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

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. Supplementary Information The online version contains supplementary material available at 10.1007/s00701-022-05154-5.


Contents
) samples of shunt responder (S-R) versus shunt non-responder (S-NR) iNPH patients is shown (n = 5 studies). This meta-analysis for T-Tau does not include the study by Tullberg et al. (2008) [7], which is the only study on T-Tau which scored "critical" level of risk of bias on the ROBINS-I tool [5] ( Table 2).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 (I 2 ) 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.  [3] , which are the only two studies included in this subgroup analysis that explicitly included patients with neurological co-morbidities and caused a significant result in the meta-regression of the Total-Tau meta-analysis [5] (Figure B, Supplementary Material and Table 4, main article).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 (I 2 ) 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.

Rationale
3 Describe the rationale for the review in the context of existing knowledge.  Selection process 8 Specify the methods used to decide whether a study met the inclusion criteria of the review, including how many reviewers screened each record and each report retrieved, whether they worked independently, and if applicable, details of automation tools used in the process.
Data collection process 9 Specify the methods used to collect data from reports, including how many reviewers collected data from each report, whether they worked independently, any processes for obtaining or confirming data from study investigators, and if applicable, details of automation tools used in the process.

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Data items 10a List and define all outcomes for which data were sought. Specify whether all results that were compatible with each outcome domain in each study were sought (e.g. for all measures, time points, analyses), and if not, the methods used to decide which results to collect. Page 6. 10b List and define all other variables for which data were sought (e.g. participant and intervention characteristics, funding sources). Describe any assumptions made about any missing or unclear information.

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Study risk of bias assessment 11 Specify the methods used to assess risk of bias in the included studies, including details of the tool(s) used, how many reviewers assessed each study and whether they worked independently, and if applicable, details of automation tools used in the process.

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Effect measures 12 Specify for each outcome the effect measure(s) (e.g. risk ratio, mean difference) used in the synthesis or presentation of results.

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Synthesis methods 13a Describe the processes used to decide which studies were eligible for each synthesis (e.g. tabulating the study intervention characteristics and comparing against the planned groups for each synthesis (item #5)).
13b Describe any methods required to prepare the data for presentation or synthesis, such as handling of Page 6.

Section and Topic Item # Checklist item
Location where item is reported missing summary statistics, or data conversions.
13c Describe any methods used to tabulate or visually display results of individual studies and syntheses. Page 6. 13d Describe any methods used to synthesize results and provide a rationale for the choice(s). If meta-analysis was performed, describe the model(s), method(s) to identify the presence and extent of statistical heterogeneity, and software package(s) used.
13e Describe any methods used to explore possible causes of heterogeneity among study results (e.g. subgroup analysis, meta-regression).
13f Describe any sensitivity analyses conducted to assess robustness of the synthesized results. Page 7-8.
Reporting bias assessment 14 Describe any methods used to assess risk of bias due to missing results in a synthesis (arising from reporting biases).

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Certainty assessment 15 Describe any methods used to assess certainty (or confidence) in the body of evidence for an outcome. Page 6.

Study selection
16a Describe the results of the search and selection process, from the number of records identified in the search to the number of studies included in the review, ideally using a flow diagram. 16b Cite studies that might appear to meet the inclusion criteria, but which were excluded, and explain why they were excluded.  Figure 4; page 38. Figure 5, page 39. Figure 6; page 40. Figure 7; page 41.
Results of syntheses 20a For each synthesis, briefly summarise the characteristics and risk of bias among contributing studies. Page 13-14.
20b Present results of all statistical syntheses conducted. If meta-analysis was done, present for each the summary estimate and its precision (e.g. confidence/credible interval) and measures of statistical heterogeneity. If comparing groups, describe the direction of the effect.
20c Present results of all investigations of possible causes of heterogeneity among study results. Figure 3; page 37.
20d Present results of all sensitivity analyses conducted to assess the robustness of the synthesized results. Pages 13-14. Tables 4-5; pages 33-34.

OTHER INFORMATION
Registration and protocol 24a Provide registration information for the review, including register name and registration number, or state that the review was not registered. Page 5.
24b Indicate where the review protocol can be accessed, or state that a protocol was not prepared. Page 5. 24c Describe and explain any amendments to information provided at registration or in the protocol. N/A Support 25 Describe sources of financial or non-financial support for the review, and the role of the funders or sponsors in the review.

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Competing interests 26 Declare any competing interests of review authors. Page 1.
Availability of data, code and other materials 27 Report which of the following are publicly available and where they can be found: template data collection forms; data extracted from included studies; data used for all analyses; analytic code; any other materials used in the review.