Cerebrospinal fluid and venous biomarkers of shunt-responsive idiopathic normal pressure hydrocephalus: a systematic review and meta-analysis

Abstract

Background: Idiopathic normal pressure hydrocephalus (iNPH) is a neurodegenerative disease and dementia subtype involving disturbed cerebrospinal fluid (CSF) homeostasis. Patients with iNPH may improve clinically following CSF diversion through shunt surgery, but it remains a challenge to predict which patients respond to shunting. It has been proposed that CSF and blood biomarkers may be used to predict shunt response in iNPH.

Objective: To conduct a systematic review and meta-analysis to identify which CSF and venous biomarkers predict shunt-responsive iNPH most accurately.

Methods: Original studies that investigate the use of CSF and venous biomarkers to predict shunt response were searched using the following databases: Embase, MEDLINE, Scopus, PubMed, Google Scholar, and JSTOR. Included studies were assessed using the ROBINS-I tool, and eligible studies were evaluated utilising univariate meta-analyses.

Results: The study included 13 studies; seven addressed lumbar CSF levels of amyloid-β 1-42, nine studies CSF levels of Total-Tau, six studies CSF levels of Phosphorylated-Tau, and seven studies miscellaneous biomarkers, proteomics, and genotyping. A meta-analysis of six eligible studies conducted for amyloid-β 1-42, Total-Tau, and Phosphorylated-Tau demonstrated significantly increased lumbar CSF Phosphorylated-Tau (- 0.55 SMD, p = 0.04) and Total-Tau (- 0.50 SMD, p = 0.02) in shunt-non-responsive iNPH, though no differences were seen between shunt responders and non-responders for amyloid-β 1-42 (- 0.26 SMD, p = 0.55) or the other included biomarkers.

Conclusion: This meta-analysis found that lumbar CSF levels of Phosphorylated-Tau and Total-Tau are significantly increased in shunt non-responsive iNPH compared to shunt-responsive iNPH. The other biomarkers, including amyloid-β 1-42, did not significantly differentiate shunt-responsive from shunt-non-responsive iNPH. More studies on the Tau proteins examining sensitivity and specificity at different cut-off levels are needed for a robust analysis of the diagnostic efficiency of the Tau proteins.

Keywords: Biomarker; Diagnosis; Normal pressure hydrocephalus; Predict; Shunt response; Tau; iNPH.

© 2022. The Author(s).

Figures

Fig. 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart outlining the study selection process

Fig. 2

A risk of bias summary plot for non-randomised studies with bar chart of the distribution of risk-of-bias judgements for all included studies (n = 13) [1, 4, 15, 33, 39, 51, 52, 58, 60, 65, 70, 73, 74] across the domains of the ROBINS-I tool, shown in percentages (%) is shown. In the bottom, an overall risk of bias, which represents the collated risk-of-bias judgements for all domains, is depicted

Fig. 3

A A funnel plot is shown, which plots every study included in the meta-analysis (n = 14; 6 original studies but used and counted multiple times due to reporting on multiple biomarkers) [4, 33, 51, 70, 73, 74], particularly their observed effect sizes (standard mean difference) on the x-axis against a measure of their standard error on the y-axis. B An Egger’s asymmetry test funnel plot of all data points included in the meta-analysis (n = 14; 6 original studies but used and counted multiple times due to reporting on multiple biomarkers indicating presence and degree of publication bias is shown). p-value < 0.05 is deemed significant and implicates publication bias. Egger’s asymmetry test yielded p = 0.0989, calculated running an Egger’s regression (see Egger’s regression line) on the collated logDOR and standard errors of all data used in the meta-analysis (n = 14)

Fig. 4

A forest plot indicating and visualising the effect size in standard mean difference (SMD) of amyloid-β 1–42 levels in lumbar CSF samples of shunt responder (S-R) versus shunt non-responder (S-NR) iNPH patients is shown (n = 4 studies) [4, 33, 51, 74]. The size of the grey square of the SMD visual correlates to study sample size, and the straight line indicated the confidence interval. The diamond at the bottom indicates the overall pooled effect. The red bar below it indicates the prediction interval. Heterogeneity is indicated by the chi-squared statistic (I2) with associated p-value. The 95% confidence intervals (CI) are shown in squared bracket ([]). Furthermore, for every study, the following are displayed: author, total number of S-R and their respective mean level and standard deviation (SD) of amyloid-β 1–42 lumbar CSF levels, as well as the respective values for S-NR, weighting of each study in percentage (%). There was no significant difference in amyloid-β 1–42 between S-R and S-NR groups

Fig. 5

A forest plot indicating and visualising the effect size in standard mean difference (SMD) of Phosphorylated-Tau (P-Tau) levels in lumbar CSF samples of shunt responder (S-R) versus shunt non-responder (S-NR) iNPH patients is shown (n = 4 studies) [4, 33, 51, 74]. The size of the grey square of the SMD visual correlates to study sample size, and the straight line indicated the confidence interval. The diamond at the bottom indicates the overall pooled effect. The red bar below it indicates the prediction interval. Heterogeneity is indicated by the chi-squared statistic (I2) with associated p-value. The 95% confidence intervals (CI) are shown in squared bracket ([]). Furthermore, for every study, the following are displayed: author, total number of S-R and their respective mean level and standard deviation (SD) of P-Tau lumbar CSF levels, as well as the respective values for S-NR, weighting of each study in percentage (%). There was a significantly higher level of P-Tau in the S-NR group compared to the S-R group

Fig. 6

A forest plot indicating and visualising the effect size in standard mean difference (SMD) of Total-Tau (T-Tau) levels in lumbar (n = 5) [4, 33, 51, 73, 74] and ventricular (n = 1, Tarnaris et al. (2011) [70] samples of shunt responder (S-R) versus shunt non-responder (S-NR) iNPH patients is shown (n = 6 studies) [4, 33, 51, 70, 73, 74]. The size of the grey square of the SMD visual correlates to study sample size, and the straight line indicated the confidence interval. The diamond at the bottom indicates the overall pooled effect. The red bar below it indicates the prediction interval. Heterogeneity is indicated by the chi-squared statistic (I2) with associated p-value. The 95% confidence intervals (CI) are shown in squared bracket ([]). Furthermore, for every study, the following are displayed: author, total number of S-R, and their respective mean level and standard deviation (SD) of T-Tau lumbar CSF levels, as well as the respective values for S-NR, weighting of each study in percentage. There was a significantly higher level of T-Tau in the S-NR group compared to the S-R group

Fig. 7

An albatross plot indicating and visualising the effect size as standard mean difference (SMD) of neurofilament light (NFL), sulfatide, and Total-Tau (T-Tau)/amyloid-β 1–42 (aβ 1–42) ratio levels in lumbar CSF samples of shunt responder (S-R) versus shunt non-responder (S-NR) iNPH patients is shown, relative to p-value on the x-axis and the sample size on the y-axis (n = 4 studies). Three differently drawn lines indicate different SMD levels as outlined in the box. Each biomarker has its own-coloured dot as shown in the box. Each dot represents a single study for the respective biomarker. Studies included for NFL: Ågren-Wilsson et al. (2007) [4], Tullberg et al. (2008) [73]. Studies included for Sulfatide: Ågren-Wilsson et al. (2007) [4], Tullberg et al. (2008) [73]. Studies included for T-Tau/ amyloid-β 1–42: Craven et al. (2017) [15], Hong et al. (2018) [33]. All markers are increased in the S-R group compared to S-NR group, but the difference is not statistically significant