supplementation in healthy volunteers and those with impaired glucose tolerance, which have reported no effect of n-3 LC-PUFAs on insulin sensitivity or glucose control. Although DHA supplementation in the last half of pregnancy was not associated with risk of gestational diabetes or preeclampsia, the significant reduction in neonatal complications and death merit attention. Zhou SJ, Yelland L, McPhee AJ, Quinlivan J, Gibson RA, Makrides M. Fish-oil supplementation in pregnancy does not reduce the risk of gestational diabetes or preeclampsia. Am J Clin Nutr 2012;95: [PubMed] Is Preterm Infant Development Undermined by High Linoleic Acid and Low DHA? Preterm infants, who have very little body fat, are especially dependent on postnatal feeding for their nutrition needs. Because the transfer of LC-PUFAs from the placenta, which is most rapid in the third trimester, has been interrupted, these infants must obtain their LC-PUFAs from breast milk or preterm infant formula. There is some evidence that LC-PUFA supplementation of preterm infants improves neurodevelopmental outcomes, but several recent reviews report inconsistent evidence of benefit from studies that vary in dose, timing and methods of testing. Nevertheless, accretion of DHA in brain depends on dietary supply. Although preterm infants are born with shortfalls in LC-PUFAs, evidence that supplementing these infants with LC-PUFAs or DHA improves outcomes is inconclusive. Could the mixed findings be related to other fatty acids? The association between prenatal LC-PUFA status and neurodevelopmental outcomes depends in part on the age at which the outcomes are measured. As discussed by Hadders- Algra, outcomes before the age of 4 months are related to the exposure to both DHA and ARA, while those measured after this critical time are dependent mainly on DHA concentrations. Other factors, such as maternal prepregnancy nutritional status and diet during pregnancy, may also contribute to the outcomes. Typical maternal diets in many Western countries are very low in LC-PUFAs, especially EPA and DHA, and are high in n-6 PUFAs, particularly linoleic acid. This dietary pattern affects breast milk fatty acid composition. High n-6 PUFAs and Mead acid, a marker of essential fatty acid deficiency, have been associated with poorer early developmental outcomes in preterm infants. These same authors also reported that early developmental status in preterm infants was associated with later developmental outcomes. The present study investigated whether the developmental outcomes in preterm infants at 3 months of age and later developmental evaluations were associated with early breast milk LC-PUFA concentrations or the infants plasma phospholipids at 44 weeks gestational age. Fifty-one preterm infants with median gestational age of 34 weeks (interquartile range, 32 to 35 weeks) participated in the study. Two mothers were unable to breastfeed and their infants received human milk from a milk bank. Seven mothers stopped breastfeeding before 44 weeks gestational age. The median length of exclusive breastfeeding was 3 months. Early development was evaluated at age 3 months using quality of general movements, a neuromotor assessment appropriate for ages 2 to 4 months post-term with high predictive value for developmental disorders. Later development, e x c e p t f o r the 3-month evaluation, was assessed using 12

13 the Bayley s Scales of Infant Development-II at 3, 6, 10 and 18 months corrected age. Breast milk fatty acids were measured in a pooled sample collected over 24 hours one week after delivery. Infant fatty acids were measured in plasma phospholipids from 45 infants taken at 44 weeks gestational age (1 month corrected age). Essential fatty acid deficiency (EFAD) was calculated as the ratio of Mead acid (20:3n-9) to ARA, sometimes called the Holman Index. At 3 months corrected age, the quality of the infants general movements was negatively associated with the EFAD index of breast milk sampled at one week postnatal. The Bayley s scores for mental and motor indexes were also inversely associated with the concentration of linoleic acid and the ratio of total n-6:n-3 PUFAs in breast milk, suggesting an adverse effect of high concentrations of linoleic acid on early development in preterm infants. At 6 months corrected age, the Bayley s mental development index and emotional scores were negatively associated with linoleic acid concentrations in breast milk, but the emotional and orientation scores and motor index were positively associated with the infants phospholipid concentrations of DHA and ARA. Negative associations between the ratio of breast milk linoleic acid:alpha-linolenic acid and the mental development index and orientation score persisted until 10 months corrected age. In contrast, positive associations were observed for the infants phospholipid DHA concentration and mental, motor, orientation and emotional measures. By 18 months of age, only infant phospholipid DHA concentration was associated with the mental development index, while the ratio of ARA:DHA was negatively associated with motor and orientation evaluations. Adjustment of these relationships with confounding variables revealed a strong, positive influence of maternal education at all ages, but the pattern of negative associations with high breast milk linoleic acid content persisted. In the first 3 months of development, adjusted associations with breast milk fatty acids were significant only for n-6:n-3 PUFAs and the mental development index. At 6 months of age, breast milk linoleic acid was negatively associated with mental and emotional development and by 10 months only the linoleic:alpha-linolenic acid ratio was significantly inversely associated with orientation assessment. The adjusted analysis also showed that the infants phospholipid ARA:DHA ratio was consistently inversely associated with mental and motor development scores at 10 and 18 months of age and with orientation at At 3 months corrected age, the Bayley s mental development index was negatively associated with the ratio of total n-6:n-3 PUFA in breast milk. At 6 months of age, a similar relationship was observed with linoleic acid for mental and emotional development. 18 months. The combined effects of PUFAs, LCPUFAs and confounders explained up to 38% of the variability in the development scores. The consistent relationships between the fatty acids in early breast milk or infant phospholipids with several aspects of infant development from 3 to 18 months of corrected age underline the importance of the fatty acid composition of breast milk and, by implication, maternal fatty acid availability in late pregnancy for preterm infants. High levels of linoleic acid were consistently associated with poorer infant development assessments, while high levels of DHA had positive associations. Interestingly, breast milk fatty acid concentrations for DHA and ARA were higher than the worldwide averages for these LC-PUFAs. This observation might suggest that the negative effects of high linoleic levels in breast milk were not overcome by the amount of DHA available. Others have reported associations between mildly abnormal quality of general movements in 3-month-old term infants with low arachidonic acid and high Mead acid in umbilical arteries and infant erythrocytes, respectively. Mead acid is usually observed only in essential fatty acid deficiency. In one report, eye and hand coordination was negatively associated with cord blood ARA in children at 2.5 years of age. There are several other reports of adverse associations between Mead acid and various measures of neurodevelopment and learning. High levels of linoleic acid were consistently associated with poorer infant development scores, while high levels of DHA had positive associations. High levels of linoleic acid were consistently associated with poorer infant development scores, while high levels of DHA had positive associations. Although fatty acid ratios may obscure changes in the components of the ratio, high levels of linoleic acid were more consistently linked to negative developmental outcomes and DHA to positive outcomes through 6 months of age. Thereafter, higher ARA:DHA ratios were 13

14 negatively associated with several developmental outcomes, suggesting an imbalance between these fatty acids with potentially suboptimal consequences for infant development. Correlations do not demonstrate causal links, but in this study they were suggestive of PUFA imbalances in the infants phospholipid fatty acids and the breast milk of women consuming typical Swedish diets apparently adequate in n-3 LC-PUFAs and high in linoleic acid. Sabel KG, Strandvik B, Petzold M, Lundqvist-Persson C. Motor, mental and behavioral developments in infancy are associated with fatty acid pattern in breast milk and plasma of premature infants. Prostaglandins Leukot Essent Fatty Acids 2012;86: [PubMed] DHA-Supplemented Healthy Term Infants Score Higher in Gesture Communication Although the need for sufficient long-chain PUFAs to meet the postnatal Consistent benefits of LC-PUFA supplementation in term and preterm infants are elusive. Inconsistent findings might indicate that more sensitive assessment tools are needed and that time of evaluation is critical. In this study the Bayley Scales and MacArthur- Bates assessments were used to evaluate language development in term infants fed DHArich fish oil. developmental needs of pre- and term infants is well recognized, trials aimed at demonstrating the neurodevelopmental benefits of providing infants with abundant LC-PUFAs are inconclusive. For example, preterm infants fed 1% DHA from day 2 to 4 of life until term corrected age did not have increased Bayley Mental Development Index scores at 18 months corrected age, but in subgroup analysis, girls scores were higher. A recent meta-analysis of 12 trials using LC-PUFA-supplemented infant formula found no significant effect on early infant cognition at about 1 year of age in term or preterm infants. Although effects on growth appear minimal, some studies have reported better psychomotor development at 30 months of age and improved attention span at 5 years in children whose mothers consumed a modest supplement of DHA and breastfed their children. Several randomized controlled trials have reported significant benefits in visual acuity among infants fed formula containing at least 0.36% DHA and 0.72% ARA for 12 months and some have reported improved cognitive outcomes with LC-PUFA supplementation. Maternal supplementation with LC-PUFAs during pregnancy has also been associated with improved global neurodevelopment performance in the offspring. Some have argued that supplementation has been too low, developmental assessments insufficiently sensitive or inappropriate for the age of measurement or interventions have been too short. It has also been more difficult to demonstrate benefits in healthy term infants who usually have sufficient LC-PUFAs from placental transfer compared with preterm infants who face shortfalls in these nutrients. With these considerations in mind, Suzanne Meldrum and colleagues at the University of Western Australia conducted a randomized controlled trial of high-dose DHA-enriched fish oil supplementation for 6 months in 420 healthy term infants. The investigators evaluated infant plasma and erythrocyte fatty acids at birth and 6 months of age, language development at 12 and 18 months and neurodevelopment at 18 months. Breast milk samples were collected and analyzed for fatty acids at 3 and 6 months after delivery. Pregnant women with a history of allergy were recruited for the study, with exclusions for fish oil supplementation of 1 g/day or more, eating more than 3 fish meals/ week, pre-existing medical conditions or high-risk pregnancy or preterm delivery. Infants were randomized to receive 250 to 280 mg DHA/day from high-dose DHA ethyl ester-enriched fish oil supplements or the equivalent amount of olive oil placebo from birth until 6 months of age. The enriched fish oil supplement contained 280 mg DHA and 110 mg EPA and was intended to be a high dose. Capsules were given in the morning either in the formula or directly into the infant s mouth by squirting out the capsule contents. The MacArthur-Bates Communicative Development Inventories were used to assess the infants words and gestures at 12 and 18 months of age. Infants were also assessed at 18 months using the Bayley Scales of Infant and Toddler Development-III, which has subscales for language development, and the Achenbach Child Behavior Checklist for mental health and behavioral development. Of the 420 participants randomized at baseline, 287 infants completed the study, with dropouts more frequent in the fish oil group, due to the smell of the oil. Adherence was included in the analysis as a confounding variable. At 6 months, erythrocyte and plasma phospholipid DHA concentrations were higher in infants consuming the fish oil, while ARA showed no change in plasma 14

15 phospholipid and was and was significantly lower in erythrocytes. EPA levels were significantly higher only in the erythrocytes. There were no significant differences between the treatment groups for the standard or composite scores on the Bayley test at 18 months. Scores for the Child Behavior Checklist categories were analyzed as two groups, either above or below a T-score of 50 because scores were skewed. Higher scores for fish-oilsupplemented children were observed only for anxious or depressed behavior (47.6 vs 33.4, P = 0.02). This unexpected observation eludes explanation. In spite of having fewer completed assessments at 12 and 18 months, children in the fish oil group had significantly better gesture communication compared with the placebo toddlers, as assessed by the MacArthur-Bates Communicative Development Inventories. Whether the scores were expressed as raw scores or percentile rank, total and later gestures were consistently better at 12 and 18 months in the fish oil group (Table). Scores for phrases and words understood and spoken were nearly always higher in the fish oil children, although these scores were not significantly different from the placebo group, in part because of the wide variation in scores. Interestingly, the language subscales on the Bayley Scales of Infant and Toddler Development, 3rd edition, did not differ significantly between the two groups. However, the MacArthur-Bates Communication evaluation revealed no between-group difference in words and phrases spoken or understood, yet detected significant differences favoring the fish oil infants in later and total gestures. These differences may suggest that the latter assessment is better suited to evaluate language development. Previous reports of the associations between n-3 LC-PUFA supplementation and language development have been mixed, with recommendations that tools more sensitive than global developmental scores be used. For example, a recent study of DHA supplementation of pregnant women reported that 18-month-old girls from the supplemented mothers had lower mean language scores and a higher risk of delayed language development compared with boys. This study used the recent third edition of the Bayley Scales to assess Table. Raw scores at 12 and 18 months of age for the MacArthur-Bates Communicative Development Inventory for healthy term infants supplemented with high-dose, DHA-enriched fish oil or placebo from birth to 6 months of age Assessment DHA-Enriched Fish oil (mean ± SD) Placebo (mean ± SD) P 12-month raw scores Phrases understood ± ± Words understood 68.3 ± ± Words spoken 6.11 ± ± Early gestures ± ± Later gestures ± ± Total gestures ± ± month raw scores Phrases understood ± ± Words understood ± ± Words spoken ± ± Early gestures ± ± Later gestures ± ± Total gestures ± ±

16 language development. In another study, preterm infants fed 3 times the standard amount of DHA after birth showed no change in language development in early childhood. Others reported lower parent-assessed vocabulary scores at 14 months of age in children consuming a DHA-supplemented formula without ARA compared with those receiving unsupplemented formula or those who were breastfed, but the differences were not detectable at 39 months of age, using age-appropriate tests. Healthy term infants supplemented from birth with DHA-rich fish oil had significantly higher scores at 12 and 18 months of age in later and total gestures compared with the placebo group. Higher scores for later and total gestures in the D H A - e n r i c h e d fish oil supplemented group described here suggest that DHA may be linked to improved spoken language and communi cation. More extensive use of gestures has been associated with communication, linguistic development and greater vocabulary, and in older children with conveying spatial relations. These observations suggest potential links to the development of vocabulary in these children. Thus, in spite of no detectable benefit on global developmental scores, greater availability of DHA to healthy term infants may have positive effects on language development. Meldrum SJ, D Vaz N, Simmer K, Dunstan JA, Hird K, Prescott SL. Effects of high-dose fish oil supplementation during early infancy on neurodevelopment and language: a randomised controlled trial. Br J Nutr 2012;21:1-12. [PubMed] Worth Noting Makrides M. DHA supplementation during the perinatal period and neurodevelopment: Do some babies benefit more than others? Prostaglandins Leukot Essent Fatty Acids 2012; doi: /j.plefa (June 12). [PubMed] Meldrum SJ, D Vaz N, Casadio Y, Dunstan JA, Niels Krogsgaard-Larsen N, Simmer K, Prescott SL. Determinants of DHA levels in early infancy: Differential effects of breast milk and direct fish oil supplementation. Prostaglandins Leukot Essent Fatty Acids 2012;86: [PubMed] Kelsall CJ, Hoile SP, Irvine NA, Masoodi M, Torrens C, Lillycrop KA, Calder PC, Clough GF, Hanson MA, Burdge GC. Vascular dysfunction induced in offspring by maternal dietary fat involves altered arterial polyunsaturated fatty acid biosynthesis. PLoS ONE 7:e [PubMed] n MENTAL HEALTH & COGNITION Depressive Illness EPA + DHA Associated with 25% Lower Risk of Depressive Symptoms in US Adults Substantial evidence links low blood concentrations of long-chain PUFAs (LC-PUFAs), especially n-3 LC-PUFAs, to the risk of depressive illness, yet the data are inconsistent. For example, serum n-3 LC-PUFAs were not associated with severe depression in middle-aged Finnish men, but were significantly lower in patients with recurrent depressive illness. Others have reported significantly lower concentrations of DHA or total n-3 LC-PUFAs in patients with major depressive illness and bipolar disorder. L o w L C - P U F A Data from a nationally concentrations representative sample of may be unrelated to dietary intake US adults linking fish or in randomized n-3 LC-PUFA consumption or case-control with a lower risk of studies, although depressive symptoms has observational been lacking until now. studies suggest This report suggests that that low seafood n-3 LC-PUFA intakes may consumption i s be important for all adults. associated with higher rates of various mental disorders including depressive illness. Long-term fish intake was associated with less severe depressive symptoms in older adults in the Mediterranean Islands Elderly study. Fish is the main dietary source of n-3 LC-PUFAs. These observations suggest that increasing the intake of fish or n-3 LC-PUFAs might have a beneficial effect in patients with depressive illness and other mental disorders. One meta-analysis concluded that supplements containing at least 60% of the total n-3 LC-PUFAs as EPA were effective against primary depression. Another study reported that n-3 LC-PUFA supplementation was associated with improved depressive symptoms and quality of life in elderly women. But another systematic review and meta-analysis of 13 randomized trials of n-3 LC-PUFA treatment of major depressive disorder concluded that n-3 LC-PUFAs gave no significant benefit, except for a trend toward increased efficacy among lower quality trials. There was significant heterogeneity and publication bias in the trials. Some encouraging reports of benefit, the limited efficacy and adverse side-effects of current medications and a strong rationale for the use of n-3 LC-PUFAs in depressive illness and mood disorders support additional investigation of these fatty acids for depressive 16

17 illness and other mental disorders. Further, the burden of mental health illness continues to grow. Predictions about world health suggest that unipolar depressive disorders will be the world s leading cause of ill health and premature death by In the U.S., the 12-month prevalence of a major depressive episode was estimated at 8.3% for all adults 18 years of age or more, the highest rate among 10 developed countries participating in the WHO World Mental Health Survey Initiative. Associations between fish consumption and the prevalence of major depressive illness in several countries have been reported, based on intake estimates according to fish disappearance from the marketplace (food balance sheets). Claire Hoffmire and colleagues at the University of Rochester, USA, conducted a more detailed examination of this relationship using fish and EPA + DHA consumption estimates from the National Health and Nutrition Examination Survey (NHANES) and the Patient Health Questionnaire to estimate the prevalence of depressive symptoms. The Patient Health Questionnaire is a self-assessment of the frequency of various signs and symptoms of depressive illness over the past 2 weeks. NHANES is a national, populationbased survey that uses multistage, stratified and clustered sampling to obtain samples representative of the total US, non-institutionalized, civilian population of adults 20 years and older. Dietary information about fish intake was collected from a food frequency questionnaire and EPA + DHA consumption was estimated from two 24-hour dietary recalls. Total fish intake over a 30-day period was not associated with the occurrence of mild or moderate to severe depressive symptoms, regardless of the frequency consumed. Likewise, non-breaded fish was unrelated to the symptoms of depression. In contrast, the consumption of any breaded fish meals was associated with a significantly greater risk of depressive symptoms, although increasing frequency of consumption compared with low consumption did not increase the risk. The consumption of EPA + DHA was associated with a 25% lower risk of depressive symptoms in multivariate analysis, although the reduced risk was consistent across all levels of intake. Considering the limitations of dietary intake estimates, which the authors discuss in detail, these observations further support the benefits of consuming nonbreaded fish and EPA + DHA reported by others. The authors assume that the consumption of breaded fish implies fried fish, the consumption of which has previously been linked to greater risk of incident heart failure in women and older adults, and death The consumption of EPA + DHA was associated with a 25% lower risk of depressive symptoms in a nationally representative sample of US adults 20 years of age or more. Eating any amount of breaded fish was linked to a higher risk of symptoms. from ischemic heart disease in adults 65 years of age or more. What distinguishes this report from previous epidemiological studies on n-3 LC-PUFAs and mental disorders is that it includes all adults 20 years of age and older regardless of risk status. As mental illness can occur at any age, the observed associations suggest that fish and n-3 LC-PUFA consumption are likely to be important throughout life. Hoffmire CA, Block RC, Thevenete-Morrison K, van Wijngaarden E. Associations between omega-3 polyunsaturated fatty acids from fish consumption and severity of depressive symptoms: an analysis of the National Health and Nutrition Examination Survey. Prostaglandins Leukot Essent Fatty Acids 2012;86: [PubMed] Neither Folate Nor Long-Chain Omega-3s Affect Depressive Symptoms in Heart Patients Depressive symptoms and anxiety are common occurrences among patients with coronary heart disease. These conditions adversely affect the prognosis of heart disease patients and increase the risk of cognitive decline. For example, one Patients with both cardiovascular disease and major depressive symptoms have a higher risk of further heart morbidity and mortality. Could treatment with long-chain omega-3 PUFAs improve the prospects and outcomes in these individuals? study reported that the risk of major adverse cardiac events over 2 years in men with acute coronary syndrome was increased in the presence of depressive illness and elevated C-reactive protein. A recent analysis of the prevalence of depressive symptoms in patients from 22 countries who were hospitalized for coronary heart disease reported a prevalence 17

18 in men of 8.2% to 35.7% and in women of 10.3% to 62.5%. In the U.S., the point prevalence ranges from 15% to 23% for patients with coronary heart disease. Depressive illness increases the risk of further cardiac morbidity and mortality and carries its own morbidity, which further undermines a patient s prognosis and quality of life. Conversely, patients with major depressive disorder without cardiovascular disease had higher cardiovascular risk factors and lower omega-3 index values compared with sex-matched healthy controls. A common factor in the origins and amelioration of cardiovascular and mental disorders is diet. Nutrients and dietary patterns associated with improved mental health include magnesium, folate, zinc, selenium, vitamins B 12 and B 6, n-3 LC-PUFAs and traditional rather than Western diets. Low folate status was reported in individuals with depressive symptoms, while higher serum folate was correlated with a lower occurrence of depressive symptoms in Japanese adults. Supplementation with folic acid plus vitamins B 6 and B 12 was not associated with reducing the severity or incidence of depressive symptoms over 2 years in older men, but low vitamin B 12 plus supplemental folate was linked to more rapid cognitive decline in older adults in the Framingham study. On the other hand, low plasma B 12, but not folate, was associated with higher depression and poorer cognition scores in 2 large US adult cohorts. Thus, several B vitamins may be associated with the risk of depressive illness, but the interactions among them and the levels involved are highly variable. Less is known about the relationship Long-chain omega-3 between n-3 LC-PUFA PUFAs have been status or treatment associated with in patients with cardiovascular disease improved outcomes and lower risks in patients and depressive illness. with cardiovascular One study in postmyocardial infarction disease or major depressive symptoms patients reported who tend to have low that patients with omega-3 status. depressive illness had significantly higher ratios of ARA:EPA compared with nondepressed patients, suggesting the n-3 LC-PUFA levels were lower in the depressed patients. A recent study assessing plasma n-3 LC-PUFAs in patients with chronic heart failure and major depressive disorder reported significantly greater survival over a median follow-up time of 496 days (1.4 years) in those with higher concentrations of DHA (3.1% vs 2.3%) and EPA (0.5% vs 0.3%) compared with those who died. However, a study of low-dose EPA + DHA supplementation for 40 months in survivors of myocardial infarction reported that neither these fatty acids nor alpha-linolenic acid affected depressive symptoms. Subgroup analysis in that study reported an inverse association between n-3 LC-PUFA supplementation and depressive symptoms. This article describes findings from a secondary analysis of a randomized controlled trial in patients who had had a myocardial infarction, unstable angina or ischemic stroke within the preceding year. Participants were randomly assigned to consume one of the following supplements: B vitamins (folate, vitamins B 6 and B 12 ), 600 mg of n-3 LC-PUFAs with EPA:DHA of 2:1, both supplements or a placebo for 1 year. Depressive symptoms were assessed with the French version of the self-administered Geriatric Depression Scale given at 3 and 5 years of follow-up. The final sample included 2,000 participants with a mean age of 61 years and a median follow-up of 4.7 years. At baseline, 6.2% of participants reported using antidepressant medications. For statistical analysis, participants were categorized in two groups: those with evidence of any depression who had an evaluation score of >10, and those without depressive symptoms having scores 10. At follow-up, 31.3% of participants reported any depressive symptoms, with 6.7% having moderate to severe symptoms (scores >20). Women were more likely than men to report symptoms of depressive illness and use of antidepressant medications. In the total sample and analysis by sex, consumption of B vitamins was not related to the presence of depressive symptoms. Similarly, there were no effects of n-3 LC-PUFA supplementation associated with depressive symptoms among all participants. However, when the analysis was stratified by sex and adjusted for multiple confounders, consumption of n-3 LC-PUFAs was positively associated with depressive symptoms in men (odds ratio = 1.28; CI, ), but not in women (odds ratio = 0.78; CI, ). The association remained when participants who used antidepressants at baseline were excluded. In a separate report, the investigators observed no significant effect of B vitamin or n-3 LC-PUFA supplementation on the occurrence of hard coronary events. 18

19 In this study of Supplementation with 600 patients with cardiovascular mg of EPA + DHA per day disease and varying and B vitamins in patients degrees of depressive symptoms, with cardiovascular disease and depressive increased intake of symptoms was associated B vitamins or lowdose n-3 LC-PUFAs with changes in depressive symptoms. In subgroup was not associated analysis by sex, men with changes in experienced a positive depressive symptoms. Subgroup association with EPA + DHA supplementation. analysis of n-3 LC-PUFA supplementation by sex revealed an unexpected positive association between n-3 LC-PUFAs and depressive symptoms. The authors pointed out that they did not have baseline measurements of depressive symptoms so that changes in symptoms over time and their onset were not measured. No follow-up data on blood fatty acid levels were presented. It requires randomized controlled trials to verify the potential adverse effect of n-3 LC-PUFA supplementation on depressive symptoms in men with cardiovascular disease. The study may have used too little n-3 LC-PUFAs to detect improvements in depressive symptoms and would be worth repeating with a dose close to 1 g/day with a preponderance of EPA, which has been reported to be more effective than DHA in treating depression in some studies. Andreeva VA, Galan P, Torrès M, Julia C, Hercberg S, Kesse-Guyot E. Supplementation with B vitamins or n-3 fatty acids and depressive symptoms in cardiovascular disease survivors: ancillary findings from the SUpplementation with FOLate, vitamins B-6 and B-12 and/or OMega-3 fatty acids (SU.FOL.OM3) randomized trial. Am J Clin Nutr 2012;96: [PubMed] Supplemental EPA or DHA May Be Linked to Improved Depression Scores in Older Adults Depressive symptoms and cognitive impairment may go hand in hand. If so, treatments for both conditions may be necessary for improving the quality of life and daily functioning of these individuals. A study conducted in the U.S. among cognitively normal 75-year-old adults reported that greater depressive symptoms and cognitive impairments were associated with more cognitive complaints. Individuals without cognitive impairments had the strongest association between depressive symptoms and cognitive complaints, suggesting that depressive symptoms may affect an individual s perception of cognitive function. Research on the relationships among depressive symptoms, chronic diseases and physical disabilities in older Americans reported that depressive symptoms were independently and strongly associated with lower baseline cognition scores, but were not predictive of future cognitive decline. Similar findings were reported in a Canadian study of 65-year-old medical inpatients who had baseline and repeated evaluations for depressive symptoms and cognition for 12 months after admission. The investigators observed that higher depressive symptom scores were associated Depressive symptoms and cognitive impairment may go hand-in-hand and higher depressive symptom scores have been linked to lower cognitive function. Could long-chain omega-3 PUFAs improve both conditions? with lower cognitive function scores, but were not predictive of future cognitive performance. Further, it has been suggested that the high rate of major depressive episodes after the onset of cognitive impairment in patients with Alzheimer s disease is another characteristic of this disease. These studies suggest that accounting for depressive symptoms in studies of cognitive function in aging is important. Some evidence suggests that supplementation with n-3 LC-PUFAs in very mild cognitive impairment slows the rate of decline or improves cognitive scores. A multicenter study in the U.S. reported that supplementation with 900 mg of DHA/day was associated with improved learning and memory function in adults whose cognitive performance had declined. Supplementation with n-3 LC-PUFAs in individuals with mild to moderate depressive symptoms was associated with improved symptoms in elderly participants. Building on this evidence base, Natalie Parletta (Sinn) and colleagues at the University of South Australia examined the effects of 6-month supplementation with high- EPA or high-dha fish oils or high-linoleic acid vegetable oil on depressive symptoms, memory, executive function and quality of life in adults 65 years of age or more with mild cognitive impairment. 19

20 Participation in the study required a Mini-Mental State Examination score of 22 ( 20 indicates possible dementia), a score on the Verbal Paired Associates Task 1.5 SD below the population mean, and/or age and education-adjusted DemTect scores between 9 and 12, suggesting mild cognitive impairment. Qualified participants maintained normal daily functioning, but had self-reported memory loss. They were also given the Geriatric Depression Scale assessment at enrolment. Fifty volunteers were recruited, of whom 40 completed the 6-month assessments. On average, the participants were 74 years of age. The supplements provided 1.67 g of EPA plus 0.16 g of DHA or 1.55 g of DHA plus 0.40 g of EPA or 2.2 g of LA in 4 capsules per day. The investigators administered a battery of health and cognitive assessments aimed at evaluating the effects of EPA or DHA treatment on depression and quality of life, memory, executive function and working memory. They identified 6 potential confounding variables and measured fatty acid profiles in erythrocytes. All assessments were conducted at baseline and after 6 months. The major finding was significantly improved depression scores in participants consuming either the high- DHA or high-epa supplements compared with the placebo group (Table) whose scores actually worsened over the 6-month period. The changes in the control group were significantly different from the treatment groups. EPA has been considered more effective in alleviating depressive symptoms than DHA in most studies, with one short-term study in a small number of patients reporting no significant effect of DHA alone. However, direct comparisons between the two n-3 LC-PUFAs are lacking. This comparison of the DHA- and EPA-enriched supplements suggests that DHA was also effective in improving the scores for depressive symptoms in these older adults. Table. Effects of EPA or DHA supplementation for 6 months in older adults with mild cognitive impairment using linear mixed model analysis of all participants randomized to treatment Assessment n* Estimate ± SE P Geriatric depression scale EPA vs LA 17, ± DHA vs LA 18, ± Initial letter fluency EPA vs LA 17, ± DHA vs LA 18, ± *No. of participants in each group. There was also as significant This study s major finding improvement in was significantly improved the initial letter depression scores in older fluency scores for adults who consumed D H A - e n r i c h e d either high-epa or high- supplementation DHA fish oil for 6 months. compared with linoleic acid, but not Scores in the linoleic acid control group worsened. for EPA-enriched supplement. Overall, 6-month supplementation with either EPA or DHA had minimal effects on cognitive scores after extensive testing. The investigators suggested that perhaps the participants initial n-3 LC-PUFA status (5% EPA + DHA in erythrocytes) was above the concentration where effects of supplementation could be observed. The study also had small numbers in each group, which limited its power. These observations and the diverse array of evaluations administered suggest that n-3 LC-PUFA supplementation in the presence of high intakes of linoleic acid may not improve cognition in older adults with mild cognitive impairment. Whether there would be effects in diets low in linoleic acid is an unanswered question. Sinn N, Milte CM, Street SJ, Buckley JD, Coates AM, Petkov J, Howe PRC. Effects of n-3 fatty acids, EPA v. DHA, on depressive symptoms, quality of life, memory and executive function in older adults with mild cognitive impairment: a 6-month randomised controlled trial. Br J Nutr 2012;107: [PubMed] Alzheimer s Disease Omega-3 Intakes and Plasma Amyloid-Beta Peptides in Non-Demented Older Adults Alzheimer s disease, a progressive and debilitating form of dementia, is most common among older adults. In the U.S., 1 in 8 people aged 65 and older or about 5.4 million of all ages have the condition. This number is predicted to treble to more than 13 million by 2050 because more people are living longer. Worldwide, the disease afflicts about 36 million people. Currently, there is no cure or effective treatment for the disease, although various medications are used to improve memory and several cognitive tasks. What determines a person s chance of developing Alzheimer s disease? In one report, more than half of individuals who exhibit mild cognitive impairment defined as cognitive decline greater than expected for a person s age and education level, but that does not interfere notably with activities of daily life develop dementia within 5 years. Others have reported 20

21 lower rates of conversion a cumulative rate of 33.6% based on a meta-analysis of 41 cohort studies. Besides cognitive decline, depressive symptoms and insulin resistance or type 2 diabetes have strong links to increased risk of vascular cognitive impairment or Alzheimer s Recent research has strengthened the links between DHA and Alzheimer s disease and explained the connections of the disease with insulin resistance. New biomarkers reveal signs of the disease in nondemented older adults. disease, but these links are complicated. Gene mutations contribute substantially to the risk of the disease, with variations in the presence of the ε4 allele of the apolipoprotein E (APOE) gene accounting for half and possibly up to 95% of the risk in the U.S. Some risk-raising gene mutations occur in the amyloid precursor protein gene (APP), presenilin-1 and presenilin-2 genes and others. Risk of Alzheimer s disease is also greater with high cerebrospinal fluid tau and Abeta42 (Aβ) peptides, age above 65 years, family history of the disease, elevated homocysteine concentrations and other health conditions such as type 2 diabetes. DHA concentration in certain brain regions has been associated with Alzheimer s disease. For example, Soderberg and colleagues reported that the hippocampus of Alzheimer s disease brains had about half the concentration of DHA as control brains. However, not all studies have observed altered DHA levels in the brains of these patients. DHA has several protective functions in Alzheimer s disease, including a reduction in the production of Aβ peptides that accumulate extracellularly in this disease, and improved neuronal survival via the DHA-derived docosanoid, neuroprotectin D1. However, amelioration of Alzheimer s disease by increasing the consumption of DHA has been ineffective. It might be that interventions must occur prior to the onset of mild impairment. Even though it cannot halt its progression, DHA helps counteract Alzheimer s disease pathology. A recent study in mouse cells and tissues described how DHA is involved in redirecting the processing of the amyloid precursor protein away from the production of dangerous Aβ peptides, toward less harmful nonamyloidogenic processing. Nutrition is also involved in the risk of dementia, particularly Alzheimer s disease. Almost 10 years ago, Martha Morris and colleagues reported that the risk of Figure. Stick and ribbon structure of amyloid-beta42. Source: Wikimedia.org. Alzheimer s disease was significantly lower in individuals who consumed fish weekly and had higher intakes of DHA. These findings have since been supported by other epidemiological studies, most recently in a casecontrol study of older US adults. In that study, participants in the highest tertile of plasma DHA concentrations had a 65% lower risk of all-cause dementia and a 60% lower risk of Alzheimer s disease. Consumption of a Mediterranean diet has also been associated with favorably lower risks for Alzheimer s disease. Community-based participants in the U.S. who averaged 77 years of age and had the highest adherence to a Mediterranean diet over 4 years experienced a 40% lower risk of the disease. Consuming a Mediterranean diet was associated with lower scores for white matter hyperintensity volumes, a marker of small vessel damage in the brain, a slower rate of cognitive decline, lower risk of converting from mild cognitive impairment to Alzheimer s disease, lower risk of Alzheimer s disease and lower mortality from this type of dementia. In the Chicago Health and Aging Project, greater adherence to a Mediterranean diet pattern was associated with slower rates of cognitive decline over Higher fish and DHA intakes have been associated with a lower risk of Alzheimer s disease, but treatment with n-3 LC-PUFAs has generally shown improved markers and cognition only in animals. 7.6 years. In contrast to these studies, the Mediterranean diet was not associated with protection against cognitive decline in healthy 60-to-64-year-old adults after 4 years. Although fish and DHA intakes have been linked to improved memory and cognition, several reviewers have concluded that the evidence supporting the benefits of B-vitamins and fatty acids for the prevention of dementia is too inconsistent for dietary recommendations. 21

22 A study in healthy older adults with mild age-related cognitive decline reported that learning and memory function improved after 6-months of supplementation with 900 mg of DHA. A recent review concluded that n-3 LC-PUFAs might slow the rate of cognitive decline in older adults, but are without effect in the prevention or treatment of Alzheimer s disease. In a study of n-3 LC-PUFA supplementation for 6 months in patients with Alzheimer s disease, treatment was not associated with any changes in disease or inflammatory biomarkers or with Aβ42 concentrations in cerebrospinal fluid. In animal models, dietary DHA stimulated the nonamyloidogenic processing of the amyloid precursor protein in cellular models of Alzheimer s disease, which resulted in lower levels of Aβ. Others have also reported an association of DHA with reduced accumulation of Aβ and tau, the abnormal intracellular peptide associated with the formation of neurofibrillary tangles. In contrast, arachidonic acid increased the production of detrimental Aβ peptides, while the combination of DHA with n-6 PUFAs diminished the effectiveness of DHA in reducing abnormal peptides. In humans, low levels of erythrocyte DHA have been associated with lower total brain volume and greater white matter hyperintensity volumes, in healthy, 67-year-old Framingham Study participants. Lower erythrocyte DHA and lower omega-3 index values were associated with lower scores on tests of visual memory, executive function and abstract thinking in the same study. With the measurement of Aβ peptides in plasma, we now have better biomarkers for the risk and development of Alzheimer s disease. Healthy, non-demented, older adults had markers of Alzheimer s disease in their blood, but those with higher intakes of n-3 LC-PUFAs had significantly lower concentrations of the abnormal peptide, Aβ42. A cross-sectional nutrition study from Nikos Scarmeas research group at Columbia University, USA, evaluated the possible associations between several nutrients and plasma Aβ peptides in older adults in New York City. Community-living participants were recruited and screened for health, neuropsychological function, presence of dementia and available dietary assessment. Those with any type of prevalent dementia were excluded. The final sample included 1,219 individuals with dietary intake and plasma Aβ measurements. Their average age was 75 years. In addition to dietary intakes of fatty acid classes, the investigators assessed the consumption of 6 vitamins, n-3 and n-6 PUFAs. Both Aβ40 and Aβ42 peptides were measured. Analyses were adjusted for age, education, energy intake, ethnicity, sex, APOE genotype and alcohol intake. Results for the plasma concentrations of Aβ peptides are shown in the table. In unadjusted linear regression analysis, higher intakes of n-3 LC-PUFAs were associated with lower levels of Aβ40 and Aβ42 peptides, but in adjusted analysis, only the reduction in Aβ42 peptides was statistically significant. No other nutrients or fatty Table. Dietary n-3 and n-6 PUFA intakes and plasma Aβ peptide concentrations in healthy non-demented older adults by tertiles of n-3 or n-6 PUFA consumption n-3 PUFA intake tertiles Variable All participants Lowest Middle Highest P* n-3 PUFA intake, g/day, mean (SD) 0.77 ± (0.4) 0.52 ± (0.2) 0.69 ± (0.3) 1.1 ± (0.4) Aβ40, pg/ml, mean (SD) 81.9 ± (58) 90.8 ± (63) 79.3 ± (52) 75.5 ± (58) <0.0001** Aβ42, pg/ml, mean (SD) 38.7 ± (27) 44.1 ± (31) 37.2 ± (24) 34.9 ± (25) <0.0001** n-6 PUFA intake tertiles n-6 PUFA intake, g/day, mean (SD) 6.3 ± (3.4) 4.8 ± (1.9) 5.5 ± (2.2) 8.7 ± (3.0) Aβ40, pg/ml, mean (SD) 81.9 ± (58) 84.8 ± (57) 83.1 ± (63) 77.7 ± (54) 0.19 Aβ42, pg/ml, mean (SD) 38.7 ± (27) 41.8 ± (30) 38.2 ± (24) 36.2 ± (26) *P values from analysis of variance for continuous variables. **Significantly different between the lowest and highest tertiles and lowest and middle tertiles. Significantly different between the lowest and middle tertiles. 22

23 acids were associated with levels of Aβ peptides. This observation is consistent with studies on n-3 LC-PUFAs in animal models of Alzheimer s disease and with a lower risk of incident Alzheimer s disease with higher intakes of n-3 LC-PUFAs in the same population. What is also striking in this report is that abnormal Aβ42 peptides, hallmarks of Alzheimer s disease, were detected in the plasma of non-demented older adults with no other symptoms of impaired cognition. It would be useful to know whether the increased consumption of n-3 LC-PUFAs would affect plasma Aβ peptide concentrations over time. Gu Y, Schupf N, Cosenetino SA, Luchsinger JA, Scarmeas N. Nutrient intake and plasma β-amyloid. Neurology 2012;78: [PubMed] EPA and DHA Intakes Linked to Better Cognition and Gray Matter Volume in Older Adults DHA is critical to the development of brain structure and function, neurotrophic factor expression, neurogenesis, neurite outgrowth, synaptogenesis and plasticity and other aspects of a healthy brain. Studies Magnetic resonance imaging is a technology that enables one to see changes in structure and brain activity and correlate these with clinical symptoms. It has the potential to detect early changes in cognition and dementia. suggest that infants whose mothers have higher DHA status have improved cognition and attention. Further, the occurrence of behavioral and psychiatric disorders has been associated with lower concentrations of n-3 LC-PUFAs in plasma and erythrocytes. Treatment of various psychiatric and behavioral disorders with DHA or n-3 LC-PUFAs was linked to improved outcomes in some, but not all studies. However, fewer data are available on the relationship between psychopathology and brain or cortex DHA content, in part because of the limitations in assessing brain DHA in living individuals. One technique to overcome that difficulty is the use of various magnetic resonance imaging techniques, which can measure cortical gray and white matter volumes, cortical activation patterns and other aspects of cortical function. In healthy adults, corticolimbic gray matter volume in 3 specific regions of the brain, including the hippocampus, was associated with the consumption of n-3 LC-PUFAs (Figure). Higher intakes were linked to greater volumes. A meta-analysis of brain volume studies in patients with borderline personality disorder reported a modest reduction in the volumes of the amygdala and hippocampus in patients compared with controls. These changes may be useful markers of the condition. In major depressive disorder, patients with smaller hippocampal volumes had worse clinical outcomes compared with patients with large hippocampal volumes and previous depressive episodes. These studies and several others in patients with various psychiatric disorders suggest that regional brain volumes may be altered in clinical conditions and might serve as biomarkers of certain disorders or responses to treatment. Greater gray matter volume in the medial temporal area has been observed in older adults who maintain their cognitive function compared with those who develop impaired cognition. Figure. Magnetic resonance image of the whole brain with gray matter shown in color. Image courtesy of Dr. Christian Benedict, Uppsala University, Sweden. Cognition has also been linked to changes in regional brain volumes. For example, in 83-yearold adults free from dementia at baseline, changes in cognition were monitored over a 9-year period with a modified Mini Mental State Test. Magnetic resonance imaging measures of total brain, white matter hyperintensity and gray matter volumes and other brain region assessments were taken to evaluate the relationship between cognitive function and changes in brain volumes. The most important finding was a significantly greater retention of volume in the medial temporal area of participants who maintained their cognitive status compared with those whose cognition declined. Retention of the microstructure of the cingulate cortex was also associated with better cognitive function. Others have also recently reported significant correlations between imaging measures of gray matter volume and cognitive function. Researchers have also reported changes in volumes in the whole brain, hippocampus and temporal horn that predict future conversion from mild cognitive impairment to Alzheimer s disease. Others have observed a 23

24 significant loss in volume in the anteromedial temporal lobe in normal individuals who subsequently developed cognitive complaints. Thus, there is a good rationale for investigating the associations between n-3 LC-PUFAs, brain volume and cognition. Older adults with the highest intakes of EPA + DHA had greater total brain gray matter volumes and higher cognitive scores compared with those whose intakes of n-3 LC-PUFAs were the lowest. In the most stringent analysis, the relationship between n-3 LC-PUFAs and gray matter volume lost its statistical significance. In the study described here, Olga Titova and colleagues at Uppsala University, Sweden, evaluated the relationship between the consumption of EPA and DHA in cognitively healthy 70-year-old Swedish adults and their global cognitive function and brain volume measurements at age 75. Participants were part of a cohort of older adults from Uppsala, Sweden, recruited from the community for a study on vasculature and aging. Normal cognitive status was defined as a Mini Mental State exam score greater than 26 at baseline. The investigators assessed fatty acid intakes from a 7-day food diary obtained at baseline. They assessed changes in cognition using the 7-minute screen test, which includes 4 subtests. Data on food intake, magnetic resonance brain imaging and normal cognition were available for 252 individuals. Participants with strokes or neurologic diseases were excluded. Subgroup analysis wa s p e r formed on 198 individuals after the elimination of those with uncertain energy intakes. Brain volume was determined using a 3D T1-weighted volumetric (Turbo Field Echo) scan and processed using Voxel Based Morphometry. Participants were divided into quartiles by percentile of EPA + DHA consumption. Gray matter, white matter and total brain volumes were expressed as percentages of the total intracranial volume. Participants with higher intakes of EPA + DHA, which averaged 520 and 980 mg/day in the 3rd and 4th quartiles, respectively, attained significantly higher cognition scores after 5 years (age 75 years) as shown in multivariate analysis adjusted for 9 confounding variables (Table). Gray matter volume was also significantly related to dietary EPA + DHA consumption when the analysis was adjusted for sex, age, education, energy intake and physical activity (P <0.05). The relationship between n-3 LC-PUFA intakes and gray matter volume was no long significant after additional adjustment for low-density lipoprotein cholesterol, systolic blood pressure, BMI and insulin resistance. White matter and total brain tissue were not significantly correlated to n-3 LC-PUFA consumption. Brain volumes and cognitive scores were not associated with plasma phospholipid fatty acid concentrations. This study documents improved cognitive scores in older adults with higher intakes of EPA + DHA when cognition was evaluated 5 years after dietary assessment. There was a clear suggestion that gray matter volumes were also larger in those with higher n-3 LC-PUFA consumption, but with further adjustment for confounding variables, the association disappeared. These observations suggest that in 70-year-old adults without impaired cognition, high intakes of EPA + DHA may preserve cognitive function or delay the onset of its decline. These findings support other reports that supplementation with 900 mg of DHA for 24 weeks in healthy adults with mild age-related cognitive decline was associated with improved scores in tests of memory Table. Brain volumes* and total cognitive scores by quartiles of EPA + DHA consumption in 70-year-old adults after 5 years Outcome Q1 lowest EPA + DHA Intake (quartiles) Q2 Q3 Q4 highest Gray matter 32.4 ± ± ± ± White matter 25.7 ± ± ± ± Brain tissue 58.1 ± ± ± ± Total cognitive score 16.1 ± ± ± ± P** *Expressed as percent total intracranial volume. **Linear regression analysis adjusted for 9 confounding variables. Total score from 7-minute screen test. 24

25 and learning. These observations also agree with those of Conklin and colleagues who reported that higher intakes of n-3 LC-PUFAs were associated with greater gray matter volume in the nodes of a corticolimbic circuitry in healthy middle-aged adults. T h e e v i d e n c e This study suggests that presented in the Titova study suggests, but falls higher intakes of EPA and DHA may be linked to short of confirming, that total gray greater gray matter brain volume and perhaps better matter volumes retention of cognitive are higher in function in aging. older adults who consume greater amounts of EPA + DHA. Thus, the associations among EPA + DHA consumption, gray matter volume and cognition, which might provide a more direct assessment of healthy brain function, await additional data. However, as the investigators did not report the gray matter volumes in specific regions of the brain related to cognition, such as the hippocampus and amygdala, these observations do not reveal whether specific regions might have been affected by n-3 LC-PUFA consumption. One might speculate that habitual consumption of n-3 LC-PUFAs in this fish-eating population might have contributed to long-term brain health and function, as suggested by the extensive involvement of n-3 LC-PUFAs in brain and neuronal structure and function. Titova OE, Sjögren P, Brooks SJ, Kullberg J, Ax E, Kilander L, Riserus U, Cederholm T, Larsson EM, Johansson L, Ahlström H, Lind L, Schiöth HB, Benedict C. Dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly. Age (Dordr) 2012; Jul 13. [PubMed] Worth Noting Harris WS, Pottala JV, Vasan RS, Larson MG, Robins SJ. Changes in erythrocyte membrane trans and marine fatty acids between 1999 and 2006 in older Americans. J Nutr 2012;142: [PubMed] Grimm MO, Kuchenbecker J, et al. Docosahexaenoic acid reduces amyloid beta production via multiple pleiotropic mechanisms. J Biol Chem 2011;286: [PubMed] Jiang W, Oken H, Fiuzat M, Shaw LK, Martsberger C, Kuchibhatla M, Kaddurah-Daouk R, Steffens DC, Baillie R, Cuffe M, Krishnan R, O Connor C; SADHART-CHF Investigators. Plasma omega-3 polyunsaturated fatty acids and survival in patients with chronic heart failure and major depressive disorder. J Cardiovasc Transl Res 2012;5: [PubMed] McNamara RK. Deciphering the role of docosahexaenoic acid in brain maturation and pathology with magnetic resonance imaging. Prostaglandins Leukot Essent Fatty Acids 2012; Apr 20. [PubMed] Pottala JV, Talley JA, Churchill SW, Lynch DA, von Schacky C, Harris WS. Red blood cell fatty acids are associated with depression in a case-control study of adolescents. Prostaglandins Leukot Essent Fatty Acids 2012; 86: [PubMed] Rapoport SI. Translational studies on regulation of brain docosahexaenoic acid metabolism in vivo. Prostaglandins Leukot Essent Fatty Acids 2012; Jul 4. [PubMed] Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Databasae Syst Rev 2012;6:CD [PubMed] Tan ZS, Harris WS, Beiser AS, Au R, Himali JJ, Debette S, Pikula A, Decarli C, Wolf PA, Vasan RS, Robins SJ, Seshadri S. Red blood cell ω-3 fatty acid levels and markers of accelerated brain aging. Neurology 2012;78: [PubMed] n FRONTIERS Stepping Stones to Treating Alzheimer s Disease: Is Insulin the Key? The development and characteristics of Alzheimer s disease have been extensively described, centered largely on the deposition of sheets of amyloid-beta (Aβ) peptides as extracellular plaques and the protein tau as intracellular neurofibrillary tangles (Figure 1). The disease increases the production of the Aβ peptides in the brain, destroys neurons and synapses, and exhibits several features of metabolic dysregulation, including insulin resistance. It has never been established whether the abnormal pathologies observed in Alzheimer s disease are a cause or consequence of the condition. Further, definitive diagnosis of Alzheimer s disease depends on postmortem autopsy. However, the failure of inhibitors of the enzymes responsible for the formation of the abnormal Aβ to improve the welfare of patients raises serious questions about the cause of this disease. Further, the heterogeneous nature of the condition, the involvement of genetics and the diseased brain s resistance to insulin and insulin-like growth factor (IGF) have expanded thoughts on the origin of Alzheimer s disease and how it might be treated. A potential breakthrough may be in sight. 25

26 Figure 1. Abnormal pathology characteristic of Alzheimer s disease. Illustration courtesy of Alzheimer s Disease Research, a program of the American Health Assistance Foundation alzheimers Type 2 diabetes is a risk factor for mild cognitive decline and may increase the risk of Alzheimer s disease up to 3-fold. The two diseases share several metabolic abnormalities. A l z h e i m e r s disease and type 2 diabetes share several metabolic abnormalities, including impaired glucose metabolism, vascular dysfunction, increased oxidative stress, insulin deficiency, insulin resistance and amyloidogenesis. Both the brain and pancreatic islet cells can develop Aβ deposition. Type 2 diabetes is a risk factor for mild cognitive decline, vascular dementia and Alzheimer s disease and may increase the risk of Alzheimer s dementia up to 3-fold. It has also been associated with accelerated progression from mildly impaired cognition to dementia. However, it does not cause Alzheimer s disease. In fact, Alzheimer pathology is observed less frequently in treated diabetics than in non-diabetics. These are among the observations that prompted investigation of insulin in the brain and central nervous system and how insulin resistance develops in individuals with Alzheimer s disease. Insulin crosses the bloodbrain barrier via a transporter mechanism and mediates its effects largely independent of glucose utilization. Its activities in brain are accomplished mainly via two pathways. One is the phosphoinositide-3 kinase (PI3K)/ Akt pathway, which is involved in insulin signaling; the other is the Ras/mitogen activated kinase (MAPK) pathway, a chain of proteins that communicate signals from a receptor on the cell surface to receptors on the nucleus. Besides its association with Alzheimer s disease, insulin resistance in the central nervous system is associated with depressive illness and impaired baroreceptor gain in pregnancy. Insulin resistance and impaired insulin signaling appear to be at the core of the abnormalities associated with Alzheimer s disease, just as in type 2 diabetes. Reduced insulin sensitivity in brain impairs neuroprotection, neuron regeneration and growth factor a c t i v i t y. H o w peripheral insulin resistance and hyperinsulinemia, characteristics of the metabolic syndrome and type 2 diabetes, relate to cognitive decline and Alzheimer s disease is unclear. For example, elderly individuals with hyperinsulinemia or insulin resistance, respectively, who were not receiving insulin, had lower scores for cognitive function, delayed memory and attention compared with individuals not having these conditions. Investigators have reported that older individuals with clinical and subclinical diabetes had poorer cognitive performance, executive function and visual memory, and smaller brain volumes compared with individuals without any symptoms of diabetes or insulin resistance. Reduced volume in the hippocampus is considered a marker of neurodegenerative disease. Comparatively smaller gray matter volumes in the medial temporal area and total brain were associated with a 34% lower probability of maintaining cognitive function in elderly adults free of dementia at baseline. The term type 3 diabetes has been coined to describe the type of diabetes that selectively affects the brain. Impaired insulin signaling appears to be at the core of the abnormalities associated with insulin deficiency in brains with Alzheimer s disease, just as in type 2 diabetes. In 2005, Eric Steen and colleagues at Brown Medical School, USA, proposed the term type 3 diabetes to describe a type of diabetes that selectively affects the brain. They described the extensive abnormalities in insulin and IGF signaling in the brains of individuals with Alzheimer s disease. These abnormalities were associated with the reduced expression of the genes for these growth factors, their receptors and associated downstream signaling enzymes. On the other hand, there was increased expression of the genes for the amyloid precursor protein and the major tau kinase enzyme, which leads to the formation of the aberrant tau protein. Similar abnormalities 26

27 were observed in the brains of individuals who died with Alzheimer s disease, type 2 diabetes, both diseases or none, providing evidence of the overlap in brain abnormalities in both conditions. Figure 2. Normal aged brain (left) and Alzheimer s patient brain showing morphological changes. Image: Wikipedia Commons. Insulin receptor signaling mediates the processing of the amyloid precursor protein and the accumulation of its amyloid-beta products. Genes for the insulin and IGF receptors are found in neurons and glial cells throughout the brain. With the progression of Alzheimer s disease (Figure 2), insulin signaling declines further and insulin and IGF regulated genes are suppressed. Impaired insulin and IGF signaling and regulation are related to the accumulation and toxicity of Aβ, but the discordant observation that diabetic brains accumulate less Aβ, have fewer neuritic plaques, neurofibrillary tangles and lower plaque load in the hippocampus, raise the question of whether impaired insulin and IGF signaling is a cause or consequence of Alzheimer s disease. Stöhr and colleagues reported that IGF-1 resistance reduces Aβ accumulation and toxicity and promotes survival. Further, these investigators observed that insulin receptor signaling mediates the processing of the amyloid precursor protein and the accumulation of its Aβ peptide products, but does not affect survival. This finding suggests that the insulin receptor is a key regulator of Aβ accumulation. Additional evidence of the protective function of insulin in Alzheimer s pathology was reported in a study on hippocampal neurons. Aβ oligomers bind to synapses in particular neurons leading to their deterioration and severe memory loss. To accomplish their destructive action, the Aβ oligomers first inhibit critical enzymes in the insulin signaling pathway, which leads to a reduction in insulin receptors and induces oxidative stress. The investigators in this study showed that insulin blocked Aβ binding, prevented the loss of insulin receptors and abolished the development of oxidative stress. In her comprehensive review of brain insulin resistance and deficiency in Alzheimer s disease, Suzanne de la Monte presents a strong case for viewing Alzheimer s disease as a metabolic disease with progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor stimulation. Evidence points to similarities among obesity, type 2 diabetes, metabolic syndrome and non-alcoholic steatohepatitis, which exhibit brain insulin and IGF resistance and contribute to mild cognitive impairment and Alzheimer s disease. Mounting evidence suggests that Alzheimer s disease is associated with insulin resistance and deficiency with or without diabetes or systemic insulin resistance; diabetic patients treated with insulin or hypoglycemic medications have improved memory (Figure 3) and slower progression of Alzheimer s disease; elderly diabetics treated with insulin have lower densities of Alzheimer s lesions compared with non-diabetic individuals; insulin treatment is associated with improved memory and cognition in Alzheimer s patients; and intracerebral or intravenous insulin treatments improve memory, cognition and neurotransmitter function. Thus, the idea of insulin as a therapeutic target in Alzheimer s disease has gained traction. As insulin infusion is not a viable long-term therapy and risks hypoglycemia, investigators turned to direct delivery of the hormone via the nose. Intranasal insulin treatment is associated with cognitive benefits and better functional abilities in patients with mildly Figure 3. Illustration of the different brain structures involved in memory. Image reproduced with permission of Allen D. Bragdon Publishers, Inc. All rights reserved. For more brain facts go to: 27