Abstract
Background: Aggregation of α-synuclein is central to the pathophysiology of PD. Biomarkers related to α-synuclein may be informative for PD diagnosis/progression. Objectives: To analyze α-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 α-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 α-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal α-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 α-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan. Conclusions: CSF α-synuclein decreases early in the disease, preceding motor PD. CSF α-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF α-synuclein may be an indirect index of changes in the balance between α-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to α-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1354-1364 |
| Number of pages | 11 |
| Journal | Movement Disorders |
| Volume | 34 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2019 |
Funding
agencies: PPMI is sponsored by the Michael J. Fox Foundation for Parkinson's Research (MJFF) and is co-funded by MJFF, AbbVie, Avid Radiopharmaceuticals, Biogen Idec, Bristol-Myers Squibb, Covance, Eli Lilly & Co., F. Hoffman-La Roche, Ltd., GE Healthcare, Genentech, GlaxoSmithKline, Lundbeck, Merck, MesoScale, Piramal, Pfizer, and UCB. The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Relevant conflicts of interest/financial disclosures: Brit Mollenhauer, Chelsea Caspell-Garcia, Christopher Coffey, Karl Kieburtz, Douglas Galasko, Ken Marek, Andrew Siderowf, and Tatyana Simuni received funding from The Michael J. Fox Foundation for Parkinson's Research. Daniel Weintraub receives salary support for serving on the Steering Committee for the PPMI study. Full financial disclosures and author roles may be found in the online version of this article.We thank the Michael J. Fox Foundation, all of our PPMI colleagues, and the many individuals who have given their time and of themselves to be participants in this study. This study is funded by The Michael J. Fox Foundation for Parkinson's Research and funding partners including Abbott, Biogen Idec, F. Hoffman-La Roche Ltd., GE Healthcare, Genentech, Pfizer Inc., Meso Scale Diagnostics and Life Molecular Imaging (formerly Piramal). J.Q.T. is supported, in part, by P50 NS053488 University of Pennsylvania. B.M., D.G., and K.M. had full access to the clinical primary data and take responsibility for the integrity of the data and the accuracy of the data analysis.
Keywords
- Parkinson's disease/parkinsonism
- cohort studies
- outcome research
ASJC Scopus subject areas
- Neurology
- Clinical Neurology