Because the main neurochemical finding in PD is the depletion of dopamine (DA) in the nigroestriatal system (Benito-León et al., 2008), it is to be expected that the CSF concentrations of the main metabolites of DA, dihydroxyphenyl-acetyc acid (DOPAC) and homovanillic acid (HVA), should be decreased. Indeed, many classical studies have shown variable degrees of decrease in the CSF HVA levels of PD patients compared with controls (Bernheimer et al., 1966; Guldberg et al., 1967; Johansson and Roos, 1967; Olsson and Roos, 1968; Gottfries et al., 1969; Curzon et al., 1970; van Woert and Bowers, 1970; Godwin-Austen et al., 1971; Mones et al., 1972; Papeschi et al., 1972; Pullar et al., 1972; Cox et al., 1973; Voto Bernales et al., 1973; Weiner and Klawans, 1973; Granerus et al., 1974; Davidson et al., 1977; Tabaddor et al., 1978; Lovenberg et al., 1979; Cunha et al., 1983; Mann et al., 1983; Cramer et al., 1984; Mena et al., 1984; Pezzoli et al., 1984; Burns et al., 1985; Gibson et al., 1985; Jolkkonen et al., 1986; Liu, 1989; Hartikainen et al., 1992; Strittmatter and Cramer, 1992; Chia et al., 1993; Mashige et al., 1994; Eldrup et al., 1995; Cheng et al., 1996; Strittmatter et al., 1996; Kanemaru et al., 1998; Goldstein et al., 2008). Engelborghs et al. (2003) reported normal CSF DA and HVA, and decreased DOPAC levels. González-Quevedo et al. (1993) described normal CSF HVA levels, Espino et al. (1994) found decreased HVA only in advanced but not in early PD, Parkinson Study Group DATATOP Investigators found normal levels in early PD (LeWitt et al., 2011). Zubenko et al. (1986) described a non-significant trend toward decreased CSF HVA levels in demented PD patients compared with controls. Tohgi et al. (1993a) found correlation of CSF DA and HVA levels with akinesia and freezing of gait.

Although levodopa treatment usually increases CSF HVA levels according to the majority of studies, this is not related with clinical improvement, with some exceptions (Durso et al., 1989), and pre-treatment CSF HVA levels does not predict levodopa response (Weiner et al., 1969; Chase, 1970; Curzon et al., 1970; Bertler et al., 1971; Casati et al., 1973; Cox et al., 1973; Mones, 1973; Weiner and Klawans, 1973; Granerus et al., 1974; Davidson et al., 1977; Liu, 1989; Nishi et al., 1989; Strittmatter et al., 1996; Antkiewicz-Michaluk et al., 1997; Durso et al., 1997; Krygowska-Wajs et al., 1997), except in one study which described an association between relatively high pre-treatment CSF HVA levels and a better response to levodopa (Gumpert et al., 1973). One study failed to show changes in ventricular CSF HVA levels after a single acute administration of levodopa (Moussa et al., 1992). On the other hand, dopamine agonists such as piribedil and bromocriptine decreased significantly both the basal level (McLellan et al., 1975; Rinne et al., 1977) and probenecid-induced accumulations of HVA in CSF (Rinne et al., 1975, 1977), indicating that the drugs reduced the turnover of endogenous dopamine. Amantadine did not change HVA levels (Cox et al., 1973). Tetrahydrobiopterin (Dissing et al., 1989) and L-threo-3,4-dihydroxyphenylserine (precursor or noraderenalin or norepinephrine –NE) (Maruyama et al., 1994) increased CSF HVA levels in PD patients, but to a lesser extent than levodopa.

Friedman et al. (Friedman, 1985) reported an HVA/5-HIAA ratio in PD patients who developed levodopa-induced dyskinesias (LID) which was significantly higher than in PD patients under levodopa therapy and in controls, but Lunardi et al. (2009) found similar HVA/DA ratios in patients with and without LID. CSF DA, levodopa, and HVA levels were similar in PD patients treated with levodopa with wearing-off motor fluctuations to those without this complication of levodopa therapy, while CSF 3-ortho-methyldopa (3-OMD) levels were higher in the fluctuating patients (Tohgi et al., 1991a). CSF DOPAC and HVA were similar in PD patients with and without depression (Kuhn et al., 1996a), and in patients with major depression with PD than in those without PD (Pålhagen et al., 2010). CSF HVA levels were correlated with striatal uptake in PD patients measured with PET imaging with carbon-11-labeled 2β-carbomethoxy-3β-(4-fluorophenyl)-tropane (¹¹C-FT) (Ishibashi et al., 2010).

Tohgi et al. (1991b, 1997) found a significant increase in tyrosine, and a significant decrease in CSF levodopa, DA, and 3-OMD in PD patients, which was related with levodopa dosage, and described an additional decrease in 3-OMD in subjects treated with tolcapone (Tohgi et al., 1995a). Other authors reported increased CSF 3-OMD related with levodopa therapy (Antkiewicz-Michaluk et al., 1997; Krygowska-Wajs et al., 1997). On the other hand, Chia et al. (1993) found normal CSF 3-OMD concentrations. Moser et al. (1996) described increased CSF levodopa/3-OMD ratio in PD patients with hallucinations. Iacono et al. (1997) found similar HVA levels in PD patients with postural instability and gait disorders to PD patients without these symptoms.

Although many of the studies of DA metabolites were performed on patients with different types of parkinsonism, with different degrees of severity, and the fact that many of these studies were made using small sample sizes, there is a general consensus that CSF HVA levels are decreased in untreated PD patients and rise after levodopa therapy starts (decreased HVA may not be present in early stages of PD). It is to be expected that low CSF HVA levels should be a reflection of DA depletion in the nigroestriatal system. However, CSF DA metabolite levels are not useful to distinguish between different parkinsonian syndromes and could be normal in early stages of the disease. To our knowledge, no studies have been published regarding the correlation of CSF DA metabolite levels and brain DA levels, although the observation of a correlation between CSF HVA levels and striatal uptake of DA markers in PET imaging (Ishibashi et al., 2010), suggests this correlation.

Several studies have described neuronal loss, and presence of Lewy body in serotonergic raphe nuclei in PD patients (Benito-León et al., 2008). Tohgi et al. (1993b,c, 1997) reported a 15–20% reduction of CSF 5-HT, tryptophan (precursor of 5-HT), kynurenine and 3-hydroxykynurenine (metabolites of tryptophan) levels in PD patients. CSF 5-HT levels showed a negative correlation with the severity of bradykinesia, rigidity and freezing of the gait, and decreased after levodopa therapy. This group also found a correlation between CSF 5-HIAA levels and akinesia and freezing of gait (Tohgi et al., 1993a). In contrast, Engelborghs et al. (2003) described increased 5-HT levels. LeWitt et al. (2013) described increased CSF 3-hydroxykynurenine levels, and Widner et al. (2002) described an increased CSF kynurenine/tryptophan ratio in PD patients.

Several studies have shown reduced CSF levels of 5-hydroxyindoleacetic acid (5-HIAA), the main metabolite of 5-HT, in PD patients (Guldberg et al., 1967; Johansson and Roos, 1967, 1971; Olsson and Roos, 1968; Gottfries et al., 1969; Chase, 1970; Rinne and Sonninen, 1972; Rinne et al., 1973; Davidson et al., 1977; Mayeux et al., 1984, 1986, 1988; Kostić et al., 1987; Tohgi et al., 1993c, 1997; Mashige et al., 1994; Strittmatter et al., 1996; Engelborghs et al., 2003). Other authors report normal CSF 5-HIAA levels (Papeschi et al., 1970, 1972; Godwin-Austen et al., 1971; Granerus et al., 1974; Davidson et al., 1977; Tabaddor et al., 1978; Cramer et al., 1984; Burns et al., 1985; Chia et al., 1993; González-Quevedo et al., 1993; Volicer et al., 1985; Fukuda et al., 1989). Liu et al. (1999) described lower ventricular CSF 5-HIAA levels in patients with rigid-akinetic PD than in patients with tremoric PD, and a negative correlation between CSF 5-HIAA levels and PD severity.

CSF 5-HIAA levels seem to be unchanged by therapy with levodopa (Godwin-Austen et al., 1971; Davidson et al., 1977), bromocriptine (Gumpert et al., 1973), or piribedil (Gumpert et al., 1973), or were found decreased by levodopa therapy (Casati et al., 1973). Gumpert et al. (1973) described an association between relatively low pre-treatment CSF 5-HIAA levels with a good response to levodopa, while Davidson et al. (1977) reported this association with higher CSF 5-HIAA levels, and others found no such relation (Granerus et al., 1974). Tetrahydrobiopterin increased (Dissing et al., 1989), and L-threo-3,4-dihydroxyphenylserine decreased (Maruyama et al., 1994) CSF 5-HIAA levels.

Some authors have described decreased CSF 5-HIAA (Mayeux et al., 1984, 1986, 1988; Mena et al., 1984; Kostić et al., 1987) and 5-HT levels (Mena et al., 1984) in PD patients with depression, while others have described normal CSF 5-HIAA in depressed PD patients (Granerus et al., 1974; Kuhn et al., 1996a), and others still have reported similar CSF 5-HIAA levels in patients with major depression with PD tothose without PD (Pålhagen et al., 2010). Moser et al. (1996) described increased CSF 5-HIAA in PD patients with hallucinations. Iacono et al. (1997) found higher CSF 5-HT and 5-HIAA and lower 5-HTP levels in PD patients with postural instability and gait disorders than in PD patients without these symptoms.

Studies on the correlation of CSF 5-HT metabolite levels and brain 5-HT levels are lacking. The majority of studies report results on CSF 5-HIAA levels, with the controversial results based on short series of cohorts of patients with PD or other parkinsonian syndromes. Current data do not lend support to the role of CSF 5-HIAA as an unequivocal marker of depression linked to PD.

Neurons containing NE in the brain, mainly in the dorsal nuclei of vagus nerve, are involved in the degenerative process of PD (Benito-León et al., 2008). CSF NE levels have been found normal (Turkka et al., 1987; Chia et al., 1993; Kuhn et al., 1996a; Engelborghs et al., 2003) or decreased (Martignoni et al., 1992; Eldrup et al., 1995) in PD patients. CSF levels of 3-methoxy-4-hydroxy-phenylethyleneglycol (MHPG), the main metabolite of NE, have been reported to be normal (Wilk and Mones, 1971; Davidson et al., 1977; Mann et al., 1983; Mena et al., 1984; Hartikainen et al., 1992; Martignoni et al., 1992; Chia et al., 1993; González-Quevedo et al., 1993; Mashige et al., 1994; Kuhn et al., 1996a; Engelborghs et al., 2003) or decreased (Granerus et al., 1974) in PD patients. CSF MHPG levels do not increase either after treatment with levodopa (Wilk and Mones, 1971; Davidson et al., 1977) or with the NE precursor L-Threo-3,4-dihydroxyphenylserine (L-threo-DOPS) (Yamamoto et al., 1986; Teelken et al., 1989), while L-threo-DOPS increases CSF NE levels (Tohgi et al., 1990, 1993d).

Several authors have described a negative correlation between CSF MHPG levels and cognitive functioning (Mann et al., 1983) and bradyphrenia (Mayeux et al., 1987) in PD patients, and others have described a relationship between CSF NE levels with severity of PD assessed by Hoehn & Yahr staging, akinesia scores, and freezing of the gait (Tohgi et al., 1993a). Pålhagen et al. reported decreased CSF MHPG levels in patients with major depression with PD compared to those without PD (Pålhagen et al., 2010).

CSF activity of dopamine-β-hydroxylase (DBH), an enzyme involved in NE synthesis, has been found decreased in PD patients when compared with controls (Matsui et al., 1981; Hurst et al., 1985).

The normality of CSF MHPG levels found in nearly all studies with PD or other parkinsonian syndromes indicates that this is not a useful marker of PD. The correlation between CSF MHPG and brain NE is unknown.

CSF levels of Ach (Duvoisin and Dettbarn, 1967; Welch et al., 1976; Yamada et al., 1996) and its precursor choline (Aquilonius et al., 1972; Welch et al., 1976; Nasr et al., 1993) have been reported to be similar in PD patients to controls with the exception of one study in which lower CSF choline levels were described in PD patients (Manyam et al., 1990).

CSF activity of acetylcholine-esterase (AchE), the main enzyme involved in Ach degradation, has been reported to be similar in PD patients and controls (Jolkkonen et al., 1986; Ruberg et al., 1986; Zubenko et al., 1986; Sirviö et al., 1987; Yoshinaga et al., 1989; Manyam et al., 1990; Hartikainen et al., 1992), although there are studies which have described increased (Ruberg et al., 1986), decreased (Konings et al., 1995), or normal activity (Zubenko et al., 1986; Sirviö et al., 1987) in demented patients, and decreased activity only in those patients with the most severe disease (Hartikainen et al., 1992).

CSF activity of butirylcholine-esterase (BchE) have been found to be similar in PD patients and controls (Ruberg et al., 1986; Sirviö et al., 1987), but increased in demented PD patients in a single study (Ruberg et al., 1986). Data on CSF Ach and related substances are scarce and based on short series of patients, and do not permit valid conclusions.

CSF GABA levels in PD patients have been found to be decreased, when compared with controls, by many authors (Lakke and Teelken, 1976; Manyam et al., 1980, 1988; Kuroda et al., 1982; Manyam, 1982; Teychenné et al., 1982; Kuroda, 1983; de Jong et al., 1984; Araki et al., 1986; Tohgi et al., 1991c), while others have found this value to be normal (Enna et al., 1977; Abbott et al., 1982; Bonnet et al., 1987; Perschak et al., 1987; Mally et al., 1997; Engelborghs et al., 2003) or even increased (Jiménez-Jiménez et al., 1996). Manyam and Tremblay (1984) found reduced CSF free GABA levels and normality of conjugated levels. Abbot et al. (Perschak et al., 1987) found decreased CSF GABA levels in PD patients treated with levodopa, but not in “de novo” PD patients, while other authors found decreased CSF GABA in untreated PD patients (Manyam, 1982; de Jong et al., 1984), with CSF GABA normal (de Jong et al., 1984; Tohgi et al., 1991c) or slightly decreased (Manyam, 1982) in PD patients under levodopa therapy, suggesting that levodopa increases CSF levels. Teychenné et al. (1982) described low CSF GABA especially in PD patients with poor response to therapy or suffering from “on-off” motor fluctuations.

Normality of CSF glutamate levels has been reported by most investigators (Van Sande et al., 1971; Gjessing et al., 1974; Lakke and Teelken, 1976; Lakke et al., 1987; Perschak et al., 1987; Espino et al., 1994; Jiménez-Jiménez et al., 1996; Kuiper et al., 2000), although 3 groups described decreased CSF glutamate levels (Gründig and Gerstenbrand, 1980; Tohgi et al., 1991c; Mally et al., 1997), while CSF glutamine (the main precursor of glutamate) has been found to be normal (Gjessing et al., 1974; Lakke and Teelken, 1976; Manyam et al., 1988; Jiménez-Jiménez et al., 1996) or increased (Mally et al., 1997).

CSF aspartate levels have been reported as normal (Lakke and Teelken, 1976; Manyam, 1982; Araki et al., 1986; Perschak et al., 1987; Mally et al., 1997; Jiménez-Jiménez et al., 1996; Engelborghs et al., 2003), except in the study by Tohgi et al. (1991c) who reported decreased CSF aspartate; CSF asparagine (the main metabolite of aspartate) has been found normal (Lakke and Teelken, 1976; Manyam, 1982; Araki et al., 1986; Perschak et al., 1987; Jiménez-Jiménez et al., 1996; Mally et al., 1997; Engelborghs et al., 2003).

The results on CSF glycine levels have been reported as normal by most investigators (Gjessing et al., 1974; Perschak et al., 1987; Manyam et al., 1988; Jiménez-Jiménez et al., 1996; Mally et al., 1997; Engelborghs et al., 2003), although two groups found them increased (Lakke and Teelken, 1976; Araki et al., 1986; Lakke et al., 1987), and another decreased (Tohgi et al., 1991c). In agreement with Tohgi et al. (1991c), our group reported lower glycine levels in untreated PD patients when compared with PD patients under levodopa therapy or with controls (Jiménez-Jiménez et al., 1996).

Data regarding other (non-neurotransmitter) amino acids are even more controversial. CSF levels of neutral and basic amino acids have been reported to be both increased (Van Sande et al., 1971; Lakke and Teelken, 1976; Lakke et al., 1987), and decreased (Molina et al., 1997a). Two groups reported decreased (Molina et al., 1997a; Engelborghs et al., 2003) and another increased CSF levels of taurine (Lakke and Teelken, 1976; Araki et al., 1986; Lakke et al., 1987). Ornithine, citruline, and arginine (implicated in the urea cycle, and the two latter in the synthesis of nitric oxide) have been found to be increased (Van Sande et al., 1971; Lakke and Teelken, 1976; Lakke et al., 1987), normal (Kuiper et al., 2000), or decreased (Molina et al., 1997a). Another group described increased CSF levels of total homocysteine but normal ones of free homocysteine in PD patients (Isobe et al., 2005), with an additional increase after treatment with levodopa, while total methionine levels decreased after this therapy (Isobe et al., 2010a).

In general, the results on CSF amino acid levels in PD patients are inconclusive, because they might be influenced by selection of study subjects, sample size, lack of adequate matching between cases and controls in many studies, differences in antiparkinsonian therapy, and differences in study techniques, storage and handling of the samples (Jiménez-Jiménez et al., 1996; Molina et al., 1997a).

Neuropeptides modulate neuronal communication by acting on cell surface receptors. Many of them are co-released with classical neurotransmitters. There have been reports of a number of changes in the concentrations of several neuropeptides in PD brain, which are mainly significant decreases in (Jiménez-Jiménez, 1994): (a) met-enkephalin (MET-ENK), substantia P (SP), and cholecystokinine 8 (CCK-8) in the substantia nigra; (b) MET-ENK and leu-enkephalin (LEU-ENK) in the putamen and globus pallidus; (c) MET-ENK in the ventral tegmental area; (d) SP, somatostatin and neurotensin in the neocortex, and (e) somatostatin and neurotensin in the hippocampus. It is likely that many of these changes are related with dopaminergic deficit, and the only clear relationship between a neuropeptide and a clinical feature of PD is that of somatostatin with the presence of cognitive impairment (Jiménez-Jiménez, 1994). Table 2 summarizes the findings of classical studies on CSF neuropeptide levels in PD patients. Most of these studies enrolled limited series of patients.

In recent years, there has been increased interest in the possible role of orexin-A/hypocretin-1, a neuropeptide hormone implicated in the pathogenesis of narcolepsia, on the development of excessive daytime sleepiness in PD patients. Since the first report by Drouot et al. (2003), who described decreased ventricular CSF orexin levels in PD patients, which were related with the severity of the disease, other authors have confirmed decreased CSF orexin in PD (Fronczek et al., 2007; Asai et al., 2009) and in other neurodegenerative parkinsonisms (Yasui et al., 2006), and the relation of CSF orexin with severity of PD (Asai et al., 2009), and with the presence of sleep attacks (Asai et al., 2009). In contrast, Compta et al. (2009a) found no significant differences in CSF orexin levels between demented PD patients, non-demented PD patients, and healthy controls, and found no relation between CSF orexine and Epworth sleepiness scale or Mini-Mental State Examination. Drouot et al. (2011) found a lack of association between low ventricular CSF orexin and sleepiness in PD, and a relation between high levels of orexin-A in PD associated with loss of REM muscle atonia (Bridoux et al., 2013), while Wienecke et al. (2012) reported association between low CSF orexin levels and sleepiness in PD. Finally, Pålhagen et al. (2010) described similar CSF orexin levels in patients with major depression with or without concomitant PD. The results regarding orexin A are controversial, and await confirmation.

Pisani et al. (2005, 2010) found increased CSF levels of the endogenous cannabinoid anandamide in untreated PD patients, which were unrelated to the severity of the disease (Pisani et al., 2005) and reversed by chronic dopaminergic replacement (Pisani et al., 2010). Zhou et al. (1997) found decreased CSF β-phenylethylamine (PEA) levels in PD patients which were correlated negatively with Hoehn & Yahr stage.

These compounds act as intracellular second messengers of neurotransmitters or other compounds such as nitric oxide (NO). The most important are cyclic adenosine 3′5′ monophosphate (cAMP) and cyclic guanosine 3′5′ monophosphate (cGMP). Belmaker et al. (1978) reported a 40–50% decrease of CSF cAMP and an 80–90% decrease of CSF cGMP levels in PD patients who were not related with levodopa therapy. Decreased CSF cAMP levels in PD have also been reported in another study (Volicer et al., 1986), while others found this value to be normal (Cramer et al., 1973, 1984; Covicković-Sternić et al., 1987; Oeckl et al., 2012), both in PD patients with and without dementia (Oeckl et al., 2012). Four further studies described normal CSF cGMP levels (Volicer et al., 1986; Covicković-Sternić et al., 1987; Ikeda et al., 1995; Oeckl et al., 2012), while another found a non-significant trend toward higher CSF cGMP levels in PD patients when compared with controls and higher levels in levodopa-treated PD patients compared with those without levodopa treatment (Navarro et al., 1998).

Biopterins act as cofactors for aromatic amino acid hydroxylases, which produce a number of neurotransmitters including DA, NE, epinepherine, and 5-HT and are also required for the production of NO. CSF levels of neopterin and biopterin have been found decreased in PD patients by several groups, especially in those with early-onset PD (Fujishiro et al., 1990; Furukawa et al., 1992), and in carriers of the PARK8 mutation (Koshiba et al., 2011), which was negatively correlated with duration of illness in those patients with akinetic-rigid PD (Furukawa et al., 1991). In contrast, another group found increased CSF neopterin in PD (Widner et al., 2002).

CSF concentration of hydroxylase cofactor, predominantly composed of tetrahydrobiopterin (BH₄), has also been found decreased (Williams et al., 1980a,b).

Thiamine is an essential cofactor for several important enzymes involved in brain oxidative metabolism. Our group found normal CSF levels of thiamine-diphosphate, thiamine-monophosphate, free thiamine, and total thiamine in PD patients (Jiménez-Jiménez et al., 1999).

Because MAPT gene is one of the main genes involved in the risk for PD (Alonso-Navarro et al., 2014), the measurement of CSF protein tau levels are hypothetically useful as a marker of this disease. Tau protein is important for maintaining the stability of axonal microtubules involved in the mediation of fast axonal transport of synaptic constituents. Hyperphosphorylation of tau causes reduces binding affinity for microtubules, leading to their malfunction. Following neuronal damage, tau is released into extracellular space and may be increased in the CSF. Tau is an important component of the neurofibrillary tangles (pairwise, helical protein filaments which are found in the cytoskeleton or neuronal cells in Alzheimer's disease (AD) brains. CSF tau protein levels are increased in AD patients, and so are a useful marker for this disease. The high risk of PD patients of developing cognitive impairment or dementia patients makes measurement of CSF tau reasonable as a possible marker of this disease.

Many studies have shown similar CSF total tau and phosphorylated tau (phosphotau) in PD patients to controls (Blennow et al., 1995; Molina et al., 1997c; Jansen Steur et al., 1998; Sjögren et al., 2002; Mollenhauer et al., 2006; Parnetti et al., 2008, 2011, 2014a,b; Ohrfelt et al., 2009; Compta et al., 2009b; Alves et al., 2010; Montine et al., 2010; Aerts et al., 2011; van Dijk et al., 2013a; Herbert et al., 2014). Several of these studies have shown increased CSF tau in demented PD patients (Mollenhauer et al., 2006; Compta et al., 2009b). The 33 KDa/55 KDa tau isoforms ratio have also been found to be normal in PD (Borroni et al., 2008, 2009), but decreased in progressive supranuclear palsy (PSP), and normal in patients with diffuse Lewy body disease (DLBD), demented PD patients (PDD), AD, and frontotemporal dementia (FTD) (Borroni et al., 2008, 2009).

Some authors have found decreased CSF total tau and phosphotau levels when compared with controls (Mollenhauer et al., 2011; Shi et al., 2011; Kang et al., 2013) and similar levels in PD to PSP, DLBD, and MSA (Mollenhauer et al., 2011), while others found higher CSF tau in DLBD compared with PDD patients (Andersson et al., 2011), and still others higher CSF total tau in MSA than in PD patients (Herbert et al., 2014). Hall et al. (2012) reported decreased CSF total tau and normal phosphotau both in PD and PDD, while total tau was increased in CBD and normal in PSP, DLBD, and MSA, and phosphotau was decreased in PSP and MSA in comparison with controls.

Přikrylová Vranová et al. (2010) found increased CSF tau levels in PD patients with less than 2 years of evolution, and increased CSF tau levels which were higher in patients with PDD than in PD, and in PD than in controls, and similar CSF tau in DLDB than in controls (Vranová et al., 2014). This group and others found increased CSF total tau levels in patients with non-tremor variants of PD as compared to tremor-dominant PD and controls (Jellinger, 2012; Přikrylová Vranová et al., 2012). Compta et al. (2011) described increased CSF tau levels in PD patients carrying the allele rs242557A. Siderowf et al. (2010) showed a lack of association between baseline CSF tau levels and cognitive decline in PD patients. Patients with corticobasal degeneration (CBD) and PSP have shown higher CSF total and phospotau levels (Aerts et al., 2011), and patients with DLBD showed similar CSF tau levels to PD patients in one study (Ohrfelt et al., 2009), while other authors found higher CSF tau levels in AD than in DLBD, in DLDB higher than in PDD, and in PDD higher than in PD (Parnetti et al., 2008).

Baseline CSF levels of total and phosphotau in the DATATOP study, involving 403 early PD patients, were negatively correlated with disease progression assessed with the Unified PD Rating Scale (UPDRS) (Zhang et al., 2013).

Beyer et al. (2013) reported a lack of correlation between CSF levels of total and phosphotau, and ventricular size in 73 non-demented PD patients and 18 PD patients with mild cognitive impairment.

The results of the studies reported on CSF tau levels in PD are summarized in Table 4. Although these results are not conclusive, CSF tau levels could be related to the progression of the disease (Zhang et al., 2013), and to the preservation of cognitive function in PD patients (Stewart et al., 2014).

Alpha-synuclein (α-synuclein) is a 140 amino acid-long presynaptic protein, which is the major component of the Lewy bodies (the neuropatologic hallmark of PD), and has been implicated in the pathogenesis of PD and in synucleinopathies such as MSA and DLBD. Mutations of the α-synuclein (SNCA) gene are related with early-onset monogenic familial PD and are associated with increased risk for sporadic PD (Alonso-Navarro et al., 2014). Although early studies failed to detect the native form of α-synuclein in the CSF of PD and control patients (Jakowec et al., 1998), later studies have detected monomeric SNC in the CSF, with similar levels in PD patients and controls (Borghi et al., 2000). Several studies have found similar CSF total α-synuclein levels in PD patients and in controls (Woulfe et al., 2002; Ohrfelt et al., 2009; Park et al., 2011; Parnetti et al., 2011; Tateno et al., 2012) and others decreased CSF α-synuclein in PD (Tokuda et al., 2006; Hong et al., 2010; Mollenhauer et al., 2011, 2013; Hall et al., 2012; Wang et al., 2012; Kang et al., 2013; Wennström et al., 2013; Parnetti et al., 2014a,b; Mondello et al., 2014; van Dijk et al., 2014), DLBD (Parnetti et al., 2011; Wennström et al., 2013), MSA (Wang et al., 2012; Mondello et al., 2014), and PSP (Wang et al., 2012). Four studies have reported increased CSF oligomeric α-synuclein levels in PD compared with controls (Tokuda et al., 2010; Park et al., 2011; Parnetti et al., 2014a,b), and one of them showed increased CSF α-Syn in PD patients compared with patients with PSP and AD (Tokuda et al., 2010). Wang et al. (2012) found increased CSF levels of the phosphorylated α-synuclein phospho-Ser129 (PS-129) in PD patients when compared with controls, but lower levels in MSA and PSP of this protein than in PD patients and controls.

Aerts et al. (2012) found similar CSF α-synuclein levels in PD patients to DLBD, PSP, and MSA. Hall et al. (2012) found higher CSF α-synuclein in PSP than in PD, PDD, DLBD, and MSA. Tateno et al. (2012) reported similar CSF α-synuclein levels in PD, MSA, DLBD, and controls but higher CSF α-synuclein levels in AD patients, while Ohrfelt et al. (2009) found higher CSF α-Syn levels in AD than in DLDB and PD, and in DLBD than in PD patients. Foulds et al. (2012) found similar post-mortem CSF total α-synuclein levels in PD, MSA, DLBD, and PSP, but increased CSF levels of phosforylated oligomers in MSA.

van Dijk et al. (2014) reported a lack of relation between CSF α-synuclein levels and striatal dopaminergic deficit measured by dopamine transporter binding and single photon emission computed tomography. In addition, a recent study by Shi et al. (2012) described a lack of relation between the loss of striatal dopaminergic function, assessed by positron emission tomography (PET), and CSF α-synuclein levels, in asymptomatic carriers of mutations in the LRRK2 gene. CSF neurosin (a protease that degrades α-synuclein) levels have been found to be decreased (Wennström et al., 2013).

Lower baseline CSF α-synuclein levels in the DATATOP study predicted a better preservation of cognitive function in early PD patients with up to 8 years of follow-up (Stewart et al., 2014).

The results of the studies reported on CSF α-synuclein levels in PD are summarized in Table 5. The majority of recent studies have shown decreased CSF α-synuclein levels both in PD and in other synucleopathies. Therefore, this should be a useful marker to distinguish this disease from controls, but not to distinguish among synucleopathies.

Amyloid beta (Aβ) are a group of different lengths peptides resulting from the enzymatic cleavage of the amyloid precursor protein (APP). The most common is the 42 amino-acid long Aβ42. These peptides have a differential trend toward aggregation (specially Aβ1-42) to form amyloid plaques, one of the pathological hallmarks of AD and DLBD. The increased risk for developing cognitive impairment and dementia of PD patients in comparison with the general population makes it reasonable to link AD markers such as Aβ42 to PDD. Several studies have shown similar (Holmberg et al., 2003; Mollenhauer et al., 2006; Ohrfelt et al., 2009; Přikrylová Vranová et al., 2010; Aerts et al., 2011; Parnetti et al., 2011; van Dijk et al., 2013a) or decreased (Sjögren et al., 2002; Compta et al., 2009b; Mollenhauer et al., 2011; Shi et al., 2011; Kang et al., 2013; Nutu et al., 2013a; Vranová et al., 2014) CSF Aβ1-42 (Aβ1-42) in PD patients, with the exception of one study which reports increased levels (Parnetti et al., 2014b). Other found decreased CSF Aβ-1-42 (Mollenhauer et al., 2006; Compta et al., 2009b; Alves et al., 2010; Montine et al., 2010; Siderowf et al., 2010) and Aβ1-40 (Alves et al., 2010) and Aβ1-38 (Alves et al., 2010) only in PDD patients or in PD patients with memory impairment.

Baseline CSF Aβ levels in the DATATOP study, were negatively correlated with disease progression assessed with UPDRS (Zhang et al., 2013). Baseline CSF levels of Aβ1-42 in two studies (Siderowf et al., 2010; Parnetti et al., 2014b); and the combination of lower baseline CSF Aβ, worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulated in precentral regions by 3T-brain-Magnetic Resonance Imaging in another (Compta et al., 2013) have been associated with further cognitive decline in PD patients.

CSF Aβ1-42 levels have been reported as decreased (Parnetti et al., 2008; Andersson et al., 2011; Parnetti et al., 2011) or similar (Ohrfelt et al., 2009; Nutu et al., 2013a) in DLBD than in PDD and PD patients, decreased in MSA (Holmberg et al., 2003; Shi et al., 2011), and decreased in DLBD in comparison with PD, PDD (Hall et al., 2012; Vranová et al., 2014), PSP, MSA, and CBD (Hall et al., 2012).

Alves et al. (2013) reported that patients with PD with the postural instability-gait disorders (PIGD) phenotype had significantly reduced CSF Aβ42, Aβ38, Aβ42/40, and Aβ38/40 levels compared with patients with the tremor-dominant phenotype and controls.

Nutu et al. (2013b) described lower CSF levels of Aβ1-15/16 in PD, PDD, PSP, and MSA compared to CBD, AD, and controls.

Beyer et al. (2013) reported a correlation between CSF levels of Aβ38, Aβ40, and Aβ42, and ventricular size in 73 non-demented PD patients and 18 PD patients with mild cognitive impairment.

The results of the studies reported on CSF Aβ levels in PD are summarized in Table 6. Many of these studies suggest the potential usefulness of CSF Aβ1-42 levels to predict cognitive impairment in PD patients.

Abnormal accumulation in the cytoplasm of neurofilaments (NF), members of the cytoskeleton proteins expressed by neurons, have been detected in neurodegenerative diseases including AD, MSA, DLBD, and PD. CSF levels of neurofilament light (NFL) proteins have been found normal in PD patients (Constantinescu et al., 2010; Hall et al., 2012), and increased in patients with PSP (Holmberg et al., 1998; Constantinescu et al., 2010; Hall et al., 2012), MSA (Holmberg et al., 1998; Constantinescu et al., 2010; Hall et al., 2012), CBD (Constantinescu et al., 2010; Hall et al., 2012), and PDD (Hall et al., 2012).

CSF neuronal thread protein (NTP) levels have been found increased when compared with controls and decreased when compared with AD patients in one study (de la Monte et al., 1992), and similar to those of controls in another (Yamada et al., 1993). CSF annexine V has been found to be decreased in PD (Vermes et al., 1999). Glial fibrilar acidic protein (GFAP) has been found to be normal in the CSF of PD, MSA, PSP, and CBD patients (Constantinescu et al., 2010). CSF levels of the glial activation marker YKL-40 have been found to be decreased in PD, MS, PSP, and CBD (Olsson et al., 2013).

Defects in the gene encoding DJ-1 protein cause an autosomal recessive early-onset PD, PARK7 (Alonso-Navarro et al., 2014). This protein is also a marker of oxidative stress. CSF levels of DJ-1 protein have been found to be increased in PD in 2 studies (Waragai et al., 2006; Herbert et al., 2014) and decreased in another 2 (Shi et al., 2011; Hong et al., 2010). One of these studies described decreased CSF DJ-1 in MSA as well (Shi et al., 2011), and other increased DJ-1 in MSA compared with PD and with controls (Herbert et al., 2014). Shi et al. (2012) described a lack of relation between the loss of striatal dopaminergic function and CSF DJ-1 levels in asymptomatic carriers of mutations in the LRRK2 gene (PARK8). The results on DJ-1 are, therefore, inconsistent and should not be considered as a marker of PD.

Defects in the gene encoding ubiquitin carboxy-terminal hydrolase 1 (UCH-L1) cause familial PD, PARK5. A recent study found decreased CSF UCH-L1 levels in PD, MSA, and PSP compared with controls (Mondello et al., 2014).

Among proteins related with apoptosis, Bcl-2 protein has not been detected in the CSF of PD patients (Mogi et al., 1996b; Mogi and Nagatsu, 1999). CSF levels of clusterin have been reported to be increased (Přikrylová Vranová et al., 2010; Vranová et al., 2014) or normal (van Dijk et al., 2013a), tissue transglutaminase (Vermes et al., 2004) increased in PD, and cystatin C normal in PD (Přikrylová Vranová et al., 2010; Yamamoto-Watanabe et al., 2010) and decreased in MSA (Yamamoto-Watanabe et al., 2010).

Studies measuring CSF levels of lysosomal hydrolases (involved in the α-Syn degradation) found decreased (Balducci et al., 2007), normal (van Dijk et al., 2013b), or increased (Parnetti et al., 2014a) β-hexosaminidase, increased cathepsin E (van Dijk et al., 2013b), decreased α-mannosidase (Balducci et al., 2007), decreased (Balducci et al., 2007) or normal β-mannosidase (Mollenhauer et al., 2011; van Dijk et al., 2013b), decreased α-fucosidase (van Dijk et al., 2013b), β-glucocerebrosidase decreased (Balducci et al., 2007; Parnetti et al., 2014a) or normal (van Dijk et al., 2013b), β-galactosidase increased (van Dijk et al., 2013b) or normal (Balducci et al., 2007; Parnetti et al., 2014a), and cathepsin D normal (van Dijk et al., 2013b) in PD patients compared with controls.

CSF Prion protein (PrP) (Meyne et al., 2009) and tetranectin (involved in tissue remodeling) (Hong et al., 2010) levels have been found to be decreased, and apolipoprotein A-1 normal (Wang et al., 2010) in PD patients. CSF levels of transthyretin (TTR, a clearance protein produced in the choroid plexus) have been found to be increased in Lewy body diseases, including PD, PDD, and DLBD in relation with controls (Maetzler et al., 2012). CSF levels of the soluble proteoglycan NG2 (sNG2), involved in proliferation, migration, and differentiation of perycites and NG2 cells in the brain, have been found to be similar in PD patients and controls, and decreased in DLBD (Nielsen et al., 2014).

In PD patients there are reports of decreased CSF post-proline cleaving enzyme (Hagihara and Nagatsu, 1987), increased dipeptidyl-aminopeptidase II (Hagihara et al., 1987), normal dipeptidyl-aminopeptidase IV (Hagihara et al., 1987), and normal glutamic oxaloacetic transaminase (GOT) (Steen and Thomas, 1962; Weiss et al., 1975; Qureshi et al., 1995) and glutamic pyruvic transaminase (GPT) (Weiss et al., 1975) levels.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.