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Plasma pS129-?-Synuclein Is a Surrogate Biofluid Marker of Motor Severity and Progression in Parkinson's Disease.

ABSTRACT: Phosphorylated ?-synuclein accounts for more than 90% of ?-synuclein found in Lewy bodies of Parkinson's disease (PD). We aimed to examine whether plasma Ser129-phosphorylated ?-synuclein (pS129-?-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-?-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-?-synuclein were significantly higher in PD patients than controls (total: 1302.3 ± 886.6 fg/mL vs. 77.8 ± 36.6 fg/mL, p < 0.001; pS129-?-synuclein: 12.9 ± 8.7 fg/mL vs. 0.8 ± 0.6 fg/mL, p < 0.001), as was the pS129-?-synuclein/total ?-synuclein ratio (2.8 ± 1.1% vs. 1.1 ± 0.6%, p = 0.01). Among PD patients, pS129-?-synuclein levels were higher with advanced motor stage (p < 0.001) and correlated with MDS-UPDRS part III scores (r = 0.27, 95% CI: 0.09-0.43, p = 0.004). However, we found no remarkable difference between PD patients with and without dementia (p = 0.75). After a mean follow-up of 3.5 ± 2.1 years, PD patients with baseline pS129-?-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-?-synuclein < 8.5 fg/mL (p = 0.03, log rank test). In conclusion, our data suggest that plasma pS129-?-synuclein levels correlate with motor severity and progression, but not cognitive decline, in patients with PD.

SUBMITTER: Lin CH

PROVIDER: S-EPMC6832465 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Plasma pS129-α-Synuclein Is a Surrogate Biofluid Marker of Motor Severity and Progression in Parkinson's Disease.

Lin Chin-Hsien CH Liu Huei-Chun HC Yang Shieh-Yueh SY Yang Kai-Chien KC Wu Chau-Chung CC Chiu Ming-Jang MJ

Journal of clinical medicine 20191003 10

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 base ...[more]

PMID: 31623323

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Project description:The most established pathognomonic protein of Parkinson's disease (PD), α-synuclein, is extensively investigated for disease diagnosis and prognosis; however, investigations into whether the free form of α-synuclein in the blood functions as a PD biomarker have not been fruitful. Extracellular vesicles (EVs) secreted from cells and present in blood transport molecules are novel platforms for biomarker identification. In blood EVs, α-synuclein originates predominantly from the brain without the interference of the blood-brain barrier. The present study investigated the role of plasma EV-borne α-synuclein as a biomarker of PD. Patients with mild to moderate stages of PD (n = 116) and individuals without PD (n = 46) were recruited to serve as the PD study group and the control group, respectively. Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess EV α-synuclein levels. Conventional statistical analysis was performed using SPSS 25.0, and p < 0.05 was considered significant. Compared with controls, we observed significantly lower plasma EV α-synuclein levels in the patients with PD (PD: 56.0 ± 3.7 fg/mL vs. control: 74.5 ± 4.3 fg/mL, p = 0.009), and the significance remained after adjustment for age and sex. Plasma EV α-synuclein levels in the patients with PD did not correlate with age, disease duration, Part I and II scores of the Unified Parkinson's Disease Rating Scale (UPDRS), or the Mini-Mental State Examination scores. However, such levels were significantly correlated with UPDRS Part III score, which assesses motor dysfunction. Furthermore, the severity of akinetic-rigidity symptoms, but not tremor, was inversely associated with plasma EV α-synuclein level. Plasma EV α-synuclein was significantly different between the control and PD group and was associated with akinetic-rigidity symptom severity in patients with PD. This study corroborates the possible diagnostic and subtyping roles of plasma EV α-synuclein in patients with PD, and it further provides a basis for this protein's clinical relevance and feasibility as a PD biomarker.

Project description:BackgroundPlasma extracellular vesicle (EV) contents are promising biomarkers of Parkinson's disease (PD). The pathognomonic proteins of PD, including α-synuclein, tau, and β-amyloid, are altered in people with PD (PwP) and are associated with clinical presentation in previous cross-sectional studies. However, the dynamic changes in these plasma EV proteins in PwP and their correlation with clinical progression remain unclear.ObjectiveWe investigated the dynamic changes in plasma EV α-synuclein, tau, and β-amyloid and their correlation with/prediction of clinical progression in PwP.DesignA cohort study.MethodsIn total, 103 PwP and 37 healthy controls (HCs) completed baseline assessment and 1-year follow-up. Clinical assessments included Unified Parkinson's Disease Rating Scale (UPDRS) parts II and III, Mini-Mental State Examination (MMSE), and Montreal Cognitive Assessment (MoCA). Plasma EVs were isolated, and immunomagnetic reduction-based immunoassay was used to assess α-synuclein, tau, and β-amyloid 1-42 (Aβ1-42) levels within the EVs.ResultsCompared with HCs, significant differences were noted in the annual changes in all three EV pathognomonic proteins in PwP. Although the absolute changes in plasma EV pathognomonic proteins did not significantly correlate with clinical changes, PwP with elevated baseline plasma EV tau (upper-half) levels demonstrated significantly greater decline in motor and cognition, and increased plasma EV α-synuclein levels were associated with postural instability and the gait disturbance motor subtype. For PwP with elevated levels of all three biomarkers, clinical deterioration was significant, as indicated by UPDRS-II scores, postural instability and gait disturbance subscores of UPDRS-III, and MMSE score.ConclusionThe combination of plasma EV α-synuclein, tau, and Aβ1-42 may identify PwP with a high risk of deterioration. Our findings can elucidate the interaction between these pathognomonic proteins, and they may serve as treatment response markers and can be applied in treatment approaches for disease modification.

Dataset Information

Plasma pS129-?-Synuclein Is a Surrogate Biofluid Marker of Motor Severity and Progression in Parkinson's Disease.

Publications

Plasma pS129-α-Synuclein Is a Surrogate Biofluid Marker of Motor Severity and Progression in Parkinson's Disease.

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