A meta-analysis of the diagnostic utility of biomarkers in cerebrospinal fluid in Parkinson's disease

Abstract

Biomarkers play important roles in the diagnosis and differential diagnosis of Parkinson's disease (PD). Thus, we carried out a systematic review and meta-analysis evaluating the diagnostic utility of cerebrospinal fluid (CSF) biomarkers to distinguish PD from atypical parkinsonian syndromes (APSs) and controls. Data for PD and APS and controls were extracted from 123 studies that reported the concentration of CSF biomarkers. Comparisons were presented using pooled Hedges' g. Sources of heterogeneity were evaluated using meta-regression, and subgroup and sensitivity analyses. We found that compared with controls, PD patients had lower levels of amyloid beta 1-42, phosphorylated tau, total tau, total α-synuclein, Zn, DJ-1, and YKL-40, and higher levels of oligomeric and phosphorylated α-synuclein. Moreover, lower CSF levels of neurofilament light chain, t-tau, YKL-40, and C-reactive protein were found in PD patients compared to those with multiple system atrophy. PD patients also had lower levels of NFL and higher levels of Aβ42 compared with patients with progressive supranuclear palsy. Reduced levels of p-tau and t-tau and higher Aβ42 levels were found in PD patients compared with patients with dementia with Lewy bodies. Finally, reduced NFL levels were found in patients with PD compared with patients with cortical basal degeneration. Therefore, we believe that the combinations of t-α-syn, Aβ42, and NFL could be promising biomarkers for the differential diagnosis of PD and APSs.

Fig. 1. Flow chart of the systematic article selection strategy.

From 19326 studies from Pubmed, and 21319 studies from Science, Cochrane and Embase identified from the search strategy, a total of 123 articles were included for review. The boxes indicate exclusions of articles during each of the following screening stages: duplicate recoeds, unrelated recos and others. Reasons for exclusion are shown inside the right boxes. The box at bottom indicates inclusion articles.

Fig. 2. The number of studies in the meta-analysis for PD versus the parkinsonism and control groups.

a The number of included studies for the PD versus parkinsonism groups. The number of studies included for the indicated biomarkers comparing PD patients to those with MSA, PSP, DLB, or CBD is illustrated. b The number of included studies for the PD versus control groups. The number of studies included for the indicated biomarkers comparing PD patients to the control group or the combined HC and OND groups is illustrated. PD Parkinson’s disease, PSP progressive supranuclear palsy, MSA multiple system atrophy, DLB dementia with Lewy bodies, CBD cortico-basal degeneration, HC healthy control, OND other neurodegenerative diseases, Aβ42 the 42-amino-acid form of Aβ, p-tau phosphorylated tau, t-tau total tau, NFL neurofilament light-chain protein, α-syn α-synuclein, IL-6 interleukin-6, CRP C-reactive protein, CHI3L1 YKL-40, chitinase-3-like protein 1, Cu copper, Mn manganese, Fe iron, Zn zinc.

Fig. 3. Meta-analysis for CSF biomarker performance measured with the effect size (ES) and 95% confidence interval (CI) for PD versus control or parkinsonism patients.

a The biomarkers illustrated in blue and marked as 1 were significantly different between PD patients and HC. The biomarkers illustrated in green and marked as 2 were significantly different between PD and OND patients. A significant difference was identified between the PD patients and those in the OND and HC groups combined for the orange-labeled biomarkers marked as 3. b The biomarkers illustrated in blue were significantly different between PD and MSA patients. The biomarkers illustrated in green were significantly different between PD and PSP patients. A significant difference was observed between the PD and DLB patients for the orange-labeled biomarkers. The biomarker marked pink was significantly different between the PD and CBD patients. PD Parkinson’s disease, OND other neurodegenerative diseases, HC healthy control, MSA multiple system atrophy, DLB dementia with Lewy bodies, PSP progressive supranuclear palsy, CBD cortico-basal degeneration, α-syn α-synuclein, Aβ42 the 42-amino-acid form of Aβ, t-tau total tau, p-tau phosphorylated tau, NFL neurofilament light-chain protein, YKL-40, CHI3L1 chitinase-3-like protein 1.

Fig. 4. SROC with prediction value for α-syn and NFL in two Groups.

a SROC with prediction value for PD and control group; b SROC with prediction value for PD and MSA. SROC summary receiver operating characteristic curve, PD Parkinson’s disease, MSA multiple system atrophy, α-syn α-synuclein, NFL neurofilament light-chain protein.