| Summary: | Phosphorylated α-synuclein accounts for more than 90% of α-synuclein found in Lewy bodies of Parkinson’s disease (PD). We aimed to examine whether plasma Ser129-phosphorylated α-synuclein (pS129-α-synuclein) is a surrogate marker of PD progression. This prospective study enrolled 170 participants (122 PD patients, 68 controls). We measured plasma levels of total and pS129-α-synuclein using immunomagnetic reduction-based immunoassay. PD patients received evaluations of motor and cognition at baseline and at a mean follow-up interval of three years. Changes in the Movement Disorder Society revision of the Unified Parkinson’s Disease Rating Scale motor score (MDS-UPDRS part III) and Mini-Mental State Examination (MMSE) score were used to assess motor and cognition progression. Our results showed that plasma levels of total and pS129-α-synuclein were significantly higher in PD patients than controls (total: 1302.3 ± 886.6 fg/mL vs. 77.8 ± 36.6 fg/mL, <i>p</i> < 0.001; pS129-α-synuclein: 12.9 ± 8.7 fg/mL vs. 0.8 ± 0.6 fg/mL, <i>p</i> < 0.001), as was the pS129-α-synuclein/total α-synuclein ratio (2.8 ± 1.1% vs. 1.1 ± 0.6%, <i>p</i> = 0.01). Among PD patients, pS129-α-synuclein levels were higher with advanced motor stage (<i>p</i> < 0.001) and correlated with MDS-UPDRS part III scores (<i>r</i> = 0.27, 95% CI: 0.09−0.43, <i>p</i> = 0.004). However, we found no remarkable difference between PD patients with and without dementia (<i>p</i> = 0.75). After a mean follow-up of 3.5 ± 2.1 years, PD patients with baseline pS129-α-synuclein > 8.5 fg/mL were at higher risk of motor symptom progression of at least 3 points in the MDS-UPDRS part III scores than those with pS129-α-synuclein < 8.5 fg/mL (<i>p</i> = 0.03, log rank test). In conclusion, our data suggest that plasma pS129-α-synuclein levels correlate with motor severity and progression, but not cognitive decline, in patients with PD.
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