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1 Introduction

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease, with an occurrence that tends to rise dramatically with increasing age, thereby amplifying the social relevance of the disease as life expectancy increases (de Rijk et al. 2000). The degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNc) that project to the striatum, the hallmark of PD, provokes functional modifications within the basal ganglia (BG) circuitry causing the typical motor symptoms (tremor, rigidity, and bradykinesia). PD is a classic movement disorder; however, the motor symptoms, which appear when the dopaminergic neuron degeneration has reached at least 70–80 %, are preceded by numerous non-motor symptoms, including autonomic dysfunction, sleep disorders, psychiatric symptoms, olfactory deficits, and gastrointestinal and cognitive dysfunctions (Poewe 2008). Idiopathic PD is a complex disorder characterized by the involvement of selected neuronal populations throughout the central and peripheral nervous systems; however, neurotransmitters other than dopamine (DA) are involved in the disease, including noradrenaline, serotonin, and acetylcholine (Jellinger 1991).

The primary cause of the degenerative process underlying PD remains unknown; however, several contributing factors have so far been identified for the idiopathic form of the disease. The most important of these include mitochondrial defects, oxidative damage, anomalous protein aggregation, and neuroinflammation (Schapira 2006). These processes, once initiated, continue to produce dopaminergic neuron liability contributing to the loss of efficacy of DA-replacement therapy.

The main therapeutic developments in the field of PD have focused, first, on improvement of DA-replacement therapies in order to better manage or prevent the onset of motor complications and, second, on the discovery of compounds that could modify the course of neurodegeneration. Among the various therapeutic approaches aimed at addressing these objectives, the manipulation of adenosine neurotransmission is one of the most valuable.

The first suggestion that manipulating adenosine neurotransmission might have a beneficial effect on PD onset or progression came from epidemiologic evidence showing that consumption of caffeine, a nonselective A1/A2A receptor antagonist, reduced the risk of developing PD (Ascherio et al. 2001; Costa et al. 2010) (see Sect. 5). Furthermore, preclinical studies investigating the adenosine receptor type involved in these effects suggested that the blockade of the A2A receptor subtype provides the best neuroprotective effect (Schwarzschild et al. 2006).

2 Neuromodulatory Role of Adenosine

Adenosine is an endogenous purine nucleoside constitutively present in mammalian tissues, where it plays a regulatory role in a variety of important physiologic processes by acting as a homeostatic modulator. Adenosine is produced as a result of hydrolysis of adenosine monophosphate (AMP) by means of an action of ecto-5’-nucleotidase (Fredholm et al. 2005); thus, its formation depends upon the metabolism of adenosine triphosphate (ATP). In the extracellular compartment, the level of adenosine also depends on the rate of hydrolysis of ATP, which is released from either neurons or glial cells, and on the adenosine carrier, which keeps adenosine at a stable level. The actions of adenosine are mediated by specific G-protein-coupled receptors. To date, four adenosine receptors have been cloned and characterized: A1, A2A, A2B, and A3 (Fredholm et al. 2005).

Adenosine plays different roles in normal physiology, which include promoting and/or maintaining sleep, regulating the general state of arousal, and coupling cerebral blood flow to energy demand (Dunwiddie and Masino 2001). Many of the effects of adenosine that are observed in normal conditions are modified during pathologic events, and the multiple roles of adenosine may produce dual neuroprotective/neurotoxic effects based on the type of insult and cellular condition (Cunha 2001).

Endogenous adenosine released during hypoxia, ischemia, electrical activity, hypoglycemia, or aglycemia reduces the subsequent damage to the neuronal tissue. The neuroprotection offered by adenosine is also effective against other kinds of damage that are not as directly related to energy metabolism, such as mechanical cell injury (Mitchell et al. 1995), methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA)-induced neuroinflammation, and neurotoxicity (Delle Donne and Sonsalla 1994; Khairnar et al. 2010). In these conditions, the neuroprotective actions of adenosine are mediated primarily via A1 receptor activation, whereas it seems that the action on the A2A receptor could result in a neurotoxic effect. Caffeine and other A2A antagonists, in fact, have induced neuroprotection and reduced glial cell activation in animal models of dopaminergic neurotoxicity utilizing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA) (Schwarzschild et al. 2006; Carta et al. 2009; Frau et al. 2011).

3 Adenosine A2A Receptors

Among the different adenosine receptors, of particular interest for PD are the A2A receptors, specifically located in the BG circuit (Fig. 1). The adenosine A2A receptors interact functionally and are co-expressed with dopaminergic D2 receptors on the striatal GABAergic neurons of the “indirect” BG pathway projecting from the striatum to the globus pallidus (Hettinger et al. 2001). In the BG circuit, A2A receptors are prevalently localized in the axons, soma, dendrites, and dendritic spines of the striatal GABAergic neurons of the indirect pathway. In contrast, very few striatonigral neurons of the “direct” pathway, containing dopaminergic D1 receptors, express A2A receptors (Schiffmann and Vanderhaeghen 1993) (Fig. 1). However, activation or blockade of A2A receptors in the indirect striatopallidal pathway impairs or facilitates dopaminergic D1-mediated responses as well (Ferre et al. 1997). In light of the neuromodulatory role of adenosine, A2A receptors have been described to interact directly or indirectly with several receptors, such as dopaminergic D2 and D3 receptors, NMDA, metabotropic glutamate receptor types 4 (mGLUR4) and 5 (mGLUR5), cannabinoid receptor type 1 (CB1), and 5-hydroxytryptamine receptor type 1A (5-HT1A), and to form heteromeric complexes with some of them (Kurokawa et al. 1996; Gerevich et al. 2002; Łukasiewicz et al. 2007; Armentero et al. 2006, 2011; Bogenpohl et al. 2012; Jones et al. 2012).

Fig. 1
figure 1

Proposed actions of A2A receptors on the indirect striatonigral pathway. Classical view of BG functions demonstrating that dopaminergic neuron degeneration provokes an increase in glutamatergic input from the cortex to the striatum and an increase in GABAergic indirect output from the striatum to the GP, leading to an increase in STN activity. In turn, an increase in STN glutamatergic activity contributes to excitotoxic dopaminergic neuron degeneration in the SN. As shown in Box 1, several reports indicate that A2A receptors control excitability of the striatopallidal GABAergic pathway and that A2A receptor antagonism counteracts the effects of dopaminergic neuron degeneration. As a result, the GABAergic control from the GP to the STN is increased, leading to a decrease in STN activity. As shown in Box 2, a decrease in STN activity and glutamatergic output from the STN to the SN counteracts excitotoxic degeneration of the dopaminergic neurons in the SN. As shown in Box 3, blockade of glutamatergic receptors in the SN reduces excitotoxic degeneration of dopaminergic neurons. Therefore, one of the mechanisms of neuroprotection by A2A receptor antagonists may be the indirect inhibition of STN activity. Box 1 (continuous line) represents a direct action of A2A receptor antagonist; Boxes 2 and 3 (dashed line) represent an indirect action of A2A receptor antagonist on neurotransmitter release. Abbreviations: BG basal ganglia, DA dopamine, GLU glutamate, GP globus pallidus, mGluR5 metabotropic glutamate receptor 5, SN substantia nigra, STN subthalamic nucleus, 6-OHDA 6-hydroxydopamine

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Besides the presence of A2A receptors in neurons, their existence has been described in astrocytes: specifically, about 3 % of A2A receptors were found in glial cells of the striatum (Hettinger et al. 2001).

4 Caffeine Properties

Caffeine is a natural xanthine alkaloid, contained in several popular dietary sources, such as coffee, tea, chocolate, and soft drinks. Its ability to elicit psychostimulatory effects, that are usually not accompanied by harmful unwanted consequences, renders caffeine the most consumed psychoactive substance (Fredholm et al. 1999).

At doses in the range of normal consumption, caffeine induces its effects by blocking the central adenosine A1 and A2A receptors (Fredholm et al. 1999). Caffeine-induced psychostimulant effects appear to be influenced by the dopaminergic transmission since enhancement of caffeine-elicited psychomotor activation is observed in experimental rodents following administration of dopaminergic agonists (Cauli and Morelli 2005), whereas an attenuation of the effects of caffeine is present after administration of dopaminergic antagonists (Green and Schenk 2002). The influence that caffeine exerts on dopaminergic transmission is of great interest, considering the critical involvement of DA in the modulation of important functions, such as movement, attention, goal-directed behavior, and associative learning (Robbins and Roberts 2007; Phillips et al. 2008).

The existence of negative correlations between PD and dietary factors, such as caffeine, is of particular interest, in the light of caffeine’s safety and widespread consumption (see Sect. 5). In this regard, the results from preclinical studies demonstrating that caffeine can exert protective effects in different models of neurotoxicity add further importance to the finding (Table 1).

Table 1 Overview of the most common paradigms of toxin-induced neurodegeneration used to investigate neuronal damage and neuroprotection in PD
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Caffeine administration has been shown to have a neuroprotective effect in rodent and primate models of dopaminergic neuron degeneration, such as the MPTP and 6-OHDA paradigms (Table 1). Caffeine neuroprotection is particularly important since it is afforded by a substance with negligible toxic or adverse effects. Often, substances proposed to be neuroprotective impair neuronal functions essential for correct cellular homeostasis or alter the levels of neurotransmitters, such as glutamate, which are important for cognitive functions. Caffeine, in contrast, is a safe substance used worldwide with no unwanted effects in the broad population.

5 Epidemiologic Studies on the Neuroprotective Role of Caffeine in Parkinson’s Disease

Numerous findings suggest that the two decades before the manifestation of motor impairments in PD are fundamental in the onset of the progressive demise of dopaminergic neurons. Therefore, epidemiologic studies investigating habits, health status, and lifestyle of individuals who developed PD are very important in order to obtain new information about PD development and to identify new approaches to prevent neurodegeneration in PD.

One of the most interesting results that has emerged from these epidemiologic studies is the inverse correlation between caffeine intake and risk of developing PD. The three main epidemiologic studies, that provided consistent suggestions regarding this relationship, are the Honolulu Heart Program (HHP, 30 years of follow-up of ∼8,000 Japanese-American men), the Health Professionals Follow-up Study (HPFS, 10 years of follow-up of ∼47,000 men), and the Nurses’ Health Study (NHS, 16 years of follow-up of ∼88,500 women) (Ross et al. 2000; Ascherio et al. 2001, 2003). In these surveys, besides information of lifestyles and health status of individuals, nutritional behaviors, including data about consumption of coffee and/or other caffeinated or decaffeinated beverages, were collected. The results of the investigation demonstrated that individuals consuming medium to high quantities of caffeine have a decreased risk of developing PD (Ross et al. 2000; Ascherio et al. 2001, 2003). Importantly, this finding was dose dependent and was adjusted for age, smoking status, alcohol use, other nutrients, or potential confounding variables (Ascherio et al. 2001, 2003). The studies described that individuals consuming caffeine (including tea and all caffeine sources) had a lower risk of developing PD compared with non-regular caffeine drinkers (less than one cup a day), whereas no association was found with consumption of decaffeinated coffee. Moreover, a 50 % risk reduction of PD was observed among men consuming less than one cup a day compared with male non-coffee drinkers (Ross et al. 2000; Ascherio et al. 2001). Notably, this inverse relationship between caffeine intake and PD risk was not so evident in women (Ascherio et al. 2001, 2003). Indeed, a clear gender difference was demonstrated by Ascherio and coworkers (2001), regarding the association between caffeine intake and risk of PD in women in the NHS. Similar findings have been reported by Benedetti and coworkers (2000). Since gender difference with regard to the effect of caffeine suggested a possible hormonal cause, in the women reported in the NHS, the correlation between use of postmenopausal estrogens, caffeine intake, and risk of PD was examined. Generally, use of postmenopausal estrogens was not correlated with risk of developing PD. On the other hand, among estrogens users, women consuming more than five cups of coffee per day were found to have a higher risk of PD compared with women who never drink coffee. In contrast, similar to men, women who were coffee drinkers and had never taken postmenopausal estrogens had a lower risk of PD than non-coffee drinkers (Ascherio et al. 2001). These data were confirmed by two separate prospective studies involving men and women which provided evidence that caffeine may decrease risk of PD only in men and in women who did not take postmenopausal estrogens, but not among estrogen consumers (Ascherio et al. 2003, 2004). Furthermore, the potential beneficial effect of caffeine might be prevented by estrogen therapy (Ascherio et al. 2003, 2004). Conversely, two prospective studies of Finnish individuals reported no gender differences in the opposite correlation between coffee intake and PD risk (Hu et al. 2007; Sääksjärvi et al. 2008). However, in the study by Saaksjarvi and coworkers (2008), the percentage of women was only about 5 % of the cohorts; therefore, the effect of estrogen therapy could not be examined for this small number of women.

Recently, an experimental study in the MPTP mouse model of PD investigated the biologic basis of the interaction between estrogen and caffeine consumption on risk of PD. This study showed that caffeine attenuated, dose dependently, the MPTP-induced striatal DA loss in both male and ovariectomized female compared with female non-ovariectomized mice (Xu et al. 2006). Moreover, chronic estrogen treatment prevented the neuroprotection induced by caffeine in male and in female ovariectomized mice, confirming that the hormonal therapy might prevent the neuroprotective effect of caffeine in this model of PD (Xu et al. 2006). Metabolic or pharmacokinetic interactions between caffeine and estrogens have been supposed, but it is not clear whether this interaction is fundamental in the reduced neuroprotective effect observed when estrogen therapy and caffeine are combined (Xu et al. 2006).

A recent statistical study by Costa and coworkers (2010) collected and statistically analyzed the majority of epidemiologic studies, which better evaluate the effect of caffeine intake and the incidence of PD, up to September 2009. This statistical review, which includes 26 studies, unequivocally confirms the inverse association between caffeine exposure and the risk of developing PD (Costa et al. 2010).

In spite of the epidemiologic and experimental findings strongly supporting the concept that dietary caffeine decreases the possibility of developing PD, very little is known about the correlation between caffeine intake and the degree of disease progression in PD patients. Two clinical studies, in which the progression of the disease and the consumption of several caffeinate beverages were evaluated by the modified Unified Parkinson’s Disease Rating Scale (UPDRS), did not demonstrate clear evidence of the neuroprotective role of caffeine with respect to degree of PD progression (Schwarzschild et al. 2003b; Simon et al. 2008). Therefore, further larger investigations are required to fully assess the neuroprotective role of caffeine on disease progression in PD patients.

6 Mechanisms of Dopaminergic Neuroprotection by Caffeine and A2A Receptors Blockade

Studies of neuroprotection in PD should carefully consider a number of factors with regard to the features of neurodegeneration, as well as to the experimental model in which the study is performed. In recent years, PD has been increasingly envisaged as a multifactorial pathology, and several factors have been proposed to be involved in the degeneration of dopaminergic neurons (Schapira 2006). Therefore, it is hypothesized that neuroprotective drugs should act by means of multiple mechanisms rather than a single mechanism. Moreover, it is worth mentioning that most of the experimental models of PD in use employ toxins according to an acute, or acute-repeated, protocol of administration (Table 1). This may significantly differ from idiopathic PD, with respect to time course of degeneration and mechanisms involved in neuronal demise. Therefore, the choice of experimental model is a critical step when addressing the mechanisms of neuroprotective agents.

Several studies in rodent models of PD demonstrate that A2A receptor antagonists counteract both the demise of dopaminergic neurons in the SNc and the drop of DA levels in the striatum (Schwarzschild et al. 2003a; Morelli et al. 2010). However, A2A antagonists exert beneficial effects not only in models of PD neurodegeneration but also in paradigms of Alzheimer’s and Huntington’s disease-like neurotoxicity (Stone et al. 2009). This evidence suggests that A2A receptor antagonists counteract PD-like neurodegeneration by means of mechanisms which are not selective towards dopaminergic neurons but are part of a broader neuroprotective action. In the light of these observations, the two major hypotheses proposed to explain the neuroprotective effects of A2A antagonists on dopaminergic neurons concern the modulation of glutamate-induced excitotoxicity and neuroinflammation, two mechanisms involved in several neurodegenerative pathologies.

Glutamate-mediated excitotoxicity has long been envisaged as an important player in PD neurodegeneration. Thus, dopaminergic neurons are vulnerable to changes in glutamate extracellular concentrations, on the one hand, while a dysregulation of glutamate transmission has been described in PD, on the other (Lancelot and Beal 1998; Greenamyre 2001). Remarkably, the stimulation of adenosine A2A receptors can elevate the extracellular concentrations of glutamate, while blockade of A2A receptors decreases glutamate extracellular levels which, in turn, may relieve the excitotoxic insult and afford neuroprotection towards dopaminergic neurons (Popoli et al. 1995). Recent evidence supports a role for nonneuronal cells in the modulation of glutamate release by A2A receptor blockade (Melani et al. 2003; Yu et al. 2008), which is in line with the localization of these receptors on glial cells (see Sect. 3).

Several reports have shown that A2A receptor antagonists modulate the activity of the indirect pathway by acting on the terminals of striatopallidal medium spiny neurons or by influencing the intrinsic excitability of indirect pathway spiny projection neurons, blunting the effects of DA depletion (Shindou et al. 2003; Floran et al. 2005; Simola et al. 2006; Kelsey et al 2009; Peterson et al. 2012) (Fig. 1). Moreover, independent investigations have shown that both lesion of the subthalamic nucleus (STN) and blockade of the NMDA receptors in the STN attenuate the loss of dopaminergic neurons induced by 6-OHDA (Piallat et al. 1996; Blandini et al. 2001; Carvalho and Nikkhah 2001). Based on these considerations, release of glutamate from the STN can be envisioned as an important mechanism in dopaminergic neuron degeneration. Moreover, it has to be considered that the overactivation of the STN progresses in the course of PD, and this can eventually exacerbate the loss of dopaminergic neurons over time. Therefore, it is conceivable that A2A antagonists, by regulating the activity of the striatopallidal pathway, besides counteracting motor disability, may also attenuate degeneration of the dopaminergic neurons through a modulation of STN firing (Schwarzschild and Ascherio 2004) (Fig. 1).

An important mechanism involved in the neurodegenerative process that characterizes PD is neuroinflammation, as suggested by preclinical and epidemiologic evidence (Hirsch and Hunot 2009; Halliday and Stevens 2011). Neuroinflammation gives rise to a complex cascade of events in the brain, resulting in the activation of glial cells (microglia, astrocytes, and oligodendrocytes) and the subsequent generation of inflammatory mediators (e.g., cytokines, interferons, interleukins) (Reale et al. 2009). Even though transient neuroinflammation can be beneficial, as it may help the brain in coping with noxious insults, protracted neuroinflammation is detrimental and may lead to neuronal damage. It has been recently suggested that glial activation plays an important role in the initiation of early response and in the progression of degenerative diseases, such as PD, in which α-synuclein accumulation in astrocytes causes recruitment of phagocytic microglia that attack selected neurons causing neuronal degeneration (Halliday and Stevens 2011). Furthermore, not only can neuroinflammation promote neurodegeneration, but neuronal death itself can trigger inflammatory responses, which may aggravate the ongoing neuronal damage (Litteljohn et al. 2010).

Both microglia and astrocytes express A2A receptors, the stimulation of which promotes the recruitment of these cells in neuroinflammatory responses (Lopes et al. 2011). Conversely, blockade of A2A receptors suppresses the activation of microglia and astrocytes, as well as the stimulation of the proinflammatory signal cascade (Armentero et al. 2011). Interestingly, recent evidence obtained in the mouse MPTP model of PD demonstrates that the increased survival of dopaminergic neurons mediated by A2A antagonists is accompanied by a significant attenuation in microgliosis and astrogliosis (Yu et al. 2008; Carta et al. 2009; Frau et al. 2011).

Based on these premises and on the current knowledge of A2A antagonists and neuroprotection, it is feasible that attenuation of glutamate-mediated excitotoxicity and neuroinflammation may participate in the protective effects of A2A antagonists on dopaminergic neurons. However, it is important to consider that in experimental models of PD, adenosine A2A receptor antagonists counteract the degeneration of dopaminergic neurons at doses lower than those required to elicit motor stimulation (Yu et al. 2008; Carta et al. 2009). It is therefore hypothesized that excitotoxicity and neuroinflammation are phenomena clearly distinct from regulation of motor function, as for the mechanisms involved. Furthermore, excitotoxicity and neuroinflammation have been envisaged as causative factors in neurodegenerative disorders other than PD (Glass et al. 2010). Therefore, an attenuation, or regulation, of these noxious phenomena by A2A antagonists, besides justifying the protective effect observed in PD models, would be in agreement with the data demonstrating that these drugs can protect neurons from a wide array of insults.

Even though the hypotheses on excitotoxicity and neuroinflammation are intriguing, caution should be taken when addressing the mechanisms underlying the neuroprotection mediated by A2A antagonists in models of PD. In this connection, it is interesting to point out that astrocytes, the activation of which has been found to be increased in the MPTP model of PD (Carta et al. 2009), regulate not only neuroinflammation but also glutamate extracellular levels and, accordingly, excitotoxicity (Melani et al. 2003). Therefore, astrocytes could be a crucial point at which A2A antagonists may promote the survival of dopaminergic neurons, perhaps by attenuating both excitotoxicity and neuroinflammation. Even though the evidence supporting the involvement of glial elements in the dopaminergic neuroprotection by A2A antagonists is increasingly growing, neuronal mechanisms cannot be disregarded. Thus, recent evidence demonstrates that the inactivation of neuronal forebrain A2A receptors completely counteracts the degeneration of dopaminergic neurons in the MPTP model of PD (Carta et al. 2009) (Fig. 2). Furthermore, it has to be considered that a number of factors have been proposed to promote and/or sustain the degeneration of dopaminergic neurons in PD, besides excitotoxicity and neuroinflammation. These include, for example, oxidative stress, proteolytic damage, and mitochondrial defects (Schapira 2006). Therefore, it is conceivable that several different mechanisms may participate in the rescue of dopaminergic transmission by A2A antagonists. In this connection, it is interesting to note that A2A antagonists have been reported to protect dopaminergic neurons in a model of mitochondrial dysfunction (Alfinito et al. 2003). In addition, it has been suggested that the different causative factors of PD neurotoxicity may engender a sort of vicious cycle, with some triggering initial neuronal damage and others perpetuating it until neuronal death is reached. Therefore, A2A antagonists could intervene at different steps of this cycle and, by interrupting it, afford neuroprotection.

Fig. 2
figure 2

FbnA2A KO mice are protected against MPTP-induced loss of dopaminergic cells in the SNc. (a) Representative sections from SNc immunostained for TH. Insets show higher magnification of TH-labeled (left) and cresyl violet-labeled (right) cells. Mice were treated with MPTP (20 mg/kg once a day for 4 days) or vehicle. (b) Graph shows analysis of TH immunostaining in fbnA2A KO mice, reported as a percentage of TH-positive cells compared with vehicle-treated mice. *p < 0.05 versus WT vehicle-treated group; #p < 0.05 versus WT MPTP-treated group, by Tukey’s post hoc test. Scale bar, 50 μm. Abbreviations: Fbn forebrain neurons, KO knock-out, MPTP 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, SNc substantia nigra pars compacta, TH tyrosine hydroxylase, WT wild type. (Reproduced from Carta et al. 2009)

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To date, blockade of adenosine A2A receptors has been demonstrated to efficiently restore motor function in PD, without exacerbating dyskinesia, both in animal models and in clinical trials of PD patients (Hauser and Schwarzschild 2005; Schwarzschild et al. 2006; Morelli et al. 2010). Therefore, their role as disease-modifying drugs in PD is of specific relevance since A2A antagonists may unequivocally affect PD with regard to both symptoms and neuroprotection.

7 Conclusion

Caffeine and adenosine A2A receptor antagonists have given new impetus to the research on PD in the latest 10 years. In the absence of effective neuroprotective treatments for PD, epidemiologic studies investigating dietary factors, such as caffeine, that may allow individuals to lower the risk of PD became compelling. Remarkably, preclinical studies have shown that the neuroprotective potential of caffeine extends to chronic administration of pesticides (Kachroo et al. 2010), suggesting that caffeine can prevent degeneration of dopaminergic neurons induced by a broad range of agents, including environmental toxins, in addition to pathophysiologic mechanisms.

Moreover, the preclinical and clinical investigations suggesting that A2A receptor antagonists represent a class of drugs that might counteract motor deficits symptomatically and, at the same time, delay or halt the progression of dopaminergic neuron degeneration are very important for future delineation of effective therapies for this disease. It should, however, be underlined that the discovery of neuroprotective strategies in chronic neurodegenerative diseases, such as PD, largely depends on the possibility of monitoring the progression of the neurodegeneration. The availability of biomarkers associated with disease progression therefore becomes crucial for the advancement of this strategy. Although the research on biomarkers is very promising (Halperin et al. 2009), none of them can predict PD with 100 % confidence nor provide a clear definition of subgroups at risk. Therefore, the future of research in PD clearly depends on the possibility of developing reliable and affordable biomarkers in order to facilitate and render the clinical trials of new molecules consistent.