J Clin Neurol.  2019 Oct;15(4):488-495. 10.3988/jcn.2019.15.4.488.

Combined Assessment of Serum Alpha-Synuclein and Rab35 is a Better Biomarker for Parkinson's Disease

• Wang HL
• Lu CS
• Yeh TH
• Shen YM
• Weng YH
• Huang YZ
• Chen RS
• Liu YC
• Cheng YC
• Chang HC
• Chen YL
• Chen YJ
• Lin YW
• Hsu CC
• Lin HL
• Chiu CH
• Chiu CC

• KMID: 2467758
• DOI: http://doi.org/10.3988/jcn.2019.15.4.488

Abstract

BACKGROUND AND PURPOSE
It is essential to develop a reliable predictive serum biomarker for Parkinson's disease (PD). The accumulation of alpha-synuclein (αSyn) and up-regulated expression of Rab35 participate in the etiology of PD. The purpose of this investigation was to determine whether the combined assessment of serum αSyn and Rab35 is a useful predictive biomarker for PD.
METHODS
Serum levels of αSyn or Rab35 were determined in serum samples from 59 sporadic PD patients, 19 progressive supranuclear palsy (PSP) patients, 20 multiple system atrophy (MSA) patients, and 60 normal controls (NC). Receiver operating characteristics (ROC) curves were calculated to determine the diagnostic accuracy of αSyn or/and Rab35 in discriminating PD patients from NC or atypical parkinsonian patients.
RESULTS
The levels of αSyn and Rab35 were increased in PD patients. The serum level of Rab35 was positively correlated with that of αSyn in PD patients. Compared to analyzing αSyn or Rab35 alone, the combined analysis of αSyn and Rab35 produced a larger area under the ROC curve and performed better in discriminating PD patients from NC, MSA patients, or PSP patients. When age was dichotomized at 55, 60, 65, or 70 years, the combined assessment of αSyn and Rab35 for classifying PD was better in the group below the cutoff age than in the group above the cutoff age.
CONCLUSIONS
Combined assessment of serum αSyn and Rab35 is a better biomarker for discriminating PD patients from NC or atypical parkinsonian patients, and is a useful predictive biomarker for younger sporadic PD patients.

Keyword

Parkinson's disease; serum; biomarker; alpha-synuclein; Rab35

MeSH Terms

alpha-Synuclein*
Humans
Multiple System Atrophy
Parkinson Disease*
ROC Curve
Supranuclear Palsy, Progressive
alpha-Synuclein

Figure

• 

  Fig. 1 The serum levels of αSyn and Rab35 are elevated in PD patients. The ultrasensitive IMR immunoassay and ELISA were used to analyze the levels of αSyn and Rab35 in serum samples, respectively, which were higher in PD patients than in NC, MSA patients, and PSP patients (A and B). Scatter plot of natural-logarithm values of the serum αSyn and Rab35 levels. The fitted regression line shows that there was a positive correlation between these levels (r=0.357, p=0.0055) in PD patients (C). Compared to age-matched controls, the serum levels of αSyn and Rab35 were not significantly altered in DIP patients (D and E). *p<0.001 compared with NC. αSyn: alpha-synuclein, DIP: drug-induced parkinsonism, IMR: immunomagnetic reduction, Ln: natural logarithm, MSA: multiple system atrophy, NC: normal controls, PD: Parkinson's disease, PSP: progressive supranuclear palsy.

• 

  Fig. 2 The levels of serum αSyn and Rab35 are increased in PD mice models. Compared with control mice, the serum levels of αSyn and Rab35 were up-regulated in mice treated with MPTP for either 1 or 2 weeks (A and B). Scatter plot of natural-logarithm values of the serum αSyn and Rab35 levels. The fitted regression line shows that there was a positive correlation between these levels in MPTP-treated mice (r=0.671, p=0.0011) (C). The levels of serum αSyn and Rab35 were increased in 6M and 9M (D331Y) PLA2G6 knockin mice compared to 6M and 9M wild-type mice (D and E). Scatter plot with a fitted regression line demonstrating a positive correlation between these levels in (D331Y) PLA2G6 knockin mice (r=0.7438, p=0.0271) (F). *p<0.05, †p<0.01 compared with NC. 6M: six-month-old, 9M: nine-month-old, αSyn: alpha-synuclein, Ln: natural logarithm, MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, NC: normal controls, PD: Parkinson's disease, WT: wild-type.

• 

  Fig. 3 The combined assessment of serum αSyn and Rab35 levels has a better accuracy in differentiating PD from NC and other parkinsonian disorders. ROC curves of serum αSyn (black line), serum Rab35 (red line), and combined assessment of serum αSyn and Rab35 (αSyn+Rab35, blue line) were examined in serum samples from NC and PD, MSA, and PSP patients. The AUCs for serum αSyn, serum Rab35, and the combined assessment of serum αSyn and Rab35 when comparing PD patients with NC were 0.8175 (95% CI=0.7429–0.8921), 0.8314 (95% CI=0.7569–0.9058), and 0.8794 (95% CI=0.8161–0.9427), respectively (A). The AUCs for serum αSyn, serum Rab35, and the combined assessment of serum αSyn and Rab35 when comparing PD and MSA patients were 0.8890 (95% CI=0.8191–0.9589), 0.7907 (95% CI=0.6870–0.8944), and 0.9110 (95% CI=0.8490–0.9731), respectively (B). The AUCs for serum αSyn, serum Rab35, and the combined assessment of serum αSyn and Rab35 when comparing PD and PSP patients were 0.8305 (95% CI=0.7362–0.9248), 0.8421 (95% CI=0.7548–0.9294), and 0.8983 (95% CI=0.8312–0.9655), respectively (C). αSyn: alpha-synuclein, AUC: area under the ROC curve, IMR: immunomagnetic reduction, MSA: multiple system atrophy, NC: normal controls, PD: Parkinson's disease, PSP: progressive supranuclear palsy, ROC: receiver operating characteristics.

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