Dataset Information

Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease.

ABSTRACT: DJ-1 and alpha-synuclein are leading biomarkers for Parkinson's disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and alpha-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these inconsistent results. In this study, the relative contribution of each blood component to blood DJ-1 and alpha-synuclein was evaluated, followed by quantification of plasma levels of both markers in a larger cohort of patients/subjects ( approximately 300 cases) whose cerebrospinal fluid DJ-1 and alpha-synuclein levels have been determined recently. The results demonstrated that the DJ-1 and alpha-synuclein in blood resided predominantly in red blood cells (>95%), followed by platelets (1-4%), white blood cells and plasma (< or =1%), indicating that variations in hemolysis and/or platelet contamination could have a significant effect on plasma/serum DJ-1 and alpha-synuclein levels. Nonetheless, after adjusting for the age, although there was a trend of decrease in DJ-1 and alpha-synuclein in patients with Parkinson's or Alzheimer's disease compared with healthy controls, no statistical difference was observed in this cohort between any groups, even when the extent of hemolysis and platelet contamination were controlled for. Additionally, no correlation between DJ-1 or alpha-synuclein and Parkinson's disease severity was identified. In conclusion, unlike in cerebrospinal fluid, total DJ-1 or alpha-synuclein in plasma alone is not useful as biomarkers for Parkinson's disease diagnosis or progression/severity.

SUBMITTER: Shi M

PROVIDER: S-EPMC2943649 | biostudies-literature | 2010 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease.

Shi Min M Zabetian Cyrus P CP Hancock Aneeka M AM Ginghina Carmen C Hong Zhen Z Yearout Dora D Chung Kathryn A KA Quinn Joseph F JF Peskind Elaine R ER Galasko Douglas D Jankovic Joseph J Leverenz James B JB Zhang Jing J

Neuroscience letters 20100609 1

DJ-1 and alpha-synuclein are leading biomarkers for Parkinson's disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and alpha-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these ...[more]

PMID: 20540987

Similar Datasets

Project description:Biomarkers are urgently needed for the diagnosis and monitoring of disease progression in Parkinson's disease. Both DJ-1 and alpha-synuclein, two proteins critically involved in Parkinson's disease pathogenesis, have been tested as disease biomarkers in several recent studies with inconsistent results. These have been largely due to variation in the protein species detected by different antibodies, limited numbers of patients in some studies, or inadequate control of several important variables. In this study, the nature of DJ-1 and alpha-synuclein in human cerebrospinal fluid was studied by a combination of western blotting, gel filtration and mass spectrometry. Sensitive and quantitative Luminex assays detecting most, if not all, species of DJ-1 and alpha-synuclein in human cerebrospinal fluid were established. Cerebrospinal fluid concentrations of DJ-1 and alpha-synuclein from 117 patients with Parkinson's disease, 132 healthy individuals and 50 patients with Alzheimer's disease were analysed using newly developed, highly sensitive Luminex technology while controlling for several major confounders. A total of 299 individuals and 389 samples were analysed. The results showed that cerebrospinal fluid DJ-1 and alpha-synuclein levels were dependent on age and influenced by the extent of blood contamination in cerebrospinal fluid. Both DJ-1 and alpha-synuclein levels were decreased in Parkinson's patients versus controls or Alzheimer's patients when blood contamination was controlled for. In the population aged > or = 65 years, when cut-off values of 40 and 0.5 ng/ml were chosen for DJ-1 and alpha-synuclein, respectively, the sensitivity and specificity for patients with Parkinson's disease versus controls were 90 and 70% for DJ-1, and 92 and 58% for alpha-synuclein. A combination of the two markers did not enhance the test performance. There was no association between DJ-1 or alpha-synuclein and the severity of Parkinson's disease. Taken together, this represents the largest scale study for DJ-1 or alpha-synuclein in human cerebrospinal fluid so far, while using newly established sensitive Luminex assays, with controls for multiple variables. We have demonstrated that total DJ-1 and alpha-synuclein in human cerebrospinal fluid are helpful diagnostic markers for Parkinson's disease, if variables such as blood contamination and age are taken into consideration.

Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Dataset Information

Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease.

Publications

Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets