Cerebrospinal fluid alpha-synuclein in neurodegenerative disorders - a marker of synapse loss? Neurosci Lett

Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry, The Sahlgrenska Academy at University of Gothenburg, Mölndal, Sweden.
Neuroscience Letters (Impact Factor: 2.03). 12/2008; 450(3):332-5. DOI: 10.1016/j.neulet.2008.11.015
Source: PubMed


The association of alpha-synuclein (alpha-syn) neuropathology with Parkinson's disease (PD) and several related disorders has led to an intense research effort to develop cerebrospinal fluid (CSF)- or blood-based alpha-syn biomarkers for these types of diseases. Recent studies show that alpha-syn is present in CSF and possible to measure using enzyme-linked immunosorbent assay (ELISA). Here, we describe a novel ELISA that allows for quantification of alpha-syn in CSF down to 50pg/mL. The diagnostic value of the test was assessed using CSF samples from 66 Alzheimer's disease (AD) patients, 15PD patients, 15 patients with dementia with Lewy bodies (DLB) and 55 cognitively normal controls. PD and DLB patients and controls displayed similar CSF alpha-syn levels. AD patients had significantly lower alpha-syn levels than controls (median [inter-quartile range] 296 [234-372] and 395 [298-452], respectively, p<0.001). Moreover, AD patients with mini-mental state examination (MMSE) scores below 20 had significantly lower alpha-syn than AD patients with MMSE scores of 20 or higher (p=0.02). There was also a tendency towards a negative correlation between alpha-syn levels and disease duration in the AD group (r=-0.247, p=0.06). Altogether, our results speak against CSF alpha-syn as a reliable biomarker for PD and DLB. The lower alpha-syn levels in AD, as well as the association of alpha-syn reduction with AD severity, approximated by MMSE, suggests that it may be a general marker of synapse loss, a hypothesis that warrants further investigation.

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    • "The degree of change of CSF aSyn in Parkinson's disease is only minor, with aSyn being in the range of 80%e90% of the level in matched controls. Discrepant findings showing no change or elevated levels have been reported by other groups (Aerts et al., 2012; Lee et al., 2011; Noguchi-Shinohara et al., 2009; Ohrfelt et al., 2009; Park et al., 2011; Reesink et al., 2010; Spies et al., 2009; Wang et al., 2012). Several factors could explain these discrepancies , including the use of different assay formats and antibodies as well as differences in sample handling (Mollenhauer et al., 2010). "
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    ABSTRACT: Decreased levels of alpha-synuclein (aSyn) in cerebrospinal fluid (CSF) in Parkinson's disease and related synucleinopathies have been reported, however, not consistently in all cross-sectional studies. To test the performance of one recently released human-specific enzyme-linked immunosorbent assay (ELISA) for the quantification of aSyn in CSF, we carried out a round robin trial with 18 participating laboratories trained in CSF ELISA analyses within the BIOMARKAPD project in the EU Joint Program - Neurodegenerative Disease Research. CSF samples (homogeneous aliquots from pools) and ELISA kits (one lot) were provided centrally and data reported back to one laboratory for data analysis. Our study showed that although factors such as preanalytical sample handling and lot-to-lot variability were minimized by our study design, we identified high variation in absolute values of CSF aSyn even when the same samples and same lots of assays were applied. We further demonstrate that although absolute concentrations differ between laboratories the quantitative results are comparable. With further standardization this assay may become an attractive tool for comparing aSyn measurements in diverse settings. Recommendations for further validation experiments and improvement of the interlaboratory results obtained are given. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of aging 05/2015; 36(9). DOI:10.1016/j.neurobiolaging.2015.05.003 · 5.01 Impact Factor
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    • "This observation was most marked (p < 0.05) in a subgroup of patients with PDD carrying the apolipoprotein genotype epsilon3/epsilon3 Parnetti et al., 2008 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., 2009 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., 2009b 20 PDND, 20 PDD, 30 controls patients CSF Aβ42 ranged from high (controls) to intermediate (PDND) and low (PDD) levels (P < 0.001). In all PD and PDD patients, in PDND, CSF Aβ42 was related with phonetic fluency Alves et al., 2010 109 PDND, 36 controls, 20 mild AD CSF Aβ42 (19%; p = 0.009), Aβ40 (15.5%; p = 0.008), and Aβ38 (23%; p = 0.004) significantly decreased in PD compared with controls CSF Aβ42 reductions in PD less marked than in AD (53%; p = 0.002) "
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    ABSTRACT: 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 tau and phosphotau protein with the progression of PD and with the preservation of cognitive function in PD patients; (c) the possible value of CSF beta-amyloid 1-42 as a useful marker of further cognitive decline in PD patients, and (d) the potential usefulness of CSF neurofilament (NFL) protein levels in the differential diagnosis between PD and other parkinsonian syndromes. Future multicentric, longitudinal, prospective studies with long-term follow-up and neuropathological confirmation would be useful in establishing appropriate biomarkers for PD.
    Frontiers in Cellular Neuroscience 11/2014; fncel.2014.00369. eCollection 2014.. DOI:10.3389/fncel.2014.00369 · 4.29 Impact Factor
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    • "In addition to muscle activity patterns, investigators have studied the utility of putative biomarkers and their prognostic features and association with PD progression. Indeed, some PD-related biomarker candidates have been prospectively proven in clinical biomarker research, of which plasma α-synuclein was found to be a comparatively ideal biomarker and valuable in the diagnosis or monitoring of PD disease progression [13]–[16]. Our collaborator's study implied a trend of decreased plasma α-synuclein and DJ-1 levels in PD patients compared with healthy controls, but no statistical difference was reached [17]. "
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    ABSTRACT: Freezing of gait (FOG) is a complicated gait disturbance in Parkinson's disease (PD) and a relevant subclinical predictor algorithm is lacking. The main purpose of this study is to explore the potential value of surface electromyograph (sEMG) and plasma α-synuclein levels as predictors of the FOG seen in PD. 21 PD patients and 15 normal controls were recruited. Motor function was evaluated using the Unified Parkinson's Disease Rating Scale (UPDRS) and Freezing of gait questionnaire (FOG-Q). Simultaneously, gait analysis was also performed using VICON capture system in PD patients and sEMG data was recorded as well. Total plasma α-synuclein was quantitatively assessed by Luminex assay in all participants. Recruited PD patients were classified into two groups: PD patients with FOG (PD+FOG) and without FOG (PD-FOG), based on clinical manifestation, the results of the FOG-Q and VICON capture system. PD+FOG patients displayed higher FOG-Q scores, decreased walking speed, smaller step length, smaller stride length and prolonged double support time compared to the PD-FOG in the gait trial. sEMG data indicated that gastrocnemius activity in PD+FOG patients was significantly reduced compared to PD-FOG patients. In addition, plasma α-synuclein levels were significantly decreased in the PD+FOG group compared to control group; however, no significant difference was found between the PD+FOG and PD-FOG groups. Our study revealed that gastrocnemius sEMG could be used to evaluate freezing gait in PD patients, while plasma α-synuclein might discriminate freezing of gait in PD patients from normal control, though no difference was found between the PD+FOG and PD-FOG groups.
    PLoS ONE 02/2014; 9(2):e89353. DOI:10.1371/journal.pone.0089353 · 3.23 Impact Factor
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