EFFECTS OF THE MEDITERRANEAN DIET ON FUNCTION: Underlying mechanisms

Bachelor Degree Project in Cognitive Basic level 22.5 ECTS Spring term 2019

Malin Nilsson

Supervisor: Boushra Dalile Examiner: Antti Revonsuo Running head: THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 1

Effects of the Mediterranean Diet on Brain Function: Underlying Mechanisms

THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 1

Table of Contents Abstract ...... 2 Effects of the Mediterranean diet on Brain Function: Underlying Mechanisms ...... 3 History of the Mediterranean diet ...... 4 The Role of the Mediterranean diet in Health and ...... 5 Effects of the Mediterranean diet on Brain Function ...... 6 Mediterranean diet and Cognitive Function ...... 7 Mediterranean diet and Emotional Function ...... 11 Underlying Nutritional Mechanisms of the Mediterranean Diet Effects‟ on the Brain ...... 16 PUFA ...... 16 - the counter force to ...... 17 Oxidative stress...... 17 Antioxidants...... 18 Polyphenols ...... 19 Dietary Fibres and Gut Microbiota ...... 23 Neural Pathways of the Mediterranean Diet ...... 25 Brain Structure ...... 25 Structural Connectivity ...... 29 ...... 30 Other -Brain Pathways ...... 31 Discussion ...... 32 Conclusion ...... 36 References ...... 38

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Abstract The Mediterranean diet (Medi) has been highlighted as the golden diet rich in protective properties associated with cognitive- and emotional health. The foundation of the Medi comprises vegetables, fruits, nuts and seeds, , and extra virgin olive oil. Research has been conducted in both holistic dietary approach and single nutrient approach regarding the impact of nutrition and diet, in this case, the Medi‟s effect on brain health. This review aims to give an up to date overview of the Mediterranean diet, outline some of the diet's abundant , and discuss studies linking the nutrient's potential effect on , cognitive decline, , and brain structure and function. In addition, this review will attempt to assess whether the Medi as a whole or if a single nutrient approach is accountable for the health-promoting findings. Furthermore, the gut-brain axis, and other potential underlying mechanisms involved in the modulation of food- and nutrient intake and their effects on the brain, will be outlined. A diet high in fruit-, vegetable-, polyunsaturated -, and monounsaturated fatty acid content has great power for health-maintenance and decreases the risk of suffering cognitive decline, dementia, and potentially depression. More randomized controlled trials are however eagerly awaited to give more substance to previous findings.

Keywords: mediterranean diet, cognitive decline, Alzheimer‟s disease, PUFA, antioxidants, polyphenols, microbiota gut-brain-axis, dietary fibre

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Effects of the Mediterranean diet on Brain Function: Underlying Mechanisms Neurodegenerative such as the most common form of dementia, Alzheimer‟s disease (AD), is an expanding issue worldwide with almost 50 million people suffering the disease (WHO, 2017), estimated to double in the next 20 years (Cheignon et al., 2018). As of yet, no treatment to cure the disease is available, forcing the need to investigate preventative strategies. For this reason, the Mediterranean diet (Medi) has been highlighted for the beneficial effects on cardiovascular diseases and also more recently, cognitive deficits (Martinez-Gonzalez & Martin-Calvo, 2016). Studies investigating the neurocognitive effects of the Medi are somewhat contradictive; also whether it is the whole diet with interacting nutrients, or single core nutrients present in the diet that drive the main beneficial effects, is still up for debate. This thesis will provide a general up to date review of the Medi and discuss some nutrient compositions in the foods making up the diet; polyunsaturated fatty acids (PUFAs), antioxidants, polyphenols, and dietary fibers, due to the widely studied effects of these nutrients linked to cognitive decline, mood, and brain structure and function. The field of nutritional neuroscience is relatively new in the scientific community. The Journal of nutritional neuroscience has been active in almost two decades and aims to provide both basic and clinical research about nutrition and how it relates to the central and peripheral nervous system. It is an interdisciplinary field which might include the investigation of how dietary components such as , fats, and , or food supplements such as and , affect the , neurobiology, and behavioural biology in humans and animals. The field can contribute by developing and investigating potential preventative strategies for diseases and conditions affecting individuals in today´s society, for example AD and depression (Nutritional Neuroscience, 2018). In comparison, is a somewhat more mature field which emerged in the late 1970s. Cognitive neuroscience combines the two disciplines of ; the process of knowing, and neuroscience; the study of how the nervous system is organized and functions (Gazzaniga, Ivry, & Mangun, 2019). Nutritional neuroscience then touches and combines several disciplines to investigate how what we ingest then affects cognitive functions as well as brain structures. The thesis will be structured in the following manner. First, the history of the Medi will be explained as well as the diet´s composition. Second, the Medi will be contextualised in relation to general health benefits and effects on cardiovascular health. Third, the effects of the diet on general brain function followed by cognitive function as well as emotional function will be discussed. Fourth, an in-depth explanation of four selected nutrients (PUFAs, THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 4 antioxidants, polyphenols, and dietary fibers) will be highlighted and discussed in relation to brain function. Fifth, the microbiota gut-brain axis will be generally outlined as a possible route from nutrient ingestion to brain function, followed by reviewing some of the current evidence of the Medi‟s influence on the neurobiology of the brain. Finally, the discussion will summarize the main aspects of the thesis and discuss the limitations in the field. In sum, this review contributes to the investigation of why the Medi has been cited as “the gold standard of preventative medicine” (Martinez-Gonzalez & Martin-Calvo, 2016, p.1) as well as an aspect to how and why studying nutrition as a preventative method can be beneficial for several diseases. History of the Mediterranean diet During the 20th century, the Medi was the dietary pattern consumed by the population in countries around the Mediterranean Sea. The traditional diet is characterized by a high intake of plant foods (cereals, fruits, vegetables, legumes, tree nuts, seeds, and olives). Back then, olive oil was (and still is) the major source of fat, accompanied by high to moderate intake of fish and seafood, and moderate consumption of eggs, poultry, and products (often in forms of low fat and yoghurt). Red meat was rarely consumed, and alcohol moderately consumed, often together with a meal (Bach-Faig et al., 2011). In 1993, Willet et al. (1995) were the first to propose the Medi pyramid model. The pyramid model was based on the typical dietary patterns held in Crete, the majority of Greece, and the southern parts of Italy in the 1960s. The adult population of Crete, Greece, and Italy were at the top of longevity worldwide and had amongst the lowest rates of cardiovascular diseases and cancers among other chronic diseases (Willett et al., 1995). The scientific community developed the pyramid to fit according to today's‟ standards, lifestyles, sociocultural-, and health challenges that the new generation confronts. The Mediterranean Foundation in collaboration with the Forum on Mediterranean Food Cultures prepared a united view and reversed the Mediterranean food- and lifestyle pyramid (Fig. 1) in 2011 (Bach-Faig et al., 2011). As the updated pyramid shows, water intake, socialization, consumption of in season-products, portion sizes, rest, and activity are also aspects to take into account for a healthy lifestyle based on the Medi. In the renewed version, the pyramid shows the recommended intake of different food groups and the frequency of those foods. To follow the full version of the Medi, all aspects in the pyramid should be applied, because the non-food aspects, for example socialization (Hawkley & Cacioppo, 2010), water intake (Pan et al., 2013), and physical activity (Reiner, Niermann, Jekauc, & Woll, 2013), are of great THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 5 importance to experience physical- and mental health. This thesis however, will purely focus on the contribution of foods and nutrients of the Medi.

Figure 1. The Mediterranean diet pyramid: a lifestyle for today. Adapted from “Mediterranean diet pyramid today. Science and cultural updates,” by A. Bach-Faig et al., 2011, Public Health Nutrition, 14(12A), p. 2277. Copyright 2010 by Fundacion dieta mediterranea.

The Role of the Mediterranean diet in Health and Disease Research has shown that adherence to high intake of plant-based foods is linked to the prevention of several chronic diseases for instance cancers and , and provide key nutrients for a healthy and balanced diet (Aridi, Walker, & Wright, 2017; Bach-Faig et al., 2011). Fruit and vegetables are high in antioxidants and have shown beneficial inflammation reducing effects in the body and brain (Wärnberg, Gomez-Martinez, Romeo, Díaz, & Marcos, 2009). Furthermore, nutrients with properties are thought to be beneficial for protection against neurodegenerative diseases and cardiovascular diseases (Aridi et al., 2017) and it is suggested to possibly help against depression (Marx, Moseley, Berk, & Jacka, 2017). The largest Medi randomized trial, the PREvención con DIeta MEDiterránea (PREDIMED) trial, in Spain included 7447 men and women, all at high cardiovascular risk at baseline (Estruch et al., 2013). Participants were randomly assigned to either the Medi + extra virgin olive oil group, the Medi + 30g mixed nuts (almonds, hazelnuts, and walnuts) group, or the control group suggested reducing the intake of dietary fat. The trial stopped after nearly 5 THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 6 years and the two groups assigned to either of the two Medi groups showed large decrease in cardiovascular risk markers such as and myocardial infarction in comparison to the control group. These results are in line with results from the previous Lyon diet study which showed that adherence to the Medi reduced the risk of recurrence after a first myocardial infarction. The Medi had a protective effect up to four years after the first infarction (De Lorgeril et al., 1999). There are indications that risk factors for vascular diseases are also possibly underlying risk factors for cognitive decline, dementia, and AD (Kivipelto et al., 2001; Luchsinger, Noble, & Scarmeas, 2007; Martínez-Lapiscina et al., 2013; Vercambre, Grodstein, Berr, & Kang, 2012). Therefore, the positive effect of the Medi on cardiovascular markers can also be valuable for indirectly protecting against cognitive decline (Martínez-Lapiscina et al., 2013). Cognitive decline was investigated in relation to the Medi in a cohort of the PREDIMED trial, comprising 522 men and women at high vascular risk. A Spanish validated version of the Mini Mental State Examination (MMSE) (Blesa et al., 2001) and the clock drawing test were utilized to test for neuropsychological aspects (Martínez-Lapiscina et al., 2013). Results showed that participants in the Medi group + extra virgin olive oil had a higher mean score on the MMSE and the clock drawing test compared to the control group. The MMSE was originally developed by Folstein, Folstein, and Mchugh (1975), adjusted to only measure the cognitive aspect of mental function, hence the "mini". Mood and form of thinking are examples of excluded aspects. The MMSE is divided into two sections, one concerning verbal response and the other regarding the ability to follow verbal and written commands (Folstein et al., 1975). The MMSE is widely used and is high in construct validity (Tombaugh, 1992). In sum, high adherence to the Medi has shown association to decrease total mortality (Trichopoulou, Costacou, Bamia, & Trichopoulos, 2003) and reduced risk of suffering high blood pressure and cardiovascular diseases (Appel et al., 1997; Aridi et al., 2017; Delaye et al., 1999; Estruch et al., 2013; Lapetra et al., 2018; Mente, de Koning, Shannon, & Anand, 2009). Effects of the Mediterranean diet on Brain Function Fruits, vegetables, and olive oil are major constituents of the Medi, all rich in antioxidants, and have shown protective effects against cognitive decline and systemic inflammation. Due to the high intake of olive oil, the Medi can be considered a high-fat diet, although due to low amounts of saturated- and trans fatty acids, and high monounsaturated fatty acids (MUFAs) and PUFAs makes it a very healthy diet (Aridi et al., 2017). Researchers point out the THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 7 importance of using extra virgin olive oil and not refined olive oil. Refined olive oil loses some of the beneficial sources of polyphenols and other components in the refining process, which the virgin olive oil retains (Martinez-Gonzalez et al., 2012). Our brain has the highest density of all organs and is composed of three different main cell types: , glia cells, and oligodendrocytes (Bourre, 2004). PUFAs are important for the formation of new , especially neurons and glia cells as well as axonal myelination for good synaptic function. Dietary Omega-3 deficiency can lead to damage of brain membrane and disrupt the function of reconstruction of cell membrane mechanisms, hence accelerate cerebral aging (Bourre, 2005). Due to the high intake of fish and olive oil, the Medi offers a balanced ratio between Omega-3 and Omega-6 fatty acids (van de Rest, Berendsen, Haveman-Nies, & de Groot, 2015). This is of great importance especially in elderly individuals, because of the decreased protective abilities against (ROS) that comes with age, which can lead to deconstruction of PUFAs in the cell membrane, which in turn becomes harder to repair and renew, hence leading to a negative loop of deconstruction of cells (Bourre, 2004). Compared to a traditional Swedish dietary pattern, the Medi showed substantially lower plasma Omega-6 to Omega-3 ratio in healthy subjects over a 4 week period, using crossover design (Ambring et al., 2006). High ratio of Omega-6 to Omega-3, as often seen in today´s Western-style diets, is associated with diseases such as cardiovascular diseases, cancer, and inflammatory- and autoimmune diseases (Simopoulos, 2006). As previously mentioned is the Medi known to reduce the risk for the same type of diseases (Trichopoulou et al., 2003). MUFA, PUFA, and antioxidants present in the Medi have beneficially been linked to reduced risk of cognitive decline and are essential for proper brain function. These nutrients might be underlying components of the Medi‟s protective effects and why it has shown great health benefits. In the following section, the effects of the Medi on the neurobiology of brain, cognitive function, and emotional function will be described.

Mediterranean diet and Cognitive Function Several aspects of the Medi contribute to the expansive reputation of health benefits in body and brain that affect cognitive functions: high levels of fat (mainly from virgin olive oil and nuts), but low saturated fats, diversity of nutrients that are rich in dietary fibers, antioxidants, and have low glycemic index, among other things (Martínez-González, Hershey, Zazpe, & Trichopoulou, 2017). Cognitive function refers to the ability to process information THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 8 and knowledge, for example, attention, executive functions, visuospatial skills (part of the short-term working accountable for storage and perception of visual and spatial stimuli), and short-and long-term memory. is the brain region principally accountable for , although the seahorse-shaped structure is connected with wide regions of the cortex. Depending on the type of memory, different structures are involved, for example as with the amygdala and fear , or the for reinforcement learning (Gazzaniga et al., 2019). One study conducted in 11 months old mice by Farr et al. (2012) investigated the effect of extra virgin olive oil (EVOO) on memory and learning, compared to coconut oil and butter during six weeks. The mice were tested by utilising the commonly used neuropsychological- and cognitive T-maze test and one-trial novel object recognition. The T-maze is explained in detail elsewhere (Viana, Tomaz, & Graeff, 1994), and the one-train novel object test is described and discussed by other scholars (Ennaceur, 2010; Ennaceur & Delacour, 1988). Results revealed that mice fed EVOO showed improvements to greater extent in both tests compared to mice fed coconut oil or butter. These results suggest that EVOO have beneficial effects on learning and memory. Furthermore, EVOO showed to increase glutathione (having antioxidant properties) levels in the brain, hence suggested reducing oxidative stress in cells (Farr et al., 2012). During the last decades, the impact of the Medi on cognitive function and risk reduction of cognitive decline leading to development of dementia and/or AD, have received great interest from researchers (Aridi et al., 2017; Sofi, Macchi, Abbate, Franco Gensini, & Casini, 2010; Trichopoulou et al., 2015). Dementia is an umbrella term for diseases characterized by degradation of cognitive functions as well as alterations in mood and motor functions, where AD is the most common (Schelke et al., 2016). AD is a chronic neurodegenerative disease expressed by gradual deterioration of cognitive abilities in different domains, such as memory, language, judgement, orientation, and comprehension, severe enough to interfere with everyday life (Daviglus et al., 2010). To date, no proper medical treatment for the underlying causal mechanism of AD is found; hence researchers are looking for possibilities of preventive methods to either push the onset forward or to slow the progression down (Kivipelto et al., 2001). For this matter, the Medi has been highlighted (Aridi et al., 2017; Solfrizzi & Panza, 2014). Luchsinger et al. (2007) claim however that by then (year 2007), no evidence for supplements, diets, or foods as preventative strategies for AD were supported. Although, Gu, Nieves, Stern, Luchsinger, and Scarmeas (2010) provided a prospective cohort study three years later, and found a dietary pattern which strongly correlated to decreased risk THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 9 for AD characterized by high intake of fish, tomatoes, dark green leafy vegetables, poultry, fruits, and cruciferous vegetables. Pathological hallmarks for AD are an increase of extracellular plaques (clumps of insoluble ) and intracellular neurofibrillary tangles (tangles of protein fibres) (Pistollato et al., 2018; Gazzaniga, Ivry, & Mangun, 2014). Research in AD has shown greater loss of acetylcholine cells connecting the hippocampus and the prefrontal cortex; hence contribute to the progressive loss of ability to form new episodic memories in AD patients (Gazzaniga et al., 2014). Research suggests that accumulation of plaques and tangles occur long before the clinical onset of AD, a period called preclinical Alzheimer's. No sign of AD is generally seen during the preclinical period, although it can develop into mild cognitive impairment (MCI) where symptoms start to reveal, and later on develop into AD. MCI has similar characteristics as dementia; problems with memory, language, or other essential cognitive functions, noticeable for others and on cognitive tests, although not severe enough to interfere with the everyday life (Daviglus et al., 2010). Research further suggests that early preventative methods during the preclinical period can be valuable to reduce the severity and occurrence of clinical AD (Kivipelto et al., 2001), with dietary and nutritional changes being one example (Aridi et al., 2017; Schelke et al., 2016). The Medi has been highlighted as “the gold standard in preventative medicine” (Martinez-Gonzalez & Martin-Calvo, 2016, p.1). As previously mentioned, the Medi is abundant in antioxidants from fruit, vegetables, and olive oil hence contributing to the defence against free radicals and oxidative stress which in turn can prevent DNA damage and cell death, hence prevent cognitive decline and dementia (Aridi et al., 2017; Knight, Bryan, & Murphy, 2016a). Consumption of red wine has shown decreasing effects on C-reactive protein (CRP), hence possibly contribute to a systemic anti-inflammatory effect (Aridi et al., 2017). Long term inflammation can lead to damages on the blood-brain-barrier (BBB), hence contribute to increased neuroinflammation, leading to cognitive decline and further on AD (Heneka & O‟Banion, 2007). Solfrizzi et al. (2006) investigated over a period of 8.5 years if high intake of MUFAs and PUFAs could have protective effects on cognitive impairment in a population adhering to the Medi. In this longitudinal sub-study 578 men and women met the inclusion criteria. The 77-item food frequency questionnaire (FFQ) addressed various dietary variables such as energy intake, , saturated fatty acids (SFA), PUFA, MUFA, protein, alcohol, and soluble fibers. Cognitive tests were administered, and the MMSE was utilized to measure global THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 10 cognitive function at baseline, second survey after 41-54 months, and third after 96-109 months. The result showed that high intake of MUFA and PUFA were significantly associated with better cognitive performance at 8.5 years follow-up (Solfrizzi et al., 2006). This longitudinal study nicely demonstrates the important role of PUFA and MUFA in cognitive performance and the preventative aspects of cognitive decline. Notably, this was not a randomized controlled trial (RCT) at the level of experimental research; hence cause-effect conclusions cannot be made. Valls-Pedret et al. (2015) conducted a sub-RCT from the original PREDIMED trial (Estruch et al., 2013) in Spain including 334 men and women. The researchers investigated if adherence to the Medi with either nut or extra-virgin oil supplements could improve cognitive function in old adults (55-80 years) compared to a control group. The control group was advised to eat a fat-reduced diet, assessed by a trained dietitian using a validated 137-item FFQ (Fernández-Ballart et al., 2010). Furthermore, the participants were at high risk of cardiovascular disease, although not confirmed at baseline, and had to be diagnosed with diabetes mellitus, or meet 3 of 5 risk factor criteria, for example, smoking and hypertension. In comparison to the control group, adherence to any of the Medi groups enhanced cognitive performance at follow-up (mean 4.1 years) compared to baseline. These results point towards beneficial effects of the Medi supplemented with extra nuts (i.e. α-linolenic acid ALA) or extra virgin olive oil on cognitive decline (Valls-Pedret et al., 2015). Intake of low dose (ca 26g/day) MUFA (in form of extra virgin olive oil) instead of other vegetable oils in addition to the Medi have shown to improve cognitive function over a one-year period in another elderly population (Mazza et al., 2018). Despite the positive reputation about the Medi, not all studies have found a significant effect of adherence to a Mediterranean-like diet. In the MedLey study, conducted in Australia, ~70-year-old men and women (N=137), were randomly assigned to either a Medi or a habitual diet (control group), when investigating cognitive performance over six months (Knight, Bryan, Wilson, et al., 2016b). Cognitive performance was measured by 11 different validated tests and scales, measuring a) executive function, b) memory (episodic-, working-, and short term), c) speed of processing, and d) visual-spatial memory ability. However, the dietary schedule for the group assigned to the Medi was not fully in accordance with the traditional Medi, as described by Martinez-Gonzalez et al. (2017) in their cumulative meta- analysis. Specifically, neither potatoes nor eggs, which were included in the Medley study, are part of the traditional Medi. The results indicated no beneficial effects of the Medi on cognitive function in healthy elderly (Knight, Bryan, Wilson, et al., 2016b). THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 11

The contradictory evidence from the three previously mentioned studies (the longitudinal sub-study by Solfrizzi et al, the RCT sub-study from the PREDIMED, and the MedLey) may be due to the exact foods consumed, which differed between the interventional groups. Furthermore, the study design differed as well as measurements, which makes it difficult to draw unified conclusions of the results from the three studies. Whether or not the participants were healthy, at high risk, or already diagnosed with, for example, some kind of cardiovascular disease at baseline could also play a great role in the study results. Studying dietary pattern can be very complex and there are many aspects to take into account to be able to generalize the results. Single nutrients can be studied in isolation and show a certain result, whereas in combination with other nutrients, in a more holistic diet approach, the interaction effect can result in another outcome. Studies investigating the effects of the Medi as a whole in relation to cognitive function have mainly reported positive correlations (Gardener et al., 2012; Solfrizzi et al., 2006; Valls-Pedret et al., 2015), although no association has also been reported (Knight et al., 2016b). More homogeneous and heterogeneous approaches are requested to broaden and deepen the knowledge about how and to what extent adherence to the Medi can reduce the risk of neurological diseases.

Mediterranean diet and Emotional Function Just like AD, mental illness targets many people worldwide. Globally, more than 300 million people of all ages suffer depression (WHO, 2018). For this reason, there is a great need to find preventative strategies for the disease. A healthy dietary pattern characterized by high intake of fruit, vegetables, fish, and whole grains (hence similar to the Medi) has shown inverse association to the risk of depression, according to recent meta-analysis (Lai et al., 2014; Marx et al., 2017). Omega-3 PUFA has been rigorously studied as a possible component in reduction of depressive symptoms and other mood disorders. Studies point toward the role of Omega-3 fatty acids as a key nutrient in the relationship between dietary intake and depression (Colangelo, He, Whooley, Daviglus, & Liu, 2009). The literature is inconsistent, yet there are converging research results regarding Omega-3 PUFA‟s association with lower depressive symptoms. A study by Colangelo et al. (2009) investigated the role of fish consumption and the Omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in association with depressive symptoms, measured by utilizing the self-report questionnaire Center for Epidemiologic Studies Depression (CES-D) scale. Men and women (N=3317) were between18-30 years of age of African-American and Caucasian ethnic backgrounds. Dietary THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 12 intake was administered via the diet history method. Participants were followed-up six times, firstly after 2 years, followed by 5, 7, 10, 15, and 20 years. When running analyses for the separately, results showed a significant and strong inverse association between DHA, EPA, and DHA + EPA and depressive symptoms in women, but not in men. The results were the same when controlling for several lifestyle-factors such as BMI, cigarette smoking, alcohol intake, physical activity, and unemployment (Colangelo et al., 2009). The results are in line with other studies in similar context (Tanskanen et al., 2001; Timonen et al., 2004). Another study by Bountziouka et al. (2009) used FFQ and the Geriatric Depression Scale (GDS) and investigated the possible association between fish intake and depressive symptoms in 1‟190 elderly men and women, living in Cyprus and Greek islands. Results showed that those who reported no or low scores on the GDS correlated with the highest fish consumption, indicating a possible positive effect of dietary Omega-3 on self-reported depression symptoms. A more recent systematic review from 2010 highlights the differing results on Omega-3 PUFAs and depression from observational-, RCTs-, and ecological studies pointing towards the different distinctions between diagnosed depressive illness and the less severe type "depressive mood", as the possible contribution of the non-converging findings (Appleton, Rogers, & Ness, 2010). On that note, Appleton and colleagues speculate that Omega-3 PUFA supplementation might be beneficial for those with severe depressive symptoms, although not for those with moderate-to-low symptoms, neither in preventative purpose. These assumptions are drawn from the 17 studies included in their meta-analysis. Furthermore, the researchers refer to previous findings (Rogers et al., 2008; Su et al., 2008), suggesting the possible role of baseline Omega-3 intake and that positive effects of supplementation can correlate with deficient baseline individuals (Appleton et al., 2010). A cohort of the PREDIMED (Sánchez-Villegas et al., 2013), included 3‟923 Spanish men and women, all at high cardiovascular risk. About half of the population was diagnosed with Type 2 Diabetes. Results showed an inverse association between the group assigned to the Medi + nuts and reported incidence of depression, although the association did not reach significance. However, when conducting a sensitivity analysis on only participants with Type 2 Diabetes comparing the Mediterranean + nuts group to the control group, the results showed a significantly reduced risk of depression in this sub-sample. However, when combining both Medi groups and analysed as one, no significant effect on depressive risk compared to the control group was found (Sánchez-Villegas et al., 2013). On the other hand, a recent meta- THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 13 analysis revealed that high adherence to a Medi was associated with a 30% reduced risk for depression (Psaltopoulou et al., 2013). The Supporting the Modification of lifestyle In Lowered Emotional States (SMILES) randomized trial investigated the effects of changes in the dietary pattern as a treatment of moderate to severe depression (Jacka et al., 2017). Individuals with major depressive disorder (MDD) (N=67) were randomly assigned to either diet support intervention group or social support control group. The intervention group adhered to a diet similar to the Medi, although slightly higher intake of red meat and chicken. The intervention group showed significant improvement in depressive symptoms from baseline to 12-week follow up compared to the control group, which received only social support in forms of meetings talking about neutral topics of the participant‟s interest (Jacka et al., 2017). The SMILES study is regarded an important contribution to the field of nutritional neuroscience, trying to keep an interdisciplinary approach to find new treatments and solutions to the major diseases of society. This study is especially important due to its interventional design and therefore was able to show a causal effect in comparison to observational studies. Although, from a traditional Medi perspective, the diet was not fully in accordance with the supposed make-up due to the higher intake of red meat and chicken. This aspect makes the result even more interesting due to previously reported studies linking red meat consumption to increased inflammatory markers, although as a component in a Western-styled diet (Wärnberg et al., 2009). B has been suggested as a major component in the Medi‟s positive effects on depression due to synthesis of neurotransmitters such as serotonin, noradrenaline, and (Sandhu et al., 2017). Furthermore, studies with depressive individuals have demonstrated abnormal levels of PUFAs (significant decreased EPA and DHA levels) in cell membranes (Su, Huang, Chiu, & Shen, 2003). The mechanism behind de potential treating effects of DHA and EPA (or a mix of both) on depression is suggested to be the PUFA‟s properties of normalizing the cell membrane microstructure and neurotransmission in depressive patients (Su et al., 2003). Lassale et al. (2018) conducted a systematic review on a total of 20 longitudinal- and 21 cross-sectional studies targeting a range of different dietary food patterns, the Medi being one of them. Results from the systematic review showed that those highest in adherence to the Medi indicated lower risk of depressive outcomes. Another systematic review by Marx et al. (2017) in the new field of nutritional , provide promising indications about a healthy diet due to the richness of for instance; vegetables, fruit, and berries, all abundant in THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 14 antioxidants, discouraging oxidative stress. Furthermore, the Medi has been highlighted as optimistic due to its anti-inflammatory properties. Marx et al. (2017) further outline the current evidence for possible pathways and biomarkers as to why healthy diet patterns can have positive impact on depression and other mental illnesses. Firstly, chronic low-grade inflammation has shown to be involved in the onset of several mental illnesses, depression included. Second, oxidative- and nitrosative stress have also been linked to several chronic diseases, including mental illness. Furthermore, compared to healthy controls, depressed individuals have shown lower levels of antioxidants, and higher levels of oxidative stress markers. Third, altered particularly in the hippocampus, involved in memory, learning, and mood regulation, can be involved in mental illness (Marx et al., 2017). Despite the rigorous amount of studies showing positive effect of Omega-3 in relation to depression, not all have found such effect. Hakkarainen et al. (2004) studied 29‟133 Finnish men ranging between 50-69 years in a sub-study of the randomized, double-blind, placebo-controlled primary prevention trial the ATBC-study (ATBC Cancer Prevention Study Group, 1994). In the sub-study, the participant‟s dietary patterns were outlined by investigating the diet history questionnaire and depression was established by self-reports. For MDD and suicide, hospital treatment reports were investigated. The researchers found no association between dietary Omega-3 PUFA intake and depressive mood, MDD, or suicide in this large population of adult Finnish men (Hakkarainen et al., 2004). It is important to mention that the original ATBC study, where the sample was retrieved from, is now an old study and primarily investigated if beta-carotene and alpha-tocopherol supplements could reduce the occurrence of lung cancer, and possibly other cancers (ATBC Cancer Prevention Study Group, 1994). Moreover, the amount of Omega-3 was quite low in the sample (2.2g/day or 0.47g/day from fish), although not lower than reported average daily intake in the US (Omega-3 1.2g/day) and other Western countries (Hakkarainen et al., 2004). This sub- study did not find association between dietary Omega-3 and depressive mood, MDD, or suicide rates. Despite the large sample, due to its original study aim, confoundings such as other lifestyle aspects or the general dietary pattern consumed can be present. Controlling for the overall diet pattern and have an intervention group compared to a control group, adhering to the same overall diet pattern except for differing levels of Omega-3 intake would be preferable. In relation to previous findings about Omega-3 supplementation on depression, aspects such as baseline severity of illness, and Omega-3 deficiency can affect the outcome measures (Marx et al., 2017). These aspects are not taken into account in this sub-study. THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 15

Rogers et al. (2008) evaluated via double-blind RCT, the effects of Omega-3 EPA + DHA supplements (1.5g/day) on mood and cognitive function in 190 mild to moderately depressed individuals for 12 weeks. No effect of increased intake of EPA + DHA on mood in depressed individuals was found. This finding suggests that long chain Omega-3 PUFA may not influence mood in depressed individuals (Rogers et al., 2008). The holistic Medi was investigated in association with depression scores by Valls-Pedret et al. (2015) but found no effect of adherence to the Medi and depression scores. The Medi has shown to alter other aspects of mood after only 10 days of adherence (McMillan, Owen, Kras, & Scholey, 2011). Young women were either assigned to the Medi (intervention group) or no diet change (control group). Mood (determined by Profile of Mood States, POMS) and cognitive abilities (determined by the Computerised Mental Performance Assessment, COMPASS) were investigated at baseline and day 10 of the trial. At baseline, no significant difference in vigor was found between the groups, although participants in the Medi group self-rated significant improvements in vigor, alertness, and contentment compared to controls on day 10. Regarding cognitive performance, the results were inconsistent, although a positive trend in overall cognitive measure for the diet change group was seen (McMillan et al., 2011). Another research team did also investigate effects of the Medi during a 10-day period, although this study focused on mood, cognitive function, and cardiovascular measures (Lee et al., 2015). Similar to the previous study by McMillan and colleagues, the study sample was young, healthy women. Furthermore were the same measurements for mood and cognition utilised (POMS and COMPASS, respectively), although this study used crossover design. Cardiovascular measures included several pressure-investigations such as systolic blood pressure, diastolic blood pressure, pulse pressure etc. Results were in line with the ones from McMillan et al. (2011), namely significant increase in self-rated alertness and contentment, and significantly reduced . Memory-recall improved significantly after adherence to the Medi and reduction in high systemic arterial stiffness (augmentation pressure) were also significantly decreased (Lee et al., 2015). These two studies show that the Medi can be mood enhancing and have positive effects on certain cognitive functions also in younger adults (mid 20‟s) after a short period of high adherence to the diet. In sum, the vast amount of evidence indicates that a healthy dietary pattern, such as the Medi, including high levels of Omega-3 fatty acids and antioxidants can reduce depressive outcome, symptoms, and has been suggested as a complementary treatment method for depression. The severity and type of depression at baseline can underlie whether Omega-3 THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 16 supplement has an effect or not on depressive symptoms (Marx et al., 2017). Whether or not Omega-3 PUFAs have a central role in depression need further investigation, and more and larger sample RCTs, in both younger and older populations. RCTs aiming for a dose-effect relationship, using a homogenous approach and other measures than self-reports could be helpful and contribute to the understanding of the relation between Omega-3 PUFAs and depression. Furthermore, since depression can be seasonal and affected by many different lifestyle factors (Melrose, 2015), that should be taken into account and be controlled for in future RCTs. Underlying Nutritional Mechanisms of the Mediterranean Diet Effects’ on the Brain In the following section a more in-depth explanation about PUFA, antioxidants, polyphenols, and dietary fibers, all widely discussed as important components of the Medi and brain function, will be discussed.

PUFA PUFAs are essential fatty acids due to the properties of neurocognitive development and brain function, as well as involvement in the formation of new tissue in neurons and glia cells, axonal myelination, and synaptic function. PUFAs are involved in neural signalling and affect the action of neurotransmitters, especially the dopamine pathways in the frontal lobes (Wärnberg et al., 2009). DHA is one of two PUFAs most abundant in the brain (Innis, 2009). EPA and DHA are considered being the most important fatty acids of the Omega-3 PUFAs (Solfrizzi et al., 2017). Certain PUFAs compose cerebral cell membranes, and abnormalities in cell membranes can lead to altered membrane microstructures, leading to disruption in signal transduction and the ability to regulate immune responses (Su et al., 2003). Additionally, EPA and DHA generate anti-inflammatory resolvins (group of anti- inflammatory Omega-3 by-products), suggesting Omega-3 PUFA having potential strong anti-inflammatory effects on the brain, protecting against (Cunnane et al., 2009; Marx et al., 2017; Mori & Beilin, 2004; Wärnberg et al., 2009). There are two families of PUFAs which are essential for humans: linoleic acid (LA) (Omega-6 series) and alpha-linolenic acid (ALA) (Omega-3 series) (Bourre, 2004; Delion et al., 1994). “Essential” refers to the body´s inability to produce sufficient amounts to meet the physiological needs, hence one need to acquire them from dietary resources (Yehuda, Rabinovitz, & Mostofsky, 1999). High intake of Omega-3 PUFAs, has shown beneficial effects especially on human cardiovascular health (Wärnberg et al., 2009), furthermore reduce the risk for cognitive decline and depression (Bourre, 2004; Su et al., 2003). THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 17

A balanced intake of both Omega-3 and Omega-6 PUFA is of great importance for mental function. The reason is suggested to be due to the fact that both ALA and LA compete for the same conversion , i.e. enzymes removing atoms from fatty acids and convert to carbons (Janssen et al., 2015). Studies conducted with DHA- EPA- and ALA deficient rodents have demonstrated the crucial role of those fatty acids in brain development, cognitive function, and vulnerability to stress (Fedorova, Alvheim, Hussein, & Salem Jr, 2009; Fedorova & Salem, 2006). A recent meta-analysis on RCTs, Cooper, Tye, Kuntsi, Vassos, and Asherson (2015) investigated the effects of Omega-3 PUFA supplementation on cognition in healthy individuals and individuals diagnosed with ADHD, adults, and school children. The researchers did not find evidence for the effect of Omega-3 PUFA supplementation on cognitive performance in the general population or in those with ADHD or related disorders. Further, the researchers suggest that Omega-3 PUFA supplementation should be focused to those having Omega-3 PUFA deficits (Cooper et al., 2015). The Medi is abundant in PUFAs due to the high intake of olive oil, nuts, and fish, giving humans the essential fatty acids for brain development and brain function. Studies have shown that higher intake of Omega-3 PUFAs can reduce the risk of cognitive decline, and in some cases depressive onsets or symptoms. Although, as Cooper et al. (2015) states, the beneficial effect of Omega-3 PUFAs on cognitive function might be linked to a prevalent deficiency from start. Furthermore, PUFAs have shown potential anti-inflammatory properties (Marx et al., 2017). Antioxidants- the counter force to oxidative stress Fruit, nuts, vegetables, and red wine have antioxidant properties and acts anti- inflammatory (Lassale et al., 2018). Antioxidants are host defenders to harassing free radicals which possibly can cause oxidative stress. In turn, oxidative stress in a cell can be the cause of neurodegenerative disease development (Wojtunik-Kulesza, Oniszczuk, Oniszczuk, & Waksmundzka-Hajnos, 2016). Oxidative stress. The mitochondria is the mechanism providing energy for the cell and require a lot of oxygen to do so, furthermore does 1-5% of the oxygen convert to reactive oxygen species (ROS- harmful oxidative by-products), thus much of the intracellular ROS is caused by the mitochondria itself (Bhat et al., 2015). There are certain highly reactive species present in the nucleus and membranes of cells, which are capable of damaging cellular components such as DNA, lipids, proteins, and carbohydrates (Lobo, Patil, Phatak, & Chandra, 2010). Lifestyle aspects such as stress, poor diet, cigarettes, alcohol, radiation, THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 18 infections, drugs, and pollution can increase free radicals (Wojtunik-Kulesza et al., 2016). When enzymes and antioxidants cannot override the excess of free radicals, imbalance occurs, referred to as oxidative stress (Gomez-Pinilla & Nguyen, 2012; Wojtunik-Kulesza et al., 2016). The glutamate is the major contributor of oxidative stress in brain cells, probably via activation of ionotropic receptors (Gilgun-Sherki, Melamed, & Offen, 2001). There are two categories of oxidative stress: acute and chronic, the latter being more harmful to the cell as it makes it difficult to neutralize the amount of ROS. Chronic oxidative stress is thought to contribute to the development of several degenerative diseases such as AD (claimed to be one of the leading causes) and Parkinson‟s disease, certain cancers, atherosclerosis, diabetes mellitus, inflammatory diseases, and cardiovascular diseases (Aridi et al., 2017; Lobo et al., 2010; Wojtunik-Kulesza et al., 2016). Amyloid beta-protein (Aβ) increase the production of free radicals in neuronal cells, leading to oxidative stress and eventually cell death (Muthaiyah, Essa, Chauhan, & Chauhan, 2011). As previously mentioned, formation of beta-amyloid plaques is one of the pathological hallmarks in AD (Cheignon et al., 2018; Gazzaniga et al., 2014). Dietary pattern has been linked to several brain damages such as oxidative stress and inflammation, and relates to depression. Systemic inflammation can affect the regulation of emotions through affected neurotransmission for example serotonin, dopamine, and noradrenaline (Lassale et al., 2018). One study suggests that depressed people have higher levels of oxidative stress-markers and lower antioxidant markers compared to healthy controls (Marx et al., 2017). Antioxidants. Keeping in mind the damage which oxidative stress can cause in the body and brain, the solution to its harm is to increase the intake of antioxidants (Wojtunik-Kulesza et al., 2016). Antioxidants are compounds aiming to protect the body against free radicals. Phytochemicals (chemical compounds in plants, fruit, and vegetables, especially present in the skin) seem to exhibit antioxidant properties and can reduce levels of oxidative stress (Wärnberg et al., 2009). Furthermore, nutrients such as vitamin E, vitamin C, carotenoid, and riboflavin have antioxidant properties (Livsmedelsverket, 2019). Humans get antioxidants both endogenously (from inside the body) and exogenously (from the food we eat) (Bourre, 2006). Free radicals can hold either oxidative or reductive properties due to their abilities to either donate one electron or accept one (Gilgun-Sherki et al., 2001). Antioxidants are molecules which can donate an electron to a harassing free radical and, by doing so, turn the free radical neutral. Antioxidants have preventative, delaying, repairing, and inhibiting properties on cell damage thanks to their ability to polish off free radicals (Lobo et al., 2010). THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 19

Riboflavin. Riboflavin from the perspective of the Medi is present to great extent in fatty fish and dark-green vegetables. Riboflavin is putative to have protective effects on cardiovascular diseases and cancer (Powers, 2003). Vitamin E. Vitamin-E is one of three essential vitamins (the other two: vitamin C and β- carotene), acting as antioxidants, and have to be supplied via diet (Lobo et al., 2010). Vitamin E is highly represented in green vegetables, vegetable oil (Bourre, 2006), and nuts and seeds (Solfrizzi et al., 2017), all of which are essentials in the Medi. That which is normally referred to as Vitamin E is in fact a mixture of several different substances, one being tocopherol. Tocopherol is important for protecting unsaturated fatty acids from peroxidation, thus contribute to the stability of cellular brain structures (Bourre, 2006). Vitamin C. Vitamin C is found in a wide variety of fruits and vegetables, for example, cantaloupe, grapefruit, kiwi, mango, orange, strawberries, watermelon, asparagus, broccoli, brussels sprouts, cabbage, cauliflower, kale, and pepper (red or green). Vitamin C is essential for life and is a water-soluble antioxidant (Padayatty et al., 2003). Carotenoid. Carotenoids are natural pigments found in plant-based foods and “clean up” reactive oxygen species, hence also protect the brain from oxidation. A diet rich in carotenoids via consumption of orange- and green-coloured fruits and vegetables, vegetable oils and soup correlated with better cognitive performance compared to controls (Kesse- Guyot et al., 2014). Carotenoids are also proposed to exhibit anti-inflammatory properties. In sum, antioxidants are essential for humans and can be generated via certain systems in the body, although not enough to maintain the balance between free radicals and antioxidants, hence the importance of consuming foods abundant in antioxidants. An excess of free radicals can lead to oxidative stress, which in the long run is harmful to humans and is thought to severely affect the development of several diseases; for example depression, dementia, AD, heart diseases, cancers, and asthma.

Polyphenols In plant-derived foods such as colourful fruit and vegetables, spices, and tea, there are certain healthy chemical compounds (micronutrients) called polyphenols (Gomez-Pinilla & Nguyen, 2012). There are different groups of polyphenols (Figure 2), flavonoids being the largest. Flavonoids have in turn six subgroups, flavanols is one of them. Flavanols are found to a large extent in green tea, dark chocolate, and red wine (Meeusen & Decroix, 2018) but also in leek, onion, broccoli, kale, apples, cherries, and berries (Solanki, Parihar, Mansuri, & Parihar, 2015), most of which are components of the Medi. THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 20

Figure 2. Representation of the main classes of polyphenols and their chemical structure. Adapted from “Modulation of neurotrophic signaling pathways by polyphenols,” by Moosavi, F., Hosseini, R., Saso, L., & Firuzi, O., 2016, Drug Design, Development and Therapy, 10, p. 24. Copyright 2016 by Dove Medical Press.

Previous studies have indicated that consumption of polyphenols have positive effect on language- and verbal memory (Kesse-Guyot et al., 2012). Grapes are abundant in flavanols and wine in resveratrol (Aguilera, Martin-Cabrejas, & González de Mejia, 2016), which might be one of the reasons why it is considered an important part of the Medi and the Mediterranean pyramid for adults. Consumption of red wine has been mentioned as a possible contributor to improved memory performance (Kesse-Guyot et al., 2012). The longitudinal study by Kesse-Guyot et al. (2012) examined the effects of high intake of different types of polyphenols on memory and executive functions in midlife adults. The individuals had participated in the Supple´mentation en Vitamines et Mine´raux Antioxydants (SU.VI.MAX) study 13 years earlier during which high intake of specific, and/or general, polyphenols had been calculated. Calculation was made via dietary records, which were then matched in the Phenol-Explorer database, containing content values for 502 polyphenols in 452 foods (Pérez-Jiménez et al., 2011). Kesse-Guyot et al. (2012) found a positive association between high total polyphenol intake and verbal- and language memory, determined by the RI-48 test (Ivanoiu et al., 2005). Surprisingly a negative association was found between total THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 21 polyphenol intake and executive functions (for example working memory and mental flexibility such as the ability to adjust one's thinking to new situations). A negative association was also found when selecting for specific polyphenol types, for example flavonols. The researchers suggest the diverse findings could be due to the variety of polyphenols, which can be involved in different cognitive functions, indicating the importance of adhering to varied and healthy dietary patterns to sustain the quality of cognitive functions (Kesse-Guyot et al., 2012). One RCT by Konstantinidou et al. (2010) investigated the effects of olive oil polyphenols on related gene expression for atherosclerosis in healthy men and women, 20-50 years, (N=90). The study used three conditions; Medi + virgin olive oil, Medi + washed virgin olive oil, and controls adhering to the habitual diet. The washed virgin olive oil was obtained from the virgin olive oil, kept the same characteristics except lower content of polyphenols (55 and 328 mg/kg respectively). Follow-up measures revealed that adherence to the Medi in general lowered plasma oxidative- and inflammatory markers, and the gene-expression related to both inflammation and oxidative stress. Furthermore, the effects were seen to greater extent in the virgin olive oil-group compared to controls and washed virgin olive oil group, indicating a crucial role of polyphenol compounds present in virgin olive oil. Depending on purpose and baseline health, it might be good to really research different polyphenols before starting with for example supplements, aiming to improve cognitive function. Notably, foods or beverages might not be beneficial as a whole, yet specific nutrients can be beneficial separately in themselves. Furthermore, the level of intake should also be considered, as with red wine for example. These aspects should be taken into account before generalizing that consuming, for example, red wine would merely give positive health benefits due to some single nutrient or compound present. According to Gomez-Pinilla and Nguyen (2012) it has been claimed that some types of polyphenols are incapable of crossing the BBB (a separator barrier deciding which nutrients, metabolites, and drugs that can enter the brain), hence postulating the possibility of another pathway to the brain, for example indirectly via the gut-brain axis. Youdim et al. (2003) on the other hand demonstrate in rodents that certain flavonoids (hesperetin and naringenin, citrus flavonoids) are capable to cross the BBB by entering endothelial cells, which is the first stage of crossing the BBB. Others have also reported flavonoids being able to cross the BBB (Abd El Mohsen et al., 2002; Peng, Cheng, Huang, Chen, & Tsai, 1998), hence there are diverging assumptions. THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 22

Polyphenols have shown neuroprotective effects via interaction with signalling pathways in cells. Some scholars have suggested that flavonoids are the new generation of therapeutics, and have been used for the improvement of cognitive function and prevention of neurodegenerative diseases for a long time (Solanki et al., 2015). Consumption of polyphenols has been linked to better cognitive performance, therapeutic effects on neurodegenerative disorders, inflammation, diabetes as well as being mood enhancing (Gomez-Pinilla & Nguyen, 2012). Currently, more than 6000 types of flavonoids have been identified and can be grouped into six sub-classes based on their structure (Figure 2) (Solanki et al., 2015). As previously discussed, pathological hallmarks of AD are the presence and increase of amyloid plaques, neuritic plaques, and neurofibrillary tangles due to increase in amyloid beta and abnormal tau protein concentrations (Gazzaniga et al., 2014). As treatment for these pathological hallmarks, flavonoids are promising nominees due to their ability to inhibit the formation of the factors causing plaque-formation (Solanki et al., 2015). Moreover, the potential protective effect of flavonoids has been investigated also in relation to neuronal death caused by oxidative stress, although the study investigating this aspect used flavonoids present in extract from the Ginkgo biloba plant (Bastianetto et al., 2000), hence not present in the Medi. Flavonoids which are present in the Medi, suggested in the prevention or protection against AD, are myricetin, rutin, quercetin, and kaempherol (flavonols- present in e.g leek, onion, broccoli, kale, apple, cherries, and red wine), genistein and glycetin (isoflavones- present in legumes), and apigenin (flavones- present in parsley and celery) (Solanki et al., 2015). Hesperetin (flavanones of sweet orange, lemon, and lime) and naringenin (flavanones of grapefruit and sour orange) have potential protective effects on cardiovascular diseases and cancer (Khan & Dangles, 2014). Polyphenols have been mentioned as chemical compounds holding several beneficial properties in human health and disease. Polyphenolic compounds both synthetic and natural from food, contribute to inducing neurit outgrowth in neurons. Outgrowth of neurits are important in the distinction of neurons, starting with signals from outside the cell. The extracellular signal starts a response for the neurit to add new plasma membranes, generate cytoplasm, and the cytoskeleton (Moosavi, Hosseini, Saso, & Firuzi, 2016). The mechanisms behind the effects of polyphenolic compounds in the brain are made up by a very complex system including pathways, receptors, and neurotransmitters. Nrf2 (one signal pathway) rejected mice have shown a susceptibility to oxidative damage, which suggests an antioxidant THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 23 defence mechanism of the Nrf2 for maintaining intracellular homeostasis (Moosavi et al., 2016).

Dietary Fibres and Gut Microbiota Fruit, vegetables, legumes, and grains have rigorous fibre properties which can affect cardiovascular health components and therefore be of great value due to its‟ suggested underlying link to increased risk for neurodegenerative diseases (Aridi et al., 2017; Aune et al., 2016; Cho, Qi, Fahey, & Klurfeld, 2013). Dietary fibres are indigestible carbohydrates which, via microbial fermentation in the , turn in to short-chain fatty acids (SCFAs) as the final product (Farzi, Hassan, Zenz, & Holzer, 2018). The most abundant SCFAs in the large intestine are acetic acid, propionic acid, and butyric acid (Cummings, Pomare, Branch, Naylor, & Macfarlane, 1987). Dietary fibres are suggested to have anti- inflammatory effects (Aridi et al., 2017), possibly due to their fermentation into SCFA. SCFAs lower the pH in the colon which contributes to a beneficial environment for good bacteria growth such as Lactobacillus and Bifidobacteriu. These good bacteria are in turn producers of SCFA and play a role in healthy immune function (McLoughlin, Berthon, Jensen, Baines, & Wood, 2017). Whether or not the immune-protective effects can be exerted outside the intestine is debatable. Although, fed a fiber-rich diet showed increased circulating levels of SCFAs and were better protected against lung infection compared to rats fed a low-fiber diet who showed decreased levels of SCFAs and struggled with airway diseases (Trompette et al., 2014). It has also been demonstrated that SCFAs can cross the BBB (Rogers et al., 2016; Sampson et al., 2016), hence affect the brain and might therefore influence autoimmune inflammation in the brain (Erny et al., 2017). There are however alternative possible routes connecting dietary fiber and the brain, via SCFAs. SCFA can interact with cells via stimulation of the sympathetic and autonomous nervous system via certain receptors, and also affect the gut-brain communication via hormonal pathways as well as activation of the vagus nerve and/or other spinal (Borre et al., 2014; Rogers et al., 2016). De Filippis et al. (2016) used cross-over design to investigate the role of habitual adherence to the Medi either as vegetarians, vegans or omnivores and the effect on the gut microbiota in 153 healthy Italian volunteers. Adherence (low, medium, high) to the Medi was calculated using 11-unit dietary score. Overall did the majority (60%) of the participants show high adherence to the Medi. Furthermore, increased faecal SCFAs was seen in participants who consumed more plant-based foods as well as higher levels of fibre degrading bacteria. THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 24

Notably, in the omnivores alone, the higher adherence to the Medi, the higher levels of faecal SCFAs. Microglia has an important role for proper brain development as well as host defence and inflammatory processes, furthermore in synapse pruning (elimination of excessive synapses) in the CNS especially during the years of adolescent development into adulthood. Host microbiota has shown to regulate microglia function and maturation in the CNS. Specifically, SCFA has shown to affect the regulation of microglia homeostasis; furthermore, dysfunction of microglia is suggested to have causal effect in the development of neurodegenerative- and neuropsychiatric disorders (Erny et al., 2017). The anti-inflammatory effects of SCFAs were investigated in a meta-analysis including five studies by McLoughlin et al. (2017). Only one (Freeland & Wolever, 2010) reached significance in decreased plasma TNF-α concentration (TNF- α being a marker of systemic inflammation) in a small sample of six women with administration of SCFA acetate via enema and intravenously. Acetate is the primary SCFA to enter the circulatory system, hence suggested to have the greatest (of the SCFAs) impact on systemic inflammation (McLoughlin et al., 2017). The exact mechanism by which the association between prebiotics, synbiotics, and SCFAs is administered needs further examination for determination. Due to SCFAs possibility to decrease systemic inflammation, and inflammation being a major contributing factor for the development of dementia, the link between the Medi and the risk-reducing effects on cognitive decline and dementia by adhering to the diet, can be due to the high content of dietary fiber. The human gut microbiota can rapidly be altered by diet (Button et al., 2013; David et al., 2014). David and colleagues investigated the difference in gut microbiota between two groups of individuals, assigned to either plant-based diet or animal-based diet for five days. The animal-based diet group indicated an increase in -tolerant microorganisms (can survive in the human stomach and can potentially trigger inflammation (Feng et al., 2017)) and a decrease in levels of Firmicutes (David et al., 2014). Dietary intake has been investigated also in children related to cognitive function (Khan et al., 2015). One study with children (aged 7-9 years) found correlation between dietary intake, specifically dietary fiber, and cognitive task performance: demanding attentional inhibitory control in a modified version of the Eriksen flanker task. Low intake of dietary fiber correlated with poorer cognitive functions in children (Khan et al., 2015). Researchers are now investigating the role of the gut microbiota also in several neuropsychiatric conditions: for instance depression, autism, stroke, and THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 25

(Sandhu et al., 2017). About 95% of the total body serotonergic 5-HT is provided by the gut, for both intrinsic roles within the gut, but also affects metabolic control as well as activates afferent nerve endings to enable communication with the CNS. In sum, the Medi is high in dietary fibers via the richness in fruits, vegetables, and legumes. SCFA is the end product in the fermentation of dietary fibers and is suggested to have systemic anti-inflammatory properties, although studies show contradictory results (Mayer et al., 2014). The microbiota composition is potentially involved in the neurochemistry and emotional regulation in humans. Autism spectrum disorder is a brain disease which has for a long time been linked to altered gut microbiota, and now researchers investigate the potential in other psychiatric disorders (Mayer, Knight, Mazmanian, Cryan, & Tillisch, 2014). Neural Pathways of the Mediterranean Diet In relation to the rest of the body, the brain consumes the vast amount of energy (glucose) despite its small size. It is likely that the transferring mechanism which gets the energy from foods to neurons is fundamental in the control of brain function (Gómez-Pinilla, 2008). The upcoming section explores the effects of the Medi on gray- and white matter volumes, structural connectivity, and neurotransmission in the brain. Magnetic resonance imaging (MRI) is a widely used and accepted measure for investigation of the anatomical structure of the brain (Ogawa, Lee, Kay, & Tank, 1990). MRI provides high-resolution 3-D images of the brain and can do so by creating an extremely strong magnetic force, resulting in parallel arranged protons (protons in hydrogen atoms), instead of having them in a random order as they normally are, spinning about its principal axis. On the other hand, functional magnetic resonance imaging (fMRI) is a method which enables researchers to also investigate activation of certain brain areas linked to certain task performances. The fMRI measures the blood oxygen level-dependent (BOLD) effect by detecting the ratio between oxygenated- and deoxygenated levels of hemoglobin in the blood (Gazzaniga et al., 2019).

Brain Structure A study investigating the association between diet habits (highlighting the Medi), cognitive control, and brain volumes was conducted by Titova et al. (2013) including 194 cognitively healthy Swedish men and women in their 70‟s. The researchers‟ investigated whether adherence to the Medi would relate to changes in cognitive function and brain structure 5 years later. By performing a 7-day diet diary, a Medi score was calculated ranging THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 26 from 0-9 (Scarmeas, Mayeux, Stern, & Luchsinger, 2007). It is somewhat unclear whether the participants aimed to adhere to a Mediterranean-like diet during five years (between the age of 70-75), or whether their individual normal dietary pattern was utilized, although the researchers calculated the core aspects of the Medi from the normal pattern. Regardless, the Medi score was calculated, although in this study potatoes (which is not included in the traditional Medi) was paired with cereals, nuts and seeds were excluded, and legumes were pooled with vegetables when conducting the calculations. Results in cognitive function (determined by the MMSE and the seven-minute screening test) revealed a positive association between Medi score and seven-minute screening test score p>.02. Results from the MRI scanning showed no association between the Medi score and total brain volume, neither for white- and gray matter separately (Titova et al., 2013). However, an association to total brain volume was shown in a more recent study by Luciano et al. (2017) where lower adherence to the Medi was associated with greater reduction in total brain volume, in a Scottish cohort, with elderly subjects, over a three year period. Titova et al. (2013) found negative association between the self- reported intake of meat and meat products and the sum of white- and gray matter (i.e. total brain volume). When investigating local concentrations of brain tissue, no association between the self-reported intake of meat and meat products, and gray matter volume was found at specific central sites. In sum, this study reports that in a Swedish elderly population, low intake of meat is linked to better results on cognitive tests and greater brain volume. Notably, this result does not enable conclusions directly relating to active adherence to the Medi. What it does link is the aspect of low meat-intake, although does not debunk what kind of meat the consumption referred to. Previous studies have highlighted the importance of the fatty acids from nuts and seeds in correlation to normal cognitive function (Solfrizzi et al., 2006). The fact that the researchers in this study excluded nuts and seeds generates insufficiency of the study which aim was to investigate the associations between the Medi and cognitive function. For these reasons and the fact that the study did not start out from the traditional Medi, the results should be cautiously generalized. Gardener et al. (2012) investigated effects of the Medi on white matter hyperintensity volume (WMHV) in a sub-study of the larger The Northern Manhattan Study (NOMAS), New York, including 1091 participants with various ethnic backgrounds. The Medi score and MRI were utilised measures. WMHV is a marker of small vessel damage in the brain and can be connected with normal ageing but also cardiovascular diseases and cognitive function (Gardener et al., 2012). At baseline, an FFQ was administered and Medi scores (range 0-9) were calculated based on daily gram intake of seven food categories, for example, fish, dairy, THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 27 meat, fruits, and vegetables. Results revealed that in those participants with greater adherence to a Mediterranean style diet, lower strain was seen in WMHV. Specifically, for every 1-point increase in the Medi score, an association to lowered WMHV was seen. Thus, there is a potential preventative role in individuals adhering to the Medi and the risk of cognitive decline and stroke (Gardener et al., 2012). Furthermore, men had higher Medi score compared to women, and those who had a score of 6 or higher correlated with lower BMI. This study did not have a control group and did not provide information about baseline WMHV, only other baseline measures such as blood pressure and fasting blood samples, hence generalisation should cautiously be made. An MRI cohort study comprising 674 elderly individuals of various ethnic backgrounds was conducted by Gu et al. (2015) in northern Manhattan, New York. The researchers investigated potential correlations between high versus low Medi adherence to total brain volume, total gray matter brain volume, total white matter brain volume, mean cortical thickness, and regional volume. Results indicated that participants with high adherence to the Medi versus those with low adherence, showed larger total brain volume, total gray matter brain volume, and total white matter brain volume. Looking into specific food intakes revealed that higher fish intake and lower meat intake was associated with larger total brain volume (Gu et al., 2015). Another MRI study conducted by Staubo et al. (2017) included 672 US men and women between 70-89 years who were cognitively normal. The study investigated the association between the Medi and its components (via FFQs and Medi scores) with cortical thickness (using MRI scan). The MRI was conducted in six summary cortical thickness measures: averaged cortical thickness in areas with regions of interest from every one of the four lobes (frontal, parietal, temporal, and occipital), average of the cortical thickness of the four lobes, and thickness measure taking the regions of interest for AD in account. Results showed that higher Medi score correlated with larger frontal, parietal, and occipital cortical thickness separately. In addition, larger cortical thickness was found when measuring the average of the four lobes. These findings are in line with a previous study by Nelson and Guyer (2014) who found that those participants with higher adherence to the Medi showed greater thickness in sensitive AD brain regions. The majority of the signature foods of the Medi (fish, vegetables, legumes, and whole grains and cereals) all positively correlated with greater averaged cortical thickness in the parietal and frontal lobes (Staubo et al., 2017). However, no association with increased hippocampal volume was found. Notably, even though fruit is a good source of antioxidants, vitamins, and fibers, it showed a negative THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 28 association with cortical thickness in this study. The researchers suggest the plausible reason to be due to its high glycemic index and furthermore point out that the results should cautiously be generalized to other populations. Elderly people tend not to be as physically active as younger people, hence not getting rid of the extra intake of simple sugars which fruits contain. The researchers further suggest that the excess of simple sugars, from fruit and/or other foods containing refined carbohydrates and are high in glycemic index, in the older population can lead to neural loss, reduced cortical thickness, and in the end cognitive impairment due to disrupted insulin signalling and harmed glucose (Staubo et al., 2017). These assumptions are in line with a previous study by Roberts et al. (2012) who found that the risk of cognitive impairment or dementia was increased in elderly subjects with a high dietary intake of carbohydrates compared to those who adhered to a diet high in protein and fat. Various types of nuts have specific roles in the Medi and as previously mentioned. Walnuts may play a role in normal cerebral function (Bourre, 2004). A recent fMRI study by Farr, Tuccinardi, Upadhyay, Oussaada, and Mantzoros (2018) investigated the role of walnuts‟ potential integration with the CNS and impact on neural responses to visual food stimuli as well as how it might impact eating . Ten adult obese men and women (BMI ≥ 30 kg/m2) were randomly assigned to either the intervention group or the control group. The study used cross-over design with a 5 week washout period. The intervention group received a smoothie containing 48g walnuts and the control group received a smoothie with the same total amount of calories, although containing safflower oil and walnut extract instead, and apart from that contained the same macronutrients. Participants lived in a controlled environment during the 5 days of trial and stuck to the same strict diet plan and the procedure was repeated a second time after a 5-week break with normal food pattern for each individual. While in the fMRI scan, the participant viewed image blocks of highly desirable foods, low desirable foods, and neutral non-food images. Results from the fMRI scans revealed increased insular activation in all participants after 5 days walnut smoothie consumption, specifically in the dorsoanterior insula. In relation to eating, the primary function of the insula is to provide a representation of taste, pleasantness, and satiety (Farr et al., 2018). Indeed, the insula is relatively large, which gives place to other functions as well, such as reward responses and cognitive control. The dorsoanterior insula was found to be related to a network of the anterior cingulate cortex and dorsolateral prefrontal cortex, which in turn are areas strongly related to cognitive- and inhibitory control (Chang, Yarkoni, Khaw, & Sanfey, 2013; Farr et al., 2018). The researchers suggest that increased activation of the THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 29 insula may increase inhibitory control when viewing highly desirable foods, which in turn might lead to lower consumption of those kinds of high fat/high sugar foods, which in turn can show improvements in metabolic parameters. Furthermore, the researchers suggest that eating walnuts might function at the insular level of alterations in food intake in obese individuals (Farr et al., 2018). To conclude these potential mechanisms, further investigation using larger samples and longer duration is recommended. Another study, by Miller et al. (2018) investigated the effects of walnut oil (i.e. PUFA, ALA) intake on learning and memory compared to participants who received cream (i.e. saturated fat source) to controls (no added fat). Intake was in the form of chocolate milkshake for all three conditions. Learning was investigated in the form of fear-based prediction. Results showed that participants assigned to the walnut oil milkshake reacted faster and astute manner in a fear-based prediction task, in relation to participants in the cream- or low-fat control group.

Structural Connectivity The Medi provide strong dietary association between decreased risk for cardiovascular diseases and stroke (Estruch et al., 2013), AD and cognitive decline (Staubo et al., 2017), and depression (Marx et al., 2017). All of the diseases are suggested to have implications of vascular components. However, based on a study by Féart et al. (2009) who did not find a link between dementia or cognitive decline caused by vascular-related conditions, it has been suggested that neurodegenerative pathways are involved in the development of dementia or cognitive decline (Pelletier et al., 2015). Pelletier et al. (2015) conducted a study in a French elderly population (N=146) examining the association between high adherence to the Medi (during on average nine years) and gray matter volume as well as white matter connectivity utilising 3-T MRI and diffusor tension imaging (DTI). The 3-T MRI provides better images of soft tissue than other MRIs and can also distinguish between normal and abnormal tissue (National cancer institute, 2019). Medi adherence was measured using FFQs divided into categories and calculated by the Medi score 0-9 (Trichopoulou et al., 2003). Results showed that greater adherence to the Medi was associated with gain in structural connectivity in white matter which was related to strong cognitive benefits up to 10 years later. Notably, no association between high adherence to the Medi and gray matter or white matter volume was found. Furthermore, the researchers suggest that increased structural connectivity may be the common link of the positive effects of the Medi on reduced risk of cognitive decline and other diseases (Pelletier et al., 2015). THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 30

Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in the regulation of energy balance and neuronal plasticity mostly present in brain areas involved in cognitive function, i.e. hippocampus and cerebral cortex. Furthermore, the survival, growth, and maintenance of neurons are affected by BDNF (Gomez-Pinilla & Nguyen, 2012) as well as axonal growth and and function (Opie et al., 2015). BDNF is thought to connect hippocampal neurogenesis, hence potentially affect the development of mental illness. Clinical evidence of levels of BDNF is limited, although high intake of carotenoid- rich fruit and vegetables increased serum levels of BDNF in schizophrenic individuals compared to controls (Gama et al., 2008). Indeed, Galbete et al. (2011) found that adherence to the Medi was associated with increased levels of BDNF in depressed individuals. Neurotransmitters Fatty acids present in the Medi have been suggested to influence neurotransmission, for example, the Omega-3 fatty acids DHA and EPA. Omega-3 PUFAs affect neurotransmitter signaling, especially the dopaminergic system in the frontal lobe (Wärnberg et al., 2009) and might also alter serotonergic neurotransmission (Kodas et al., 2004). Early studies in rats investigated the effects of ALA deficiency on serotoninergic- and dopaminergic neurotransmission by measuring the density of receptors in three singled out cerebral regions: the frontal cortex, striatum, and the cerebellum (Delion et al., 1994). Sixty days old male rats were fed with peanut oil (Omega-3 deficient) or peanut oil 60% + rapeseed oil 40% (controls). Results revealed that DHA was the predominant Omega-3 in all three areas studied. Furthermore, the group of rats fed with the Omega-3 deficient food, a reduced level of DHA and increased levels of Omega-6 fatty acids in all of the studied cerebral regions was found. The DHA deficiencies did not alter to the same extent in all regions; the relative levels were lowest in the frontal cortex which seemed to keep more DHA than the cerebellum and striatum. Furthermore, the study showed that chronic ALA deficiency alters some factors involved in the dopaminergic- and serotoninergic neurotransmission pathway in the frontal cortex. An increase in serotoninergic 5-TH receptor density and a decrease in dopamine D2 bindings were found in the frontal cortex in the deficient mice, indicating a decrease in endogenous dopamine levels in the frontal cortex. Frontal cortex is involved in the regulation of attention and other types of cognitive functions (Delion et al., 1994), hence sufficient Omega-3 intake can provide a possible reason to why the Medi has shown beneficial effects on cognitive function. THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 31

Other Nutrient-Brain Pathways Several nutrients with beneficial health effects have previously been mentioned. How and why ingested nutrients can affect the brain will be discussed upon. It is a complex system connecting the gastrointestinal tract, gut microbiota, and the CNS. The autonomic nervous system (ANS), the (ENS), the immune system, and the bacterial metabolites are all contributing to the possible communication (Grenham, Clarke, Cryan, & Dinan, 2011; Sandhu et al., 2017). The bidirectional communication between the gut and the microbiota within on the one hand, and the brain on the other hand (the so-called microbiota gut-brain-axis) is assumed to affect mental health-related behaviours via multiple pathways (Fung, Olson, & Hsiao, 2017). For example, BDNF, serotonin neurotransmission, immune function, and the hypothalamic-pituitary-adrenal-axis mediated stress response (Marx et al., 2017). The brain and the make up the CNS which is in charge of the nervous system. The ANS is involved in involuntary movements, reflexes, and behaviours. Part of the ANS is the sympathetic and parasympathetic branches. The sympathetic branch is activated in the presence of stress or time for action, releasing adrenaline, resulting in increased heart rate, blood retrieves from the digestive tract to the bigger muscles, and increased breathing. The parasympathetic branch calms the system down and basically does the opposite to the sympathetic branch (Gazzaniga et al., 2014). The major nerve of the parasympathetic branch is the vagus nerve (Sandhu et al., 2017) and it is directly linking the large intestine and the brain (Stilling, Dinan, & Cryan, 2014). Moreover, the ENS is a branch of the ANS controlling gut functions and maintaining homeostasis (Schemann & Neunlist, 2004). The ENS can function without input from the CNS because it holds afferent neurons, interneurons, and efferent neurons, the components needed for a reflex pathway. The ENS is made up of two major networks of nerves and vessels (i.e. plexuses) containing cell bodies, ganglia, and linking chains containing nerve fibers (Yamada et al., 2009). The hypothalamic-pituitary-adrenal (HPA) axis is the core neuroendocrine pathway in humans (Grenham et al., 2011). When faced or induced with environmental factors such as stress, physical or psychological, or emotional activation, the HPA axis activates. The HPA activates a range of hormonal responses and in the end release cortisol from the adrenal glands, which affects many bodily organs, the brain included. The same neural and hormonal cells which allow the communication between brain and intestinal functional effector cells are on the other hand under the influence of the gut microbiota. The HPA is driven by the limbic THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 32 system, which includes the amygdala, hippocampus, and (Carabotti, Scirocco, Maselli, & Severi, 2015). Activation of the HPA axis is beneficial in acute or temporary moments but is suggested to be involved in several conditions such as nervosa, obsessive-compulsive disorder, panic anxiety, , and excessive exercising as chronically activated (Tsigos & Chrousos, 2002). When a meal has been consumed, complex neural- and hormonal responses in the gastrointestinal tract signal to the brain that a change in the nutritional balance has occurred (Sandhu et al., 2017). In the gut, there are first and foremost afferent nerve fibres from both sympathetic- and parasympathetic arms of the ANS, connecting information from the gut to the subcortical and cortical areas of the brain, for example, cerebral cortex, cingulate, and insular regions. Efferent fibers are directed to the muscles of the gut (Sandhu et al., 2017). Moreover, the gut also signals to the brain via excretion of certain molecules (peptides) present in the intestine. In turn, these communicate with the CNS via nearby afferent fibers or via secretion into the circulatory system by which the signal enters the brain and convey the central effect (Sandhu et al., 2017). Even though it is more complicated and sparse with human microbiota gut-brain axis studies compared to animal studies, it is possible to study the signalling by modulating the gut microbiota for instance via foods, supplements (for example prebiotics and probiotics), and medications, for instance antibiotics (Mayer, Knight, Mazmanian, Cryan, & Tillisch, 2014). In sum, the gut-brain-axis is a relatively new field, inviting future research to investigate as a possible mechanism behind the effects of the Medi on brain health and cognitive function. Discussion This review has discussed the up to date knowledge about the Medi and its link to brain health. The potential underlying mechanisms and nutrients of the Medi in relation to emotional- and cognitive function were also outlined. Finally, mechanisms behind the nutrient‟s route from ingestion to effects on brain health have been proposed. Foods in the Medi are rich sources of MUFAs, PUFAs, antioxidants, and fibers which all are suggested to contribute to better cognitive function and overall brain health (Aridi et al., 2017). PUFAs are essential fatty acids important for neurocognitive development and brain function due to the involvement in new tissue formation in neurons and glia cells, as well as axonal myelination and synaptic function (Wärnberg et al., 2009). EPA and DHA are considered the most important fatty acids of the Omega-3 PUFAs (Solfrizzi et al., 2017) and have shown to be important for brain development, cognitive function, and resistance to stress in rodents THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 33

(Fedorova et al., 2009). However, there are divergent results whether or not Omega-3 PUFAs have direct effect on cognitive function. Conquer, Tierney, Zecevic, Bettger, and Fisher (2000) found decreased levels of DHA and EPA in adults with AD, other , and in cognitively impaired but nondemented individuals. Studies including vegetarian participants have shown a lowered blood pressure compared to omnivores, although when trials have investigated the nutrients abundant in vegetarian food (for example magnesium, potassium, calcium, and fiber) separately, the effects on reduction in blood pressure has been very low and inconsistent (Appel et al., 1997). Keeping this in mind, the same aspect could be applied to the diverse results of the Medi linked to for example depression, cognitive function, and dementia. Cooper et al. (2015) found no effect of Omega-3 PUFA in relation to cognitive function, whereas Solfrizzi et al. (2006) did so and even reached significance. Trials investigating specific nutrients from the Medi should cautiously be integrated with trials aiming to investigate the whole dietary pattern approach. Possible reasons for the discrepancy are many, for example, study design and methodology including participant´s age, gender differences, dose differences, measurement differences, sample sizes, genetics, and differing baseline measurements. Studies regarding Omega-3 PUFA´s effect on depression also seem to differ in general, but also between genders. Women seem to benefit from such a supplement to greater extent than men (Colangelo et al., 2009). Polyphenols have antioxidant properties, and via interaction with signalling pathways also neuroprotective effects (Solanki et al., 2015). Antioxidants are essential for human health due to their properties to scavenge ROS, hence counteract oxidative stress in cells. Oxidative stress is proposed as a key factor for the development of neurodegenerative diseases possibly caused by systemic inflammation (Gomez-Pinilla & Nguyen, 2012). Dysfunction of microglia in cells has been proposed as having causal effects in the development of neurodegenerative- and neuropsychiatric disorders. Due to high fibre content in the Medi, and that SCFA has shown to affect microglia homeostasis, it can be postulated that dietary fibres also are key contributors for the health benefits of adherence to the Medi (Erny et al., 2017). Neurodegenerative diseases are a heavy burden for people in today‟s society. Therefore the Medi has been studied as a promising preventative dietary method for delaying the onset of cognitive decline or dementia (Schelke et al., 2016), as well as for reduction in depressive symptoms or decrease in MDD (Marx et al., 2017). Nutritional neuroscience research is a relatively new field and highlights the importance, and impact of diet- and nutrient intake on brain structure, function, and mental processes. Moreover, studying nutrition is very complex and to control for confoundings can THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 34 be arduous, hence also lowers the statistical powers. The ability to determine and distinguish cause and effect can appear challenging. The literature presents a variety of plausible reasons to why the Medi so often has shown beneficial effects on brain health, although one definite answer is not available. These issues will be discussed below. There has been a shift in science from studying single nutrients or foods in relation to disease, to a more holistic dietary pattern approach (Hu, 2002). Martinez-Gonzalez and Martin-Calvo (2016) state that research benefits from studying whole dietary patterns rather than studying single nutrient's effects on several diseases, which others agree upon (Lai et al., 2014; Wu & Sun, 2017). The reasons are said to be due to the complexity a diet holds and the difficulty to secure for interactional confoundings between single nutrients. Furthermore, a food pattern approach gives better examination of the full diet and captures between-food synergies (Martinez-Gonzalez & Martin-Calvo, 2016). Again, people tend not to eat only isolated nutrients, but a complex composition of nutrients in meal symmetry (Hu, 2002). Two large trials, the PREDIMED, and the MedLey study investigated the same aspects, namely the effects of adherence to the Medi on cognitive function. Although, results were contradictive with PREDIMED reporting significant results on cognitive function of adherence to the Medi, and the MedLey study did not report any improved cognitive functions. Possible reasons to the divergent results could be: sample size: PREDIMED N=334 vs. MedLey N=137, baseline health: participants in the PREDIMED were all at high cardiovascular risk whereas MedLey participants were considered healthy, follow-up period: PREDIMED had mean follow-up by 4.1 years, whereas 6 months in the MedLey study, measurements: the PREDIMED did not utilise as many measurements for assessing cognitive decline as the MedLey study. These aspects give a clear indication of possible limitations in comparing and generalizing results from studies utilising this type of observational design. Predominantly research is focused to the elderly population at high risk for developing a range of age-related diseases (for example cardiovascular diseases, dementia, and stroke), or focused to a certain population with common diseases, and are of observational character rather than experimental, which lowers the power of the results. Studying singled out populations also lowers the generalizability to the healthy population. The vast amount of studies included in this review utilised self-rating questionnaires when investigating, for example, both depression and cognitive function, such as with the widely used MMSE. One could question the validity of outcomes from such studies. Utilising subjective self- determining questionnaires or scales are prone to bias, for example the psychological dissonance between the remembering self and experiencing self (i.e. does one really THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 35 remember correctly when asked to rate how often certain food is consumed, or about portion sizes for example, or the social desirability bias (i.e. ratings depend on what one thinks is appropriate and desired to answer and not fully in accordance with what actually is true). Also, other uncontrolled lifestyle factors which can affect ratings and outcomes might be present in these kinds of studies. Although, in the majority of studies included, other lifestyle factors such as maternal status, smoking, BMI, physical activity, income, education level, etc. have been set as covariates. Observational study designs cannot control for these kinds of confounding variables to the same extent as RCTs as experimental study design for example. Furthermore, these study designs cannot contribute to causative effects, but rather correlational, hence what really is cause and effect, and what might be cannot be determined. Although, correlational studies can be of great value as well, for example, to predict future events and to provide data which are either in line with- or not in line with scientific theories (Graziano & Raulin, 2013). There is a value of longitudinal studies too, although more RCTs are warranted to enrich the field. The walnut study by Farr et al. (2018) is a good example which nicely demonstrates a study possibly revealing causal effects and which has solid control over possible confoundings. Studies with similar design are suggested to be conducted but to investigate for example intake of extra virgin olive oil, similar to the PREDIMED trial (or other actual foods which is important compounds of the Medi) although to be conducted in a controlled environment and for a set period of time. Cognitive decline was in general determined by the MMSE and in some cases with additional cognitive tests (as in the MedLey study) in the studies included in this review. MMSE is a widely used measure to detect cognitive decline or dementia in studies, although additional measurements are suggested to fully determine such a state. According to the DSM-5 diagnosis criteria, there are more components to such diagnosis than what the MMSE can provide by itself. Indeed, MMSE is not a diagnostic tool per se, but rather a measurement which reveals cognitive (in)abilities and changes in these (Demenscentrum, 2016). Some studies included in this review have utilised additional measurements to increase the accuracy of whether a person counts as cognitive impaired or not. Furthermore, cognitive performance could benefit from other examining methods, such as computerized reaction- or recall tasks, memory comparison task or the letter-matching task instead. The major issues in measuring nutrition linked to cognition could be due to the complexity a diet holds. It can be difficult to distinguish what exactly it is the nutritional components are affecting, and also again if it is a specific nutrient or the interaction between nutrients which convey the effects. Also, nutritional neuroscience as a field could benefit from a more holistic and gathered way of THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 36 conducting research, for example by utilising the same type of measurements so the comparison between study results could more accurately be made. As mentioned by way of introduction, in the updated version of the Medi pyramid, factors beyond nutrition were included due to its‟ great impact on subjective health. There is now an ongoing large trial, PREDIMED-PLUS, which goes beyond only the Mediterranean foods by taking physical activity and social context in to account in relation to host health and long-term cardiovascular effects. This is backed up with a full package of the Medi lifestyle and results are expected in the year 2021 (Martinez-Gonzalez & Martin-Calvo, 2016). Diverging results regarding nutritional compounds in the Medi and the diet as a whole, are reported in the literature. Even if researchers have changed focus to study more whole diet approaches, single nutrient trials with rodents are still of great value due to the ability to investigate neurobiological effects in the brain to greater extent than what is possible in humans. While the of rodents can give good indications of nutrition's effect on for example brain cells and neurotransmission, the transferability to humans should somewhat be cautiously implemented. Before generalizing the positive effects of the Medi on brain function, the study designs should be taken in to account. Although, the vast amount of studies agrees upon that adherence to a plant-based diet with PUFA/MUFA sources of fat is to aim for and is beneficial for general- and brain host health.

Conclusion The Medi is based on the dietary pattern predominantly consumed in Spain, Greek islands, and south of Italy (Bach-Faig et al., 2011). Adherence to the Medi has shown to decrease the risk of suffering cardiovascular diseases, cognitive decline, AD, and depression (Aridi et al., 2017), although studies not revealing positive correlations are also present (Hakkarainen et al., 2004; Knight et al., 2016b). Cardiovascular diseases are proposed as one underlying factor for cognitive decline and dementia (Martinez-Lapiscina et al., 2013) as well as dysfunctional microglia regulation (Erny et al., 2017), and oxidative stress (Wojtunik- Kulesza et al., 2016). High intake of vegetables, fruit, fibres, and nuts/seeds/olive oil, seem to possess the key nutrients (PUFAs, antioxidants, polyphenols, and dietary fibres) for good general host- and brain health and flavonoids have been suggested as the new generation of therapeutics (Solanki et al., 2015). This review has also proposed that high adherence to the Medi can increase total brain volume, total gray matter volume, and total white matter volume in healthy elderly (Gu et al., 2015). Furthermore, higher adherence to the Medi is correlated with THE MEDITERRANEAN DIET FROM A NEUROCOGNITIVE PERSPECTIVE 37 greater cortical thickness in brain regions sensitive for AD (Staubo et al., 2017), and white matter structural connectivity increase (Pelletier et al., 2015). Several possible routes for nutrient-brain pathways have been mentioned. There is a complex make-up connecting the gut and the CNS, involving the ANS, ENS, vagus nerve and other spinal nerves, immune pathways, hormonal pathways, and the ability to cross the BBB (Borre et al., 2014; Rogers et al., 2016). Hopefully, the field of nutritional neuroscience continues to flourish due to the urgent need for preventative strategies for mental health. To get the original positive effects of the Medi, the whole aspect including social connections and physical health should be taken into consideration. This aspect has not been included in this review. Neither is there, to my knowledge, any studies as of today including this aspect when investigating the correlation between the Medi, cognitive function, or depression, hence the great value of the ongoing PREDIMED-PLUS trial.

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