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

Background Aggregation of alpha-synuclein is central to the pathophysiology of PD. Biomarkers related to alpha-synuclein may be informative for PD diagnosis/progression. Objectives To analyze alpha-synuclein in CSF in drug-naive PD, healthy controls, and prodromal PD in the Parkinson's Progression Markers Initiative. Methods Over up to 36-month follow-up, CSF total alpha-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 alpha-synuclein was lower in manifest and prodromal PD versus healthy controls. Longitudinal alpha-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 alpha-synuclein changes did not correlate with longitudinal MDS-UPDRS motor scores or dopamine transporter scan. Conclusions CSF alpha-synuclein decreases early in the disease, preceding motor PD. CSF alpha-synuclein does not correlate with progression and therefore does not reflect ongoing dopaminergic neurodegeneration. Decreased CSF alpha-synuclein may be an indirect index of changes in the balance between alpha-synuclein secretion, solubility, or aggregation in the brain, reflecting its overall turnover. Additional biomarkers more directly related to alpha-synuclein pathophysiology and disease progression and other markers to be identified by, for example, proteomics and metabolomics are needed. (c) 2019 International Parkinson and Movement Disorder Society