Omega-3 Fatty Acids and Cognitive Behavior

C H A P T E R

25 Omega-3 Fatty Acids and Cognitive Behavior Grace E. Giles, Caroline R. Mahoney and Robin B. Kanarek INTRODUCTION Omega-3 and omega-6 fatty acids are the main dietary components of the family of polyunsaturated fatty acids (PUFAs). Omega-3 fatty acids include α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), whereas omega-6 PUFAs include linoleic acid (LA) and arachidonic acid (AA). Since our bodies cannot synthesize these compounds, they must be obtained from our diet. The primary dietary sources of EPA and DHA are fatty fish such as salmon, herring, tuna, and halibut, while ALA comes mainly from plant sources such as canola oil, walnuts, and flaxseed. Omega-6 PUFAs are most commonly consumed as LA, which is found predominantly in plant oils (e.g. corn oil, sunflower oil, and soybean oil), as well as in products made from these oils (Kris-Etherton et al., 2000). Both omega-3 and omega-6 PUFAs are necessary for cells to maintain normal structure, function, and signal transduction. However, there is growing evidence to demonstrate that the ratio of omega-3 to omega-6 is more important than their absolute levels for these cellular processes (Loef and Walach, 2013; Simopoulos, 2011). For example, the ratio of omega-3 to omega-6 PUFA influences inflammation. Intake of omega-6 PUFA increases proinflammatory cytokine production, whereas omega-3 PUFAs reduce omega-6 PUFA activity, and thus decrease proinflammatory cytokine activity (Calder, 2009, 2010). In the nervous system, PUFAs are released via neurotransmitter stimulation and metabolized to active compounds including prostaglandins, thromboxanes, and leukotrienes. These compounds: 1) act as neuronal second messengers; 2) interact with G-protein coupled receptors on glial cells, thereby affecting neuromodulation and synaptic output; 3) affect cell migration; 4) moderate neurogenesis and synaptogenesis; and 5) increase adenylate cyclase and protein kinase A, which mediate serotonin, norepinephrine, and dopamine receptors (Fontani et al., 2005b; Innis, 2007). Additionally, the omega-3 fatty acid

Omega-3 Fatty Acids in Brain and Neurological Health. DOI: http://dx.doi.org/10.1016/B978-0-12-410527-0.00025-9

DHA is a major component of the neuronal membrane, where it plays both a functional and a structural role. DHA helps to maintain the fluidity of the membrane at optimum levels for the transmission of neuronal information and moderates the characteristics of the hydrophobic core of the membrane to permit interactions with membrane proteins (for a review see Crawford, 2006). The importance of omega-3 PUFAs in brain function has been extensively studied in relation to psychological and neurological disorders. For instance, research indicates a beneficial influence of omega-3 PUFAs on depressive symptoms in individuals with major depressive disorder, although the relationship is far from understood (Giles et al., 2013; Lin et al., 2010; Martins, 2009; Parker et al., 2006; Sinclair et al., 2007). Omega-3 PUFAs may also benefit individuals with bipolar disorder (Turnbull et al., 2008), anxiety disorders (Ross, 2009) and attention deficit hyperactivity disorder (Frensham et al., 2012). Despite the reported benefits of omega-3 PUFAs when brain functions go awry, as in psychological and neurological disorders, less research has examined the influence of omega-3 PUFAs on cognitive function in healthy individuals. Recent research has begun to fill this gap by examining how omega-3 PUFAs influence cognitive development in infants and children, cognitive performance in young adults, and age-related cognitive impairments in older adults. Just as the brain changes throughout the lifespan, so too may nutritional influences on cognition (Benton, 2010; Luchtman and Song, 2013). Thus, this chapter will review recent research examining the cognitive effects of omega-3 intake across the lifespan.

Infants and Children Omega-3 PUFAs are critical for neurocognitive development from conception through early childhood

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© 2014 Elsevier Inc. All rights reserved.

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25. OMEGA-3 FATTY ACIDS AND COGNITIVE BEHAVIOR

(Rogers et al., 2013). In the developing neonate, high levels of DHA are found in the cerebral cortex and photoreceptors in the retina (Innis, 2007). DHA accumulates in these areas during the last trimester of pregnancy and first months of life, which are periods of active neurogenesis, neuroblast migration, differentiation, and synaptogenesis (McNamara, 2010). As a result, pre-term infants who do not receive the thirdtrimester intrauterine supply of DHA may be particularly susceptible to the detrimental consequences of DHA deficiency, which include deficits in visual acuity, reductions in neural growth, and decreases in regional cortical gray matter volumes (Helland et al., 2003; McNamara, 2010). After birth, infants obtain DHA from breast milk or formula, as most infant formulas now contain DHA and AA (Consumer Reports, 2012). Initial epidemiological studies explored the relationship between maternal intake of fish and other foods containing omega-3 PUFAs and cognitive behavior in their offspring. In the majority of studies, intakes of fish by the mother during pregnancy and lactation were determined using food frequency questionnaires, while cognitive performance in the offspring was measured with standardized tests including the Fagan Test of Infant Intelligence, which measures novelty preference and is thought to predict IQ later in life (Fagan and Detterman, 1992), the MacArthur Communicative Development Battery, which assesses infant and toddler linguistic abilities (Fenson et al., 1993), the Peabody Picture Vocabulary Test, which measures listening comprehension and vocabulary (Dunn and Dunn, 1997), and the Bayley Scales of Infant Development, which evaluates cognitive and motor development (Bayley, 1969). Results of these studies revealed a positive relationship between mothers’ fish intake during pregnancy and lactation and cognitive development in their infants and young children (e.g. Boucher et al., 2011; Daniels et al., 2004; Hibbeln et al., 2007; Oken et al., 2008a,b). For example, Daniels and colleagues (2004) reported that maternal fish intake during pregnancy and infants’ fish intake during the first year of life were positively associated with scores on tests of language comprehension and social activity determined when the children were 15 and 18 months of age. Similarly, in an observational cohort study, Hibbeln and co-workers (2007) observed a direct relationship between maternal seafood intake measured at 32 weeks’ gestation and children’s cognitive performance between the ages of 6 months to 8 years. However, it should be noted that not all studies have observed a positive relationship between early exposure to omega-3 PUFAs and later cognitive functions (Keim et al., 2012). Although limited in number, epidemiological studies have also assessed the relationship between omega-3 PUFA intake and cognitive performance in adolescents.

In two studies conducted in Sweden, adolescents who regularly consumed fish performed better on a variety of cognitive measures including IQ, verbal performance, visuospatial performance, and academic achievement than adolescents who infrequently ate fish (Aberg et al., 2009; Kim et al., 2010). Similarly, in a study in Holland, adolescents who consumed the recommended levels of fish did better with respect to vocabulary and academic performance than those who consumed less than the recommended levels of seafood. However, caution must be exercised in reaching conclusions from this study, as exceeding the recommended level of fish intake actually decreased performance on a number of cognitive tasks (de Groot et al., 2012). While the results of these epidemiological studies suggest that dietary exposure to omega-3 PUFAs can have positive effects on cognitive behavior, their correlational design makes it impossible to assign causality. Moreover, a number of factors must be considered as possible confounds in such studies. For example, mothers who consume more fish may have a generally healthier diet, a greater level of education, and/or be older (or younger) than mothers who consume less fish. Another concern is that to quantify PUFA intake, these studies generally rely on food frequency questionnaires, which are subject to under-reporting of energy and food, including fats and fatty acids (Schaefer et al., 2000). To begin to address causality, randomized, doubleblind, placebo-controlled trials (RCTs) on the effects of omega-3 PUFAs on behavior are required. As a result, the following sections will concentrate on RCTs investigating the effects of omega-3 PUFAs on cognitive behavior. These trials can generally be divided into three categories, depending on the age at supplementation: (1) prenatally or infancy, via maternal supplementation; (2) infancy via formula supplementation; and (3) childhood.

Maternal Supplementation As shown in Table 25.1, results of experiments assessing the effects of maternal supplementation of omega-3 PUFA on cognitive development have not been consistent. On the negative side, Helland and colleagues (2001) found no differences in cognitive development of 6- and 9-month-old infants whose mothers had received supplements of either omega-3 PUFArich cod liver oil or omega-6 PUFA-rich corn oil during pregnancy and lactation. In contrast, the same researchers reported that children whose mothers had consumed cod liver oil during pregnancy and lactation did better on the mental processing subscale of the Kaufman Assessment Battery for Children at 4 years of

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

TABLE 25.1 Randomized Controlled Trials Assessing the Influence of Maternal Omega-3 PUFA Intake on Cognitive Development of Offspring

Authors

Mothers n

Maternal Age (Years)

Omega-3 PUFA Manipulation

Infants n Age at (Female) Testing

Childhood Cognitive Measures a

Results

(Helland 341 et al., 2001)

19 35

Cod liver oil (2632 mg/10 mL omega-3, 235 mg/ 10 mL omega-6) versus corn oil (350 mg/10 mL omega-3, 4747 mg/10 mL omega-6) 17 19 weeks pregnant until three months post-partum

288 (175)

27, 39 weeks

FTII

341 (Helland et al., 2003)

19 35 Cod liver oil: 28.5 6 3.3 Corn oil: 28.0 6 2.4 years

Cod liver oil (2494 mg/10 mL omega-3) versus corn oil (4747 mg/10 mL omega-6) 8 weeks pregnant until three months post-partum

84 (43)

4 years

K-ABCb

Cod liver . corn oil Mental Processing Composite Positive association plasma [DHA] and K-ABC subscales. Positive association between maternal DHA, EPA intake during pregnancy, and K-ABC subscales. Maternal DHA intake predicted Mental Processing Composite

(Lauritzen 150 et al., 2005)

X

FOc (1500 mg omega-3 PUFA: 900 mg DHA) versus OOd 9 6 3 days post-delivery until four months postpartum versus high habitual fish intake

148 (65)

9 months 1, 2 years

Motor function (9 months) Means-end problem solving (9 months) MCDIe (1, 2 years)

No differences in motor function. Higher problem-solving scores in FO than OO in girls only. Lower vocabulary production in FO than OO at 1 year (no differences at 2 years). Negative association between active vocabulary and RBC [DHA] at 1 year

98 (Dunstan et al., 2008)

X-X FO (2200 mg DHA, 1100 mg EPA) versus OO FO: 30.9 6 3.7 20 weeks pregnant until birth Control: 32.6 6 3.6

72 (39)

2.5 years

GMDSf PPVTg CBCLh

Higher hand eye coordination score on GMDS in FO than OO. Hand eye coordination positively associated with erythrocyte [EPA] and [DHA] and negatively correlated with [AA]. No differences between PPVT or CBCL

No differences

(Continued)

TABLE 25.1 (Continued)

Authors

Mothers n

Maternal Age (Years)

Omega-3 PUFA Manipulation

Infants n Age at (Female) Testing

Childhood Cognitive Measures

Results

(Makrides 2320 et al., 2010)

X-X Fish oil (800 mg DHA, 100 mg EPA) FO: 28.9 6 5.7, versus vegetable oil Control: 28.9 6 5.6

1196 (600)

18 months

BSID-IIIi

Mean scores did not differ by maternal treatment group. FO , control group for language score, language development, adaptive behavior (girls only)

(Cheatham 107 et al., 2011)

X

98 (44)

7 years

Woodcock Johnson Tests of Cognitive Abilities III Day/Night Stroop Task SDQj

No differences in speed of processing, Stroop Score, SDQ. Lower prosocial functioning in FO than OO (boys only). Total maternal omega-3 PUFA intake negatively associated with speed of processing scores

a

FO (1500 mg/day omega-3 PUFA: 790 mg DHA, 62 mg EPA) versus OO versus high habitual fish intake

Fagan Test of Infant Intelligence (FTII) Kaufman Assessment Battery for Children (K-ABC) c Fish oil (FO) d Olive oil (OO) e MacArthur Communicative Development Inventory (MCDI) f Griffiths Mental Development Scales (GMDS) g Peabody Picture Vocabulary Test (PPVT) IIIA h Child Behavior Checklist (CBCL) i Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) j Strengths and Difficulties Questionnaire (SDQ) X Not Reported b

INTRODUCTION

age than children whose mothers had consumed corn oil. Additionally, the children’s mental processing scores correlated significantly with maternal intake of DHA and EPA during pregnancy (Helland et al., 2003). In more recent studies, the use of DHA-rich fish oil capsules compared with vegetable oil capsules during pregnancy did not result in improved cognitive and language development as measured by the Bayley Scale of Infant and Toddler Development (Makrides et al., 2010). Although the aforementioned studies suggest that maternal levels of omega-3 PUFAs may influence infant development, they are limited by the use of corn oil or vegetable oil which are high in omega-6 PUFAs as the control treatment. As a consequence, it is possible that rather than high levels of omega-3 PUFAs having a positive effect, high levels of omega-6 PUFAs, or a decreased ratio of omega-3 to omega-6 PUFAs, had a detrimental effect on cognitive behavior. To overcome this problem, recent studies have used olive oil, which contains monounsaturated fatty acids (MUFAs), and thus does not disrupt the balance between omega-3 and omega-6 PUFAs for the control condition (Cheatham et al., 2011; Dunstan et al., 2008; Lauritzen et al., 2005). A particularly well-designed RCT compared the effects of maternal fish oil and olive oil supplementation on infants’ behavior in women whose habitual fish intake fell below the population median (i.e. # 4 g/day omega-3 PUFA) to non-supplemented women whose habitual consumption of fish fell within the upper quartile of the population ($8 g/day omega-3 PUFA). When infants reached 9 months of age, better problemsolving skills were seen in girls whose mothers had been supplemented with fish oil relative to girls whose mothers had received olive oil. No differences emerged for boys or for other cognitive measures. At 1 year of age, however, vocabulary production was actually lower in children whose mothers had been supplemented with fish oil than in those whose mothers had received olive oil. Moreover, higher red blood cell DHA levels were associated with lower vocabulary scores. By 2 years of age, children did not differ in measures of cognitive behavior. Using a similar design, the same research group assessed executive function in children when they reached 7 years of age. Boys whose mothers had been supplemented with olive oil during the first four months of breastfeeding had lower prosocial behavior scores, as assessed by the Strengths and Difficulties Questionnaire, than boys whose mothers were given corn oil. In contrast, prosocial behavior in girls did not differ as a function of maternal supplementation. Moreover, no group effect of the intervention was evident in the speed of processing, inhibitory control or working memory abilities of 7 year olds whose mothers were or were not supplemented with

307

DHA during the first 4 months of breastfeeding (Cheatham et al., 2011). In a study in which mothers were supplemented with fish oil or olive oil from 20 weeks gestation through birth, hand eye coordination, as measured by the Griffiths Mental Development Scales, was more developed in 2.5 year old children whose mothers had received fish oil than in children whose mothers had been given olive oil. Moreover, hand eye coordination was positively associated with maternal erythrocyte EPA and DHA concentrations, and negatively associated with AA concentrations. However, performance on the MacArthur Communicative Development Inventory and the Child Behavior Checklist, which evaluates internalizing versus externalizing behavior, did not differ between treatment groups (Dunstan et al., 2008). Thus, while some studies found beneficial effects of maternal omega-3 PUFA supplementation on cognitive measures such as mental processing, problem solving, and hand eye coordination (Dunstan et al., 2008; Helland et al., 2003; Lauritzen et al., 2005), other studies have found few differences (Helland et al., 2001) and even negative effects (Cheatham et al., 2011; Makrides et al., 2010). Differences in the type, dose, and duration of supplementation with omega-3 PUFA, control conditions, cognitive measures which were employed, and age at assessment may contribute to inconsistent results among studies. Additionally, a recent review points out several methodological limitations that may influence results, including small sample size compounded with high attrition rates, as well as a lack of clear reporting of randomization and intent-to-treat analysis (Gould et al., 2013). Taken together, these factors make it premature to conclude that maternal intake of omega-3 PUFAs plays a significant role in cognitive development.

Supplementation During Infancy To assess the influence of omega-3 PUFA levels on cognitive development in a more direct manner than through maternal supplementation, researchers have supplemented the infant’s diet with omega-3 PUFAs (Table 25.2). Using this method, it was found that preterm infants fed human milk supplemented with DHA and AA for approximately 2.25 months displayed enhanced problem-solving skills and recognition memory at 6 months of age relative to infants fed milk without DHA and AA (Henriksen et al., 2008). Further support for a role for DHA in cognitive development comes from work investigating the effects of a formula containing either one of three doses of DHA or the same formula without DHA on cognitive performance.

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

308

25. OMEGA-3 FATTY ACIDS AND COGNITIVE BEHAVIOR

TABLE 25.2 Development

Authors

Randomized Controlled Trials Assessing the Influence of Infant Omega-3 PUFA Supplementation on Cognitive

Sample n (Female) Term

Gestational Age

Omega-3 PUFA Manipulation

Supplement Duration (Months)

Age at Cognitive Testing (Months) Measures

Results

(Scott et al., 274 (X) term 1998)

X

0.2% DHA formula versus 0.12% DHA 1 0.43% AA formula versus control formula versus BFa

14

12, 14

BSIDb MCDIc

No differences in BSID DHA , BF vocabulary comprehension. DHA , control vocabulary production

(Auestad et al., 2001)

404 (203) term

Egg-DTGd: 39.0 6 1.3 FOe Fungal: 39.3 6 1.2 Control: 39.4 6 1.2 Egg-DTG BF: 39.6 6 1.3 Control BF: 39.2 6 1.2

FO 1 fungal oil formula (0.46 g/100 g AA, # 0.04 g/100 g EPA, 0.13 g/100 g DHA) versus Egg-DTG formula (0.45 g/100 g AA, 0.14 g/100 g DHA) versus control formula versus BF 1 Egg-DTG versus BF control

12

1, 2, 4, 6, 9, 12, 14

BSID MCDI FTIIf Infant Behavior Questionnaire

No differences in BSID, FTII. FO-Fungal . egg-DTG formula vocabulary expression. Egg-DTG formula , control formula smiling and laughter (Infant Behavior Questionnaire)

(O’Connor et al., 2001)

470 (214) Pre-term

Egg-DTG: 29.7 6 2.0 FO-Fungal: 29.8 6 2.1 Control: 29.6 6 1.9 BF: 29.7 6 2.1

FO 1 fungal oil formula (0.43 g/100 g AA, 0.08 g/100 g EPA, 0.27 g/100 g DHA) versus egg-DTG formula (0.41 g/100 g AA, 0.24 g/100 g DHA) versus control formula versus BF

12

2, 4, 6, 9, 14

BSID MCDI FTII

No differences in BSID, except FO-Fungal . control motor score in infants # 1250 g birth weight. Egg-DTG . fish-fungal, control groups novelty preference. No differences in MCDI, except egg-DTG, FO-fungal , control vocabulary comprehension after removing infants from Spanishspeaking families

(Auestad et al., 2003)

157 (71) term

All: 39 6 1

AA 1 DHA (0.43 g/100 g AA 1 0.12 g/100 g DHA) versus DHA (0.23 g/100 g DHA) versus control formula versus BF

52

14, 39

SBISg PPVT-Rh BVMi MLUj

No differences

(Henriksen et al., 2008)

141 (64) pre-term

48 mg/kg day Omega-3: DHA 1 48 mg/kg day AA 28.4 6 X Control: 28.9 6 X versus soybean

2.25 (median)

6

Ages and Omega-3 . control problem solving. Stages Omega-3 . control recognition Questionnaire memory Recognition memory via ERPk

oil 1 medium-chain triglyceride oil

(Drover et al., 2011)

131 (52) term

All: 37 42

0.32% DHA (17 mg/ 100 kcal), 0.64% DHA (34 mg/100 kcal) or 0.96% DHA (54 mg/100 kcal) 10.64% AA (54 mg/ 100 kcal) versus control formula

12

18

BSID BRSl

No differences between groups analyzed separately. Combined DHA groups . control mental development, language. Combined DHA groups . controls BRS emotion regulation

(Meldrum et al., 2012)

420 (139) term

FO: 39.1 6 1.1 Control: 29.4 6 1.3

FO (230 mg DHA, 110 mg EPA) versus OOm

6

12, 18

BSID MCDI CBCLn

FO . control MCDI later developing gestures, and total number gestures. No differences in BSID. FO . control CBCL anxious/ depressed behaviors

a

i

b

j

Breastfed (BF) Bayley Scales of Infant Development (BSID) c MacArthur Communicative Development Inventories (MCDI) d Egg-derived triglyceride (Egg-DTG) e Fish oil (FO) f Fagan Test of Infant Intelligence (FTII) g Stanford-Binet Intelligence Scale (SBIS) Form L-M h Peabody Picture Vocabulary Test-Revised (PPVT-R)

Beery Visual-Motor Index Test (BVM) Mean length of utterance (MLU) k Event Related Potential (ERP) l Behavior Rating Scale (BRS) m Olive oil (OO) n Achenbach Child Behavior Checklist (CBCL) X Not Reported

INTRODUCTION

While no differences were found among the four groups at 18 months of age, when the three DHA groups were combined, infants supplemented with DHA had enhanced language development on the Bayley Scales of Infant Development and emotion regulation behavior on the Behavior Rating Scale relative to those fed the control formula. In addition, higher red blood cell concentrations of the omega-6 PUFA, LA, were associated with lower language development and lower emotion regulation (Drover et al., 2011). More recently, Meldrum and co-workers (2012) reported no differences in global development at 12 and 18 months of age between infants supplemented with a high dose of fish oil and those supplemented with olive oil from birth to 6 months of age. However, infants supplemented with fish oil did display a higher number of gestures on the MacArthur Communicative Development Inventory than infants supplemented with olive oil. Moreover, erythrocyte DHA concentrations were directly associated with communication scores on the Bayley Scales of Infant and Toddler Development. In contrast to results of studies that suggest beneficial effects of omega-3 supplementation on infants’ cognition, other studies have found null effects or even detrimental effects. For instance, Auestad et al. (2003) observed no differences in IQ (Fagan Test of Infant Intelligence), language (MacArthur Communicative Development Inventory) or motor function (Bayley Scales of Infant and Toddler Development) at 1 through 14 months of age in infants supplemented with DHA with or without AA. Similarly, in a comparison between breast-fed infants and infants receiving DHA-supplemented, DHA and AA-supplemented or control formula for 14 months, no differences were found in mental or motor development at 12 or 14 months of age. Results from the MacArthur Communicative Development Inventory showed lower vocabulary comprehension in infants fed DHAsupplemented formula than in breast-fed infants, and lower vocabulary production than in infants fed the control formula. The potentially detrimental influence of DHA supplementation on language development was further evidenced by results showing that red blood cell DHA was negatively correlated with vocabulary production in breast-fed and formula-fed children, and with vocabulary comprehension in breast-fed children (Scott et al., 1998). Omega-3 PUFAs are found in a variety of sources which vary in terms of the relative DHA and EPA composition (Barcelo-Coblijn et al., 2008; Gebauer et al., 2006). Plant sources of PUFAs such as walnuts and flaxseed are relatively high in ALA, whereas marine sources such as salmon and fish oil contain a greater percentage of EPA and DHA. If the cognitive effects of omega-3 PUFAs are contingent upon the

309

relative constitution of EPA, DHA, and ALA, research into the differential cognitive effects of plant versus marine omega-3 PUFAs is essential (Auestad et al., 2001; O’Connor et al., 2001). To begin to examine this issue, infants were fed formulas containing fish oil plus fungal oil or egg-derived triglyceride, or breast fed for 12 months and tested on a range of cognitive measures including novelty preference, information processing, cognitive development, and motor development at 1, 2, 4, 6, 9, and 12 months of age. Few differences in cognitive behavior were observed among the groups, with the exception that infants fed the fish oil fungal oil formula scored higher in vocabulary expression on the MacArthur Communicative Development Inventory than those the fed egg-derived triglyceride formula (Auestad et al., 2001). However, in another study, infants fed either the fish oil fungal oil or the egg-derived triglyceride formulas scored lower in vocabulary comprehension than control groups, but only after removing infants from Spanish-speaking households (O’Connor et al., 2001). Although the influence of omega-3 PUFA supplementation on language remains poorly understood, the extant data suggest that higher DHA intake and levels are associated with poorer language development. In summary, while some studies have found a beneficial influence of omega-3 PUFAs on measures of problem solving and memory (Henriksen et al., 2008) and language (Drover et al., 2011; Meldrum et al., 2012), this has not universally been the case, as others have found detrimental effects of omega-3 PUFAs, particularly on language development (O’Connor et al., 2001; Scott et al., 1998). Like maternal omega-3 PUFA supplementation, infant omega-3 PUFA supplementation does not seem to influence global indices of cognitive development, but may have more circumscribed effects on certain cognitive domains.

Supplementation During Childhood As we move up the lifespan a few years, we will now examine RCTs assessing omega-3 PUFA supplementation in children from 4 to 12 years of age (Table 25.3). Relatively few researchers have looked at this age group, and from the few studies that do exist, there is no strong support for a positive effect of omega-3 PUFAs on cognitive performance. For example, no differences in episodic memory, working memory, psychomotor performance or mood measured at multiple time points, i.e. before and after breakfast, were found in 10 to 12 year old children who received either 400 mg/day DHA, 1000 mg/day DHA or a placebo. DHA did enhance self-reported feelings of relaxation, but this result was interpreted with caution, as

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

TABLE 25.3 Randomized Controlled Trials Assessing the Influence of Omega-3 PUFA Supplementation on Cognitive Development in Childhood

Authors

Sample n (Female)

Age Range (Mean 6 SD) Years

Omega-3 PUFA Manipulation

Duration (Weeks)

Cognitive Measures

Results

(Kennedy et al., 2009)

88 (42)

10 12 (400 mg DHA: 11.11 6 0.79 1000 mg DHA: 10.70 6 0.79 Control: 10.87 6 1.1)

400 mg/day DHA versus 1000 mg/day DHA versus vegetable oil

8

IB CDRb

Control . 400 mg, 1000 mg DHA relaxation ratings at baseline. Post . pre-DHA treatment relaxation ratings. 400 mg , placebo word recognition reaction time before and after breakfast. 1000 mg DHA . placebo word recognition reaction time before breakfast

(Ryan and Nelson, 2008)

175 (79)

4.0 4.67 (Omega-3: 4.3 6 0.2 Control: 4.3 6 0.2)

400 mg DHA versus sunflower oil

16

Leiter-Rc PPVTd Day-Night Stroop Test kCPTe

No differences

(Muthayya et al., 2009)

598 (204)

6 10 (All: 8.7 6 1.2)

Micronutrient (100% RDAf: high versus 15% RDA: low) x omega-3 PUFA (900 mg ALA 1 100 mg DHA: high versus 140 mg ALA: low)

52

KABC-IIg WISC-R, WISC-4h RAVLTi NEPSYj Number Cancellation

High . low micronutrient short-term memory (6 months only). Low . high micronutrient fluid reasoning (6 and 12 months). No differences in omega-3 groups

(Richardson et al., 2012)

362 (170) below 33rd centile in reading

6 10 (Omega-3: 8.6 6 0.8 Control: 8.7 6 0.8)

Algal oil (600 mg DHA) versus corn/ soybean oil

16

BAS-IIk Recall of Digits Forward Backward CTRS-Ll, CPRS-L

No changes in working memory or reading scores across entire sample. DHA . control reading score in children below 22nd centile in reading. DHA . control anxiety, restless-impulsive, emotional lability, global index from parent but not teacher ratings

a

a

Internet Battery (IB): Word Presentation, Picture Presentation, Arrow Reaction Time Test, Arrow Flanker Test, Paired Associate Learning, Sentence Verification, Delayed Word Recognition, Mood and Fatigue Visual Analogue Scales b Cognitive Drug Research (CDR) Battery: Picture Presentation, Word Presentation/Immediate Word Recall, Simple Reaction Time, Spatial Working Memory, Numeric Working Memory, Delayed Word Recall, Delayed Word Recognition, Delayed Picture Recognition c Leiter-R Test of Sustained Attention (Leiter-R) d Peabody Vocabulary Test (PPVT) e Conner’s Kiddie Continuous Performance Test (kCPT) f Recommended Dietary Allowance (RDA) g Kaufman Assessment Battery for Children, second edition (KABC-II) h Wechsler Intelligence Scales for Children (WISC-R and WISC-4) i Rey Auditory Verbal Learning Test (RAVLT) j Neuropsychological Assessment Tool (NEPSY) k British Ability Scales (BAS-II) l Conner’s Rating Scales (CTRS-L, CPRS-L)

INTRODUCTION

relaxation ratings were lower in the DHA groups than in the control group at baseline. Reaction time on a word recognition task was lower following 400 mg/day DHA intake both before and after breakfast and higher following 1000 mg/day DHA intake, before breakfast only (Kennedy et al., 2009). Similar results were found in a study using pre-school aged children in which DHA supplementation had no effect on cognitive measures including attention, vocabulary, and executive function. The only positive results showed that capillary whole blood DHA levels were positively associated with vocabulary scores (Ryan and Nelson, 2008). Recent work indicates that omega-3 PUFA supplementation not only affects behavior but also may modify brain activation. Using functional magnetic resonance imaging it was found that compared with placebo, DHA supplementation increased activation in the dorsolateral prefrontal cortex (DLPFC) during a sustained attention task in 8 to 10 year old boys. Lower activation was observed in low-dose (occipital cortex) and high-dose (cerebellar cortex) DHA groups compared with placebo. Despite similar performance on the behavioral task, erythrocyte DHA composition was positively correlated with DLPFC activation and inversely correlated with reaction time at baseline and endpoint, suggesting that omega-3 PUFAs, particularly DHA, may influence PFC-associated cognitive outcomes (McNamara et al., 2010). It is possible that omega-3 PUFAs may be more effective in improving mental functioning in children with cognitive or nutritional deficits than in healthy children. To investigate this possibility, the effects of 600 mg/day DHA versus control oil were examined in 6 to 10 year old children initially underperforming in reading, i.e. below the 33rd centile on reading ability, working memory, and behavior. Across the entire sample of children initially underperforming in reading, children did not differ in reading as a function of DHA supplementation. However, DHA improved reading scores relative to controls in children initially below the 20th centile. Parent ratings suggested that DHA elevated several behaviors including anxiety, restlessness, and emotional lability, but no such differences were found through teacher ratings (Richardson et al., 2012). Thus, DHA supplementation may aid reading performance in children with relatively low reading ability, but whether behavioral differences also emerge is questionable due to the mismatch in parent and teacher ratings. Another study looked at children with compromised nutrition, specifically marginally nourished children from low-income households in India. Although micronutrient supplementation improved memory and reasoning, omega-3 PUFA supplementation had no effects (Muthayya et al., 2009). Thus, little evidence exists for a beneficial influence of

311

omega-3 PUFA supplementation on cognitive performance in school-age children.

Young Adults To date only a handful of studies have assessed the cognitive effects of omega-3 PUFA supplementation in young adults (Table 25.4). Among the few studies that exist, Fontani and colleagues (2005a) found that relative to olive oil supplementation, five weeks of fish oil supplementation increased feelings of vigor and reduced feelings of anger, anxiety, fatigue, depression, and confusion. In a subsequent study, fish oil had similar effects on mood and reduced reaction time on tasks of response inhibition (Go/No-Go) and sustained attention (complex Go/No-Go). Measuring electromyography (EMG) activation showed that reduced reaction time was not due to increased muscle contraction but instead due to enhanced central processing (Fontani et al., 2005a). Thus, evidence from Fontani’s group suggests that omega-3 PUFAs have beneficial effects on mood, but does not present a clear picture on psychomotor performance, as fish oil did not influence straightforward tests of simple and choice reaction time. In contrast to the previous results, more recent data showed that, in comparison to olive oil supplements, four weeks of fish oil supplements only reduced ratings of fatigue, and had no effect on other mood scales measuring vigor, anger, anxiety, depression or confusion in healthy 18 to 27 year old men and women. Further, fish oil did not influence cognitive performance across a range of tasks measuring response inhibition, facial expression recognition, and memory. Fish oil did increase risk-seeking decision-making in gains only trials of a gambling task as well as reaction time in both gains-only and losses-only trials relative to placebo, together suggesting that omega-3 PUFA supplementation increased willingness to make calculated risks rather than increased impulsiveness (Antypa et al., 2009). However, the risk-based decision-making task was only administered after supplementation, making it impossible to determine whether fish oil and olive oil differentially changed risk taking pre- to post-supplementation. Another study found that fish oil improved verbal learning, but did not influence response inhibition or mood (Karr et al., 2012). A recent study found that DHA supplementation improved episodic memory in women and working memory in men, but not attention or processing speed in either sex (Stonehouse et al., 2013). Inconsistent results among studies may be due to differences in DHA content of fish oil (e.g. 0.8 g/day in Fontani et al. (2005a) compared to 0.25 g/day in Antypa et al. (2009) and 0.24 g/day in Karr et al. (2012)).

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

TABLE 25.4 Randomized Controlled Trials Assessing the Influence of Omega-3 PUFA Supplementation on Cognitive Performance in Young Adults

Authors

Sample n Age Mean Age (Female) Range 6 SD

Omega-3 PUFA Manipulation

Duration (Weeks)

Cognitive Measures

Results

(Fontani et al., 2005b)

33 (20)

22 51 33 6 7

Diet (40% carb, 30% pro, 30% fat versus 55% carb, 15% pro, 30% fat) x FOa (4 g/day FO: 0.8 g DHA, 1.6 g EPA versus OOb)

5

POMSc

FO . control vigor FO , control anger, anxiety, fatigue, depression, confusion

(Fontani et al., 2005a)

36 (32)

22 51 FO: 33 6 7 4 g/day FO (0.8 g DHA, 1.6 g Control: 33 6 3 EPA) versus OO

5

POMS, SRTd, CRTe, GNGf, Complex GNG (sustained attention)

FO . control vigor FO , control anger, anxiety, fatigue, depression, confusion FO , control GNG reaction time, number of errors No differences in SRT, CRT

(Antypa et al., 2009)

54 (44)

18 27 FO: 22.2 6 3.6 Control: 22.6 6 4.1

3 g/day FO (0.25 g DHA, 1.74 g EPA)

4

Affective GNG Attentional GNG Facial Expression Recognition Task Decisionmaking (gambling) task M.I.N.I.g BDI-IIh, POMS BIS/BASi LEIDS-Rj

FO , control fatigue, LEIDS-R Control/perfectionism, risk aversion and total score FO . control gambling task risk-seeking decision-making in gains-only trials No differences in GNG, facial expression recognition

(Jackson et al., 2012c)

140 (94)

18 35 DHA-rich FO: 21.96 6 0.54 EPA-rich FO: 22.74 6 0.61 Control: 21.94 6 0.50

1 g/day DHA-rich FO (0.45 g 12 DHA, 0.09 g EPA) versus EPArich FO (0.2 g DHA, 0.3 g EPA) versus OO

COMPASSk CDBl Bond-Lader VASm DASSn

DHA-rich FO , control Stroop reaction time EPA-, DHA-rich FO , control names-to-faces task (episodic memory) EPA-rich FO , control CBD self-reported fatigue No differences in mood or other cognitive measures

(Jackson et al., 2012a)

22 (13)

X

All: 21.96 6 X

1 g/day DHA-rich FO (0.45 g 12 DHA, 0.09 g EPA) versus EPArich FO (0.2 g DHA, 0.3 g EPA) versus OO

Stroop Task Peg-and-ball task 3-back task Wisconsin card sort task NIRSo

DHA-rich FO . control oxy-HB following DHA-rich FO during Stroop Task DHA-rich FO . control total-HB during Stroop Task, peg-and-ball, 3-back tasks

(Jackson et al., 2012b)

65 (49)

18 29 1 g FO: 20.5 6 0.43 2 g FO: 19.95 6 0.34 Control: 21.35 6 0.62

1 g/day FO (0.45 g DHA, 12 0.09 g EPA) versus 2 g/day FO (0.9 g DHA, 0.18 g EPA) versus OO

COMPASS

1, 2 g FO . control oxy-HB during all tasks 2 g FO . control total-HB during all tasks 1 g FO . FO control during Stroop, RVIPp tasks

(Karr et al., 2012)

41 (29)

1 g/day FO (240 mg DHA, 360 mg EPA) versus coconut oil

RAVLTq, Stroop Test, TMTr, PANASs

FO . control final stages (6 and 7) RAVLT FO , control TMT No differences in Stroop Test, PANAS

a

FO: 19.90 6 18.3 Control: 20.43 6 1.63

4

Fish oil (FO) Olive oil (OO) Profile of Mood States (POMS) d Simple Reaction Time (SRT) e Choice Reaction Time (CRT) f Go/No-Go (GNG) g Mini International Neuropsychiatric Interview (M.I.N.I) h Beck Depression Inventory-II (BDI-II) i Behavioral Inhibition/Behavioral Activation Scales (BIS/BAS) j Leiden Index of Depression Sensitivity Revised (LEIDS-R) k Computerized Mental Performance Assessment System (COMPASS): episodic memory, psychomotor performance, attention, executive function, working memory l Cognitive Demand Battery (CDB) m Visual Analogue Scales (VAS) n Depression, Anxiety, and Stress Scales (DASS) o Near IR spectroscopy (NIRS) p Rapid Visual Information Processing (RVIP) q Rey Auditory Verbal Learning Test (RAVLT) r Trail Making Test (TMT), Parts A and B s Positive and Negative Affect Schedule (PANAS) X Not Reported b c

314

25. OMEGA-3 FATTY ACIDS AND COGNITIVE BEHAVIOR

Subsequent research has compared DHA-rich fish oil to EPA-rich fish oil to better understand whether the DHA or EPA content moderates differences in cognitive performance. DHA-rich fish oil lowered reaction time on the Stroop Task relative to olive oil and EPArich fish oil lowered self-reported fatigue during high cognitive demand. Both DHA- and EPA-rich fish oil impaired episodic memory on the Names-to-Faces task, but this task was one of five tasks measuring episodic memory, the other four of which did not generate differences, indicating that the influence of fish oil on episodic memory is not entirely reliable (Jackson et al., 2012c). Near-infrared spectroscopy (NIRS) is a brain imaging method that measures light absorbance to calculate oxy-hemoglobin (oxy-HB) and deoxy-hemoglobin (deoxy-HB), which provides an indirect measure of brain activity, particularly in the frontal cortex. Given that previous research had found increased prefrontal activation following DHA treatment (McNamara et al., 2010), this technique could shed further light on the relationship between omega-3 PUFA intake and prefrontal-related cognition. DHA- but not EPA-rich fish oil increased oxy-HB and total-HB in participants performing the Stroop Task as well as tasks measuring executive function, cognitive flexibility, and working memory (Jackson et al., 2012a). These effects were replicated in a subsequent study that compared two doses of DHA-rich fish oil (1 g/day and 2 g/day) to olive oil on a number of cognitive tasks, including those measuring episodic memory, psychomotor performance, executive function, and working memory. Both doses increased oxy-HB during all of the cognitive tasks relative to olive oil and whereas 2 g/day fish oil increased total-HB during all tasks, 1 g/day increased total-HB only during the Stroop Task and a rapid visual information processing task which measured sustained attention. Thus, two studies have found enhanced response inhibition following fish oil relatively high in DHA content (Fontani et al., 2005a; Jackson et al., 2012c). In addition, the influence of fish oil on the performance of the Stroop Task is further evidenced by increased oxy-HB and total-HB across multiple studies and doses (Jackson et al., 2012a c). However, the effects on mood and other cognitive measures are less consistent.

Older Adults Older adulthood poses an additional critical period in cognitive development, as aging is associated with a number of cognitive changes, including decline in episodic and working memory (for a review, see Nyberg et al., 2012). Although cognitive decline often occurs

with normal aging, it may also serve as an early indicator of Alzheimer’s disease (Britton and Rao, 2011). Age-related cognitive impairments range from mild cognitive impairments to intermediate degrees of dementia to more severe cases, as in Alzheimer’s disease. In elderly individuals the estimated prevalence of mild cognitive impairment is 16% (Petersen et al., 2010), while the estimated prevalence of Alzheimer’s disease is 13% (Alzheimer’s Association, 2009) and all forms of dementia is 46% (Wimo et al., 2010). Rates of Alzheimer’s disease are higher in women than in men; however, it is important to note that the gender difference may owe to the fact that women have a longer lifespan than men (Alzheimer’s Association, 2009). Well-established risk factors for Alzheimer’s disease include advancing age, family history of Alzheimer’s disease, and carrying the apolipoprotein E ε4 (APOE ε4) gene as well as modifiable conditions such as hypertension, diabetes, and smoking (Reitz et al., 2010). A number of epidemiological studies as well as RCTs have assessed the relationship between omega-3 PUFA intake and age-related cognitive decline, dementia, and Alzheimer’s disease. We will begin with epidemiological studies and then move to RCTs in: (1) healthy older adults; and (2) individuals with mild cognitive impairment and Alzheimer’s disease.

EPIDEMIOLOGICAL STUDIES: THE ASSOCIATION BETWEEN OMEGA-3 PUFA INTAKE, OMEGA-3 PUFA LEVELS, AND COGNITIVE DECLINE Epidemiological studies assessing the influence of omega-3 PUFAs on cognitive decline in older adults generally measure dietary intake of fatty acids and/or plasma or erythrocyte levels of the fatty acids. Associations with cognitive performance are then determined at one or more time points (Table 25.5). The most common behavior measure utilized in such designs is the Mini Mental State Exam, which measures general cognitive impairment and is often used to characterize mild cognitive impairment or cognitive decline on a discrete yes-or-no basis. For example, older adults completed the Mini Mental State Exam at two time points four years apart, and were put into cognitive decline and no-decline categories. Individuals who had experienced cognitive decline had lower erythrocyte DHA, EPA, omega-3 to omega-6 ratio, DHA:AA ratio, and higher total omega-6 PUFA levels than those who had not experienced cognitive decline (Heude et al., 2003). Other researchers have reported that higher initial levels of plasma EPA and total omega-3 PUFAs are associated with reduced risk of dementia over a four-year follow-up period.

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

TABLE 25.5 Epidemiological Studies Assessing the Association Between Omega-3 PUFAs and Age-Related Cognitive Decline

Authors

Sample n (Female)

Age Range

FollowUp Duration (Years)

Cognitive and Physiological Measures a

b

Results

(Kalmijn et al., 1997)

476 (0)

69 89

3

MMSE , FA intake

Baseline: Higher intake of total fat, PUFAs, and LA and lower intake of total energy, fish, EPA, and DHA associated with cognitive impairment (no association with total omega3 PUFA). 3-year: No association between FA intake and cognitive decline in sample as a whole, but higher intake of LA and lower intake of fish associated with cognitive decline in individuals free of cognitive decline at baseline

(Heude et al., 2003)

246 (143)

63 74

4

MMSE, Erythrocyte FA (baseline only)

Lower DHA, omega-3:omega-6, DHA:AA and higher total omega-6 in individuals showing cognitive decline than no decline

(Laurin et al., 2003)

174 (117)

$65

5

MMSE, DSM-III-Rc dementia diagnosis, Plasma FA (baseline only), APOE ε4 genotype

No association with dementia risk and plasma FA. Lower omega-6 and total PUFAs in individuals with dementia than without (APOE ε4carriers only) Higher DHA in individuals with dementia than without (APOE ε4 non-carriers only) Prospective analysis (only participants free of dementia at baseline): Higher EPA in individuals who developed CIND than those who did not (free of dementia at baseline only). Higher DHA, omega-3 PUFAs, and total PUFAs in individuals who developed dementia than in those who did not (free of dementia at baseline only)

(Whalley et al., 2004)

350 (171)

B64

B53

MHTd (11 years old), MMSE, RPMe, RAVLTf, Uses of Common Objects Test, Digit Symbol Test, Block Design Test, FFQg, Erythrocyte FA, APOE ε4 genotype

No association between childhood IQ and supplement use. Higher IQ and digit symbol score for fish oil, vitamin, and other supplement users than non-users. Higher block design scores in fish oil users than non-users. Higher erythrocyte omega-3 PUFA, EPA, DHA, and omega3:omega-6 associated with higher IQ in childhood and 64 years. Higher erythrocyte AA:DHA associated with higher block design and RPM scores. Higher erythrocyte DHA and DHA:AA associated with higher digit symbol scores

(Huang et al., 2005)

2233 (1306)

$65

0.1 8.4 (mean 5.4)

MMSE, Digit Symbol Test, Benton Visual Retention Test, CES-Dh, ADLsi, TICSj, IQCoDEk, APOE ε4 genotype

No association between risk of dementia or AD and fried fish intake. Reduced risk of dementia and AD in individuals consuming $ 4 servings/week tuna or non-fried fish. (Continued)

TABLE 25.5 (Continued)

Authors

Sample n (Female)

Age Range

FollowUp Duration (Years)

Cognitive and Physiological Measures

Results Reduced risk dementia in $ 2 servings/week fatty fish in individuals (APOE ε4 non-carriers only)

(Morris et al., 2005)

3178 (2306)

$65

3, 6

MMSE, East Boston Tests of Immediate and Delayed Recall, Symbol Digit Modalities Test, Harvard FFQ

Less cognitive decline in individuals who consumed $ 1 serving fish/week. No association between cognitive decline and omega-3 PUFA intake

(Beydoun et al., 2008)

2251 (1141)

45 64

N/A

Delayed Word Recall, Digit Symbol Substitution, Word Fluency, Plasma FA

Higher plasma AA and lower LA associated with GCIl. No associations between plasma omega-3 and GCI. Higher omega-3 PUFAs associated with reduced decline in verbal fluency (individuals with higher hypertensive and dyslipidemic markers and lower depressive symptoms only)

(Dullemeijer et al., 2007)

807 (226)

50 70

3

Concept Shift Test, Stroop Test, Word Learning Test, Letter Reduced 3-year cognitive decline in participants with higher Digit Substitution Test, Verbal Fluency Test, Plasma FAs omega-3 PUFAs (placebo group in RCT). No differences in memory, information processing speed, word fluency. No associations between omega-3 PUFAs and cognitive performance (all participants in RCT)

(van Gelder et al., 2007)

210 (0)

70 89

5, 10

MMSE FFQ

Greater cognitive decline in men who consumed no fish than in men who consumed fish. Greater cognitive decline in lowest than highest tertile of EPA 1 DHA intake

(Samieri et al., 2008)

1214 (748)

$65

2, 4

Dementia diagnosis, CES-D, Plasma FA (baseline only), APOE ε4 genotype

Higher EPA and total omega-3 PUFA associated with reduced risk of dementia. Association between AA:DHA ratio and dementia risk higher in subjects with depression than without

(Whalley et al., 2008)

120 (68)

63.8 65.3

64, 66, 68

MHT (11 years old) Positive association between total omega-3 PUFA and RPM, RAVLT, Uses of Common Objects Test, Digit Symbol cognitive performance at 11 and 64 years (APOE ε4 nonTest, Block Design Test, APOE ε4 genotype carriers only) Erythrocyte FA (64 years only)

(Devore et al., 2009)

5395 (3185)

$55

10

MMSE, GMSm, DSM-III-R dementia diagnosis, Semi quantitative FFQ

No association between fish or omega-3 PUFA intake and risk of dementia

(Kroger et al., 2009)

663 (401)

$65

5, 10

MMSE, DSM-III-R dementia diagnosis, Plasma FA, APOE ε4 genotype

No association between FA and dementia

(van de Rest et al., 2009)

1025 (0)

68 6 X

3, 6

MMSE, Tests of memory, language, perceptual speed, and attentionn, 126-item Willet FFQ

No associations between cognitive performance and omega3 PUFA intake

(Gonzalez et al., 2010)

304 (177)

X(75.3 6 6.7)

N/A

MMSE FFQ

Higher cognitive score associated with higher intake of omega-3 PUFA, EPA, DHA, LNA, and lower omega-6: omega-3 ratio (no differences in total energy, lipids, SFA, MUFA, PUFA or omega-6 PUFA). In regression, higher intake of EPA and DHA and lower intake of omega-6:omega-3 PUFA predicted lower cognitive impairment

(Roberts et al., 2010)

1223 (592) free of 70 89 dementia

N/A

CDRo Scale, Neuropsychological test battery, DSM-IV dementia diagnosis, Modified Block 1995 Revision of the Health Habits History Questionnaire

MCI associated with lower intake of PUFA, omega-6 PUFA, omega-3 PUFA, fatty acids, LA, ALA, and (MUFA 1 PUFA): SFA ratio. Lower risk of MCI associated with higher intake of MUFA (men only)

(Gao et al., 2011)

1475 (969) free of dementia

$55

1.5

MMSE FFQ

Lower cognitive decline associated with omega-3 supplement use

(Milte et al., 2011)

79 (29) With MCI: 50 (16) HC: 27 (13)

$65

MMSE, Memory Functioning Questionnaire, SF-36 Health Survey, GDSp, RAVLT, Stroop Test, Boston Naming Test, Digits Forward, Digits Backward, Letter-Number Sequencing, Trail Making Task Erythrocyte FA

Lower EPA and higher omega-6 PUFAs in individuals with MCI than HC and associated with impaired cognitive performance. Higher DHA associated with impaired self-reported mental health

(Chiu et al., 2012)

132 (96) With history of MDD without cognitive impairment

$60

WAIS-IIIq CTTr, Semantic verbal fluency, Erythrocyte and plasma membrane FA, APOE ε4 genotype

Higher erythrocyte ALA, total omega-3 PUFA associated with greater immediate verbal memory

(Ronnemaa et al., 2012)

2009 (0)

50

Dementia diagnosis , Serum FA (baseline only), APOE ε4 genotype

Higher LA in individuals who developed dementia than in those did not (no difference with omega-3 PUFAs)

a

35

Mini Mental State Exam (MMSE) Fatty acid (FA) Diagnostic & Statistical Manual of Mental Disorders—3rd Edition Revised (DSM-III-R) d Moray House Test (MHT) e Raven’s Standard Progressive Matrices (RPM) f Rey’s Auditory Verbal Learning Test (RAVLT) g Food frequency questionnaire (FFQ) h Center for Epidemiological Studies of Depression Scale (CES-D) i Activities of Daily Living scale (ADLs) j Telephone Interview for Cognitive Status (TICS) k Informant Questionnaire for Cognitive Decline in the Elderly (IQCoDE) l Global cognitive decline (GCI) m Geriatric Mental State schedule (GMS) n Word list memory test, Backward digit span test, Pattern memory, Verbal fluency, Boston Naming Test-short-form, Vocabulary, Pattern comparison, Continuous performance test, Spatial copying task-constructional praxis o Clinical Dementia Rating (CDR) Scale p Geriatric Depression Scale (GDS) q Wechsler Memory Scale (III) (WAIS-III) r Color Trail Test (CTT) X Not Reported b c

318

25. OMEGA-3 FATTY ACIDS AND COGNITIVE BEHAVIOR

Additionally, in this study, depressive symptoms were used as a covariate, a factor which is often overlooked but nevertheless important to consider, given that history of major depressive disorder increases risk of Alzheimer’s disease (Samieri et al., 2008). Other studies have compared cognitive impairment at one time point rather than across multiple years, and have found similar results. Individuals with mild cognitive impairment had lower erythrocyte EPA and higher omega-6 PUFAs than those without mild cognitive impairment. Moreover, erythrocyte levels were associated with performance on cognitive tests (Milte et al., 2011). However, higher erythrocyte DHA levels were associated with lower self-reported mental health, suggesting that enhanced cognitive performance does not necessarily equate to enhanced subjective wellbeing. The previous studies point to a positive association between omega-3 PUFA levels and global cognitive function in older adults, although other studies have failed to correlate omega-3 PUFA levels with performance in specific cognitive domains. For instance, higher erythrocyte ALA and total omega-3 PUFAs were associated with enhanced verbal memory, but in the same study no associations were found between fatty acid levels and other cognitive measures including intelligence, attention, psychomotor speed, and executive function (Chiu et al., 2012). Higher plasma omega-3 PUFA levels were associated with reduced global cognitive decline over a three year period, though no differences were found in specific cognitive domains such as executive function, memory or visual information processing (Dullemeijer et al., 2007). The association between plasma fatty acid levels and cognitive decline may also depend on other health-related factors, including cardiovascular and psychological impairments. For instance, plasma omega-3 PUFAs were associated with reduced decline in verbal fluency in individuals with higher hypertensive and dyslipidemic markers, and in individuals with lower depressive symptoms (Beydoun et al., 2007). In an attempt to determine the relationship between fatty acids and cognitive decline, other cross-sectional and prospective studies have measured dietary intake of fatty acids. For instance, higher intake of total fat, PUFAs, and LA and lower intake of total energy, fish, EPA, and DHA were associated with lower cognitive scores at baseline, however, only individuals initially free of cognitive impairment showed associations between high LA and lower fish intake and cognitive decline (Kalmijn et al., 1997). Across six years, individuals who consumed at least one serving per week of fish showed less cognitive decline, but no association was found between total omega-3 PUFA intake and cognitive decline (Morris et al., 2005). Across ten years, individuals who consumed fish and those in the

highest tertile of EPA and DHA intake experienced less cognitive decline than those who consumed less fish, EPA, and DHA (van Gelder et al., 2007). Additionally, lower cognitive impairment was associated with higher intake of EPA and DHA and lower intake of omega-6 versus omega-3 PUFAs (Gonzalez et al., 2010) as well as the use of omega-3 PUFA supplements (Gao et al., 2011). Mild cognitive impairment was associated with lower intake of total omega-3 and omega-6 PUFAs, as well as LA and ALA (Roberts et al., 2010). Thus, although data from food frequency questionnaires give us some indication that increased omega-3 PUFA intake is associated with reduced cognitive decline, the reliability of such measures is questionable, given the inconsistencies in many studies, e.g. correlations between cognitive function and fish but not omega-3 PUFA intake (Morris et al., 2005). Using retrospective data, Whalley and colleagues (2004, 2008) correlated intelligence scores of individuals measured when they were 11 years of age with their intelligence scores, cognitive behavior, and erythrocyte fatty acid levels at 64 years of age. Higher erythrocyte total omega-3 PUFAs, EPA, DHA, and omega-3 to omega-6 ratio at 64 years of age were associated with higher IQ at both 11 and 64 years of age. Moreover, 1) a higher erythrocyte AA to DHA ratio was associated with higher constructional ability and nonverbal reasoning at 64 years of age and 2) older adults who consumed fish oil supplements had higher IQ, psychomotor performance, and constructional ability than those who did not use supplements (Whalley et al., 2004). In a subsequent study, the positive association between erythrocyte total omega-3 PUFA levels and cognitive performance at 11 and 64 years was found to be stronger for individuals who did not carry the APOE ε4 gene than for APOE ε4 carriers (Whalley et al., 2008). The results suggest that omega-3 PUFA intake and levels may have greater beneficial effects for individuals not already at increased risk for Alzheimer’s disease by carrying the APOE ε4 gene. Genetic variations located near the APOE ε4 gene are most consistently associated with Alzheimer’s disease, particularly the late onset form of the disease (Bertram and Tanzi, 2008). Indeed, another study found that APOE ε4 noncarriers who consumed at least two servings per week of fish were at reduced risk for dementia, but no such association was found for APOE ε4 carriers. Across all subjects, only those who consumed more than four servings per week of non-fried fish or tuna had a reduced risk of dementia and Alzheimer’s disease (Huang et al., 2005). Although these studies focus on the APOE gene associated with late-onset Alzheimer’s disease, future studies should also address correlations with genes associated with early-onset Alzheimer’s disease, including PSEN1, PSEN2, and APP (Rao et al., 2013).

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

EPIDEMIOLOGICAL STUDIES: THE ASSOCIATION BETWEEN OMEGA-3 PUFA INTAKE, OMEGA-3 PUFA LEVELS, AND COGNITIVE DECLINE

Despite the evidence above that omega-3 PUFA intake may confer protection against age-related cognitive decline, other studies have failed to find such effects. A number of studies found no association between the risk of dementia and fish or omega-3 PUFA intake (Devore et al., 2009; van de Rest et al., 2009) or serum or plasma fatty acid levels (Kroger et al., 2009; Ronnemaa et al., 2012). Some studies have even found negative associations between omega-3 PUFA intake and cognitive performance in older adults. In individuals initially free of dementia, plasma EPA levels were higher in those who developed cognitive impairment than those who did not, and plasma DHA, total omega-3 PUFA, and total PUFA levels were higher in those who developed dementia than those who did not. When all subjects beginning with and without dementia were analyzed together, plasma fatty acids were not associated with dementia. However, higher plasma DHA and lower total omega6 PUFA and total PUFA levels were associated with dementia in APOE ε4 carriers only (Laurin et al., 2003). Thus, although evidence from epidemiological studies is somewhat inconsistent, with some studies failing to find associations, a larger number of studies suggest that higher omega-3 PUFA intake and/or blood levels are associated with lower risk of age-related cognitive decline.

RCTs: Healthy Older Adults Conclusions drawn from epidemiological studies are limited to possible associations between omega-3 PUFAs and cognitive decline, whereas RCTs are necessary to determine whether increased omega-3 PUFA intake plays a causal role in reducing cognitive decline. A number of studies have assessed the influence of omega-3 PUFA supplementation on cognitive function in healthy older adults (Table 25.6). DHA improved aspects of verbal, visuospatial, and episodic memory (Johnson et al., 2008; Yurko-Mauro et al., 2010). These results were supported by physiological data showing associations between higher serum DHA and improved verbal fluency (Johnson et al., 2008), and between higher plasma DHA and improved visuospatial and episodic memory (Yurko-Mauro et al., 2010). Similar to results from epidemiological studies in which omega-3 PUFA levels were differentially associated with cognitive decline between APOE ε4 carriers and non-carriers (Huang et al., 2005; Whalley et al., 2008), low and high doses of EPA and DHA (i.e. 226 mg EPA 1 176 mg DHA and 2093 mg EPA and 847 mg DHA, respectively) enhanced attention relative to placebo only in APOE ε4 carriers (van de Rest et al., 2008). However, a lower dose of DHA

319

(i.e. 252 mg/day DHA compared to 800 mg/day and 900 mg/day in Johnson et al. (2008) and Yurko-Mauro et al. (2010), respectively) did not influence cognitive function (Stough et al., 2012). The discrepancy in results may be due to methodological differences in the Stough and colleagues (2012) study design, including differences in DHA dose, treatment duration (limited to 90 days), or wide age range (45 77 years). Nonetheless, the majority of research to date points to a beneficial influence of omega-3 PUFA, and particularly DHA, intake on cognitive function in older adults.

RCTs: Older Adults with Mild Cognitive Impairment or Alzheimer’s Disease Evidence suggests omega-6 PUFAs exacerbate β-amyloid deposition, a hallmark outcome of Alzheimer’s disease, and omega-3 PUFAs (or low omega-6 to omega-3 ratios) may reduce the effects (Corsinovi et al., 2011). Yet few RCTs have evaluated whether omega-3 PUFA supplementation results in behavioral changes in mild cognitive impairment and Alzheimer’s disease, and results are largely inconsistent (Table 25.7). Omega-3 PUFAs had few cognitive effects in individuals with a range of Alzheimer’s disease severity. However, omega-3 PUFAs prevented declines in memory in samples of individuals with either mild or severe Alzheimer’s disease (Freund-Levi et al., 2006). Additionally, omega-3 PUFAs reduced depressive symptoms in individuals with Alzheimer’s disease more in APOE ε4 non-carriers than carriers (Freund-Levi et al., 2008). DHA-rich fish oil has been shown to improve verbal fluency in individuals with mild cognitive impairment, and both EPA- and DHArich fish oil improved depressive symptoms, a result further supported by associations between higher erythrocyte DHA 1 EPA and lower AA:EPA levels and improved depressive symptoms (Sinn et al., 2012). In a small study of individuals with mild to moderate Alzheimer’s disease or mild cognitive impairment, omega-3 PUFAs improved global clinical Alzheimer’s disease status. Although no differences in cognitive impairment were found, higher red blood cell membrane EPA was associated with improved cognitive Alzheimer’s disease symptoms (Chiu et al., 2008). However, other researchers failed to find cognitive effects of omega-3 PUFA supplementation in individuals with mild to moderate Alzheimer’s disease (Quinn et al., 2010). A recent meta-analysis summarized the effects of RCTs evaluating the influence of omega-3 PUFAs on cognitive performance in healthy adults and those with cognitive impairment but no dementia and those with Alzheimer’s disease

OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

TABLE 25.6 Randomized Controlled Trials Assessing the Influence of Omega-3 PUFA Supplementation on Cognitive Function in Healthy Older Adults

Authors

Sample n Age Range (Female) (Mean 6 SD)

Omega-3 PUFA Manipulation

Duration (Weeks)

Cognitive Measures

Results

Verbal Fluency, Digit Span Forward and Backward, Shopping Test Task, Word List Memory Test, Memory in Reality Apartment Test, Stroop Test, NES2 Mood Scales: selfreported mood

DHA, lutein, DHA 1 lutein . control verbal fluency. DHA 1 lutein , control response time on Shopping List Memory Test, delayed recall in Memory in Reality Apartment Test

(Johnson et al., 2008)

49 (49)

60 80 DHA: 68.5 6 1.3 Lutein: 66.7 6 1.9 DHA 1 lutein: 68.6 6 1.3 Control: 68.0 6 1.2

800 mg/day DHA versus 12 mg/day lutein versus DHA 1 lutein versus placebo

(van de Rest et al., 2008)

196 (88)

65 High EPA-DHA: 69.9 6 3.4 Low EPADHA: 69.5 6 3.2 Control: 70.1 6 3.7

900 mg/day fish oil high EPA-DHA 26 (226 6 3 mg EPA, 176 6 4 mg DHA) versus low EPA-DHA (2093 6 17 mg EPA, 847 6 23 mg DHA) versus sunflower oil

Verbal Fluency, Word Learning Test, Digit Span Forward and Backward, Trail Making Test version A and B, Stroop Test

Low EPA-DHA , control memory at 13 but not 26 weeks. Low and high EPADHA . control attention at 26 weeks in APOE ε4 carriers only. Low EPA-DHA . control attention at 26 weeks in men only

(YurkoMauro et al., 2010)

485 (282)

$ 55 DHA: 70 6 9.3 Control: 70 6 8.7

Algal triglyceride oil (900 mg/day DHA) versus corn 1 soybean oil

24

WAIS-IIIa logical memory, MMSEb, CANTABc Subtests: PALd, PRMe, VRMf, SOCg, SWMh, Frequency of Forgetting-10 Scale, ADCS-ADL PIi, GDSj

DHA . control CANTAB PAL, VRM

(Stough et al., 2012)

74 (43)

45 77 DHA: 55.08 6 8.70 Control: 57.66 6 8.67

1000 mg/day tuna oil (252 mg DHA, 60 mg EPA) versus soybean oil

90 days

STAIk, CDR assessmentl

No differences in CDR factors

a

Wechsler Memory Scale (III) (WAIS-III) Mini Mental State Exam (MMSE) c Cambridge Neuropsychological Test Automated Battery (CANTAB) d Paired Associative Learning (PAL) e Pattern Recognition Memory (PRM) f Verbal Recognition Memory (VRM) g Stockings of Cambridge (SOC) h Spatial Working Memory (SWM) i Alzheimer’s Disease Cooperative Study-Activities of Daily Living Prevention Instrument (ADCS-ADL PI) j Geriatric Depression Scale (GDS) k State Trait Anxiety Inventory (STAI) l Cognitive Drug Research (CDR) assessment b

16

TABLE 25.7 Randomized Controlled Trials Assessing the Influence of Omega-3 PUFA Supplementation on Cognitive Function in Older Adults with Mild Cognitive Impairment or Alzheimer’s Disease Sample n Authors (Female)

Age Range (Mean 6 SD)

Omega-3 PUFA Manipulation

Duration (Weeks)

Cognitive Measures b

c

Results d

(Freund- 204 (110) Levi ADa et al., 2006)

Omega-3 PUFA: 72.6 6 9.0 Placebo: 72.9 6 8.6

(Chiu et al., 2008)

Omega-3 Omega-3 PUFA (1080 mg EPA, PUFA: 720 mg DHA) versus olive oil 70.1 77.8 (74.0) Placebo: 71.8 81.1 (76.5)

24

(Freund- 204 (90) AD Levi et al., 2008)

Omega-3 PUFA: 72.6 6 9.0 Placebo: 72.9 6 8.6

Omega-3 PUFA (600 mg EPA, 1700 mg DHA) versus corn oil

24 (1 24 weeks NPIh, MADRSi, CGBj, DADk open label omega-3 for all participants)

(Quinn et al., 2010)

402 (210) mildmoderate AD

Omega-3 PUFA: 76 6 9.3 Placebo: 76 6 7.9

2 g Algal DHA (0.9 1.1 g DHA) versus corn or soy oil

72

MMSE (baseline only), ADAS-cog, CDR, ADCSADLl, Quality of Life of Alzheimer’s Disease Scale

No differences

(Sinn et al., 2012)

50 (16) MCI 65 EPA-rich FO: 74.88 6 5.06 DHA-rich FO: 74.22 6 7 Control: 73 6 3.96

EPA-rich fish oil (1.67 g EPA, 0.16 g DHA) versus DHA-rich fish oil (1.55 g DHA, 0.4 g EPA) versus safflower oil (2.2 g LA)

24

GDSm, SF-36 Health Survey: health and quality of life, RAVLTnWAIS-IIIo (Digits Forward, Boston Naming Task, Letter-Number Sequencing, Digits Backward), Trail-Making Task, Stroop Test, Verbal Fluency

EPA, DHA . LA depressive symptoms. DHA . LA verbal fluency. No differences in quality of life

a

43 (20) mildmoderate AD (23) or MCIe (23)

Omega-3 PUFA (150 mg EPA, 430 mg DHA) versus corn oil

Alzheimer’s disease (AD) Mini Mental State Exam (MMSE) c Cognitive portion of Alzheimer’s Disease Assessment Scale (ADAS-cog) d Clinical Dementia Rating (CDR) Scale e Mild cognitive impairment (MCI) f Clinician’s Interview-Based Impression of Change (CIBIC) Scale g Hamilton Depression Rating Scale (HDRS) h Neuropsychiatric Inventory (NPI) i Montgomery A˚sberg Depression Rating Scale (MADRS) j Caregiver Burden Scale (CGB) k Disability Assessment for Dementia Scale (DAD) l ADCS Activities of Daily Living (ADCS-ADL) Scale m Geriatric Depression Scale (GDS) n Rey Auditory Verbal Learning Test (RAVLT) o Wechsler Memory Scale (III) (WAIS-III) b

24 (1 24 weeks MMSE , ADAS-cog , CDR open label omega-3 for all participants)

ADAS-cog, CIBICf, HDRSg

No differences in MMSE or ADAScog across all participants. Omega-3 . control MMSE delayed recall, attention (very mild AD). Omega-3 . control ADAS-cog delayed recall (severe AD) Omega-3 . control CIBIC. No differences in ADAS-cog, MMSE, HDRS

322

25. OMEGA-3 FATTY ACIDS AND COGNITIVE BEHAVIOR

(Mazereeuw et al., 2012), and found more support for a beneficial effect of omega-3 PUFAs in studies focusing on cognitive impairment without dementia than on healthy or Alzheimer’s populations. The majority of evidence of a beneficial effect of omega-3 supplementation on Alzheimer’s disease progression comes from epidemiological trials whereas RCTs are less conclusive. Thus, additional RCTs are necessary to determine whether omega-3 PUFA supplementation may prevent or reverse age-related cognitive decline, specifically Alzheimer’s disease (Barberger-Gateau et al., 2011).

CONCLUSION Multiple studies have found positive effects of maternal and formula supplementation on infant cognitive development, particularly in problem solving, memory, and language development (Drover et al., 2011; Helland et al., 2003; Henriksen et al., 2008; Lauritzen et al., 2005; Meldrum et al., 2012). However, others have found no differences, suggesting that although omega-3 PUFA supplementation may not influence global cognitive development among infants, it may aid particular cognitive functions. The opposite may be true in older adults, as prospective and crosssectional studies suggest that higher omega-3 PUFA intake and plasma levels are associated with reduced overall cognitive decline with less evidence for specific cognitive domains (e.g. Heude et al., 2003; Milte et al., 2011; Samieri et al., 2008). Epidemiological results are supported by some RCTs showing that omega-3 PUFA supplementation, particularly DHA, reverses agerelated cognitive decline in otherwise healthy individuals (Johnson et al., 2008; van de Rest et al., 2008; Yurko-Mauro et al., 2010), but there is less evidence to suggest such an effect in individuals with mild cognitive impairment and Alzheimer’s disease. Alzheimer’s disease risk factors including history of depression and carrying the APOE ε4 gene may influence the efficacy of omega-3 PUFAs in preventing cognitive decline in older adults (Heude et al., 2003; Huang et al., 2005; Whalley et al., 2008). Research in young adults remains fairly limited, and although some data suggest positive effects of omega-3 PUFA supplementation on mood and executive function (Fontani et al., 2005a,b), other studies have failed to replicate these effects. Thus, though the evidence to date points to a beneficial influence of omega-3 PUFAs on cognitive performance across the lifespan, the conclusions remain tenuous, and additional research is necessary to more fully tease apart which omega-3 PUFAs are most beneficial to which cognitive processes at which stage of life, as well as to more fully understand the mechanism by which omega-3 PUFAs may influence brain function.

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OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH

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OMEGA-3 FATTY ACIDS IN BRAIN AND NEUROLOGICAL HEALTH