FATS OF LIFE NEWSLETTER Volume 7 Issue 2 August 2012 Contents HEART HEALTH Omega-3s and Sex Affect Lipoprotein Concentrations and Sizes in Alaska Natives...2 Atrial Fibrillation No Escape from Inconsistencies about Omega-3s and Risk of Atrial Fibrillation...3 MOTHERS AND INFANTS Added DHA in Pregnancy Linked to Fewer Medical Complications and Less Frequent Very Low Birthweights...4 Do Preterm Infants Get Too Much Linoleic Acid and Too Little DHA in Breast Milk?...6 DHA-Supplemented Term Infants Score Higher in Gesture Communication...7 MENTAL HEALTH Depressive Illness EPA + DHA Associated with 25% Lower Risk of Depressive Symptoms in US Adults...8 Possible Links Among Depressive Symptoms, Cognitive Function and Seafood Omega-3s...9 Supplementation Without Effect in Depressive Heart Patients... 10 Alzheimer s Disease Omega-3 Intakes Linked to Fewer Harmful Amyloid-Beta Peptides in Older Adults... 11 Higher EPA and DHA Intakes Linked to Better Cognition in Older Adults...12 Fats of life Staff Editor Joyce A. Nettleton, DSc sciencevoice@q.com Communications Manager Angela Dansby angela@fatsoflife.com Sponsor DSM Nutritional Products, Inc., Columbia, MD, USA www.dsm.com Letters and editorial comments should be submitted to Nettleton at sciencevoice@q.com and technical comments to Dansby at angela@fatsoflife.com. Subscribe to Fats of Life at www.fatsoflife.com. FRONTIERS Stepping Stones to Treating Alzheimer s Disease: Is Insulin the Key?... 13 1
HEART HEALTH Patterns of lipoproteins in blood are linked to the risk of heart disease. These patterns can be affected by dietary fatty acids and sex, as recently reported in native Alaskans. Omega-3s and Sex Affect Lipoprotein Concentrations and Sizes in Alaska Natives One of the most commonly used assessments of a person s risk of heart disease is the profile of lipoproteins in the blood. These include low-density lipoprotein cholesterol (LDL), the infamous bad cholesterol; highdensity lipoprotein cholesterol (HDL) or good cholesterol; triglycerides or blood fats and total choles terol. A favorable distribution of these lipoproteins and normal values for them are associated with a significantly lower risk of heart disease. These measures are some of the many factors that contribute to the risk of heart disease. As with many things, size matters. LDL particles that are smaller and denser are associated with a higher risk of ischemic heart disease than larger, less dense ones. Similarly, small HDL particles are associated with greater disease risk. In contrast, larger very-low-density lipoproteins (VLDL) are linked to greater disease risk. These lipoproteins carry triglycerides and other lipids produced in the liver and circulation. These complexities mean that the total amounts of these lipids tell only part of the story. The size distribution of these particles is illustrated in the Figure. Dietary fats affect the levels of these circulating lipids. As is well known, vegetable oils rich in omega-6 fatty acids tend to lower LDL-cholesterol levels, while the omega-3 fatty acids found mainly in seafood (seafood omega-3s) tend to raise HDL-cholesterol levels, lower triglycerides, but may modestly increase LDL-cholesterol. Dietary fats and their derivatives also affect other factors that contribute to the risk of heart disease, such as inflammation, blood clotting and the dilation or constriction of blood vessels. In general, the effects of omega-6 fatty acids are counteracted by seafood omega-3s, but most Western diets have large amounts of omega-6s and only small amounts of Figure. Relative size of the major lipoprotein subfractions measured in Angstroms. 1 Angstrom = 0.1 nm. Source: Lipoprotein Subfractions; Clinical Chemistry and Toxicology Advisory Committee Meeting December 2006, Center for Devices and Radiological Health. D.O. Wood. omega-3s, especially those found mainly in fish and shellfish. The net effect is that the health-protective effects of seafood omega-3s are often not widely experienced. A few populations customarily consume large amounts of seafood omega-3s because they eat plenty of fish and seafood. These include the Japanese living in Japan, other island nations and native Alaskans and Inuit. These populations usually have much less heart disease than Western populations, in part because of their omega-3 consumption. However, in native Alaskans and the Inuit, dietary habits have changed rapidly and heart disease, type 2 diabetes and other chronic diseases have increased dramatically. Studying the changes in the lipid and lipoprotein profiles of these populations may provide more clues about their relationship to heart disease. An ongoing study of Alaska natives from the Norton Sound Region of Alaska has reported data on the lipoprotein profiles of the majority of adults living in 8 villages in the region. The study examined the differences between men and women in lipoprotein pattern and the effect of seafood omega-3 consumption on these measures. Women had a more favorable pattern of lipoproteins with 2
lower VLDL and LDL levels and higher HDL concentrations than men. The size distribution of the lipoproteins was also more favorable, with women having fewer small dense LDL particles and more large HDL particles than men. In both men and women, higher intakes of seafood omega-3 fatty acids were associated with larger HDL particles and fewer large VLDL particles, characteristics linked to a lower risk of heart disease. Women with the highest intakes of seafood omega-3s also had more favorable lipoprotein sizes compared with women in the lowest consumption group. For example, women with the highest intakes of omega-3s had significantly fewer large VLDL particles but more large HDL particles, patterns favorable to their risk of heart disease. They also had significantly lower triglycerides. In men, the highest omega-3 intake group did not differ from the lowest intake group in their VLDLs, but did have significantly larger HDL particles. They also had lower triglycerides, but the difference was not statistically significant. Even in a population with high intakes of seafood omega-3s, those with the highest intakes appeared to have more favorable lipoprotein-cholesterol profiles than those with lower intakes. These advantages appeared as fewer large VLDL particles and more of the larger HDL particles in both sexes. Women had more favorable lipid profiles overall and higher intakes of seafood omega-3s had some advantage in both men and women. A major caution, however, is that the effects of concentrations and particle sizes can be confounded by relationships with other lipid characteristics, so that the ultimate effects of these observations may remain unknown. Atrial Fibrillation No Escape from Inconsistencies about Omega-3s and Risk of Atrial Fibrillation Fats of Life has previously reported studies on the relation ship between long-chain or seafood omega-3 fatty acids and the risk of atrial fibrillation, a potentially Although there have been many studies on the relationship between seafood omega-3s and the risk of developing atrial fibrillation, what stands out from the studies is the utter lack of consistency in the findings. Several new reports illustrate the inconsistencies. dangerous, rapid quivering of the upper chambers of the heart. In this condition, the electrical signals in the heart s upper chambers become disordered and rapid, which compromises the lower chambers ability to pump blood effectively. What stands out from all the studies on omega-3s and atrial fibrillation is the utter lack of consistency in the findings. The majority of studies have reported either no association or a significantly lower risk with higher omega-3 status or consumption. Such mixed results do not support a recommendation that might help patients with the condition. However, the effect of seafood omega-3s continues to be investigated because the risk of stroke, heart attack or death is substantial for individuals with the condition and ways of controlling the abnormality are limited. It would be more than convenient if greater intakes of seafood omega-3s could be counted on to lower the risk of recurrence or development in the first place. Data on 74-year-old adults without heart disease reported that those with the highest level of total seafood omega-3s or DHA had a significantly lower risk of developing atrial fibrillation. Several new reports illustrate the inconsistencies. A study on 74-year-old US adults without atrial fibrillation examined the relation ship between total and individual seafood omega-3s in blood and the likelihood of developing atrial fibrillation according to the concentration of omega-3s. They observed that individuals with the highest levels of all seafood omega-3s were significantly less likely (29% lower risk) to develop atrial fibrillation compared with 3
participants in the lowest omega-3 consumption group. The same relationship was seen for the highest intakes of DHA (23% lower risk). EPA levels were not associated with risk. In 54-year-old US adults, neither fish consumption nor blood EPA+DHA levels were associated with risk of atrial fibrillation. One reason for the lack of association might be the low seafood intakes of these participants. Analysis of data from another similar-sized US study of 54-yearold adults reported that neither the consumption of fish or plasma EPA plus DHA level was associated with risk of atrial fibrillation over more than 17 years of monitoring. Why were these studies so different? Was the difference in risk largely due to the age of the participants? Were fish consumption or plasma fatty acid levels too low? Participants in the first study consumed more than twice as much fish as in the second study and had higher blood levels, so it is possible that seafood omega-3 intakes were too low for any effect in the second study. Supporting that idea was the observation in the second study that participants who had the highest intakes of oily fish or canned tuna had lower risks of atrial fibrillation, but the numbers were too small to reach statistical significance. A third study among Japanese patients with atrial fibrillation examined blood fatty acids in those with and without ischemic heart disease and compared the observations with patients having ischemic heart disease and no atrial fibrillation and with healthy controls with neither condition. Among patients with atrial fibrillation, those who did not have ischemic heart disease had significantly higher blood EPA and DHA levels, suggesting that higher seafood omega-3s were associated with a lower risk of ischemic heart disease. Overall, DHA concentrations did not differ among the groups. The study also observed that patients with the more long-lasting types of atrial fibrillation had higher EPA concentrations in their blood. When taking all possible confounding factors into consideration, only EPA was associated with a slightly higher risk of atrial fibrillation. However, the small numbers of A third study of patients with atrial fibrillation, those without heart disease had higher blood EPA and DHA levels than those with heart disease. This suggests that seafood omega-3s may have contributed to a lower risk of heart disease in these patients. However, higher EPA was linked to a slightly higher risk of atrial fibrillation in those with long-lasting disease. patients in this study limit the strength of the results. Thus, one cannot draw conclusions about EPA from these observations. What do these studies tell us about omega-3s and atrial fibrillation? One point they illustrate is that intakes of seafood omega-3s have to be sufficiently great to affect risk favorably. It is also possible that older adults who remain free of cardiovascular disease at the time they are observed may already be at lower risk of heart disease and atrial fibrillation, even though they were originally drawn randomly from the community. Alas, we remain without clear answers about the relationship between seafood omega-3s and the risk of developing atrial fibrillation. MOTHERS AND INFANTS Added DHA in Pregnancy Linked to Fewer Medical Complications and Less Frequent Very Low Birthweights Two of the most common medical complications of pregnancy are preeclampsia and gestational diabetes. Preeclampsia is a condition of high blood pressure and protein in the urine in women without a history of high blood pressure that may develop after the 20 th week of pregnancy. It is more common in women who have hypertension before they become pregnant, are experiencing their first pregnancy or are overweight. Preeclampsia increases the chance of preterm delivery and poses a high risk to the mother s health. It occurs in 3% to 5% of all US pregnancies and is observed more frequently in developing countries where access to prenatal care may 4
Few data indicate whether seafood omega-3s affect the risk of developing preeclampsia or gestational diabetes, two of the most common medical complications of pregnancy. A new study examined the occurrence of these conditions in women supplemented with DHA in the last half of pregnancy. be limited. Because the omega-3 fatty acids found mainly in seafood (seafood omega-3s) are associated with modestly lower blood pressure and blood vessel function there is reason to find out whether a greater intake of these fatty acids might reduce the risk of preeclampsia. G e s t a t i o n a l d i a b e t e s, t h e appearance of abnormal glucose tolerance that is first detected in pregnancy, occurs in about 2% to 12% of pregnancies in developed countries. It is more frequently observed among African Americans, Hispanics, Native Americans and Asians. Overweight, high blood pressure and age above 30 years increase the likelihood of the condition. Both the mother and her offspring have a higher risk of developing type 2 diabetes and obesity later in life, if the mother has gestational diabetes. The condition is also associated with excessive infant birthweight. There are few, if any, data about the relation ship between seafood omega-3s and the risk of developing gestational diabetes. However, a recently published study on the supplementation of healthy pregnant women with 800 mg of DHA per day in the last half of pregnancy examined the occurrence of gestational diabetes and preeclampsia in these mothers compared with control women who consumed a placebo oil. In the total group of women, the occurrence of both conditions was within the reported range; 5% developed preeclam psia and 6% developed abnormal glucose tolerance. When the incidence of these conditions was compared between the two groups of women, there was no significant difference between the groups. Infants of mothers who consumed the DHA supplement had significantly higher birthweights and lengths. Fewer were born weighing less than 2,500 grams (5.5 pounds) and significantly fewer were born before 34 weeks gestation. These last observations strongly favor healthy infant outcomes. The DHA-supplemented mothers had more infants born weighing more than 4,000 grams (8.8 pounds) compared with the control mothers, but there was no difference between the groups in the number of infants born large for their gestational age. Births among the DHA-supplemented mothers experienced fewer medical complications and deaths compared with the control group. For example, 5 control group infants experienced neonatal convulsion or brain injury at birth, whereas none in the DHA group did. There were 12 deaths between birth and 28 days after Supplementation with 800 mg of DHA in the last half of pregnancy was not associated with the risk of preeclampsia or gestational diabetes. However, the infants of supplemented mothers had fewer medical complications and were less likely to be born before 34 weeks gestation or to weigh less than 5.5 pounds. delivery in the control group and 3 in the DHA group. These differences between groups were statistically significant, meaning that they were unlikely due to chance. The study is important in several ways. It is the first report of the relation ship between the mother s consumption of DHA during pregnancy and her likelihood 5
of developing preeclampsia or gestational diabetes. DHA supplementation had no effect on the risk of these complications. Second, there were clear health benefits in the infants of DHA-supplemented mothers. They weighed more, were less likely to be born very preterm (before 34 weeks gestation) and were less likely to be born weighing less than 2,500 grams (5.5 pounds). Very low birthweight puts the infant at risk of medical com plications and impaired cognitive and social development. Finally, the infants of supplemented mothers were less likely to develop medical complications or die. These findings add to the many reasons why pregnant women are strongly advised to consume at least 200 mg of DHA per day or more during pregnancy. Do Preterm Infants Get Too Much Linoleic Acid and Too Little DHA in Breast Milk? Preterm infants are at risk for medical Current dietary patterns reflect high intakes of omega-6 fatty acids, mainly as linoleic acid, and low levels of omega-3s, especially the long-chain forms. This study questions the effect of this fatty acid pattern on the development of preterm infants. complications, poorer developmental outcomes and nutrient shortages for several reasons. One is their early birth deprives them of the transfer of long-chain fatty acids from the mother that occurs mainly in the last trimester. Another is that their lack of body fat means they have no appreciable nutrient stores to see them through their early days. Finally, preterm infants are totally dependent upon breast milk or preterm infant formula to meet all their nutrient needs. Of particular importance is the preterm infant s lack of long-chain fatty acids, namely arachidonic acid (ARA) and DHA that are needed for brain growth and development of the retina, blood vessels and other organs. These fatty acids are especially important in the first 4 months after birth when they are still rapidly accumulating. Breast milk contains these fatty acids, but mothers who have had low intakes of fish or DHA, as is typical in Western diets, may have low DHA levels in their milk. ARA levels are usually adequately maintained. Typically, the breast milk of women eating Western foods is high in linoleic acid, the main polyunsaturated fatty acid (PUFA) found in most vegetable oils and many processed foods. Evidence suggests that high levels of linoleic acid, especially in the presence of low levels of ARA, EPA and DHA are associated with poorer early development in these infants. A new study took a close look at this issue. Researchers in Sweden evaluated several developmental outcomes in a group of preterm infants who were born at approximately 34 weeks gestational age. Full term is considered 38 to 40 weeks. All infants were breastfed or received human milk from a milk bank exclusively for about 3 months. The investigators assessed early development at 3 months of age using a test that evaluates the quality of the infant s general movements. This evaluation is able to detect mild to distinctly abnormal developmental disorders as early as 2 to 4 months post term age. Later development at 6 months of age and older was assessed using standard Bayley s developmental scales. The investigators measured the fatty acids in each mother s breast milk and calculated an index of essential fatty acid deficiency, which depends on the presence of a fatty acid not usually present in appreciable amounts. With this index, they could relate the relative deficiency of long-chain fatty acids to the infants early and later developmental assessments. At 3 months of age, corrected for preterm birth, the quality of the infants general movements was negatively associated with the essential fatty acid index of breast milk fatty acids. In other words, the higher the deficiency index, the poorer the quality of movements. A similar relationship was observed between the Bayley scores for 6
The early development of preterm infants was negatively linked to an index of long-chain fatty acid deficiency and high levels of omega-6s relative to low levels of omega-3s. These observations suggest that high levels of linoleic acid may be linked to poorer early infant development. mental and motor function and the ratio of omega-6 PUFAs to omega-3 PUFAs. That is, the higher the omega-6 PUFA level, the lower the Bayley s scores. The main omega-6 PUFA in breast milk is linoleic acid. These observations suggest, but do not prove, that high concentrations of linoleic acid in the presence of low concentrations of omega-3s may be linked to poorer early development in preterm infants. When infant development was assessed with the Bayley scores at 6 months of age, higher scores for mental and emotional development were associated with lower levels of linoleic acid in breast milk. The emotional, orientation scores and motor scores were positively associated with the infants levels of DHA and ARA. That is, the higher the infants levels of long-chain PUFAs, the better these developmental scores were. The investigators also noted that the negative relationships between mental development and orientation scores and ratios with high linoleic acid persisted until 10 months of age, whereas the positive associations with DHA and High levels of breast milk and infant DHA were consistently linked to higher developmental scores through 18 months of age in preterm infants. The data suggest, but do not prove, that high levels of linoleic acid may undermine preterm infant development. mental, motor and emotional scores continued through 18 months of age. The finding that diverse measures of early and later infant development are positively associated with higher levels of DHA and negatively linked to high linoleic acid levels through 18 months of age call into question the effect of high dietary levels of linoleic acid in infant development. Others have described these patterns as fatty acid imbalances, which are tilted toward linoleic acid, and are a direct reflection of the fatty acid composition of typical Western diets. Consistent with other reports, higher levels of breast milk DHA favor infant development. Only recently, however, has the topic of infant exposure to high linoleic acid in the presence of relatively low DHA been studied. This is not the first report to question high linoleic acid intakes and should encourage other investigators to examine this issue. DHA-Supplemented Term Infants Score Higher in Gesture Communication Many studies of infant development have reported improved visual, cognitive and neurodevelopmental scores in infants with higher consumption of long-chain polyunsaturated There have been mixed findings associated with the increased intake of long-chain PUFAs in infants, but many studies have reported benefits in visual acuity, cognition and neurodevelopment. Less information is available about language development. This study addresses that topic. fatty acids (PUFAs). Improvements have been easier to demon strate in preterm infants compared with term infants because of the nutrient s hor t ages many preterm infants have. However, not all studies have observed improved development scores, so the value of providing higher levels of long-chain PUFAs through breast milk or infant formula has been controversial. Some reasons for the mixed findings are the inadequacy of the dose, sensitivity of the assessment tool, age when the evaluation is conducted and variations in infants themselves. Sometimes, a battery of tests is needed. In an effort to overcome these difficulties, researchers in Australia designed a study of healthy term infants who were supplemented with high-dose, DHA-rich fish 7
oil or a placebo from birth until 6 months of age. The amount of DHA provided was approximately 250 mg per day. The oil was given either in the infant s formula or squirted directly into the infant s mouth. The investigators focused on the child s language and gestures to assess communication, but also included the Bayley Scales of Infant and Toddler Development, which have a language component, when the children were 18 months of age. At 6 months of age, the DHA-supplemented infants had higher levels of DHA in their blood and red blood cells, an expected finding. Evaluations at 12 and 18 months of age revealed some differences between the DHA and placebo groups. At both times, the DHA-supplemented children had higher scores for gesture communication compared with the placebo group. The supplemented children also had higher scores for phrases and words understood, but these were not significantly different from the placebo children because of the wide variation in scores in both groups. None of the language scores on the Bayley Scales differed between the groups. Healthy term infants supplemented from birth with DHA-rich fish oil had significantly higher scores at 12 and 18 months of age in later and total gestures compared with the placebo group. Using a different communications assessment, the MacArthur-Bates Communicative Development Inventory, the investigators observed significantly higher scores in the DHAsupplemented children for later and total gestures compared with the unsupplemented children at 12 and 18 months of age. The authors of the study suggested that higher gesture scores, that is more extensive use of gestures, might be linked to improved spoken language and communication, vocabulary and linguistic development, as evidence has suggested. There are only a few other studies that have examined language development in relation to omega-3 PUFA consumption in infants and children. Some have reported lower language scores with supplementation, but the differences disappeared with time. Others have found no effects of omega-3s. MENTAL HEALTH Low fish consumption is linked to a higher risk of depressive illness in many countries. Seafood omega-3s are also lower in the blood and brains of patients with this illness, though findings have been mixed. This report examined the link between seafood omega-3s and depressive illness in US adults. Depressive Illness EPA + DHA Associated with 25% Lower Risk of Depressive Symptoms in US Adults There is an extensive accumulation of studies linking low intakes of long-chain or seafood omega-3 fatty acids (seafood omega-3s) with a greater likelihood of developing depressive symptoms. Eating little or no seafood has also been associated with higher risks of this condition across several countries. Investigators have reported that the red blood cells of patients with major depressive illness have significant deficits in DHA. Further, postmortem examination of the frontal cortex in the brains of individuals who died with major depressive illness revealed that only DHA was significantly lower in these individuals compared with those not having the illness. On the positive side, supplementation of patients with depressive illness with modest amounts of EPA or both EPA and DHA has been associated with significant improvements in symptoms and quality of life in several studies. Even though not all studies have observed 8
improvements and the quality of the studies varies, there is sufficient evidence for the American Psychiatric Association to recommend seafood omega-3s or EPA as an adjunct to existing treatments for depressive illness. These fatty acids have the advantages of being economical, free of side effects and without harm. Nevertheless, omega-3s have not been recommended as the sole treatment for this condition. Countries with Western dietary The U.S. has the habits and low highest prevalence of seafood intakes depressive illness among have higher rates 10 developed countries, of depressive illness, as reported by with a rate of 8.3% of all adults. the World Health Organization s World Mental Health Survey Initiative. This study described the U.S. as having the highest rate (8.3%) among 10 developed countries for the 12-month prevalence of a major depressive episode in adults 18 years of age or more. Taking the investigation of major depressive illness a step further, scientists at the University of Rochester, USA, examined in detail the relationship between fish and EPA + DHA consumption and the prevalence of depressive symptoms in the U.S. The population survey was based on data from the National Health and Nutrition Examination Survey (NHANES), a representative sampling of adults and children. It includes periodic physical examinations and interviews and has been conducted continuously since 1999. The researchers observed that total fish intake over a 30-day period was not associated with the occurrence of mild or moderate to severe depressive symptoms, no matter how much fish was consumed. However, they found that eating any breaded fish was associated with a significantly higher risk of depressive symptoms. The disadvantages of consuming breaded fish, which are usually made of lean fish and fried in fats of questionable health quality, have been reported previously. The consumption of EPA + DHA in US adults was associated with a 25% lower likelihood of depressive illness. When the investigators analyzed the relationship between the consumption of EPA + DHA and the risk of depressive symptoms, intakes of these fatty acids were associated with a 25% lower likelihood of depressive symptoms. Even considering the limitations of dietary studies, this was a remarkable finding. What makes this study different from most other observational studies is that it represented all adults 20 years of age and older, regardless of their risk. Depressive illness strikes all ages, so these findings suggest that the regular consumption of seafood omega-3s throughout life is important throughout life, not just in infancy and aging. Some evidence suggests that depressive symptoms and lower cognitive performance go handin-hand in older adults. Seafood omega-3s might be effective in improving both these conditions if consumption is increased. Possible Links Among Depressive Symptoms, Cognitive Function and Seafood Omega-3s Some evidence suggests that depressive symptoms and lower cognition performance go hand-in-hand in older adults. A high rate of depressive episodes has been reported in patients with Alzheimer s disease and it has been suggested that depressive symptoms may affect an individual s perception of cognitive function. A possible link with long-chain or seafood omega-3 fatty acids (seafood omega-3s) is their association with slower 9
rates of cognitive decline and improved learning and memory among those with mildly impaired cognition. There is also evidence that increased consumption of seafood omega-3s is associated with less severe symptoms of depressive illness. However, few studies have examined the effect of seafood omega-3 consumption in individuals with mild symptoms of both conditions. Natalie Parletta and colleagues in Australia took on the challenge of recruiting adults older than 65 years who were able to maintain normal daily functioning, but had selfreported memory loss. In addition, the participants had to meet certain criteria on mental and verbal tests and were given an evaluation for depressive symptoms. Those who enrolled were assigned to consume daily supplements of EPA or DHA or linoleic acid (an omega-6 fatty acid) for 6 months. In addition to their mental health and cognition assessments, the participants provided a blood sample at the beginning and end of the study. After 6 months, the participants who consumed either EPA or DHA experienced significant improvements in their depression scores compared with those consuming the linoleic acid supplement. In fact, scores in the control group worsened. Ideally, conditions are not expected to change in the control group, so this observation raises the question of whether increased linoleic acid consumption might have been detrimental. However, this study was not designed to answer that question. Overall, the 6-month supplementation with either EPA or DHA had little effect on cognitive scores. One assessment, the test of initial letter fluency, showed improvements with DHA supplementation. This study addressed a complex issue that is not easy to explore among older adults whose function is declining. Only in one measure of cognition was there an effect of DHA, but not EPA. The observation that warrants additional scrutiny is whether Six months supplementation with EPA or DHA in older adults with mildly impaired cognition and depressive symptoms was associated with improvements in their symptoms, but had little effect on cognitive scores. high intakes of linoleic acid are detrimental in individuals with depressive symptoms or mildly impaired cognition. The study provides additional evidence that higher intakes of seafood omega-3s in older adults may have multiple health benefits. Seafood Omega-3 Supplementation Without Effect in Depressive Heart Patients There have been several encouraging studies reporting improved symptoms in depressive illness among those who consumed long-chain (seafood) omega-3s. Other research has observed lower levels of these fatty Patients with heart disease and depressive symptoms have higher risks of adverse heart events compared with those free of depressive symptoms. They should be good candidates for treatment with seafood omega-3s. acids in patients with heart disease and/or depressive illness. The benefits to heart health of increased consumption of these fatty acids, especially among survivors of a heart attack, suggest that higher intakes of these substances might improve both conditions in heart patients who develop depressive symptoms. Thus, increasing the consumption of seafood omega-3s in heart patients with depressive illness appears an obvious intervention to evaluate. It is also known that heart patients with depressive illness face a higher risk of adverse heart events and mortality than similar patients without depressive symptoms. In addition, individuals with both conditions and higher levels of seafood omega-3s in their blood survived longer than those whose omega-3 levels were low. This 10
information provided the rationale for a controlled study of patients with several types of heart disease or stroke and varying degrees of depressive symptoms who were supplemented with B vitamins or EPA + DHA or both for 1 year. Participants were 61 years of age on average and were monitored for approximately 5 years. At follow-up, 31% of participants experienced some symptoms of depressive illness, with nearly 7% experiencing moderate to severe symptoms. Neither the consumption of B vitamins nor EPA + DHA was associated with these observations. B vitamins or seafood omega-3s were not associated with any effect on depressive symptoms in heart patients who consumed EPA + DHA for 1 year. Interestingly, when the investigators examined the results according to the sex of the participant, they noted that men taking the omega-3 supplements were more likely to develop depressive symptoms, but women were less likely to do so. The observation in men was unexpected and the investigators had no explanation for it. Also, this finding is not supported by previous studies and would need additional confirmation to be considered a likely outcome. Given that the dose of EPA + DHA consumed in this study was well below the level associated with improved symptoms in depressive illness, the analyses tell us little about the potential usefulness of seafood omega-3s in heart patients with depressive symptoms. destroyed (Figure). It occurs most frequently among older adults. In the U.S., 1 in 8 people aged 65 and older about 5.4 million Americans of all ages have the condition. With people living longer, this number is expected to treble by the year 2050. Right now, there is no cure or effective treatment for the disease, although various medications are used to improve memory Alzheimer s disease and functionality. is a progressive degenerative form What determines of dementia that whether a person will develop Alzheimer s occurs mainly in disease? The condition older adults. Many has no single cause, factors affect the risk but is more likely to of developing the develop in individuals disease, including with mildly impaired diet and seafood cognition, depressive omega-3s. symptoms, insulin resistance and a mutation in the apolipoprotein E gene for the ε4 allele. It has also been observed that individuals who consume a Mediterranean diet have a lower risk of the disease, lower mortality from it and slower rates of cognitive decline. The consumption of fish and shellfish or having high levels of the omega-3 fatty acid DHA in the blood is also linked to a lower chance of developing the disease. However, providing DHA to those with the early signs of Alzheimer s disease has not been able to slow or halt the progression of the disease. Alzheimer s Disease Omega-3 Intakes Linked to Fewer Harmful Amyloid-Beta Peptides in Older Adults Alzheimer s disease is a progressive and debilitating form of dementia in which brain tissue is gradually Figure. Left, cross section of a normal aged brain; right, cross-section of a brain affected by Alzheimer s disease, showing destruction of tissue in different areas. Source: Wikimedia Commons. 11
How might DHA or seafood omega-3s protect against Alzheimer s disease? Considerable research has found that DHA protects neurons from damage and destruction and from harmful metabolic products associated with the disease. Studies in animals suggest that DHA might affect the production of the abnormal amyloid-beta peptides characteristic of the disease. In this article, Nikos Scarmeas and his research group at Columbia University, USA, describe the association between seafood omega-3 consumption and levels of two abnormal amyloid-beta proteins in blood in older adults who did not have symptoms of dementia. In healthy non-demented older adults, those with the highest intakes of omega-3s had the lowest levels of the harmful amyloid-beta42 peptide in their blood compared with those having the lowest omega-3 consumption. The investigators collected dietary information and blood samples from over 1,200 adults living in New York City who averaged 75 years of age. They assessed the participants consumption of omega- 3 and omega-6 fatty acids and measured the concentrations of two abnormal peptides, amyloid-beta40 and amyloid-beta42, characteristic of Alzheimer s disease. They observed that those with the highest intakes of omega-3 fatty acids had the lowest levels of both amyloid-beta proteins. When they took into consideration other possible confounding variables, only the amyloid-beta42 peptide decreased as omega-3 intakes increased. This peptide is believed to be the more harmful of the two. These observations, if confirmed by others, suggest that higher intakes of omega-3 fatty acids might reduce the production of the most damaging type of beta-amyloid protein. However, because this study describes an association, it cannot show that omega-3 consumption caused the reduced amyloid-beta42 production. It is noteworthy that these abnormal proteins were present in the blood of patients who had no other symptoms of Alzheimer s disease. Higher EPA and DHA Intakes Linked to Better Cognition in Older Adults DHA, one of the Changes in the volume of different areas of the brain have been linked to cognition and some psychosocial disorders and to DHA. This study examined the relationship between intakes of EPA + DHA, gray and white matter volumes and cognition in older adults. main long-chain omega-3 fatty acids in seafoods, is found in large quantities in the brain where it affects the structure and function of neurons and the growth of new ones. It has been linked to cognitive function, attention, visual acuity, behavior and some psychiatric disorders. It also helps protect neurons from the damaging effects of Alzheimer s disease. It is difficult to study the brain and neurons directly in living individuals, so that substitute methods must be used. One of the most useful of these is magnetic resonance imaging, which distinguishes between gray and white matter volumes and reveals patterns of cortical activation (Figure). The technique is being used more frequently to study how different parts of the brain change in response to certain conditions and in some diseases. For example, smaller volume in the hippocampus is associated with worse clinical outcomes in patients with major depressive disorder. Changes in brain volumes have been used to study cognitive function. It was reported that individuals who had greater volumes in the medial temporal area maintained their cognitive Figure.Magnetic resonance image of the whole brain with gray matter shown in color. Image courtesy of Dr. Christian Benedict, Uppsala University, Sweden. 12
status better than those whose cognition declined. Researchers have also used changes in the volumes of the whole brain and of specific regions to predict the conversion from mild cognitive impairment to Alzheimer s disease. In this report, investigators examined the relationships between omega-3 fatty acid consumption (particularly of EPA This study suggests that higher intakes of EPA + DHA were associated with higher cognitive scores and possibly greater gray matter volume in 75-year-old adults without dementia. and DHA), brain volumes and cognitive status in adults at 70 years of age and 5 years later. The investigators assessed the participants EPA + DHA intakes, measured the total volumes of gray and white matter using magnetic resonance imaging and evaluated cognitive performance after 5 years. When the observations were analyzed according to 4 categories of omega-3 consumption, those with the highest intakes had the highest cognition scores and greatest gray matter volumes compared with those in the lowest omega-3 intake group. However, when the analysis was adjusted for additional confounding variables the relationship between EPA + DHA intakes and gray matter volume was no longer significant. EPA + DHA intakes remained significantly related to higher cognitive scores. The study demonstrated a clear relationship between higher cognitive scores and higher intakes of EPA + DHA and suggested, but fell short of confirming, that gray matter volumes were also greater among those with the highest omega-3 intakes. The study did not report changes in gray and white matter volumes in different regions of the brain, so that possibly certain brain regions might be more sensitive to seafood omega-3 intakes than others. It should also be noted that those with the highest intakes of EPA + DHA consumed an average of 980 mg per day, nearly 10 times the current intakes of US adults. FRONTIERS Stepping Stones to Treating Alzheimer s Disease: Is Insulin the Key? Descriptions of Alzheimer s disease, a progressive degenerative condition that robs its victims of their memory, cognitive function, language Recently, there has been a great leap forward in understanding Alzheimer s disease, possibly opening new paths to better treatment. These developments relate to the function of insulin and its related growth factor in the brain. and ability to take care of themselves, centers on the accumulation of abnormal proteins amyloid-beta and tau. Amyloid-beta proteins form plaques outside the cell, while tau builds up inside the cell to form neuro fibrillary tangles (Figure 1). It remains uncertain whether these abnormalities are a cause or consequence of the disease. Neither do we know what causes Alzheimer s disease, nor can we cure it. Figure 1. Abnormal pathology characteristic of Alzheimer s disease. Illustration courtesy of Alzheimer s Disease Research, a program of the American Health Assistance Foundation. 2012. http://www.ahaf.org/alzheimers 13
Recently, however, there has been a great leap forward in understanding the disease and possibly opening new paths to better treatment. It has been known for some time that receptors for the hormone insulin and its various growth factors are scattered throughout the brain and are concentrated in the hippocampus a center for learning and memory. Further, increasing the insulin in the brain via direct injection or inhalation through the nose improves memory and recall in animals and improves verbal memory in healthy young men. Observational studies also established links between insulin resistance, impaired cognition and reduced glucose uptake (glucose is the brain s primary fuel) in patients with type 2 diabetes and those with Alzheimer s disease. Investigators recognized the parallels between these two diseases noting that both conditions entail impaired glucose metabolism, abnormal blood vessel function, insulin deficiency and insulin resistance and the formation of abnormal amyloid proteins. In addition, type 2 diabetes increases the risk of developing impaired cognition and Alzheimer s disease, yet ironically, diabetic patients treated with insulin are less likely to develop Alzheimer s pathology. These similarities led Eric Steen and colleagues at Brown Medical School, USA, to propose the term type 3 diabetes to describe the type of diabetes that selectively affects the brain. They noted that abnormalities in insulin and insulin-like growth factor activities in patients with Alzheimer s disease were associated with the reduced expression of genes for these proteins, their cellular receptors and the signaling enzymes that carry out the actions initiated by insulin. On the other hand, the expression of genes for the amyloid precursor protein, which gives rise to the abnormal amyloid-beta peptides, and the gene for the major tau enzyme was increased. As Alzheimer s disease progresses, insulin signaling declines further and the abnormal amyloidbeta peptides accumulate. It turns out that insulin signaling those activities dependent upon insulin and insulin-like growth factor is the key to the production of the abnormal amyloid-beta peptides. Insulin resistance in the brain can occur with or without diabetes or insulin resistance in the rest of the body. Figure 2. Illustration of the different brain structures involved in memory. Image reproduced with permission of Allen D. Bragdon Publishers, Inc. All rights reserved. For more brain facts go to: www.brainwaves.com. This observation accounts for the fact that Alzheimer s disease can develop in individuals who have no symptoms of diabetes. However, once insulin resistance develops in the brain and abnormal amyloid-beta peptides begin to accumulate, the clinical symptoms of impaired memory and cognition appear. Memory loss develops because the amyloid-beta peptides bind specifically to neurons in the hippocampus and other regions of the brain that function in memory processes (Figure 2). This binding contributes to neuronal destruction. Impaired insulin function is also involved in the activation of the tau protein, which forms the neurofibrillary tangles, another characteristic of Alzheimer s pathology. Several key studies confirmed the involvement of insulin in the development of Alzheimer s disease. One was the demonstration that insulin can stem the loss of hippocampal neurons that is associated with amyloid-beta peptides. Another study showed that impaired insulin signaling in the central nervous system increased the loss of brain tissue associated with Alzheimer s disease. Third, 14
Insulin resistance in the brain is involved in the development of Alzheimer s disease and the loss of memory and cognition. Insulin resistance promotes the formation of abnormal amyloid-beta peptides and the loss of neurons. the administration of intravenous insulin in patients with Alzheimer s dementia led to striking improvements in memory. Other observations in diabetic patients treated with insulin, such as improved memory, lower density of lesions and slower progression of Alzheimer s disease, reinforced the idea that insulin treatment might be effective in early Alzheimer s disease or mild cognitive impairment. As insulin infusion is not an appropriate long-term therapy and risks excessively low blood sugar and other endocrine derangements, researchers turned to intranasal insulin treatment. This way of delivering insulin provides the most direct route to the brain. In patients with mild cognitive impairment, intranasal insulin treatment was associated with greatly improved memory. Another study in adults with mildly impaired cognition or early Alzheimer s disease reported that 4 months of intranasal insulin treatment preserved general cognition and improved the metabolic integrity of the brain as revealed by PET scan. Two recent studies now open the doors to more effective treatment of early Alzheimer s disease and mildly impaired cognition. The first report examined enzymes in the insulin signaling pathway in the brains of individuals who died with or without Alzheimer s disease. The investigators firmly established the presence of insulin and insulin-like growth factor resistance in the brains of Alzheimer s patients who did not have diabetes. They reported increased levels of markers of insulin resistance in the hippocampus of individuals with mild cognitive impairment and in the cortex of those with advanced Alzheimer s disease. The cortex is affected only late in Alzheimer s dementia. These findings and others in the report established that insulin resistance and impaired insulin signaling are definitive characteristics of preclinical and established Alzheimer s disease. In an animal model of Alzheimer s disease, drugs that reduced inflammation or enhanced insulin signaling reduced the pathology associated with Alzheimer s disease and improved cognition. The second report investigated the effects of blocking inflammatory mediators or enhancing insulin sensitivity in an animal model of Alzheimer s disease. As Alzheimer s disease develops, amyloid-beta peptides activate a potent mediator of inflammation that leads to insulin resistance. The researches showed that by blocking the inflammatory mediator with a drug, they could protect neurons from the damage caused by amyloid-beta peptides. When they enhanced insulin signaling using a different drug, they were able to reverse the pathology associated with insulin resistance and improved cognition in the animals. These studies demonstrated the importance of inflammation and the insulin signaling pathway in the develop ment of Alzheimer s disease and suggest different strategies to treat the disease in its early stages, each targeting an aspect of insulin resistance. Where do polyunsaturated fatty acids such as seafood omega-3s fit into this picture? Higher intakes of seafood omega-3s are associated with lower levels of the harmful amyloid-beta42 peptide in healthy older adults, as described earlier in this issue. DHA affects the processing of the amyloid precursor protein, which gives rise to the abnormal amyloid-beta peptides. It appears to direct the process toward less harmful peptides. DHA is also the precursor of neuroprotectin D1, a substance that promotes cell survival, protects neurons, reduces 15
Intranasal insulin may reduce or overcome insulin resistance in the brain, which leads to Alzheimer s disease. Treatment with intranasal insulin was associated with improved memory and cognition in individuals with mildly impaired cognition or early Alzheimer s disease. Other drugs that improve insulin signaling may also limit or reverse the damage of early stages of the disease. oxidative stress and slows the progression of neurodegenerative disease. DHA and neuroprotectin D1 also reduce inflammation. Individuals with higher intakes of EPA and DHA have greater gray matter volume in the brain and higher cognitive and behavioral scores. Moreover, several observational studies have reported that those with higher seafood intakes or greater seafood omega-3s are less likely to develop Alzheimer s disease. Although seafood omega-3s may have only modest effects on disease symptoms and cognition, the value of adequate omega-3 intakes may be greatest in reducing the risk of these conditions in the first place. 16