Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies

-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 437025, 9 pages doi:10.1155/2012/437025 Review Article α-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies 1, 2 1 1 Kensaku Kasuga, Masatoyo Nishizawa, and Takeshi Ikeuchi Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA Correspondence should be addressed to Takeshi Ikeuchi, ikeuchi@bri.niigata-u.ac.jp Received 8 June 2012; Revised 24 July 2012; Accepted 24 July 2012 Academic Editor: Walter Maetzler Copyright © 2012 Kensaku Kasuga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. Although α-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids. α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB and α-synuclein-related disorders, because α-synuclein is characteristically accumulated in the brain of patients with these disorders. The α-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSF α-synuclein level in DLB and α-synuclein-related disorders. Discrepant findings of studies of plasma α-synuclein level in patients with DLB have been reported. Because the level of α-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of α-synuclein. Here, the recent progress in the studies of α-synuclein as a biomarker of DLB and their potential clinical applications are reviewed. 1. Introduction intensive research has given hope for disease-modifying therapeutics for DLB to become a reality. The evaluation Dementia with Lewy bodies (DLB) is a common subtype of of such therapies largely depends on reliable diagnostic and dementia and is reported to be the second most common prognostic biomarkers for early detection and monitoring of neurodegenerative dementia after Alzheimer’s disease (AD) the stage of DLB. Candidates of such biomarkers are diverse; in the elderly in several studies [1–3]. DLB is a progressive clinical biomarkers detected on the basis of olfactory func- tion [9], myocardial I-metaiodobenzylguanidine (MIBG) cognitive disorder characterized by fluctuating cognitive impairment, visual hallucination, and parkinsonism [4]. scintigraphy [10], neuroimaging biomarkers detected by Diagnosis of DLB in patients with such characteristic clinical magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) [11], positron emission features would not be difficult by taking medical history and careful neurological examinations. However, it could tomography (PET), and biochemical biomarkers. In this be laborious to make an accurate diagnosis of DLB when paper, fluid biomarkers, particularly α-synucleinincere- patients have a substantial degree of concomitant AD pathol- brospinal fluid (CSF) and blood in patients with DLB and ogy, which affects the clinical symptoms with lower rates α-synuclein-related disorders were extensively reviewed. of visual hallucinations and parkinsonism [5, 6]. Accurate clinical diagnosis of DLB is important because patients 2. Lewy Bodies and α-Synuclein may benefit from cholinesterase inhibitors, which improve cognitive function and neuropsychiatric symptoms of DLB A century ago, in 1912, Lewy originally described neuronal [7]. Furthermore, it should be noted that DLB patients are inclusions in the brain of patients with Parkinson’s dis- particularly sensitive to neuroleptic drugs [4, 8]. Recent ease (PD). Seven years later, a Russian neuropathologist, 2 International Journal of Alzheimer’s Disease Tretiakoff,named the inclusionsas“corpsdeLewy(Lewy study, however, the intensity of the bands immunoreactive bodies)” [12]. Since the discovery, Lewy bodies have been to the anti-α-synuclein antibodies showed no significant considered as intracytoplasmic, spherical, and eosinophilic difference between patients with PD and control subjects neuronal inclusions in the substantia nigra of PD patients. In [30]. El-Agnaf et al. also confirmed that α-synuclein is 1976, Kosaka et al. reported the detection of Lewy bodies in detectable in CSF by a similar methodology [27]. the cerebral cortex of an elderly patient with dementia [13]. Subsequently, Tokuda et al. demonstrated using a new After his detailed description of cortical Lewy bodies [14], system for enzyme-linked immunosorbent assay (ELISA) many similar cases were subsequently reported. Because the that PD patients showed significantly lower α-synuclein characteristic pathological features of DLB and PD are Lewy levels in CSF than the control groups [31]. Since then, bodies and Lewy neurites, these disorders are considered to several studies to determine the total α-synuclein level belong to a continuum disorder, and the generic term Lewy in CSF have been carried out by ELISA or bead-based body disease (LBD) was proposed [4, 15]. flow cytometric assay using various combinations of anti- In 1997, Spillantini et al. found that α-synuclein is the α-synuclein antibodies (Tables 1 and 2). A significantly main component of Lewy bodies in the brains of PD and low level of α-synuclein in CSF from patients with LBD DLB patients [16]. Only two months before this report, (PD and/or DLB) has been shown by independent studies a mutation was identified in SNCA, which encodes α- [28, 31–38]. Our study revealed that total CSF α-synuclein synuclein in families with autosomal dominant PD [17]. A level shows a significant positive correlation with the CSF different SNCA mutation was subsequently reported in a Aβ42 level in DLB patients [32]. It has been suggested that family with DLB [18]. In addition, SNCA multiplication by alow CSFAβ42 level may be related to amyloid-related duplication/triplication has been identified in a large family pathology in the brains of DLB patients [39]. In addition, with phenotypes ranging from DLB to PD [19]. These neu- experimental studies have suggested that the Aβ42 species ropathological and genetic findings suggest that α-synuclein strongly enhances the accumulation of α-synuclein [40]. is essentially implicated in the pathogenesis of LBD including In the CSF from LBD patients, the level of Aβ42 shows a DLB and PD. Recent studies have suggested that the Lewy positive correlation with the activity of neprilysin, an enzyme body pathology propagates throughout the brain via neuron- that degrades Aβ [41]. Taken together, the reduction in α- to-neuron transmission of α-synuclein aggregates [20]. It synuclein and Aβ42 levels in CSF suggests the extent of Lewy has been demonstrated that glial cytoplasmic inclusions, body pathology and the co-occurrence of amyloid pathology, which are unique pathological inclusions found in brains respectively, in the brain of DLB patients. Interestingly, of patients with multiple system atrophy (MSA), are also patients with SNCA duplication who showed abundant Lewy composed of α-synuclein [21], suggesting an unexpected link body pathology in the brain [42] also show low levels of between MSA and LBD. These disorders with pathological CSF α-synuclein [32]. Because the predominant source of accumulation of α-synuclein in brains are termed as α- α-synuclein in CSF is considered to be the central nervous synucleinopathies [22]. system [43], the decrease in the level of CSF α-synuclein α-Synuclein is a 140-residue ubiquitous protein and is in DLB may reflect a dysfunction in the metabolism or highly expressed in neuronal presynaptic terminals under clearance of α-synuclein in the brain, similarly to AD patients physiological conditions. Although its physiological func- with Aβ accumulation in the brain showing a decrease in the tions remain unclear, α-synuclein is implicated in synaptic level of Aβ42 in CSF. vesicle trafficking particularly in the regulation of synaptic In contrast, comparable levels of total α-synuclein in vesicle release [23] and stabilization of SNARE complexes CSF between patients with LBD and control subjects have [24]. Deposited α-synuclein in the brain with synucle- also been reported [45–50]. This discrepancy is probably not inopathies is aberrantly phosphorylated at Ser129 [25]. It due to the misdiagnosis of LBD, because different studies has been demonstrated that the C-terminal truncated form using CSF samples derived from autopsy-confirmed patients of α-synuclein promotes the aggregation of α-synuclein showed significantly decreased or comparable α-synuclein [26]. Because α-synuclein has no signal sequence, it was levels in LBD patients [34, 50]. In addition to methodolog- initially considered to be an exclusively intracellular protein. ical differences in the quantification of α-synuclein, blood However, it has been shown that α-synuclein is secreted into contamination of CSF during lumbar puncture should be biological fluids [27, 28]. taken into account when considering the discrepant results. The level of α-synuclein in blood, particularly that stored in red blood cells, is much higher than that in CSF [33, 3. α-Synuclein in CSF 53]. Haemolysis in the course of sample collection and A year after Spillantini et al. reported that α-synuclein is the processing should be considered as a confounding factor main component of Lewy bodies, Jakowec et al. examined for quantification of α-synuclein level in CSF and blood. whether α-synuclein is detectable in CSF [29]. They exam- Other factors such as level fluctuations over time and drug ined the expression of α-synuclein in CSF from PD patients treatment may have less effect on the level of α-synuclein in CSF. Although the level of Aβ in CSF fluctuates over time and control subjects by Western blot analysis using an anti- α-synuclein specific antibody, but failed to detect α-synuclein [54], the level of α-synuclein in CSF does not significantly in CSF [29]. Borghi et al. detected α-synuclein by a method change [52]. It is also reported that drugs such as L-dopa and dopamine agonists do not affect the level of α-synuclein in combining immunoprecipitation with immunoblot analysis using two different anti-α-synuclein antibodies [30]. In their CSF [34, 35]. International Journal of Alzheimer’s Disease 3 Table 1: Studies on quantification of α-synuclein level in CSF of patients with DLB and other synucleinopathies. Blood Controls Synucleinopathies Level of total Study contamination Healthy Neurological AD Results Lewy body diseases α-synuclein was considered controls controls DLB PD MSA PD patients showed significantly lower α-syn level than the controls (P< 0.0001). The level of α-syn decreased significantly with age (P = 0.0076) and Tokuda et al. [31] No 9 29 — — 33 — correlated to inversely assigned Hoehn and Yahr stage (P< 0.0001). The level of α-syn in DLB and PD patients were Mollenhauer et al. [28] No — 13 13 38 8 — lower than AD patients and controls (P = 0.025). The level of α-syn in DLB patients was significantly lower than those in patients with AD (P< 0.05) and other dementias (P< 0.01). In DLB patients, Kasuga et al. [32] No — 21 31 34 — — reduced α-syn level correlated with the lower level of CSF Aβ42 (P = 0.01). Patients with SNCA duplication showed a decrease of CSF α-syn. The level of total α-syn was lower in PD patients than in age-matched controls. The level of α-syn Tokuda et al. [44]No 16 12 — — 32 — oligomers was significantly higher in PD patients than in age-matched controls. Upper and lower rows indicate training and validation cohorts, respectively. The level of α-syn — 76 62 55 51 29 Yes Mollenhauer et al. [34] was significantly lower in DLB, PD, and MSA — 20 3 66 273 15 patients than in other neurological diseases. The level of α-syn was decreased in PD and MSA Hong et al. [33] Yes 92 — 38 — 86 20 patients. The level of α-syn was lower in patients with neurodegenerative diseases than in cognitively normal subjects, but the level of α-syn alone did not Parnetti et al. [37]Yes — 32 48 32 38 — distinguish synucleinopathies from tauopathies. An inverse correlation between α-syn and total tau levels was observed (P< 0.01). The levels of α-syn of DLB, PD, and MSA were lower Tateno et al. [36] No — 11 9 6 11 11 than AD. The level of α-syn in female DLB patients was lower Wennstrom et al. [38] No 24 — 26 18 — — than AD (P = 0.041) patients and controls (P = 0.028). 4 International Journal of Alzheimer’s Disease Table 1: Continued. Blood Controls Synucleinopathies Level of total Study contamination Healthy Neurological AD Lewy body diseases Results α-synuclein was considered controls controls DLB PD MSA PD, DLB patients and controls showed comparable levels of α-syn. AD patients showed significantly lower level of α-syn than the controls (P< 0.001). Ohrfeltetal. [45]Yes 55 — 66 15 15 — AD patients with MMSE scores below 20 had significantly lower level of α-syn than AD patients with MMSE scores of 20 or higher (P = 0.02). The level of α-syn did not differ between DLB and AD patients. In DLB patients, the duration of illness Noguchi-Shinohara et al. [46]No — — 21 16 — — was associated with lower level of α-syn (P< 0.05). The level of α-syn was comparable between DLB, AD, and controls. The level of α-syn decreased with Spies et al. [47] No 57 — 131 40 — — age (P = 0.001). The level of α-syn was not different among PD, DLB, AD, and controls. In DLB patients, lower α-syn was Reesink et al. [48]Yes 34 — 63 35 18 — related to lower MMSE scores (P< 0.05) and worse category fluency (P< 0.05). The level of α-syn was comparable among PD, MSA, DLB patients and controls. In PD group, the level of Aerts et al. [49]Yes 57 — — 3 58 47 α-syn was negatively correlated with age at time of lumber puncture (P< 0.006). The level of total α-syn was not different between PD, DLB, MSA and control groups. Oligomeric Foulds et al. [50] Yes 20 — — 16 38 8 phosphorylated α-syn was significantly high in patients with MSA (P< 0.001). The level of total α-syn in PD patients was comparable to that of control groups. The level of Park et al. [51]No 18 11 — — 23 — α-syn oligomer in PD patients was significantly higher than controls (P = 0.005). Arrows indicate decreased (↓) and comparable (→)levels α-synuclein. Sample numbers are shown in each category. Erythrocyte counts or haemoglobin levels were considered as a confounding factor. AD: Alzheimer’s disease; DLB: dementia with Lewy bodies; PD: Parkinson’s disease; MSA: multiple system atrophy; α-syn: α-synuclein; MMSE: minimental state examination. International Journal of Alzheimer’s Disease 5 Table 2: Summary of antibodies used to quantify α-synuclein in biofluids. Anti-α-synuclein antibodies Study Target molecule Capture antibody Detecting antibody Tokuda et al. [31]Total α-synuclein 211 (m) FL-140 (p) Mollenhouer et al. [28]Total α-synuclein mSA-1 (p) Syn-1 (m) Ohrfelt et al. [45]Total α-synuclein Syn1b (m) Syn3b (m), Syn5d (m) Noguchi-Shinohara et al. [46]Total α-synuclein 211 (m) FL-140 (p) Spies et al. [52]Total α-synuclein 211 (m) FL-140 (p) Kasuga et al. [32]Total α-synuclein Syn-1 (m) FL-140 (p) Reesink et al. [48]Total α-synuclein 211 (m) FL-140 (p) Total α-synuclein 211 (m) FL-140 (p) Tokuda et al. [44] Oligomeric α-synuclein 211 (m) Biotinylated 211 (m) Aerts et al. [49]Total α-synuclein 211 (m) FL-140 (p) Mollenhouer et al. [34]Total α-synuclein mSA-1 (p) Syn-1 (m) Biotinylated goat 211 (m), LB509 (m), Hong et al. [33]Total α-synuclein anti-human α-synuclein rabbit anti-α-synuclein (p) (p) Parnetti et al. [37]Total α-synuclein 211 (m) FL-140 (p) Total α-synuclein 211 (m) FL-140 (p) Foulds et al. [50] Oligomeric α-synuclein 211 (m) Biotinylated 211 (m) Phosphorylated α-synuclein N-19 (p) pS129 (m) Oligomeric phosphorylated pS129 (m) Biotinylated pS129 (m) α-synuclein Tateno et al. [36]Total α-synuclein Not described Not described Commercial kit (Invitrogen) Wennstrom et al. [38]Total α-synuclein Total α-synuclein 211 (m) FL-140 (p) Park et al. [51] Oligomeric α-synuclein 211 (m) Biotinylated 211 (m) m: monoclonal antibody; p: polyclonal antibody. Several groups have recently conducted studies to detect methods may be heterogeneous in size and toxicity; hence, the oligomeric forms of α-synuclein in CSF, because the further validation is still needed. oligomer species of α-synuclein are considered to be toxic Correlation analysis of clinical parameters, such as and could enhance pathological accumulation of α-synuclein minimental state examination (MMSE) and Hoehn Yahr and disease propagation [55]. Tokuda et al. demonstrated scale scores with the total α-synuclein level in CSF, has that the levels of α-synuclein oligomers in CSF are signif- shown inconsistent results. Tokuda et al. showed an inverse icantly higher in patients with PD than in patients with correlation between the total α-synuclein level in CSF and progressive supranuclear palsy (PSP) or AD [44]. In their disease severity determined by the Hoehn Yahr scale [31]. A study, the level of total α-synuclein in the CSF from PD low α-synuclein level was reported to correlate with a low patients tends to decrease [44]. Increased level of α-synuclein MMSE score of DLB patients [48]. These findings suggest oligomers in CSF from PD patients was also shown by that α-synuclein level in CSF may reflect the severity of other investigator [51]. Foulds et al. showed that the level of pathological changes occurring in patients with LBD. This oligomers composed of phosphorylated α-synuclein is higher notion is supported by the findings of a study that the disease in the postmortem CSF from MSA patients than in that from duration in patients with DLB is closely associated with a low with PD, DLB, or PSP patients [50]. Sierks et al. also showed α-synuclein level in CSF [46]. In contrast to these findings, a significant increase in the level of α-synuclein oligomers in other studies revealed no significant association of the α- postmortem CSF from patients with PD by electrochemical synuclein level in CSF with MMSE score, gender, age at impedance spectroscopy [56]. These findings suggest a examination, or disease duration in DLB or AD patients possibility that α-synuclein oligomer species are detectable in [32]. Shi et al. examined whether CSF α-synuclein level CSF and that their levels may increase in some patients with correlates with dopaminergic dysfunction determined by synucleinopathies. A potential concern is that the oligomeric PET in asymptomatic carriers with leucine-rich repeat kinase forms of α-synuclein detected in their studies using different 2 (LRRK2) gene mutation [64]. They detected no significant 6 International Journal of Alzheimer’s Disease Table 3: Studies of quantification of α-synuclein level in blood of patients with DLB and other synucleinopathies. ∗ ∗∗ Methods Samples Results Plasma α-Synuclein oligomers were elevated in patients El-Agnaf et al. [57]ELISA Cont (27), PD/DLB (34) with PD/DLB compared to controls. The α-synuclein level was increased in patients with PD (79.9 pg/mL) and in those with MSA Plasma (78.1 pg/mL) compared with controls Lee et al. [58]ELISA Cont (51), PD (105), MSA (38) (76.1 pg/mL). The α-synuclein level was significantly higher in patients with PD than in those with MSA. The α-synuclein level was elevated in patients Plasma with PD compared to healthy controls. Duran et al. [59]ELISA Cont (60), PD (95) Antiparkinsonian treatment does not change plasma α-synuclein level. The level of phosphorylated α-synuclein was higher in patients with PD than healthy controls. Plasma None of the levels of total α-synuclein, oligomeric Foulds et al. [60]ELISA (not described) α-synuclein, or oligomeric phospohorylated α-synuclein was different between PD patients and controls. No significant difference was found among Bead-based flow Plasma Shi et al. [61] patients with PD (36.8 ng/mL), AD (32.4 ng/mL), cytometric assay Cont (95), AD (33), PD (117) and those with healthy controls (39.5 ng/mL). There was no difference in oligomeric and total Plasma Park et al. [51]ELISA α-synuclein in plasma between PD patients and Cont (29), PD(23) controls. The α-synuclein level was significantly lower in patients with PD than in those with age-matched Plasma Li et al. [62] IP-Western blot healthy controls. Early-onset PD patients had Cont (11), PD (27) lower α-synuclein levels than late-onset PD patients. The α-synuclein level was significantly lower in Serum Laske et al. [63]ELISA patients with DLB (4.7 ng/mL) than in those with Cont (40), AD (80), DLB (40) AD (7.0 ng/mL) and healthy controls (8.1 ng/mL). ∗ ∗∗ Arrows indicate increased (↑), comparable (→ ), and decreased (↓)levelsof α-synuclein. Sample numbers are shown in parenthesis. Values are indicated as mean or median. AD: Alzheimer’s disease; Cont: controls; DLB: dementia with Lewy bodies; IP: immunoprecipitation; MSA: multiple system atrophy; PD: Parkinson’s disease. correlations, indicating that CSF total α-synuclein level may in plasma quantified by ELISA as well as Western blot analysis not be a sensitive biomarker of the preclinical phase of PD. is higher in patients with PD than in control subjects [60]. In their study, the level of α-synuclein remained stable within the same individuals at least over 3 months. 4. α-Synuclein in Blood By contrast, Li et al. found a significantly decreased α- Several studies on the quantification of α-synucleininblood synuclein level in plasma from patients with PD by Western have been carried out because drawing blood is much less blot analysis, which detected only full-length monomeric α- invasive than lumbar puncture to obtain CSF from patients synuclein [62]. Laske et al. also reported a similar decrease (Table 3). El-Agnaf et al. detected α-synuclein in plasma of in serum α-synuclein level in DLB patients compared with patients with LBD by immunoprecipitation using an anti- AD patients and control subjects [63]. Comparable levels of α-synuclein antibody [27]. Subsequently, they found higher plasma α-synuclein were found among patients with PD, AD, levels of α-synuclein oligomers in plasma from PD patients and control subjects in other studies [61]. than in that from control subjects by ELISA [57]. A similar increase in α-synuclein level was observed in plasma from 5. Conclusions patients with PD and MSA [58, 59]. Lee et al. found that plasma α-synuclein level is higher in patients with PD than Results of measurements of α-synuclein level in CSF and in those with MSA [58]. Duran et al. demonstrated that blood have been variable; hence, it is difficult to unequiv- drugs such as L-dopa, dopamine agonists, and MAO/COMT ocally conclude whether α-synuclein is a promising fluid inhibitors do not affect the plasma α-synuclein level in biomarker of DLB and other α-synucleinopathies. More patients with PD [59]. The phosphorylated α-synuclein level discriminating results for DLB patients could be obtained International Journal of Alzheimer’s Disease 7 by examining specific α-synuclein species such as truncated, [11] I. McKeith, J. O’Brien, Z. Walker et al., “Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT phosphorylated, and oligomeric species on the basis of their SPECT in dementia with Lewy bodies: a phase III, multicentre analogy to Aβ42 and phosphorylated tau species whose study,” The Lancet Neurology, vol. 6, no. 4, pp. 305–313, 2007. changesinlevelsare foundtobereliableCSF biomarkers of [12] A. M. Rodrigues E Silva, F. Geldsetzer, B. Holdorff et al., “Who AD. In addition, a multicenter study is required to validate was the man who discovered the “Lewy bodies”?” Movement the usefulness of α-synuclein as a biomarker by standardized Disorders, vol. 25, no. 12, pp. 1765–1773, 2010. methods of quantifying α-synuclein. Continuous efforts [13] K. Kosaka, S. Oyanagi, and M. Matsushita, “Presenile demen- will be required to establish useful fluid biomarkers for tia with Alzheimer, Pick and Lewy body changes,” Acta early diagnosis of DLB and evaluation of disease-modifying Neuropathologica, vol. 36, no. 3, pp. 221–233, 1976. therapeutics for DLB. [14] K. Kosaka, “Lewy bodies in cerebral cortex. Report of three cases,” Acta Neuropathologica, vol. 42, no. 2, pp. 127–134, Acknowledgments [15] C. F. Lippa, J. E. Duda, M. Grossman et al., “DLB and PDD The authors would like to thank Drs. Takayoshi Tokutake, boundary issues: diagnosis, treatment, molecular pathology, Atsushi Ishikawa, and Osamu Onodera for their helpful and biomarkers,” Neurology, vol. 68, no. 11, pp. 812–819, 2007. discussion on this paper. [16] M. G. Spillantini, M. L. Schmidt, V. M. Y. Lee, J. Q. Trojanowski, R. Jakes, and M. Goedert, “α-synuclein in Lewy References bodies,” Nature, vol. 388, no. 6645, pp. 839–840, 1997. [17] M. H. Polymeropoulos, C. Lavedan, E. Leroy et al., “Mutation [1] Y. Matsui, Y. Tanizaki, H. Arima et al., “Incidence and survival in the α-synuclein gene identified in families with Parkinson’s of dementia in a general population of Japanese elderly: disease,” Science, vol. 276, no. 5321, pp. 2045–2047, 1997. the hisayama study,” Journal of Neurology, Neurosurgery and [18] J. J. Zarranz, J. Alegre, J. C. Gomez-Est ´ eban et al., “The new Psychiatry, vol. 80, no. 4, pp. 366–370, 2009. mutation, E46K, of alpha-synuclein causes Parkinson and [2] T. Rahkonen, U. Eloniemi-Sulkava, S. Rissanen, A. Vatanen, Lewy body dementia,” Annals of Neurology, vol. 55, no. 2, pp. P. Viramo, and R. Sulkava, “Dementia with Lewy bodies 164–173, 2004. according to the consensus criteria in a general population [19] A. B. Singleton, M. Farrer, J. Johnson et al., “α-synuclein locus aged 75 years or older,” Journal of Neurology Neurosurgery and triplication causes Parkinson’s disease,” Science, vol. 302, no. Psychiatry, vol. 74, no. 6, pp. 720–724, 2003. 5646, p. 841, 2003. [3] D. Aarsland, A. Rongve, S. Piepenstock Nore et al., “Frequency [20] P. Desplats,H.J.Lee,E.J.Bae et al., “Inclusion formationand and case identification of dementia with Lewy bodies using the neuronal cell death through neuron-to-neuron transmission revised consensus criteria,” Dementia and Geriatric Cognitive of α-synuclein,” Proceedings of the National Academy of Sciences Disorders, vol. 26, no. 5, pp. 445–452, 2008. of the United States of America, vol. 106, no. 31, pp. 13010– [4] I. G. McKeith, D. Galasko, K. Kosaka et al., “Consensus guide- 13015, 2009. lines for the clinical and pathologic diagnosis of dementia [21] K. Wakabayashi, M. Yoshimoto, S. Tsuji, and H. Takahashi, “α- with Lewy bodies (DLB): report of the consortium on DLB synuclein immunoreactivity in glial cytoplasmic inclusions in international workshop,” Neurology, vol. 47, no. 5, pp. 1113– multiple system atrophy,” Neuroscience Letters, vol. 249, no. 2- 1124, 1996. 3, pp. 180–182, 1998. [5] I. G. McKeith, D. W. Dickson, J. Lowe et al., “Diagnosis and [22] M. G. Spillantini and M. Goedert, “The α-synucleinopathies: management of dementia with Lewy bodies: third report of Parkinson’s disease, dementia with Lewy bodies, and multiple the DLB Consortium,” Neurology, vol. 65, no. 12, pp. 1863– system atrophy,” Annals of the New York Academy of Sciences, 1872, 2005. vol. 920, pp. 16–27, 2000. [6] A. R. Merdes, L. A. Hansen, D. V. Jeste et al., “Influence [23] A. Abeliovich, Y. Schmitz, I. Farinas ˜ et al., “Mice lacking of Alzheimer pathology on clinical diagnostic accuracy in α-synuclein display functional deficits in the nigrostriatal dementia with Lewy bodies,” Neurology, vol. 60, no. 10, pp. dopamine system,” Neuron, vol. 25, no. 1, pp. 239–252, 2000. 1586–1590, 2003. [24] J. Burre, ´ M. Sharma, T. Tsetsenis, V. Buchman, M. R. Etherton, [7] J. T. O’Brien and A. Burns, “Clinical practice with anti- andT.C.Sudhof, ¨ “α-synuclein promotes SNARE-complex dementia drugs: a revised (second) consensus statement from assembly in vivo and in vitro,” Science, vol. 329, no. 5999, pp. the British Association for Psychopharmacology,” Journal of 1663–1667, 2010. Psychopharmacology, vol. 25, no. 8, pp. 997–1019, 2011. [25] H. Fujiwara, M. Hasegawa, N. Dohmae et al., “α-synuclein [8] D. Aarsland, R. Perry, J. P. Larsen et al., “Neuroleptic sensitivity is phosphorylated in synucleinopathy lesions,” Nature Cell in Parkinson’s disease and Parkinsonian dementias,” Journal of Biology, vol. 4, no. 2, pp. 160–164, 2002. Clinical Psychiatry, vol. 66, no. 5, pp. 633–637, 2005. [26] W. Li, N. West, E. Colla et al., “Aggregation promoting C- [9] A. Haehner, T. Hummel, and H. Reichmann, “Olfactory terminal truncation of α-synuclein is a normal cellular process dysfunction as a diagnostic marker for Parkinson’s disease,” and is enhanced by the familial Parkinson’s disease-linked Expert Review of Neurotherapeutics, vol. 9, no. 12, pp. 1773– mutations,” Proceedings of the National Academy of Sciences of 1779, 2009. the United States of America, vol. 102, no. 6, pp. 2162–2167, [10] S. Orimo, M. Suzuki, A. Inaba et al., “(123)I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other [27] O. M. El-Agnaf,S.A.Salem,K.E.Paleologouetal., “Alpha- neurodegenerative parkinsonism: a systematic review and synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma,” The meta-analysis,” Parkinsonism and Related Disorders, vol. 18, no. 5, pp. 494–500, 2012. FASEB Journal, vol. 17, no. 13, pp. 1945–1947, 2003. 8 International Journal of Alzheimer’s Disease [28] B. Mollenhauer, V. Cullen, I. Kahn et al., “Direct quantification neurons of the central nervous system,” Journal of Neural of CSF α-synuclein by ELISA and first cross-sectional study Transmission, vol. 119, no. 7, pp. 739–746, 2012. in patients with neurodegeneration,” Experimental Neurology, [44] T. Tokuda, M. M. Qureshi, M. T. Ardah et al., “Detection of vol. 213, no. 2, pp. 315–325, 2008. elevated levels of α-synuclein oligomers in CSF from patients [29] M. W. Jakowec, G. M. Petzinger, S. Sastry, D. M. Donaldson, with Parkinson disease,” Neurology, vol. 75, no. 20, pp. 1766– A. McCormack, and J. W. Langston, “The native form of α- 1772, 2010. synuclein is not found in the cerebrospinal fluid of patients ¨ [45] A. Ohrfelt, P. Grognet, N. Andreasen et al., “Cerebrospinal with Parkinson’s disease or normal controls,” Neuroscience fluid α-synuclein in neurodegenerative disorders—a marker Letters, vol. 253, no. 1, pp. 13–16, 1998. of synapse loss?” Neuroscience Letters, vol. 450, no. 3, pp. 332– [30] R. Borghi, R. Marchese, A. Negro et al., “Full length α- 335, 2009. synuclein is present in cerebrospinal fluid from Parkinson’s [46] M. Noguchi-Shinohara, T. Tokuda, M. Yoshita et al., “CSF α- disease and normal subjects,” Neuroscience Letters, vol. 287, no. synuclein levels in dementia with Lewy bodies and Alzheimer’s 1, pp. 65–67, 2000. disease,” Brain Research, vol. 1251, pp. 1–6, 2009. [31] T. Tokuda, S. A. Salem, D. Allsop et al., “Decreased α-synuclein [47] P. E. Spies, R. J. F. Melis, M. J. C. Sjog ¨ ren, M. G. M. O. in cerebrospinal fluid of aged individuals and subjects with Rikkert, and M. M. Verbeek, “Cerebrospinal fluid α-synuclein Parkinson’s disease,” Biochemical and Biophysical Research does not discriminate between dementia disorders,” Journal of Communications, vol. 349, no. 1, pp. 162–166, 2006. Alzheimer’s Disease, vol. 16, no. 2, pp. 363–369, 2009. [32] K. Kasuga, T. Tokutake, A. Ishikawa et al., “Differential levels [48] F. E. Reesink,A.W.Lemstra,K.D.van Dijk et al., “CSF α- of α-synuclein, β-amyloid42 and tau in CSF between patients synuclein does not discriminate dementia with Lewy bodies with dementia with Lewy bodies and Alzheimer’s disease,” from Alzheimer’s disease,” Journal of Alzheimer’s Disease, vol. Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 22, no. 1, pp. 87–95, 2010. 6, pp. 608–610, 2010. [49] M. B. Aerts, R. A. J. Esselink, W. F. Abdo, B. R. Bloem, and M. [33] Z. Hong, M. Shi, K. A. Chung et al., “DJ-1 and α-synuclein M. Verbeek, “CSF α-synuclein does not differentiate between in human cerebrospinal fluid as biomarkers of Parkinson’s parkinsonian disorders,” Neurobiology of Aging, vol. 33, no. 2, disease,” Brain, vol. 133, pp. 713–726, 2010. pp. 431–433, 2012. [34] B. Mollenhauer, J. J. Locascio, W. Schulz-Schaeffer, F. Sixel- [50] P. G. Foulds, O. Yokota, A. Thurston et al., “Post mortem Dor ¨ ing, C. Trenkwalder, and M. G. Schlossmacher, “α- cerebrospinal fluid alpha-synuclein levels are raised in mul- synuclein and tau concentrations in cerebrospinal fluid of tiple system atrophy and distinguish this from the other patients presenting with parkinsonism: a cohort study,” The alpha-synucleinopathies, Parkinson’s disease and dementia Lancet Neurology, vol. 10, no. 3, pp. 230–240, 2011. with Lewy bodies,” Neurobiology of Disease,vol. 45, no.1,pp. [35] M. Shi, J. Bradner, A. M. Hancock et al., “Cerebrospinal fluid 188–195, 2012. biomarkers for Parkinson disease diagnosis and progression,” Annals of Neurology, vol. 69, no. 3, pp. 570–580, 2011. [51] M. J. Park,S.M.Cheon,H.R.Bae et al., “Elevatedlevelsof alpha-synuclein oligomer in the cerebrospinal fluid of drug- [36] F. Tateno, R. Sakakibara, T. Kawai et al., “Alpha-synuclein in the cerebrospinal fluid differentiates synucleinopathies naive patients with Parkinson’s disease,” Journal of Clinical (Parkinson disease, dementia with lewy bodies, multiple Neurology, vol. 7, no. 4, pp. 215–222, 2011. system atrophy) from Alzheimer disease,” Alzheimer Disease [52] P. E. Spies, D. Slats, M. G. Rikkert et al., “CSF alpha-synuclein and Associated Disorders, vol. 26, no. 3, pp. 213–216, 2012. concentrations do not fluctuate over hours and are not [37] L. Parnetti, D. Chiasserini, G. Bellomo et al., “Cerebrospinal correlated to amyloid beta in humans,” Neuroscience Letters, fluid Tau/α-synuclein ratio in Parkinson’s disease and degener- vol. 504, no. 3, pp. 336–338, 2011. ative dementias,” Movement Disorders, vol. 26, no. 8, pp. 1428– [53] R. Barbour, K. Kling, J. P. Anderson et al., “Red blood 1435, 2011. cells are the major source of alpha-synuclein in blood,” [38] M. Wennstrom, E. Londos, L. Minthon et al., “Altered Neurodegenerative Diseases, vol. 5, no. 2, pp. 55–59, 2008. CSF orexin and alpha-synuclein levels in dementia patients,” [54] R. J. Bateman, G. Wen, J. C. Morris, and D. M. Holtzman, Journal of Alzheimer’s Disease, vol. 29, no. 1, pp. 125–132, 2012. “Fluctuations of CSF amyloid-β levels: implications for a [39] D. Strozyk, K. Blennow, L. R. White, and L. J. Launer, “CSF diagnostic and therapeutic biomarker,” Neurology, vol. 68, no. Aß 42 levels correlate with amyloid-neuropathology in a 9, pp. 666–669, 2007. population-based autopsy study,” Neurology, vol. 60, no. 4, pp. [55] K. Vekrellis, M. Xilouri, E. Emmanouilidou et al., “Patholog- 652–656, 2003. ical roles of alpha-synuclein in neurological disorders,” The [40] O. Pletnikova, N. West, M. K. Lee et al., “Aβ deposition is Lancet Neurology, vol. 10, no. 11, pp. 1015–1025, 2011. associated with enhanced cortical α-synuclein lesions in Lewy [56] M. R. Sierks, G. Chatterjee, C. McGraw et al., “CSF levels of body diseases,” Neurobiology of Aging, vol. 26, no. 8, pp. 1183– oligomeric alpha-synuclein and beta-amyloid as biomarkers 1192, 2005. for neurodegenerative disease,” Integrative Biology, vol. 3, no. [41] W. Maetzler, V. Stoycheva, B. Schmid et al., “Neprilysin 12, pp. 1188–1196, 2011. activity in cerebrospinal fluid is associated with dementia [57] O. M. A. El-Agnaf,S.A.Salem,K.E.Paleologouetal., and amyloid-β42 levels in lewy body disease,” Journal of “Detection of oligomeric forms of α-synuclein protein in Alzheimer’s Disease, vol. 22, no. 3, pp. 933–938, 2010. human plasma as a potential biomarker for Parkinson’s [42] T. Ikeuchi, A. Kakita, A. Shiga et al., “Patients homozygous disease,” The FASEB Journal, vol. 20, no. 3, pp. 419–425, 2006. and heterozygous for SNCA duplication in a family with parkinsonism and dementia,” Archives of Neurology, vol. 65, [58] P. H. Lee, G. Lee, H. J. Park, O. Y. Bang, I. S. Joo, and no. 4, pp. 514–519, 2008. K. Huh, “The plasma alpha-synuclein levels in patients with [43] B. Mollenhauer, E. Trautmann, B. Otte et al., “Alpha-synuclein Parkinson’s disease and multiple system atrophy,” Journal of in human cerebrospinal fluid is principally derived from Neural Transmission, vol. 113, no. 10, pp. 1435–1439, 2006. International Journal of Alzheimer’s Disease 9 [59] R. Duran, F. J. Barrero, B. Morales, J. D. Luna, M. Ramirez, and F. Vives, “Plasma α-synuclein in patients with Parkinson’s disease with and without treatment,” Movement Disorders, vol. 25, no. 4, pp. 489–493, 2010. [60] P. G. Foulds, J. D. Mitchell, A. Parker et al., “Phosphorylated alpha-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson’s disease,” The FASEB Journal, vol. 25, no. 12, pp. 4127–4137, 2011. [61] M. Shi, C. P. Zabetian, A. M. Hancock et al., “Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease,” Neuroscience Letters, vol. 480, no. 1, pp. 78–82, 2010. [62] Q. X. Li, S. S. Mok, K. M. Laughton et al., “Plasma α-synuclein is decreased in subjects with Parkinson’s disease,” Experimental Neurology, vol. 204, no. 2, pp. 583–588, 2007. [63] C. Laske, A. J. Fallgatter, E. Stransky, K. Hagen, D. Berg, and W. Maetzler, “Decreased alpha-synuclein serum levels in patients with Lewy body dementia compared to Alzheimer’s disease patients and control subjects,” Dementia and Geriatric Cognitive Disorders, vol. 31, no. 6, pp. 413–416, 2011. [64] M. Shi, A. R. Furay, V. Sossi et al., “DJ-1 and alphaSYN in LRRK2 CSF do not correlate with striatal dopaminergic function,” Neurobiology of Aging, vol. 33, no. 4, pp. 836.e5– 836.e7, 2012. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png International Journal of Alzheimer's Disease Hindawi Publishing Corporation

-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies

Download PDF
10 pages

Loading next page...
 
/lp/hindawi-publishing-corporation/synuclein-as-csf-and-blood-biomarker-of-dementia-with-lewy-bodies-EhkLK4nyu0

References (93)

Publisher
Hindawi Publishing Corporation
Copyright
Copyright © 2012 Kensaku Kasuga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
ISSN
2090-8024
DOI
10.1155/2012/437025
Publisher site
See Article on Publisher Site

Abstract

Hindawi Publishing Corporation International Journal of Alzheimer’s Disease Volume 2012, Article ID 437025, 9 pages doi:10.1155/2012/437025 Review Article α-Synuclein as CSF and Blood Biomarker of Dementia with Lewy Bodies 1, 2 1 1 Kensaku Kasuga, Masatoyo Nishizawa, and Takeshi Ikeuchi Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, La Jolla, San Diego, CA 92093, USA Correspondence should be addressed to Takeshi Ikeuchi, ikeuchi@bri.niigata-u.ac.jp Received 8 June 2012; Revised 24 July 2012; Accepted 24 July 2012 Academic Editor: Walter Maetzler Copyright © 2012 Kensaku Kasuga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Dementia with Lewy bodies (DLB) is a common subtype of dementia in the elderly. DLB is neuropathologically characterized by the presence of Lewy bodies and Lewy neurites, both of which are composed of α-synuclein. Although α-synuclein was initially considered to be an exclusively intracellular protein, it has been found to be secreted into biological fluids. α-Synuclein in biological fluids such as cerebrospinal fluid (CSF) and blood has been discussed as a potential biomarker of DLB and α-synuclein-related disorders, because α-synuclein is characteristically accumulated in the brain of patients with these disorders. The α-synuclein level in CSF has been examined by several investigators, and the majority of studies have shown a reduction in CSF α-synuclein level in DLB and α-synuclein-related disorders. Discrepant findings of studies of plasma α-synuclein level in patients with DLB have been reported. Because the level of α-synuclein stored in red blood cells is considerably high, blood contamination and haemolysis during sample collection and processing should be considered as a confounding factor for quantification of α-synuclein. Here, the recent progress in the studies of α-synuclein as a biomarker of DLB and their potential clinical applications are reviewed. 1. Introduction intensive research has given hope for disease-modifying therapeutics for DLB to become a reality. The evaluation Dementia with Lewy bodies (DLB) is a common subtype of of such therapies largely depends on reliable diagnostic and dementia and is reported to be the second most common prognostic biomarkers for early detection and monitoring of neurodegenerative dementia after Alzheimer’s disease (AD) the stage of DLB. Candidates of such biomarkers are diverse; in the elderly in several studies [1–3]. DLB is a progressive clinical biomarkers detected on the basis of olfactory func- tion [9], myocardial I-metaiodobenzylguanidine (MIBG) cognitive disorder characterized by fluctuating cognitive impairment, visual hallucination, and parkinsonism [4]. scintigraphy [10], neuroimaging biomarkers detected by Diagnosis of DLB in patients with such characteristic clinical magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT) [11], positron emission features would not be difficult by taking medical history and careful neurological examinations. However, it could tomography (PET), and biochemical biomarkers. In this be laborious to make an accurate diagnosis of DLB when paper, fluid biomarkers, particularly α-synucleinincere- patients have a substantial degree of concomitant AD pathol- brospinal fluid (CSF) and blood in patients with DLB and ogy, which affects the clinical symptoms with lower rates α-synuclein-related disorders were extensively reviewed. of visual hallucinations and parkinsonism [5, 6]. Accurate clinical diagnosis of DLB is important because patients 2. Lewy Bodies and α-Synuclein may benefit from cholinesterase inhibitors, which improve cognitive function and neuropsychiatric symptoms of DLB A century ago, in 1912, Lewy originally described neuronal [7]. Furthermore, it should be noted that DLB patients are inclusions in the brain of patients with Parkinson’s dis- particularly sensitive to neuroleptic drugs [4, 8]. Recent ease (PD). Seven years later, a Russian neuropathologist, 2 International Journal of Alzheimer’s Disease Tretiakoff,named the inclusionsas“corpsdeLewy(Lewy study, however, the intensity of the bands immunoreactive bodies)” [12]. Since the discovery, Lewy bodies have been to the anti-α-synuclein antibodies showed no significant considered as intracytoplasmic, spherical, and eosinophilic difference between patients with PD and control subjects neuronal inclusions in the substantia nigra of PD patients. In [30]. El-Agnaf et al. also confirmed that α-synuclein is 1976, Kosaka et al. reported the detection of Lewy bodies in detectable in CSF by a similar methodology [27]. the cerebral cortex of an elderly patient with dementia [13]. Subsequently, Tokuda et al. demonstrated using a new After his detailed description of cortical Lewy bodies [14], system for enzyme-linked immunosorbent assay (ELISA) many similar cases were subsequently reported. Because the that PD patients showed significantly lower α-synuclein characteristic pathological features of DLB and PD are Lewy levels in CSF than the control groups [31]. Since then, bodies and Lewy neurites, these disorders are considered to several studies to determine the total α-synuclein level belong to a continuum disorder, and the generic term Lewy in CSF have been carried out by ELISA or bead-based body disease (LBD) was proposed [4, 15]. flow cytometric assay using various combinations of anti- In 1997, Spillantini et al. found that α-synuclein is the α-synuclein antibodies (Tables 1 and 2). A significantly main component of Lewy bodies in the brains of PD and low level of α-synuclein in CSF from patients with LBD DLB patients [16]. Only two months before this report, (PD and/or DLB) has been shown by independent studies a mutation was identified in SNCA, which encodes α- [28, 31–38]. Our study revealed that total CSF α-synuclein synuclein in families with autosomal dominant PD [17]. A level shows a significant positive correlation with the CSF different SNCA mutation was subsequently reported in a Aβ42 level in DLB patients [32]. It has been suggested that family with DLB [18]. In addition, SNCA multiplication by alow CSFAβ42 level may be related to amyloid-related duplication/triplication has been identified in a large family pathology in the brains of DLB patients [39]. In addition, with phenotypes ranging from DLB to PD [19]. These neu- experimental studies have suggested that the Aβ42 species ropathological and genetic findings suggest that α-synuclein strongly enhances the accumulation of α-synuclein [40]. is essentially implicated in the pathogenesis of LBD including In the CSF from LBD patients, the level of Aβ42 shows a DLB and PD. Recent studies have suggested that the Lewy positive correlation with the activity of neprilysin, an enzyme body pathology propagates throughout the brain via neuron- that degrades Aβ [41]. Taken together, the reduction in α- to-neuron transmission of α-synuclein aggregates [20]. It synuclein and Aβ42 levels in CSF suggests the extent of Lewy has been demonstrated that glial cytoplasmic inclusions, body pathology and the co-occurrence of amyloid pathology, which are unique pathological inclusions found in brains respectively, in the brain of DLB patients. Interestingly, of patients with multiple system atrophy (MSA), are also patients with SNCA duplication who showed abundant Lewy composed of α-synuclein [21], suggesting an unexpected link body pathology in the brain [42] also show low levels of between MSA and LBD. These disorders with pathological CSF α-synuclein [32]. Because the predominant source of accumulation of α-synuclein in brains are termed as α- α-synuclein in CSF is considered to be the central nervous synucleinopathies [22]. system [43], the decrease in the level of CSF α-synuclein α-Synuclein is a 140-residue ubiquitous protein and is in DLB may reflect a dysfunction in the metabolism or highly expressed in neuronal presynaptic terminals under clearance of α-synuclein in the brain, similarly to AD patients physiological conditions. Although its physiological func- with Aβ accumulation in the brain showing a decrease in the tions remain unclear, α-synuclein is implicated in synaptic level of Aβ42 in CSF. vesicle trafficking particularly in the regulation of synaptic In contrast, comparable levels of total α-synuclein in vesicle release [23] and stabilization of SNARE complexes CSF between patients with LBD and control subjects have [24]. Deposited α-synuclein in the brain with synucle- also been reported [45–50]. This discrepancy is probably not inopathies is aberrantly phosphorylated at Ser129 [25]. It due to the misdiagnosis of LBD, because different studies has been demonstrated that the C-terminal truncated form using CSF samples derived from autopsy-confirmed patients of α-synuclein promotes the aggregation of α-synuclein showed significantly decreased or comparable α-synuclein [26]. Because α-synuclein has no signal sequence, it was levels in LBD patients [34, 50]. In addition to methodolog- initially considered to be an exclusively intracellular protein. ical differences in the quantification of α-synuclein, blood However, it has been shown that α-synuclein is secreted into contamination of CSF during lumbar puncture should be biological fluids [27, 28]. taken into account when considering the discrepant results. The level of α-synuclein in blood, particularly that stored in red blood cells, is much higher than that in CSF [33, 3. α-Synuclein in CSF 53]. Haemolysis in the course of sample collection and A year after Spillantini et al. reported that α-synuclein is the processing should be considered as a confounding factor main component of Lewy bodies, Jakowec et al. examined for quantification of α-synuclein level in CSF and blood. whether α-synuclein is detectable in CSF [29]. They exam- Other factors such as level fluctuations over time and drug ined the expression of α-synuclein in CSF from PD patients treatment may have less effect on the level of α-synuclein in CSF. Although the level of Aβ in CSF fluctuates over time and control subjects by Western blot analysis using an anti- α-synuclein specific antibody, but failed to detect α-synuclein [54], the level of α-synuclein in CSF does not significantly in CSF [29]. Borghi et al. detected α-synuclein by a method change [52]. It is also reported that drugs such as L-dopa and dopamine agonists do not affect the level of α-synuclein in combining immunoprecipitation with immunoblot analysis using two different anti-α-synuclein antibodies [30]. In their CSF [34, 35]. International Journal of Alzheimer’s Disease 3 Table 1: Studies on quantification of α-synuclein level in CSF of patients with DLB and other synucleinopathies. Blood Controls Synucleinopathies Level of total Study contamination Healthy Neurological AD Results Lewy body diseases α-synuclein was considered controls controls DLB PD MSA PD patients showed significantly lower α-syn level than the controls (P< 0.0001). The level of α-syn decreased significantly with age (P = 0.0076) and Tokuda et al. [31] No 9 29 — — 33 — correlated to inversely assigned Hoehn and Yahr stage (P< 0.0001). The level of α-syn in DLB and PD patients were Mollenhauer et al. [28] No — 13 13 38 8 — lower than AD patients and controls (P = 0.025). The level of α-syn in DLB patients was significantly lower than those in patients with AD (P< 0.05) and other dementias (P< 0.01). In DLB patients, Kasuga et al. [32] No — 21 31 34 — — reduced α-syn level correlated with the lower level of CSF Aβ42 (P = 0.01). Patients with SNCA duplication showed a decrease of CSF α-syn. The level of total α-syn was lower in PD patients than in age-matched controls. The level of α-syn Tokuda et al. [44]No 16 12 — — 32 — oligomers was significantly higher in PD patients than in age-matched controls. Upper and lower rows indicate training and validation cohorts, respectively. The level of α-syn — 76 62 55 51 29 Yes Mollenhauer et al. [34] was significantly lower in DLB, PD, and MSA — 20 3 66 273 15 patients than in other neurological diseases. The level of α-syn was decreased in PD and MSA Hong et al. [33] Yes 92 — 38 — 86 20 patients. The level of α-syn was lower in patients with neurodegenerative diseases than in cognitively normal subjects, but the level of α-syn alone did not Parnetti et al. [37]Yes — 32 48 32 38 — distinguish synucleinopathies from tauopathies. An inverse correlation between α-syn and total tau levels was observed (P< 0.01). The levels of α-syn of DLB, PD, and MSA were lower Tateno et al. [36] No — 11 9 6 11 11 than AD. The level of α-syn in female DLB patients was lower Wennstrom et al. [38] No 24 — 26 18 — — than AD (P = 0.041) patients and controls (P = 0.028). 4 International Journal of Alzheimer’s Disease Table 1: Continued. Blood Controls Synucleinopathies Level of total Study contamination Healthy Neurological AD Lewy body diseases Results α-synuclein was considered controls controls DLB PD MSA PD, DLB patients and controls showed comparable levels of α-syn. AD patients showed significantly lower level of α-syn than the controls (P< 0.001). Ohrfeltetal. [45]Yes 55 — 66 15 15 — AD patients with MMSE scores below 20 had significantly lower level of α-syn than AD patients with MMSE scores of 20 or higher (P = 0.02). The level of α-syn did not differ between DLB and AD patients. In DLB patients, the duration of illness Noguchi-Shinohara et al. [46]No — — 21 16 — — was associated with lower level of α-syn (P< 0.05). The level of α-syn was comparable between DLB, AD, and controls. The level of α-syn decreased with Spies et al. [47] No 57 — 131 40 — — age (P = 0.001). The level of α-syn was not different among PD, DLB, AD, and controls. In DLB patients, lower α-syn was Reesink et al. [48]Yes 34 — 63 35 18 — related to lower MMSE scores (P< 0.05) and worse category fluency (P< 0.05). The level of α-syn was comparable among PD, MSA, DLB patients and controls. In PD group, the level of Aerts et al. [49]Yes 57 — — 3 58 47 α-syn was negatively correlated with age at time of lumber puncture (P< 0.006). The level of total α-syn was not different between PD, DLB, MSA and control groups. Oligomeric Foulds et al. [50] Yes 20 — — 16 38 8 phosphorylated α-syn was significantly high in patients with MSA (P< 0.001). The level of total α-syn in PD patients was comparable to that of control groups. The level of Park et al. [51]No 18 11 — — 23 — α-syn oligomer in PD patients was significantly higher than controls (P = 0.005). Arrows indicate decreased (↓) and comparable (→)levels α-synuclein. Sample numbers are shown in each category. Erythrocyte counts or haemoglobin levels were considered as a confounding factor. AD: Alzheimer’s disease; DLB: dementia with Lewy bodies; PD: Parkinson’s disease; MSA: multiple system atrophy; α-syn: α-synuclein; MMSE: minimental state examination. International Journal of Alzheimer’s Disease 5 Table 2: Summary of antibodies used to quantify α-synuclein in biofluids. Anti-α-synuclein antibodies Study Target molecule Capture antibody Detecting antibody Tokuda et al. [31]Total α-synuclein 211 (m) FL-140 (p) Mollenhouer et al. [28]Total α-synuclein mSA-1 (p) Syn-1 (m) Ohrfelt et al. [45]Total α-synuclein Syn1b (m) Syn3b (m), Syn5d (m) Noguchi-Shinohara et al. [46]Total α-synuclein 211 (m) FL-140 (p) Spies et al. [52]Total α-synuclein 211 (m) FL-140 (p) Kasuga et al. [32]Total α-synuclein Syn-1 (m) FL-140 (p) Reesink et al. [48]Total α-synuclein 211 (m) FL-140 (p) Total α-synuclein 211 (m) FL-140 (p) Tokuda et al. [44] Oligomeric α-synuclein 211 (m) Biotinylated 211 (m) Aerts et al. [49]Total α-synuclein 211 (m) FL-140 (p) Mollenhouer et al. [34]Total α-synuclein mSA-1 (p) Syn-1 (m) Biotinylated goat 211 (m), LB509 (m), Hong et al. [33]Total α-synuclein anti-human α-synuclein rabbit anti-α-synuclein (p) (p) Parnetti et al. [37]Total α-synuclein 211 (m) FL-140 (p) Total α-synuclein 211 (m) FL-140 (p) Foulds et al. [50] Oligomeric α-synuclein 211 (m) Biotinylated 211 (m) Phosphorylated α-synuclein N-19 (p) pS129 (m) Oligomeric phosphorylated pS129 (m) Biotinylated pS129 (m) α-synuclein Tateno et al. [36]Total α-synuclein Not described Not described Commercial kit (Invitrogen) Wennstrom et al. [38]Total α-synuclein Total α-synuclein 211 (m) FL-140 (p) Park et al. [51] Oligomeric α-synuclein 211 (m) Biotinylated 211 (m) m: monoclonal antibody; p: polyclonal antibody. Several groups have recently conducted studies to detect methods may be heterogeneous in size and toxicity; hence, the oligomeric forms of α-synuclein in CSF, because the further validation is still needed. oligomer species of α-synuclein are considered to be toxic Correlation analysis of clinical parameters, such as and could enhance pathological accumulation of α-synuclein minimental state examination (MMSE) and Hoehn Yahr and disease propagation [55]. Tokuda et al. demonstrated scale scores with the total α-synuclein level in CSF, has that the levels of α-synuclein oligomers in CSF are signif- shown inconsistent results. Tokuda et al. showed an inverse icantly higher in patients with PD than in patients with correlation between the total α-synuclein level in CSF and progressive supranuclear palsy (PSP) or AD [44]. In their disease severity determined by the Hoehn Yahr scale [31]. A study, the level of total α-synuclein in the CSF from PD low α-synuclein level was reported to correlate with a low patients tends to decrease [44]. Increased level of α-synuclein MMSE score of DLB patients [48]. These findings suggest oligomers in CSF from PD patients was also shown by that α-synuclein level in CSF may reflect the severity of other investigator [51]. Foulds et al. showed that the level of pathological changes occurring in patients with LBD. This oligomers composed of phosphorylated α-synuclein is higher notion is supported by the findings of a study that the disease in the postmortem CSF from MSA patients than in that from duration in patients with DLB is closely associated with a low with PD, DLB, or PSP patients [50]. Sierks et al. also showed α-synuclein level in CSF [46]. In contrast to these findings, a significant increase in the level of α-synuclein oligomers in other studies revealed no significant association of the α- postmortem CSF from patients with PD by electrochemical synuclein level in CSF with MMSE score, gender, age at impedance spectroscopy [56]. These findings suggest a examination, or disease duration in DLB or AD patients possibility that α-synuclein oligomer species are detectable in [32]. Shi et al. examined whether CSF α-synuclein level CSF and that their levels may increase in some patients with correlates with dopaminergic dysfunction determined by synucleinopathies. A potential concern is that the oligomeric PET in asymptomatic carriers with leucine-rich repeat kinase forms of α-synuclein detected in their studies using different 2 (LRRK2) gene mutation [64]. They detected no significant 6 International Journal of Alzheimer’s Disease Table 3: Studies of quantification of α-synuclein level in blood of patients with DLB and other synucleinopathies. ∗ ∗∗ Methods Samples Results Plasma α-Synuclein oligomers were elevated in patients El-Agnaf et al. [57]ELISA Cont (27), PD/DLB (34) with PD/DLB compared to controls. The α-synuclein level was increased in patients with PD (79.9 pg/mL) and in those with MSA Plasma (78.1 pg/mL) compared with controls Lee et al. [58]ELISA Cont (51), PD (105), MSA (38) (76.1 pg/mL). The α-synuclein level was significantly higher in patients with PD than in those with MSA. The α-synuclein level was elevated in patients Plasma with PD compared to healthy controls. Duran et al. [59]ELISA Cont (60), PD (95) Antiparkinsonian treatment does not change plasma α-synuclein level. The level of phosphorylated α-synuclein was higher in patients with PD than healthy controls. Plasma None of the levels of total α-synuclein, oligomeric Foulds et al. [60]ELISA (not described) α-synuclein, or oligomeric phospohorylated α-synuclein was different between PD patients and controls. No significant difference was found among Bead-based flow Plasma Shi et al. [61] patients with PD (36.8 ng/mL), AD (32.4 ng/mL), cytometric assay Cont (95), AD (33), PD (117) and those with healthy controls (39.5 ng/mL). There was no difference in oligomeric and total Plasma Park et al. [51]ELISA α-synuclein in plasma between PD patients and Cont (29), PD(23) controls. The α-synuclein level was significantly lower in patients with PD than in those with age-matched Plasma Li et al. [62] IP-Western blot healthy controls. Early-onset PD patients had Cont (11), PD (27) lower α-synuclein levels than late-onset PD patients. The α-synuclein level was significantly lower in Serum Laske et al. [63]ELISA patients with DLB (4.7 ng/mL) than in those with Cont (40), AD (80), DLB (40) AD (7.0 ng/mL) and healthy controls (8.1 ng/mL). ∗ ∗∗ Arrows indicate increased (↑), comparable (→ ), and decreased (↓)levelsof α-synuclein. Sample numbers are shown in parenthesis. Values are indicated as mean or median. AD: Alzheimer’s disease; Cont: controls; DLB: dementia with Lewy bodies; IP: immunoprecipitation; MSA: multiple system atrophy; PD: Parkinson’s disease. correlations, indicating that CSF total α-synuclein level may in plasma quantified by ELISA as well as Western blot analysis not be a sensitive biomarker of the preclinical phase of PD. is higher in patients with PD than in control subjects [60]. In their study, the level of α-synuclein remained stable within the same individuals at least over 3 months. 4. α-Synuclein in Blood By contrast, Li et al. found a significantly decreased α- Several studies on the quantification of α-synucleininblood synuclein level in plasma from patients with PD by Western have been carried out because drawing blood is much less blot analysis, which detected only full-length monomeric α- invasive than lumbar puncture to obtain CSF from patients synuclein [62]. Laske et al. also reported a similar decrease (Table 3). El-Agnaf et al. detected α-synuclein in plasma of in serum α-synuclein level in DLB patients compared with patients with LBD by immunoprecipitation using an anti- AD patients and control subjects [63]. Comparable levels of α-synuclein antibody [27]. Subsequently, they found higher plasma α-synuclein were found among patients with PD, AD, levels of α-synuclein oligomers in plasma from PD patients and control subjects in other studies [61]. than in that from control subjects by ELISA [57]. A similar increase in α-synuclein level was observed in plasma from 5. Conclusions patients with PD and MSA [58, 59]. Lee et al. found that plasma α-synuclein level is higher in patients with PD than Results of measurements of α-synuclein level in CSF and in those with MSA [58]. Duran et al. demonstrated that blood have been variable; hence, it is difficult to unequiv- drugs such as L-dopa, dopamine agonists, and MAO/COMT ocally conclude whether α-synuclein is a promising fluid inhibitors do not affect the plasma α-synuclein level in biomarker of DLB and other α-synucleinopathies. More patients with PD [59]. The phosphorylated α-synuclein level discriminating results for DLB patients could be obtained International Journal of Alzheimer’s Disease 7 by examining specific α-synuclein species such as truncated, [11] I. McKeith, J. O’Brien, Z. Walker et al., “Sensitivity and specificity of dopamine transporter imaging with 123I-FP-CIT phosphorylated, and oligomeric species on the basis of their SPECT in dementia with Lewy bodies: a phase III, multicentre analogy to Aβ42 and phosphorylated tau species whose study,” The Lancet Neurology, vol. 6, no. 4, pp. 305–313, 2007. changesinlevelsare foundtobereliableCSF biomarkers of [12] A. M. Rodrigues E Silva, F. Geldsetzer, B. Holdorff et al., “Who AD. In addition, a multicenter study is required to validate was the man who discovered the “Lewy bodies”?” Movement the usefulness of α-synuclein as a biomarker by standardized Disorders, vol. 25, no. 12, pp. 1765–1773, 2010. methods of quantifying α-synuclein. Continuous efforts [13] K. Kosaka, S. Oyanagi, and M. Matsushita, “Presenile demen- will be required to establish useful fluid biomarkers for tia with Alzheimer, Pick and Lewy body changes,” Acta early diagnosis of DLB and evaluation of disease-modifying Neuropathologica, vol. 36, no. 3, pp. 221–233, 1976. therapeutics for DLB. [14] K. Kosaka, “Lewy bodies in cerebral cortex. Report of three cases,” Acta Neuropathologica, vol. 42, no. 2, pp. 127–134, Acknowledgments [15] C. F. Lippa, J. E. Duda, M. Grossman et al., “DLB and PDD The authors would like to thank Drs. Takayoshi Tokutake, boundary issues: diagnosis, treatment, molecular pathology, Atsushi Ishikawa, and Osamu Onodera for their helpful and biomarkers,” Neurology, vol. 68, no. 11, pp. 812–819, 2007. discussion on this paper. [16] M. G. Spillantini, M. L. Schmidt, V. M. Y. Lee, J. Q. Trojanowski, R. Jakes, and M. Goedert, “α-synuclein in Lewy References bodies,” Nature, vol. 388, no. 6645, pp. 839–840, 1997. [17] M. H. Polymeropoulos, C. Lavedan, E. Leroy et al., “Mutation [1] Y. Matsui, Y. Tanizaki, H. Arima et al., “Incidence and survival in the α-synuclein gene identified in families with Parkinson’s of dementia in a general population of Japanese elderly: disease,” Science, vol. 276, no. 5321, pp. 2045–2047, 1997. the hisayama study,” Journal of Neurology, Neurosurgery and [18] J. J. Zarranz, J. Alegre, J. C. Gomez-Est ´ eban et al., “The new Psychiatry, vol. 80, no. 4, pp. 366–370, 2009. mutation, E46K, of alpha-synuclein causes Parkinson and [2] T. Rahkonen, U. Eloniemi-Sulkava, S. Rissanen, A. Vatanen, Lewy body dementia,” Annals of Neurology, vol. 55, no. 2, pp. P. Viramo, and R. Sulkava, “Dementia with Lewy bodies 164–173, 2004. according to the consensus criteria in a general population [19] A. B. Singleton, M. Farrer, J. Johnson et al., “α-synuclein locus aged 75 years or older,” Journal of Neurology Neurosurgery and triplication causes Parkinson’s disease,” Science, vol. 302, no. Psychiatry, vol. 74, no. 6, pp. 720–724, 2003. 5646, p. 841, 2003. [3] D. Aarsland, A. Rongve, S. Piepenstock Nore et al., “Frequency [20] P. Desplats,H.J.Lee,E.J.Bae et al., “Inclusion formationand and case identification of dementia with Lewy bodies using the neuronal cell death through neuron-to-neuron transmission revised consensus criteria,” Dementia and Geriatric Cognitive of α-synuclein,” Proceedings of the National Academy of Sciences Disorders, vol. 26, no. 5, pp. 445–452, 2008. of the United States of America, vol. 106, no. 31, pp. 13010– [4] I. G. McKeith, D. Galasko, K. Kosaka et al., “Consensus guide- 13015, 2009. lines for the clinical and pathologic diagnosis of dementia [21] K. Wakabayashi, M. Yoshimoto, S. Tsuji, and H. Takahashi, “α- with Lewy bodies (DLB): report of the consortium on DLB synuclein immunoreactivity in glial cytoplasmic inclusions in international workshop,” Neurology, vol. 47, no. 5, pp. 1113– multiple system atrophy,” Neuroscience Letters, vol. 249, no. 2- 1124, 1996. 3, pp. 180–182, 1998. [5] I. G. McKeith, D. W. Dickson, J. Lowe et al., “Diagnosis and [22] M. G. Spillantini and M. Goedert, “The α-synucleinopathies: management of dementia with Lewy bodies: third report of Parkinson’s disease, dementia with Lewy bodies, and multiple the DLB Consortium,” Neurology, vol. 65, no. 12, pp. 1863– system atrophy,” Annals of the New York Academy of Sciences, 1872, 2005. vol. 920, pp. 16–27, 2000. [6] A. R. Merdes, L. A. Hansen, D. V. Jeste et al., “Influence [23] A. Abeliovich, Y. Schmitz, I. Farinas ˜ et al., “Mice lacking of Alzheimer pathology on clinical diagnostic accuracy in α-synuclein display functional deficits in the nigrostriatal dementia with Lewy bodies,” Neurology, vol. 60, no. 10, pp. dopamine system,” Neuron, vol. 25, no. 1, pp. 239–252, 2000. 1586–1590, 2003. [24] J. Burre, ´ M. Sharma, T. Tsetsenis, V. Buchman, M. R. Etherton, [7] J. T. O’Brien and A. Burns, “Clinical practice with anti- andT.C.Sudhof, ¨ “α-synuclein promotes SNARE-complex dementia drugs: a revised (second) consensus statement from assembly in vivo and in vitro,” Science, vol. 329, no. 5999, pp. the British Association for Psychopharmacology,” Journal of 1663–1667, 2010. Psychopharmacology, vol. 25, no. 8, pp. 997–1019, 2011. [25] H. Fujiwara, M. Hasegawa, N. Dohmae et al., “α-synuclein [8] D. Aarsland, R. Perry, J. P. Larsen et al., “Neuroleptic sensitivity is phosphorylated in synucleinopathy lesions,” Nature Cell in Parkinson’s disease and Parkinsonian dementias,” Journal of Biology, vol. 4, no. 2, pp. 160–164, 2002. Clinical Psychiatry, vol. 66, no. 5, pp. 633–637, 2005. [26] W. Li, N. West, E. Colla et al., “Aggregation promoting C- [9] A. Haehner, T. Hummel, and H. Reichmann, “Olfactory terminal truncation of α-synuclein is a normal cellular process dysfunction as a diagnostic marker for Parkinson’s disease,” and is enhanced by the familial Parkinson’s disease-linked Expert Review of Neurotherapeutics, vol. 9, no. 12, pp. 1773– mutations,” Proceedings of the National Academy of Sciences of 1779, 2009. the United States of America, vol. 102, no. 6, pp. 2162–2167, [10] S. Orimo, M. Suzuki, A. Inaba et al., “(123)I-MIBG myocardial scintigraphy for differentiating Parkinson’s disease from other [27] O. M. El-Agnaf,S.A.Salem,K.E.Paleologouetal., “Alpha- neurodegenerative parkinsonism: a systematic review and synuclein implicated in Parkinson’s disease is present in extracellular biological fluids, including human plasma,” The meta-analysis,” Parkinsonism and Related Disorders, vol. 18, no. 5, pp. 494–500, 2012. FASEB Journal, vol. 17, no. 13, pp. 1945–1947, 2003. 8 International Journal of Alzheimer’s Disease [28] B. Mollenhauer, V. Cullen, I. Kahn et al., “Direct quantification neurons of the central nervous system,” Journal of Neural of CSF α-synuclein by ELISA and first cross-sectional study Transmission, vol. 119, no. 7, pp. 739–746, 2012. in patients with neurodegeneration,” Experimental Neurology, [44] T. Tokuda, M. M. Qureshi, M. T. Ardah et al., “Detection of vol. 213, no. 2, pp. 315–325, 2008. elevated levels of α-synuclein oligomers in CSF from patients [29] M. W. Jakowec, G. M. Petzinger, S. Sastry, D. M. Donaldson, with Parkinson disease,” Neurology, vol. 75, no. 20, pp. 1766– A. McCormack, and J. W. Langston, “The native form of α- 1772, 2010. synuclein is not found in the cerebrospinal fluid of patients ¨ [45] A. Ohrfelt, P. Grognet, N. Andreasen et al., “Cerebrospinal with Parkinson’s disease or normal controls,” Neuroscience fluid α-synuclein in neurodegenerative disorders—a marker Letters, vol. 253, no. 1, pp. 13–16, 1998. of synapse loss?” Neuroscience Letters, vol. 450, no. 3, pp. 332– [30] R. Borghi, R. Marchese, A. Negro et al., “Full length α- 335, 2009. synuclein is present in cerebrospinal fluid from Parkinson’s [46] M. Noguchi-Shinohara, T. Tokuda, M. Yoshita et al., “CSF α- disease and normal subjects,” Neuroscience Letters, vol. 287, no. synuclein levels in dementia with Lewy bodies and Alzheimer’s 1, pp. 65–67, 2000. disease,” Brain Research, vol. 1251, pp. 1–6, 2009. [31] T. Tokuda, S. A. Salem, D. Allsop et al., “Decreased α-synuclein [47] P. E. Spies, R. J. F. Melis, M. J. C. Sjog ¨ ren, M. G. M. O. in cerebrospinal fluid of aged individuals and subjects with Rikkert, and M. M. Verbeek, “Cerebrospinal fluid α-synuclein Parkinson’s disease,” Biochemical and Biophysical Research does not discriminate between dementia disorders,” Journal of Communications, vol. 349, no. 1, pp. 162–166, 2006. Alzheimer’s Disease, vol. 16, no. 2, pp. 363–369, 2009. [32] K. Kasuga, T. Tokutake, A. Ishikawa et al., “Differential levels [48] F. E. Reesink,A.W.Lemstra,K.D.van Dijk et al., “CSF α- of α-synuclein, β-amyloid42 and tau in CSF between patients synuclein does not discriminate dementia with Lewy bodies with dementia with Lewy bodies and Alzheimer’s disease,” from Alzheimer’s disease,” Journal of Alzheimer’s Disease, vol. Journal of Neurology, Neurosurgery and Psychiatry, vol. 81, no. 22, no. 1, pp. 87–95, 2010. 6, pp. 608–610, 2010. [49] M. B. Aerts, R. A. J. Esselink, W. F. Abdo, B. R. Bloem, and M. [33] Z. Hong, M. Shi, K. A. Chung et al., “DJ-1 and α-synuclein M. Verbeek, “CSF α-synuclein does not differentiate between in human cerebrospinal fluid as biomarkers of Parkinson’s parkinsonian disorders,” Neurobiology of Aging, vol. 33, no. 2, disease,” Brain, vol. 133, pp. 713–726, 2010. pp. 431–433, 2012. [34] B. Mollenhauer, J. J. Locascio, W. Schulz-Schaeffer, F. Sixel- [50] P. G. Foulds, O. Yokota, A. Thurston et al., “Post mortem Dor ¨ ing, C. Trenkwalder, and M. G. Schlossmacher, “α- cerebrospinal fluid alpha-synuclein levels are raised in mul- synuclein and tau concentrations in cerebrospinal fluid of tiple system atrophy and distinguish this from the other patients presenting with parkinsonism: a cohort study,” The alpha-synucleinopathies, Parkinson’s disease and dementia Lancet Neurology, vol. 10, no. 3, pp. 230–240, 2011. with Lewy bodies,” Neurobiology of Disease,vol. 45, no.1,pp. [35] M. Shi, J. Bradner, A. M. Hancock et al., “Cerebrospinal fluid 188–195, 2012. biomarkers for Parkinson disease diagnosis and progression,” Annals of Neurology, vol. 69, no. 3, pp. 570–580, 2011. [51] M. J. Park,S.M.Cheon,H.R.Bae et al., “Elevatedlevelsof alpha-synuclein oligomer in the cerebrospinal fluid of drug- [36] F. Tateno, R. Sakakibara, T. Kawai et al., “Alpha-synuclein in the cerebrospinal fluid differentiates synucleinopathies naive patients with Parkinson’s disease,” Journal of Clinical (Parkinson disease, dementia with lewy bodies, multiple Neurology, vol. 7, no. 4, pp. 215–222, 2011. system atrophy) from Alzheimer disease,” Alzheimer Disease [52] P. E. Spies, D. Slats, M. G. Rikkert et al., “CSF alpha-synuclein and Associated Disorders, vol. 26, no. 3, pp. 213–216, 2012. concentrations do not fluctuate over hours and are not [37] L. Parnetti, D. Chiasserini, G. Bellomo et al., “Cerebrospinal correlated to amyloid beta in humans,” Neuroscience Letters, fluid Tau/α-synuclein ratio in Parkinson’s disease and degener- vol. 504, no. 3, pp. 336–338, 2011. ative dementias,” Movement Disorders, vol. 26, no. 8, pp. 1428– [53] R. Barbour, K. Kling, J. P. Anderson et al., “Red blood 1435, 2011. cells are the major source of alpha-synuclein in blood,” [38] M. Wennstrom, E. Londos, L. Minthon et al., “Altered Neurodegenerative Diseases, vol. 5, no. 2, pp. 55–59, 2008. CSF orexin and alpha-synuclein levels in dementia patients,” [54] R. J. Bateman, G. Wen, J. C. Morris, and D. M. Holtzman, Journal of Alzheimer’s Disease, vol. 29, no. 1, pp. 125–132, 2012. “Fluctuations of CSF amyloid-β levels: implications for a [39] D. Strozyk, K. Blennow, L. R. White, and L. J. Launer, “CSF diagnostic and therapeutic biomarker,” Neurology, vol. 68, no. Aß 42 levels correlate with amyloid-neuropathology in a 9, pp. 666–669, 2007. population-based autopsy study,” Neurology, vol. 60, no. 4, pp. [55] K. Vekrellis, M. Xilouri, E. Emmanouilidou et al., “Patholog- 652–656, 2003. ical roles of alpha-synuclein in neurological disorders,” The [40] O. Pletnikova, N. West, M. K. Lee et al., “Aβ deposition is Lancet Neurology, vol. 10, no. 11, pp. 1015–1025, 2011. associated with enhanced cortical α-synuclein lesions in Lewy [56] M. R. Sierks, G. Chatterjee, C. McGraw et al., “CSF levels of body diseases,” Neurobiology of Aging, vol. 26, no. 8, pp. 1183– oligomeric alpha-synuclein and beta-amyloid as biomarkers 1192, 2005. for neurodegenerative disease,” Integrative Biology, vol. 3, no. [41] W. Maetzler, V. Stoycheva, B. Schmid et al., “Neprilysin 12, pp. 1188–1196, 2011. activity in cerebrospinal fluid is associated with dementia [57] O. M. A. El-Agnaf,S.A.Salem,K.E.Paleologouetal., and amyloid-β42 levels in lewy body disease,” Journal of “Detection of oligomeric forms of α-synuclein protein in Alzheimer’s Disease, vol. 22, no. 3, pp. 933–938, 2010. human plasma as a potential biomarker for Parkinson’s [42] T. Ikeuchi, A. Kakita, A. Shiga et al., “Patients homozygous disease,” The FASEB Journal, vol. 20, no. 3, pp. 419–425, 2006. and heterozygous for SNCA duplication in a family with parkinsonism and dementia,” Archives of Neurology, vol. 65, [58] P. H. Lee, G. Lee, H. J. Park, O. Y. Bang, I. S. Joo, and no. 4, pp. 514–519, 2008. K. Huh, “The plasma alpha-synuclein levels in patients with [43] B. Mollenhauer, E. Trautmann, B. Otte et al., “Alpha-synuclein Parkinson’s disease and multiple system atrophy,” Journal of in human cerebrospinal fluid is principally derived from Neural Transmission, vol. 113, no. 10, pp. 1435–1439, 2006. International Journal of Alzheimer’s Disease 9 [59] R. Duran, F. J. Barrero, B. Morales, J. D. Luna, M. Ramirez, and F. Vives, “Plasma α-synuclein in patients with Parkinson’s disease with and without treatment,” Movement Disorders, vol. 25, no. 4, pp. 489–493, 2010. [60] P. G. Foulds, J. D. Mitchell, A. Parker et al., “Phosphorylated alpha-synuclein can be detected in blood plasma and is potentially a useful biomarker for Parkinson’s disease,” The FASEB Journal, vol. 25, no. 12, pp. 4127–4137, 2011. [61] M. Shi, C. P. Zabetian, A. M. Hancock et al., “Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson’s disease,” Neuroscience Letters, vol. 480, no. 1, pp. 78–82, 2010. [62] Q. X. Li, S. S. Mok, K. M. Laughton et al., “Plasma α-synuclein is decreased in subjects with Parkinson’s disease,” Experimental Neurology, vol. 204, no. 2, pp. 583–588, 2007. [63] C. Laske, A. J. Fallgatter, E. Stransky, K. Hagen, D. Berg, and W. Maetzler, “Decreased alpha-synuclein serum levels in patients with Lewy body dementia compared to Alzheimer’s disease patients and control subjects,” Dementia and Geriatric Cognitive Disorders, vol. 31, no. 6, pp. 413–416, 2011. [64] M. Shi, A. R. Furay, V. Sossi et al., “DJ-1 and alphaSYN in LRRK2 CSF do not correlate with striatal dopaminergic function,” Neurobiology of Aging, vol. 33, no. 4, pp. 836.e5– 836.e7, 2012. MEDIATORS of INFLAMMATION The Scientific Gastroenterology Journal of World Journal Research and Practice Diabetes Research Disease Markers Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 International Journal of Journal of Immunology Research Endocrinology Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Submit your manuscripts at http://www.hindawi.com BioMed PPAR Research Research International Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Journal of Obesity Evidence-Based Journal of Journal of Stem Cells Complementary and Ophthalmology International Alternative Medicine Oncology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 Parkinson’s Disease Computational and Behavioural Mathematical Methods AIDS Oxidative Medicine and in Medicine Research and Treatment Cellular Longevity Neurology Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation Hindawi Publishing Corporation http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014 http://www.hindawi.com Volume 2014

Journal

International Journal of Alzheimer's Disease – Hindawi Publishing Corporation

Published: Sep 26, 2012

There are no references for this article.