Objectives Parkinson’s disease (PD) patients frequently develop mild cognitive impairment (PD-MCI) and may progress to Parkinson’s disease dementia (PDD). Despite progress in understanding PD pathophysiology, reliable blood-based biomarkers for early detection and monitoring of cognitive decline remain lacking. This study aims to systematically evaluate and compare blood-based protein biomarkers for cognitive impairment in PD through a network meta-analysis (NMA). Methods A systematic search was conducted across PubMed, Embase, Web of Science, Scopus, and the Cochrane Library from database inception to January 23, 2025, to identify studies investigating blood protein biomarkers for cognitive impairment in PD patients. Studies comparing biomarker levels between PD patients with cognitive impairment (PD-CI) and those with normal cognition (PD-NC) were included. Two independent reviewers extracted data, and risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). A frequentist NMA was performed using Stata 15.0 with a random-effects model to estimate standardized mean differences (SMD) and 95% confidence intervals (CI). Results A total of 47 studies were included, encompassing biomarkers from five functional categories: metabolic function, neuronal function, inflammatory and immune functions, blood and vascular functions, and others. Key findings demonstrated significant alterations in several biomarkers in PD-CI compared with PD-NC. Cystatin C (Cys C) levels were significantly elevated in PD-CI (SMD = 0.81, 95% CI: 0.32, 1.30). Glial cell line-derived neurotrophic factor (GDNF) levels were significantly reduced in PD-CI (SMD = −1.06, 95% CI: −1.71, −0.41). Neurofilament light chain (NfL) levels were significantly elevated in PD-CI (SMD = 0.72, 95% CI: 0.39, 1.05). Interleukin-6 (IL-6) levels were significantly higher in PD-CI (SMD = 0.20, 95% CI: 0.01, 0.92). Conclusion This NMA identifies Cys C, GDNF, NfL, and IL-6 as promising blood-based biomarkers for detecting cognitive impairment in PD. These biomarkers reflect diverse pathological processes and hold potential for facilitating early diagnosis and monitoring, thereby improving patient management. Further research is warranted to validate these findings and explore their clinical utility. Systematic review registration https://www.crd.york.ac.uk/PROSPERO/view/CRD42023488801 , Identifier: CRD42023488801.
Tu et al. (Tue,) studied this question.