PUFA NEWSLETTER. December 2007 Contents. Volume 12 Issue 4 PUFA NEWSLETTER STAFF SCIENCE ADVISORY BOARD

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1 PUFA NEWSLETTER Volume 12 Issue 4 December 2007 Contents EDITORIAL Milestone Report Links Long-Chain Omega-3s with Prevention of Parkinson s Disease... 2 MATERNAL AND INFANT HEALTH Long-Chain PUFA Synthesis in Preterm Infants... 3 Maternal Fish Oil Supplementation in Pregnancy Increases Breast Milk EPA and DHA... 4 IMMUNE FUNCTION Fish Oil Supplementation in Pregnancy Reduces Key Inflammatory Mediators in Neonates... 6 Higher Fish Intake in Childhood Linked to Less Atopy at Age PUFA NEWSLETTER STAFF Editor Joyce A. Nettleton, DSc Communications Manager Angela Dansby Sponsor DSM Nutritional Products, Kaiseraugst, Switzerland, MENTAL HEALTH AND COGNITION Incidence of Dementia and Alzheimer s Disease Lower with Weekly Fish Intake... 8 Higher Omega-3 Status Linked to Slower Decline in Some, But Not All Cognitive Measures Eating Any Type of Fish May Benefit Cognitive Performance in Older Individuals BRAIN LC-PUFAs Increase DHA Content and Neurite Growth in Neurons From Stem Cell CLINICAL CONDITIONS Parkinson s Disease DHA-Enriched Diet Protects Against Early Parkinson s Pathology in Animal Model Type 1 Diabetes Omega-3 PUFAs Linked to Lower Risk of Type 1 Diabetes in High Risk Children SCIENCE ADVISORY BOARD Stefan Endres, M.D. University of Munich Munich, Germany William S. Harris, Ph.D. South Dakota Health Research Foundation, Sioux Falls, SD Gerard Hornstra, Ph.D. Maastricht University Maastricht, The Netherlands Maria Makrides, Ph.D. Child Health Research Institute Adelaide, Australia FRONTIERS Fatty Acid Gene Variant Modifies Effect of Breast-Feeding on Intelligence ISSFAL MEETING Kansas City, May 17-22, LETTERS DHA and Statins 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 Milestone Report Links Long-Chain Omega-3s with Prevention of Parkinson s Disease Papers with the potential to redirect our thinking about diseases are rare, but the report from Laval University s Frederic Calon might do it for Parkinson s disease. In an elegant series of experiments using a time-tested mimic of Parkinson s disease induced by a chemical, Calon s group showed that the consumption of long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs) mainly DHA protected Parkinson s animals from losing their dopamine-producing neurons. Animals without n-3 LC-PUFAs lost 30% of these essential cells. The implication is that sufficient brain docosahexaenoic acid (DHA) might be able to prevent the onset of Parkinson s disease. The study says nothing about the usefulness of DHA once the disease has begun and Parkinson s is seldom detected before most of the neurons in the substantia nigra have been destroyed. Could this study nudge us to nourish the brain more effectively? This year-end issue includes several articles relating to infant and child health. Researchers in Italy and the Netherlands used a novel stable isotope method to determine how much LC-PUFAs a preterm infant can make and concluded that LC-PUFA synthesis is far from trivial in early life. Two studies from Australia reported that taking a high dose of fish oil in the last part of pregnancy increased the content of n-3 LC-PUFAs in the mother s milk and in the infant for at least 6 weeks after delivery. High breast milk DHA was associated with higher cognitive scores in the children at age 2½ years. Maternal fish oil consumption was also related to diminished inflammatory immune responses in the infants, all of whom had a family history of allergic diseases. A study from Spain reported that more frequent fish consumption in children 6½ years of age at higher risk of allergies was linked to significantly lower chance of developing allergic conditions. Evidence now suggests that maternal intake of n-3 LC-PUFAs in pregnancy and a child s consumption of fish are associated with lower risk of childhood allergies. Additional evidence that eating fish regularly or having higher amounts of n-3 LC-PUFAs in the blood are characteristic of older people who have escaped dementia or Alzheimer s disease, came from studies in France and the Netherlands. In Norway, participants in their 70s who consumed fish at least once a week had superior mental abilities compared with those who avoided eating fish. But genes have an effect, too. Not only was this fact demonstrated with fish consumption and risk of dementia, but a different gene version turned out to be a co-conspirator in a study of nature and nurture related to breast-feeding and IQ. Read more about it in Frontiers. This year contributed many advances to our understanding of how and where PUFAs work. It brought bolder recommendations for higher n-3 LC-PUFA consumption for heart health and infant development, and for treating certain mental disorders. The new year s challenge will be to urge their widespread adoption. We wish all readers peace, caring friendships and banishment of worries during the holidays. Joyce A. Nettleton Editor, PUFA Newsletter and Fats of Life joyce@fatsoflife.com 2

3 MATERNAL & INFANT HEALTH Long-Chain PUFA Synthesis in Preterm Infants Fetal and infant needs for docosahexaenoic acid (DHA), an omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA), are now well appreciated because of DHA s importance in the growth and development of the brain and retina. During fetal development, DHA transfer from the mother to the fetus increases dramatically as pregnancy progresses. After birth, infants obtain DHA from breast milk, LC-PUFA-supplemented infant formula and their own fat stores. In contrast with term infants, infants born before term have lower DHA concentrations and less body fat. Nevertheless, stable isotope studies have shown that preterm and low birth weight infants can synthesize small amounts of DHA from its 18-carbon precursor, alpha-linolenic acid. The difficulty is that this synthesis is highly variable among infants and the amounts produced Infants born before term have lower DHA concentrations than term infants. They can make some DHA, but how much do they actually synthesize? This study found a clever way to measure DHA synthesis. appear insufficient to support optimum neurodevelopment. Nonetheless, there are only limited data on the actual amounts of LC-PUFAs, mainly arachidonic acid (ARA) and DHA, synthesized in preterm infants. Investigators at the Polytechnic University of Marche, Ancona, Italy, with colleagues in the Netherlands, examined LC-PUFA synthesis in 22 Dutch infants born with an average gestational age of 31 weeks and birth weight of 1.15 kg. All consumed infant formula exclusively for 7 months, at which time they were weaned. Infants were assigned randomly to consume formula without or with ARA (0.84% by wt) and DHA (0.64% by wt). The investigators measured the naturally occurring concentration of the stable isotope ratio of 13 C: 12 C in the fatty acid methyl esters in the plasma lipid classes and formula fats using gas chromatography and high precision isotope ratio mass spectrometry. The stable isotope natural abundance approach measures the differences in naturally occurring stable isotope ratios in various dietary components and uses these to assess endogenous fatty acid synthesis at steady state. The method is based on the fact that most plant foods consumed in Europe come from C3 plants, i.e., where photosynthesis incorporates CO 2 into the 3-carbon compound 3-phosphoglycerate. More than 95% of the earth s plant species are this type w(e.g., wheat, barley, rice, oats and most trees), and baseline measurements of the 13 C: 12 C ratio of nutrients reflect the usual diet. However, introduction of dietary C4 plants, such as corn and sugar cane, which incorporate CO 2 into oxalacetate with 4 carbons, can act as natural tracers because 13 C: 12 C is slightly greater in plants using the C4 pathway. In this instance, the microalgal source of the DHA added to the infant formula, Crypthecodinium, is isotope-enriched by being cultivated on C4 plant products having a slightly greater 13 C: 12 C ratio. This property means the supplementary LC-PUFAs can be used as a stable isotope tracer to measure the contribution of dietary LC- PUFAs to plasma lipids. Calculation of the endogenous and absolute LC- PUFAs synthesized assumed that there was no metabolic discrimination between endogenously produced LC-PUFAs and those provided in the diet, and that LC-PUFA oxidation was negligible. Infants in both study groups grew normally during the study period and did not differ in weight gain at any of the study time points. Over the course of 7 months, both ARA and DHA in plasma phospholipids declined exponentially from a similar concentration at birth, reaching a plateau at 3 months. Infants fed the LC-PUFA-supplemented formula lost significantly less ARA than infants not receiving LC-PUFAs, with differences between the groups reaching statistical significance at all study points from 1 through 7 months. The final plasma phospholipid concentrations of ARA were 5.6 mol% in the supplemented infants and 1.9 mol% in the unsupplemented ones. In contrast with ARA, plasma phospholipid DHA concentrations in the LC-PUFA-supplemented infants increased from 2.9 mol% at 1 month after birth to 5.1 mol% at 7 months. In the unsupplemented group, DHA declined from 3.1 mol% to 1.5 mol% over the same period. Isotope enrichment of the precursor fatty acids, linoleic and alpha-linolenic, did not change in either the LC-PUFA-supplemented or unsupplemented groups. ARA was enriched only in the LC-PUFA supplemented group, with maximum enrichment attained at 3 months. Enrichment remained below the dietary level. Similarly, DHA isotope enrichment occurred only in the supplemented group and attained values at 3 months approaching those of the diet. Endogenous and absolute synthesis of ARA and DHA relative to metabolizable dietary intakes (Figure) indicated appreciable LC-PUFA synthesis, especially in the first month of postnatal life. Formation of ARA 3

4 the maternal background diet and the LC-PUFA supplement provided to the infant. Sufficient time was available for equilibration between the plasma and tissue fatty acid pools and it was assumed that in the growing fully fed infant the breakdown of stored fatty acids would be low. The study also had the advantage of an unchanged diet over its duration. Finally, the oxidation of LC-PUFAs has been reported to be low in growing preterm infants and was assumed to be so in these well fed infants. The study indicated that preterm infants fed LC-PUFAsupplemented formula make appreciable amounts of ARA and DHA, especially in the first month after birth. Thereafter, LC-PUFA synthesis diminishes rapidly and continues to fall. Synthesis of ARA is approximately twice that of DHA during the first month and exceeds DHA formation at all times thereafter. Figure. Percentage and absolute synthesis of ARA and DHA in LC-PUFA-supplemented preterm infants at 1, 3 and 7 months of age. Reproduced with permission from Am J Clin Nutr 2007;86: American Society for Nutrition. exceeded that of DHA at 1, 3 and 7 months, with synthesis of each declining over time. Absolute synthesis of ARA was approximately 27, 14 and 12 mg/kg/day and of DHA was about 13, 3 and 2 mg/kg/day at 1, 3 and 7 months, respectively. This is the first report using stable isotope ratios to estimate long-term endogenous LC-PUFA synthesis in young infants. Preterm infants fed LC-PUFA-supplemented formula make appreciable amounts of LC-PUFAs, especially in the first month after birth. This study is the first report using stable isotope ratios to estimate longterm endogenous LC-PUFA synthesis in young infants. The method took advantage of naturally occurring stable carbon isotopes that differed in isotope enrichment between Carnielli VP, Simonato M, Verlato G, Luijendijk I, De Curtis M, Sauer PJJ, Cogo PE. Synthesis of long-chain polyunsaturated fatty acids in preterm newborns fed formula with long-chain polyunsaturated fatty acids. Am J Clin Nutr 2007;86: Maternal Fish Oil Supplementation in Pregnancy Increases Breast Milk EPA and DHA The long-chain polyunsaturated fatty acid (LC-PUFA) composition of breast milk and infant formula can affect the visual function, neural, cognitive and behavioral development of the infant, with generally improved outcomes associated with higher intakes of omega- 3 (n-3) LC-PUFAs. Specifically, breast milk or formula enriched in n-3 LC-PUFAs, particularly docosahexaenoic acid (DHA), is associated with higher infant development scores in a variety of assessments. For breast-fed infants, the primary determinant of the n-3 LC-PUFA content of the mother s milk is her consumption of fish, especially fatty fish. A recent review of the DHA and arachidonic acid (ARA) content of breast milk worldwide reported an average content of ARA and DHA in mature human milk of 0.47% and 0.32%, respectively. The authors noted that the variability of DHA was significantly greater than of ARA. Countries with generally low fish intakes reported correspondingly lower breast milk DHA concentrations of ~0.2%. Although all breast milk contains LC-PUFAs, the effect of maternal fish oil supplementation given only during pregnancy on the LC-PUFA concentrations in breast milk over successive months has not been reported. In this report from a study on maternal fish oil supplementation in pregnant women with a clinically diagnosed history of allergy, breast milk fatty acids were 4

5 determined in samples collected at 3 days, 6 weeks and 6 months postpartum. Women consumed a high dose (3.7 g/day) of fish oil n-3 LC-PUFAs from 20 weeks of gestation until delivery. Women in the control group consumed a similar amount of olive oil. The fatty acid composition of maternal red blood cells was determined at 36 weeks of gestation and 6 weeks postpartum, and for the infants, at delivery and 1 year of age. The investigators assessed the children s cognitive development when they were 2.5 years of age, using the Griffiths Mental Development Scales, Peabody Picture Vocabulary Test and Child Behavior Checklist. From the 83 women who completed the study, 74 provided milk samples at 1 or more time points. As expected, DHA remained significantly colostrum at 3 higher in the breast milk of days postpartum contained the women taking fish oil supplements compared with controls highest proportion of n-3 LCat 6 weeks postpartum. PUFAs compared with the control samples of any time point examined. The concentrations of n-3 LC-PUFAs fell significantly over the first 6 weeks, with the decline being greater in the fish oil group than in the controls (Figure). There were no significant differences between the groups in the concentration of arachidonic acid at any time. With the exception of eicosapentaenoic acid (EPA) and DHA, concentrations of LC-PUFAs did not differ between the groups at 6 weeks or thereafter. However, DHA remained significantly higher in the breast milk of women taking fish oil supplements compared with controls at 6 weeks postpartum (0.42% vs 0.25%). Although EPA was also statistically significantly higher in the fish oil group, the difference was marginal (0.09% vs 0.07%, P<0.01). At 6 months, there were no significant differences between the groups in any fatty acid concentrations. In a different study, women who stopped consuming fish oil at delivery did not differ in their breast milk n-3 LC-PUFA concentrations at 30 days postpartum compared with women who did not take fish oil. Fish oil-supplemented women had significantly higher red blood cell membrane n-3 LC-PUFAs compared with controls at 36 weeks gestation, as would be expected. Although the total n-3 LC-PUFA concentration had declined by 6 weeks postpartum, the difference between the 2 groups remained statistically significant (19.4% vs 15.4%, P<0.001). Maternal red cell EPA and DHA concentrations were strongly correlated with breast milk EPA and DHA concentrations at 36 weeks of gestation and 6 weeks postpartum, but not at 6 months. Figure. Breast milk long-chain PUFAs at 3, 42 and 180 days postpartum in women supplemented with fish oil or olive oil in pregnancy. Each fatty acid was significantly lower at 42 days compared with 3 days except for EPA in control women. DHA in fish oil-supplemented women was significantly different from control values at 3 and 42 days. Maternal red cell EPA and DHA concentrations were strongly correlated with breast milk EPA and DHA concentrations at 36 weeks gestation and 6 weeks postpartum, but not at 6 months. EPA and DHA concentrations in a subsample of the infants red cell membranes were significantly elevated in cord blood compared with control infants, as previously reported. At age 1, DHA and ARA contents were significantly lower in both groups, but EPA was significantly higher in the control group and lower in the fish oil group compared with values at birth. When the relationship between breast milk DHA at different times and infant DHA status at age 1 year was examined, there was a significant association between breast milk DHA at 3 days, 6 weeks and 6 months postpartum and infant DHA status at 1 year. Infants breast-fed for 6 months or more had higher DHA status at 1 year of age than those breast-fed for less than 6 months or not at all. However, when the analysis adjusted for infant feeding method, maternal fish oil supplementation was not related to infant DHA status at one year. 5

6 Although the investigators have previously reported that the infants of mothers supplemented with fish oil were 3 times less likely to have a positive skin prick test to egg white and to have less severe atopic dermatitis when they were 1 year of age, a relationship with breast milk composition had not been examined. In this report, the investigators observed that infants breast-fed for 6 months were more likely to be sensitized to egg white than infants breast-fed for less time. However, sensitization was unrelated to any breast milk fatty acids. In addition, neither breast milk n-3 LC-PUFA status nor fish oil supplementation was related to any growth parameters at 2.5 years of age. Both the infant s DHA status at birth, which is affected by the mother s n-3 LC- PUFA intake during pregnancy, and the continued intake of DHA from breast milk influence the infant s DHA status at age 1. The relationships between breast milk EPA and DHA content at 3 days and 6 months postpartum and cognitive outcomes from the Griffiths Mental Development Scales at 2.5 years of age were assessed. The investigators had reported significantly higher eye-hand coordination scores for infants of the fish oil-supplemented mothers, and here, they reported other significant relationships, specifically with breast milk EPA and DHA content. For breast milk EPA or DHA content at 3 days postpartum, there were significant associations between locomotor, speech and hearing, eye and hand coordination, performance and general quotient scores and higher breast milk EPA and DHA content. Significant associations were also observed with EPA in 6-month milk samples and eye and hand coordination, performance, practical reasoning and general quotient, and between DHA content and general quotient. The investigators further observed an inverse association between breast milk ARA in 6-month breast milk samples and vocabulary skills, reflected in the length of phrases and number of words. In summary, the key findings from this report are the significantly higher concentrations of EPA and DHA in breast milk at 6 weeks postpartum in women consuming a high dose of fish oil during pregnancy, and the association between breast milk DHA at 6 months and the infant s DHA status at age 1. This observation suggests that both the infant s DHA status at birth, which is affected by the mother s n-3 LC-PUFA intake during pregnancy, and the continued intake of DHA from breast milk influence the infant s DHA status at age 1. Further, higher DHA and EPA breast milk concentrations at 3 days postpartum were associated with improved cognitive outcomes assessed 2.5 years later. As neurological development continues in the first few years of life, and DHA has been linked to improved neurodevelopmental outcomes, it appears prudent to ensure that pregnant and nursing women have abundant access to n-3 LC-PUFAs throughout pregnancy and lactation. Thus, the recent recommendations from an international working group of experts that pregnant and nursing women consume at least 200 mg/day of DHA one-tenth the amount used in this study would seem well aimed. Dunstan JA, Mitoulas LR, Dixon G, Doherty DA, Hartmann PE, Simmer K, Prescott SL. The effects of fish oil supplementation in pregnancy on breast milk fatty acid composition over the course of lactation: a randomized, controlled trial. Pediatr Res 2007; 62: IMMUNE FUNCTION Fish Oil Supplementation in Pregnancy Reduces Key Inflammatory Mediators in Neonates Maternal consumption of fish oil during pregnancy not only increases the supply of long-chain omega-3 fatty acids (n-3 LC-PUFAs) to the infant for neurodevelopment, it also affects the maturation of the immune system and favors the infant s neurodevelopment. It may lower the infant s chance of developing allergic conditions, but findings are inconsistent. Omega-3 LC- PUFAs provided in childhood rather than during fetal development may reduce their potential effectiveness in deterring infant and childhood allergies. However, at least one report suggests that fish oil supplementation in late infancy may hasten the maturation of the immune system. Susan Prescott and colleagues at the University of Western Australia in Perth have been investigating the effects of maternal consumption of n-3 LC-PUFAs in pregnancy on immune function in the offspring for several years. They reported that high doses of fish oil consumed in pregnancy reduce cytokine responses in the infants at birth and the severity of atopic dermatitis at age 1. In the study described here, these investigators examined the effect of maternal fish oil supplementation on the production of leukotrienes, potent mediators of inflammation, in the neutrophils of newborns. Ninety-eight pregnant women with a clinical history of allergies and a positive skin prick test to one or more common allergens were randomized to consume either 3.7 g/day of n-3 LC-PUFAs from fish oil or a placebo (olive oil) for the final 20 weeks of pregnancy. Of these 6

7 Maternal consumption of fish oil during pregnancy was associated with significantly lower production of leukotriene B4, a potent mediator of inflammation, in their neonates at birth. women, 83 completed the study and blood samples were available from 64 of them. Groups did not differ in maternal characteristics, gestation, birth weight or length. As expected, maternal and neonatal total and long-chain n-3 PUFAs were significantly higher in the red blood cell membranes of fish oil participants than in the placebo group; n-6 PUFAs were significantly lower. Leukotriene production was measured in cultured cord blood fetal mononuclear cells stimulated with phytohemaglutinin mitogen. Leukotriene B 4 production, especially for the leukotriene B 4 isomer 2, was significantly lower in the neonates of mothers who had consumed fish oil compared with those in the placebo group. Another product of lipoxygenase activity, 5-HETE, was also appreciably lower in the neonates of the fish oil mothers, but the difference from the placebo group did not quite reach statistical significance (P=0.054). LTB 4 was associated with higher maternal levels of adrenic acid (22:4n-6), but not significantly with arachidonic or linoleic acid levels. Leukotriene B 5, the lipoxygenase product of eicosapentaenoic acid, was present at low levels in some samples of fish oil neonates, but not in placebo neonates. Its presence was consistently and significantly associated with higher levels of maternal n-3 LC-PUFAs and lower n-6 PUFAs in red blood cell phospholipids. The investigators also looked at the neonatal antigen presenting cell responses to stimulation with interferon-γ and lipopolysaccharide in mononuclear cells. These cells produced the proinflammatory mediator interleukin-6 and responses were correlated with LTB 4, and 5-HETE production. Production of interleukin-10, which inhibits inflammatory responses, increased. The authors suggested that this might have been the cells attempt to diminish the effects of inflammation. In the fish oil neonates, these responses were significantly down-regulated. Other assessments of immune function, T cell stimulation and up-regulation of antigen presentation, were consistent with these findings. The key finding from this study is that maternal LC- PUFA status, as affected by fish oil consumption during pregnancy, significantly altered the pattern of neonatal red cell LC-PUFAs and eicosanoid metabolites, and inhibited neutrophil LTB 4 production. This and other Maternal fish oil consumption in pregnancy can modify the infant s immune responses, having a dampening effect on them. effects on immune function indicate that maternal fatty acid intake during pregnancy can modify the infant s immune responses, with fish oil consumption having a dampening effect. Moderation of the production of pro-inflammatory cytokines may discourage or delay the development of allergic diseases which are characterized by inflammation. The observed immune responses were highly correlated with maternal and infant red blood cell LC-PUFA composition. These observations accord with previous studies in adults. These studies have provided useful information in showing the various ways that maternal fatty acid intake and status can affect an infant s maturing immune system. They underline the need to understand much more about neonatal and childhood immune responses to nutrient status, especially regarding LC-PUFAs, so that eventually we may lessen the burden and severity of immune-based diseases. Prescott SL, Barden AE, Mori TA, Dunstan JA. Maternal fish oil supplementation in pregnancy modifies neonatal leukotriene production by cord blood derived neutrophils. Clin Sci (London) 2007;113: Higher Fish Intake in Childhood Linked to Less Atopy at Age 6 In the September 2007 PUFA Newsletter, we reported that children in Spain, whose mothers had the highest fish intakes during pregnancy more than 2 fish meals per week were significantly less likely to develop eczema at age 1 year or atopic wheeze at age 6. These findings were independent of whether the mothers had allergic conditions. Although the children s fish intake at age 4 appeared to have no effect on their chance of developing allergic conditions, the investigators further explored the children s fish and food intakes for potential relationships with the development of asthma or atopy at 6.5 years of age. Of the original 482 mothers and children that participated in the study, 412 children had skin prick tests for allergies and 468 mothers provided information about the foods consumed by their children at 6.5 years of age. Allergic symptoms in the children were divided into 4 categories: wheeze + atopy, wheeze according to questionnaire response, atopy alone and neither wheeze nor atopy. Relationships between allergy category and dietary variables were assessed by multivariate logistic regression analysis with adjustment for 7

8 Both maternal fish consumption during pregnancy and the children s subsequent fish intake were linked to lower risk of atopic conditions when the children reached 6.5 years of age. gender, parental asthma, parental atopy, maternal smoking, body mass index at age 6.5, parental education and social class, breast-feeding, fish intake during pregnancy and number of siblings at age 6.5 years. Total energy intake was also controlled in the analysis. The investigators calculated odds ratios to estimate the degree of association between dietary variables and allergies. Although maternal fish consumption during pregnancy was associated with lower risk of eczema at age 1 and atopy and atopic wheeze at age 6 in this cohort, there was no significant interaction between the mothers and the children s fish intakes on atopic outcomes. Thus, both maternal fish consumption during pregnancy and the child s subsequent fish intake are linked to lower risk of atopic conditions in this population. These findings support an epidemiological report of lower chance of allergies when children eat fish in early childhood. However, other studies in which the consumption of n-3 LC-PUFAs has been increased in early life have found no effect on the prevalence of asthma or wheeze, eczema and atopy in the first 5 years of life. One study reported increased risk of asthma among children aged 6 to 15 years with increasing fish consumption. Although the immune function-modifying effects of n-3 LC-PUFA consumption are well documented, the paths between fish or n-3 LC-PUFA intake and possible improvements in risk or severity of allergic conditions, especially in children, appear to be highly complex. Chatzi L, Torrent M, Romieu I, Garcia-Esteban R, Ferrer C, Vioque J, Kogevinas M, Sunyer J. Diet, wheeze, and atopy in school children in Menorca, Spain. Pediatr Allergy Immunol 2007;18: Figure. Association of daily fish intake with risk of current wheeze, atopy or atopic wheeze in children at 6.5 years of age. Mean fish intakes for each tertile were 25, 49 and 87 g/day. The prevalences of current wheeze, atopic wheeze and atopy in the 6.5-year-old children were 8.7%, 5.8% and 17%, respectively. Prevalence of each condition decreased with increasing fish consumption, but the difference was statistically significant only for atopy. When the odds ratios were calculated and analyzed, accounting for multiple confounding factors (Figure), the chance of atopy was significantly reduced as fish consumption increased. The odds ratio for the highest tertile of fish intake, 60.5 g/day or more was 0.43 (95% CI= ). Increased consumption of fruity vegetables (tomatoes, eggplant, cucumber, green beans, zucchini) was also significantly associated with reduced risk of current wheeze and atopic wheeze, but not atopy. The associations with vegetables and fish were independent of each other. MENTAL HEALTH People over the age of 65 who eat fish at least once/week have a significantly lower chance about 25% less of developing dementia and Alzheimer s disease. Eating fruits and vegetables at least once/day also reduced risk by nearly 30%. Incidence of Dementia and Alzheimer s Disease Lower with Weekly Fish Intake Epidemiological or observational studies have contributed substantially to the awareness that food habits have a powerful influence over the chance of developing various chronic diseases later in life, especially cardiovascular disease, type 2 diabetes and dementia. Knowledge about diet and the underlying pathologies in cardiovascular disease is relatively far advanced, but the dietary factors affecting dementia and cognitive decline have emerged only recently. The two conditions have much in common. Food habits that include the regular consumption of fish and the Mediterranean diet have both been 8

9 associated with lower risk of Alzheimer s disease (the predominant type of dementia in the elderly). Dietary lipids may increase (e.g., saturated and trans fatty acids) or decrease (e.g., omega-3 long-chain polyunsaturated fatty acids, n-3 LC-PUFAs) the risk of dementia, while other nutrients, such as B vitamins and antioxidants, may affect risk. Age and genotype having the ApoEε4 allele (gene variant) increase the risk of Alzheimer s disease, but one cannot alter these aspects. This section includes 3 recent epidemiological studies on dietary patterns or fish consumption and dementia. One report comes from France, another from the Netherlands and the third from Norway. Each adopted a different experimental design and measures of cognitive performance, but all report benefits associated with eating fish or n-3 LC-PUFAs. The Three-City Cohort study involved 8,085 participants aged 65 years or older who lived in Bordeaux, Dijon or Montpellier, France. All participants had at least one follow-up examination over the next 4 years. Dietary information was collected by food frequency questionnaire and screening for dementia was conducted by trained psychologists at baseline. At two centers, all enrollees were further examined by a neurologist and at the third center, only those who screened positive for dementia received further examination. At follow-up, those suspected of dementia were examined by a neurologist. A committee of neurologists determined the final classification of dementia or Alzheimer s disease according to established medical criteria. Foods having a significant association with risk of dementia in univariate analysis were re-evaluated adjusting for multiple confounding factors, including sociodemographic characteristics, ApoE genotype and vascular risk factors. The investigators also tested for interactions between food sources of n-3 PUFAs and antioxidants and performed stratified analyses where significant interactions existed. After an average of 3.5 years, there were 281 incident cases of dementia (3.5%), of which 183 were considered Alzheimer s disease. Patients eating fish 2 or 3 times/week had a significantly lower incidence of all-cause dementia, but after taking ApoEε4 status into account, the relationship with fish consumption was observed only among noncarriers (Figure). Frequent fish consumers (at least once/week) also had a significantly lower risk of Alzheimer s disease, which was independent of ApoE genotype. Figure. Relationship between multiply adjusted risk (Hazard ratios) of dementia or Alzheimer s disease and frequency of eating fish per week in healthy participants 65 years of age or older. Those who ate fruits and vegetables frequently, at least once a day, also had a significantly lower (30%), risk of all-cause dementia and Alzheimer s disease. A beneficial effect of eating 3 servings of vegetables a day has been reported by others. Those consuming n-3 oils, which included walnut, soybean and colza (a relative of rapeseed or canola) oils, had a 60% lower chance of developing dementia, but the risk reduction for Alzheimer s did not reach statistical significance. In marked contrast with fish and n-3 oil consumption, those who consumed sunflower or grape seed oils, rich in n-6 PUFAs, but not fish or n-3 oils, had twice the risk of dementia (P=0.003), if they were not carriers of the ApoEε4 allele. In carriers, n-6 oil consumption was associated with significantly lower risk of dementia. The authors noted that although fish consumption and fruit and vegetable intake were each protective against dementia, there were no significant interactions between them. Neither was there an association between dementia and saturated fat intake, an association Participants without the ApoEε4 genotype who consumed sunflower or grape seed oils rich in n-6 PUFAs and did not eat fish had twice the risk of dementia as those who consumed fish or n-3 oils. previously reported by others for dementia and Alzheimer s. These findings are notable for their detailed examination of major dietary constituents and fats, control of many potentially confounding variables and 9

10 for separate analysis of patients carrying the ApoEε4 allele, which is known to increase the risk of Alzheimer s disease. While confirming the association between fish consumption and lower risk of dementia and Alzheimer s disease, the study renews questions about how the ApoEε4 genotype modifies the association between dietary fatty acids and these conditions. It also supports the benefits associated with the frequent consumption of fruits and vegetables, although there is no agreement about which components may be the most beneficial, nor how such advantages may be mediated. The authors discuss this literature in the paper. Fish, fruits and vegetables worth remembering. Barberger-Gateau P, Raffaitin C, Letenneur L, Berr C, Tzourio C, Dartigues JF, Alperovitch A. Dietary patterns and risk of dementia: The Three-City cohort study. Neurology 2007;69: Higher Omega-3 Status Linked to Slower Decline in Some, But Not All, Cognitive Measures A study in the Netherlands took a different approach in assessing cognitive change from that used in the preceding report among 65-year-old French participants. The investigators were interested in changes in specific types of cognitive function rather than the chance of developing dementia. They recruited 807 participants ranging in age from 50 to 70 years (mean age 60) and having elevated blood homocysteine levels, a risk factor for cardiovascular Fish consumption may reduce the chance of developing dementia, but are all aspects of cognition affected? disease. Participants had been recruited for a different study (on folic acid) and thus the study was not based on a random population sample. Their cognitive status at baseline was assessed using the Mini-Mental State Examination (maximum score=30); only 7 participants had scores <24. Cross-sectional analysis included all participants, but only those in the placebo group (404) of the original study were included in the longitudinal analysis. Folic acid supplementation has been associated with improved mental performance. The investigators assessed which, if any, of 5 cognitive domains would change over a 3-year follow-up period and whether such changes were related to the concentrations of long-chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFAs) in their plasma cholesteryl esters. Using blood levels of fatty acids avoids the problems inherent in dietary assessments and is considered a valid reflection of n-3 LC-PUFA intake and likely fish consumption. The tests of cognitive performance included the Concept Shifting Test for the ease of switching between 2 psychological concepts; Stroop Color-Word Test, a general measure of cognitive flexibility and executive functioning; Word Learning Test, which evaluates the declarative memory, the part used for specific facts or experiences; Letter Digit Substitution Test, an assessment of general speed of visual information processing; and the Verbal Fluency Test, a measure of the ability to recollect as many words in a specific category as possible from memory. Cognitive performance was evaluated at baseline and 3 years later. In addition to food frequency questionnaire assessment of alcohol and fish consumption, other evaluations covered ApoE genotype, physical activity, education, body mass index and health status. The investigators used the baseline measures of cognition to correct the scores obtained after 3 years in order to control for baseline imbalances. At baseline, no significant associations between any cognitive score and plasma n-3 LC-PUFA concentrations or DHA levels were observed. The same was true for total n-6 PUFAs, which included linoleic, After 3 years, those with higher plasma levels of n-3 LC-PUFAs showed 9% to 12% less decline in sensorimotor speed and speed of information processing compared with participants having lower levels of these fatty acids. gamma-linolenic arachidonic acids. and After 3 years, there was a significant decline in 3 of the 5 measures of cognition: sensorimotor speed, complex speed and information processing speed. However, participants improved in memory and word fluency, but only the change in memory was significant. This was attributed to procedural learning effects. Those with higher plasma n-3 LC-PUFAs had significantly less decline in sensorimotor and complex speed scores. The investigators calculated that for an increase from 1% to 2% in plasma n-3 LC-PUFAs there was 9% and 12% less decline in sensorimotor and complex speed, respectively. There were no other associations with n-3 LC-PUFAs. Readers should note that when the authors compared the changes in actual cognitive scores over 3 years by one-sample t-tests, there were significant changes in 4 of the 5 cognitive assessments (3 poorer, 1 improved scores). In contrast, when the analysis was based on more rigorous multiple regression, adjusted for baseline scores and 5 confounding variables, only 2 scores for sensorimotor and complex speed showed significantly less change with higher plasma n-3 LC-PUFA levels. 10

11 The authors noted that changes in sensorimotor and complex speed in the order of 9% to 12% for a doubling of plasma n-3 LC-PUFA concentrations may be of questionable clinical relevance. Further, whether declining cognition leads to dementia is debatable. However, this report extends the growing literature suggesting that higher n-3 LC-PUFA status and intakes go along with a lower chance of developing dementia and Alzheimer s disease and a slower rate of cognitive decline. Although we can t say much about which mental functions are most affected, more details are emerging. To date, effects have been reported in people from 50 to 80 years of age. Not all studies agree, so alert minds know that conclusions remain premature. Dullemeijer C, Durga J, Brouwer IA, van de Rest O, Kok FJ, Brummer R-JM, van Boxtel MPJ, Verhoef P. n 3 Fatty acid proportions in plasma and cognitive performance in older adults. Am J Clin Nutr 2007;86: Eating Any Type of Fish May Benefit Cognitive Performance in Older Individuals A sample of community-living individuals aged 70 to 74 years in Hordaland, the county surrounding Bergen, Norway, was recruited from participants in an earlier study on homocysteine. Of the 2,841 people originally invited to enroll, 2,031 agreed; they completed a food frequency questionnaire when they were first examined and a modified version of the Mini-Mental State Examination (12 of 20 items) to assess a range of cognitive abilities. The food frequency questionnaire contained detailed questions about the type, amount and frequency of eating 5 categories of fish, including fish used as a sandwich spread and fish or cod liver oil capsules. The investigators also gathered data on the participants history of cardiovascular disease and education level. They examined several cognitive assessments in relation to the frequency of eating fish. In this snapshot of cognitive performance in the elderly, poor performance was observed 2 to 3 times less often among fish eaters compared with those who did not eat fish. Five cognitive function tests in addition to the Mini-Mental State Examination included the Kendrick Object Learning Test for episodic memory and dementia status; Trail Making Test for visual and visuomotor tracking function; a modified Digit Symbol Test, which measures focused attention and visual-motor coordination; Block Design Test for visuospatial and motor skills; and an abridged version of the Controlled Oral Word Association Test, a test of verbal fluency and psychomotor speed. As would be expected from a coastal area with a tradition of eating fish, only 2% of the participants reported never eating fish or fish products. Mean total fish and fish product consumption was 85 g/day, with fatty fish being part of the main course for about 80% of participants. Because of the small number of non-consumers, the investigators included in this group those who consumed <10 g/day of seafood. Poor cognitive performance was observed 2 to 3 times less often among fish eaters compared with those who did not eat fish. Participants with poor scores on more than one cognitive test were more common among those not eating seafood (27%) than among fish eaters (11%). Nonconsumers also exhibited poorer health status than fish eaters, and had a higher prevalence of epilepsy, asthma, chronic bronchitis and osteoporosis compared with those who ate fish. The relationships between the type of fish consumed and each of the cognitive test results were compared for fish eaters and non-eaters after adjusting for variables such as sex, ApoE_4 status, education, cardiovascular variables and homocysteine. Participants who ate fatty or lean fish had significantly better scores on all cognitive tests except the Mini-Mental State Examination (5 out of 6 tests). Those who ate processed fish (e.g., fish balls, fish cakes, fish fingers, fish stew) performed significantly better in all tests except for the Trail Making, Digit Symbol and S-task (abridged version) of the controlled oral word test. Those eating fish sandwiches scored better in all tests except the Trail Making and Kendrick object learning tests. In marked contrast to these outcomes, those taking cod liver or fish oil seasonally (mainly in winter) and not eating fish, had significantly higher cognitive scores only on the S-task evaluation compared with non-users. Outcome scores improved as fish intakes increased to 70 to 80 g/day, close to the mean fish intake of the sample (85 g/day). Above those intakes, performance showed no further improvement. The type of fish made little difference. All types of fish and fish oil consumption were associated with significantly lower likelihood of poor scores on 4 or more tests. Fish consumption was associated with better performance on most of the cognitive tests, but the global assessment in the Mini-Mental State Examination appeared to be the least sensitive to fish intakes. Others have reported an effect of fish consumption on mental processing speed and the rate of cognitive decline, but data on specific cognitive function in aging are sparse. This study and the preceding one help fill these gaps. 11

12 This study provided a snapshot of different types of cognitive function in healthy participants 70 to 74 years of age and showed that mental abilities were superior in those who consumed fish at least once a week. It is noteworthy that the type of fish consumed made little difference on cognitive performance. It may be that a lifelong history of fish consumption ensured adequate tissue availability of the long-chain omega-3 fatty acids often credited with health benefits. It would be useful to observe these individuals in another 3 to 5 years to learn whether these relationships remained strong and whether fish consumption affected the rate of cognitive decline that usually accompanies aging. Nurk E, Drevon CA, Refsum H, Solvoll K, Vollset SE, Nygard O, Nygaard HA, Engedal K, Tell GS, Smith AD. Cognitive performance among the elderly and dietary fish intake: the Hordaland Health Study. Am J Clin Nutr 2007;86: BRAIN LC-PUFAs Increase DHA Content and Neurite Growth in Neurons From Stem Cells The irreparable loss of neurons in neurodegenerative diseases, such as Parkinson s and Alzheimer s, has stimulated research to develop cells that could replace the damaged ones. Three properties of stem cells their ability to divide many times, their lack of specialization and their potential to differentiate into various types of specialized cells make these cells the subject of intense investigation for cell replacement therapy. Stem cells occur in several tissues, but those cultivated from embryonic or adult tissues, particularly bone marrow and brain, are among the most widely studied. Under the right conditions, bone marrow stem cells can differentiate into neuron-like cells having various neuronal markers and transcription factors. Stem cells from bone marrow are more Could stem cells from bone marrow that differentiate into neuron-like cells be used to repair damaged brain tissue in patients with Parkinson s or Alzheimer s disease? A new study suggests yes. readily accessible than from the brain, although brain cells have been used in many cell culture studies and are essential in vivo for brain tissue repair. The ability of brain stem cells to generate new cells is linked to memory and learning functions, which in turn depend, in part, on adequate amounts of docosahexaenoic acid (DHA), an omega-3 long-chain polyunsaturated fatty acid (n-3 LC-PUFA). DHA and arachidonic acid comprise nearly all the LC-PUFAs in neuronal cell membranes. Animal studies have reported that DHA stimulates neuronal stem cell differentiation, inhibits stem cell death, promotes the development of more mature neurons and promotes the generation of new neurons. LC-PUFAs also stimulate the formation of membranes during neurite growth and promote neurite growth in hippocampal neurons. Neurites are projections from the neuron that develop into the axon and dendrites of a mature neuron. In this study, Inna Kan and colleagues at Tel Aviv University, Israel, examined the effects of enriching bone marrow stem cell culture with DHA and arachidonic acid on the growth and differentiation of the cells into neuron-like cells. As important as DHA is to neuronal structure and function, neurons depend on astrocyte synthesis or the cerebrovascular endothelium to supply it, because neurons do not synthesize the fatty acid itself. The investigators compared the effect of different concentrations of these LC-PUFAs on stem cell differentiation, composition and neurite development. The process of inducing cell differentiation itself did not alter the DHA and arachidonic acid concentrations in stem cell membranes or the differentiated neuronlike cells. The concentration of arachidonic acid was approximately twice that of DHA. When DHA alone was added to the cells in increasing concentrations, the differentiated neurons increased their concentration of DHA, but did so at the expense of arachidonic acid. When both LC-PUFAs were added in equimolar concentrations (30 to 50 µm) at the time of differentiation, differentiated cells increased their incorporation of DHA up to the addition of 40 µm. Arachidonic acid concentrations remained stable. At 40 µm concentration of each LC-PUFA, the final proportions of DHA and arachidonic acid were 8.9 ± 0.2% (mean ± SEM) and 7.9 ± 0.2%, respectively. Differentiated neuron-like cells from LC-PUFA-supplemented cultures developed more neurons with longer neurites and fewer with shorter ones compared with cells differentiated without the additional LC-PUFAs. For example, those without LC-PUFAs had 33% of neuronlike cells with neurites in the 0-50 µm range, whereas those differentiated with LC-PUFAs had only 9% of cells with neurites of that length. At the other end of the spectrum, LC-PUFA supplemented cells had 91% of their neurites in the 50 µm to 200 µm range, compared with 67% in the unsupplemented cells. The latter had none exceeding 150 µm, whereas the supplemented cells had some cells with neurites longer than 200 µm. Longer neurite outgrowth reflects more mature cells. 12

13 The study showed Supplementing cultured that supplementing bone marrow stem cells cultured bone marrow stem cells with with LC-PUFAs prior to inducing cell differentiation equimolar amounts significantly increased the of DHA and arachidonic acid prior to DHA content and neurite growth of the differentiated inducing cell differentiation significantly neuron-like cells. increased the DHA content of the differentiated neuron-like cells, leaving the arachidonic acid content unaltered. The increase in DHA was dose-dependent up to a concentration of 40 µm DHA, at which point the concentration of DHA and arachidonic acid did not differ significantly. Differentiated neuron-like cells exhibited a higher frequency of cells with longer neurite projections, an indication of greater cell maturity. Enhanced neurite growth was previously observed in DHA-supplemented cultured hippocampal neurons, suggesting that the differentiated neuron-like cells produced from bone stem cells resemble those of neuronal origin. Although many obstacles remain before cultured stem cells can be used in repairing human tissues, these studies illustrate that some advances will depend on including LC-PUFAs. Kan I, Melamed E, Offen D, Green P. Docosahexaenoic acid and arachidonic acid are fundamental supplements for the induction of neuronal differentiation. J Lipid Res 2007;48: CLINICAL CONDITIONS Parkinson s Disease DHA-Enriched Diet Protects Against Early Parkinson s Pathology in Animal Model Epidemiological studies have reported that consumption of polyunsaturated fatty acids (PUFAs) is associated with a lower chance of developing Parkinson s disease, a neurodegenerative disease that destroys Parkinson s disease patients with motor complications from taking levodopa, the main treatment for the disease, have higher levels of arachidonic acid and less docosahexaenoic acid (DHA) in their brain cortex. Could increasing the brain s DHA help these patients? the neurons in the substantia nigra region of the brain. These cells make dopamine, a neurotransmitter involved in the coordination of movement. The condition is characterized by tremor, stiffness in the limbs and slowness of movement. It has recently been estimated that the number of individuals with the condition in the most populous countries will increase from 4.1 to 4.6 million in 2005 to 8.7 to 9.3 million by Although the cause(s) of Parkinson s disease is unknown, several environmental factors, including dietary fat, have been associated with the condition. Parkinson s is second only to Alzheimer s disease among neurodegenerative disorders. A recent report from the laboratory of Frederic Calon and colleagues at Laval University in Quebec City, Canada, described higher arachidonic acid levels in the cortex of Parkinson s patients who experienced motor complications from taking levodopa (L-dopa), the firstline treatment of this disease. This fatty acid increase, along with a reduction in docosahexaenoic acid (DHA), a long-chain omega-3 polyunsaturated fatty acid (n- 3 LC-PUFA) abundant in brain cell membranes, also occurred in monkeys with Parkinson s that were treated with L-dopa. In a different study, DHA was associated with a significant reduction in the involuntary distorted movements that may accompany treatment of the disease with L-dopa. Thus, the investigators reasoned that n-3 LC-PUFAs might have neuron-protecting properties in Parkinson s disease. To find out, the researchers used an animal model of the disease induced by the administration of the drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) a neurotoxin that selectively affects the dopamine-producing neurons in the substantia nigra. This substance has neurotoxic effects on the dopamine-producing neurons in the substantia nigra of the brain where Parkinson s strikes. Two-month old mice were fed a 5% fat diet enriched in n-3 PUFAs (7.8 g/kg diet), predominantly DHA (5.3 g/kg diet), or high in linoleic acid (36.0 g/kg) and very low in n-3 PUFAs. At 1 year of age, the mice were treated with MPTP to produce a moderate loss of dopamine-producing neurons. This level of treatment does not produce the motor symptoms characteristic of the clinical condition. Approximately 17 days later, the animals brains were examined. The investigators evaluated the relative health of dopaminergic neurons in the substantia nigra and of their striatal axons, the most distal part of the cell. Consumption of the DHA-enriched diet was associated with a significant 31% increase of DHA in the frontal cortex, with no change occurring in the concentration of arachidonic, linoleic or eicosapentaenoic acids. The concentration of n-6 docosapentaenoic acid (22:5n-6 or Osbond acid), which usually increases in n-3 PUFA deficiency, was reduced by 77% compared with the controls. Administration of 13

14 Figure 1. Photomicrographs of the effect of MPTP treatment on nigral TH-immunoreactive neurons in untreated (A, B) and treated (C, D) animals. Neuronal cell counts are significantly reduced in MPTP-treated animals fed the control diet (C) compared with the treated animals fed a n-3 PUFA diet (D). Figure 2007 by The Federation of American Societies for Experimental Biology. Reproduced with permission of the Copyright Clearance Center from FASEB J 2007; doi: /fj com. Figure 2. Effect of MPTP treatment on the number of neurons from the substantia nigra in animals fed a control high n-6 PUFA diet or a n-3 PUFA-enriched diet. Figure 2007 by The Federation of American Societies for Experimental Biology. Reproduced with permission of the Copyright Clearance Center from FASEB J 2007; doi: /fj com. MPTP was followed by a 31% decrease in the number of dopamine-producing neurons in the substantia nigra in control animals. In contrast, there was no reduction in the number of dopamine-producing neurons in the n-3 LC-PUFA-fed animals as observed by anti-tyrosine hydroxylase immno-staining (Figures 1, 2). The research team also measured the amounts of messenger RNA for the Nurr1 nuclear receptor in the substantia nigra neurons and observed the same pattern protection of messenger RNA levels against MPTP-induced reductions. Assessment of nigral cells producing dopamine transporter protein showed that MPTP reduced both the number of transporter protein-producing cells and the expression of messenger RNA for the protein. In the n-3 PUFA-fed animals, the number of transporter protein-producing cells and messenger RNA for the protein were significantly reduced, but to a lesser extent than in the control animals. In contrast to the protective effects of the n-3 PUFAenriched diet on the dopamine-producing neurons described above, the dopamine system was not protected by the n-3 PUFAs in the striatal fibers (axon terminals). The number of fibers and their content of dopamine transporter protein were significantly and similarly reduced with MPTP treatment in both control and n-3 PUFA-fed animals. This observation supports previous reports that the striatal terminals are more sensitive to MPTP treatment than the neuronal cell bodies and is consistent with observations in Parkinson s patients who have died. The investigators also measured the concentrations of dopamine and its metabolite in the striatum, which may still be able to release the neurotransmitter if the cell bodies are intact. MPTP treatment reduced the level of dopamine and its metabolite by 80% in the striatum in the control animals, but there was significant, though not complete, protection in the n-3 PUFA-fed animals. Although these studies do not suggest mechanisms by which n-3 PUFAs might exert their neuroprotective effects, the authors discussed several possibilities in the paper. These include antioxidant effects, anti-apoptosis, activation of nuclear receptors and changes in ion channels or signal transduction pathways. This is a key study in several respects. It is the first demonstration that dietary n-3 LC-PUFAs, mainly DHA, protect against neuronal loss in the early stages of MPTP-induced Parkinson s disease. The study also demonstrated that the DHA-enriched diet protected the Nurr1 nuclear protein messenger RNA, an effect consistent with a neuroprotective action of DHA. Nurr1 is believed to be a susceptibility factor for neurodegeneration in Parkinson s 14