Background for a proof of concept study on the effects of tyrosine supplementation on cognitive functions in the PFC in elderly

(1)

10-1-2014

Background for a proof of concept study on the effects of tyrosine

supplementation on cognitive functions in the PFC in elderly

Anne Westerink

U

NIVERSITY OF

A

MSTERDAM

T

HE USE OF

NIRS

AND

EEG

TO INVESTIGATE THE

EFFECTS OF TYROSINE ON DOPAMINE METABOLISM

IN COGNITIVE AGING

Supervisor: Dr. ir. Ondine Nieuwerth - van de Rest (Wageningen University)

Co-assessor: Prof. dr. Reinout Wiers (University of Amsterdam)

MSc in Brain and Cognitive Sciences

Track: Cognitive science

(2)

Abstract

As the number of older adults with cognitive decline and dementia is rapidly increasing, the need arises to gain more knowledge about the processes underlying cognitive aging, so that preventive measures can be developed. Diet is thought to be a promising preventive measure against cognitive decline and therefore very important in the field of (cognitive) aging. The amino acid tyrosine is an important constituent of a healthy diet as it is the precursor for the neurotransmitter dopamine. Dopamine plays a key role in cognitive functioning and is believed to be involved in cognitive aging due to decreasing levels of this neurotransmitter with age. Supplementing dietary tyrosine therefore might increase brain dopamine levels and improve cognitive functioning in older adults. This idea has never been tested and therefore the present paper provides a background for a proof of concept study on the effects of tyrosine supplementation on cognitive functions in the prefrontal cortex (PFC). In addition, electroencephalography (EEG) and near infrared spectroscopy (NIRS) will be discussed to explore whether these techniques might be useful to measure the biological effects of tyrosine supplementation. A large number of studies focused on the course of cognitive decline in normal aging and together provide evidence for the fact that cognitive decline is not global but rather specific, even within domains. Episodic memory for instance declines with age whereas implicit memory is relatively unaffected by age. Evidence from numerous different fields show that dopamine is related to cognition. Most of the different subsets of the dopaminergic system are found to be altered in older adults, resulting in lower dopamine levels and thereby dopamine is considered to play a role in cognitive aging. As dopamine levels are depleted in stressful situations, being stressed might be comparable to the dopamine status in older adults. Tyrosine supplementation studies are only performed in younger adults, and report positive effects on cognitive functioning in stressful situations only, not under normal circumstances. Animal studies reported different effects of tyrosine in younger and older mice, indicating that older adults indeed might react differently to tyrosine under normal circumstances, in a way it might be beneficial. Both EEG and NIRS are relatively cheap and non-invasive techniques that require technically easy procedures. Although these techniques have not been used before to measure the effects of tyrosine before, a growing number of studies used these techniques in nutritional interventions to assess the effects of other dietary supplements in a quantified manner. These studies show the usefulness of these techniques in nutritional neuroscience and therefore the present paper argues that EEG and NIRS together will be suitable to be used in studies examining the effects of tyrosine supplementation in older adults.

(3)

List of abbreviations

PFC Prefrontal cortex EEG Electroencephalography NIRS near infrared spectroscopy

DR Dopamine receptor

COMT Catechol O-methyltransferase TH Tyrosine hydroxylase

L-DOPA L-DOPA

DDC Decarboxylase

VMAT Vesicular monoamine transporter DAT Dopamine transporter

MAO monoamine oxidase

PET Positron emission tomography

VMAT2 Vesicular monoamine transporter type 2 SPECT Single-photon emission computed tomography ROS Reactive oxygen species

MCI Mild cognitive impairment

(f)MRI (function) magnetic resonance imaging SSVEP Steady state visually evoked potential qEEG Quantitative

ω Omega

PUFAs Polyunsaturated fatty acids ERP Event related potential CBF Cerebral blood flow Oxy-Hb Oxygenated hemoglobin Deoxy-Hb Deoxygentated hemoglobin EOC Essence of chicken

(5)

The use of NIRS and EEG to investigate the effects of tyrosine on dopamine

metabolism in cognitive aging

Background for a proof of concept study on effects of tyrosine supplementation on cognitive functions in the PFC in elderly

Introduction

Nutritional neuroscience is a rapidly growing interdisciplinary field of interest. It is getting more and more apparent that dietary factors not only play a profound role in brain maturation, but also have important impact on our cognitive abilities and mental performance. Furthermore, the idea that adding certain nutrients to your diet might have beneficial effects on people suffering from various psychiatric diseases gets more and more attention. However, the biological mechanisms of this interaction between our brain and diet are complex and for a large part not yet understood. Nevertheless, research so far described several ways in which diet may affect brain function and neurochemistry. Composition of neural cell membranes and synapses partly depends on dietary intake. Fatty acids for instance are fundamental constituents of nerve cell membranes and thereby play an important role in proper cell functioning (Piomelli, Astarita, & Rapaka, 2007). As several fatty acids can only be obtained from our diet, the choices we make regarding our food have direct impact on our brain. Furthermore, the availability of precursors required for the synthesis and function of neurotrophic factors, psychoactive hormones and neurotransmitters can also be modulated by food and nutrient intake (Georgieff, 2007). In addition, nutrients can act as enzyme cofactors required for the above-mentioned processes. Nutritional effects on brain function (e.g. changes related to cell signaling and energy supply) can be short lasting. For example, in patients suffering from remitted major depressive disorder, acute tryptophan depletion induced a transient return of depressive symptoms over a 24 hour period (Neumeister et al., 2004). Supplementation of nutrients on the other hand, can have long-term effects on brain function and structure. Isaacs, Morley, and Lucas (2009) for example assessed cognitive functioning at age 8 and 16 of children who were born at or below 30 weeks of gestation and who participated in a randomized trial on the effects of an early dietary intervention. The children received either a standard-nutrient diet or a high-nutrient diet for a couple of weeks after birth. At age 16 as well as at age 8, children who received the high-nutrient diet had higher scores on several cognitive measures than children who received the standard-nutrient diet. Thus, short-term interventions can have quite important long-term effects on neurodevelopment.

(6)

Another field where diet seems to be very be important, is (cognitive) aging, as diet is thought to be a promising preventive measure against cognitive decline. The number of older adults with cognitive decline and dementia is rapidly increasing. Subsequently, its burden on society and the health-care system will increase as well. Therefore, the need arises to gain more knowledge about the processes underlying cognitive aging, so that preventive measures can be developed. One of the factors that have been proposed to influence the decline in cognitive functioning seen in normal aging is a decrease in the levels of the neurotransmitter dopamine (Bäckman, Lindenberger, Li, & Nyberg, 2010). Dopamine plays a key role in processes such as reward-motivated behavior, motor control and cognitive functioning. The precursor for dopamine is the amino acid tyrosine. Therefore, supplementing dietary tyrosine for older adults might be a possible preventive strategy to improve cognitive functioning by increasing dopamine levels. This idea however, has never been tested and therefore the present paper will provide a background for a proof of concept study on the effects of tyrosine supplementation on cognitive functions in the prefrontal cortex (PFC). The following research question will be discussed:

 Can tyrosine supplementation increase brain dopamine levels of older adults, and thereby improve cognitive functioning?

To answer this question, the following sub questions will be discussed: o What is the course of cognitive aging?

o How is dopamine related to cognitive aging?

o What is known in the current literature about the relation between tyrosine and

cognition?

Besides this relation between cognitive aging, dopamine and tyrosine, electroencephalography (EEG) and near infrared spectroscopy (NIRS) will be discussed to explore whether these techniques might be useful to measure the biological effects of tyrosine supplementation. Therefore, an additional research question is:

 Can the biological effects of tyrosine supplementation be measured with EEG/NIRS?

The focus will be on the PFC, as it is a key region for cognitive functioning, neurons in the PFC are thought to be particularly sensitive to (cognitive) aging, and because the PFC is the best region to measure when using NIRS (Bäckman, Nyberg, Lindenberger, Li, & Farde, 2006; Mather, 2010).

(7)

Cognitive aging and decreasing dopamine levels

Although we gain more knowledge and experience greater emotional balance, we also experience a decrease of our bodily functions, processing speed and memory as we grow older. We all know that these declines are part of a normal aging process, but we also know that there is an enormous variability between persons in the declines they experience when growing older. This variability depends on several factors; how healthy our brain and body are, cognitive challenges we encounter, and skills that are practiced in everyday life.

Aging and cognition

As the number of older adults with cognitive decline and dementia is rapidly increasing, a growing number of studies has been focusing on the course of normal aging and its neural substrates. After all these different studies, a general consensus emerged about which cognitive abilities are sensitive to aging and which are not (Salthouse, 2010). Normal aging is not associated with global cognitive decline, but rather specific to certain domains, and even within domains. Memory for instance, declines with age for some subsets (episodic memory, autobiographical memory, false memory, source memory, prospective memory), whereas other subsets are unaffected by age (implicit memory, flashbulb memory, familiarity), or even increases with age (semantic memory) (for review see Drag & Bieliauskas, 2010). In addition, sustained attention is relatively unaffected by age whereas selective attention is susceptible to age-related decline. Although older adults often have difficulties finding the right words, language is also relatively unaffected by age. The difficulties they encounter are mostly due to retrieval difficulties rather than a loss of semantic information (Mortensen, Meyer, & Humphreys, 2006). Emotion, as mentioned above, even increases its influence on cognition, making older adults more positive (Mather, 2010). Visuospatial and executive functioning on the other hand do decline with age. In a review, Salthouse concluded that there are two trends typically found in cognitive aging research; for measures regarding acquired knowledge an increase until about the age of 60 followed by an onwards decrease is seen, and regarding measures of efficiency or effectiveness of processing a nearly linear decline from early adulthood is typically found (Salthouse, 2012). Although not all of the mentioned cognitive abilities are located in the PFC, this region plays a key role in the organization of these abilities as it is the main region associated with executive functions. Executive functions modulate the activity of other cognitive functions in a flexible and goal-directed manner. Components of executive functioning are diverse but share a common dependence on the PFC, which is extensively connected to other brain regions (Drag & Bieliauskas, 2010). For executive functions the same idea holds as for the other mentioned cognitive abilities; some components decline with age, whereas others are relatively unaffected. What makes the

(8)

discussion of executive functions difficult however, is the fact that there is no clear agreement about what executive functions are, as was concluded in a review by Jurado and Rosselli. In addition, Jurado and Rosselli discuss several processes often studied and believed to be subcomponents of executive functions, that are thought to decline with age, including attentional and inhibition control, planning, set shifting and verbal fluency. However, caution is warranted as they conclude that evidence is inconsistent, partly due to differences in measuring methods (Jurado & Rosselli, 2007).

Working memory is an example of a component that is said to be part of the executive functions by some scholars, whereas other scholars believe it is a process related to executive functions. Whether it is a subcomponent or not, it is really important process as all executive functions are considered to rely on this capacity-limited short-term information store, and is studied very often. Working memory enables the maintenance of rules and of the information that guides the execution of those rules. Therefore, it places a high demand on cognitive resources and is highly susceptible to cognitive aging as more demanding cognitive processes are more influenced by age than processes demanding less cognitive resources (for review, see Reuter-lorenz & Park, 2010). This phenomenon is explained by neuroimaging studies showing that older adults activate more and other brain regions during cognitive tasks than younger adults, a process called overactivation (Reuter-lorenz & Park, 2010). It is hypothesized that due to aging the ‘normal’ brain regions associated with certain tasks (those seen in younger adults) are not capable anymore to complete the task, and therefore other brain regions are activated to compensate, often in the frontal lobes. So with relatively easy tasks, no differences in performance are found between younger and older adults, but there is a difference in the activation of brain regions. With more complex tasks, demanding more cognitive resources, a difference in performance can be seen between younger and older adults. It is hypothesized that this is the case because older adults already had to activate their extra executive resources for the less demanding task, so there is no cognitive reserve left to complete more demanding tasks (Cappell, Gmeindl, & Reuter-Lorenz, 2010). However, increased activity is not always related to better performance, and therefore it is sometimes hypothesized that increased activation during tasks seen in older adults reflects less efficient use of neural resources, instead of overcompensation (for review, see Grady, 2012). In addition, dedifferentiation as a mechanism to explain the observed differences between older and younger adults also has been proposed. This concept holds that older adults experience a reduction in the selectivity of responses. Where younger adults have activation patterns that are quite selective for specific stimuli or tasks, activation patterns of older adults are much less distinct between different tasks and stimuli (Grady, 2012).

(9)

Although many studies investigated these changes in cognitive abilities that accompany normal aging, there is still debate about which specific mechanisms underlie these changes. Several theories try to explain these changes on different levels. At the process level for instance, the inhibitory control hypothesis and the speed of processing hypothesis argue that a large portion of age-related changes can be explained by either a decreased efficiency in inhibitory processes or by the speed in which older adults process information. Arguing for a more localized level, the frontal aging hypothesis states that many of the cognitive deficits associated with cognitive aging can be accounted for by declines in frontal efficiency, as the frontal lobes are particularly sensitive to the aging process. A neurochemical level theory that received a lot of attention is the dopamine hypothesis of aging. It posits that the cognitive deficits associated with normal aging are mediated by age-related dysregulation in the dopamine system. This hypothesis will be further elaborated below.

Cognitive aging and dopamine

Before discussing the dopamine hypothesis, the role of dopamine in cognitive processes will be discussed. The link between dopamine and cognition became apparent when patients suffering from Parkinson’s disease had difficulties accomplishing executive functions. As Parkinson disease is caused by a loss of dopamine neurons in the substantia nigra, it was already known that these patients had dopamine deficiencies and therefore the association between dopamine and cognition gained attention. After many years of research, it is known that dopamine indeed is related to cognition and the regulation of behavior (for review, see Nieoullon, 2002). Although the exact working mechanism is not yet known, evidence from patient, animal, electrophysiological, genetic, pharmacological and neurocomputational studies shows several ways in which dopamine is related to cognition (Bäckman et al., 2006). Glickstein and colleagues for example observed that mutant mice, lacking dopamine D2 and D3 receptors (DR) had impaired spatial working memory (Glickstein, Hof, & Schmauss, 2002) and showed differential activation of prefrontal cortical neurons in tasks requiring sustained attention (Glickstein, Desteno, Hof, & Schmauss, 2005). An example of genetic studies involves allelic variants of the gene encoding for Catechol O-methyltransferase (COMT), an enzyme that inactivates extracellular dopamine, particularly dominant in regulating dopamine levels in the PFC (Karoum, Chrapusta, & Egan, 1994). Two common variants of the gene are Val and Met, of which the enzymatic activity of the Val variant is three to four times higher than of the Met variant (Lotta et al., 1995). As a result, dopamine activity in the PFC is lower for Val carriers than for Met carriers (Egan et al., 2001). One example of the many COMT-related studies that have been performed comes from De Frias and colleagues. They observed that carriers of the Met/Met genotype (low enzymatic activity) performed better on tasks assessing episodic and semantic

(10)

memory (de Frias et al., 2004), executive functioning and visuospatial tasks (de Frias et al., 2005). In addition, they observed that carriers of the Met allele remained stable in performance, whereas carriers of the Val/Val genotype declined in executive functioning over a period of 5 years (de Frias et al., 2005). These examples of the enormous body of evidence available these days show that dopamine is involved in cognition. An experimental study from Morcom et al. nicely illustrates that dopamine is also involved in the relation between age and cognitive functions. In their study, younger and older adults received a DR2-like antagonist, agonist and a placebo. They observed that boosting or suppressing the dopaminergic system yielded different responses in brain regions and cognitive measures of memory between older and younger adults (Morcom et al., 2010). This implies that the dopaminergic system may be a key in understanding age-related changes seen in brain systems underlying memory. Many different components make up the dopaminergic system. The rate of dopamine synthesis is limited by tyrosine hydroxylase (TH). TH catalyzes the hydroxylation of tyrosine to levodopa (L-DOPA), which is converted into dopamine through decarboxylation by the enzyme dopamine decarboxylase (DDC). The vesicular monoamine transporter (VMAT) transfers dopamine to the synaptic vesicle for storage until release through depolarization at the terminal site. The dopamine transporter (DAT) terminates dopamine transmission through reuptake into the presynaptic neuron. Termination also occurs through metabolism by COMT, monoamine oxidase (MAO)-B within glia surrounding the terminals, and within the neuron itself by MAO-A. Postsynaptic, there are five different dopamine receptors that either lead to stimulation via GTP-binding proteins (DR1 and DR5 subtypes) or inhibition via the adenylate cyclase second messenger system (DR2, 3, 4 subtypes; Reeves, Bench, & Howard, 2002).

Several of these dopaminergic markers, both pre- and postsynaptic, have been investigated to be potentially involved in the decline of dopamine levels (see Reeves et al. 2002 and Rollo, 2009 for review). Although in vivo data of TH measures are unfortunately not yet available, postmortem studies suggest that TH levels declines with age (Reeves et al., 2002). Weickert et al. for instance investigated TH changes throughout postnatal life in healthy individuals (age 2 months – 86 years). They observed the highest TH concentrations in the PFC of neonates and concentrations then declined in ages 14 and above (Weickert et al., 2007). Haycock et al. observed an increase in TH levels until two years of age, followed by an onwards age-related decrease in striatal regions of healthy subjects (age 1 day to 103 years), although this decrease was not statistically significant (Haycock et al., 2003). Regarding DDC, Haycock et al. found the same trend as for TH levels, an increase until age 2, followed by a decrease, although the oldest age group had higher levels as the three age groups below. This decrease however, was not significant

(11)

either. Reeves et al. suggested in their review that DDC decreases with age, based on both postmortem and in vivo studies, although they concluded that more research was needed as many inconsistencies were reported (Reeves et al. 2002). More recently, Braskie et al. used positron emission tomography (PET) to study striatal DDC levels in healthy younger and older adults. In contrast with earlier studies, they observed an upregulation of DDC function with age (Braskie et al., 2008). They argued that this inconsistency with earlier studies was due to the fact that DDC activity is highly susceptible to postmortem conditions, and therefore influences the results. Clearly, more research is needed to investigate age-related DDC changes. Troiano et al. used PET in healthy human subjects to determine the expression of DAT and the VMAT type 2 (VMAT2) in striatal regions. They observed a linear decline of DAT with age in all striatal segments, whereas VMAT did not display an aging effect (Troiano et al., 2010). Regarding DAT, these findings are in concordance with earlier PET-studies (Erixon-Lindroth et al., 2005; Ishibashi et al., 2009; Volkow et al., 1998). Studies using post-mortem samples (Haycock et al., 2003) and single-photon emission computed tomography (SPECT; Eusebio et al., 2012) also observed age-related declines in DAT. However, regarding VMAT2, Frey et al. did observed an age-related decrease in putamen using PET (Frey et al., 1996). These discrepancies might be partly explained by a difference in the chemical structure of the ligand both studies used. In addition, studies using post-mortem samples from human brains did not find a reduction with age either (Haycock et al., 2003; Tong et al., 2011). As there are no other in vivo PET studies available yet, more research is needed to create a clear picture of the age-related changes. Nicotra et al. reviewed studies on the expression of monoamine oxidase during development and aging. They reported that human postmortem studies to MAO-A and B activity have shown a generalized age-related increase in MAO-B activity, and little or no variation in MAO-A activity (Nicotra, Pierucci, Parvez, & Senatori, 2004). In addition, studies using PET also observed increases in MAO-B activity with age (Fowler et al., 1997). The postsynaptic markers are the dopamine receptors, of which subtype D1 and D2 received a lot of attention during the past decades. Several studies used PET to assess receptor densities with age and observed age-related declines in, amongst others, striatal regions and frontal cortex for both DR1 and DR2 (Bäckman et al., 2011; Ishibashi et al., 2009; Kaasinen et al., 2000; J.-H. Kim et al., 2011; MacDonald, Karlsson, Rieckmann, Nyberg, & Bäckman, 2012; Volkow et al., 1998; Wang et al., 1998). This is consistent with studies using post-mortem samples (Rinne, Lönnberg, & Marjamäki, 1990; Weickert et al., 2007).

All these changes that occur during aging in the expression and activity of dopaminergic markers might explain why less dopamine is available in older adults. When tyrosine hydroxylase activity is decreased, less tyrosine will be catalyzed into L-DOPA so less dopamine can be synthesized. Although at first more

(12)

dopamine might be available when a lower number of dopamine transporters is expressed, it is possible that these increased dopamine levels lead to a functional down-regulation of dopamine receptors in these neurons (Erixon-Lindroth et al., 2005). When less receptors are available, the effect of dopamine will decrease as fewer receptors are available to transport the signal. In addition, increased MAO-B activity will decrease the available dopamine in the synaptic terminal as more dopamine will be metabolized. During the past decades, several hypotheses have been proposed to explain this molecular basis of aging. The most studied and accepted one is the free radical theory of aging (Harman, 2006). Oxidative stress is the imbalance between pro-oxidants (reactive oxygen species [ROS]; mainly produced by mitochondria using oxygen for energy production) and antioxidants (enzymes, endogenous and dietary). ROS are essential for several physiological systems, like immunity and intracellular signaling, but are potentially toxic at high levels and may cause oxidative damage (cellular impairment) by altering DNA, proteins and lipids (for review see: Salmon, Richardson, & Pérez, 2010). Despite the efficient defense of antioxidants and other damage repair systems we have, some oxidative damage is inherent to a life depending on oxygen. As this damage accumulates during the lifespan, this is how oxidative stress is thought to control the aging process.

Tyrosine supplementation

As mentioned above, dopamine plays an important role in cognition, and decreasing dopamine levels play a role in the decline of cognitive functions in older adults. As there are currently no treatments available to cure or stop the progression of neurodegenerative disorders, the search for preventive measures is very important. Diet is one of those measures, of which several aspects have been investigated already. A recent longitudinal study followed elderly over a mean period of 3.7 years and assessed the association between the percent of daily energy from macronutrients and incident mild cognitive impairment (MCI) or dementia. A high % carbohydrate intake was associated with an increased risk of MCI. High % fat and high % protein intake on the other hand were associated with a reduced risk of MCI or dementia (Roberts et al., 2012). This indicates that supplementing essential dietary components such as fatty acids and proteins – and its constituents amino acids – might be a promising strategy to prevent neurodegenerative disorders among elderly. As mentioned above, tyrosine is the precursor for dopamine, and therefore essential for proper neurotransmission. The ingestion of tyrosine modifies the tyrosine uptake in the brain, and consequently the dopamine synthesis and release, which in turn has effects on mood, cognition and physical performance as will be discussed below (Fernstrom, 2013).

(13)

Tam and Roth reviewed studies on the influence of tyrosine availability on mesoprefrontal dopaminergic neurons (neurons that originate in the ventral mescencephalon and innervate the medial PFC). Compared to other dopamine neurons such as the mesolimbic and nigrostriatal, these mesoprefrontal neurons possess unique characteristics including a faster firing rate and more bursting activity, increased transmitter turnover and they are more susceptible to activation by stress or conditioned fear. Because of their rapid firing rate in basal state, these neurons are especially susceptible to the influence of precursor availability (Tam & Roth, 1997). Under normal circumstances, tyrosine administration or depletion does not affect the synthesis of catecholamines (epinephrine, norepinephrine and their precursor dopamine) in, and their release from, catecholamine neurons. However, when these neurons were experimentally manipulated to increase firing rates and transmission turnover, administration of tyrosine did enhance catecholamine metabolism. So only when the neurons showed increased activity, tyrosine availability had influence. Although the mesoprefrontal neurons show an increased basal firing rate, they are not influenced by tyrosine supplementation under normal circumstances. Animal studies using different doses of tyrosine to enhance dopamine synthesis revealed that a higher dose increased tyrosine hydroxylation rapidly, but the increased levels of endogenous dopamine were normalized by end-product inhibition. A smaller dose of tyrosine, however, caused tyrosine hydroxylation to increase more persistently, as the levels of endogenous dopamine did not increase enough to activate the negative feedback control on tyrosine hydroxylase activity. On the one hand, these mesoprefrontal neurons are very susceptible to precursor availability, but on the other hand synthesis is tightly regulated by feedback control through changes in endogenous dopamine levels. So under normal circumstances, these neurons are not significantly influenced by tyrosine supplementation. However, stress elevates the activity of dopamine neurons, which increases the need for precursor availability. A recent study using PET to measure in vivo dopamine release in the medial PFC, provided human evidence for the stress-induced hypothesis of increased dopamine activity. In humans as well, stress induces an increased activity in medial prefrontal dopamine neurons (Nagano-Saito et al., 2013). When dopamine activity is increased, more tyrosine is needed for dopamine synthesis. Indeed, animal studies revealed that tyrosine supplementation under stressful circumstances does influence dopamine output, in contrast to supplementation under normal circumstances (Tam & Roth, 1997).

This depletion of dopamine under stress has drastic consequences for cognitive performance. Both animal and human studies observed decrements in cognitive functioning of subjects under stressful circumstances (Lupien, Maheu, Tu, Fiocco, & Schramek, 2007; Tam & Roth, 1997). Interesting is then to see whether supplementation of tyrosine in these stressful circumstances might prevent a decline in

(14)

cognitive functioning. Unfortunately, not many studies addressed this hypothesis, as was concluded by Van de Rest et al. in a recent review about the role of dietary protein and amino acids in cognitive functioning and decline. Regarding tyrosine, Van de Rest and colleagues discussed nine human tyrosine supplementation studies, and concluded that eight studies observed improvements in cognitive performance under stressful conditions after tyrosine supplementation (van de Rest, van der Zwaluw, & de Groot, 2013). Five studies observed improvements in working memory, which is in line with findings that the mesoprefrontal dopamine neurons are critical for the processing of working memory (Tam & Roth, 1997). Furthermore, three studies observed improvements in reaction time after tyrosine supplementation, and two studies reported beneficial effects of tyrosine supplementation on vigilance and psychomotor time after sleep deprivation.

Unfortunately, all of these supplementation studies are performed in young men and women, whereas it would be very interesting to test the effect of tyrosine supplementation in older adults, as aging is associated with a decline of dopamine levels. Aging therefore, might be comparable to stressful situations where depleted dopamine levels are the reason for the effectiveness of tyrosine supplementation. Scarce evidence from animal studies is available that compares the effects of tyrosine supplementation in younger and older animals. Brady et al. observed that a tyrosine rich diet enhanced aggressive behavior in younger mice (3 months), but not in older mice (21 months). In addition, dietary tyrosine supplementation strongly reduced aggression and debilitating motor effects induced by cold swim stress in older mice, whereas this reduction was much smaller in the younger mice (Brady, Brown, & Thurmond, 1980). On the other hand, Thurmond and Brown did not find any differences between younger mice (3 months) and older mice (22 months) regarding motor activity and aggressive behavior under control conditions or after cold swim stress. Also, the administration of dietary tyrosine did not significantly influence behavior in both groups under control and stressful circumstances. However, when they tested even older mice (30 months) they observed large differences in both behaviors in the stress condition in comparison with the younger mice groups. Aggressive behavior and motor activity were strongly reduced in the stress condition in the oldest mice. Administration of dietary tyrosine did not reverse these differences. Interestingly, when the oldest mice were fed a tyrosine-rich diet in the non-stressed condition, their motor activity significantly increased, which was not the case when they received a casein-rich diet (control supplement) in the non-stressed condition, and was not the case either for the younger mice groups (Thurmond & Brown, 1984). Normally, tyrosine supplementation only influences dopamine output under conditions where the activity of the neurons is increased, as we

(15)

situation with increased neuron activity (in both situations dopamine levels are low) and thus tyrosine supplementation might be beneficial for the aging brain as well.

Although these results are partly inconsistent and preliminary as they have not been replicated yet, they indicate that older and younger mice react different to dietary tyrosine supplementation. Therefore, it would be very interesting to see if tyrosine supplementation would be beneficial for older human adults under normal circumstances. In light of the mice experiments, an improvement in motor activity can be expected, but an increase in cognitive functioning as well when looking at the human studies to stress, tyrosine supplementation and cognitive functioning. Protein supplementation already has been shown to positively influence physical performance in frail elderly (Tieland et al., 2012). Since dopamine is also involved in physical performance, these findings show that nutritional interventions are at least beneficial for this particular dopamine system. This might be an indication that the cognitive dopamine system could benefit from nutritional interventions as well, being a promising future for the cognitive aging brain. However, what is important to keep in mind in nutritional intervention studies using amino acids, tyrosine is dependent for its transport through the blood brain barrier on the same transporter as several other amino acids like tryptophan, phenylalanine and valine. So when concentrations of one of these amino acids increases, concentrations of the other amino acids decrease (Fernstrom, 2013).

The use of NIRS and EEG in nutritional interventions

The tyrosine supplementation studies discussed above, all used paper and pencil or computerized tests to measure the effects of tyrosine. However, nowadays imaging techniques are becoming more popular as these methods are more objective and sensitive. Some studies for instance might not find behavioral effects using paper and pencil tests, but because the nutrient that is supplemented is present in the body/brain, it might be the case that certain biological changes do occur in the absence of measurable behavioral changes, which can be measured with imaging techniques. In the field of nutritional neuroscience, quite some different brain imaging techniques are available, which enable us to deepen our understanding of dietary influences on our brain on a more biological level (Sizonenko et al., 2013). Both structural and functional magnetic resonance imaging ([f]MRI) are techniques that are often used for studies in many different fields, including nutritional neuroscience to measure biological effects of nutritional intervention studies. For instance, the effect of different breakfasts on brain activity was measured with fMRI, showing increased activity in the medial PFC during a working memory task after a nutritionally balanced breakfast than after either water or a water/sugar mixture (Akitsuki, Nakawaga, Sugiura, & Kawashima, 2011). Using MRI scans, Smith and colleagues assessed effects of the lowering of

(16)

plasma homocysteine through vitamin B supplementation on the rate of brain atrophy in elderly subjects with MCI. They concluded that treatment with homocysteine-lowering B vitamins slows the accelerated rate of brain atrophy in these elderly (Smith et al., 2010). These examples show that imaging studies are very useful to measure nutritional effects on brain measures. As fMRI and MRI are quite expensive and time consuming methods, the present paper will focus on two techniques that are relatively cheap, non-invasive and require procedures that are technically easy: electroencephalography (EEG) and near infrared spectroscopy (NIRS). Although these techniques have been shown to be feasible methods to measure neural correlates of human behavior and have been used before in a few nutritional interventions, to the best of our knowledge they have never been used before to measure the effects of tyrosine supplementation.

Electroencephalography

EEG recordings measure electrical brain waves that can be detected at the scalp. These brain waves are elicited by neural communication, which is electrochemical. Neurotransmitters released in the synapse create voltage changes in the receiving neuron, which causes the neuron to release its own neurotransmitter affecting other neurons. Rather than reflecting the firing of one single neuron, the EEG signal reflects the summed dendritic field potential of groups of neurons aligned in the same direction; perpendicularly to the cortical surface. Only the synchronized firing of many neurons (pyramidal cells; 10.000 – 100.000) elicits enough fluctuations in voltage to be picked up by the scalp electrodes (Paus, 2010).

Several nutritional intervention studies showed that dietary components can influence the EEG signal, often in relation with cognitive measures. In a randomized controlled trial, Macpherson et al. tested the effect of multivitamin supplementation in elderly women on the steady state visually evoked potential (SSVEP) measure of brain activity. They observed that in the women who received the multivitamin treatment, the midline SSVEP latency, but not the amplitude during working memory retrieval increased significantly. No effects of the multivitamin supplementation on behavioral measures were identified (Macpherson, Silberstein, & Pipingas, 2012). The effects of cobalamin (vitamin B12) on cognitive performance and cerebral function in older cobalamin-deficient persons were assessed by Van Asselt et al. in a placebo controlled intervention study. Besides alterations in brain activity, Van Asselt and colleagues observed improvements in cognitive functioning in elderly after receiving cobalamin supplementation. After five months of supplementation, subjects improved their scores on several neuropsychological tests compared to baseline measures. This improvement was not seen after one

(17)

month of treatment with placebo, where on the contrary a decrease in test score of some of the neuropsychological tests was seen. Regarding brain activity, quantitative EEG (qEEG) worsened as well after the placebo period; more slow activity was seen and less fast activity. However, after the cobalamin period, the improvements in cognitive functioning were accompanied by electrographically improved cerebral function; qEEG showed less slow activity and more fast activity (Asselt et al., 2001). A recent study by Konagai et al. assessed the effects of krill oil containing omega (ω) 3 polyunsaturated fatty acids (PUFAs) incorporated in phosphatidylcholine on brain function in healthy elderly males. Besides krill oil, one group received sardine oil, rich in PUFAs incorporated in triglycerides, and another group received medium-chain triglycerides as placebo. They focused on the P300, which is an event related potential (ERP) component and is considered to reflect cognitive processes such as decision making. The latency of the P300 is thought to reflect the rate of information processing, whereas the amplitude reflects the amount of mobilization of processing resources. At 12 weeks a significant decrease in P300 latency during a working memory task was observed in the group who received krill oil supplementation compared to the placebo group. No differences in amplitude between the treatment groups were observed. The authors argued that the supplementation of krill oil in elderly might improve the reduction of cerebral function associated with aging, as the P300 latency is known to be prolonged with aging. No data regarding the scores on the cognitive tests of the different groups were reported by the authors (Konagai, Yanagimoto, et al., 2013). Foxe et al. recorded brain activity using EEG while testing the effects of caffeine and theanine on the maintenance of vigilance during a sustained attention task. They observed that caffeine significantly reduced alpha-band oscillatory activity, particularly in the first hour, which suggests improved attentional processing. When theanine was added to the caffeine ingestion, this effect did not change. In addition, theanine alone did not alter brain activity. However, both nutrients alone and combined, indeed improved sustained attention, as was suggested by the decrease in alpha activity regarding caffeine (Foxe et al., 2012).

These studies show that nutrients can influence brain functioning – with or without measurable effects on cognitive performance – and that EEG is a useful technique to measure these electrophysiological effects of nutritional interventions. Besides measuring the effects of nutrients, EEG is also used to assess effects of aging on brain activity, as was already shortly mentioned above regarding the prolonged P300 latency seen in aging. Prichep et al. used EEG to predict the longitudinal cognitive decline in normal elderly with subjective complaints. They argued that although a lot of studies demonstrated significant relationships between cognitive decline and brain electrical activity, few studies used these relationships to predict future deterioration. Over a 7-year period, Prichep and colleagues followed elderly with

(18)

subjective cognitive complaints without objectively manifest cognitive deficits. When cognitive impairment increased over time, the elderly were named decliners; the group whose impairments did not increase were called decliners. When baseline qEEG of decliners was compared to that of non-decliners, highly significant differences were found. Decliners showed increases in theta power, slowing of mean frequency and covariance among regions (Prichep et al., 2006). In an earlier study, Prichep et al. already showed that qEEG measures are a sensitive index of degree of cognitive impairment (Prichep et al., 1994).

Near infrared spectroscopy

NIRS is a technique that uses light to detect changes in cerebral blood flow (CBF). Because human tissue is relatively transparent to light in the NIR spectral window (650-1000 nm), this light can pass through the scalp and illuminate brain tissue. Diodes placed on the head emit light, which passes through the brain tissue in a predictable banana-shaped pattern to photodetectors, placed at a set distant away from the diode. The light is either absorbed by pigmented compounds (chromophores) or scattered in tissues. Oxygenated hemoglobin (oxy-Hb) and deoxygenated hemoglobin (deoxy-Hb) are both chromophores, but absorb light at slightly different wavelengths (800-940 nm and 600-750 nm, respectively). When the amount of light absorbed in these specific wavelengths is measured, it is possible to quantify their concentration when light passes through the brain tissue. By measuring the changes in oxy-Hb and deoxy-Hb, neuronal activity can be assessed indirectly based on the neurovascular coupling principle of neuronal activity and blood flow, on which fMRI measures are based as well. NIRS has a high temporal resolution, whereas the spatial resolution is limited because the distant between the source and photodetectors should be sufficient to allow sensitive measurements of tissue absorption. Therefore, only the hemodynamic response and CBF in the upper layers of the cortex can be measured. Most of the measurements done so far only assessed the PFC, as hair does not interfere with the diodes and photodetectors placed on the forehead. The history, use and technique of NIRS as an index of brain and tissue oxygenation is reviewed in more detail by Ferrari and Quaresima (2012).

Since several years an increasing number of studies uses NIRS in many different fields of interest; psychiatry (Ehlis, Schneider, Dresler, & Fallgatter, 2013), clinical neurology (Obrig, 2013), anesthesia (Murkin & Arango, 2009), and also within the field of nutritional neuroscience the use of NIRS is growing. Two recent reviews addressed the use of NIRS in nutritional neuroscience. Jackson and Kennedy reviewed the application of NIRS in nutritional intervention studies (Jackson & Kennedy, 2013) and Sizonenko et al. discussed several brain imaging techniques that can be used in intervention studies,

(19)

including NIRS (Sizonenko et al., 2013). Both reviews discuss several nutritional studies that used NIRS to measure the effects of different nutrients on the hemodynamic response/CBF, including caffeine, resveratrol, epigallocatechin gallate (the principle pholyphenol found in green tea), soybean peptide, fish oil, creatine and alcohol, to measure either direct or chronic effects. All of the reported studies observed significant changes in the concentrations of total Hb, oxy-Hb or deoxy-Hb during cognitive tasks between placebo and treatment. Based on these studies both reviews conclude that NIRS is a feasible method to detect changes in the hemodynamic response following the administration of nutrients or dietary components. However, they also mention several limitations that should be overcome to get the best results out of the use of NIRS. For instance, the studies discussed in the reviews failed to observe a relationship between the changes in hemodynamic response and changes in cognitive function. In addition, hypothesis-driven research is necessary in this area, but this is difficult, as it is not yet known exactly what the physiological and cognitive responses are of the studied nutrients. The use of more complex protocols and quantitative NIRS systems that are recently developed and the use of NIRS in combination with other imaging techniques might overcome these issues. However, also no standardized way of analyzing NIRS data is currently available.

The studies discussed by the reviews were all performed in young healthy subjects. NIRS however is also very useful to assess age-related differences in hemodynamic response (Kim et al., 2011). In addition, although the hemodynamic response is thought to decrease with normal aging (Kameyama, Fukuda, Uehara, & Mikuni, 2004; Safonova et al., 2004), NIRS still is a useful technique to measure changes in CBF in reaction to nutrients in elderly. Using NIRS, Gagnon et al. measured the acute effects of glucose ingestion on prefrontal brain activation during the execution of a divided attention task in healthy older adults. When the subjects received glucose, they were able to execute both tasks at the same time better than when they received placebo. Accuracy did not differ between the conditions, but in the placebo condition the subjects prioritized one task over the other. In addition, in the glucose condition increased brain activation for oxy-Hb and deoxy-Hb was observed in the right ventral prefrontal regions (Gagnon et al., 2012). Konagai et al. used NIRS to measure the effects of essence of chicken (EOC; a chicken meat-extract rich in proteins, peptides and amino acids) on cognitive brain function in healthy older adults. After 7 days of EOC supplementation increased oxy-Hb concentrations were observed in prefrontal areas during a working memory task. This increase was not seen after the placebo period. During a reaction task and the Groton maze learning test no differences in brain activation were seen. In addition, no effects on cognitive performance or reaction time were observed between the two conditions (Konagai, Watanabe, Abe, Tsuruoka, & Koga, 2013). Another study of Konagai et al. is

(20)

discussed above as well, as they used both EEG and NIRS to assess the effects of krill oil on cognitive function in healthy older adults. Regarding hemodynamic activation, Konagai et al. observed greater changes in oxy-Hb and deoxy-Hb during a working memory task for the groups who received krill oil and sardine oil, than for the group who received medium-chain triglycerides. During a calculation task greater changes in oxy-Hb were observed in the krill oil group compared to the medium-chain triglycerides group. Unfortunately, as mentioned above, no test scores were reported (Konagai, Yanagimoto, et al., 2013).

(21)

Discussion

The present paper discussed the course of normal cognitive aging, the role of dopamine in this and the influences of tyrosine supplementation to provide a background for a proof of concept study on the effects of tyrosine supplementation on cognitive functions in the PFC in older adults. In addition, EEG and NIRS were discussed as possible techniques to measure the biological effects of tyrosine supplementation.

Decades of behavioral aging research led to a sufficient amount of information to draw conclusions about the course of normal cognitive aging. The studies discussed in the present paper regarding the course of normal cognitive aging are all, with exception of the experimental study of Cappell et al. (2010), quite recent reviews about cognitive aging in general or about specific cognitive functions and aging. Salthouse (2010), Drag and Bieliauskas (2010), Mather (2010) and Reuter-Lorenz and Park (2010) all discuss many different experimental studies testing cognitive functions between groups of different ages or using longitudinal designs. In addition, Mortensen et al. (2006) reviewed the effects of age on speech, Jurado and Rosselli (2007) on executive functions and Salthouse (2012) and Grady (2012) reviewed neural substrates underlying cognitive aging, as well by comparing many experimental studies comparing different age groups or using longitudinal designs. Together, it can be concluded from these reviews that cognitive decline is not global but rather specific, even within domains. Regarding the course of normal cognitive aging, the findings reported here are therefore considered quite solid. However, a lot of uncertainties still exist about whether the observed changes are caused by common underlying factors, or that there is no such thing as a unitary or dominant cognitive mechanism underlying all these changes. Although neuroimaging methods largely improved our understanding of these mechanisms, answers to questions regarding the neuroscience of cognitive aging remain preliminary as several concepts are unclear and general held assumptions might be not true after all. Overactivation for instance, has been interpreted as compensation when there was both a negative correlation between activity and behavior and a positive correlation (Grady, 2012). This seems very unlikely and therefore a more consistent explanation of what exactly defines compensation is needed, perhaps in the form of several definitions for different types of compensation. Furthermore, the assumption that more gray matter volume in the aging brain is better for cognitive functioning should be reexamined as the evidence for this link is weak (Mather, 2010). As age cannot be manipulated, the most desired study design in the form of random assignment and experimental manipulation of the relevant factor is not applicable. In addition, studies with follow-up designs over such a long-term period

(22)

matching the rate of aging are seldom feasible with humans. Therefore, aging research is for a large part restricted to use correlation-based procedures to investigate causal relations, which makes the search for underlying mechanisms causing age related cognitive decline hard.

This limitation can be seen in the discussion of the role that the dopaminergic system plays in cognitive aging. For many of the dopaminergic markers inconsistencies are observed, or available evidence is scarce. Regarding the age-related changes in TH activity, no conclusions can be drawn yet from the available evidence. As no in vivo human measures are available yet, the mechanisms that modulate TH activity, metabolism and expression are not yet understood. However, recently increasing numbers of studies are focusing on these processes as TH is thought to be a promising drug target for neurodegenerative diseases. Although the discussed studies observed a decline in prefrontal and striatal TH levels, more research is needed to confirm these findings. This also holds for the age-related DDC changes, as there are studies reporting decreased activity as well as studies reporting increased activity (Haycock et al., 2003; Reeves et al. 2002). The findings regarding DAT are more solid, as all discussed studies (postmortem, PET and SPECT studies) observed age-related declines in DAT expression (Erixon-Lindroth et al., 2005; Eusebio et al., 2012; Haycock et al., 2003; Ishibashi et al., 2009; Troiano et al., 2010; Volkow et al., 1998). The studies were quite homogeneous as they all used both men and women, subjects within the same age range and measured DAT expression in the striatum. In addition, they reported similar decline rates, and all reported higher decline rates in the caudate compared to the rates in the putamen (with exception of Volkow et al. [1998] who did not differentiate between these two regions). Together it can be concluded from these studies that DAT expression in striatal regions decreases with age. Regarding VMAT expression, no conclusion can be made yet as not enough evidence is available yet. Frey et al. (1996) observed a significant decrease with age, but the other studies did not observe significant decreases with age. The observations regarding MAO are more solid, especially regarding MAO-B, as Nicotra et al. (2004) reviewed studies measuring the MAO activity and concluded that MAO-B activity increased with age, whereas MAO-A activity remains more or less the same. However, since then, unfortunately not many other studies assessed age-related MAO activity. This is in contrast with the post synaptic markers of the dopaminergic system. Several studies recently focused on the age-related changes regarding the type 1 and 2 dopamine receptors. All of the studies discussed in the present paper observed a decrease in DR type 1 and/or 2, regardless of differences in study design and reported rates of decline. Five of the nine studies assessed DR1 decline and six of the nine studies assessed DR2 (including Kaasinen et al. [2012] who used a DR2/3 selective radioligand). Seven of the

(23)

(2002; they only tested men) all studies tested both men and women. In addition, six of the nine tested participants in the range from young adults (starting from 19-24 years old) to older adults (74-86), the two postmortem studies used tissues from neonates until the age of 80+, and Kim et al. (2011) tested participants between 24 and 53 years old. Seven of the nine studies assessed DR expression in striatal regions, and four of the nine studies measured DR expression in prefrontal regions. The rates of decline are higher in the PET studies than in the postmortem studies, and higher in prefrontal than striatal regions. Together it can be concluded from these studies that both DR1 and DR2 decline with age in striatal and prefrontal regions.

The evidence regarding tyrosine supplementation is not very extensive. The available human studies all used young and healthy participants, so solid conclusions about the influence of tyrosine on older adults cannot be made yet. However, although preliminary, the findings from the discussed mice studies suggest that tyrosine supplementation has different effects on older than younger mice. As indicated by the reviews of Tam and Roth (1997, both human and animal studies) and Van de Rest et al. (2013, only human studies), dopamine levels are not influenced by tyrosine availability under normal circumstances in younger adults. In stressful situations on the other hand, dopamine levels are depleted and increased tyrosine levels do influence dopamine levels, and improve several behavioral measures. As older adults also suffer from lowered dopamine levels, tyrosine supplementation might be beneficial for them. However, the dopaminergic system changes with age so it is unsure which effect increased tyrosine levels will have for older adults. Based on the observed changes, possible scenarios of how tyrosine supplementation might influence dopamine levels in older adults can be thought of. The first, and rate limiting, step in the dopamine metabolism is the conversion of tyrosine to L-DOPA, which is catalyzed by TH. If the findings regarding TH levels are true, and TH activity decreases with age, increasing tyrosine levels might not be beneficial, as it will not be conversed to L-DOPA. However, TH rate is influenced by local concentrations of tyrosine (Fernstrom, 2013), so when TH activity is indeed decreased with age, increasing tyrosine concentrations might lead to increased TH activity which will lead to increased dopamine levels. As stated above, not enough evidence is available yet to conclude whether TH activity indeed decreases, but this might be an important indication that tyrosine supplementation indeed might be beneficial for older adults. How the next step, the conversion of L-DOPA to dopamine, is influenced by age remains unsure as both increased and decreased levels of DDC have been reported. Increased levels would obviously be the most beneficial, as more tyrosine that is converted to L-DOPA will indeed become dopamine. Increased tyrosine levels do not have such a direct impact on the other markers of the dopaminergic system, but if dopamine levels indeed are increased, less dopamine will be taken up in

(24)

the terminal because of the decreased expression of DAT as would be taken up in younger adults. However, as many aspects of the dopaminergic system remain unknown, it is the question whether increased dopamine levels remain increased over long term periods or that they affect regulatory mechanisms – for instance a down regulation of DAT – to stabilize increased dopamine levels again. More research is needed to test the long-term effects of tyrosine supplementation on the dopaminergic system. Although dopamine levels might increase through tyrosine supplementation, MAO-B activity possibly increase with age which increases dopamine metabolism and reduce dopamine levels. In addition, decreased numbers of DR1 and DR2 decrease the effects of dopamine as less receptors are available to transport the signal. Based on the current evidence, it seems that the crucial step for tyrosine supplementation to be beneficial for older adults is the conversion from tyrosine into L-DOPA. Because even if DDC and MAO-B activity and the number of DR’s are decreased, the relative amount of dopamine increases if more tyrosine is available to be converted to L-DOPA than when tyrosine would not be supplemented and less tyrosine would be available for conversion. It is important to keep in mind though that these are all assumptions, as it is not clear yet which exact changes happen in the dopaminergic system during aging, and whether regulatory mechanisms come into play that adapt the dopaminergic system to the increase in dopamine levels.

When dopamine levels indeed will be elevated through tyrosine supplementation several behavioral changes can be expected, based on observations of other supplementation studies. Van de Rest and colleagues recently reviewed all human studies examining the effects of tyrosine supplementation. Improvements in working memory, reaction time, vigilance and motor performance were observed when tyrosine was supplemented under stressful conditions (van de Rest et al., 2013). As performance of these functions is decreased in older adults, it would be very beneficial if these functions will improve as well when older adults receive tyrosine supplementation. Especially working memory, as this cognitive function is highly susceptible to cognitive aging, but is a crucial component for normal cognitive functioning as all executive functions are considered to rely on it. However, for these improvements, the same holds as with the biological changes, as none of the studies was performed in older adults, it remains unknown whether the improvements for younger adults with stress induced dopamine depletion will also be found in older adults with age induced dopamine depletion. In addition, it is hard to make more detailed assumptions on a biological level about which cognitive domains might improve through tyrosine supplementation as dopamine is involved in so many different brain functions.

(25)

The fact that it is hard to predict what exactly might change on a biological level makes it also hard to judge whether EEG and or NIRS might be useful techniques to measure the changes that will be induced by tyrosine supplementation. However, the discussed EEG and NIRS studies, together with the reviews of Sizonkeno (2013) and Jackson and Kennedy (2013), show the usefulness of the techniques in the field of nutritional neuroscience. Regardless of their differences in study design, all studies show how EEG or NIRS can be used to measure biological effects of the supplemented nutrient. Some of the studies observed changes in biological measures in the absence of behavioral differences, indicating that EEG and NIRS are more sensitive to detecting changes than behavioral tests. This way, EEG and NIRS are able to show that supplementation indeed induces changes, although yet without measurable behavioral effects, but therefore might indicate that supplementing the nutrient on a more long term period might be beneficial. As it is expected that tyrosine supplementation will induce improvements in several cognitive functions, and changes in cognitive functions are accompanied by changes in neural activity, it is expected that both NIRS and EEG will be able to measure tyrosine induced changes in older adults. NIRS will be useful to measure brain activation in prefrontal regions, therefore it is recommended to use NIRS during a working memory task, as working memory processes are located in the PFC. In addition, this would be useful as improvements in working memory are in line with expectations for older adults receiving tyrosine. EEG measurements are useful during working memory tasks as well, for instance to measure the P300 component, which reflects the rate of information processing by its latency and the amount of mobilization of processing resources by its amplitude. In addition, more general measures like alpha band oscillations, which are important in several selective attentional processes, can be assessed as well. What makes NIRS and EEG extremely useful is the fact that they can be measured simultaneously, as was done by Konagai, Yanagimoto et al. (2013). This way, information about the influence of tyrosine supplementation on both prefrontal activation and brain wave components, such as the P300 and alpha band activity, can be obtained. What is important to keep in mind regarding NIRS, is the fact that it is still a relatively new technique and that several limitations should be overcome to get the best results out of the use of NIRS. Therefore, it is warranted that developments regarding the use of NIRS should be followed closely, as new protocols and systems will be established in the future.

(26)

Conclusions

In conclusion, the present paper argues that due to the cognitive and biological changes seen in normal aging, supplementing dietary tyrosine to older adults might be beneficial for their cognitive performance. This is based on the findings that older adults have lowered dopamine levels, which decreases their cognitive functioning. Tyrosine is the precursor for dopamine, and will therefore hopefully increase dopamine levels again in older adults. However, a lot of uncertainties remain about the changes the dopaminergic system undergoes with aging, so therefore it is not predictable what precisely will happen when tyrosine levels will increase. Despite these uncertainties, based on the present findings, this paper argues that new research should be done to test the effects of tyrosine supplementation in older adults. What should be kept in mind however, is the fact that increases in tyrosine levels might decrease levels of other amino acids. In addition, the present paper argues that EEG and NIRS both are suitable techniques to measure the biological effects that tyrosine probably will have. Regarding this part, it is unsure as well what precise changes tyrosine might induce and whether this will indeed be measurable by these techniques. However, the present paper discussed both reviews and experimental studies that together show the usefulness of the techniques in nutritional neuroscience and therefore argues that EEG and NIRS together will be suitable to be used in studies examining the effects of tyrosine supplementation in older adults.

(27)

References

Akitsuki, Y., Nakawaga, S., Sugiura, M., & Kawashima, R. (2011). Nutritional Quality of Breakfast Affects Cognitive Function: An fMRI Study. Neuroscience & Medicine, 02(03), 192–197.

Asselt, D. Z. Van, Pasman, J. W., Lier, H. J. Van, Vingerhoets, D. M., Poels, P. J., Kuin, Y., … Hoefnagels, W. H. (2001). Cobalamin Supplementation Improves Cognitive and Cerebral Function in Older,

Cobalamin-Deficient Persons. Journal of gerontology: medical sciences, 56(12), 775–779. Bäckman, L., Karlsson, S., Fischer, H., Karlsson, P., Brehmer, Y., Rieckmann, A., … Nyberg, L. (2011).

Dopamine D(1) receptors and age differences in brain activation during working memory.

Neurobiology of aging, 32(10), 1849–56.

Bäckman, L., Lindenberger, U., Li, S.-C., & Nyberg, L. (2010). Linking cognitive aging to alterations in dopamine neurotransmitter functioning: recent data and future avenues. Neuroscience and

biobehavioral reviews, 34(5), 670–7.

Bäckman, L., Nyberg, L., Lindenberger, U., Li, S.-C., & Farde, L. (2006). The correlative triad among aging, dopamine, and cognition: current status and future prospects. Neuroscience and biobehavioral

reviews, 30(6), 791–807.

Brady, K., Brown, J. W., & Thurmond, J. B. (1980). Behavioral and neurochemical effects of dietary tyrosine in young and aged mice following cold-swim stress. Pharmacology, biochemistry, and

behavior, 12(5), 667–74.

Braskie, M. N., Wilcox, C. E., Landau, S. M., O’Neil, J. P., Baker, S. L., Madison, C. M., … Jagust, W. J. (2008). Relationship of striatal dopamine synthesis capacity to age and cognition. The Journal of

neuroscience : the official journal of the Society for Neuroscience, 28(52), 14320–8.

Cappell, K. a, Gmeindl, L., & Reuter-Lorenz, P. a. (2010). Age differences in prefontal recruitment during verbal working memory maintenance depend on memory load. Cortex; a journal devoted to the

study of the nervous system and behavior, 46(4), 462–73.

De Frias, C. M., Annerbrink, K., Westberg, L., Eriksson, E., Adolfsson, R., & Nilsson, L.-G. (2004). COMT gene polymorphism is associated with declarative memory in adulthood and old age. Behavior

genetics, 34(5), 533–9.

De Frias, C. M., Annerbrink, K., Westberg, L., Eriksson, E., Adolfsson, R., & Nilsson, L.-G. (2005). Catechol O-methyltransferase Val158Met polymorphism is associated with cognitive performance in nondemented adults. Journal of cognitive neuroscience, 17(7), 1018–25.

Drag, L. L., & Bieliauskas, L. a. (2010). Contemporary review 2009: cognitive aging. Journal of geriatric

psychiatry and neurology, 23(2), 75–93.

Egan, M. F., Goldberg, T. E., Kolachana, B. S., Callicott, J. H., Mazzanti, C. M., Straub, R. E., … Weinberger, D. R. (2001). Effect of COMT Val108/158 Met genotype on frontal lobe function and risk for

Background for a proof of concept study on the effects of tyrosine supplementation on cognitive functions in the PFC in elderly

10-1-2014