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Memory, Learning and Cognition

Summary of Key Points:

1. In animals, omega-3 fatty acids improve cognitive performance in learning and memory tasks.
2. Maternal fish consumption during pregnancy results in higher novelty preference on visual recognition memory and higher scores of verbal intelligence in the children up to eight years of age.
3. Maternal omega-3 is associated with better scores on infant standardized tests of intelligence.
4. Children born to mothers with low fish intake are more likely to be in the lowest quartile for verbal intelligence and are at risk for suboptimum pro-social behaviour, fine motor movements, communication, and social development.
5. Omega-3 fatty acids led to improvements in reading speed in dyslexic children.
6. Omega-3 supplementation in adults (average age 33) led to improvements in sustained attention, a reduction in errors on the attention tests and improvements in reaction time.
7. Fish intake diminishes and protects against age related cognitive decline.
8. Omega-3 fatty acids reduce the risk for dementia.
9. Persons with Alzheimer’s disease (AD) have less neural omega-3 fatty acids.
10. Omega-3 fatty acids improve cognitive function in AD patients.
11. Omega-3 fatty acids slow cognitive decline in AD patients.

OMEGA-3 FATTY ACIDS AND COGNITON
Fat is one of the major components of the brain and is highly involved in cognition, memory and development. In fact, about 50% of the adult brain is lipids of which 20–25% is long-chain polyunsaturated fatty acids (LC-PUFA)1. The LC-PUFAs that make up the greatest percentage of fatty acids in the brain are the omega-3 fatty acid docosahexaenoic acid (DHA) and the omega-6 fatty acid arachidonic acid (AA). The average diet is however very low in omega-3 compared to omega-6 which suggests that omega-3 supplementation is necessary to ensure adequate amounts of this necessary FA3,4.  Both DHA and AA have short chain fatty acid precursors: alpha-linolenic acid (ALA) and linolenic acid (LA), respectively. However, human capacity to convert ALA to EPA and DHA is very low, and therefore preformed DHA and EPA must be obtained from dietary sources2. LC-PUFAs have several biological functions in brain development and function, which include among others: the maintenance of membrane structure and function, the synthesis of eicosanoids (local hormones participating in a number of physiological and pathophysiological conditions) and finally, LC-PUFAs are involved in gene expression1,5.

Recently the use of EFAs to improve brain health has grown in popularity. Omega-3 regulates corticotrophin factor, increases seretonergic function, increases dentritic arborization, prevents neural apoptosis, improves cerebral blood flow and regulates gene expression6. Omega-3 fatty acids are the most efficient for the development of adequate brain cell membranes and intercellular neuronal connections7. A lack of omega-3, results in the use of other types of fatty acids, which weakens cellular networks and brain stability leading to several types of mental illnesses8.

Omega-3 fats and Animal Cognition
Studies done in animals have concluded that omega-3 fatty acid intake improves cognitive performance on several learning and memory tasks9. A study in rats10 found that a diet enriched with EPA led to the successful acquisition of spatial memory after cytokine (IL)-1, a proinflammatory cytokine known to cause memory and cognitive impairment. Chung et al. 200811 determined that reference and working memory performance can be enhanced in control male rats and improved in omega-3 deficient male rats when given a fish oil supplement. From the embryo to postnatal day 140, four groups of rats were fed an omega-3 deficient diet or a diet supplemented with omega-3 fatty acids from fish oil. The male rats were tested at postnatal day 102-130 for spatial learning memory performance in the Morris water maze. Rats that were not fed the omega-3 fatty acids showed significantly poorer reference and working memory, and fish oil supplementation partially rescued both memory performances. Furthermore, fish oil supplementation during brain development and adulthood in normal rats resulted in significant enhancement of both memories. Following dietary DHA repletion, the memory areas of the brain; the hippocampus and olfactory bulbs accumulated more DHA, were more resistant to dietary DHA deprivation, and showed better DHA recovery than the visual cortex, frontal cortex, and cerebellum. These results demonstrated that DHA is critical for the development and maintenance of learning and memory performance.

Omega-6 fatty acids lead to inflammatory changes in the brain and can have a negative impact on cognitive functioning. In animal studies these inflammatory changes are associated with impairment in hippocampal-dependent learning paradigms and in long-term potentiation (a model for long-term memory formation).
Lipopolysaccharide (LPS), a component of the cell wall of gram negative bacteria, can also induce inflammatory changes in the brain and causes impairment in LTP. In vivo, EPA was able to inhibit these changes in long-term memory12.

Omega-3 fats and Infant/Child Cognitive Development
The effect of LC-PUFA on cognitive development in infants has been extensively researched. Evidence from epidemiological studies suggests there is an association between higher levels of maternal fish consumption during pregnancy and developmental outcomes. Higher maternal fish consumption during pregnancy has resulted in short term benefits for infants such as higher novelty preference on visual recognition memory13, and longer term benefits like higher scores of verbal intelligence quotient in the children up to eight years of age14. In breastfed infants, higher DHA status at two months leads to better language production and comprehension at 14 and 18 months of age15,16. Jensen et al.17 found that children of lactating mothers given a daily DHA supplement had significantly better scores in psychomotor development. In a double-blind randomized trial, maternal supplementation during pregnancy and lactation with 1200 mg DHA and 800 mg EPA led to a 4% point advantage in children’s scores on a standardized intelligence test at the age of four years18. In another double-blind, placebo-controlled, randomized trial, pregnant women consumed a DHA-containing functional food or a placebo from gestation week 24 until delivery. The Infant Planning Test and Fagan Test of Infant Intelligence were administered to infants at age nine months and treatment with DHA had a significant effect on the performance of problem-solving tasks19. Finally, the data from a food frequency questionnaire on seafood consumption in 11,875 pregnant women at 32 weeks gestation was used to compare developmental, behavioural, and cognitive outcomes of children (age six months to eight years). Maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor movements, communication, and social development scores20.

Omega-3 and Child Cognition
In addition to the advantages in mental development observed when omega-3 is supplemented to infants and pregnant mothers, omega-3 fatty acids are also beneficial in child learning difficulties. In an open pilot study the effects of a DHA rich supplement on learning ability in a group of 20 dyslexic children was assessed in Sweden. Children formally diagnosed as dyslexic took eight capsules of high-DHA fish oil and evening primrose oil. Subjective assessments by the children and their parents were completed at baseline and 6, 12, and 20 weeks after supplementation. Quantitative evaluation by word-chain test was completed before and after four months of supplementation to measure word decoding (speed of reading) and letter decoding (motoric-perceptual speed). Subjective parent and child assessments showed increasing numbers of positive responders over time in reading speed, general schoolwork, and overall perceived benefit. Significant improvements were observed in reading speed and motor-perceptual velocity. Thirteen of 17 children had a significant improvement on the word-chain test and reading speed and motoric-perceptual velocity improved after supplementation. Thus, LC-PUFA supplementation for five months provided positive and clear beneficial effect on variables usually impaired by dyslexia21.

Omega-3 and Adult Cognition
The brain's reliance on EPA and DHA continues throughout adult life. For 35 days, a double-blind randomized control study was performed with 33 healthy volunteers (average age 33). Subjects consumed either 4 g fish oil/day (providing 1600 mg EPA and 800 mg DHA) or 4 g olive oil as placebo. Participants took attention tests, and brain physiology recordings (electroencephalogram/EEG and electromyogram/EMG) were made at baseline and on day 35. Measures of attention were improved in the participants given EPA + DHA. Omega-3 supplemented participants demonstrated marked improvements in sustained attention and a significant reduction in errors on the attention test. Significant improvements were also found on physiological measures. Reaction time was significantly improved, as measured by EMG. The EEG which measures brain wave activity is typically hard to interpret. Participants who had consumed EPA + DHA demonstrated a significant reduction in the high-frequency beta-2 band and an increase in the low-frequency theta and alpha bands. The researchers suggested that these changes in brain activity are consistent with the notion that omega-3 fatty acids have a direct action on the central nervous system which then leads to improved cortical function. They concluded that supplementation with EPA + DHA can improve higher brain functioning, reactivity, attention and cognitive performance in young, healthy adults22.

The Atherosclerosis Risk in Communities Study analyzed plasma fatty acids in cholesterol esters and phospholipids in 2,251 participants. At baseline subjects were on average 57 years of age. Two years later and again four years after baseline participants were tested for word recall, psychomotor speed, and verbal fluency. Higher plasma omega-3 fatty acid levels were correlated with reduced risk for decline in verbal fluency, particularly in hypertensive subjects and subjects with dyslipidemia23. Omega-3 is also beneficial in adult learning dysfunctions. Thirty-two dyslexic adults and 20 controls completed standardized tests of reading and spelling and gave venous blood samples for analysis of the fatty acid composition of red blood cell (RBC) membranes. Better word reading was associated with higher total omega-3 concentrations in both dyslexic and control groups. In dyslexic subjects only, reading performance was negatively associated with the ratio of arachidonic acid/eicosapentaenoic acid (AA/EPA) and with total omega-6 concentrations24.

Cognitive Decline and Risk of Dementia
In 2006 a study was conducted to examine whether intakes of fish protect against age-related cognitive decline in 6158 residents 65 years and older. Fish intake was associated with a slower rate of cognitive decline in mixed models adjusted for age, sex, race, education, cognitive activity, physical activity, alcohol consumption, and total energy intake. Compared with a decline rate of −0.1 standard unit/year among persons who consumed fish less than weekly, the rate was 10% slower (−0.09 SU/y) among persons who consumed one fish meal per week and 13% slower (−0.088 SU/y) among persons who consumed two or more fish meals per week25.

Over the last decade, epidemiological studies indicate relatively high DHA and EPA intake is linked to lower relative risk of dementia incidence or progression. In a longitudinal cohort study, 5,386 participants ages 55 or older were screened for dementia26. Dietary habits were evaluated using a semi-quantitative food frequency questionnaire and then re-evaluated after 2.1 years. Fish consumption was inversely related to dementia incidence, and more specifically to the risk of developing Alzheimer's disease. Five years later, participants who ate fish demonstrated a statistically significant prevention of cognitive decline. In fact, there was a linear relationship whereby the higher the intake of EPA + DHA the lower the rate of cognitive decline. The men who consumed an average of 400 mg omega-3 per day experienced significantly less cognitive decline compared with the men who consumed an average of only 20 mg/day26. During the Zutphen Elderly Study cognitive tests were administered in 476 men, ages 69-89 and data was correlated with reported food intakes. At baseline, they found that high fish consumption was associated with less cognitive impairment and after three years, high fish consumption was associated with less cognitive decline27.

In a population-based, prospective study, 704 non-demented elderly subjects (65-84 years) were evaluated for global cognitive functioning (Mini-Mental State Examination, MMSE) at three times over a ten year span. High omega fatty acid energy intakes and total energy intake were significantly associated with a better cognitive performance. In this prospective population-based study on older non-demented subjects with a typical Mediterranean diet, high fatty acid intakes appeared to be protective against age related cognitive decline28.

Alzheimer’s Disease
The applicability of omega-3 to Alzheimer’s disease (AD) has also been extensively examined. AD patients have a lower content of DHA in the gray matter, compared with individuals without Alzheimer's disease at death. Furthermore it has been suggested that dietary DHA entering the brain could correct DHA insufficiencies in cerebral cortical cell membranes. It has also been hypothesized that dietary EPA could help counter pro-inflammatory processes contributing to neurodegeneration29. Morris et al. in 200330 found that subjects who consumed fish once a week had a 60% lower risk of developing AD.

A 24-week, randomized, double-blind placebo-controlled study was carried out to test the feasibility of using omega-3 PUFAs in people with cognitive impairment and to explore its effects on cognitive function. Twenty-three participants with mild or moderate AD and twenty-three with mild cognitive impairment were randomized to receive omega-3 PUFAs 1.8 g/day or placebo (olive oil). The treatment group showed better improvement on the Clinician's Interview-Based Impression of Change Scale (CIBIC-plus) than those in the placebo group over the 24-week follow-up. The omega-3 fatty acids group showed significant improvement in the Alzheimer's Disease Assessment Scale (ADAS-cog) compared to the placebo group in participants with mild cognitive impairment, which was not observed in those with Alzheimer's disease. Also, higher proportions of EPA on RBC membranes were associated with better cognitive outcome31. In another longitudinal cobort study, serum phosphatidylcholine-DHA (PC-DHA) levels of 1,188 elderly Americans (average age 75 years) were analyzed at baseline and ten years later. Those in the lower half of the distribution of DHA levels at the time the first sample was taken, but who did not have AD at that time, appeared to have a 67% greater risk of developing AD within the subsequent 10-year period32.

As part of the U.S. Framingham Heart Study, a cohort of 899 men and women (median age 76 years), who were free of dementia at baseline, were followed for a mean 9.1 years for development of all-cause dementia and Alzheimer's disease; the findings were published in 2006. Ninety-nine new cases of dementia (including 71 of AD) occurred. Baseline and follow-up blood samples were tested for fatty acids in the plasma phospholipid fraction. After controlling for other variables, subjects in the upper quartile of plasma RBC DHA levels had approximately half the relative risk of developing all-cause dementia compared to subjects in the three lower quartiles. The upper quartile (n=488) had a mean DHA intake of 180 mg/day and a mean fish intake of 3.0 servings per week33.

Finally, in a double-blind randomized control trial the administration of DHA and EPA was assessed in 74 patients with mild-to-moderate Alzheimer's disease. Patients received either 1700 mg DHA and 600 mg EPA daily or a placebo for six months, after which all received the DHA/EPA supplements for six more months. In a subgroup with less severe cognitive dysfunction, a significantly slower decline was observed in the DHA/ EPA group. A similar slowing was observed in the placebo group after crossover to DHA/EPA for the second six months. The authors suggested that patients with mild Alzheimer deterioration could benefit from taking DHA and EPA34.

References
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10. Song, C., Horrobin, B. Omega-3 fatty acid ethyl-eicosapentaenoate, but not soybean oil, attenuates memory impairment induced by central IL-1 administration. Journal of lipid research. 2004; 45: 1112-1121.


11. Chung WL, Chen JJ, Su HM. Fish oil supplementation of control and (n-3) fatty acid-deficient male rats enhances reference and working memory performance and increases brain regional docosahexaenoic acid levels. J Nutr. 2008;138:1165-71.


12. Kavanagh T., Lonergan P.E. and Lynch M.A. Eicosapentaenoic acid and gamma-linolenic acid increase hippocampal concentrations of IL-4 and IL-10 and abrogate lipopolysaccharide-induced inhibition of long-term potentiation. Prostaglandins Leukotrienes and Essential Fatty Acids 2004 70: 391-397.


13. Oken E, Wright RO, Kleinman KP, Bellinger D, Amarasiriwardena CJ, Hu H, et al. Maternal fish consumption, hair mercury, and infant cognition in a U.S. Cohort. Environ Health Perspect. 2005;113:1376–80.


14. Hibbeln JR, Davis JM, Steer C, Emmett P, Rogers I, Williams C, et al. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study. Lancet. 2007;369: 578.


15. Innis SM, Gilley J, Werker J. Are human-milk long-chain polyunsaturated fatty acids related to visual and neural development in breast-fed infants? J Pediatr. 2001;39:532.


16. Innis SM, Gilley J, Werker J. N-3 docosahexaenoic acid is related to measures of visual and neural development in breast-fed infants to 14 months of age. Am J Clin Nutr. 2002;75:406S.


17. Jensen DL, Voigt RG, Prager TC, Zou YL, Fraley JK, Rozelle JC, et al. Effects of maternal docosahexaenoic acid intake on visual function and neurodevelopment in breastfed term infants. Am J Clin Nutr. 2005;82:125–32.


18. Helland IB, Smith L, Saarem K, Saugstad OD, Drevon CA. Maternal supplementation with very-long-chain n-3 fatty acids during pregnancy and lactation augments children’s IQ at 4 years of age. Pediatr. 2003;111:e39.


19. Judge MP, Harel O, and Lammi-Keefe CJ. Maternal consumption of a docosahexaenoic acid– containing functional food during pregnancy: benefit for infant performance on problem-solving but not on recognition memory tasks at age 9 mo. Am J Clin Nutr 2007;85:1572–7.


20. Hibbebln JR, Davis JM, Steer C, Emmett P, Rogers I, Williams C and Golding J.  Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): an observational cohort study Lancet 2007; 369: 578–85.


21. Lindmark L, Clough P.A 5-month open study with long-chain polyunsaturated fatty acids in dyslexia. J Med Food. 2007;10:662-6.


22. Fontani G, Corradeschi F, Felici A, et al. Cognitive and physiological effects of omega-3 polyunsaturated fatty acid supplementation in healthy subjects. EurJ Clin hivcst 2005:35:691-699.

23. Beydoun MA, Kaufman JS, Satia JA, Rosamond W, Folsom AR. Plasma n-3 fatty acids and the risk of cognitive decline in older adults: the Atherosclerosis Risk in Communities Study. Am J Clin Nutr. 2007;85:1103-11.


24. Cyhlarova E, Bell JG, Dick JR, Mackinlay EE, Stein JF, Richardson AJ. Membrane fatty acids, reading and spelling in dyslexic and non-dyslexic adults. Eur Neuropsychopharmacol. 2007;17:116-21.


25. Morris MC, Evans DA, Tangney CC, Bienias JL, Wilson RS Fish Consumption and Cognitive Decline With Age in a Large Community Study. Arch Neurol. 2005;62:1849-1853.


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27. b) Kalmijn S, Feskens BJ, Launer LJ, Kromhout D. Polyunsaturated fatty acids, antioxidants, and cognitive function in very old men. Am J Epidemiol 1997:145:33-41.


28. Solfrizzi V, Colacicco AM, D'Introno A, Capurso C, Torres F, Rizzo C, Capurso A, Panza F. Dietary intake of unsaturated fatty acids and age-related cognitive decline: a 8.5-year follow-up of the Italian Longitudinal Study on Aging. Neurobiol Aging. 2006; 27:1694-704.


29. Connor WE, Connor SL. The importance of fish and docosahexaenoic acid in Alzheimer disease. AmJ Clin Nutr 2007:85:929-930.


30. Morris MC, Evans DA, Bienias JL, Tangney CC, Bennett DA, Wilson RS, Aggarwal N, Schneider J. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol. 2003 Jul;60(7):940-6.


31. Chiu CC, Su KP, Cheng TC, Liu HC, Chang CJ, Dewey ME, Stewart R, Huang SY. The effects of omega-3 fatty acids monotherapy in Alzheimer's disease and mild cognitive impairment: a preliminary randomized double-blind placebo-controlled study. Prog Neuropsychopharmacol Biol Psychiatry. 2008;32:1538-44.


32. Kyle DJ, Schaefer E, Patron G, Beiser A. Low serum doiosahexacnoic acid is a significant risk factor for Alzheimer dementia. Lipids 1999;34:S245.


33. Schaefer E, Botigard V, Beiser AS. er al. Plasma phosphatidylcholine docosahexaenoic acid content and risk of dementia and Alzheimer disease: the Framingham Heart Study. Arch Neurol 2006;63:1545-1550.


34. Freund-Levi Y, Eriksdorrer-Jonhagen M, Cederholm T, et al. Otiiega-3 fatty acid treatment in 174 patients with mild to moderate Alzheimer disease: Omega-3AD study: a randomized double-blind trial. Arch Neurol 2006;63:1402-1408.

©2009 Ascenta Health Ltd.
This research is not intended to diagnose, treat or cure any illness or disease. 

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