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Glial cell line-derived neurotrophic factor (GDNF) plays an important role in the protection of dopaminergic neurons, but there are few reports of the relationship between GDNF and its precursors (α-pro-GDNF and β-pro-GDNF) and cognitive impairment in Parkinson’s disease. This study aimed to investigate the relationship between the serum levels of GDNF and its precursors and cognitive impairment in Parkinson’s disease, and to assess their potential as a diagnostic marker. Fifty-three primary outpatients and hospitalized patients with Parkinson’s disease (23 men and 30 women) with an average age of 66.58 years were enrolled from the Affiliated Hospital of Xuzhou Medical University of China in this case-control study. The patients were divided into the Parkinson’s disease with cognitive impairment group (n = 27) and the Parkinson’s disease with normal cognitive function group (n = 26) based on their Mini-Mental State Examination, Montreal Cognitive Assessment, andClinical Dementia Rating scores. In addition, 26 age- and sex-matched healthy subjects were included as the healthy control group. Resultsdemonstrated that serum GDNF levels were significantly higher in the Parkinson’s disease with normal cognitive function group than in theother two groups. There were no significant differences in GDNF precursor levels among the three groups. Correlation analysis revealed that serum GDNF levels, GDNF/α-pro-GDNF ratios, and GDNF/β-pro-GDNF ratios were moderately or highly correlated with the Mini-Mental State Examination, Montreal Cognitive Assessment, and Clinical Dementia Rating scores. To explore the risk factors for cognitive impairment inpatients with Parkinson’s disease, logistic regression analysis and stepwise linear regression analysis were performed. Both GDNF levels and Hoehn-Yahr stage were risk factors for cognitive impairment in Parkinson’s disease, and were the common influencing factors for cognitivescale scores. Neither α-pro-GDNF nor β-pro-GDNF was risk factors for cognitive impairment in Parkinson’s disease. A receiver operatingcharacteristic curve of GDNF was generated to predict cognitive function in Parkinson’s disease (area under the curve = 0.859). This resultindicates that the possibility that serum GDNF can correctly distinguish whether patients with Parkinson’s disease have cognitive impairment is 0.859. Together, these results suggest that serum GDNF may be an effective diagnostic marker for cognitive impairment in Parkinson’sdisease. However, α-pro-GDNF and β-pro-GDNF are not useful for predicting cognitive impairment in this disease. This study was approved by Ethics Committee of the Affiliated Hospital of Xuzhou Medical University, China (approval No. XYFY2017-KL047-01) on November 30, 2017.