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, and Clinical Dementia Rating scores. In addition, 26 age- and sex-matched healthy subjects were included as the healthy control group. Results demonstrated that serum
GDNF levels were significantly higher in the
Parkinson's disease with normal cognitive function group than in the other 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 in patients 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 cognitive scale scores. Neither α-pro-
GDNF nor β-pro-
GDNF was risk factors for
cognitive impairment in
Parkinson's disease. A receiver operating characteristic curve of
GDNF was generated to predict cognitive function in
Parkinson's disease (area under the curve = 0.859). This result indicates 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's disease. 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.