Edited by: Ramon Santos El-Bachá, Universidade Federal da Bahia, Brazil
Reviewed by: Ana I. Duarte, University of Coimbra, Portugal; Victor P. Andreev, Arbor Research Collaborative for Health, USA; Naruhiko Sahara, National Institute of Radiological Sciences, Japan
*Correspondence: Félix J. Jiménez-Jiménez, Section of Neurology, Hospital Universitario del Sureste, Ronda del Sur 10, E-28500, Arganda del Rey, Madrid, Spain e-mail:
This article was submitted to the journal Frontiers in Cellular Neuroscience.
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The blood-brain barrier supplies brain tissues with nutrients and filters certain compounds from the brain back to the bloodstream. In several neurodegenerative diseases, including Parkinson's disease (PD), there are disruptions of the blood-brain barrier. Cerebrospinal fluid (CSF) has been widely investigated in PD and in other parkinsonian syndromes with the aim of establishing useful biomarkers for an accurate differential diagnosis among these syndromes. This review article summarizes the studies reported on CSF levels of many potential biomarkers of PD. The most consistent findings are: (a) the possible role of CSF urate on the progression of the disease; (b) the possible relations of CSF total
The diagnosis of Parkinson's disease (PD) in live patients is fundamentally clinical, and is based on the presence of its cardinal signs (rest tremor, rigidity, bradykinesia, and postural instability), and the absence of atypical data for idiopathic PD. The final confirmation of the diagnosis is made by post-mortem neuropathological analysis. To date, there are no definitive biomarkers to make an accurate differential diagnosis with other parkinsonian syndromes.
Because the cerebrospinal fluid (CSF) is in close contact with the extracellular space of the brain, it is believed that many of the biochemical modifications in the brain should be reflected in the CSF. Therefore, CSF has been widely investigated in PD and in other parkinsonian syndromes with the aim of acquiring knowledge on the pathogenesis of this disease. This article summarizes the data on analyses performed in the CSF of patients diagnosed with PD compared with controls, with regard to: (1) concentrations of neurotransmitters (mainly monoamines and their metabolites), neuromodulators, and related substances as possible biological markers of the disease itself or its complications; (2) concentrations of endogenous neurotoxins; (3) status of oxidative stress markers or substances which could be related with the induction of oxidative stress or with “neuroprotection” against it; (4) status of inflammation and immunological markers, neurotrophic and growth factors, and (5) concentrations of proteins related with the pathogenesis of PD or other compounds.
The aim of this review is to provide an extensive descriptive overview of studies published on this issue (including references to many reports in the last six decades which have historical interest).
References for this review were identified by searching in PubMed from 1966 until June 20, 2014. The term “
(A) Neurotransmitters, neuromodulators, and related substances |
Dopamine (DA) metabolites: dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), 3-orthomethylDOPA (3-OMD) Serotonin (5-hydroxytryptamine or 5-HT) metabolites or precursors: 5-hydroxytryptophan (5-HTP), 5-hydroxyindoleacetic acid (5-HIAA), kynurenine, 3-hydroxykynurenine Noradrenalin (norepinephrine or NE) metabolites or precursors: 3-methoxy-4-hydroxy-phenylethylenglycol (MHPG), dopamine-beta-hydroxylase (DBH) Acetylcholine (Ach) and related substances: choline, acetylcholine-esterase (AchE), butiryl-cholin-esterase (BchE) Neurotransmitter amino acids: gamma-amino butyric acid (GABA), glutamate, aspartate, glycine Neuropeptides: substantia P (SP), cholecystokinin-8 (CCK-8), met-enkephalin (MET-ENK), leu-enkephalin (LEU-ENK), dynorphin A(1-8), somatostatin, neuropeptide Y (NPY), beta-endorphin, arginine-vasopressine (AVP), vasoactive intestinal peptide (VIP), delta sleep-inducing peptide (DSIP), alpha-melanocyte-stimulating hormone-like, diazepam-binding inhibitor, neurokinin A, corticotropin-releasing hormone (CRH), adrenocorticotropin hormone (ACTH), beta-lipotropine, angiotensin, chromogranins A and B, secretogranin II, orexin-A/hypocretin-1 Other neurotransmitters: endogenous cannabinoids, β-phenylethylamine Cyclic nucleotides: cyclic adenosine 3′5′ monophosphate (cAMP), cyclic guanosine 3′5′ monophosphate (cGMP) Biopterin derivatives and other cofactors |
(B) Endogenous neurotoxins |
Tetrahydroisoquinolin (TIQ) derivatives: 2-methyl-6,7-dihydroxy1,2,3,4-TIQ (2-MDTIQ), 1-MDTIQ (salsolinol). 1-benzyl-1,2,3,4-TIQ β-carbolinium cations (BC+s) |
(C) Oxidative stress markers |
Lipid peroxidation markers: Malonyl-dialdehyde (MDA) (E)-4-hydroxynonenal (HNE) Low density lipoprotein (LDL) oxidation products Schiff bases, conjugated dienes, oxidized proteins, and aldehyde polymers DNA oxidation markers: 8′-hydroxy-2′deoxyguanine (8-OHdG) 8-hydrosyguanosine (8-OHG) 8-OHdG/8-OHG ratio Transition metals and related proteins: iron, ferritin, transferring, copper, cerulopasmin, ferroxidase, manganese, zinc Other metals: selenium, chromium, magnesium, calcium, aluminum, silicon, cobalt, tin, lead, barium, bismuth, cadmium, mercury, molibdenum, nichel, antimony, strontium, thallium, vanadium, wolfram, and zirconium |
(D) Inflamatory and immunological markers |
Inteleukins (IL) Tumor necrosis alpha (TNF-α) Other: leukotrienes. α-1-antichymotrypsin |
(E) Growth and neurotrophic factors |
Brain-derived neurotrophic factor (BDNF) Transforming Growth Factors: TGF-α, TGF-β1, TGF-β2 Insulin-like growth factor-1 (IGF-1) and IGF-binding proteins (IGFBPs) Neuroregulins (Epidermal Growth Factor or EGF family) |
(F) Proteins involved in the pathogenesis of PD |
Microtubular-Associated Protein Alpha-synuclein Amiloyd beta Neurofilament proteins Other proteins: DJ-1, UCH-L1 |
(G) Other compounds |
Because the main neurochemical finding in PD is the depletion of dopamine (DA) in the nigroestriatal system (Benito-León et al.,
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.,
Friedman et al. (Friedman,
Tohgi et al. (
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.,
Several studies have described neuronal loss, and presence of Lewy body in serotonergic raphe nuclei in PD patients (Benito-León et al.,
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.,
CSF 5-HIAA levels seem to be unchanged by therapy with levodopa (Godwin-Austen et al.,
Some authors have described decreased CSF 5-HIAA (Mayeux et al.,
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.,
Several authors have described a negative correlation between CSF MHPG levels and cognitive functioning (Mann et al.,
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.,
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,
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.,
CSF activity of butirylcholine-esterase (BchE) have been found to be similar in PD patients and controls (Ruberg et al.,
CSF GABA levels in PD patients have been found to be decreased, when compared with controls, by many authors (Lakke and Teelken,
Normality of CSF glutamate levels has been reported by most investigators (Van Sande et al.,
CSF aspartate levels have been reported as normal (Lakke and Teelken,
The results on CSF glycine levels have been reported as normal by most investigators (Gjessing et al.,
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.,
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.,
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,
Substantia P (SP) | Pezzoli et al., |
12/10 | Increased 5-fold |
Cramer et al., |
15/9 | Normal | |
Cramer et al., |
23/9 | Decreased by 30% (controls were essential tremor patients) | |
Cholecystokinin-8 (CCK-8) | Lotstra et al., |
20/68 | Decreased by 50% |
Met-enkephalin (MET-ENK) | Pezzoli et al., |
12/10 | Increased 3-fold in PD patients with slight or moderate disability ( |
Yaksh et al., |
8/9 | Decreased by 37% | |
Baronti et al., |
16/19 | Decreased by 31.7% | |
Leu-enkephalin (LEU-ENK) | Liu, |
22/19 | Increased by 122% in untreated PD patients without further modification by levodopa therapy |
Dynorphin A(1-8) | Baronti et al., |
16/19 | Normal |
Somatostatin | Jolkkonen et al., |
35/19 | Decreased by 22% ( |
Strittmatter and Cramer, |
38/12 | Decreased by 27.5% ( |
|
Strittmatter et al., |
35/11 | Decreased |
|
Cramer et al., |
15/9 | Decreased by 39% | |
Dupont et al., |
39/29 | Decreased by 40% | |
Christensen et al., |
48/32 | Decreased by 40% | |
Cramer et al., |
50/6 | Decreased by 34%(controls were patients with essential tremor) | |
Masson et al., |
35/11 | Decreased ( |
|
Jost et al., |
68/6 | Decreased by 28% | |
Hartikainen et al., |
35/34 | Normal | |
Volicer et al., |
10/9 | Normal | |
Beal et al., |
6/84 | Normal | |
Poewe et al., |
22/11 | Normal in PD patients with dementia ( |
|
Espino et al., |
23/26 | Increased by 47%, especially in demented patients | |
Neuropeptide Y (NPY) | Martignoni et al., |
10/20 | Decreased by 31% |
Yaksh et al., |
8/9 | Normal | |
Beta-endorphin | Nappi et al., |
24/15 | Decreased ( |
Jolkkonen et al., |
36/35 | Normal | |
Arginine-vasopressine (AVP) | Sundquist et al., |
11/21 | Decreased by 68% |
Olsson et al., |
12/32 OND | Decreased by 71% | |
Vasoactive intestinal peptide (VIP) | Sharpless et al., |
19/12 | Normal |
Delta sleep-inducing peptide (DSIP) | Ernst et al., |
9/20 | Decreased by 28.7% (Ferrero et al., |
Alpha-melanocyte-stimulating hormone-like | Rainero et al., |
9/12 | Increased by 2-fold |
Diazepam-binding inhibitor | Ferrero et al., |
25/82 | Increased by 42.5% (80% in depressed PD patients and normal in non-depressed PD patients |
Ferrarese et al., |
28/10 | Decreased by 50% in PDD ( |
|
Neurokinin A | Galard et al., |
12/11 | Decreased by 24% |
Corticotropin-releasing hormone (CRH) | Suemaru et al., |
10/5 | Normal |
ACTH | Nappi et al., |
24/15 | Normal |
Beta-lipotropine | Nappi et al., |
24/15 | Normal |
Angiotensin converting enzyme (ECA) | Konings et al., |
88 PDND/18 PDD/20 | Increased in PDND patients under levodopa therapy ( |
Zubenko et al., |
10 PDD/30 | Decreased by 27% in demented PD patients | |
Zubenko et al., |
15/10 | Decreased by 24% | |
Chromogranin A and B and secretogranin II | Eder et al., |
8/29 | Normal |
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. (
Pisani et al. (
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. (
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.,
CSF concentration of hydroxylase cofactor, predominantly composed of tetrahydrobiopterin (BH4), has also been found decreased (Williams et al.,
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.,
One of the classical etiological hypotheses of PD is related with the presence of endogenous substances which share structural similarities with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a neurotoxin that induces a parkinsonism resembling PD.
Moser et al. (Moser and Kömpf,
CSF salsolinol levels have been reported to be increased in PD patients compared with controls by other groups (Maruyama et al.,
Matsubara et al. (
The results of studies on neurotoxins related with the risk for PD are based on small series and are not conclusive.
Because there is much evidence on the contribution of oxidative stress in the pathogenesis of PD (Figure
Lipid peroxidation markers | Malonyl-dialdehyde (MDA) | Ilić et al., |
31/16 | Increased ( |
Ilic et al., |
33/16 | Increased ( |
||
Shukla et al., |
21/20 | Normal | ||
(E)-4-hydroxynonenal (HNE) | Selley, |
10/10 | Increased 4-fold | |
Low density lipoprotein (LDL) oxidation products | Buhmann et al., |
70/60 OND/31 HC | Increased 3-fold with –SH decreased 1.5-fold | |
Schiff bases, conjugated dienes, oxidized proteins, and aldehyde polymers | Boll et al., |
22/41 | Increased 1,5 fold (Isobe et al., |
|
DNA oxidation markers | 8'-hydroxy-2'deoxyguanine (8-OHdG) | Kikuchi et al., |
48/22 | Increased ( |
Isobe et al., |
20/20 | Increased ( |
||
8-hydrosyguanosine (8-OHG) | Kikuchi et al., |
48/22 | Increased | |
Abe et al., |
24/15 | Increased 3-fold ( |
||
8-OHdG/8-OHG ratio | Kikuchi et al., |
48/22 | Increased 2-fold ( |
|
Transition metals and related proteins | Iron | Campanella et al., |
13/5 | Normal |
Pall et al., |
24/34 | Normal | ||
Gazzaniga et al., |
11/22 | Normal | ||
Takahashi et al., |
20/25 | Normal | ||
Pan et al., |
NS/NS | Normal | ||
Jiménez-Jiménez et al., |
37/37 | Normal | ||
Hozumi et al., |
20/15 | Normal | ||
Forte et al., |
26/13 | Decreased ( |
||
Alimonti et al., |
42/20 | Decreased ( |
||
Qureshi et al., |
36/21 | Increased | ||
Ferritin | Campanella et al., |
13/5 | Normal | |
Dexter et al., |
26/11 | Normal | ||
Pall et al., |
24/21 | Normal | ||
Kuiper et al., |
72 PDND/15 PDD/20 HC | Normal | ||
Transferrin | Loeffler et al., |
12/11 | Normal | |
Copper | Campanella et al., |
13/5 | Normal | |
Gazzaniga et al., |
11/22 | Normal | ||
Takahashi et al., |
20/25 | Normal | ||
Pan et al., |
NS/NS | Increased ( |
||
Jiménez-Jiménez et al., |
37/37 | Normal | ||
Forte et al., |
26/13 | Normal | ||
Alimonti et al., |
42/20 | Normal | ||
Qureshi et al., |
36/21 | Normal | ||
Boll et al., |
22/41 | Increased 2-fold | ||
Pall et al., |
24/34 | Increased ( |
||
Hozumi et al., |
20/15 | Increased 2-fold ( |
||
Boll et al., |
49/26 (35 PD untreated) | Increased 1,5 fold | ||
Ceruloplasmin | Campanella et al., |
13/5 | Normal | |
Loeffler et al., |
12/11 | Normal | ||
Ferroxidase | Boll et al., |
22/41 | Decreased activity by 20% | |
Boll et al., |
49/26 (35 PD untreated) | Decreased activity by 1.5-fold | ||
Manganese | Gazzaniga et al., |
11/22 | Normal | |
Pan et al., |
NS/NS | Normal | ||
Jiménez-Jiménez et al., |
37/37 26/13 | Normal Normal | ||
Forte et al., |
||||
Alimonti et al., |
42/20 | Normal | ||
Hozumi et al., |
20/15 | Increased 1.5-fold ( |
||
Zinc | Takahashi et al., |
20/25 | Normal | |
Pan et al., |
NS/NS | Normal | ||
Forte et al., |
26/13 | Normal | ||
Jiménez-Jiménez et al., |
37/37 | Decreased ( |
||
Qureshi et al., |
36/21 | Decreased | ||
Hozumi et al., |
20/15 | Increased 3-fold ( |
||
Other metals | Selenium | Takahashi et al., |
20/25 | Normal |
Qureshi et al., |
36/21 | Increased | ||
Aguilar et al., |
28/43 | Increased only in untreated PD patients ( |
||
Chromium | Aguilar et al., |
28/43 | Normal | |
Alimonti et al., |
42/20 | Decreased by 50% | ||
Magnesium | Hozumi et al., |
20/15 | Normal | |
Forte et al., |
26/13 | Normal | ||
Alimonti et al., |
42/20 | Normal | ||
Calcium | Pan et al., |
NS/NS | Normal | |
Forte et al., |
26/13 | Normal | ||
Alimonti et al., |
42/20 | Normal | ||
Aluminum | Forte et al., |
26/13 | Decreased ( |
|
Alimonti et al., |
42/20 | Normal | ||
Silicon | Forte et al., |
26/13 | Normal | |
Alimonti et al., |
42/20 | Decreased ( |
||
Cobalt | Alimonti et al., |
42/20 | Decreased ( |
|
Tin | Alimonti et al., |
42/20 | Decreased ( |
|
Lead | Alimonti et al., |
42/20 | Decreased by 50% | |
Various | Alimonti et al., |
42/20 | Normal levels of barium, bismuth, cadmium, mercury, molibdenum, nickel, antimony, strontium, thallium, vanadium, wolfram, and zirconium | |
Nitric oxide metabolites/nitroxidative stress | Nitrates | Ikeda et al., |
11/17 | Normal |
Molina et al., |
31/38 | Normal | ||
Kuiper et al., |
103/20 | Decreased | ||
Boll et al., |
22/41 | Increased 2-fold | ||
Nitrites | Ikeda et al., |
11/17 | Normal | |
Ilic et al., |
33/? | Normal | ||
Kuiper et al., |
103/20 | Normal | ||
Boll et al., |
22/41 | Increased 2-fold | ||
Qureshi et al., |
16/14 | Increased 2-fold both in untreated ( |
||
Nitrotyrosine-containing proteins | Fernández et al., |
54/40 | Increased ( |
|
Aoyama et al., |
10/6 | Increased 1.8-fold | ||
Antioxidant enzymes or substances | Total superoxide-dismutase (SOD) | Marttila et al., |
26/26 OND | Normal |
De Deyn et al., |
12/58 | Normal | ||
Cu/Zn-SOD (SOD-1) | Ilić et al., |
31/16 | Increased ( |
|
Ilic et al., |
33/16 | Increased ( |
||
Boll et al., |
22/41 | Decreased ( |
||
Mn-SOD (SOD-2) | Aoyama et al., |
10/6 | Normal | |
Catalase | Marttila et al., |
26/26 OND | Normal | |
Glutathione peroxidase (GPx) | Marttila et al., |
26/26 OND | Normal | |
Glutathione reductase (GR) | Ilić et al., |
31/? | Increased | |
Ilic et al., |
33/? | Increased | ||
Reduced glutathione (GSH) | Marttila et al., |
26/26 OND | Normal | |
Tohgi et al., |
22/15 | Increased ( |
||
Konings et al., |
71 PD/13 PDND/21 HC | Normal | ||
Oxidized glutathione (GSSG) | LeWitt et al., |
48/57 | Decreased ( |
|
Tohgi et al., |
22/15 | Decreased ( |
||
Alpha-tocopherol (vitamin E) | Buhmann et al., |
70/60 OND/31 HC | Decreased by 44–48% | |
Tohgi et al., |
22/15 | Normal | ||
Molina et al., |
34/47 | Normal | ||
Alpha-tocopherol-quinone | Tohgi et al., |
22/15 | Decreased ( |
|
Urate | Tohgi et al., |
11/14 | Normal | |
Constantinescu et al., |
6/18 | Normal | ||
Ascherio et al., |
713/0 | Relation of higher CSF levels of urate with slower rates of clinical decline | ||
Xantine (uric acid precursor) | LeWitt et al., |
217/26 | Normal | |
Ascorbate | Buhmann et al., |
70/60 OND/31 HC | Normal | |
Carnitine | Jiménez-Jiménez et al., |
29/29 | Normal | |
Oxidized coenzyme Q10/total Q10 ratio | Isobe et al., |
20/20 | Increased 18% ( |
|
Isobe et al., |
20/20 | Increased 18% ( |
||
Osteopontine | Maetzler et al., |
30/30 | Increased 2-fold ( |
Transition metals such as iron, copper, and manganese, act as prooxidant agents, although copper is also essential for the antioxidant function of the protein ceruloplasmin, and copper and manganese are constituents of the cytosolic Cu+2/Zn+2 and the mitochondrial Mn+2-superoxide-dismutases (SOD, protective against oxidative processes). Zinc has antioxidant activity and is a constituent of Cu+2/Zn+2-SOD (Jiménez-Jiménez et al.,
Together with its role in glutamate excitotoxity, NO could contribute to oxidative stress mechanisms in the pathogenesis of PD by interacting with ferritin to release iron, inducing mitochondrial complex I damage (Molina et al.,
Among other antioxidant enzymes and substances (Table
CSF interleukin (IL) 1-β levels were found to be normal in one study (Pirttila et al.,
CSF levels of pros-methylimidazol acetic acid, an isomer of the histamine metabolite tele-methylimidazol acetic acid, have been found to be decreased in PD (Prell et al.,
CSF complement 3 (C3) and factor H (FH) levels were reported to be normal in one study (Wang et al.,
Oligoclonal IgG bands have not been detected in the CSF of PD patients (Chu et al.,
The results of studies on inflammatory and immunological markers in PD have a low number of patients and controls enrolled, and are inconclusive.
CSF Brain Derived Neurotrophic Factor (BDNF) levels have been found to be similar in PD patients with major depression to those in patients with major depression without PD in one study (Pålhagen et al.,
Because
Many studies have shown similar CSF total
Some authors have found decreased CSF total
Přikrylová Vranová et al. (
Baseline CSF levels of total and phospho
Beyer et al. (
The results of the studies reported on CSF
Blennow et al., |
44 AD, 31 controls, 17 VAD, 11 FTD, 15 PDND, major depression | CSF total tau and phosphorylated tau (phosphotau) higher in AD than in controls, VAD, FTD, PDND, and major depression (PDND similar than controls) |
Molina et al., |
26 PDND, 25 controls | CSF total tau similar in PD and controls |
Jansen Steur et al., |
115 PD (48 with MMSE lower than 25) 15 controls | CSF total and phosphotau similar in PD (not related with MMSE scores) and controls |
Sjögren et al., |
19 AD, 14 FTD, 11 ALS, 15 PD, 17 controls | CSF total tau and phosphotau increased in AD compared with FTD ( |
Mollenhauer et al., |
73 PDD, 23 PDND, 41 controls (non-demented neurological patients) | CSF total tau significantly higher in PDD than in PDND and controls. This observation was most marked ( |
Parnetti et al., |
19 DLBD, 18 PDD, 23 AD, 20 PDND, 20 controls | CSF total tau of DLBD patients significantly lower than in AD patients, but twofold to threefold higher than in PDD, PDND, or control subjects |
CSF total tau levels similar in PDD and PDND | ||
Phosphotau increased in the AD group only | ||
Borroni et al., |
21 PSP, 20 CBD, 44 FTD, 29 AD, 10 PDND, 15 DLBD, 27 controls | CSF tau 33/55 kDa ratio significantly reduced in PSP when compared to controls and to patients with other neurodegenerative conditions |
CSF tau 33/55 kDa ratio decrease correlated significantly with brainstem atrophy | ||
Borroni et al., |
78 patients with neurodegenerative disorders and 26 controls | CSF tau 33/55 kDa ratio significantly decreased in patients with PSP (0.46 ± 0.16) when compared to healthy controls ( |
Ohrfelt et al., |
66 AD, 15 PD, 15 DLBD, 55 controls | CSF total tau and phosphotau increased significantly in AD, similar levels in PD, DLBD, and controls |
Compta et al., |
20 PDND, 20 PDD, 30 controls patients | CSF total tau and phosphotau higher in PDD than in PDND and controls ( |
Alves et al., |
109 PDND, 36 controls, 20 mild AD | CSF total tau and phosphotau similar in PD and controls |
CSF tau did not correlate with cognitive measures | ||
Montine et al., |
150 controls (115 >50 years; 24 amnestic Mild Cognitive Impairment (aMCI), 49 AD, 49 PD, 11 PDD 62 PD-CIND (cognitive imparment non-demented) | CSF total tau and phospho181-tau significantly increased in AD and aMCI in comparison with the other groups |
Total tau similar in PDD, PDD and PD-CIND and controls | ||
Phospho181-tau slightly decreased when compared with controls >50 years | ||
Přikrylová Vranová et al., |
32 PD, 30 controls | CSF total tau and total tau/beta-amyloid (1-42) ratio higher in PD than in controls ( |
Siderowf et al., |
45 PD, longitudinal follow-up at least 1 year | No association between CSF total tau and phospo181-tau and cognitive decline |
Aerts et al., |
21 PSP, 12 CBD, 28 PD, 49 controls | CSF total tau CBD > PSP > PD = controls |
CSF phospotau CBD > PSP = PD = controls | ||
Parnetti et al., |
38 PD, 32 DLBD, 48 AD, 31 FTD, 32 controls with other neurological diseases ( |
CSF total tau and phosphotau AD > FTD > DLBD = PD = controls |
Shi et al., |
137 controls, 126 PD, 50 AD and 32 MSA | CSF total tau and phosphotau AD > controls > PD = MSA |
Mollenhauer et al., |
Cross-sectional cohort: 51 PD, 29 MSA, 55 DLBD, 62 AD, and 72 neurological controls | CSF total tau AD > DLBD > PD = controls = MSA |
Mollenhauer et al., |
Validation cohort: 275 PD, 15 MSA, 55 66 DLBD, 8 PSP,22 normal pressure hydrocephalus (NPH) and 23 neurological controls | CSF total tau MSA < DLBD = PD < DLBD < controls |
Andersson et al., |
47 DLBD, 17 PDD ( |
CSF total-tau higher in DLBD than in PDD |
CSF phosphotau similar in DLBD and PDD | ||
Compta et al., |
38 PD patients (19 PDD, 19 PDND). All cases were genotyped for a series of tau gene polymorphisms rs1880753, rs1880756, rs1800547, rs1467967, rs242557, rs2471738, and rs7521 | The A-allele rs242557 polymorphism was the only tau gene variant significantly associated with higher CSF tau and phospho-tau levels, under both dominant and dose-response model. This association depended on the presence of dementia, and was only observed in individuals with low (<500 pg/mL) CSF Aβ levels |
Hall et al., |
90 PDND, 33 PDD, 70 DLBD, 48 AD, 45 PSP, 48 MSA, 12 CBD, 107 controls | CSF total tau AD > MSA = CBD > PSP = Controls = DLBD > PDND = PDD |
CSF phosphotau increased in AD, AD > PDD = DLBD = controls = CBD > PDND > PSP = MSA | ||
Přikrylová Vranová et al., |
48 PD (17 early-onset PD, 15 tremor dominant, 16 non-tremor-dominant), 19 neurological controls, 18 AD | CSF tau and index tau/amiloid beta42 increased in non-tremor-dominant PD compared with controls, and other PD groups, and siminar to those of AD |
Jellinger, |
12 PD (6 tremor-dominant PD and 6 non-tremor-dominant PD), 27 AD, 17 controls | CSF total tau higher in AD compared with the other groups, and higher in tremor-dominant PD compared with non-tremor dominant PD and controls |
van Dijk et al., |
52 PD, 50 controls | CSF total tau and phosphotau similar in PD and controls |
Kang et al., |
63 PD, 39 controls | CSF total tau and phosphotau181 significantly lower in PD than in controls |
Zhang et al., |
403 early stage PD patients enrolled in the DATATOP study | Baseline CSF phosphotau/total tau and phosphotau/amyloid beta significantly and negatively correlated with the rates of the Unified Parkinson Disease Rating Scale change |
Beyer et al., |
73 PDND, 18 PD with mild cognitive impairment | No associations between CSF total tau and phosphotau and hippocampal atrophy |
Herbert et al., |
43 PD, 23 MSA, 30 controls | CSF total tau significantly lower in PD than in MSA, but similar to those of controls |
CSF phosphotau similar in PD, MSA and controls | ||
Parnetti et al., |
71 PD (8 of 44 carriers of a mutation in the beta-glucocerebrosidase gene ( |
CSF total tau and phosphotau similar in PD and controls |
Parnetti et al., |
44 PD and 25 controls with other neurological diseases | CSF total tau and phosphotau similar in PD and controls, and unrelated with prognosis and cognitive impairment |
Vranová et al., |
27 PDND, 14 PDD, 14 DLBD, 17 AD 24 controls | CSF total tau AD > PDD > PDND > DLBD = controls |
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-
Aerts et al. (
van Dijk et al. (
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.,
The results of the studies reported on CSF α-synuclein levels in PD are summarized in Table
Borghi et al., |
12 PD, 10 controls | Identification of a 19 kDa band that corresponds to monomeric α-synuclein (similar levels in PD and controls) |
Woulfe et al., |
5 PD, 4 controls | Similar anti-α-synuclein antibodies in PD and controls |
Tokuda et al., |
33 PD, 38 controls (9 healthy and 29 with OND) | CSF α-synuclein levels significantly lower in PD than in controls ( |
Ohrfelt et al., |
66 AD, 15 PD, 15 DLBD, 55 controls | CSF α-synuclein AD > Controls = DLBD = PD |
Hong et al., |
117 PD, 132 controls, 50 AD | CSF α-synuclein PD < Controls = AD (after correcting for hemoglobin levels) |
Tokuda et al., |
32 PD, 28 controls (12 healthy and 16 with OND) | CSF α-synuclein oligomers and oligomers/total-α-synuclein ratio in CSF higher in PD group ( |
Tokuda et al., |
25 PD, 18 PSP, 35 AD, 43 controls | CSF α-synuclein PD > PSP = Controls > AD |
Parnetti et al., |
38 PD, 32 DLBD, 48 AD, 31 FTD, 32 controls with other neurological diseases ( |
CSF α-synuclein Controls > PD > DLBD = AD = FTD |
Mollenhauer et al., |
Cross-sectional cohort: 51 PD, 29 MSA, 55 DLBD, 62 AD, and 72 neurological controls | CSF α-synuclein PD < DLBD < MSA < controls < AD |
Kang et al., |
Validation cohort: 275 PD, 15 MSA, 55 66 DLBD, 8 PSP, 22 NPH, and 23 neurological controls | CSF α-synuclein MSA < DLBD = PD < NPH = PSP < controls |
Park et al., |
23 PD, 29 neurological controls | CSF α-synuclein oligomer significantly higher in PD than in neurological controls |
Kang et al., |
63 PD, 39 controls | Slightly, but significantly, lower CSF levels of α-synuclein in PD compared with healthy controls |
Lower levels of CSF α-synuclein associated with increased motor severity | ||
Hall et al., |
90 PDND, 33 PDD, 70 DLBD, 48 AD, 45 PSP, 48 MSA, 12 CBD, 107 controls | CSFα-synuclein AD > PSP = Controls > PDD = DLBD = MSA = CBD = PDND |
Tateno et al., |
9 AD, 6 DLBD, 11 PD, 11 MSA, 11 neurological controls | CSFα-synuclein levels in AD higher than in controls ( |
Wang et al., |
Discovery series: 93 PD, 26 AD, 78 controls, 33 PSP, 16 MSA | CSF Phosphorylated α-synuclein (PS-129) PD > Controls > AD > MSA = PSP |
Replication series: 116 PD, 50 AD, 126 controls, 27 PSP, 25 MSA | CSFα-synuclein MSA < PD < PSP > AD = Controls | |
CSF PS-199/α-synuclein ratio MSA > PK > AD > PSP = Controls | ||
Aerts et al., |
58 PD, 47 MSA, 3 DLBD, 22 Vascular Parkinsonsim, 10 PSP, 2 CBD, 57 controls | CSFα-synuclein did not differ significantly among the study groups |
Foulds et al., |
13 PDND, 10 PD with cognitive impairment, 16 PDD, 17 DLBD, 12 PSP, 8 MSA, 20 controls (ventricular CSF obtained post-mortem) | CSF total α-synuclein, oligomeric α-synuclein and phosphorylated α-synuclein similar in PDND, PDCI, PDD, DLBD, PSP, MSA, and control groups |
CSF oligomeric phosphorylated α-synuclein significantly higher in MSA ( |
||
Shi et al., |
8 symptomatic and 18 asymptomatic carriers of the G2019 mutation in the |
Lack of correlation between PET scan evidence of loss of striatal dopaminergic and CSF α-synuclein levels |
Mollenhauer et al., |
78 PD (drug naive), 48 controls | CSF α-synuclein lower in PD than in controls |
Wennström et al., |
52 controls, 46 AD,38 PDND, 22 PDD, 33 DLBD | AD > controls > DLBD > PD > PDD |
Parnetti et al., |
71 PD (8 of 44 carriers of a mutation in the beta-glucocerebrosidase gene ( |
CSF α-synuclein lower and oligomeric/total α-synuclein ratio higher in PD than in controls |
Parnetti et al., |
44 PD and 25 controls with other neurological diseases | CSF total α-synuclein lower and oligomeric α-synuclein higher in PD than in controls. No relation with prognosis and cognitive impairment |
van Dijk et al., |
53 PD, 50 controls | CSF α-synuclein levels reduced in patients with PD, but not correlated with measures of disease severity, and striatal dopaminergic deficit assessed with neuroimaging |
Mondello et al., |
22 controls, 52 PD, 34 MSA, 32 PSP, 12 CBD | CSF α-synuclein MSA < PD < PSP < CBD < Controls |
Stewart et al., |
304 early PD patients enrolled in the DATATOP study. Longitudinal follow-up | CSF α-synuclein showed a longitudinal decrease over follow-up period |
CSF α-synuclein was not correlated with the rate of clinical progression of the motor symptoms | ||
Lower basal levels of CSF α-synuclein were associated with better preservation of cognitive function |
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.,
Baseline CSF Aβ levels in the DATATOP study, were negatively correlated with disease progression assessed with UPDRS (Zhang et al.,
CSF Aβ1-42 levels have been reported as decreased (Parnetti et al.,
Alves et al. (
Nutu et al. (
Beyer et al. (
The results of the studies reported on CSF Aβ levels in PD are summarized in Table
Sjögren et al., |
19 AD, 14 FTD, 11 ALS, 15 PD, 17 controls | CSF Aβ42 markedly decreased in AD = ALS < FTD < PD < controls |
Holmberg et al., |
36 MSA, 48 PD, 15 PSP, 32 controls | CSF Aβ42 MSA < PSP = controls = PD |
Mollenhauer et al., |
73 PDD, 23 PDND, 41 controls (non-demented neurological patients) | CSF Aβ42 lower in the PDD patients compared to PDND patients and controls. This observation was most marked ( |
Parnetti et al., |
19 DLBD, 18 PDD, 23 AD, 20 PDND, 20 controls | DLBD showed the lowest mean CSF Aβ42 levels, with a negative association to dementia duration. PDD patients had mean CSF Aβ42 similar to those seen in PD patients |
Ohrfelt et al., |
66 AD patients, 15 PD patients, 15 patients with dementia with Lewy bodies (DLBD) and 55 cognitively normal controls | CSF Aβ42 AD < DLBD < PD = Controls |
Compta et al., |
20 PDND, 20 PDD, 30 controls patients | CSF Aβ42 ranged from high (controls) to intermediate (PDND) and low (PDD) levels ( |
Alves et al., |
109 PDND, 36 controls, 20 mild AD | CSF Aβ42 (19%; |
CSF Aβ42 reductions in PD less marked than in AD (53%; |
||
Associations between CSF levels of Aβ42 (β = 0.205; |
||
Montine et al., |
150 controls (115 >50 years; 24 amnestic Mild Cognitive Impairment (aMCI), 49 AD, 49 PD, 11 PDD 62 PD-CIND (cognitive imparment non-demented) | CSF Aβ42 levels reduced in AD ( |
Přikrylová Vranová et al., |
32 PD, 30 controls | CSF Aβ1-42 similar in PD and controls |
Siderowf et al., |
45 PD, longitudinal follow-up at least 1 year | Lower baseline CSF Aβ1-42 associated with more rapid cognitive decline |
Subjects with CSF Aβ1-42 levels =192 pg/mL declined an average of 5.85 (95% confidence interval 2.11–9.58, |
||
Aerts et al., |
21 PSP, 12 CBD, 28 PD, 49 controls | CSF Aβ1-42 similar in CBD, PSP, PD, and controls |
Parnetti et al., |
38 PD, 32 DLBD, 48 AD, 31 FTD, 32 controls with other neurological diseases | CSF Aβ1-42 controls = PD > DLBD = AD = FTD |
Shi et al., |
137 controls, 126 PD, 50 AD and 32 MSA | CSF Aβ1-42 controls = PD = _MSA > AD |
Mollenhauer et al., |
Validation cohort: 275 PD, 15 MSA, 55 66 DLBD, 8 PSP, 22 NPH, and 23 neurological controls | CSF Aβ1-42 DLBD < MSA = NPH = PD < controls < PSP |
Andersson et al., |
47 DLBD, 17 PDD | Aβ42 lower in DLBD than in PDD |
Kang et al., |
63 PD, 39 controls | Slightly, but significantly, lower levels of Aβ1-42 in PD compared with controls |
Hall et al., |
90 PDND, 33 PDD, 70 DLBD, 48 AD, 45 PSP, 48 MSA, 12 CBD, 107 controls | CSF Aβ1-42 AD < DLBD = PDD = PSP = MSA = CBD = PDND = Controls |
Přikrylová Vranová et al., |
48 PD (17 early-onset PD, 15 tremor-dominant, 16 non-tremor-dominant), 19 neurological controls, 18 AD | CSF Aβ42 lower in AD than in the other groups, and lower in non-tremor-dominant PD compared with controls |
Jellinger, |
12 PD (6 tremor-dominant PD and 6 non-tremor-dominant PD), 27 AD, 17 controls | CSF Aβ42 lower in tremor-dominant PD than in non-tremor-dominant PD and AD, and lower in these three groups than in controls |
van Dijk et al., |
52 PD, 50 controls | CSF Aβ42 similar in PD and controls |
Zhang et al., |
403 early stage PD patients enrolled in the DATATOP study | CSF baseline levels of Aβ42 weakly but negatively correlated with baseline Unified Parkinson Disease Rating Scale total scores |
Beyer et al., |
73 PDND, 18 PD with mild cognitive impairment | Association between CSF Aβ38, Aβ40, and Aβ42 with the radial distance of the occipital and frontal horns of the lateral ventricles in PDND. Negative association between CSF Aβ38 and Aβ42 with enlargement in occipital and frontal horns of the lateral ventricles in the pooled sample, and with enlargemente of the occipital horns in PD with mild cognitive impairment |
Nutu et al., |
43 PDND, 33 PDD, 51 DLBD, 48 AD, 107 controls | CSF Aβ1-40 AD < DLDB < PDD < PDND = controls |
CSF Aβ1-42 PDD = DLBD = PDND < controls = AD | ||
CSF Aβ1-40/Aβ1-42 ratio AD < DLDB < PDD = controls = PD | ||
Compta et al., |
27 PDND, longitudinal following (11 developed dementia) | Lower CSF amyloid-β predicted development of dementia together with worse verbal learning, semantic fluency and visuoperceptual scores, and thinner superior-frontal/anterior cingulate and precentral regions |
Alves et al., |
99 PD |
CSF Aβ42, Aβ38, Aβ42/40, and Aβ38/40 levels significantly reduced in PIGD phenotype compared with TD phenotype and with controls (TD similar to controls) |
Nutu et al., |
90 PDND, 32 PDD, 68 DLBD, 48 AD, 45 PSP, 46 MSA, 12 CBD, 107 controls | Significantly lower levels of Aβ1-15/16 were detected in PD, PDD, PSP, and MSA compared to other neurodegenerative diseases and controls |
Parnetti et al., |
44 PD and 25 controls with other neurological diseases | CSF Aβ42 lower in PD than in controls. This value was related with cognitive impairment |
Vranová et al., |
27 PDND, 14 PDD, 14 DLBD, 17 AD 24 controls | CSF Aβ42 PDND > PDD > DLBD >AD > controls |
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.,
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.,
Defects in the gene encoding DJ-1 protein cause an autosomal recessive early-onset PD, PARK7 (Alonso-Navarro et al.,
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.,
Among proteins related with apoptosis, Bcl-2 protein has not been detected in the CSF of PD patients (Mogi et al.,
Studies measuring CSF levels of lysosomal hydrolases (involved in the α-Syn degradation) found decreased (Balducci et al.,
CSF Prion protein (PrP) (Meyne et al.,
In PD patients there are reports of decreased CSF post-proline cleaving enzyme (Hagihara and Nagatsu,
In patients with PD there have been reports of normal CSF levels of the proteoglycan N-acetyl neuraminic acid (Lipman and Papadopoulos,
The CSF levels of corticosterone (Pålhagen et al.,
Paik et al. (
The majority of classical biochemical studies on neurotransmitter and related substances have described decreased CSF HVA, and normal NE, MHPG, ACh, AChE, glutamate, aspartate, and glycine levels in patients with PD. Results on CSF GABA and 5-HIAA levels are controversial. Many of these classical studies included patients with different types of Parkinsonism and had a limited number of patients and controls.
Studies on the possible value of endogenous neurotoxins, oxidative stress markers, inflammatory and immunological markers, and growth and neurotrophic factors as biological markers of PD should be considered as inconclusive. The most consistent finding related with these issues is the possible role of CSF urate on the progression of the disease (Ascherio et al.,
Data regarding the role of CSF total
CSF α-synuclein levels have been found to be decreased in most, but not all, studies in PD patients compared with controls. This marker should be useful for the differential diagnosis between synucleopathies and other parkinsonian syndromes, but its usefulness to differentiate among synucleopathies (PD, PDD, DLBD, and MSA), remains to be elucidated.
CSF Aβ1-42 levels could be considered as a useful marker of the presence of further cognitive decline in PD patients.
CSF NFL protein levels should be useful for the differential diagnosis of PSP, MSA, CBD, and PDD from PD, but not to discriminate between PD and healthy controls.
While possible biomarkers for PD in classical studies have been hypothesis-driven, attempts to develop effective procedures for the differential diagnosis of PD in its early stages have led to the performance of CSF multianalyte methods including systematic measurements of patterns of variation in proteins (proteomics) or small molecules (metabolomics). These methods have led to the identification of possible unexpected biomarkers of diseases involved in neurodegenerative processes. However, the results of these types of studies, which are briefly described below, are not clearly established and await replication.
Guo et al. (
Zhang et al. (
Maarouf et al. (
Trupp et al. (
Ideally, future studies should fulfill the following conditions: (a) a multicenter and prospective design; (b) inclusion of patients diagnosed with PD and other types of parkinsonism according to standardized criteria; (c) measurement of multiple potential biological markers in the CSF; (d) a very long-term follow-up period (till death as end-point), with assessment of both clinical features and serial determinations of the biological markers; and (e) final neuropathological confirmation by examination of the brains of patients at death (this is lacking in most of the studies published).
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.
English grammar was reviewed by Professor James McCue. Natalia Gutiérrez Casado (Librarian of Hospital Universitario del Sureste) contributed in getting many of the classical references. Research at authors' laboratories is financed by grants PI12/00241, PI12/00324, and RETICS RD12/0013/0002 from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Spain, Innovation and GR10068 from Junta de Extremadura, Spain. Financed in part with FEDER funds from the European Union.