Role of fruits, nuts, and vegetables in maintaining cognitive health

Role of fruits, nuts, and vegetables in maintaining cognitive health

    Role of Fruits, Nuts, and Vegetables in Maintaining Cognitive Health Marshall G. Miller, Nopporn Thangthaeng, Shibu M. Poulose, Barba...

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    Role of Fruits, Nuts, and Vegetables in Maintaining Cognitive Health Marshall G. Miller, Nopporn Thangthaeng, Shibu M. Poulose, Barbara Shukitt-Hale PII: DOI: Reference:

S0531-5565(16)30606-4 doi:10.1016/j.exger.2016.12.014 EXG 9958

To appear in:

Experimental Gerontology

Received date: Revised date: Accepted date:

21 October 2016 14 December 2016 16 December 2016

Please cite this article as: Miller, Marshall G., Thangthaeng, Nopporn, Poulose, Shibu M., Shukitt-Hale, Barbara, Role of Fruits, Nuts, and Vegetables in Maintaining Cognitive Health, Experimental Gerontology (2016), doi:10.1016/j.exger.2016.12.014

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Review

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Role of Fruits, Nuts, and Vegetables in Maintaining Cognitive Health Marshall G. Millera

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[email protected]

[email protected]

Shibu M. Poulosea

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[email protected]

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Nopporn Thangthaenga

Barbara Shukitt-Halea

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USDA-ARS Human Nutrition Research Center on Aging at Tufts University 711 Washington Street Boston, MA 02111 USA

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a.

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[email protected]

Word Count: 3,851

Conflicts of Interest: None

Note: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Correspondence: Barbara Shukitt-Hale, Ph.D. USDA-ARS, HNRCA at Tufts University 711 Washington Street Boston, MA 02111 Tel: 617-556-3118; Fax: 617-556-3299 E-Mail: [email protected]

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Abstract Population aging is leading to an increase in the incidence of age-related cognitive dysfunction

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and, with it, the health care burden of caring for older adults. Epidemiological studies have shown that consumption of fruits, nuts, and vegetables is positively associated with cognitive

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ability; however, these foods, which contain a variety of neuroprotective phytochemicals, are

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widely under-consumed. Surprisingly few studies have investigated the effects of individual

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plant foods on cognitive health but recent clinical trials have shown that dietary supplementation with individual foods, or switching to a diet rich in several of these foods, can improve cognitive

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ability. While additional research is needed, increasing fruit, nut, and vegetable intake may be an

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Highlights

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effective strategy to prevent or delay the onset of cognitive dysfunction during aging.



Population aging is increasing the incidence of age-related cognitive dysfunction



Many fruits, nuts, and vegetables are neuroprotective yet widely under-consumed



Intake of these foods is positively associated with cognitive ability



Dietary supplementation with these foods can improve cognitive ability



Increasing fruit, nut, and vegetable intake may forestall cognitive dysfunction

Keywords Fruits, nuts, vegetables, cognition, brain, aging

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1.0 Introduction Many developed nations are currently undergoing a rapid demographic shift toward an

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aging population, and the incidence of age-related cognitive decline and neurodegenerative diseases, along with morbidity and chronic disability, are predicted to increase dramatically in

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coming years. A systematic analysis of descriptive epidemiology of nearly 291 diseases indicates

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a greater than 100-fold increase in the incidence of neurological disease from 1990-2010, with

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diet composition being the largest risk factor (Murray and others 2013). While there is a lack of effective treatments or cures for age-related cognitive decline and neurodegenerative disease,

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there is a large interest in dietary approaches to maintaining better cognitive health. Ancient medicine largely prescribed combinations of fruits, vegetables, nuts, herbs,

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spices, and their extracts to treat specific ailments (Totelin 2015). In recent years, numerous

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preclinical studies involving fruits, nuts, and vegetables have identified potential beneficial

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effects to brain health and cognition resulting from their nutrient and non-nutrient phytochemical content. These phytochemicals have the ability to alter cellular function by modulating transcription factors and altering the expression of genes, cellular metabolism, and cellular signaling (Traka and Mithen 2011; Tsao 2010). In vitro and in vivo studies have firmly established the mechanistic effects of these phytochemicals on cognitive function, with many studies demonstrating their ability to counter oxidative stress (Shukitt-Hale and others 2008; Thangthaeng and others 2016) and inflammation (Heim and others 2012; Lau and others 2007), as well as promote neuronal signaling (Miller and Shukitt-Hale 2012b; Poulose and others 2012; Rendeiro and others 2015) and regulate transcription (Milenkovic and others 2013). These bioactive properties have the potential to prevent or delay brain aging (Baldrick and others 2011). The World Health Organization (WHO) recommends a daily intake of five to eight portions (400–600 g) of fruits and vegetables to reduce the risk of micronutrient deficiencies,

ACCEPTED MANUSCRIPT 4 cardiovascular disease, cancer, cognitive impairment, and other diet-related health conditions (Rodriguez-Casado 2016). However, during 2007–2010, half of the total U.S. population

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consumed less than 1 cup of fruit and less than 1.5 cups of vegetables daily; in other words, 76% did not meet recommended fruit intake and 87% did not meet vegetable intake recommendations

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(NCI 2015). Increasing the consumption of fruits and vegetables to align with the recommended

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intake levels could be an initial step in reducing the risk of cognitive decline and may provide

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opportunities to reduce the risk of age-related brain disorders with an effectiveness that is currently underestimated. This review outlines the most recent literature addressing the benefits

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of fruits, nuts, and vegetable on human cognitive health.

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on cognition

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2.0 Epidemiological evidence for protective effects of fruits, nuts, and vegetables

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Epidemiological studies that have focused on fruit and vegetable intake and cognitive function have largely found that their consumption can prevent cognitive decline. Similarly, a low intake of vegetables and legumes was associated with increased cognitive decline among illiterate Chinese older adults (Chen and others 2012), and low fruit and green tea consumption were associated with cognitive impairment in Japanese outpatients (Kitamura and others 2016). In a systematic review of cohort studies prior to 2012, Loef and Walach (Loef and Walach 2012) concluded that increased intake of vegetables was associated with a lower risk of dementia and a slower rate of cognitive decline in old age; however, there was less evidence for such an association for fruits. Their review included nine studies with a follow-up of 6 months or longer. Five of the six studies that analyzed fruit and vegetable consumption separately found that higher consumption of vegetables, but not fruit, was associated with a decreased risk of cognitive decline or dementia. The one study with negative results found that, although cognitive decline was not associated with higher intake of either fruits or vegetables, improved activities of

ACCEPTED MANUSCRIPT 5 daily living were associated with higher intake of vegetables. The remaining three studies which looked at combined fruit and vegetable consumption found reduced risk of dementia among

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those with higher intakes. In these studies, the vegetables most associated with slower cognitive decline included cruciferous vegetables, legumes, and green leafy vegetables, particularly

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cabbage, zucchini, squash, broccoli, and lettuce, at a daily intake of three servings (200g) a day

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(Loef and Walach 2012). The authors speculate that these beneficial effects might be due to

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higher intake of flavonoids or antioxidants in both fruits and vegetables, or increased vitamin E in vegetables, compared to fruits, which have more vitamin C. Furthermore, people frequently

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consume vegetables with added fats (e.g., oils) which may aid in absorption of other nutrients (Loef and Walach 2012).

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Another review, which updated and added to this previous review, examining the

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cognitive effects of fruit, vegetable, and juice consumption, confirmed that findings from seven

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longitudinal studies of healthy older adults suggest that fruit, and particularly vegetable consumption, may reduce the rate of cognitive decline (Lamport and others 2014). They also showed evidence from four longitudinal studies that a diet high in fruits and vegetables may reduce the risk of developing neuropsychological disease (Lamport and others 2014). Positive associations between fruit and vegetable intake and cognition were also observed in six of eight cross-sectional studies, although the strength of the association was weaker than those of the longitudinal epidemiology studies, which is not surprising given that cross-sectional studies look at a single point in time, whereas longitudinal studies make comparisons over time (Lamport and others 2014). Consumption of a Mediterranean Diet, which features high fruit and vegetable intake, has also been associated with decreased risk of cognitive impairment based on several observational studies [for reviews see (Feart and others 2015; Yannakoulia and others 2015)]. In contrast, other studies have found no association between adherence to the Mediterranean Diet and

ACCEPTED MANUSCRIPT 6 prospectively assessed measures of cognitive decline (Feart and others 2015; Yannakoulia and others 2015). The explanation for the discrepancies between studies is not known, although the

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contribution of other lifestyle behaviors related to the Mediterranean way of life, such as social interaction, sleep quality, and exercise have also been associated with cognition and may be a

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mitigating factor (Yannakoulia and others 2015), as may socioeconomic status (Feart and others

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2015).

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To determine the contribution of the Nurses’ Health Study in identifying the role of lifestyle, diet, and genetic or biological factors in several neurodegenerative diseases, including

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cognition, Dr. Grodstein’s group at Harvard University (Hagan and others 2016) reviewed publications from this large cohort study published between 1976 and 2016. They found that a

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higher intake of nuts, moderate alcohol consumption, and higher physical activity levels were

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associated with better cognitive function and that flavonoids, physical activity, and

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postmenopausal hormone therapy were related to slower cognitive decline over 2 to 6 years. Specific to this review, one study found that increased intake of blueberries and strawberries, as well as increased intakes of anthocyanidins and total flavanoids, were associated with slowing the rate of cognitive decline by up to 2.5 years (Devore and others 2012). They also found that higher long-term nut intake, particularly walnuts, was associated with better cognitive function, and women consuming at least 5 servings of nuts/week had better scores equivalent to approximately 2 years of cognitive aging (O’Brien and others 2014). Another study found a positive association between a carotenoid-rich dietary pattern (composed of orange- and greencolored fruits and vegetables) in midlife and subsequent cognitive function, particularly executive functioning and episodic memory (Kesse-Guyot and others 2013a). Recent research has, therefore, focused on both the whole foods found in these fruit- and vegetable-rich diets and the wide variety of phytochemicals found within them, particularly phenolics.

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3.0 Clinical evidence for protective effects of individual fruits, nuts, and vegetables on cognition

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Current epidemiological evidence shows that overall intake of fruits, nuts, and vegetables

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is associated with mental health, but surprisingly few clinical trials have been conducted to

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examine the individual effects of these foods on cognition. Within this literature, berry fruit have received considerable attention due to their high concentrations of antioxidant and anti-

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inflammatory phytochemicals. A growing body of preclinical evidence supports the

see (Miller and Shukitt-Hale 2012a)].

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neuroprotective and beneficial effects of dietary berry fruit on the brain and cognition [for review

Grapes and their byproducts have a long history of medicinal use and are among the most

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consumed and best-studied berry fruit (Singh and others 2015). An initial double-blind, placebocontrolled, crossover study (Hendrickson and Mattes 2008) including thirty-five young (mean

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age 26 years) smokers found no acute effect of Concord grape juice (10 mL/kg) on cognition. However, subsequent studies in older adult populations have shown efficacy. In a randomized, double-blind, placebo-controlled study (Krikorian and others 2010a), twelve older men and women (mean age 78.2 years) with mild memory decline consumed Concord grape juice (6-9 mL/kg/d) or a placebo beverage. Following 12 weeks of supplementation, participants that consumed grape juice showed improved verbal learning and trended toward improved verbal recall. A subsequent randomized, double-blind, placebo-controlled study (Krikorian and others 2012) of twenty-one older men and women (mean age 76.9 years) with mild cognitive impairment, and being treated for hypertension, compared cognition prior to and following 16 weeks of supplementation with Concord grape juice (6.3-7.8 ml/kg/d) or placebo. At the end of the trial, participants that had consumed grape juice committed significantly fewer intrusion errors on a word list learning task, relative to placebo controls, indicating better ability to discriminate learned list words from non-list foils, a measure of executive function. Furthermore,

ACCEPTED MANUSCRIPT 8 functional magnetic resonance imaging (fMRI) revealed greater activation in two brain areas that are associated with working memory (right superior parietal and right middle frontal cortices)

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among participants consuming grape juice, relative to placebo controls, during an n-back task. In a recent study (Lamport and others 2016), twenty-five working mothers (40-50 years) completed

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a battery of cognitive tests and were evaluated in a driving simulator following 12 weeks of daily

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Concord grape juice (335 mL) or placebo consumption in a randomized, double-blind, crossover

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trial. Following treatment with grape juice, participants showed improved recall on a spatial learning test as well as improved accuracy in maintaining following distances in the driving

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simulator, relative to treatment with the placebo.

Blueberry is another commonly consumed berry fruit. Preclinical research, over the past

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decade, has shown that blueberry has a variety of potentially beneficial antioxidant, anti-

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inflammatory, and neuroprotective effects (Pribis and Shukitt-Hale 2014). One clinical study

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evaluated dietary blueberry evaluated in a blinded study involving sixteen older men and women with age-related memory decline (mean age 76.2 years) who consumed either blueberry juice (69 mL/kg/d) or a grape placebo juice for 12 weeks (Krikorian and others 2010b). Participants that consumed blueberry juice significantly improved word list recall and paired associate learning, relative to baseline, with paired associate learning also significantly improved relative to placebo controls. Another study examined the acute effect of blueberry in fourteen healthy children [8-10 years; (Whyte and others 2015)]. Participants completed a battery of cognitive tests following consumption of a beverage containing 200g of blueberry or a placebo beverage, in a crossover study design. The children showed significantly better word-list recall following a 25 min delay on the Rey auditory-verbal learning test. A staple of eastern medicine, Goji berry (Lycium barbarum), sometimes known as “wolfberry,” has recently enjoyed a growth in popularity in the United States. Preclinical research has shown that Goji berries have potential antioxidant and neuroprotective effects (Li

ACCEPTED MANUSCRIPT 9 and others 2002; Li and others 2007; Wu and others 2004). In a randomized, double-blind, placebo-controlled study (Amagase and Nance 2008), thirty-four men and women consumed

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either Goji berry juice (GoChi™; 120 mL/d) or a placebo beverage. After 14 days of supplementation, participants that consumed Goji berry juice reported increased focus on

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activities, calmness, and positive affect along with reduced feelings of fatigue and stress, relative

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to baseline. However, further research is required to demonstrate the efficacy of Goji berry

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supplementation on cognition.

Cranberry was also evaluated in a double-blind, placebo-controlled, randomized trial

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(Crews Jr and others 2005) in which fifty healthy men and women (mean age 69 years) consumed either 27% cranberry juice (32 oz/d) or a placebo beverage. After 6 weeks, no

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significant effect of cranberry on cognition was observed; however, the authors reported a non-

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significant trend toward an improvement in self-reported memory ability.

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While berry fruit have been a focal point for clinical research into dietary interventions for brain health, other plant foods have also been evaluated. In a randomized, double-blind, placebo-controlled crossover study (Kean and others 2015), 37 healthy older men and women (mean age 66.7 years) consumed dilute orange juice (500 mL/d) or an orange-flavored placebo beverage for 8 weeks. While overall cognitive function declined for participants that consumed the placebo, dietary supplementation with orange juice significantly improved overall cognitive function following 8-weeks of supplementation, relative to placebo. A similar significant treatment by time point interaction was observed for tests of executive function. Other commonly consumed fruit have also shown potential brain health benefits. In a randomized, controlled crossover study (Bondonno and others 2014), thirty men and women (mean age 47.3 years) were given a single dose of 1) low-flavonoid apple flesh (120 g) and lownitrate rice milk, 2) high-flavonoid apple skin (80 g) and flesh (120 g) and low-nitrate rice milk, 3) low-flavonoid apple flesh (120 g) and high nitrite spinach (200 g), or 4) high-flavonoid apple

ACCEPTED MANUSCRIPT 10 skin (80 g) and flesh (120 g) and high nitrite spinach (200 g), with a 1-week washout in between each condition. However, a computerized battery of cognitive tests revealed no significant

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effects of this acute supplementation on cognition. A prior open-label trial (Remington and others 2010) that included 21 institutionalized men and women (mean age 82 years) who

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consumed apple juice for 1 month showed no effects on cognitive measures; however, caregivers

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reported an improvement in behavioral and psychotic symptoms associated with dementia.

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Conversely, beets, another dietary source of nitrates, have been shown to produce an acute effect on cognition. In a randomized, double-blind, placebo-controlled study (Wightman

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and others 2015), forty healthy adults (mean age 21.3 years) consumed either organic beetroot juice (450 mL) or a blackcurrant-flavored placebo drink. Ninety minutes following ingestion,

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participants that consumed beetroot juice showed improved performance during serial 3

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subtractions and altered prefrontal hemodynamic response to the cognitive tasks, as measured by

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near-infrared spectroscopy, relative to the placebo. In light of these mixed results, further research will be required to verify the acute and chronic effects of dietary nitrate on cognition. Mushrooms have also been investigated for potential neuroactive effects. In a randomized, double-blind, placebo-controlled trial (Mori and others 2009), thirty older men and women (50-80 yo) consumed either yamabushitake mushroom tablets (3 doses/d; 3,000 mg/d total) or placebo tablets for 16 weeks. Participants that consumed mushroom tablets scored significantly higher on the Revised Hasegawa Dementia Scale (Imai and Hasegawa 1994) in weeks 8-16, relative to placebo controls and baseline performance, indicating improved cognitive function. Four weeks after stopping the intervention, the improvements observed among mushroom consumers were attenuated, relative to week 16, but still significantly better than baseline or those of placebo controls. Walnuts are a commonly consumed nut that has been the focus of recent research into their cardioprotective and neuroprotective abilities (Poulose and others 2014). In a randomized,

ACCEPTED MANUSCRIPT 11 placebo-controlled, crossover trial (Pribis and others 2012), sixty-four men and women (18-25 yo) consumed either banana bread with or without walnuts (60g/d) for 8 weeks with a 6-week

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washout period. Participants showed significant improvement in inference scores on the WatsonGlaser Critical Thinking Appraisal after consuming banana bread with walnuts, but not after

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consuming banana bread without nuts.

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4.0 Clinical evidence for effects of diets rich in fruits, nuts, and vegetables on cognition

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Based on numerous epidemiological and individual fruit and vegetable supplementation studies, there is compelling evidence that a dietary pattern rich in fruits and vegetables supports

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cognitive health improvement. One of the earliest randomized controlled clinical studies using a whole dietary pattern as an intervention to prevent cognitive decline in older adults was

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performed by Kwok and colleagues (Kwok and others 2012). In this study, 429 cognitively normal older adults (average age of 83 years) from 14 different old age hostels were assigned to receive either advice on the hostel menu only or regular group dietary counseling and menu changes to the “brain preservation diet,” which includes 5 portions of fish per week, 2 portions of fruits and 3 portions of vegetables per day, and reduction in salt intake, for 33 months. Each participant was given a battery of cognitive tests prior to the intervention, at the 24-month follow-up and again at the end of the study. After controlling for confounding factors, the dietary intervention failed to yield a significant reduction in cognitive decline. However, several prospective studies indicated that high adherence to a Mediterranean dietary pattern (MedDiet) is associated with a reduction in the rate of cognitive decline, improvement in cognitive outcomes (independent of cardiovascular disease risk factors), and preservation of cognitive function in populations with mild cognitive impair (MCI) or family history of dementia who are at risk for Alzheimer’s disease (Hardman and others 2016; Knight

ACCEPTED MANUSCRIPT 12 and others 2016a; Trichopoulou and others 2015). Recently, Hardman and colleagues performed a qualitative evaluation and systematic literature review of longitudinal and prospective trials to

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examine the effect of long-term MedDiet on cognitive function. They discovered that MedDiet improved various aspects of memory (i.e., delayed recognition, long-term, and working

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memory), executive function, and visual constructs (Hardman and others 2016). To date, there

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are two randomized, controlled intervention trials that have independently evaluated the efficacy

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of MedDiet alone or in conjunction with other supplements on cognitive function: the PREvención con DIeta MEDiterránea (PREDIMED) study and the MedLey study.

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The PREDIMED study was a multi-center, randomized, parallel-group cardiovascular prevention trial conducted in Spain from May 2005 to December 2010. The trial evaluated the

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effect of the two intervention groups, MedDiet supplemented with either 1) extra-virgin olive oil

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(EVOO; 1 L/week) or 2) 30 g/day raw, unprocessed mixed nuts (15 g walnuts, 7.5 g almonds and

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7/5 g hazelnuts), versus the recommended low-fat diet for cardiovascular disease (CVD) prevention. One study conducted neuropsychological analysis of a subsample from one recruitment center (PREDIMED-NAVARRA) in which a total of 522 participants at high CVD risk (44.6% men, age 74.6 ± 5.7 years) completed tests of global cognitive ability after 6.5 years of the nutritional intervention (Martínez-Lapiscina and others 2013). After adjusting for any potential confounding factors, both the MedDiet + EVOO group and MedDiet + mixed nuts group had significantly higher scores than the low-fat control group, indicating improved cognitive ability. Similar results were reported in another parallel-group study in Barcelona, Spain which followed the PREDIMED protocol (Valls-Pedret and others 2015). In this study, 447 older adults (47.9% men, mean age 66.9 years) with high CVD risk were given a battery of cognitive tests and were then randomly assigned to low-fat control diet, MedDiet + EVOO, or MedDiet + mixed nuts. Follow-up cognitive tests were given (median 4.1 years), and the mean z-scores of change

ACCEPTED MANUSCRIPT 13 in each test were used to construct three cognitive composites: memory, global cognition, and frontal cognition (attention and executive function). After adjusting for confounding factors, all

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cognitive composites were significantly lower from the baseline in the low-fat controls, indicating a slight reduction in cognitive ability. Both the MedDiet supplemented with EVOO

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and mixed nuts showed significant improvement on the memory composite, relative to baseline,

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and improved cognitive function when compared to low-fat controls.

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Although the findings from the PREDIMED studies strongly indicated the beneficial effects of MedDiet on cognitive function, the studies did not provide any information about the

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effect of the MedDiet alone, without any supplementation, on normal healthy older adults. This lack of information led to another randomized, controlled intervention study, the MedLey study.

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The MedLey study was a randomized, controlled, 2-cohort, parallel group study (nenrolled

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= 166 healthy men and women, ages 65 years and above, with normal cognitive function)

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comparing the effect of habitual diet (HabDiet, control) or MedDiet on cognitive function (Knight and others 2015). Each participant was given a battery of cognitive tests at the beginning of the study and then repeated every 3 months. After 6 months, data analysis revealed that there was no significant difference between the MedDiet and the HabDiet on any of the cognitive tests. The authors cited educated healthy volunteers, length of intervention, and sample size (n final = 137) as potential contributing factors to the null results reported (Knight and others 2016b). However, the lack of a beneficial effect of the MedDiet on cognitive function in normal healthy adults has been reported in other MedDiet prospective longitudinal studies (Cherbuin and Anstey 2012; Kesse-Guyot and others 2013b; Samieri and others 2013a; Samieri and others 2013b). Although evidence from numerous epidemiological and intervention studies has shown that consumption of fruits, nuts, and vegetables, rich in phytonutrients, offers beneficial effects on cognitive function, randomized, controlled dietary pattern intervention studies where high consumption of fruits and vegetables were included have yielded contradictory results. Two new

ACCEPTED MANUSCRIPT 14 randomized controlled clinical studies, the Exercise and Nutritional Interventions for Cognitive and Cardiovascular Health Enhancement (ELIGHTEN) study, sponsored by Duke University

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(NCT01573546), and the MIND Diet Intervention and Cognitive Decline (MIND) study, sponsored by Rush University Medical Center (NCT02817074), are currently ongoing. Both

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study designs (Blumenthal and others 2013; Morris and others 2015) address some of the

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concerns brought up by the existing dietary pattern intervention studies and address new research

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questions in the field of nutrition and cognitive function.

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5.0 Conclusions

Despite a growing preclinical literature describing the potential health benefits of fruit,

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nut, and vegetable consumption on cognition, the literature contains surprisingly few clinical

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trials that specifically test their efficacy in maintaining cognitive health. Studies show that these

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foods contain a variety of bioactive phytochemicals that may be able to prevent or delay agerelated neurological dysfunction and cognitive decline; however, more studies are necessary to map the neurological benefits provided by individual whole foods and the potential synergistic effects of their combination in the diet. Currently, a large proportion of people consume these plant foods in insufficient quantities; therefore, increasing overall consumption of fruits, nuts, and vegetables may be an effective strategy to maintain the cognitive health of our increasingly aging population.

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References

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Amagase, H.; Nance, D.M. A randomized, double-blind, placebo-controlled, clinical study of the general effects of a standardized Lycium barbarum (goji) juice, GoChi™. The Journal of Alternative and Complementary Medicine. 14:403-412; 2008 Baldrick, F.R.; Woodside, J.V.; Elborn, J.S.; Young, I.S.; McKinley, M.C. Biomarkers of fruit and vegetable intake in human intervention studies: a systematic review. Crit Rev Food Sci Nutr. 51:795-815; 2011 Blumenthal, J.A.; Smith, P.J.; Welsh-Bohmer, K.; Babyak, M.A.; Browndyke, J.; Lin, P.-H.; Doraiswamy, P.M.; Burke, J.; Kraus, W.; Hinderliter, A. Can lifestyle modification improve neurocognition? Rationale and design of the ENLIGHTEN clinical trial. Contemporary clinical trials. 34:60-69; 2013 Bondonno, C.P.; Downey, L.A.; Croft, K.D.; Scholey, A.; Stough, C.; Yang, X.; Considine, M.J.; Ward, N.C.; Puddey, I.B.; Swinny, E. The acute effect of flavonoid-rich apples and nitrate-rich spinach on cognitive performance and mood in healthy men and women. Food & function. 5:849-858; 2014 Chen, X.; Huang, Y.; Cheng, H. Lower intake of vegetables and legumes associated with cognitive decline among illiterate elderly Chinese: a 3-year cohort study. The journal of nutrition, health & aging. 16:549-552; 2012 Cherbuin, N.; Anstey, K.J. The Mediterranean diet is not related to cognitive change in a large prospective investigation: the PATH Through Life study. The American Journal of Geriatric Psychiatry. 20:635-639; 2012 Crews Jr, W.D.; Harrison, D.W.; Griffin, M.L.; Addison, K.; Yount, A.M.; Giovenco, M.A.; Hazell, J. A double-blinded, placebo-controlled, randomized trial of the neuropsychologic efficacy of cranberry juice in a sample of cognitively intact older adults: pilot study findings. J Altern Complement Med. 11:305-309; 2005 Devore, E.E.; Kang, J.H.; Breteler, M.; Grodstein, F. Dietary intakes of berries and flavonoids in relation to cognitive decline. Ann Neurol. 72:135-143; 2012 Feart, C.; Samieri, C.; Barberger-Gateau, P. Mediterranean diet and cognitive health: an update of available knowledge. Current Opinion in Clinical Nutrition & Metabolic Care. 18:5162; 2015 Hagan, K.A.; Munger, K.L.; Ascherio, A.; Grodstein, F. Epidemiology of Major Neurodegenerative Diseases in Women: Contribution of the Nurses’ Health Study. Am J Public Health. 106:1650-1655; 2016 Hardman, R.J.; Kennedy, G.; Macpherson, H.; Scholey, A.B.; Pipingas, A. Adherence to a Mediterranean-Style Diet and Effects on Cognition in Adults: A Qualitative Evaluation and Systematic Review of Longitudinal and Prospective Trials. Frontiers in Nutrition. 3; 2016 Heim, K.C.; Angers, P.; Léonhart, S.; Ritz, B.W. Anti-inflammatory and neuroactive properties of selected fruit extracts. J Med Food. 15:851-854; 2012 Hendrickson, S.J.; Mattes, R.D. No acute effects of grape juice on appetite, implicit memory and mood. Food & nutrition research. 52; 2008 Imai, Y.; Hasegawa, K. The revised Hasegawa's dementia scale (HDS-R)-evaluation of its usefulness as a screening test for dementia. Hong Kong Journal of Psychiatry. 4:20; 1994 Kean, R.J.; Lamport, D.J.; Dodd, G.F.; Freeman, J.E.; Williams, C.M.; Ellis, J.A.; Butler, L.T.; Spencer, J.P. Chronic consumption of flavanone-rich orange juice is associated with cognitive benefits: an 8-wk, randomized, double-blind, placebo-controlled trial in healthy older adults. The American journal of clinical nutrition. 101:506-514; 2015

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