A systematic review and meta-analysis of inflammatory biomarkers in Parkinson's disease

Abstract

Neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD), but controversies persist. Studies reporting concentrations of blood or cerebrospinal fluid (CSF) markers for patients with PD and controls were included and extracted. Pooled Hedges'g was adopted to illustrate comparisons, and covariates were used to explore sources of heterogeneity. Finally, 152 studies were included. Increased IL-6, TNF-α, IL-1β, STNFR1, CRP, CCL2, CX3CL1, and CXCL12 levels and decreased INF-γ and IL-4 levels were noted in the PD group. In addition, increased CSF levels of IL-6, TNF-α, IL-1β, CRP and CCL2 were revealed in patients with PD compared to controls. Consequently, significantly altered levels of inflammatory markers were verified between PD group and control, suggesting that PD is accompanied by inflammatory responses in both the peripheral blood and CSF. This study was registered with PROSPERO, CRD42022349182.

Fig. 1. Flowchart of study inclusion and exclusion.

A total of 16,161 records were identified. After literature searching, selection and deduplication, 152 studies measuring peripheral blood or CSF inflammatory markers were finally included in the systematic reviews and meta-analyses.

Fig. 2. Comparative outcomes of peripheral blood and cerebrospinal fluid biomarkers in the meta-analysis.

The peripheral blood (a) and cerebrospinal fluid (b) inflammatory markers with significant effect sizes (Hedges’ g) were displayed in comparisons for PD patients versus controls. Orange spots indicate Hedges’ g of each marker, and green and pink bars indicate the number of studies included. CCL chemokine (C-C motif) ligand, CRP C-reactive protein, CX3CL CX3 chemokine ligand, CXCL chemokine (C-X-C motif) ligand, IFN Interferon, IL interleukin, MCP monocyte chemoattractant protein, NT-pro BNP N-terminal pro-B-type natriuretic peptide, PD Parkinson’s disease, SDF stromal cell-derived factor, STNFR soluble tumour necrosis factor receptor, TNF tumour necrosis factor.

Fig. 3. Comparative outcomes of peripheral blood and cerebrospinal fluid biomarkers in the systematic review.

The peripheral blood (a) and cerebrospinal fluid (b) inflammatory markers with significant effect sizes (Hedges’ g) were displayed in comparisons for PD patients versus controls. Violet spots indicate Hedges’ g of each marker, and blue and orange bars indicate the number of studies included. CCL chemokine (C-C motif) ligand, CSF macrophage-colony stimulating factor, CXCL chemokine (C-X-C motif) ligand, FGF fibroblast growth factor, GRO growth-regulated oncogene, IL interleukin, HMGB high-mobility group box, MCP monocyte chemoattractant protein, MEC mucosae-associated epithelial chemokine, MIP macrophage inflammatory protein, NGAL neutrophil gelatinase-associated lipocalin, NGF nerve growth factor, PD Parkinson’s disease, PDGFB platelet-derived growth factor-B, PTX pentraxin, PD-L programmed death-ligand, SCF stem cell factor, SDF stromal cell-derived factor, sVCAM soluble vascular cell adhesion molecule, VEGF-A vascular endothelial growth factor A.

Fig. 4. Subgroup comparative outcomes of fluid biomarkers stratified by different assay types in the meta-analysis.

Significant comparisons of peripheral blood and CSF biomarkers using ELISA (a) and multiplex cytokine (b) are shown. Inflammatory markers with significant effect sizes (Hedges’ g) were displayed in comparisons of PD patients versus controls. Violet (a) and dark green (b) spots indicate Hedges’ g of each marker, and green (a) and pink (b) bars indicate the number of studies included. Abbreviations: CRP C-reactive protein, CSF cerebrospinal fluid, CX3CL CX3 chemokine ligand, ELISA enzyme-linked immunosorbent assay; IFN interferon, IL interleukin, IL-1RA IL-1 receptor antagonist, MCP monocyte chemoattractant protein, TGF transforming growth factor, TNF tumour necrosis factor, YKL chitinase-3-like protein.

Fig. 5. The KEGG pathway enrichment analysis and PPI network construction analysis of inflammatory markers.

The KEGG pathway enrichment analysis showed that the inflammatory markers related to PD were mainly involved in cytokine–cytokine receptor interactions, human cytomegalovirus infection, rheumatoid arthritis, influenza A and the malaria pathway (a). The PPI analysis revealed that the major functions were involved in cytokine receptor binding, cytokine activity, leucocyte migration, chemokine receptor binding, myeloid leucocyte migration, cellular response to chemokine and leucocyte chemotaxis (b).