PUFA NEWSLETTER. September 2008 Contents. Volume 13 Issue 3. EDITORIAL Paradoxes Unravelled...2

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1 PUFA NEWSLETTER Volume 13 Issue 3 September 2008 Contents EDITORIAL Paradoxes Unravelled...2 CARDIOVASCULAR DISEASE Does Fish Consumption Explain the Japanese Paradox?...3 Higher Plasma EPA Linked to Fewer Nonfatal Coronary Events in Women...5 Stroke EPA Plus Statin Treatment Reduces Risk of Recurrent Stroke...6 Fewer Omens of Future Stroke in People Who Eat Fish Frequently...7 Ventricular Arrhythmias Omega-3 Index Linked to Ventricular Arrhythmias in Heart Failure Patients with ICDs...8 Omega-3 Index Linked to Less Ventricular Fibrillation in Myocardial Infarction MATERNAL & INFANT HEALTH High Fish Consumption Insufficient to Prevent Maternal DHA Decline at Delivery DHA Supplementation Improves Maternal and Infant DHA Status...12 Omega-3 Supplementation in Pregnancy Unrelated to Childhood Cognition at Age Interplay Between Nutrients and Methylmercury in Child Neurodevelopment MENTAL HEALTH Attention Deficit Hyperactivity Disorder Inattentive But Not Other ADHD Children Respond to LC-PUFA Supplementation PUFA Supplementation in ADHD Children Improves Inattention Cognitive Function DHA Supplementation Linked to Higher Picture Vocabulary Scores in 4-Year Olds Depression Low Dose DHA Improves Clinical Scores in Major Depression...22 Low Plasma EPA Associated with Major Depression in the Elderly...23 CLINICAL CONDITIONS Alzheimer Disease Mild Alzheimer Patients Improve Cognition with Omega-3s...25 PUFA NEWSLETTER STAFF Editor Joyce A. Nettleton, DSc Communications Manager Angela Dansby Sponsor DSM Nutritional Products, Kaiseraugst, Switzerland, SCIENCE ADVISORY BOARD J. Thomas Brenna, Ph.D. Cornell University Ithaca, NY, USA Stefan Endres, M.D. University of Munich Munich, Germany Marlene P. Freeman, M.D. Massachusetts General Hospital Boston, MA, USA William S. Harris, Ph.D. University of Missouri Kansas City, MO, USA Maria Makrides, Ph.D. Women s and Children s Hospital Adelaide, Australia Letters and editorial comments should be submitted to joyce@fatsoflife.com and technical comments to angela@fatsoflife.com. Subscribe to the PUFA Newsletter at

2 EDITORIAL Paradoxes Unravelled This issue of the PUFA Newsletter unravels the paradox why Japanese men, who have half the mortality from heart disease as American Caucasians, escape this fate in spite of having high cholesterol, smoking, diabetes and hypertension. However, when they migrate to America, Japanese men develop atherosclerosis as readily or more so than their Caucasian compatriots. The answer is in giving up their fish-eating habits, not in their genes. In another report, eicosapentaenoic acid (EPA) in seafood was linked to fewer nonfatal heart disruptions in women. New research on the occurrence of stroke suggests that eating tuna or other baked or broiled fish more than three times/week is associated with fewer tiny hemorrhages in the brain. People without these brain lesions are less likely to have a stroke or suffer impaired cognition. In other research, supplementation with EPA reduced the likelihood of having a second stroke in those who had already had one. In news about maternal and child health, a 200 mg daily supplement of docosahexaenoic acid (DHA) taken during pregnancy was sufficient to improve the DHA status of mothers and their infants and to double the mothers DHA milk content. These findings occurred in women who eat very little fish, as is the case in many western countries. The supplement provided the amount of DHA recommended by international experts for pregnant and nursing mothers. Another study reported that the improvements in child cognition from maternal consumption of long-chain omega-3 fatty acids observed in early childhood were not apparent at age 7. Another paradox is why mothers who eat plenty of fish and have higher levels of mercury as a result, have children without adverse effects. In fact, these children outperform those whose mothers avoid eating fish. Researchers from the Seychelle Islands report that when the data are analyzed to account for both favorable and unfavorable exposures, the benefits of nutrients generally outweigh the adverse effects. Only one of 16 developmental outcomes was significantly related to methylmercury exposure, but its adverse effect was small and weakened as maternal omega-3 levels increased. While seafood consumption carries a small risk of possible harm, it also delivers nutrients to mitigate it. In other studies, long-chain polyunsaturated fatty acids significantly improved attention in children with attention deficit hyperactivity disorder, especially those whose main characteristic was inattention. In patients with major depression, EPA was significantly lower compared with non-depressed individuals. In another study, low-dose DHA improved the symptoms of depression, but high doses did not. Omega-3 fatty acids appear integral to the healthy performance of nearly all the body s major systems. They are also contributing to a deepened understanding of how the body works. Joyce A. Nettleton Editor, PUFA Newsletter and Fats of Life joyce@fatsoflife.com 2

3 CARDIOVASCULAR HEALTH Does Fish Consumption Explain the Japanese Paradox? What explains the Japanese paradox very low mortality from cardiovascular disease despite high cardiovascular risk factors? n-3 LC-PUFAs from eating fish often may be the answer. In spite of having levels of blood cholesterol and blood pressure similar to those in western countries, and high rates of smoking and diabetes, the Japanese have the lowest incidence of myocardial infarction among industrialized countries and one of the lowest rates of cardiovascular mortality in the world. This contradiction to western cardiovascular patterns has been described as the Japanese paradox. In Japanese men who migrated to Hawaii, rates of cardiovascular disease increased, yet they still have less atherosclerosis and lower mortality from the condition than US Caucasians. Are the Japanese uniquely protected from this scourge? Akira Sekikawa and colleagues in Pittsburgh, USA, tested the hypothesis that the consumption of fish or long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs) provides primary protection against cardiovascular disease. It is widely believed that fish or fish oil consumption provides significant protection against the recurrence of various cardiovascular events in people who have already experienced a myocardial infarction, but there is limited evidence that n-3 LC-PUFAs offer primary cardioprotection. These doubts rest mainly on the scarcity of data from randomized intervention trials in individuals at relatively low risk for cardiovascular disease, i.e., those who have not yet had cardiac events. Moreover, most data have come from western populations with limited fish intakes. The striking exception to prevailing wisdom is Japan, where fish consumption, up to 8 times/wk or more, is one of the world s highest. There, fish consumption is associated with significantly lower risk of coronary heart disease and nonfatal coronary events compared with rates for people having modest fish intakes. Rates of sudden death, however, were not related to fish consumption, mainly because these rates were already very low. In this study, Sekikawa and colleagues examined serum fatty acid profiles in Japanese men living in Japan or Hawaii and Caucasian men living in the U.S. They compared these to the extent of atherosclerosis assessed in two ways: electron beam computed tomography to measure coronary artery calcification (an independent predictor of cardiovascular events) and carotid artery intima-media thickness (IMT), measured by ultrasonography. Japanese study participants aged 40 to 49 years were recruited from Kusatsu, Japan. Japanese-American men were the offspring (without ethnic admixture) of fathers who participated in the Honolulu Heart Program (a group of men unusually knowledgeable about heart disease risk factors). Caucasian men were recruited from the Pittsburgh area, Pennsylvania, USA. All participants were without clinical cardiovascular disease, type 1 diabetes or other serious diseases. After exclusions for heavy alcohol consumption and missing data, there were 281 Japanese men, 281 Japanese-American men and 306 Caucasian men. As previous studies have reported, Japanese men in Japan have cardiovascular risk factors as ominous or worse than US Caucasian men with respect to hypertension, diabetes, alcohol consumption, low-density lipoprotein levels and exercise. However, they are less obese and have significantly lower C-reactive protein concentrations. Japanese-American men have even higher rates of hypertension, diabetes, triglyceride and C-reactive protein levels compared with the other two groups. The healthiest arteries were observed in the Japanese men, who had significantly less atherosclerosis in their coronary and carotid arteries than either Japanese- American or Caucasian men (Figure 1). Healthier Japanese artery assessments were maintained even when those in the comparison groups with diabetes, hypertension or lipid-lowering medications were removed from the analysis. The higher prevalence of 3

4 atherosclerosis in Japanese-Americans suggests that genetics is not the underlying reason for the difference between Japanese and Caucasian men. Japanese men also had twice the concentrations of total n-3 LC-PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid than both other groups (Figure 2). Concentrations of total n-6 PUFAs, linoleic and arachidonic acids were also significantly lower in Japanese men than the other groups. Saturated fatty acid levels were slightly, but significantly, higher in the same comparisons. In Japanese men, there was a significant inverse association between serum n-3 LC-PUFA levels and IMT thickness, after adjustment for blood pressure, high-density lipoprotein cholesterol, triglycerides and other potential confounders. Coronary artery calcification decreased with n-3 LC-PUFA intake, especially in Japanese men, but the trends were not statistically significant in any group. No relationship was observed between n-3 LC-PUFAs and IMT or coronary artery calcification in any other group than the Japanese men. The authors noted that the serum n-3 LC-PUFA concentration in the lowest 5 th percentile of Japanese men was still greater than the mean levels in either Caucasian or Japanese-American men. The significant relationships in Japanese men between n-3 LC-PUFAs and the prevalence of coronary and carotid artery disease became nonsignificant when each analysis was adjusted for serum n-3 LC-PUFAs. However, in combined, multivariable-adjusted analysis taking n-3 LC-PUFAs into consideration, the prevalence of atherosclerosis in Japanese men remained significantly lower than in Caucasian men. Japanese men, aged 40 to 49, had one-third the prevalence of coronary artery calcification and significantly less carotid thickening compared with Caucasian men and Japanese-Americans. Their low prevalence of atherosclerosis was significantly associated with their high serum n-3 LC-PUFA levels. Correlation does not signify causation, of course, but the significantly lower prevalence of atherosclerosis in Japanese men coupled with the 2-fold higher levels of n-3 LC-PUFAs in their serum is compelling evidence. No other serum fatty acids were related to atherosclerosis in any group. Even significantly higher levels of saturated fatty acids, widely believed to increase the risk of cardiovascular disease, were unrelated to atherosclerosis in Japanese men. These observations are consistent with others in Japanese individuals. These include a lower incidence of coronary heart disease and high n-3 LC-PUFA and fish consumption, and fewer nonfatal cardiac events with supplemental EPA. We must remain open to the possibility that some other environmental factor not measured in this study (some trace mineral or fish-derived substance, a different way of handling stress, etc.) may be cardioprotective. Together, the evidence points to n-3 LC-PUFAs as a critical, possibly key, factor behind the Japanese paradox and Japan s low prevalence of cardiovascular disease. The authors of this study suggest that fish or n-3 LC-PUFA consumption well above the amount associated with reduced cardiac death in western populations, e.g., 250 mg of n-3 LC-PUFAs/day, may be necessary to achieve the lower prevalence of atherosclerosis, coronary heart disease and cardiac mortality seen in the Japanese population, particularly in men. This study has firmly opened the door to a relationship between n-3 LC-PUFAs and the prevention of coronary heart disease itself. Sekikawa A, Curb JD, Ueshima H, El-Saed A, Kadowaki T, Abbott RD, Evans RW, Rodriguez BL, Okamura T, Sutton-Tyrrell K, Nakamura Y, Masaki K, Edmundowicz D, Kashiwagi A, Willcox BJ, Takamiya T, Mitsunami K, Seto TB, Murata K, White RL, Kuller LH; ERA JUMP (Electron-Beam Tomography, Risk Factor Assessment Among Japanese and U.S. Men in the Post-World War II Birth Cohort) Study Group. Marine-derived n-3 fatty acids and atherosclerosis in Japanese, Japanese- American, and white men: A cross-sectional study. J Am Coll Cardiol, :

5 Higher Plasma EPA Linked to Fewer Nonfatal Coronary Events in Women For reasons that are For reasons that are not not understood, understood, fish and fish oil fish and fish oil consumption that pro- consumption that protects against cardiovascular tects against cardiovascular mortal- mortality and sudden death, has only inconsistent or little ity and sudden cardiac death has only effect on nonfatal coronary inconsistent or little events. This is not the case effect on nonfatal among the Japanese who coronary events in eat fish up to 8 times/week. western populations. In contrast, Why? the Japanese, who consume nearly 10 times as much fish as most western populations, have less than half the mortality from coronary heart disease as Americans. In Japan, those who eat fish about 8 times/wk have a 40% lower incidence of coronary heart disease and 60% fewer nonfatal coronary events than those who eat fish only once/week. No factors other than fish consumption, including genetic differences, have been identified that could account for these population-based differences. Thus, it appears premature to dismiss fish consumption as a possible protective factor against nonfatal coronary heart disease in western populations. One difficulty is that the range of fish consumption in many western countries is small. In the study described here, epidemiologists from the Harvard School of Public Health, Boston, USA, examined the relationship between fish and long-chain omega-3 polyunsaturated fatty acid (n-3 LC-PUFA) intake and nonfatal myocardial infarction in a cohort of US women whose lifestyle habits have been monitored since Instead of relying solely on dietary intake data, the investigators obtained blood samples from the participants about 15 years after enrolment, when the women were 60 years old on average. They determined the n-3 LC-PUFAs in whole plasma and erythrocytes. Using a case-control study design, the investigators compared the n-3 LC-PUFA profiles in 146 women who incurred a nonfatal myocardial infarction over a 6-year period with those of 288 control women matched to the case participants in age, smoking status and fasting status at the time of blood sampling. Cases were identified from the nurses biennial questionnaire responses, confirmed by medical records. Participants who had a nonfatal myocardial infarction were significantly heavier, consumed less alcohol, and were much more likely to have diabetes, hypertension, hypercholesterolemia and parental history of myocardial infarction compared with controls. They also had less favorable lipoprotein profiles. Fish consumption was significantly associated with plasma and red blood cell eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), but not with docosapentaenoic acid (n-3). Plasma, but not red blood cell, EPA and total n-3 LC- PUFA concentrations were significantly associated with a lower risk of nonfatal myocardial infarction in multivariate analysis. Nurses in the highest quartile of plasma EPA had a 77% lower risk of a nonfat al myocardial infarction compared with women in the lowest quartile (Figure). Neither plasma nor red blood cell DHA or alpha-linolenic acid was associated with this risk in multivariate analysis. Alphalinolenic acid in plasma and red blood cells was associated with a nonsignificant higher risk of nonfatal myocardial infarction. Interestingly, plasma docosapentaenoic acid (n-3) was significantly associated with a 60% lower risk of a nonfatal myocardial infarction, but this fatty acid was not associated with fish consumption. That observation suggests that this fatty acid arises mainly from the metabolism of other n-3 LC-PUFAs, mainly conversion from EPA. Docosapentaenoic acid (n-3) is usually found in low concentrations in most fish, except tuna, which has up to 10% of the n-3 LC-PUFAs in this form. Plasma EPA, DHA and docosapentaenoic acid (n-3) concentrations were also significantly associated with higher levels of high-density lipoproteins, and lower concentrations of triglycerides, but were not related to levels of most inflammatory markers assessed. 5

6 This observational study links higher plasma levels of EPA, but not DHA, to a significantly lower risk of nonfatal coronary events in older women. These findings contrast with several other epidemiological studies, but suggest that n-3 LC- PUFAs may be preventive in women with moderate fish intakes. This study supports previous reports of a lower risk of nonfatal coronary events with fish or higher levels of n-3 LC-PUFAs and is consistent with a report of fewer nonfat al coronary events in hypercholesterolemic Japanese patients supplemented with EPA. On the other hand, it raises several questions. Why was the association observed for plasma EPA and not for DHA? As the authors noted, DHA is a better marker of dietary fish and n-3 LC-PUFA intake than EPA. In this study, however, the variability in DHA concentrations and the confidence intervals for the multivariate relative risks derived from them were substantially larger than for EPA and docosapentaenoic acid (n-3). This variability could account for the lack of statistical significance in the trend toward reduced risk with higher DHA levels. Another question is why the associations were observed in plasma, but not red blood cell fatty acid concentrations. Plasma fatty acids are thought to reflect more recent dietary intake, whereas red blood cell concentrations are a better reflection of habitual consumption, at least for the past two months. Yet, n-3 LC-PUFA concentrations in both blood fractions are highly correlated. Plasma EPA may represent a more readily available supply of n-3 LC-PUFAs to the tissues than red blood cell n-3 LC-PUFAs. A third question is the significant inverse association with docosapentaenoic acid, an n-3 LC- PUFA usually found in lower concentrations than EPA and DHA. This report indicates that it is too soon to take n-3 LC-PUFAs off the table for the prevention of nonfatal coronary events. It suggests that even in populations with lower fish consumption than the Japanese, higher intakes of n-3 LC-PUFAs from fish and shellfish have cardioprotective effects long before a myocardial infarction certifies the risk. Sun Q, Ma J, Campos H, Rexrode KM, Albert CM, Mozaffarian D, Hu FB. Blood concentrations of individual long-chain n-3 fatty acids and risk of nonfatal myocardial infarction. Am J Clin Nutr 2008;88: Stroke EPA Plus Statin Treatment Reduces Risk of Recurrent Stroke Readers of the PUFA Newsletter may recall the JELIS trial conducted among hypercholesterolemic patients treated with statins to lower their low-density lipoprotein cholesterol. Half the participants received 1.8 g/day of eicosapentaenoic acid (EPA) with their statin medication. Five years later, patients taking both a statin and EPA incurred significantly fewer major coronary events, such as fatal or nonfatal myocardial infarctions and cardiac-related hospital admissions. In this report, the authors conducted a subanalysis of the original 18,645 JELIS participants with respect to the incidence of stroke. In Japan, mortality from stroke is more than twice that of US men and about 1.5 times higher for women. The risk is related mainly to hypertension and also to diabetes, hypercholesterolemia and smoking. In this analysis of the JELIS study participants, the authors investigated the occurrence of a first or subsequent stroke in both treatment groups. Overall, the incidence of stroke was low, 114 (1.3%) in the statin group and 133 (1.5%) in the statin plus EPA group. This difference between the two groups was not statistically significant. Consumption of 1.8 g/day of EPA for 5 years along with statin medication significantly reduced the recurrence of stroke in Japanese patients with high cholesterol. To assess secondary prevention, the investigators examined the 5-year recurrence of stroke (for example, cerebral thrombosis, embolism or hemorrhage) in patients who had a previous stroke. There were 457 stroke patients in the control group and 485 in the EPA group. Stroke recurred in 48 controls (10.5%) and 33 EPA patients (6.8%), a significant 20% reduction in risk with EPA consumption. This is the first study to report a significantly reduced risk of stroke recurrence with EPA. Although this investigation observed no effect of EPA on the prevention of stroke, one epidemiological study reported an inverse association between fish or omega-3 fatty acid consumption and the risk of stroke in women. Other epidemiological studies have not observed a relationship between fish consumption and stroke. As the authors noted, the plasma concentration of EPA (2.8 mol%) prior to supplementation was already 10-fold higher than in the US Caucasian population, yet a benefit of increased consumption was still observed. If validated in western populations with low fish consumption, this 6

7 study suggests that there may be substantial opportunity to lower the risk of recurrent stroke with EPA. Tanaka K, Ishikawa Y, Yokoyama M, Origasa H, Matsuzaki M, Saito Y, Matsuzawa Y, Sasaki J, Oikawa S, Hishida H, Itakura H. Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; JELIS Investigators, Japan. Reduction in the recurrence of stroke by eicosapentaenoic acid for hypercholesterolemic patients: subanalysis of the JELIS trial. Stroke 2008;39: Fewer Omens of Future Stroke in People Who Eat Fish Frequently Identifying individuals at high risk of stroke before symptoms appear is elusive. Brain images showing subclinical abnormalities can detect increased risk of stroke. Fish consumption may reduce the occurrence of these abnormalities, thus reducing risk of stroke. Although heart disease is the leading cause of death in developed countries, stroke is the leading cause of adult disability. Stroke is to the brain what a heart attack is to the heart a blocked or ruptured blood vessel that deprives the tissue of oxygen, destroying brain cells. The most common type of stroke in developed countries is ischemic, the result of a blood clot being carried to the brain from elsewhere or forming in the brain because of impaired blood flow. Arterial plaque in the brain can lead to thrombotic stroke. On the other hand, if a blood vessel in the brain is weakened and breaks, the resulting hemorrhage can be fatal. Hypertension is the leading cause of these strokes. Most strokes are preventable with healthy lifestyle habits, blood pressure control and medical checkups. An important harbinger of a future stroke is a transient ischemic attack (TIA). This symptom is a temporary disturbance in blood supply to the brain resulting in brief neurologic dysfunction that lasts less than 24 hours. In the U.S., about a quarter million TIAs are diagnosed every year, with many more going undiagnosed. About one-third of people who experience a TIA eventually develop a stroke. Other preclinical signs of a potential stroke can be detected by magnetic resonance imaging (MRI) of the brain. This technique reveals silent brain infarcts that become common as people age. Individuals with these infarcts experience greater cognitive decline and risk of stroke than people without them. The enormous burden of stroke disability makes it compelling to identify individuals at risk of stroke before clinical symptoms occur. In epidemiological studies, high fish consumption has been associated with a significant 35% lower chance of stroke. The consumption of 1.8 g of EPA/day by hypercholesterolemic Japanese patients was associated with a 20% reduction in recurrent stroke over 5 years, but was without effect on the occurrence of a first stroke. Other studies have reported a higher risk of stroke in British women with low fish intakes, but no relationship between stroke and fish consumption in the overall sample. In Swedish men with higher fish consumption, risk of stroke increased. Although the majority of studies report a protective effect of fish consumption on risk of stroke, the population data are not consistent. With the aim of identifying early markers for risk of stroke in people with no clinical evidence of stroke and to detect possible stroke-protective factors, investigators at the University of Kuopio in Finland, along with colleagues in the U.S., examined the relationship between fish consumption and subclinical brain infarcts and other brain abnormalities in men and women at least 65 years of age (average of 75) who participated in the Cardiovascular Health Study. From the original 5,888 participants in four US communities, 5,201 were randomly selected to participate in the study, with the exclusion of participants having a history of TIA or stroke, incomplete data on fish consumption or MRI results. At baseline, 3,660 participants were assessed by an MRI brain scan and 5 years later, 2,313 of these were scanned again. Fish consumption data was obtained by food frequency questionnaire at enrolment into the study and categorized into tuna, dark-meat fish (mackerel, salmon, sardines, etc.) and other white fish. The final analysis used fish categories of tuna/other fish and fried fish. In the initial brain imaging, the incidence of one or more subclinical infarcts was 23%, which was unchanged on the second MRI. For those individuals who consumed tuna/ other non-fried fish 3 or more times/wk, the relative risk (odds ratio) of having a subclinical infarct in multivariate analysis was 0.74 (95% CI= 0.54 to 1.01, P for trend = 0.03) compared with fish consumption of less than once/month 7

8 (Figure). Eating fried fish was associated with an increased, though nonsignificant, risk of subclinical infarct. For each serving of tuna/other non-fried fish a week, the relative risk of having any subclinical infarct fell by 7%. Over the 5-year period, 17% of participants developed one or more new subclinical infarcts. The relative risk of incurring one or more new lesions for those who ate tuna/other fish 3 or more times/wk was 0.56 (95% CI= 0.39 to 1.07, P for trend = 0.04) compared with participants eating these fish less than once/month. For each weekly serving of tuna/other non-fried fish, the relative risk of any incident subclinical infarct was reduced by 11%, whereas the risk for each additional multiple infarct was reduced by 12%. Increased tuna/other non-fried fish intake was also associated with better white matter grade scores, with scores being nearly 11% better for those who ate 3 or more servings/wk compared with less than once/ month. Eating fried fish was unrelated to any white matter scores. In a large cohort of adults 65 years of age or older, who had no history of stroke or transient ischemic attacks, eating tuna or other fish that was not fried was associated with a 25% lower prevalence of subclinical brain infarcts detected by brain imaging. These abnormalities are linked to a higher risk of stroke and cognitive decline. In this large cohort of older adults, high consumption of tuna or other non-fried fish was associated with a lower prevalence of subclinical MRI-detected brain infarcts and a better grade of white matter in individuals with no history of stroke or TIA. There was no association between eating fried fish and any subclinical brain abnormalities. As these abnormalities are associated with greater cognitive decline and stroke risk, they can be considered omens of future clinical problems. MRI is a costly procedure that may be unsuitable for general health screening, but it may be a useful tool for identifying individuals at increased risk of stroke. The findings reported here suggest that increased consumption of fish rich in n-3 LC-PUFAs, but not fried, are associated with lower risk of dementia, stroke and cognitive loss, may be an effective preventive strategy for preserving mental and brain health in aging. Virtanen JK, Siscovick DS, Longstreth WT Jr, Kuller LH, Mozaffarian D. Fish consumption and risk of subclinical brain abnormalities on MRI in older adults. Neurology 2008;71: Ventricular Arrhythmias Omega-3 Index Linked to Ventricular Arrhythmias in Heart Failure Patients with ICDs Patients with implantable cardioverter defibrillators (ICDs) respond to n-3 LC-PUFAs in diverse ways, not always desirably. The nature of the underlying disease may contribute to these inconsistent responses. This study examined ICD patients with heart failure relative to their omega-3 index. The question of whether all those at risk for cardiovascular disease or events would benefit from increased consumption of long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs) does not have a simple answer. Fish and fish oil consumption significantly reduces the chance of sudden cardiac death in healthy men and patients who have had a myocardial infarction. The most common underlying cause of sudden death is ventricular arrhythmia, yet in patients with implantable cardioverter defibrillators (ICDs), who are at high risk of ventricular fibrillation, the consumption of fish oil has had mixed results, ranging from antiarrhythmic to pro-arrhythmic effects and no response. The nature of the underlying disease is also likely to influence how a patient responds to increased intake of n-3 LC-PUFAs. However, the potential for adverse effects in high-risk patients has generated wariness of these fatty acids for patients with certain types of heart disease, particularly those with ICDs. In this study, Matthias Wilhelm and colleagues at two German universities enrolled 102 patients with heart failure (low ejection volume) who had ICDs and structural heart disease, including ischemic and non-ischemic cardiomyopathy, and had not consumed fish oil nor had a myocardial infarction in the past 3 months. Other exclusion criteria included hypertrophic cardiomyopathy, ion channel abnormalities, severe valvular heart disease and other serious non-cardiac pathologies. Controls were 25 individuals without structural heart disease. All participants were monitored for 12 months. Patients with ICDs were monitored every 3 months and their devices evaluated and tested. The investigators recorded all ventricular arrhythmias requiring antitachycardia (rhythm stabilizing) pacing or shock therapy. An experienced cardiologist assessed all episodes to determine whether they were mono- or polymorphic according to cycle length. Fatty acids were measured in red blood cells as a surrogate for n-3 LC-PUFAs in cardiac muscle and the omega-3 index was calculated. The omega-3 index is the sum of eicosapentaenoic acid and 8

9 docosahexaenoic acid as a percent of the total fatty acids in red blood cells. Patients had significantly higher omega-3 index values compared with controls (5.1% vs 4.2%, P < 0.001), even though the groups had similar frequencies (about 50%) of twice-weekly fish consumption. This difference may be meaningless in terms of cardioprotection, as an omega-3 index of 5.1% is close to the zone of least protection against coronary heart disease mortality. The greatest protection occurs with an omega-3 index of 8% or more and the least protection is associated with an omega-3 index of 4% or less. Thirty percent of patients experienced ventricular arrhythmias with ICD intervention during the 12 months of followup. Patient mortality was 5%. After one year, 12% of patients in the lowest quartile of omega-3 index had ventricular arrhythmias, whereas 54% of those in the highest quartile experienced such episodes (Figure). The absolute number of arrhythmias increased from 14 in the lowest omega-3 index quartile to 137 in the highest quartile. More ventricular arrhythmias were observed in the highest compared with the lowest omega-3 index quartile at each time period. However, the high number of ventricular arrhythmias in the highest quartile was attributable to three patients experiencing ventricular tachycardia storm with repetitive discharges. Two patient characteristics significantly predicted ventricular arrhythmias: higher omega-3 index (odds ratio 1.8, 95% CI 1.2 to 2.8, P= 0.009) after 3, 6, 9 and 12 months and an ejection fraction less than 35% (odds ratio 4.0, 95% CI 1.3 to 12.4, P= 0.02) after 12 months. It has been reported that energy metabolism is compromised in heart failure and fatty acid oxidation is reduced, possibly as a means of conserving energy substrates. The observed increase in n-3 LC-PUFAs is consistent with a conservation of fatty acids in heart failure and was not observed in healthy controls, in spite of similar fish consumption in both groups. The authors suggested that the heart s attempt to conserve n-3 LC-PUFAs might deplete these fatty acids from the circulation, where they are associated with reduced cardiac excitability. As left ventricular function diminishes, myocardial metabol ism shifts from fatty acid to glucose utilization. The observed arrhythmias had a longer average cycle length and were not necessarily life-threatening. The investigators cautioned, however, that slower arrhythmias might degenerate to ventricular fibrillation and contribute to sudden death. Patients with heart failure and ICDs were more likely to experience ventricular arrhythmias with increasing omega-3 index. This observation contrasts with findings in patients with ischemic heart disease. Seventy percent of patients did not experience ventricular arrhythmias and those who did had a slower type, which may be less harmful. Overall, caution about n-3 LC-PUFAs in heart failure patients with ICDs is warranted. In an editorial accompanying this study, Christine Albert suggested that this study raises the possibility that n-3 LC-PUFAs may be pro-arrhythmic in patients with ICDs and heart failure and that in these patients, the omega-3 index may not predict risk of sudden death or heart disease mortality. She noted that the omega-3 index was related to the cycle length of the tachycardia, slower being less harmful. It is possible that higher n-3 LC-PUFA concentrations promote a less risky type of ventricular tachycardia and in this way would be beneficial. One might add that the range of omega-3 index values was small and mostly in the least protective range, thereby precluding conclusions about its value in reducing heart disease mortality. The mechanisms that trigger ventricular arrhythmias differ according to the type of cardiac pathology. It has already been noted that patients with cardiac ischemia differ in their responses from patients with angina pectoris or ventricular tachycardia. Further, the severity of heart failure, which increases the likelihood of ICD therapy, was associated with a higher omega-3 index and may be a confounding factor. As with the interpretation of the three intervention trials conducted with n-3 LC-PUFAs in ICD patients, 9

10 these findings raise many questions without pointing to a definitive interpretation. This study does not undermine the predictive value of the omega-3 index in healthy populations and in those who have survived a myocardial infarction or have ischemic heart disease. Neither does it rule out the usefulness of n-3 LC-PUFAs in heart failure, but it does suggest caution in patients with ICDs. Larger intervention trials in patients with more uniform disease characteristics are the only way to answer the outstanding questions about the usefulness of n-3 LC-PUFAs in patients with ICDs. Wilhelm M, Tobias R, Asskali F, Kraehner R, Kuly S, Klinghammer L, Boehles H, Daniel WG. Red blood cell omega-3 fatty acids and the risk of ventricular arrhythmias in patients with heart failure. Am Heart J 2008;155: Albert CM. Omega-3 fatty acids and ventricular arrhythmias: Nothing is simple. [Editorial] Am Heart J 2008;155: Omega-3 Index Linked to Less Ventricular Fibrillation in Myocardial Infarction Do n-3 LC-PUFAs lessen the danger of potentially fatal ventricular arrhythmias at the time of a myocardial infarct ion? They appeared to do so in this study of ischemic heart disease. Sudden cardiac death accounts for about half of all cardiovascular deaths and is attributable for the most part to ventricular arrhythmias. Patients who succumb to sudden cardiac death usually have coronary artery disease and myocardial ischemia (insufficient oxygen). Often, sudden death is the first sign of underlying heart disease and its occurrence has been difficult to predict. Unlike traditional cardiovascular risk factors, high concentrations of omega-3 long-chain polyunsaturated fatty acids (n-3 LC-PUFAs) in the blood are associated with significantly reduced risk of sudden death in both primary and secondary prevention studies. They are thought to be most protective in patients with myocardial ischemia, rather than some other types of heart disease, such as angina pectoris or heart failure. In the latter, the primary disorder is significantly reduced ejection volume, the amount of blood pumped by the heart. Consumption of fish or fish oil supplements increases the concentration of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) in cardiac membranes and favorably alters the electrical properties of the heart. As a result, n-3 LC-PUFAs are considered anti-arrhythmic under most circumstances. Dr. Hildegunn Aarsetøy and colleagues at Stavanger University Hospital, Norway, sought evidence for the effect of n-3 LC-PUFAs on ventricular fibrillation during the acute ischemic phase of a myocardial infarction. From 871 patients experiencing a myocardial infarction, 265 were identified as having a first episode. Ten of these patients (9 men) experienced ventricular fibrillation within 6 hours of having symptoms, with half developing ventricular fibrillation prior to reaching the hospital and the remainder within 2 hours of admission. None received revascularization therapy, thrombolytic treatment or percutaneous coronary intervention before or during fibrillation. Control participants (185) were selected from the remaining 255 patients, were matched to cases for age and were free of ventricular fibrillation or sustained ventricular tachycardia for at least 30 days of followup. Blood samples for measurement of fatty acids and other biochemical parameters were taken upon hospital admission and 8 hours thereafter. The omega-3 index was calculated as the sum of EPA and DHA expressed as a percent by weight of the total blood fatty acids. There were two deaths in this study, one among the 10 ventricular fibrillation patients, who died from a nonarrhythmic cardiac cause 7 days after hospitalization, and one non-sudden cardiac death among the controls. One of the case patients had angina pectoris prior to cardiac arrest, but for the remaining nine, this episode was the first evidence of coronary artery disease. The median omega-3 index in heart attack patients with ventricular fibrillation was significantly lower than in patients without ventricular fibrillation. The omega-3 index was below the range of greatest protection in both patient groups. The median omega-3 index among the ventricular fibrillation patients was significantly lower compared with the controls, 4.9% vs 6.1%, P= There was no significant difference between the five patients experiencing ventricular fibrillation prior to hospital admission and those whose episode occurred after admission. Based on logistic regression analysis, for every 1% increase in the omega-3 index, the risk of ventricular fibrillation decreased 44% (P= 0.02). Adjustment for confounding factors, such as age, sex, ejection fraction and others reduced the risk slightly to 48%. In these patients, higher red blood cell n-3 LC-PUFA concentrations were associated with significantly lower risk of ventricular fibrillation during the ischemic phase of a myocardial infarction. 10

11 Other studies examining the risk of primary cardiac arrest, sudden cardiac death and fatal ischemic heart disease in relation to the concentration of EPA and DHA in red blood cells or plasma phospholipids reported risk reductions from 70% to 90% for an omega-3 index of 6.1 to 10.1%. In patients with ischemic heart disease and implantable cardioverter defibrillators, those free of arrhythmias for 12 months had significantly higher serum phospholipid n-3 LC-PUFA levels compared with patients experiencing more than one arrhythmic event. In that study, n-3 LC-PUFA concentrations in the low and high groups were much higher (7.1% and 9.2% in the arrhythmia and no arrhythmia groups, respectively) than levels for the control patients in the present report. As an omega-3 index of 8% or more is associated with the lowest risk, the evidence suggests that patients with myocardial infarction and ischemic heart disease could reduce their future risks even further than reported in this study. Although this study reveals little about the potential mechanisms for reducing the likelihood of ventricular arrhythmias, the results are consistent with the modulation of ion channels. In ischemia, sodium and calcium flow is disturbed and the threshold for ventricular arrhythmia drops. In other types of heart disease, such as heart failure, where ejection volume is significantly reduced, n-3 LC-PUFAs may have little influence on the underlying pathology and subsequent risk. Thus, differences in the mechanisms of action of n-3 LC-PUFAs in different types of heart disease could partly explain the strikingly different responses in studies such as this and the preceding one. Aarsetøy H, Pönitz V, Nilsen OB, Grundt H, Harris WS, Nilsen DW. Low levels of cellular omega-3 increase the risk of ventricular fibrillation during the acute ischaemic phase of a myocardial infarction. Resuscitation 2008;78: MATERNAL AND INFANT HEALTH High Fish Consumption Insufficient to Prevent Maternal DHA Decline at Delivery A well recognized feature of the third trimester of pregnancy is the accelerated transfer of long-chain polyunsaturated fatty acids (LC-PUFAs) from the mother to the fetus. This transfer entails mainly docosahexaenoic acid (DHA) and arachidonic acid, fatty acids important for the rapidly developing brain and central nervous system. As a result, the essential fatty acid status of the mother declines during pregnancy. Mothers who consume fish oil supplements or 200 mg/day of DHA during pregnancy still lose DHA by the time of delivery, but their DHA status declines less than in women who do not consume additional DHA. Similarly, in women who consumed 1 g/day of DHA from fish and fish oil from the 26 th to 35 th week of pregnancy, DHA declined at delivery, but less so than in controls. These observations may relate to the dose of DHA provided. Supplementation of pregnant women with about 2 g of DHA/day did prevent the decline in maternal DHA status for as long as 6 weeks postpartum. Infants of DHAsupplemented mothers were born with 35% more DHA in their red blood cells than unsupplemented infants. Although experts now recommend that pregnant and lactating women consume at least 200 mg of DHA/day to ensure adequate amounts for the fetus, it is not certain that this amount will stem the decline in maternal DHA status. Besides improving the DHA status of the mother and fetus, the consumption of n-3 LC-PUFAs or fatty fish (rich in DHA) during pregnancy is associated with other maternal and infant benefits, including greater gestation length in women with low fish consumption, higher breast milk n-3 LC-PUFAs, better infant cognition, visual acuity and eye/hand coordination and perhaps a lower risk of postpartum depression. Little has been reported about high fish consumption alone, without n-3 LC-PUFA supplementation, and the decline of maternal n-3 LC-PUFA status during pregnancy. The examination of this question among women in the Seychelle Islands, where fish consumption is about 9 servings/week, addressed this issue. Maternal loss of DHA at delivery appears preventable only with large amounts of DHA, about 2 g/day. High fish consumption alone does not prevent this decline in DHA, unless the fish consumed are high in DHA. Maxine Bonham and colleagues from the University of Ulster, Northern Ireland, and colleagues from the Seychelles Child Development Nutrition Study, recruited 300 women on their first visit to prenatal clinics on the island of Mahé in the Republic of Seychelles. Non-vegetarian women over the age of 16, native Seychellois, who were free of diabetes and genetic blood cell disorders, were eligible to participate. Participants were 27 years of age, on average. The investigators collected blood samples at 28 weeks gestation and 1 day postpartum and breast milk samples one month after delivery. Fish consumption was ascertained from a food use questionnaire administered at 28 weeks gestation. Serum fatty acid determinations from both time points were available for 196 women and the geometric mean used for statistical analysis. 11

12 As this study demonstrates, consuming high n-3 LC-PUFA fish remains the only way to minimize the decline in maternal DHA status and ensure plenty of DHA for maternal and fetal health. The mean breast milk DHA concentration was 0.31%, a figure almost identical with the global average for DHA of 0.32%. Arachidonic acid concentrations averaged 0.29%, substantially below the worldwide average of 0.47%. Unlike many western populations where breast milk arachidonic acid exceeds that of DHA by as much as 3-fold, these Seychellois mothers provide their infants with similar concentrations of both LC-PUFAs. Serum n-3 LC-PUFA concentrations are usually considered biomarkers for fish consumption, but in the Seychelle Islands, serum DHA was not significantly associated with fish intake at 28 weeks gestation or with breast milk DHA at one month after delivery. A previous study of fish consumption and serum fatty acids also reported no relation between total fish consumption and serum n-3 LC-PUFAs, in a population consuming nearly half its fish from freshwater species. But in that study, consumption of fatty fish, especially salmonids, was significantly associated with serum n-3 LC-PUFAs. Similar associations have been reported among Norwegian fish-eaters where serum n-3 LC-PUFAs reflect the consumption of fatty, but not lean, fish. Thus, the relationship between fish consumption and serum n-3 LC-PUFAs appears to hold in populations with low or moderate fish consumption, but not where mixed species are consumed habitually more than once a day or where lean fish predominates. Serum n-3 LC-PUFAs are a better biomarker of fatty fish intake. Comparison between the maternal serum DHA concentrations at 28 weeks and delivery revealed a significant drop in DHA, but not arachidonic acid, by the time of parturition (Figure). The inability of high fish consumption to prevent the maternal decline in DHA in late pregnancy is likely a reflection of insufficient DHA from the varieties of fish consumed. Alternatively, it is possible that these women may have achieved their maximal DHA status under their present dietary habits. Because this report did not provide information on the DHA intake of these mothers, the findings cannot be viewed in the context of previous reports on n-3 LC-PUFA consumption and maternal DHA levels at delivery. As the proverb says so wisely, the devil is in the details. It is not just fish consumption, but the adequate intake of fatty fish rich in n-3 LC-PUFAs that counts. Consuming plenty of n-3 LC-PUFA-rich fish, such as salmon, mackerel, sardines and herring, or n-3 LC-PUFA supplements, remains the only way to minimize the decline in maternal DHA status and ensure plenty of DHA for maternal and fetal health. Bonham MP, Duffy EM, Wallace JMW, Robson PJ, Myers GJ, Davidson PW, Clarkson TW, Shamlaye CF, Strain JJ. Habitual fish consumption does not prevent a decrease in LCPUFA status in pregnant women (the Seychelles Child Development Nutrition Study). Prostaglandins, Leukot Essent Fatty Acids 2008;78: DHA Supplementation Improves Maternal and Infant DHA Status Concerned that pregnant women in most Pregnant women who eat little fish have low n-3 western countries, LC-PUFA status. Experts where fish consumption is low, do not recommend consuming 200 mg of DHA/day during obtain sufficient longchain omega-3 polyunsaturated fatty pregnancy and lactation. Is 200 mg of DHA enough acids (n-3 LC-PUFAs) to to improve the DHA status meet the needs of the of these women? This developing fetus, an study suggests that it is. international group of experts recommended that pregnant and lactating women consume at least 200 mg of DHA/day. As the developing nervous system needs DHA for proper structure and function and this fatty acid is not widely distributed in foods, the experts recommended the consumption of 1 to 2 meals of fatty fish/week. These types of fish, such as salmon, mackerel, sardines, herring are the richest sources of DHA in the food supply. Fish oil or n-3 LC-PUFA supplements also furnish DHA. 12

13 The experts agreed that 200 mg of DHA/day would meet known fetal requirements and that consumption of as much as 1 g of DHA/day was without adverse effects. Studies of n-3 LC-PUFA supplementation in pregnant women have used varying amounts of DHA, with or without eicosapentaenoic acid (EPA), so there is limited evidence of the effectiveness of 200 mg of DHA/day on maternal and infant LC-PUFA status. The study described here, conducted by Renate Bergmann and colleagues at Charité Universitätsmedizin, Berlin, examined the effect of 3 different supplements, including one with DHA, on the LC-PUFA status of pregnant women and their infants at delivery and 3 months later in the infants. In Germany, the DHA intake of women is less than 100 mg/day, an amount similar to some regions of the U.S. and Australia. The investigators recruited 144 non-smoking Caucasian women at least 18 years of age, who were free of severe disease, increased risk of premature delivery, multiple pregnancy, cow s milk allergy or lactose intolerance and not taking other supplements. On average, women were 31 years of age. Infants were excluded if they were born before 37 weeks gestation, were malformed or hospitalized for more than 1 week. Women were randomly assigned to consume a basic, acidified, milk-based dietary supplement containing vitamins and minerals supplemented with either nothing else; vitamins and minerals plus 4.5 g/day of fructo-oligosaccharides, a prebiotic; or the vitamins, minerals and the prebiotic with 200 mg of DHA from fish oil. Supplementation occurred from 21 through 37 weeks gestation and optionally for 3 months after delivery. Blood samples were obtained at 21 and 37 weeks, at delivery, and 1 and 3 months thereafter. The study was double-blinded. supplementation with 200 mg of DHA from 15 weeks gestation reduced, but did not completely prevent, the decline reported at delivery. Arachidonic acid concentrations were slightly, but not significantly, lower in the DHA-supplemented women. Blood samples were obtained from 142 women at 21 weeks gestation, 115 mothers at 37 weeks and 89 mothers at 3 months after delivery. Only 50 samples (43% of 116 infants) were obtained from the infants because of mothers refusal. The supplements were consumed by an average of 83% of women in the vitamin and prebiotic groups and 87% in the DHA-prebiotic group. Eighty percent of infants were exclusively breastfed up to 3 months in all groups. Maternal red blood cell DHA concentrations increased in all groups from 21 to 37 weeks gestation, but at 37 weeks and 3 months postpartum the DHA concentrations were significantly higher in the DHA-prebiotic mothers compared with the other two groups (Figure 1). Between 21 and 37 weeks, maternal red cell DHA concentration increased significantly, without exhibiting the oft-observed decrease at delivery. This observation contrasts with an earlier report in which Breast milk DHA content 3 months postpartum was twice as high in the DHA-prebiotic mothers (0.5% of total fatty acids) than the other two groups (0.25%), but arachidonic acid levels did not differ. Similarly, the infants of the DHA-supplemented mothers had significantly higher red blood cell DHA concentrations at 3 months than the infants in the other groups (Figure 2). Infant DHA concentrations were significantly associated with maternal red cell DHA, but were only weakly associated with 13

14 breast milk DHA. These investigators also observed that when breast milk DHA concentration exceeded 0.5%, infant red cell DHA did not increase. This observation suggests that under the conditions of this study, infants whose mothers consumed 200 mg of DHA/day in the last half of pregnancy had achieved sufficient DHA status. Australian researchers reached a similar conclusion in DHA-supplemented nursing mothers. The data showed that maternal and infant red blood cell eicosapentaenoic acid (EPA) concentrations (Figure 2), as well as breast milk levels also increased significantly in the DHA supplemented group. Three months after delivery, these values remained significantly higher in the supplemented group compared with both unsupplemented groups. The findings reported here demonstrate the effectiveness of maternal consumption of 200 mg of DHA/day from the latter half of pregnancy until 37 weeks gestation in healthy women with very low fish or DHA intakes. This level of supplementation increased the average maternal red blood cell DHA concentration by 50% without significantly affecting arachidonic acid concentrations. It also doubled the 3-month breast milk DHA concentration from 0.25% to 0.50% compared with women not consuming supplemental DHA. Supplementation with prebiotics or vitamins and minerals alone had no effect on LC-PUFA status. This study supports the recommendations of the Perilip Working Group for pregnant and lactating women to consume at least 200 mg of DHA/day. Bergmann RL, Haschke-Becher E, Klassen-Wigger P, Bergmann KE, Richter R, Dudenhausen JW, Grathwohl D, Haschke F. Supplementation with 200 mg/day docosahexaenoic acid from mid-pregnancy through lactation improves the docosahexaenoic acid status of mothers with a habitually low fish intake and of their infants. Ann Nutr Metab. 2008;52: Omega-3 Supplementation in Pregnancy Unrelated to Childhood Cognition at Age 7 Women who consume fatty fish or Do the early signs of higher cognition in long-chain omega-3 infants exposed to plenty polyunsaturated fatty of n-3 LC-PUFAs in fetal acids (n-3 LC-PUFAs) during pregnancy development carry over have offspring with to childhood? This study improved neurodevelopmental outcomes, provides one answer. ranging from higher mental development scores, better infant sleep patterns, greater visual acuity, improved behaviors and more mature neurological performance. Some longterm studies have explored whether the early signs of higher cognition in infants exposed to plenty of n-3 LC-PUFAs in fetal development carries over to childhood. A maternal n-3 LC-PUFA intervention trial in Norway observed higher cognition and intelligence quotient (IQ) scores in 4-year old children, while in the Netherlands, an observational study reported no effect of n-3 LC-PUFA status at birth and cognitive performance in children of the same age. Higher cognitive performance was reported in a US study of 3-year old children whose mothers had the highest fish consumption. At the age of 7, children in the Dutch study showed no cognitive advantage related to their n-3 LC-PUFA status at birth. Now, the same Norwegian investigators mentioned above report the effect of maternal n-3 LC-PUFA supplementation in pregnancy on the cognitive assessments of the same children at age 7. Both the Dutch and Norwegian studies used the Kaufman Assessment Battery for Children to evaluate cognition. In this study, investigators provided cod liver or corn oil to 143 pregnant women from 18 weeks gestation until 3 months postpartum. The cod liver oil supplied 1.2 g of docosahexaenoic acid (DHA)/day and 800 mg of eicosapentaenoic acid (EPA)/day (total n-3 LC-PUFAs, 2.5 g/day), while the corn oil provided 4.7 g/day of linoleic acid. Approximately half the children in the cod liver oil group consumed cod liver oil regularly during their preschool years and another 27% had taken it sporadically. Among the corn oil children, 46% took cod liver oil regularly and another 23% took it occasionally. Results from the Kaufman assessments showed no statistically significant differences between the corn and cod liver oil groups of children on the composite mental processing assessment (intelligence) and on any of the test subscales. Results from the Kaufman assessments showed no statistically significant differences between the two groups of child ren on the composite mental processing assessment (intelligence) and on any of the subscales measured. There were significant associations between maternal phospholipid DHA at 35 weeks gestation and the mental composite and sequential processing scores. Both maternal and infant phospholipid EPA and alpha-linolenic acid levels were also associated with sequential processing scores. At 3 months postpartum, breast milk EPA, but not DHA, was significantly related to sequential process- 14

15 ing scores. These observations suggest that the cognitive advantage of higher n-3 LC-PUFAs seen at 4 years of age had largely disappeared in the subsequent 3 years. The researchers suggested two possible explanations. One is a dilution effect by factors such as nutrients, drugs, social stimulation and diseases. This interpretation is consistent with the significant confounding effect of parental education on the relationships between DHA and alpha-linolenic acid in maternal phospholipids and the sequential processing scores. Breastfeeding and length of breastfeeding, which supplies DHA and other LC-PUFAs to the infant, was associated with higher intelligence scores in a Swedish study, findings that were linked to the provision of LC-PUFAs. Alternatively, n-3 LC-PUFA concentrations in fetal development and at birth may ultimately have no effect on cognition in later childhood. There is considerable evidence against the latter possibility. The children of mothers with high fish consumption were reported to have fewer social and learning problems at about the same age. Although this report cannot be attributed solely to DHA, it supports the value of eating plenty of fish during pregnancy, which supplies this important LC-PUFA. There is also comfort in knowing that cognitive function in childhood may benefit from other inputs besides fetal and infant nutrition. Helland IB, Smith L, Blomen B, Saarem K, Saugstad OD, Drevon CA. Effect of supplementing pregnant and lactating mothers with n-3 very-long-chain fatty acids on children s IQ and body mass index at 7 years of age. Pediatrics 2008;122:e472-e479. Interplay Between Nutrients and Methylmercury in Child Neurodevelopment Although methylmercury exposure increases with fish consumption, protect ive nutrients in fish, such as long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), selenium, iron, choline and iodine are thought to blunt the neurotoxicity of methylmercury. Three papers from the ongoing longitudinal study in the Seychelle Islands of maternal nutrition during pregnancy and developmental outcomes in the offspring describe the complex interactions between simultaneous exposures during pregnancy to nutrients and toxicants. People in the Seychelles consume ocean fish more than once a day, on average, 9 servings or 537 g/week. The concern about the potentially harmful effects of methylmercury exposure from maternal fish consumption on fetal neurodevelopment has been allayed in part by the frequent reports from this study of no consistent adverse effects in the offspring through 9 years of age. Although methylmercury exposure usually increases with fish consumption, protective nutrients in fish, such as long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs), selenium, iron, choline and iodine are thought to blunt the neurotoxicity of methylmercury. That interpretation was supported by recent findings among fish-eating Inuit mothers and their children. In spite of exposure to substantial levels of methylmercury and other contaminants, infants with higher blood docosahexaenoic acid (DHA) concentrations at 6 and 11 months of age scored higher on visual acuity, novelty preference, mental and psychomotor assessments. Other studies in the U.S. have reported similar observations. In the Davidson paper from the Seychelles Child Development Study, the investigators looked specifically at the relationships between methylmercury and neurodevelopmental outcomes, adjusted for multiple covariates plus thyroid-stimulating hormone, iron stores, choline and fish intake. In the paper by Strain and colleagues from the same study, the investigators evaluated the relationship between maternal n- 3 and omega-6 (n-6) LC-PUFA status, particularly DHA and arachidonic acid, and the Bayley Scales of Infant Development-II at ages 9 and 30 months. The latter assessments are a widely used evaluation of mental and psychomotor development. The psychomotor scales are considered the best evaluation of fine and gross motor skills in children under the age of 4 years. In both papers, the investigators used a single value for the third trimester serum fatty acid values based on the geometric means of samples obtained at 28 weeks gestation and at delivery. They did so to compensate for the decrease in maternal LC-PUFAs in the third trimester as these fatty acids are transferred to the fetus. The offspring of nearly 300 participating mothers were assessed at 5, 9, 25 and 30 months of age using the Bayley Scales-II. The final sample consisted of 229 mother-infant pairs. In the Davidson paper, the relationship between methylmercury exposure and Bayley scores was adjusted for the nutrition, fish consumption, thyroid hormone assessments and other covariates associated with child development, such as birthweight. The analyses for methylmercury and nutrients were repeated without correcting for nutrition or methylmercury, respectively. In the paper by Strain, the analyses of the relationships between the maternal serum LC-PUFAs and developmental assessment scores were performed using models that adjusted for various combinations of LC-PUFAs, but not for other nutrition variables. The five fatty acid adjustments included DHA and arachidonic acid; DHA, 15

16 eicosapentaenoic acid (EPA) and arachidonic acid; the sum of DHA, EPA and alpha-linolenic acid and the sum of linoleic and arachidonic acids; the ratios of arachidonic acid to DHA; and the ratio of total n-6 to n-3 PUFAs. Secondary analysis included additional adjustment for maternal hair methylmercury concentration. In the Seychelle Islands, where fish consumption and hair mercury levels are high, maternal fish intake was not significantly associated with prenatal methylmercury or any nutritional status indicator. This may reflect the wide variation in types of fish consumed. The mean Bayley scores for both psychomotor and mental development declined by nearly one standard deviation from 9 to 30 months of age. At 9 months of age, there was no association between the Bayley scores and prenatal methylmercury or with maternal nutrient status unless the analytical models adjusted for dietary intake or nutritional status, or for methylmercury, respectively. In other words, adjustment for important confounding factors revealed or strengthened the relationships. The Bayley mental index scores were not related to any of the variables evaluated. However, all the psychomotor scores were related to methylmercury and nutrient status. Interestingly, maternal fish intake was not significantly associated with prenatal methylmercury, DHA or with any nutritional status indicator, except dietary choline. The authors suggested that this reflects the considerable variation in the types of fish consumed. At 9 months of age, DHA, arachidonic acid and methylmercury were not significant predictors of any of the Bayley scores. Adjustment for other nutrients, as reported in the Davidson paper, did not alter the results. Prenatal methylmercury exposure had no significant effect in any of the other models adjusted for different combinations of LC-PUFAs. When the sums of n-3 and n-6 PUFAs were examined, greater total n-3 LC-PUFA values were associated with higher 9-month psychomotor development scores. When the ratio of all n-6 PUFAs to total n-3 PUFAs was analyzed, higher ratios were associated with significantly lower psychomotor scores. At 30 months of age, prenatal methylmercury was associated with a significantly lower psychomotor development score, but was unrelated to the mental index score. This relationship was observed only when dietary intake and maternal nutrition were taken into consideration. For each 1 ppm increase in methylmercury exposure, the psychomotor index fell by 0.55 points (Table). This was the only significant adverse effect of methylmercury on any of the 16 endpoints assessed, at any age, in the main analysis. None of the LC-PUFAs were significantly related to any of the Bayley scores alone or in any other analytical model. Although the psychomotor scores increased with higher levels of DHA, the association was not significant. The ratio of total n-6 PUFAs to total n-3 PUFAs was negatively related to methylmercury levels. Thus, as methylmercury levels increased, a lower n-6/n-3 ratio was needed to achieve the same psychomotor score. Similarly, with lower methylmercury values, higher n-6/ n-3 ratios were needed to attain the same psycho motor score. These relationships occurred at both 9 and 30 months of age and were reported in the Strain paper. In summary, these studies reported that prenatal exposure to methylmercury adversely affected the Table. Multiple linear regression coefficients (p values) for 30-mo. scores on the Bayley Scales of psychomotor development with different variables Variable Primary Analysis* Secondary Analysis** all data (P) MeHg model Nutrition model Prenatal MeHg, (0.04) - - ppm in hair DHA, mg/ml 25.0 (0.34) (0.82) ARA, mg/ml (0.49) (0.75) Fish intake, g/day 0.02 (0.29) (0.32) Sex, girls 7.79 (<0.0001) 8.1 (<0.0001) 7.7 (<0.0001) Maternal age, yr 0.35 (0.03) 0.3 (0.05) 0.3 (0.05) *Association between psychomotor score and MeHg exposure adjusted for nutrition variables. **Covariate-adjusted association between MeHg and psychomotor score without adjusting for nutrition (MeHg model) and between nutrition and psychomotor score without correcting for MeHg. 16

17 Bayley Scales psychomotor In 30-month-old children, score prenatal exposure to at age 30 months methylmercury was when maternal associated with lower nutritional status was included psychomotor scores when in the analysis. nutritional status was taken Of 16 neurodevelopmental out- into consideration. Scores increased with higher n-3 comes assessed, LC-PUFA levels, but declined this was the only as the proportion of n-6 adverse outcome PUFAs increased. Thus, that was related childhood neuro-development to methylmercury is affected in complex ways exposure, in multivariate by nutritional status and analy- contaminants, but in opposite directions. sis. However, as maternal n-3 LC- PUFA concentrations increased, psychomotor scores also increased, and conversely, as the proportion of n-6 PUFAs increased, psychomotor scores declined. The relationships were strongest when the analysis included methylmercury as a covariate. The analyses showed that failure to account for confounding factors obscures the impact of nutrients and contaminants on child development. Further, the adverse impact of methylmercury on the psychomotor score was strengthened by a higher n-6 to n-3 ratio when the children were 9 months of age, but not at age 30 months. DHA and arachidonic acid are important in the developing nervous system. What the relative amounts of n-6 PUFAs and n-3 LC-PUFAs in maternal blood means for the infant s psychomotor development is not well understood. Transfer of DHA to the fetus is related to maternal blood levels and is heavily influenced by dietary intake. In these mothers, the mean DHA concentration between 28 weeks gestation and delivery was 0.2 mg/ml and that of arachidonic acid 0.6 mg/ml. The findings in these papers suggest that both methylmercury and nutritional status affect childhood neurodevelopment in complex ways, but in opposite directions. In the authors view, these relationships are detected only with careful measurement and statistical modeling. Their observations may help explain the paradoxical finding that some neurodevelopmental outcomes improve with higher prenatal methylmercury. They also reinforce the current wisdom that recommends pregnant women consume fish species low in mercury to ensure adequate DHA for the fetus without risking adverse neurodevelopmental effects. Davidson PW, Strain JJ, Myers GJ, Thurston SW, Bonham MP, Shamlaye CF, Stokes-Riner A, Wallace JM, Robson PJ, Duffy EM, Georger LA, Sloane-Reeves J, Cernichiari E, Canfield RL, Cox C, Huang LS, Janciuras J, Clarkson TW. Neurodevelopmental effects of maternal nutritional status and exposure to methylmercury from eating fish during pregnancy. Neurotoxicology 2008; doi: / j.neuro Strain JJ, Davidson PW, Bonham MP, Duffy EM, Stokesriner A, Thurston SW, Wallace JM, robson PJ, Shamalaye CR, Georger LA, Sloane-Reeves J, Cernichiari E, Canfield RL, Cox C, Huang LS, Janciuras J, Myers GJ, Clarkson TW. Associations of maternal long-chain polyunsaturated fatty acids, methyl mercury, and infant development in the Seychelles Child Development Nutrition Study. Neurotoxicology 2008; doi: /j.neuro MENTAL HEALTH Attention Deficit Hyperactivity Disorder Inattentive But Not Other ADHD Children Respond to LC-PUFA Supplementation Children and adolescents with attention Children and adolescents with ADHD often have deficit hyperactivity disorder (ADHD) lower concentrations of LC-PUFAs than children often have overlapping behavioral prob- without this disorder. However, supplementation lems with learning difficulties, reading or with LC-PUFAs has yielded writing abnormalities, mixed results. In this trial motor coordination, with LC-PUFAs, responses defiant behavior and varied with the child s others. It has been particular symptoms. frequently noted that although ADHD children consume similar amounts of omega-3 polyunsaturated fatty acids (n-3 PUFAs) as children without this disorder, they have lower concentrations of these and other long-chain (LC) PUFAs. This observation was recently confirmed in a case-control study reporting a significant correlation between red blood cell docosahexaenoic acid (DHA) concentrations and severity of ADHD symptoms on the Conners rating scale. These observations and the need for an effective treatment with no adverse side effects have generated interest in the relationship between LC-PUFAs and the constellation of behavioral difficulties associated with ADHD and related disorders. That the situation is more complex than simply providing LC-PUFAs was demonstrated in a study comparing 17

18 healthy and ADHD children s responses to supplementation with n-3 and omega-6 (n-6) LC-PUFAs. ADHD symptoms improved in both groups after supplementation, but there was no improvement in fatty acid deficiency symptoms with supplementation in the ADHD children. Further, results of trials where children with ADHD were supplemented with n-3 LC-PUFAs, with or without other fatty acids and nutrients have been mixed. Nevertheless, results with PUFA supplementation in carefully controlled trials have been encouraging. Providing only docosahexaenoic acid, however, has yielded no significant improvements. for increased irritability. Children in both groups did not differ significantly in their ADHD, inattention or hyperactivity/impulsivity scores at baseline. Overall, compliance with supplementation, as reported by the parents, was 93% for both study periods. Two of the largest LC-PUFA supplementation trials to date, one in the U.K. and one in Australia, have reported significant reductions in ADHD symptoms, although the participants in each had somewhat different diagnoses. Both studies included n-3 and n-6 LC-PUFAs for a minimum of 12 weeks. In the study described here, Mats Johnson and colleagues at Göteborg University, Sweden, sought to replicate these trials in a one-way crossover design using the same daily dose of LC-PUFAs (558 mg eicosapentaenoic acid (EPA), 174 mg DHA, 60 mg γ-linolenic acid) or olive oil placebo for 3 months followed by a 3-month period in which both groups received the LC- PUFA supplements. There were 75 participants, 48 aged 8 to 12 years and 27 aged 13 to 18 years. Children were diagnosed according to the type of ADHD, i.e., combined, hyperactive/impulsive (35) or inattentive (40) and the presence of associated conditions such as reading/writing disorder, developmental coordination disorder, oppositional defiant behavior, learning difficulties, and others. Most of the children (78%) had at least one associated condition. The majority of the children (64/75) were boys. Children with autism, mental retardation, significant medical conditions, or use of psychoactive drugs, including sertraline treatment (a selective serotonin reuptake inhibitor), in the past 3 months were excluded. Upon enrolment, children and their parents were given several assessments, including the Global Assessment of Functioning Scale (children), the Five to Fifteen Parent Scale (parents) and several other questionnaires. Primary outcome measures were the investigator-rated ADHD Rating Scales (Parent Version) and the Clinical Global Impression severity scale. A clinically meaningful response was predetermined to be at least a 25% reduction in symptom score on the ADHD Rating Scales. A total of 64/75 children (78%) completed the first 3 months of the study and 59 (72%) completed both study periods. The 16 participant withdrawals were due mainly to lack of motivation, side effects such as dyspepsia or difficulty swallowing the capsules and one After the first 3 months, there was a trend for greater reduction in the ADHD Rating Scales in the LC-PUFA group compared with the placebo group, but the trend did not reach statistical significance (Figure). The trend was similar after the second 3-month period when all children consumed the LC-PUFAs. The Clinical Global Impression scores showed significant improvement in the LC-PUFA children after 3 months, but the scores at 6 months, while declining further, no longer differed significantly between the two groups. The drop in these scores for the children who consumed the LC-PUFAs for 6 months was significantly greater than for those taking the supplements for just 3 months (-1.24 vs -0.93). None of the scores worsened during the study. Participants in both groups who showed at least 25% improvement on their ADHD Rating Scales were considered responders. After the first 3 months, 26% in the active group and 7% in the placebo group were considered responsive. Nearly half the responders in the LC-PUFA group (4/9) had more than a 50% reduction in their symptoms, whereas none in the placebo group responded so strongly. By the end of the study, the number of responders increased from 9 to 28 or 47%, of whom 7 improved by more than 50%. Subgroup analysis revealed that responders were significantly more likely to have inattention, rather than the combined type, of ADHD. 18

19 Although the study did not find an overall effect of LC-PUFA supplementation on ADHD symptoms, those with predominantly inattentive symptoms experienced substantial clinical improvement. A small number of boys experienced a more than 50% reduction in symptoms. The study reported a substantial, but not statistically significant, response among the placebo children, suggesting that environmental influences contribute to symptom expression in this disorder. Although the overall findings from this study were neutral, the study illustrated the differences among ADHD symptoms and behavior patterns particularly inattention, motor control problems and perception difficulties in those more likely to respond to LC-PUFA supplementation. These responders accounted for most of the changes in the behavioral scores. Responders were more likely to be older, 13 to 18 years of age. After 6 months of treatment, nearly half the children responded to the supplements. The authors noted that in the small group of boys who experienced more than a 50% reduction in ADHD symptoms, all treated for 6 months, the improvements made a substantial clinical difference in their daily functioning. This randomized, placebo-controlled, double-blind trial found that LC-PUFA supplementation of clinically diagnosed ADHD children for up to 6 months made no statistically significant difference in the children s behavior overall, but in a subgroup of predominantly inattentive ADHD children, LC-PUFA supplementation provided substantial clinical improvement. At the end of 6 months, nearly half of all participants showed some improved responses. The study suggests that careful selection of ADHD patients mainly for inattention might increase the odds of a positive response to long-term LC-PUFA supplementation. Although it was not evaluated here, the low risk of n-3 LC-PUFA supplementation may be a reasonable adjunctive strategy in addition to standard care for ADHD children, even among those who do not respond to LC-PUFA monotherapy. Johnson M, Ostlund S, Fransson G, Kadesjö B, Gillberg C. Omega-3/omega-6 fatty acids for attention deficit hyperactivity disorder: A randomized placebo-controlled trial in children and adolescents. J Atten Disord 2008; Posted online April 30. PUFA Supplementation in ADHD Children Improves Inattention Disruptive, impulsive and inattentive behavior among children, adolescents and some adults is part of a spectrum of symptoms characterizing attention deficit hyperactivity Some studies have reported significant improvements in attention and cognition in children with ADHD who consume supplements of n-3 and n-6 PUFAs. Not all behaviors and not all children respond. Sorting out which types of ADHD are amenable to PUFA supplements is becoming better understood, as this study suggests. disorder (ADHD). Because this disorder in children often overlaps symptoms affecting reading and learning, developmental coordination and social behavior, the ability to learn and function is often compromised. In the U.S., the Centers for Disease Control estimate that nearly 4.5 million children aged 4 to 17 may be affected, a prevalence of about 8%. Estimates of prevalence in children aged 6 to 12 years in western countries range from 4% to 12%. Some children receive medications, but these may have undesirable side effects. A dietary supplement intervention, if proven efficacious with low risk, would be attractive to many children, parents, and health care providers. For that reason, some encouraging results with the supplementation of longchain polyunsaturated fatty acids (LC-PUFAs) in children with ADHD offers some hope of an alternative treatment. Overall findings with LC-PUFA supplementation have been mixed, so finding the right combination and dose of LC-PUFAs and the patients most likely to respond are important aspects of this research. The literature to date suggests that omega-6 (n-6) PUFAs alone (mainly γ-linolenic acid) or docosahexaenoic acid (DHA), an omega-3 (n-3) LC-PUFA, by itself are ineffective. At least two studies using a combination of n-3 and n-6 PUFAs reported statistically significant improvements in cognition and reading and in attention and core ADHD symptoms. In some studies, parent ratings show improvement, whereas clinical assessments may not. In a continuation of her studies of LC-PUFA supplementation in children with ADHD, Natalie Sinn and colleagues at the University of South Australia, Adelaide, conducted a randomized controlled trial of children aged 7 to 12 years (average, 9 years) with Conners ADHD scores 2 SD above the US population average. Of 167 eligible children, 132 completed phase 1 and 109 children completed the entire 30-week study. Participating children were not taking any stimulant medication or PUFA supplements during the previous 3 months. The investigators assessed the children s cognitive ability using the WISC-III test, which has vocabulary and block design subtests. Block design assesses visuo-spatial organization, problem-solving ability, non-verbal reasoning and concept formation. To avoid ceiling effects 19

20 from repeated test administration, block designs from the Wechsler Adult Intelligence Scale were added to the evaluation, although only the results from the WISC-III were used to estimate intelligence (IQ). Other assessments included speed of processing, learning and memory (Frey Auditory-Verbal Learning Test), executive functioning (Creature Counting subtest of the Test of Everyday Attention for Children), working memory, ability to inhibit responses (Knock and Tap test from a developmental neuropsychological assessment battery) and distractibility (Stroop color-word test). Unless indicated, these tests were included in the WISC-III evaluation. Supplements for the active treatment children included PUFAs from fish and evening primrose oils supplying 558 mg of eicosapentaenoic acid (EPA), 174 mg DHA, and 60 mg of γ-linolenic acid/day. Placebo capsules contained palm oil, predominantly palmitic and oleic acids. Children were randomly assigned to receive PUFAs plus multivitamin/mineral supplements for the entire study period, PUFAs only or a placebo for the first 15 weeks of the study. In the second half, all children received the vitamin/mineral and PUFA supplements from weeks 16 to 30. The study was designed as a one-way crossover, with placebo participants given the active treatment in the second half of the study, while those receiving the active treatment continued to do so for the entire 30-week study. After the first 15 weeks of the study, data from 129 participants were available for analysis. Three children dropped out bowing to low compliance and lack of cognitive assessment. There were 104 children completing the 30-week study. Participants had lower (94) than an average IQ (100), a difference for children with ADHD noted previously. Children completing one or both phases of the study did not differ in demographics. After 15 weeks, children consuming the PUFAs had significantly improved scores on the Creature Counting test of executive functioning/ attention. Scores on this test and on vocabulary continued to improve over the second 15-wk period. After 15 weeks, children consuming the PUFAs had significantly improved scores on the Creature Counting test of executive functioning/attention, with no difference between PUFAs alone or with vitamins and minerals. After the crossover of the placebo group to PUFA treatment, Creature Counting, Vocabulary, Coding, Block Design and Inspection Time scores all improved significantly. The greater number of test improvements may reflect the effect of practising the tests. For the continuing participants, Creature Counting scores and Vocabulary showed additional improvements. There were also improvements in other tests, including learning and memory, Digit-Symbol Coding (processing speed) and Block Design, likely attributable to practice effects. Stroop scores for mental flexibility and the ability to ignore distraction also improved in the PUFA groups. The investigators examined the relationships between baseline parent-reported scores in inattention, hyperactivity and impulsivity and baseline cognitive assessments. Inverse correlations were observed for ADHD index scores and better performance on attention control, speed of processing and memory. Vocabulary scores were inversely related with hyperactivity/impulsivity. The cognitive problems score was only inversely related to IQ, memory and attention control. After 15 weeks, changes in cognitive scores and attention control mediated the PUFA treatment interactions for the ADHD index, hyperactivity/ impulsivity and cognitive problems/ inattention. After 15 weeks, there were no differences between the groups receiving PUFAs alone or the PUFAs plus vitamins and minerals. Therefore, the results of these groups were combined. In the first half of the study, analysis of covariance was used to determine which changes mediated the various outcomes. These analyses showed that the changes in cognitive scores and attention control mediated the PUFA treatment/condition interactions for the ADHD index, hyperactivity/impulsivity and cognitive problems/inattention scores. Improvements in immediate recall memory mediated a small portion of the treatment effects on these same scores. IQ and improved vocabulary had small mediating effects on cognitive problems/inattention and inattention and hyperactivity/impulsivity, respectively. ADHD children treated with PUFAs for 15 weeks demonstrated strongly improved ability to switch and control their attention compared with the placebo group. These improvements increased with an additional 15 weeks of PUFA supplementation. After the first 15 weeks of PUFA supplementation, the children demonstrated strongly improved ability to switch and control their attention compared with the placebo group. Although vocabulary improved, those changes were not statistically significant. When all participants received the PUFAs, those from 20

21 the first half of the study continued to improve in attention control and vocabulary. Improvements in vocabulary appeared consistent with previously reported improvements in reading and spelling in children with developmental coordination disorder who consumed PUFA supplements. It is also possible that increased attention and concentration resulted in longer reading and better vocabulary. The authors suggested that these key improvements, which mediated the effects on inattention and hyperactivity/impulsivity observed by parents, support links between inattention and hyperactivity/impulsivity. They commented that attention is a multifaceted cognitive ability with domains that might respond differently to PUFA supplementation. These relationships might be worth teasing apart. This study, as in the preceding one, observed beneficial effects of PUFA supplementation on inattention in children with ADHD. Other aspects of cognitive ability were unaltered by the treatment, indicating that some aspects of this complex disorder are more amenable to dietary PUFAs than others. Both research groups used at least three different PUFAs in their treatments and both suggested that identifying ADHD children most likely to respond to PUFA supplements would be an important development in the field. If it turns out that much larger doses of PUFAs than used in these studies are needed to affect behavior, then it would be particularly important to identify those individuals most likely to benefit. It would be useful to know which of the PUFAs or PUFA combinations was most effective. The rationale for including γ-linolenic acid would benefit from additional scrutiny. In this study, continued long-term intervention, 30 weeks, led to further improvements beyond those observed after 15 weeks. This observation would be consistent with fundamental changes in the lipid composition of brain structures involved in cognitive and behavioral function. Both studies show the complexity and value of continued research on how PUFAs affect various aspects of ADHD. Sinn N, Bryan J, Wilson C. Cognitive effects of polyunsaturated fatty acids in children with attention deficit hyperactivity disorder symptoms: A randomised controlled trial. Prostaglandins, Leukot Essent Fatty Acids 2008;78: Cognitive Function DHA Supplementation Linked to Higher Picture Vocabulary Scores in 4-Year Olds Several studies have reported improvements in cognitive function with increased prenatal exposure to omega-3 long-chain polyunsaturated fatty acids (n- 3 LC-PUFAs), breastfeeding or the consumption of There are too few studies of the relationship between LC-PUFA intakes or early exposure to these nutrients to know whether LC-PUFAs affect the cognitive development of preschool children. This study attempts to meet this need by examining the effect of DHA supplementation in 4-year olds. n-3 LC-PUFAsupplemented infant formula. Fewer data are available about the effects of early exposure to these fatty acids and cognitive performance after 18 months of age. In a study of fish oil supplementation of lactating mothers, infant problem-solving at 9 months of age did not differ between the supplemented and placebo control mothers. Passive vocabulary in the infant of the fish oil mothers was lower at one year of age compared with the placebo controls, but no differences were observed at age 2. Word comprehension at one year was inversely associated with red blood cell docosahexaenoic acid (DHA) at 4 months. The effect of DHA on language development was deemed small. Four-year-old children whose mothers consumed cod liver oil during pregnancy, scored higher on the Kaufman Assessment Battery for Children compared with children whose mothers were given corn oil. US children aged 3, whose mothers had the highest fish consumption, scored higher on the Wide Range Assessment of Visual Motor Abilities compared with children whose mothers did not eat fish, but in the Netherlands, cognitive development of 4-year-old children was not associated with DHA or arachidonic acid status at birth. A recent review of the effect of n-3 LC-PUFA supplementation on childhood cognitive development concluded that the evidence for benefits in children older than 2 years is too limited to permit a conclusion. Supplementation of mothers or young infants with LC-PUFAs has usually included both n-3 LC-PUFAs and arachidonic acid. Few studies have examined supplementation with just DHA, the main n-3 LC-PUFA found in brain lipids. This study examined the effects of DHA supplementation alone in healthy children aged 4 years to 4 years and 8 months. Children were enrolled from 10 US states, from homes where English was the main language. Children were between the 10 th and 95 th percentiles for weight and height according to the National Center for Health Statistics growth curves and were excluded if they were born prematurely, had ADHD or a family history of the disorder, any inborn error of metabolism or other serious medical condition. Participants were not taking medications for seizures, anxiety, psychosis, depression or bipolar disorder. 21

22 Two hundred and two children were randomized to consume either 400 mg of DHA/day or a high-oleic sunflower oil placebo supplied as chewable softgel capsules. The study was of 4 months duration. Several cognitive assessments were performed, including the Leiter-R test of sustained attention for the ability to remain attentive during repetitive tasks, Peabody Picture Vocabulary Test for listening comprehension, Day-Night Stroop Test to assess impulsivity and the kcpt test, a computerized test to measure the ability to sustain attention and accuracy in a timed test. The primary outcomes were changes from baseline in these tests. Of the 202 children enrolled in the study, 175 completed the study with at least one post-baseline cognitive assessment. There were 163 children who completed the whole study. Blood samples were available for 93 participants at baseline and the end of the study. After 4 months, the DHA treatment group experienced a significant 300% increase in whole blood DHA content and a 9% nonsignificant decrease in arachidonic acid. The concentration of eicosapentaenoic acid also increased, but not significantly. Results from the cognitive assessments revealed a ceiling effect on the Leiter-R test, where 36% of children in the DHA group and 19% in placebo group scored 100% at baseline and the end of the study. A smaller ceiling effect also occurred in the Day-Night Stroop Test with 2% in the DHA group and 10% of placebo children scored 100% at both time points. DHA supplementation of preschool children for 4 months was associated with higher scores on the Peabody Picture Vocabulary Test, which assesses listening comprehension. Other tests proved unsuitable for this age group. In intention-to-treat regression analysis, which included all children who completed at least one post-baseline assessment, DHA was positively associated with higher scores on the Picture Vocabulary test (P= 0.02). A similar association was observed when the analysis included only those children who completed the entire protocol (P= 0.04). Thus, DHA supplementation was associated with improved scores on the test of receptive vocabulary, an evaluation of memory and cognitive function. Scores on the Picture Vocabulary test reportedly correlate well with other tests of intelligence and are useful in classifying children into average and above average categories. The study is useful in confirming an effect of DHA on children s cognitive ability as assessed by the Peabody Picture Vocabulary Test, a relationship previously reported for maternal fish consumption and outcomes with this test. It also provides useful information about the appropriate cognitive assessment tests recommended for preschool children, as the observed ceiling effects were unexpected. Although it is well known that n-3 LC-PUFA intakes in western diets are very low, especially among children, more robust data will be needed to support recommendations to boost children s consumption of these fatty acids. Ryan AS, Nelson EB. Assessing the effect of docosahexaenoic acid on cognitive function in healthy, preschool children: A randomized, placebo-controlled, double-blind study. Clin Pediatr 2008;47: Depression Low Dose DHA Improves Clinical Scores in Major Depression A growing body of evidence It is generally suggests that long-chain thought that omega-3 polyunsaturated eicosapentaenoic fatty acids (n-3 LC-PUFAs) are acid (EPA) or EPA promising or beneficial in the combined with treatment of major depressive disorder, at least as an docosahexaenoic acid (DHA) is more adjunct to current therapies. They have the distinct advantage of minimal side effects effective than DHA alone. This pilot compared with pharmacological agents. Based on the cur- study disputes that assumption. rent literature, it is generally thought that eicosapentaenoic acid (EPA) or EPA combined with docosahexaenoic acid (DHA) is more effective than DHA alone. One study using only DHA as a treatment, failed to detect a significant effect of 2 g of DHA/day for 6 weeks. Because DHA is the major n-3 LC-PUFA in the brain and is reduced in the frontal cortex of severely depressed patients, it would be imprudent to dismiss the possibility that it may be useful in depressed patients because of a single study of relatively short duration. To clarify the effectiveness of DHA in the treatment of patients with major depressive disorder, David Mischoulon and colleagues at the Massachusetts General Hospital in Boston conducted a study among 35 adults with Hamilton Depression Rating Scale scores of 18 or higher. Patients were randomly assigned to consume 1, 2 or 4 g/day of DHA for 12 weeks. Participants were excluded if they had a serious or unstable medical condition including psychoses or bipolar disorder, if they used anticoagulants, were pregnant or breastfeeding, or did not use a medically accepted means of contraception (women of childbearing age) and for several other 22

23 medical attributes. Those who consumed 800 mg/day of DHA or took other n-3 fatty acids within the past 6 months were also ineligible. Participants were allowed psychotropic medications at the discretion of the study physician, depending on the indication and dose, and could continue, but not initiate, psychotherapy. Patients assigned to 2 g/day or more consumed the dose in weekly increments of 1 g/day for one week, 2 g/day for the second week and 4 g/day for the remainder of the study. Participants were asked to complete daily food diaries for estimating n-3 PUFA consumption. Blood samples were obtained at baseline, 6 and 12 weeks for the analysis of plasma fatty acids. The primary outcome measure was a 50% or greater decrease in the Hamilton Depression score over the entire study. As happens often in studies of mental illness, dropouts were numerous, with 40% (14) of the original participants completing the 12-week period. Twentyeight participants completed at least 2 visits. Among those finishing the study, half responded to treatment. Response rates were highest for those consuming 1 g of DHA/day (83%), with 40% responding to the 2 g/day dose and none responding to the highest dose. Of those completing the 12-week period, 43% were in remission at the end of the study, with remission rates greatest for those consuming 1 g/day. When all participants were included in the analysis (intention-to-treat) the response rate was 32% with a similar pattern of responses according to dose as seen in the analysis of those who completed the study. Examination of the Hamilton Depression scores revealed the greatest improvement (i.e., decreased scores) in patients completing the study and taking the lowest dose, 1 g of DHA/day. Their scores changed from 21.5 to 6.0 after 12 weeks (Figure). In those taking 2 g/day, scores fell from 21.8 to 12.6 and in the 4 g/day group, score changes were not significant, 20.7 to For all patients who completed the study combined, the Hamilton score changed from 21.4 to 10.1 (P= 0.001). Intention-to-treat analysis yielded similar results, although the decreases in scores were less dramatic. As expected, plasma DHA concentrations increased in the treatment groups, with a mean increase among those completing the study of 85% (75.1 to nmol/ml). EPA values did not change significantly. The relationships between plasma DHA and depression scores were either nonsignificant or lost significance when corrected for 3 comparisons. This study is valuable for at least two reasons: it demonstrated a significant improvement in the depression scores of low dose DHA alone and it showed an inverse response as the dose of DHA increased. DHA treatment was essentially the only treatment among these patients. The investigators suggested that there might be a therapeutic window for treatment effects with n-3 LC-PUFAs, at least for DHA alone. DHA supplementation was associated with few mild side effects, mainly gastrointestinal and headache, in eight participants. Only two participants dropped out for these reasons. The study is limited by the small number of patients and the lack of a placebo control group. Currently, a randomized controlled trial is underway to evaluate EPA versus DHA in the treatment of major depression. Mischoulon D, Best-Popescu C, Laposata M, Merens W, Murakami JL, Wu SL, Papakostas GI, Dording CM, Sonawalla SB, Nierenberg AA, Alpert JE, Fava M. A doubleblind dose-finding pilot study of docosahexaenoic acid (DHA) for major depressive disorder. Eur Neuropsychopharmacol 2008;18: Low Plasma EPA Associated with Major Depression in the Elderly Depression affects approximately 8% to 16% of older adults and is more likely among those with impaired cognition. It is recognized that the reasons for depression are multifactorial and relate to biological, emotional and social factors. Although the risk of depression in the elderly may be increased because of physiological factors, such as vascular changes and heart disease, the frequency of depression is lower in older compared with younger adults. 23

24 A modifiable and potentially important risk factor for depression in the elderly is the consumption of fish or long-chain omega-3 fatty acids. This study examined whether omega-3 status was linked to the severity of depression. A modifiable and potentially important risk factor for depression in the elderly is the consumption of fish or long-chain omega- 3 polyunsaturated fatty acids (n-3 LC- PUFAs). In older adults, greater fish consumption and higher plasma n-3 LC-PUFAs are related to lower risk of Alzheimer disease, slower cognitive loss and less decline in speed-related cognitive domains, but some studies have reported no cognitive benefits from increased consumption of these fatty acids in the elderly. In a long-term study among the elderly in Rotterdam, the Netherlands, depression was higher in individuals with low concentrations of n-3 PUFAs in the absence of elevated C-reactive protein, a marker for acute inflammation. Others have linked low n-3 LC-PUFAs with depression, but not in older adults. Catherine Féart and colleagues at the Institut National de la Santé et de la Recherche Médicale, France, investigated the relationship between plasma fatty acids and the severity of depressive symptoms in population-based sample of individuals 65 years of age or older living in Bordeaux. Assessment of depressive symptoms was conducted with the Center for Epidemiologic Depression Scale, a questionnaire frequently used in studies of older adults. Scores 17 for men and 23 for women indicated clinically relevant depression. The consumption of 5 or more drugs/day was considered an indicator of comorbidity. Cognitive function was assessed using the Mini- Mental State Examination. The study included 1390 individuals, 547 men and 843 women whose average age was 75 years. The investigators identified 117 participants (8.4%) who met the criteria for depression. These individ uals were significantly older (76 years, on average), more likely to be female, widowed or single and had lower monthly income. These participants had significantly higher depression scores compared with the remaining controls (26.8 vs. 6.2). They took more drugs, including antidepressants, had lower cognitive scores and less hypercholesterolemia. They were also more likely to have suffered recent weight loss of more than 3 kg. Compared with the non-depressed participants, those with depressive symptoms had significantly lower eicosapentaenoic acid (EPA) concentrations in their plasma (Figure). No other fatty acids differed significantly between the two groups. In multivariate regression analysis, lower plasma EPA was significantly and inversely related to the presence of depression. With additional adjustment for cognitive score, hypercholesterolemia, number of drugs and weight loss, the association remained significant and was little changed. Plasma EPA concentrations were significantly and inversely associated with the severity of depression, but only in individuals receiving antidepressant drugs. Additional adjustment for the variables noted above increased the strength of the association and statistical significance remained. The relationship between plasma EPA concentrations and the severity of depression in patients not taking antidepressants was not significant. Whether anti-depressants themselves affect n-3 LC-PUFA concentrations is not known. This report documents modestly, but significantly, lower plasma EPA concentrations in patients with major depression, an observation that has been noted previously for serum cholesteryl esters and phospholipids and for total n-3 LC-PUFAs in red blood cell membranes. Lower levels of DHA in depression have also been reported. At least one study observed a negative relationship between red cell n-3 LC-PUFAs and the severity of depression. In the present study, severity of depression was significantly related to low concentrations of EPA, but not DHA, in patients taking anti-depressant medications. Consistent with these observations is the finding that DHA concentrations were significantly lower in the orbitofrontal cortex of patients who died with major depression. 24

25 This report documents a significant decrease in plasma EPA in patients with major depression. Moreover, in patients taking antidepressants, the reduction in EPA was significantly associated with the severity of depressive symptoms. Whether the reductions in EPA or DHA imply a meaningful difference between these fatty acids in depression is not known. The two go hand in hand in foods and fish oil supplements, with DHA being more abundant in the body s membrane phospholipids and EPA more concentrated in circulating triglycerides. This study does not address the question of whether the observed reduction in n-3 LC-PUFAs relates to the development of depression or is a consequence of it. Some think that low n-3 LC-PUFA status may increase the susceptibility to depression. In this population, low fish consumption was associated with increased likelihood of depressive symptoms. Several investigators have suggested that inflammation contributes to depression and if so, would be consistent with the anti-inflammatory effects of EPA in the treatment of depression. These observations add to the evidence implicating low n-3 LC-PUFA consumption in the occurrence of depressive symptoms. Féart C, Peuchant E, Letenneur L, Samieri C, Montagnier D, Fourrier-Reglat A, Barberger-Gateau P. Plasma eicosapentaenoic acid is inversely associated with severity of depressive symptomatology in the elderly: data from the Bordeaux sample of the Three-City Study. Am J Clin Nutr 2008:87: CLINICAL CONDITIONS Alzheimer Disease Mild Alzheimer Patients Improve Cognition with Omega-3s An emerging potential preventive for the onset or progression of Alzheimer disease is the daily consumption of n-3 LC-PUFAs. Promising evidence from small trials suggests these fatty acids may slow cognitive decline in aging. As people live longer, the chance that their mental faculties will decline increases greatly. People who exhibit mild cognitive impairment, particularly involving memory and language, are nearly 3 times more likely to develop Alzheimer disease, the primary neurodegenerative disease of aging. At present, there are few strategies to deter this scourge, but an emerging potential preventive is the consumption of long-chain omega- 3 fatty acids (n-3 LC-PUFAs) found in fatty fish and fish oils. Those with higher intakes of these fatty acids and weekly fish consumption were reported to have a significantly lower chance of developing Alzheimer disease. Patients who died with Alzheimer disease have less docosahexaenoic acid (DHA) in their brains than those free of this affliction. A study in France reported that frequent consumption of fish was associated with a lower risk of dementia and Alzheimer disease in people who did not have the ApoEε genotype. In a 6-month randomized controlled trial in older patients with mild or moderate Alzheimer disease, consumption of a DHA-rich supplement containing 2.3 g of n-3 LC-PUFAs was associated with significantly retarded disease progression in those with mild symptoms. In a Dutch study, older men with the highest intakes of n-3 LC-PUFAs experienced a significantly slower loss of cognitive function compared with men with low n-3 LC-PUFA intakes. Other investigators have observed only modest results with n-3 LC-PUFAs in patients with early Alzheimer disease. Given the mixed results from observational and intervention studies, there is scope for better defining the dose, patient population and circumstances under which n-3 LC-PUFAs might be beneficial in maintaining cognitive function. This challenge attracted investigators at the Taipei City Psychiatric Center, Taiwan, to conduct a randomized controlled trial using n-3 LC-PUFAs as the sole treatment in patients with mild cognitive impairment or Alzheimer disease. Eligible patients were diagnosed with mild or moderate Alzheimer disease or amnesic mild cognitive impairment as confirmed by subjective and objective evaluations according to standardized criteria. Patients ranged from 55 to 90 years of age, averaging 75 years. Exclusion criteria included inadequate motor or sensory function to comply with testing, ischemic brain lesions, Hamilton Depression score >13, abnormal folic acid, vitamin B 12 levels or thyroid, severe comorbidity or other severe diseases. If participants had consumed vitamin E, fish oil or Ginkgo biloba prior to the enrolment, use of these supplements was discontinued during the study. Of the 49 eligible participants, 46 were randomized to consume n-3 LC-PUFAs (1,080 mg of eicosapentaenoic acid (EPA), 720 mg DHA) or olive oil capsules daily for 24 weeks. The sample included 23 patients with mild or moderate Alzheimers and 23 with mild cognitive impairment. Cognitive assessments administered at baseline and 6, 12, 18 and 24 weeks after enrolment included the cognitive portion of the Alzheimer disease Assessment 25

26 Scale and the clinician s interview-based Clinical Global Impression of Change Scale. The latter assessment also included information provided by the patient s caregiver. Secondary outcome measures included the Mini Mental State Examination and the Hamilton Depression Rating Scale administered at enrolment and 24 weeks. Fasting plasma and red blood cell fatty acids were measured at enrolment and 24 weeks. Twenty-nine participants completed the study, with 35 attaining at least one assessment. Loss to follow-up was greater in the placebo group than in those taking the n-3 LC-PUFAs, but the difference was not statistically significant. In the unadjusted analysis, of those who completed the study, patients consuming the n-3 LC-PUFAs experienced a progressive and statistically significant improvement in the Clinical Impression of Change scores with each 6-week assessment (Figure). Placebo patients showed no improvement. Secondary analysis showed that the group-time interaction changes were stronger for the cognitive rather than the function components of the assessment. With the Alzheimer assessments, there was a trend toward improved scores in the n-3 LC-PUFA group that did not reach statistical significance. However, higher red blood cell EPA concentrations were significantly associated with better Alzheimer scores. There were no significant associations with total n-3 LC-PUFAs or DHA. Mini Mental State and Hamilton Depression Scale ratings did not change in either group and assessment scores did not differ between patients diagnosed with Alzheimer disease or mild cognitive impairment. In this small study In this small study of mild of mild cognitive cognitive impairment and impairment and Alzheimer conditions, the Alzheimer conditions, the consump- consumption of 1.8 g/day of n-3 LC-PUFAs for 6 months tion of 1.8 g/day of was associated with n-3 LC-PUFAs for 6 months was associated with progres- progressive improvements in cognitive scores. sive improvements in cognitive scores. Only one of the two assessments showed significant changes with the treatment. The trend for improved Alzheimer scores might have reached statistical significance with a larger sample. These findings contribute to the promising results from previous studies that even late in life, consuming nearly 2 g/day of n-3 LC-PUFAs may keep the mind sharp. How much better is it to establish healthier n-3 LC-PUFA habits earlier in life? Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, Stewart R, Huang SY. The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: A preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry 2008;32: