Chapter 19

Nootropics, Functional Foods, and Dietary Patterns for Prevention of Cognitive Decline

Francesco Bonetti, Gloria Brombo and Giovanni Zuliani,    University of Ferrara, Ferrara, Italy

Abstract

Actual prevention of cognitive decline is probably the best strategy to address the rise in dementia expected in the coming decades, especially since therapeutic choices to revert or stop disease progression are lacking. Dietary approaches for preventing cognitive decline seem to be among the most promising options to slow age- and disease-related degeneration of the central nervous system. Several dietary patterns seem to be related to better cognitive performances late in life (the Mediterranean diet, dietary approaches to stop hypertension, and the Okinawan diet are good examples). The presence of vitamins, polyphenols, unsaturated fatty acids, and other bioactive compounds with neuroprotective effects is a core characteristic for functional foods useful for a healthy cognitive aging. Food- and spice-derived complements could be helpful before or alongside a pharmaceutical approach in cognitive decline, and medical foods composed of wide-spectrum bioactive compounds have the best chance of becoming an effective multilevel intervention.

Keywords

Nootropic; dietary pattern; medical food; Mediterranean diet; polyphenols; flavonoids; vitamins; unsaturated fatty acids; cognitive; dementia

Introduction

Over the last century we have assisted the aging of the world population, the resulting changes in epidemiology are modifying the problems perceived as fundamental by governments, clinicians, and the general population. In this context of global aging and prolonged life span, the prevalence of dementia has risen to hardly sustainable levels and is expected to triple in a few decades, with severe impacts on communities and health systems (WHO, 2012). Moreover, since achievements in health and medicine are granting more of the population more years (especially in industrialized countries), the concept of spending old age with a good quality of life is gaining popularity, and “normal” (or should we say “common”?) brain aging is becoming less acceptable in a society in which elderly people can live active, satisfying lives while remaining highly productive and socially integrated. Because it is difficult to define normality in terms of cognitive performances among the elderly, it is hard to select the target to aim for in pursuit of satisfactory cognition in this part of the population. If the target is the preservation of a good capability of daily life and activity, then an early intervention with neuroprotective intent could be sufficient. If, on the other hand, we are aiming to restore the function of a central nervous system (CNS) that has already undergone major detrimental modifications, we have to shift from neuroprotection to cognitive enhancement, knowing that current results for the latter approach have been far from excellent.

Based on actual knowledge, it is impossible not to approach cognitive modification during the life span as a holistic problem; the simple and reassuring anatomical subdivision of organs and systems is simply outdated. Nowadays clinicians have to face the fact that the phenotypical manifestation of single system modification (the symptom) is often the result of systemic processes influencing a local condition; the crosstalk among organic systems has to be considered when approaching such complex subjects as CNS function. A demonstration of the latter consideration is the strong association between metabolic derangements or systemic inflammation and cognitive decline (Duarte, 2015; Verdile et al., 2015). Insulin resistance and the consequent metabolic cascade seems to play a major role in cognitive dysfunction (Kim and Feldman, 2015; Verdile et al., 2015). An even more direct correlation can be made between vascular disease and decline in CNS performance, because it markedly influences brain structure and causes easily detectable morphological alterations. So, to plan an efficient program of healthy cognitive aging along with specific neuronal directed care, cardiovascular and metabolic prevention must be considered. Moreover, it is necessary to understand that the human body is not a closed system, so interactions with the environment could have strong repercussions on many physiological and pathological conditions. Nutrition is one major channel of interaction with the environment, largely because of its singular characteristic of frequency and duration in our life. It therefore offers unique possibilities to modulate organic functions both in preventing risky conditions and curing established diseases. Epidemiological data support the possible adoption of specific dietary patterns that seem beneficial in preventing or deferring the onset of cognitive decline and dementia (Gillette Guyonnet et al., 2007; Swaminathan and Jicha, 2014; Canevelli et al., 2016). We will now discuss the main evidences about dietary recommendations with possible impacts on cognitive functions, classes of nutrients hypothesized to be beneficial for cognition and the prevention of dementia, and groups of substances that could act as cognitive enhancers.

Dietary Patterns and Complete Nutritional Plans With Cognitive Implications

The main body of evidence on the effects of diet on cognition has been deduced by retrospective observations. Different cultures have specific dietary habits and because the knowledge that diet has noteworthy repercussions on health is solid and growing, epidemiological research has focused on identifying possible a posteriori protective factors in large cohorts of individuals. In the last two decades, the Mediterranean diet (MeD) has emerged as promising not only for cardiovascular protection but also for preventing cognitive decline (Smith and Blumenthal, 2016). Even if the MeD is largely the most well known nutritional approach to a healthy life, other examples of nutritional habits associated with a successful aging are reaching the attention of the scientific community (Willcox et al., 2014).

Mediterranean Diet

The MeD is representative of a healthy cultural approach to food adopted in many countries in southern Europe. Considered the strong regional characterization of eating habits in countries like Italy, Spain, France, and Greece, united to the geographical modifications in typical recipes that occur even inside the same region at impressive short-distance, it would be naive to think that a monomorphic eating style exists in these countries. The diet regimens historically adopted in states bordering the Mediterranean Sea have a few things in common: a wide base of plant-derived flavonoid-rich products (with seasonal production-oriented rotations that ensure a variety of vegetables, fruits, and spices available for consumption), a daily moderate wine consumption (preferably red), an extensive use of olive oil instead of animal fats, and a preference for low-fat dairy products and limited meat intake substituted by more healthy fish consumption. The actual dietary patterns of Mediterranean countries are the result of repeated and massive beneficial cross-contaminations of cultural heritages (Altomare et al., 2013). The MeD itself has been recognized by the United Nations Educational, Scientific, and Cultural Organization. On the other hand, it is true that nowadays the real mean intake of nutritional component is far from MeD standards in southern Europe (Karamanos et al., 2002), although this highly beneficial nutritional pattern survives in small contexts that maintain high longevity and successful aging phenotypes. The MeD is perfectly in agreement with European Food Safety Authority (EFSA) recommendations on macronutrient composition of a healthy diet (EFSA, 2010a,b, 2012) considering that it should be characterized by a high intake of carbohydrates (approximately 65%—and EFSA recommends 45–65%) with large amounts of vegetables (wild edible herbs included), legumes, fruits and (whole) cereals, moderate consumption of fats (approximately 30%, mostly unsaturated—and EFSA recommends 20–35%) of prevalent origin from plants (olive oil and nuts), low-fat dairy products and fish, and just minor contribution of red meat and animal fat, and lesser amounts of proteins (approximately 15%—and EFSA recommends 10–20%). The typical low-dose alcohol intake should come preferably from red wine (high polyphenol content, resveratrol included), but theoretically it could also come through other forms of fermentation-derived beverages (which often happens because of economic and cultural factors) that could have beneficial effects even if of slightly smaller magnitude (e.g., good-quality beer with low alcohol concentration and high yeast, polyphenols, B vitamins, and silicon, an antagonist of aluminum absorption, content) (Kondo, 2004; González-Muñoz et al., 2008; Arranz et al., 2012).

Only in the last decades has MeD been widely recognized as an effective lifestyle modification that is useful in preventing age-related cognitive decline and dementia (Solfrizzi and Panza, 2014; Valls-Pedret et al., 2015). While the notion of the whole-diet effect was growing, single components—macronutrients and micronutrients—arose as possible functional foods having protective roles (Frisardi et al., 2010; Panza et al., 2004), especially mono- and polyunsaturated fatty acids (MUFAs and PUFAs) with particular regard to omega-3 (O3) and omega-6 (O6), light to moderate alcohol consumption, and fruit and vegetables intake (mainly because of their high vitamin, flavonoid, and antioxidant contents) (Frisardi et al., 2010; Mecocci et al., 2014; Polidori et al., 2009; Solfrizzi et al., 2011). Some authors suggest that the reduced risk of obesity, diabetes, and cardiovascular events in individuals adhering to MeD could at least partially justify the postulated effect of cognitive decline prevention (Solfrizzi et al., 2011), especially considering the impact of brain vascular damage on cognitive vulnerability in the elderly and on the progression of dementia of any etiology, including Alzheimer’s disease (AD) (Solfrizzi et al., 2011; Polidori et al., 2012). Moreover, insulin resistance, obesity-related inflammatory state, and obviously overt diabetes are strongly associated with cognitive decline (Biessels and Reagan, 2015; Duarte, 2015; Verdile et al., 2015). Anyway, due to recent scientific acquisitions in terms of synergy among nutraceuticals with neuroprotective effects (Mecocci et al., 2014), it is reasonable to differentiate the vascular protection from the other possible beneficial effects of these substances on CNS.

Dietary Approaches Other Than the Mediterranean Diet

MeD is not the only dietary pattern epidemiologically correlated with successful aging (and cognitive function sparing). In southern Japan, e.g., the Ryukyu Islands (Okinawa prefecture) represent a model of lifestyle compatible with long life and healthy aging (Willcox and Willcox, 2014). The Okinawan traditional diet is a low-caloric nutritionally dense dietary pattern that has been associated with a low incidence of age-related chronic diseases (cardiovascular diseases, cancer, and dementia) (Willcox and Willcox, 2014). Being similar to the MeD, it is characterized by high consumption of vegetables (flavonoid- and antioxidant-rich products) and legumes (mainly soy); moderate consumption of alcohol, fish, and carbohydrates with low glycemic index; and low animal protein and fat intake (the main part of fats are represented by O3 and monounsaturated fats). Willcox and colleagues emphasize the extensive use of functional foods as staple dietary elements that are rich in fiber, antioxidants, and vitamins such as the Okinawan sweet potato (Ipomoea batatas), a good source of calories with a really low glycemic index (reportedly as low as 55). Furthermore, Okinawans highlight the habit of mixing herbs and spices (turmeric, pepper, artemisia, seaweeds) to the dishes to enrich them with functional micronutrients and the use of soy-based products and mushrooms as low fat sources of protein (associated in these foods with minerals, vitamins, and flavonoids as isoflavones of the soy). One interesting extract of white-skinned sweet potato peel (caiapo) used in traditional medicine seems to have insulin sensitizer properties (Ludvik et al., 2003); when added to the diet of patients affected by type 2 diabetes, it seems able to reduce adiponectin and surrogate markers of systemic inflammation and ameliorate lipid profile (Ludvik et al., 2004).

The eating plans just described are derived from observations of “naturally occurring dietary patterns”, recently also structured complete nutritional plans expressly created for specific health targets are discussed for their possible neuroprotective properties. The Dietary Approaches to Stop Hypertension (DASH), e.g., has shown that it may be able to prevent cognitive decline (Smith and Blumenthal, 2016). DASH has a high-fiber and plant-derived food content and a moderate protein content, with extremely low fat and sodium intake. In this dietary pattern, probably the huge reduction of cardiovascular risk is one of the major contributors of the reported brain health gained by individuals adopting this eating style (Tangney, 2014). DASH is strikingly capable of reducing blood pressure in a short time of adherence (Conlin et al., 2000), and has demonstrated good efficacy in reducing cardiovascular events and deaths (Fung et al., 2008; Salehi-Abargouei et al., 2013; Wengreen et al., 2013). While there is evidence that the DASH eating plan is associated with reduced age-related cognitive decline (Tangney, 2014; Tangney et al., 2014), a specific retrospective analysis of participants in the Memory and Aging Project seems to show evidence that a combination of this pattern with MeD could be more beneficial in terms of cognitive prevention. This approach has been relabeled as the Mediterranean–DASH Diet Intervention for Neurodegenerative Delay (MIND) (Morris et al., 2015).

Other dietary patterns based on different recommendations have been investigated in relation to neurodegeneration: e.g., the Healthy Diet Indicator, Healthy Eating Index, Programme National Nutrition Santé, and Recommended Food Score (van de Rest et al., 2015). Globally, the most common characteristics could be summarized as high consumption of legumes, nuts, and whole grains (Wengreen et al., 2013); low consumption of red meat and saturated fats (Granic et al., 2016) in deference to more fish and unsaturated fats of plant origin (Panza et al., 2004); and the presence of low-caloric, nutrient-dense functional foods such as vegetables, herbs, and spices (Mecocci and Polidori, 2012; Willcox and Willcox, 2014).

Micronutrients With Possible Effects on Cognition

Currently, it is not easy to find an official definition of nutraceutical (a portmanteau of the words nutrient and pharmaceutical), but Mecocci and colleagues (2014) synthesized a common meaning that defines nutraceuticals as foods or food components with properties potentially beneficial in terms of health maintenance or disease treatment. For didactic purposes, in this chapter we will describe first the micronutrients hypothesized to be biologically active to better understand the complexity of the foods defined as “functional.” It is important to understand that preclinical studies investigating the activity of a single micronutrient are far away from providing a clear idea of what happens when a particular food is eaten, especially if it is of plant origin, which usually contains a multitude of micronutrients whose interactions in terms of bioavailability, pharmacokinetics, and pharmacodynamics are hardly predictable. So, even if a substance has demonstrated high beneficial activity in vitro or in animal models, high-quality trials conducted on real-life subjects are necessary to demonstrate a clear repercussion on health and disease. Unfortunately, this level of evidence is lacking for many nutraceuticals at the moment. For similar reasons, the biological activity of a food component is not surely inferable from retrospective analyses of the intake of foods containing high concentrations of the substance under consideration, and the same substance cannot be considered a full substitute for the functional food in which it is a single component. That said, some observations coming from both laboratory and dietary analyses are a good starting point for programming future investigations and hypothesizing effective interventions.

Monounsaturated and Polyunsaturated Fatty Acids

The CNS is characterized by a relatively low regenerative reserve when compared with most other organs, but a residual neurogenesis has been demonstrated in at least two brain regions; in fact, axonal and dendritic plasticity are part of normal brain functioning (Lazarov et al., 2010) and even adult neurons and all glial cells require continuous structural maintenance to guarantee the efficiency and integrity of the system. These remodeling processes are modulated by the availability of substances fundamental to the cell machinery (Angulo-Guerrero and Oliart, 1998). Neuronal cell membrane is of primary importance in modulating the genesis and conduction of the nerve signal and in transmitting it from cell to cell via the specialized membrane that characterizes the synaptic junctions. Lipid membrane components and their quantitative ratios directly influence the density and activity of membrane proteins (ion channels, enzymes, and receptors) that are responsible for efficacious neurotransmission (Kamphuis and Wurtman, 2009). Over a wide range of dietary variations in lipid intake, membranes remain relatively constant in their saturated and monounsaturated fatty acid levels; on the other hand, n-6 and n-3 PUFA levels in the diet influence sensibly quantity and type of phospholipids in neuron membranes, which seem to be most sensitive to O3 and the O3–O6 PUFA ratio. These differences probably are justified by lack of de novo O3 and O6 PUFA synthesis by higher animals (Hulbert et al., 2005). Membrane phospholipids require PUFA, choline, and uridine monophosphate for their synthesis. When all three compounds are administered together to animals, they increase levels of phosphatides, synaptic proteins, dendritic spines, and cholinergic tone in the CNS (Kamphuis and Wurtman, 2009). Among PUFAs present in the human brain, arachidonic acid (AA) and docosahexaenoic acid (DHA) are reported to contribute to about 6% of dry cerebral cortex weight (Svennerholm, 1968). These PUFAs can be obtained by dietary intake (fish and plant oils) or be synthesized from precursors: AA can be produced from linoleic acid (an O6 PUFA present in plant oils, nuts, and legumes) and DHA from α-linolenic acid (an O3 PUFA found in fish and flax seeds) with an intermediate passage through eicosapentaenoic acid and docosapentaenoic acid. In addition to direct metabolic activity on the SNC, these long-chain O3 PUFAs exert various degrees of antiinflammatory effects (Dyall, 2015), a fact that renders them hypothetically useful in mitigating brain aging and many neurodegenerative processes (Janssen and Kiliaan, 2014). PUFA supplementation has shown promising results in experimental studies, and O3 intake over a substantial part of rodent life showed reduced neuronal damage (in terms of hippocampal atrophy and the deposition of amyloid beta, Aβ) and slowing cognitive decline (Cederholm et al., 2013). In humans, our knowledge is derived primarily from epidemiological studies in which fish intake or DHA plasma concentrations correlated with the delay of cognitive decline, better performances at neurological testing, and less brain atrophy (Cederholm et al., 2013); limited good quality trials are available, however. Even if it seems that O3 PUFA supplementation could be beneficial in healthy adults with mild memory complaints, similar positive effects in patients with dementia seem to be restricted to those that are ApoE4 allele negative (Salem et al., 2015), actually there is no conclusive evidence of efficient prevention of incident dementia or significant cognitive advantages in healthy subjects or dementia patients (Sydenham et al., 2012; Burckhardt et al., 2016).

Polyphenols

Polyphenols are constituents of foods of plant origin characterized by one or more hydroxyl groups on an aromatic ring (phenol group). The number of phenol rings and structural elements that bind them are used to classify them. The main groups are flavonoids, phenolic acids, phenolic alcohols, stilbenes, and lignans (D’Archivio et al., 2007). Neuroprotection mediated by polyphenols is mainly due to their antioxidant, antiinflammatory, and antiamyloidogenic effects (Pérez-Hernández et al., 2016). Experimental data strongly support a possible activity of polyphenols in neuroprotection, and epidemiological data indirectly agree with such evidence even though randomized trials are scant and controversial.

Flavonoids

Flavonoids are a group of polyphenolic substances commonly found in several types of food of plant origin. They are easily found in high concentration in vegetables, fruits, cereals (Gupta and Prakash, 2014), herbs, and spices (Mecocci et al., 2014) and sometimes contributing significantly to color, flavor or taste of foods. Flavonoids are a large family of substances (more than 4000, of which several hundred are found in edible plants) and have multiple roles in plants—from attracting pollinating insects to protecting plants from environmental stressors (Kumar and Pandey, 2013). A chemical classification can be adopted to divide them into six categories: flavanols, flavonols, flavones, isoflavones, flavanones, and anthocyanidins (Kumar and Pandey, 2013; Mecocci et al., 2014). Their hypothesized properties, however, can belong to different but often overlapping chemical classes. Flavonoids are reported to interact with neuronal and glial cellular signaling pathways (Moosavi et al., 2015) to perform several functions: promote peripheral and locoregional vasodilation modulating cerebral blood flow (Spencer et al., 2009; Nehlig, 2013; Rendeiro et al., 2015), exert antioxidant and antiinflammatory activity in biological systems that mitigates neuronal and endothelial damage (González et al., 2011; Magalingam et al., 2015), contain pathological damage in neurodegenerative diseases (Magalingam et al., 2015; Moosavi et al., 2015), and act as hormone mimetics that induce possible beneficial modifications (Mecocci et al., 2014; Kridawati et al., 2016). Considering the cognitive impact of these molecules, probably the most interesting proposal has been a possible role for flavonoids in modulating neuroplasticity in terms of both neurogenesis (Spencer et al., 2009) and synaptogenesis (Rendeiro et al., 2015). All of these activities render flavonoids a promising option in attempting to slow age-related declines in cognitive performances and possibly treat neurodegenerative diseases (Spencer et al., 2009). Estimated dietary intakes from multiple databases in the United States seem to suggest that individuals aged 19 years and older consume approximately 200–250 mg/day of flavonoids: mostly flavanols (about 80%) followed by minor quantities of flavonols, flavanones, and anthocyanidins, and less than 1% of isoflavones and flavones (Sebastian et al., 2015; Kim et al., 2016).

Due to the chemical differences of the various compounds belonging to the flavonoid family and the different characteristics of plants that hosts them, their bioavailability varies broadly among subtypes. β-glycosidic bonds of flavonoids are a critical limit to absorption (Nemeth et al., 2003), and aglycan forms (e.g., catechins) are usually considered to be more readily absorbed. Glycosylated forms are more available after degradation by bacterial flora (such as soy isoflavones during fermentation or others in colonic microambient with the side effect of partial degradation of the flavonoids themselves) or small intestine brush border enzymes. An exception that must be mentioned is the active absorption in the small intestine of some hydrophilic flavonoid glycosides (such as quercetin) by membrane transporters that could enhance the bioavailability of these molecules and possibly render it even better than that of their aglycan forms (Hollman et al., 1999; Manach et al., 2004; Makino et al., 2009). It is intuitive that, along with the potency of their biological effects, the bioavailability of flavonoids is a crucial element considering the possible clinical efficacy of a nutritional intervention.

Flavanols

Flavanols, specifically monomeric flavanols (catechin, epicatechin, epigallocatechin, gallocatechin, and their gallate derivatives) and their polymerization products (proanthocyanidine), are present in noteworthy concentrations in cocoa powder and chocolate (Nehlig, 2013), teas, and grapes (Mecocci et al., 2014). In black teas, teaflavin and tearubigin also can be found in significant concentrations. Catechins are the most readily absorbable flavonoids because they are the only form not bound to sugars (flavonoids glicosides are more easily absorbed after transformation in aglycan form) (Kumar and Pandey, 2013). It is debatable whether this class of substances should be grouped with flavonoids since they have a slightly different chemical structure, but they will be discussed here because they share with other compounds of this class a high antioxidant activity, common food sources, and possible beneficial biological functions. Grape and grape juice (rich in catechin and epicatechin) seem capable of reducing glutamate excitotoxicity and exert powerful antioxidant activity and thus ameliorate endothelial function and reduce platelet aggregation and low-density lipoprotein (LDL) oxidation (Mecocci et al., 2014). These effects are a good basis from which to approach reducing the risk of onset or progression of cerebrovascular damage, even if they come from indirect evidence (grape juice and not a single micronutrient administration). Results from preclinical and human studies on flavanol- rich cocoa administration (in which epicatechin is the most represented flavanol) have shown that it could result in the reduction of age-related cognitive decline, the risk of AD, and depression. Moreover, as previously described for the flavonoid class, this substance seems capable of improving cerebral blood flow, synaptic plasticity, and mitochondrial function (Nehlig, 2013). A high-flavanol dietary supplement administered to elder adults was found to enhance activity in brain regions involved in age-related cognitive decline (dentate gyrus, assessed by functional MRI) and to improve performance at cognitive testing (Brickman et al., 2014). Epigallocatechin gallate, the most abundant flavanol in green and black tea, has shown promising preclinical results in reducing AD and cognitive decline induced by vascular damage (Mecocci et al., 2014).

Flavonols

Among flavonols, quercetin is probably the most studied. Along with kaempferol and myricetin, quercetin is probably the most represented flavonol in edible foods (onions, apples, green teas, and capers are good dietary sources of flavonols). Quercetin has shown promising antioxidant (Kelsey et al., 2010) and antiinflammatory capabilities (Bischoff, 2008; Bureau et al., 2008; Mecocci et al., 2014) in preclinical models of neuronal damage, and it is especially known for its ability to chelate and stabilize the generation of iron-reducing radicals (Kumar and Pandey, 2013). The combined antioxidant and antiinflammatory activity could be partially responsible for improvements seen in models of cerebrovascular damage after flavonols administration (Dajas et al., 2003). Moreover, due to its impact on multiple mechanisms related to neurodegenerative diseases, quercetin has been proposed also as a complementary treatment for AD. Preclinical investigations seem to support a favorable interaction with Aβ42, reducing its direct neurotoxicity (Ansari et al., 2009; Tchantchou et al., 2009) and even providing a potential role in improving memory (possibly due to its anticholinesterase activity) (Orhan et al., 2007), hippocampal synaptic plasticity (as observed in models of neuronal damage induced by exposure to lead) (Mecocci et al., 2014), and neurogenesis (Tchantchou et al., 2009). Similar to quercetin, kaempferol has demonstrated an ability to contain oxidative damage in cellular cultures and to improve memory and learning in mice models (Mecocci et al., 2014). Spencer and colleagues report that flavonol intake (including quercetin, kaempferol, and myricetin) has favorable effects on learning and memory (Spencer et al., 2009). The proposed mechanisms of neuroprotection, other than direct interaction with Aβ42 oligomers (Tchantchou et al., 2009), are increased activation of cyclic-AMP response element binding protein and subsequent release of neurotrophins that are important in memory processes (Spencer et al., 2009; Tchantchou et al., 2009). Recently, fisetin also received attention due to its strong antioxidant activity (Ishige et al., 2001), and subsequent studies identified it as a promising neuroprotective compound since it showed antiinflammatory, neurotrophic, and antiamyloid properties and has been proposed to be able to improve memory, probably by facilitating long-term potentiation in hippocampal neuron cells (Currais et al., 2014). Due to its many beneficial properties, fisetin has been proposed as a possible integration in the treatment of AD and Parkinson’s disease (PD) (Navabi et al., 2016).

Isoflavones

Isoflavones (genistein, daidzein, glycitin) can be found in high concentrations in soybeans; their supposed beneficial activity seems to be attributable to estrogenic agonism via beta receptors present in the brain (Mecocci et al., 2014). Estrogen-replacement therapy for prevention of cognitive decline and normal brain function maintenance is a debated subject; the supposed increased cholinergic activity and possible neuroprotective effects support a use of this approach (Engler-Chiurazzi et al., 2016) even if the last Cochrane review on the matter found insufficient evidence to support this indication (Hogervorst et al., 2009). Preclinical exploration on administration of soy isoflavones obtained discrete results in terms of improvement of memory and cognition (Kridawati et al., 2016), but epidemiological data on soy consumption are controversial (Gleason et al., 2009), and evidence of active dietary integration in humans is scant (Mecocci et al., 2014). Meta-analyses and interventional trials on this subject showed little or no statistically significant benefits of integration in postmenopausal women (Hogervorst et al., 2009; Henderson et al., 2012; Cheng et al., 2015) as well as in older people of both genders with and without dementia (Gleason et al., 2009, 2015). Some authors suggest that a possible explanation of failures of integration could be found in timing (Cheng et al., 2015) or in the capacity to metabolize the isoflavones (Gleason et al., 2015) (S-equol, a potent agonist of beta estrogen receptors is produced through daizdein elaboration by gut microbiota of some but not all individuals) (Setchell and Clerici, 2010). Nowadays, conclusive evidence on cognitive benefits of soy isoflavones intake is lacking, and their relationship with possible health issues is debated: some authors suggest a possible role in cancer prevention in healthy individuals (Varinska et al., 2015), while others recommend caution especially in administering pure isoflavones to individuals who can be harmed by estrogen replacement (Allred et al., 2004).

Flavones

Several flavones have been explored for neuroprotection in preclinical models. Luteolin, a flavonoid found in parsley, celery, and rosemary (Mecocci et al., 2014), has demonstrated a clear neuroprotective effect in streptozotocin-induced AD rat model ameliorating spatial learning and memory impairment (Wang et al., 2016). Luteolin effects are at least partially explainable by inhibition of microglia-induced inflammation (Jang et al., 2010; Navabi et al., 2015a). In humans, luteolin has shown promising effects on so-called brain fog—impaired cognition, concentration, and multitasking abilities—i.e., sometimes associated with reductions in short- and long-term memory occurring in a wide range of neuropsychiatric disorders and as cognitive complications of systemic syndromes with notable inflammatory components (Theoharides et al., 2015). A liposomal luteolin formulation in olive fruit extract improved attention in children affected by autism spectrum disorders and brain fog in patients affected by systemic diseases with mild cognitive implications (Theoharides et al., 2015). Apigenin, another common flavone, has shown similar prevention activity on neuroinflammation as reported by Millington and colleagues: apigenin-treated mice improved memory and learning abilities reducing fibrillar amyloid deposits via beta-secretase 1 modulation (Millington et al., 2014). Moreover, this flavone seems capable of restoring the cortical extracellular signal-regulated kinasecAMP-response element binding proteinbrain-derived neurotrophic factor pathway typically compromised in AD patients and exerts neurovascular protective effects. Finally, in animal models of inflammatory response, it acted to reduce inflammatory cytokines (Millington et al., 2014), and in rat models of diabetes it was able to attenuate diabetes-associated cognitive decline by modulating apoptotic signals and nitric oxide production (Mao et al., 2015). Similar to apigenin, other flavones also have been studied in relation to their neuroprotective capabilities. Chrysin, a flavone present in various fruits, vegetables, and mushrooms, has been proposed as antiinflammatory, antiamyloidogenic, and neurotrophic for nervous cells (Navabi et al., 2015b). Baicalein, oroxylin A, and wogonin (all isolated from Scutellaria baicalensis root) enhanced cognitive and mnestic functions in animal models of aging brains and neurodegeneration and demonstrated neuroprotective potential in models of oxidative stress–induced, Aβ and alpha-synuclein–induced neuronal damage (Gasiorowski et al., 2011).

Flavanones

Among flavanones, pinocembrin (present in honey, propolis, ginger roots, wild marjoram, piper leaves, oregano, licorice aerial parts) (Rasul et al., 2013; Lan et al., 2016) is emerging for its neuroprotective characteristics. In animal models of cerebral ischemic damage, pinocembrin ameliorated cognitive impairment and energy metabolism (Guang and Du 2006; Meng et al., 2014) and demonstrated the ability to counteract Aβ toxicity (Liu et al., 2012). In elderly adults, an 8-week consumption of flavanone-rich orange juice was associated with cognitive benefits (Kean et al., 2015).

Anthocyanins

Anthocyanins and their aglycone forms (antocyanidins—malvidin, cyanidin, peonidin, and delphinidin) are flavonoids present in noteworthy concentrations in berries (blueberries, bilberries, cranberries, elderberries, raspberry seeds, and strawberries) (Mecocci et al., 2014). Their intense red, blue, and purple colors render these substances attractive for industries as food coloring additives. Their activity may involve control of inflammation, amelioration of global metabolic profile and mitochondrial energy metabolism, scavenging of reactive oxygen species, and promotion of neuronal plasticity (Domitrovic 2011; de Pascual-Teresa, 2014; Mecocci et al., 2014). It is interesting that anthocyanins can be found in rat brain when fed with blueberries (cerebellum, cortex, hippocampus, or striatum), and their concentration correlates with the rat performance in the Morris water maze, suggesting a possible direct activity on memory and learning (Andres-Lacueva et al., 2005). Anthocyanins demonstrated beneficial effects in both AD (Badshah et al., 2015) and PD (Strathearn et al., 2014) cellular models of neurodegeneration.

Other Polyphenols

Flavonoids are not the only naturally occurring bioactive phenolic compounds to show neuroprotective activity. Among the growing mass of polyphenols subject to investigation as neuroprotectors, resveratrol and curcumin surely reached the attention of the scientific world due to their potential for multiple health implications. Resveratrol is present in high concentrations in grapes and wine, while curcumin is easily isolable by turmeric and other plants of the Zingiberaceae family (ginger family). Both substances have been described as enhancing cerebral blood flow (Awasthi et al., 2010; Kennedy et al., 2010) and acting as antidepressants (plausibly modulating the monoaminergic system) (Kulkarni et al., 2008; Ogle et al., 2013; Al-Karawi et al., 2016); some of these effects are enhanced by piperine (an alkaloid present in the piper family) (Shoba et al., 1998; Bhutani et al., 2009; Huang et al., 2013; Wightman et al., 2014). Sadly, the measured increments in cerebral blood flow did not produce detectable cognitive enhancement (Wightman et al., 2015), and there is the possibility that the augmented bioavailability obtained with coadministration of piperine could decapitate the bioactivity of polyphenols (Arcaro et al., 2014). Resveratrol and curcumin act on a variety of biological processes involved with chronic diseases (Ghosh et al., 2015; Diaz-Gerevini et al., 2016; Pulido-Moran et al., 2016) and have been proposed as anti-AD medications due to their antioxidant, antiinflammatory and antiamyloidogenic properties (Villaflores et al., 2012). In a group of healthy elderly volunteers, acute administration of solid lipid curcumin formulation enhanced attention and working memory tasks when compared with placebo, while chronic supplement has shown benefits to working memory and mood along with reduced total and LDL cholesterol (Cox et al., 2015). The available human trials on dementia patients are few and undersized, and they did not show significant and clinically relevant amelioration of cognition measured with neuropsychological tests or in functional reserve or neuropsychiatric symptomatology (Brondino et al., 2014). Resveratrol, on the other hand, has shown controversial results in AD patients that are difficult to interpret, especially in light of previous experimental evidence: resveratrol altered Aβ40 in cerebrospinal fluid (CSF) and in the plasma of AD patients, resulting in a lesser reduction of the marker over time. Aβ42 has shown a similar trend, but it is not statistically significant; resveratrol-treated patients had increased volume loss as measured with MRI (Turner et al., 2015). These results show that it is probable that oral resveratrol administration would exert effects on the CNS, reaching and modifying the CSF environment. However, because the cited study found no clinical difference between AD patients treated with resveratrol and placebo, it is still not possible to determine if the observed changes reflect a change in the pathological course of the illness or if this eventual change consists in amelioration or worsening of the baseline condition. Aβ42 in CSF has been observed to be reduced by more than 50% in AD patients versus healthy controls (Buchhave et al., 2009), so the trend to lesser reduction in time in the resveratrol group could still emerge as a sign of good interaction between resveratrol and the amyloid-burdened CNS. It is more difficult to interpret the brain volume loss, usually a marker of worse prognosis, as a sign of better CNS functioning; in studies of human immunization against Aβ and in trials on bapinezumab (a murine antibody against Aβ), brain volume loss has been observed in the absence of significant clinical implications (Turner et al., 2015). Until new evidence sheds light on the relationship between resveratrol and dementia, caution should be used in administering high doses of resveratrol supplements to patients affected by AD. Similar caution is advised for high-dose supplementation in healthy subjects because experimental findings on animal models suggest possible inhibition of neural progenitor cell duplication (Park et al., 2012). Further studies are needed to better understand this phenomenon.

Vitamins and Related Substances

Vitamin deficiencies often affect the CNS. The role of different vitamins for prevention and treatment of cognitive decline has been investigated in experimental models, epidemiological studies, and interventional trials. In this field, the possible role of B group vitamins and choline (although the latter is not strictly a vitamin) as either a direct metabolic effect or as a homocysteine-lowering therapy, has been treated elsewhere in this book (see Chapter 15 on the role of B group vitamins and choline in cognition and brain aging). Other vitamins recently investigated for the same purpose are vitamins A (Obulesu et al., 2011), C (Harrison, 2012), D (van der Schaft et al., 2013; Schlögl and Holick, 2014), and E (La Fata et al., 2014).

Vitamin A, Retinoids, and Carotenoids

Vitamin A is a generic name that describes substances with activities similar to retinol (Hinds et al., 1997). Retinoids are substances of natural (mainly animal) or synthetic origin, some of which exert biological activity, but not all the members of this group of substances have the same properties. For example, retinol is a precursor of visual pigments while retinoic acid has no visual functions but is a strong modulator of cellular growth and differentiation (Hinds et al., 1997). Carotenoids, on the other hand, are pigments of plant origin with antioxidant properties, some of which can be converted into retinol or retinyl esters (Hinds et al., 1997). Of the hundreds of different members of the carotenoid family, more than 40 have been found in the human body, among them β-carotene, lycopene, and lutein, which have been investigated in search of neuroprotective properties (Mecocci et al., 2014). Common food sources of vitamin A analogs and precursors are liver, eggs, milk, and some vegetables, especially the orange-yellow ones. Vitamin A has a known role in CNS development and differentiation; in the adult brain, its role is poorly understood, but it plausibly maintains regulatory capacities on genic expression and synaptic plasticity, seriously impacting memory and learning. That suggests a possible role in neurodegenerative diseases (Tafti and Ghyselinck, 2007). Plasma and cerebrospinal concentrations of vitamin A have been reported to be lower in AD patients than in controls, and in vitro evidence supports antiamyloidogenic activities for vitamin A and its precursor, β-carotene (Ono and Yamada, 2012). Although suggested as an addition to therapeutic protocols for a wide range of pathologies (skin, blood, retinal, and pulmonary diseases), vitamin A has a narrow therapeutic index that often limits its use. The CNS activity seems to be no exception: animal models indicate that the beneficial neurotrophic activity of retinoic acid can be disrupted by both deficiency and excess intake of this vitamer, resulting in reduced cell proliferation and synaptic activity in the hippocampus (Olson and Mello, 2010). Being provitamins, carotenoids have a better tolerability profile and exert a significant antioxidant effect different from liposoluble retinoids; concerns of teratogenicity and possible cancer promotion for high-dose supplementation in certain populations suggest caution in choosing dosages of supplementation (Russell, 2004). Among carotenoids lycopene and β-carotene have been found to be associated with better cognitive performance in cognitively healthy individuals (Mecocci et al., 2014). Further studies are necessary to determine the possible role of bioactive compounds with vitamin A activity on normal brain aging and neurodegenerative diseases.

Vitamins C and E

Both vitamins C (ascorbic acid) and E (a family of compounds of which alpha-tocopherol is probably one of the most studied in the field of neurodegeneration) are potent antioxidants. In patients affected by AD, lower plasma levels of vitamin C and E have been reported (Lopes da Silva et al., 2014), and dietary intake of both vitamins seems to be protective in terms of AD onset (Li et al., 2012). Different results have been observed when supplementation was adopted. From interventional studies, it emerged that vitamin E could be beneficial in treating patients affected by dementia (Sano et al., 1997; Dysken, 2014). Evidence is not conclusive on the effect of vitamin E supplementation (mainly in the form of alpha-tocopherol) to treat mild cognitive impairment and dementia, and a recent meta-analysis did not show any solid effect (Farina et al., 2012). Similar results emerged from vitamin C supplementation studies (Boothby and Doering, 2005). While vitamin C administration has virtually no side effect, prolonged administration of high dosages of vitamin E (twice or more the recommended tolerable upper intake limit of 1100 international units/day) is discouraged due to suspicions of a possible relationship with increased mortality (Miller et al., 2005), possibly due to reduced vitamin K bioavailability and increased hemorrhagic risk.

Vitamin D

Vitamin D comprises a group of a few natural and synthetic vitamers with similar biological activities (Cashman, 2012). Adequate sunlight exposure on the skin in the presence of normal kidney and liver function is usually sufficient to meet the requirements of young and adult individuals; dietary intake has a minor role in these individuals (Cashman, 2012). Older individuals have a high prevalence of deficiency; in these subjects, dietary intake is often fundamental, especially in terms of supplements (Souberbielle, 2016). Cod oil, eggs, and dairy products are food with sensible concentrations of vitamin D (Stephen, 1975; Cortese et al., 2015). In recent years, vitamin D deficiency has been related to cognitive impairment and reduced hippocampal volume (Annweiler et al., 2013; Karakis et al., 2016). Supplementation with exogenous vitamin D has shown to ameliorate the observed impairment, but the level of performance obtained by supplementation was not statistically different from that of the control group (Annweiler et al., 2013). It is not clear if supplementation of healthy individuals could ameliorate cognitive function.

Methylxanthines

Methylxanthines are alkaloids that can be found in high concentrations in tea, coffee, and chocolate. Theophilline, theobromine, and caffeine are the most popular. They can be found in different concentrations in coffee, chocolate, and tea. Caffeine is the main methilxanthine of coffee; theobromine is abundant in chocolate in which the theobromine–caffeine ratio varies widely, but it is typically higher than 1; and theophilline is the primary methylxanthine in tea (Franco et al., 2013). The common experience is that coffee increases attention; in effect, caffeine and other methylxanthines have been described as being able to act as mild psychostimulants (Lorist and Tops, 2003; Nehlig, 2010; Mitchell et al., 2011; Franco et al., 2013). Epidemiological studies related caffeine consumption in healthy subjects with prevention of neurodegenerative diseases (Nehlig, 2010); in particular it seems that consumption of caffeinated coffee could prevent or defer the onset of AD and PD (Maia and de Mendonca, 2002; Eskelinen et al., 2009; Costa et al., 2010). Methylxanthine mechanisms of action at the CNS level include antagonism of adenosine receptors, regulation of intracellular calcium levels, phosphodiesterase inhibition, and modulation of GABA receptor action (Franco et al., 2013). Moderate consumption of methylxanthine from food sources is safe, but high doses (e.g., caffeine supplements) could produce anxiety and increase heart rate and gastric acid secretion (Franco et al., 2013).

Terpenes

Carnosic and rosmarinic acids, two phenolic acids that can be found in rosemary, seem to act as neuroprotectors in vitro and in animal models (Mecocci et al., 2014). Their mechanism of action is far from being completely understood, and more evidence, especially on human subjects, is needed to express a preliminary opinion on the matter. Surely, as with many other compounds cited in this chapter, terpenes have the requisites to be considered seriously for future research.

Foods, Herbs, Spices, and Dietary Complements With Functional Properties in Terms of Neuroprotection and Possible Cognitive Enhancement

So far we have described the full dietary patterns that are actually identified from retrospective analyses as the healthiest for achieving a successful cognitive aging. We also have examined more extensively the micronutrients assumed to be among the causes of the aforementioned epidemiological data. Now we can focus on complex dietary elements (containing more than one beneficial micronutrient) that have the characteristics to be described as functional foods for cognition with a better comprehension of the possible underlying mechanisms. The majority of them exert mainly neuroprotective effects, while others can be defined nootropics (from the Greek root noos for mind and tropein for toward) (Lanni et al., 2008)—in other words, substances that are able to ameliorate cognitive performances as either acute or chronic effects.

Berries

With the name berries, we group fruits belonging to different plant families (e.g., strawberry, raspberry, and blackberry belong to Rosacee, and blueberry and cranberry to Ericaceae) that have in common a high content of polyphenolic compounds (Skrovankova et al., 2015), vitamins (A, C, E, and B group vitamins with the exception of vitamin B12) in various concentrations. All of them have strong antioxidant capacities (Pribis and Shukitt-Hale, 2014). Currently, several experiments have demonstrated the capacity of berry consumption to slow age-related cognitive decline, enhance neuroplasticity, and ameliorate cognitive functions in animal models of dementia (Balk et al., 2006; Subash et al., 2014). On the basis of experimental evidence, several longitudinal studies are ongoing to ascertain if berries consumption can achieve results in human that are similar to the ones observed for laboratory animals (Pribis and Shukitt-Hale, 2014). Recently, a long-term longitudinal observation conducted on participants in the Nurses’ Health Study has shown lesser cognitive decline in patients with greater intakes of blueberries and strawberries (Devore et al., 2012).

Nuts

Nuts exhibit a singular mix of neuroprotective compounds. They are particularly rich in fats (mainly MUFAs and PUFAs) and soluble fibers, high-quality vegetal proteins, vitamins (folate, riboflavin, and tocopherols), phytosterols and polyphenols, and minerals and trace elements (Ros, 2010; Pribis and Shukitt-Hale, 2014). The most consumed tree nuts are cashews, macadamias, pistachios, hazelnuts, almonds, and walnuts (the latter two are probably the ones among nuts with more evidence of possible effects on cognition). Peanuts, although botanically grouped as legumes, have nutritional characteristics similar to tree nuts and can be grouped with them for the purpose of this chapter (Pribis and Shukitt-Hale, 2014). Numerous experimental and epidemiological studies have correlated nut consumption with better cognitive performance. Antioxidant, anticholinesterase, procholinergic, and cholesterol-reducing activities have been suggested as possible mechanisms of action (Pribis and Shukitt-Hale, 2014). Recently, in a cohort of cognitively healthy adult and elderly Spanish volunteers, the addition of nut intake (30 g/daily of mixed nuts) to a Mediterranean dietary pattern showed improved cognitive function versus a control group fed only with a low-fat diet (Valls-Pedret et al., 2015). Although the latter evidence is biased by the coadoption of MeD (known to exert beneficial effects on cognition), these data should be considered as a solid base for future investigation on the matter.

Olive Oil

Virgin olive oil is a cornerstone of MeD. Although it is a fat, olive oil contains a unique pattern of MUFAs and PUFAs united to a variety of polyphenols (mainly oleuropein aglycone and oleocanthal) that have shown promising results in experimental AD models (Rigacci, 2015). It seems that the polyphenols associated with this plant-derived product could also ameliorate patient lipid profile by reducing LDL and increasing HDL cholesterol and preventing atherosclerosis, maybe due to their capacity to contain lipoprotein oxidation (Hernáez et al., 2014, 2015). Few randomized controlled trials correlate virgin olive oil intake with improved cognitive function (Martínez-Lapiscina et al., 2013; Valls-Pedret et al., 2015), but evidence is still insufficient to determine the real impact of virgin olive oil supplementation.

Fish

Fish is an important source of long-chain n-3 PUFAs, high quality animal proteins, trace elements, and vitamins A, D, and B group (Gil and Gil, 2015). A meta-analysis of 21 cohort studies suggests that consumption of fishery products is associated with reduced incidence of cognitive impairment and dementia (Zhang et al., 2016). This effect on cognitive performance preservation seems to be appreciable even in cohorts of elderly people (Nurk et al., 2007). Actually, there are no sufficient data from randomized controlled trials to establish a sure direct causal effect between fish consumption and cognition, and often researchers focus mainly on O3 rather than on fish itself. However, there is no question that the strong correlation between fish intake and neuroprotection is solid evidence that could itself justify the recommendation to regularly consume fish products. The only concerns emerge from the widespread finding of pollutants in fish, especially those higher in the food chain. Methylmercury is one of the most common pollutants found in fish, but other compounds also have neurotoxic and cancerogenic potential (heavy metals and organic compounds such as organochlorine pesticides, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, dioxins, and dibenzofurans) (Gil and Gil, 2015). Actually, there is no reason to contain an a priori fish intake (Gil and Gil, 2015); the only recommendation is to choose safe and controlled products—as with all other foods.

Allium sativum

Garlic (Allium sativum) has been extensively investigated for its multiple potential health benefits. The documented antioxidant, antiatherogenic, antiapoptotic, and antiamyloidogenic activities of various types of garlic extracts are promising features that define this vegetable generally used for seasoning as a possible functional food for neuroprotection at least in terms of preventing AD and neurovascular damage (Mathew and Biju, 2008). Both aged garlic extract (a specific garlic preparation) (Ray et al., 2011) and fresh garlic (Haider et al., 2008) administration seem to be able to improve memory and cognitive functions in laboratory animals. In the last decades, many bioactive compounds have been extracted from garlic. Allicin seems able to slow down atherosclerotic processes in humans (Mahdavi-Roshan et al., 2013) and prevent oxidative stress–induced apoptosis in cellular models (Chen et al., 2014), thiacremonone exhibited antiinflammatory and antioxidant effects and ameliorated cognitive performance in mouse AD models (Yun et al., 2016), and S-allyl-L-cysteine ameliorated cognitive impairment in mouse AD models, probably like the aforementioned compounds that reduce oxidative stress (Javed et al., 2011) and modulate the intracellular pathways related to synaptic degeneration and neuroinflammation (Ray et al., 2011). Moreover, in addition to cognitive improvement, studies examining the whole extract and not the single components have shown reduced mitochondrial impairment, insulin resistance, plasma cholesterol, visceral fat, and body weight in obese insulin-resistant rats fed with a high-fat diet (Pintana et al., 2014) and increased serotoninergic activity in adult rats (Haider et al., 2008).

Another proposed possible mechanism of action for both neuro- and cardioprotective effects of garlic is enhancement of hydrogen sulfide synthesis (Gupta et al., 2010; Kashfi and Olson, 2013), which was recently identified as a gasotransmitter with beneficial effects on endothelial cells and neuromodulatory properties (facilitating long-term potentiation in hippocampal cells via activation of N-methyl-D-aspartate receptors, which promotes calcium influx in astrocytes and modulates several intracellular signaling cascades related to neurodegeneration) (Kimura, 2013). The only concern about garlic extract administration could be the impaired hippocampal neurogenesis observed after diallyl disulfide administration (Ji et al., 2013). Better characterization of the compounds contained in garlic extract could assist understanding of the effects on the CNS and improve cognitive outcomes. Considering the similarities observed in sulfur-containing bioactive principles in garlic and onion (Allium cepa) (Lanzotti, 2006), it would be interesting also to explore the possible activity on the CNS of this latter vegetable extract.

Cruciferous Vegetables

Epidemiological results from the Hordaland Health Study correlated the consumption of cruciferous vegetables (cauliflower, cabbage, garden cress, bok choy, broccoli, and brussels sprouts, among many others) with better cognitive performance in elderly subjects (Nurk et al., 2010). A possible bioactive molecule responsible for the effects observed in relation to cruciferous vegetable consumption could be sulforaphane, an organosulfur compound (Lee et al., 2014). Sulforaphane reduces cognitive impairment in animal models, seems involved in improving cholinergic neurotransmission (Lee et al., 2014), exerts anxiolytic and antidepressant effects (plausibly inhibiting the hypothalamic–pituitary–adrenal axis and the stress-induced inflammatory response) (Wu et al., 2016), attenuates microglial detrimental interactions with neurons modulating inflammatory response and oxidative stress (Townsend and Johnson, 2016), and improves mitochondrial function (Carrasco-Pozo et al., 2015). Moreover, it has shown significant action on reducing blood–brain barrier disruption when administered acutely in animal models of brain traumatic injury (Dash et al., 2009) and focal cerebral ischemia (Ma et al., 2015). Prospective studies on humans are required to understand the real impact of this family of vegetables on brain aging and the prevention and treatment of neurodegenerative diseases.

Wine, Grape Juice, and Alcohol

Alcohol is a psychotropic substance known to be neurotoxic in a dose-dependent manner, both in acute intoxication and chronic abuse (Costardi et al., 2015). Similar to what has been observed for coronary heart disease (Roerecke and Rehm, 2014), however, light to moderate alcohol intake seems to be protective for the development of cognitive decline and dementia (Peters et al., 2008; Anstey et al., 2009). Some authors observed a J-shaped relationship between alcohol consumption and progression from mild cognitive impairment to dementia (Xu et al., 2009), confirming the strong suspect that the advantage gained by light alcohol consumption is rapidly lost in heavy drinkers. Wine could represent a good form of alcoholic beverage to be consumed in small quantities daily to prevent cognitive decline due to its modest alcohol concentration and concomitant high polyphenols content (Basli et al., 2012) (for resveratrol hypothesized mechanisms of neuroprotection, see the previous section title “Other Polyphenols”). To support this hypothesis, concord grape juice alone (not fermented) has also shown the ability to enhance memory functions even in the absence of alcohol (Krikorian et al., 2010). The possibility of enriching the diet plan of an individual with limited wine intake should balance the possible benefits and risks (biological and psychological) based on the subject’s characteristics and eventual conditions or comorbidities.

Zingiberaceae

Plants belonging to the Zingiberaceae family are rich in polyphenols. Turmeric (Curcuma longa) has been proposed as a neuroprotector. The hypothetical effects of its active metabolite curcumin were previously discussed. In one randomized controlled trial, curcumin ameliorated working memory and attention (Cox et al., 2015), but more evidence is required to understand the possible clinical effect of C. longa on cognition. Zingiber officinalis (ginger) also belongs to the Zingiberaceae family and contains substances similar to the ones found in turmeric; dry ginger extract (Mathew and Subramanian, 2014) and 6-shoganol (Moon et al., 2014) demonstrated neuroprotective activity in vitro. Human evidence is lacking. The only concern is for patients treated with anticoagulants because Zingeiberaceae intake in large quantities could modify their bleeding risk.

Piper nigrum

Black pepper (Piper nigrum) is a spice used widely in many traditional cuisines. Recently, the alkamides present in piper have been studied for their antioxidant and anticholinesterase activities (Tu et al., 2015). Among the alkamides isolated from P. nigrum extract, piperine, piperettine, and piperettyline exhibited inhibitory activities against both acetylcholinesterase and butyrylcholinesterase, while feruperine was a potent inhibitor only of butyrylcholinesterase (Tu et al., 2015). Piper nigrum and piperine improved cognitive functions and exerted antiamyloidogenic activities in animal models of AD (Subedee et al., 2015). Pharmacological research is now aiming to improve piperine bioavailability to develop possible treatments for AD, and there are reports of formulations that have effects similar to donepezil in animal models (Yusuf et al., 2012; Elnaggar et al., 2015). Human studies are lacking, and the utility of piperine still has to be demonstrated in AD patients. Actually, piperine has a recognized role in amplifying the effect of other substances such as curcumin (which increases the bioavailability up to 20-fold when coadministered with piperine) (Patil et al., 2016).

Plants With Anticholinesterase Activity

It has been proposed that AD and age-related cognitive decline could be sustained by an extensive loss of cholinergic activity (Terry and Buccafusco, 2003), which is why AD therapy is now based mainly on cholinesterase inhibitors. Other drugs that improve the cholinergic system activity are considered possible cognitive enhancers. Several plant-derived compounds exhibit anticholinesterase activity in preclinical studies (Konrath et al., 2013; Pinho et al., 2013), but for most molecules human studies are needed to clarify whether these experimental results could be confirmed in vivo. Among actual approved therapies for AD, galanthamine, an alkaloid of natural origin derived from plants belonging to the Amaryllidaceae family, is derived from traditional Chinese medicine and exerts selective action on the enzyme acetylcholinesterase (Ortiz et al., 2012). In addition to cholinergic neurotransmission potentiation, galanthamine has also been described as easing oxidative stress, modulating N-methyl-D-aspartate receptor activity, and upregulating antiapoptotic protein expression (Wu et al., 2011). Trials on humans have shown that galanthamine could be beneficial in ameliorating cognitive deficits in AD patients (Tan et al., 2014) and perhaps also in individuals who suffer vascular-induced cognitive impairment even if to a lesser extent (Birks and Craig, 2006). Other herbal remedies used in Chinese and Ayurvedic medicine have been described as having cholinesterase inhibition properties, among them Huperzia serrata, Salvia officinalis, and Bacopa monnieri have also been studied on humans. Huperzine A is an alkaloid extracted from the plant H. serrata, which was identified in the 1980s as a potent acetylcholinesterase inhibitor. More recently, a meta-analysis of 20 randomized clinical trials found huperzine to be capable of improving cognitive function, daily living activities, and global clinical assessment in AD patients (Yang et al., 2013). Cognitive effects have also been described for vascular dementia (Xu et al., 2012). A small low-quality study reported mnesic benefits in young healthy subjects (Sun et al., 1999). Some authors report an effect comparable to approved treatments for AD like galanthamine and donepezil (Yang et al., 2013). Leafy parts of plants belonging to Salvia species are used in Chinese medicine as herbal remedies for cognitive impairments. At least two sage species (S. officinalis and Salvia lavandulaefolia) have been studied for their hypothetical nootropic properties (Miroddi et al., 2014). S. officinalis extract has antioxidant properties and inhibits acetylcholinesterase in vitro (Wu et al., 2011). A randomized controlled trial in which S. officinalis extract was matched against a placebo in mild to moderate AD patients has shown a better cognitive outcome in the treated group (Akhondzadeh et al., 2003). Essential oil and monoterpenoid extract from S. lavandulaefolia exhibited cognitive-enhancing properties on small groups of healthy adults (Tildesley et al., 2005; Kennedy et al., 2011). A possible bioactive compound responsible for the cognitive effects of sage has been identified as ursolic acid, a pentacyclic triterpenoid carboxylic acid (Wu et al., 2011). B. monnieri, also known as Indian pennywort, is a perennial creeping plant used in Ayurvedic medicine that seems able to improve cognitive performance in neuropsychological tests that require divided attention and programming, reducing choice reaction time (Kongkeaw et al., 2014). The putative bioactive compound responsible for cognitive effects of B. monnieri has been named Bacoside A (a mix of saponins) (Ramasamy et al., 2015). The hypothesized nootropic mechanisms are acetylcholinesterase inhibition, choline acetyltransferase activation, Aβ reduction, increased cerebral blood flow, and monoamine (dopamine and serotonin) potentiation (Aguiar and Borowski, 2013; Ramasamy et al., 2015).

Tea, Coffee, and Cocoa

Tea, coffee, and cocoa share similar micronutrients. The main bioactive compounds found in these foods with possible cognitive implications are polyphenols (flavonoids) and methylxanthines. The hypothesized effects of these substances have been extensively explored in this chapter. Cocoa has shown neuroprotective properties (Nehlig, 2013), and in the Cocoa, Cognition, and Aging Study, the administration of cocoa drinks containing variable concentrations of flavanols in 90 elderly individuals affected by mild cognitive impairment showed a reduction in blood pressure and insulin resistance and an improvement in cognitive functions measured with neuropsychological tests after just 8 weeks of treatment (Desideri et al., 2012); the effect was proportional to flavanol concentration in the treatment. The consumption of tea, coffee, or caffeine has been often related in epidemiological studies to reduce the incidence of cognitive decline and dementia (Arab et al., 2013), but the variability of the populations studied, the small sample size of cohorts, and the short- to mid-term observations do not ensure that these results could not be biased by confounders (Panza et al., 2015); larger and better designed trials are needed to confirm the beneficial effects of tea and coffee on dementia prevention. Acute administration of caffeine, on the other hand, increases alertness and seems to improve performance in memory tasks, but not all individuals respond equally (several studies have shown that extroverts perform better than introverts after caffeine intake) (Liguori et al., 1999; Smith, 2013), and it is possible that caffeine biological mechanisms modulate neural networks strongly affected by mood and behavior.

Gingko biloba

Ginkgo biloba is an ancient plant and has been found in fossils dating to more than 200 million years ago. Ginkgo biloba leaf extract—mainly identified with a mixture of flavonoids, terpenes, and organic acids labeled Egb761—possesses several beneficial properties. In experimental studies, it has been related to improved mitochondrial impairment, antagonism of N-methyl-D-aspartate receptors, scavenging of free radicals, inflammation containment, neuroprotection, and reduction of platelet aggregation (Wu et al., 2011). Meta-analyses on G. biloba’s nootropic and neuroprotective effects have brought controversial results. In 2009, a Cochrane review concluded that no conclusive evidence supported the use of G. biloba for cognitive decline (Birks and Grimley Evans, 2009). More recently, two different meta-analyses agreed on the beneficial effect of Ginkgo extract versus placebo (Weinmann et al., 2010; Tan et al., 2015). This plant extract seems to be safe (the only concern is the augmented risk of hemorrhage, especially in patients who use anticoagulants) (Jiang et al., 2005; Birks and Grimley Evans, 2009). Good-quality trials with adequate statistical power will be required to confirm and quantify the effects of G. biloba leaf extract.

Crocus sativus

Extracts of Crocus sativus, a plant belonging to the Iridaceas family, have shown promising neuroprotective activities in experimental studies. Saffron, a spice derived from the flower of C. sativus, contains three bioactive compounds—crocin, crocetin, and saffranal—that exert antioxidant and antiinflammatory effects on the CNS (Khazdair et al., 2015). Due to interactions with dopaminergic, cholinergic, and glutamatergic systems, it has been proposed as an integration in the treatment of various neurodegenerative disorders, especially AD and PD (Khazdair et al., 2015). In AD patients, saffron supplementation has obtained short-term improvement of cognition measured with neuropsychological testing (Akhondzadeh et al., 2010). To date, there is still not sufficient evidence to confirm the efficacy of saffron’s bioactive components on cognitive decline prevention or dementia treatment, but preclinical and preliminary clinical data are encouraging.

Medical Foods

The definition of medical food in the US Orphan Drug Act (21 U.S.C. 360ee (b) (3)) is “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation” (FDA, 2014). Several medical foods have been developed for treatment of cognitive decline (mainly AD), but we focus here on products that have some evidence of effects on humans (Thaipisuttikul and Galvin, 2012).

Souvenaid®

Souvenaid® is a drink low in calories that has been enriched with a combination of substances (known as Fortasyn Connect) that is supposed to enhance synaptogenesis as observed in animal models (Wurtman, 2014). It contains uridine monophosphate, phospholipids, choline, O3 fatty acids, vitamins, and antioxidants (Thaipisuttikul and Galvin, 2012). Many of these substances can be found in food, but it is difficult to reach the dosages supposed to improve dendritic spine outgrowth with just dietary intake; moreover, uridine in foods usually has a very low bioavailability (Wurtman, 2014). Theoretically improved synaptogenesis should slow or revert cognitive impairment in AD patients, where the disruption of neural networks is a key event in the progression of cognitive decline (de Waal et al., 2014). Few randomized controlled trials are available on human subjects. This medical food appears to be safe, at least for midterm use (48 weeks) (Olde Rikkert et al., 2015). Early instrumental findings in a 24-week trial on drug-naive patients with mild AD treated with Souvenaid® (Souvenir II study) seems to confirm the capability of this medical food of maintaining brain network organization versus a placebo (de Waal et al., 2014). Results from a direct comparison of neuropsychological performances in the Souvenir II study group has shown an improvement in the memory subscale of the neuropsychological test battery used to measure cognitive trajectories, but not in the whole battery score, which presented a not statistically significant trend toward better results in the treated group (Scheltens et al., 2012). New data on long-term administration of this drink will be necessary to properly assess possible effects on AD patients.

Axona®

Axona® is a medical food that contains a medium-chain triglyceride, caprylic acid, that acts as a ketogenic compound and is supposed to bypass the energy metabolism impairment observed in AD patients (Thaipisuttikul and Galvin, 2012). AD patients seem to suffer from decreased glucose use in the CNS, especially the carriers of ApoE4 allele (Ohnuma et al., 2016). Ketogenic diets have shown to be able to improve cognitive performances in AD patients, and these findings have been the basis for the development of a ketogenic medical food. Axona® has shown an ability to ameliorate cognitive functions in ApoE4-negative patients with mild to moderate AD when compared to placebo (Henderson, 2008; Henderson et al., 2009; Roman, 2010; Henderson and Poirier, 2011; Ohnuma et al., 2016). This medical food appears to be safe; the main adverse effects are mild gastrointestinal symptoms and diarrhea (Ohnuma et al., 2016). Further studies are needed to select the patients that can benefit most from this medical food, which still must be assessed to determine whether the effects are only symptomatic or if even a transient amelioration of the energy metabolism resolves in an enhanced neuron survival.

Conclusions

It is incontrovertible that dietary impact on cognitive function is massive. Actually, since effective therapeutic choices are lacking, preventing cognitive decline is the better strategy for facing the expected rise in dementia prevalence. A dietary plan that contemplates low-caloric dishes rich in micronutrients; is low in refined sugars, salt, and fats (especially of animal origin); and has a predominance of plant-derived products and a minor contribution of high-quality animal foods (fish, eggs, low-fat dairy products) is a good approach to pursuing healthy cognitive aging. Particular attention should be paid to reaching an adequate vitamin status, especially late in life when vitamin deficiencies are more common and requirements could be altered by concomitant diseases. In the presence of specific diseases and polypharmacy, a personalized approach (preferably guided by a medical consultant) is certainly more effective than the simple adherence to global guidelines and is safer when speaking of intervention with dietary complements (a product of “natural origin” is not synonymous with “harmless,” especially when rich in bioactive compounds). In the presence of cognitive decline, several foods and spice-derived complements could be helpful before or alongside a pharmaceutical approach. In the face of mounting epidemiological data, few high-quality randomized controlled trials are available to confirm and quantify the effect of the multitude of food-derived substances with possible cognitive effects. Medical foods composed of wide-spectrum bioactive compounds have the possibility of multilevel intervention, which represents a great advantage when compared to the high selectivity of tightly targeted drugs. Actually, only two structured medical foods present evidence of a possible effective approach to cases of severe cognitive impairment. Hopefully, in the next decades a better understanding of the biological mechanisms that underlie neurodegeneration and neuroplasticity will grant us a wider choice of effective therapeutic approaches.

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