Cerebrospinal Fluid Inflammatory Cytokine Aberrations in Alzheimer's Disease, Parkinson's Disease and Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis

Abstract

It has been suggested that cytokine-mediated inflammation plays a key role for the onset and/or development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD) and Amyotrophic lateral sclerosis (ALS). However, clinical studies have yielded inconsistent results for the aberrant cytokine levels in circulation of patients with AD, PD, and ALS. Previous studies have used meta-analysis to address the inconsistent data for blood cytokine levels in the patients with AD, PD, and ALS. Here, we performed a systemic review of cerebrospinal fluid inflammatory cytokine data in patients with AD, PD and ALS, and sought to quantitatively summarize the CSF inflammatory cytokine data with a meta-analytical technique. The systematic search from Pubmed and Web of Science identified 71 articles with 2629 patients and 2049 controls for the meta-analysis. Random-effects meta-analysis demonstrated that CSF TGF-β, MCP-1, and YKL-40 levels were significantly elevated in AD patients when compared with controls. In addition, patients with PD had heightened levels of TGF-β1, IL-6, and IL-1β in CSF. Furthermore, G-CSF, IL-2, IL-15, IL-17, MCP-1, MIP-1α, TNF-α, and VEGF levels were significantly increased in patients with ALS as compared with controls. Taken together, these results not only strengthen the clinical evidence that neurodegenerative diseases are accompanied by the increased inflammatory response, but also reveal the unique inflammatory response profile in the central nervous system of patients with AD, PD and ALS. Given the robust associations between some cytokines and neurodegenerative diseases found in this meta-analysis, CSF inflammatory cytokines may be used as biomarkers for these diseases in the future.

Keywords: cerebrospinal fluid; cytokine; inflammation; meta-analysis; neurodegenerative diseases.

Figure 1

PRISMA flowchart of the literature search.

Figure 2

Studies of cerebrospinal fluid YKL-40, MCP-1 and TGF-β in Alzheimer's disease. Forest plot displaying random-effects meta-analysis results of the association between YKL-40 (A), MCP-1 (B), TGF-β (C) and Alzheimer's disease. The sizes of the squares are proportional to study weights.

Figure 3

Studies of cerebrospinal fluid IL-1β, IL-6 and TGF-β1 in Parkinson's disease. Forest plot displaying random-effects meta-analysis results of the association between IL-1β (A), IL-6 (B), TGF-β1 (C) and Parkinson's disease. The sizes of the squares are proportional to study weights.

Figure 4

Studies of cerebrospinal fluid TNF-α, VEGF and MIP-1α in Amyotrophic lateral sclerosis. Forest plot displaying random-effects meta-analysis results of the association between TNF-α (A), VEGF (B), MIP-1α (C) and Amyotrophic lateral sclerosis. The sizes of the squares are proportional to study weights.

Figure 5

Studies of cerebrospinal fluid MCP-1, IL-17, and IL-15 in Amyotrophic lateral sclerosis. Forest plot displaying random-effects meta-analysis results of the association between MCP-1 (A), IL-17 (B), IL-15 (C) and Amyotrophic lateral sclerosis. The sizes of the squares are proportional to study weights.

Figure 6

Studies of cerebrospinal fluid G-CSF and IL-2 in Amyotrophic lateral sclerosis. Forest plot displaying random-effects meta-analysis results of the association between G-CSF (A), IL-2 (B) and Amyotrophic lateral sclerosis. The sizes of the squares are proportional to study weights.