Dataset Information

Longitudinal analyses of cerebrospinal fluid ?-Synuclein in prodromal and early Parkinson's disease.

ABSTRACT: BACKGROUND:Aggregation of ?-synuclein is central to the pathophysiology of PD. Biomarkers related to ?-synuclein may be informative for PD diagnosis/progression. OBJECTIVES:To analyze ?-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative. METHODS:Over up to 36-month follow-up, CSF total ?-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were assessed. RESULTS:The inception cohort included PD (n = 376; age [mean {standard deviation} years]: 61.7 [9.62]), healthy controls (n = 173; age, 60.9 [11.3]), hyposmics (n = 16; age, 68.3 [6.15]), and idiopathic rapid eye movement sleep behavior disorder (n = 32; age, 69.3 [4.83]). Baseline CSF ?-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal ?-synuclein decreased significantly in PD at 24 and 36 months, did not change in prodromal PD over 12 months, and trended toward an increase in healthy controls. The decrease in PD was not shown when CSF samples with high hemoglobin concentration were removed from the analysis. CSF ?-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan. CONCLUSIONS:CSF ?-synuclein decreases early in the disease, preceding motor PD. CSF ?-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF ?-synuclein may be an indirect index of changes in the balance between ?-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to ?-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. © 2019 International Parkinson and Movement Disorder Society.

SUBMITTER: Mollenhauer B

PROVIDER: S-EPMC7098385 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson's disease.

Mollenhauer Brit B Caspell-Garcia Chelsea J CJ Coffey Christopher S CS Taylor Peggy P Singleton Andy A Shaw Leslie M LM Trojanowski John Q JQ Frasier Mark M Simuni Tanya T Iranzo Alex A Oertel Wolfgang W Siderowf Andrew A Weintraub Daniel D Seibyl John J Toga Arthur W AW Tanner Caroline M CM Kieburtz Karl K Chahine Lana M LM Marek Kenneth K Galasko Douglas D

Movement disorders : official journal of the Movement Disorder Society 20190730 9

<h4>Background</h4>Aggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression.<h4>Objectives</h4>To analyze α-synuclein in CSF in drug-naïve PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative.<h4>Methods</h4>Over up to 36-month follow-up, CSF total α-synuclein and its association with MDS-UPDRS motor scores, cognitive assessments, and dopamine transporter imaging were ...[more]

PMID: 31361367

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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:BackgroundPD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α-synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α-synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers.ObjectiveTo cross-validate two α-synuclein seeding aggregation assays developed to detect pathogenic oligomeric α-synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort.MethodsCSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α-synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real-time quaking-induced conversion (Green lab). Results were analyzed by an independent statistician.ResultsMeasuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real-time quaking-induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false-positive and -negative subjects were not different from true-negative and -positive subjects, respectively.ConclusionsThese α-synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Dataset Information

Longitudinal analyses of cerebrospinal fluid ?-Synuclein in prodromal and early Parkinson's disease.

Publications

Longitudinal analyses of cerebrospinal fluid α-Synuclein in prodromal and early Parkinson's disease.

Similar Datasets

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