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. 2021 Jun 16;3(1):e000143.
doi: 10.1136/bmjno-2021-000143. eCollection 2021.

Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis

Jasmini Alagaratnam  1   2 , Sophia von Widekind  3 , Davide De Francesco  4 , Jonathan Underwood  1   5 , Paul Edison  6 , Alan Winston  1   2 , Henrik Zetterberg  7   8 , Sarah Fidler  1   2
Affiliations

Correlation between CSF and blood neurofilament light chain protein: a systematic review and meta-analysis

Jasmini Alagaratnam et al. BMJ Neurol Open. .

Abstract

Objective: To assess the overall pooled correlation coefficient estimate between cerebrospinal fluid (CSF) and blood neurofilament light (NfL) protein.

Methods: We searched Medline, Embase and Web of Science for published articles, from their inception to 9 July 2019, according to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies reporting the correlation between CSF and blood NfL in humans were included. We conducted a random-effects meta-analysis to calculate the overall pooled correlation coefficient estimate, accounting for correlation technique and assay used. Heterogeneity was assessed using the I2 statistic test. In sensitivity analyses, we calculated the pooled correlation coefficient estimate according to blood NfL assay: single-molecule array digital immunoassay (Simoa), electrochemiluminescence (ECL) assay or ELISA.

Results: Data were extracted from 36 articles, including 3961 paired CSF and blood NfL samples. Overall, 26/36 studies measured blood NfL using Simoa, 8/36 ECL, 1/36 ELISA and 1 study reported all three assay results. The overall meta-analysis demonstrated that the pooled correlation coefficient estimate for CSF and blood NfL was r=0.72. Heterogeneity was significant: I2=83%, p<0.01. In sensitivity analyses, the pooled correlation coefficient was similar for studies measuring blood NfL using Simoa and ECL (r=0.69 and r=0.68, respectively) but weaker for ELISA (r=0.35).

Conclusion: Moderate correlations are demonstrated between CSF and blood NfL, especially when blood NfL was measured using Simoa and ECL. Given its high analytical sensitivity, Simoa is the preferred assay for measuring NfL, especially at low or physiological concentrations, and this meta-analysis supports its use as the current most advanced surrogate measure of CSF NfL.

Prospero registration number: CRD42019140469.

Keywords: CSF; CSF dynamics; clinical neurology; neurobiology; systematic reviews.

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Conflict of interest statement

Competing interests: JA has received financial support to attend scientific conferences from MSD and Gilead Sciences. JU has received honoraria for preparation of educational materials and has served on an advisory board for Gilead Sciences. PE has received grants from the Medical Research Council, Alzheimer’s Research UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Association, Alzheimer’s Society, Novo Nordisk®, Life Molecular Imaging, GE Healthcare, Eli Lilly and Company, Novartis International AG and NIHR Imperial Biomedical Research Centre (BRC). PE was also a consultant to Pfizer, is now a consultant to Novo Nordisk, and serves on the advisory board for Novo Nordisk. PE has received consultancy and speaker fees from Piramal Life Sciences, Pfizer and Novo Nordisk. AW has received honoraria or research grants on behalf of Imperial College London or been a consultant or investigator in clinical trials sponsored by Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, Roche and ViiV Healthcare. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed and CogRx, has given lectures in symposia sponsored by Fujirebio, Alzecure and Biogen, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, a GU Ventures-based platform company at the University of Gothenburg (outside submitted work). SF received funding and research grants from the National Institutes of Health (NIH), Bill & Melinda Gates Foundation (BMGF) and Medical Research Council (MRC).

Figures

Figure 1
Figure 1
PRISMA flowchart of study selection. Search strategies generated 1058 articles using the search terms as detailed in the Methods section. Thirty-six studies were included in the meta-analysis of pooled correlation coefficient estimate. CSF, cerebrospinal fluid; NfL, neurofilament light chain protein; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-analyses.
Figure 2
Figure 2
(A) Forest plot of the overall pooled correlation coefficients for CSF and blood neurofilament light protein. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from all eligible studies. (B) Funnel plot with 95% CIs. The rank correlation test of funnel plot asymmetry (Fisher’s Z-transformed correlation coefficient of the individual studies (horizontal axis) against the standard error (vertical axis)) shows no asymmetry (p=0.53) and no obvious publication bias. CSF, cerebrospinal fluid
Figure 3
Figure 3
(A) Forest plot of the pooled correlation coefficients for CSF and blood neurofilament light protein, in studies that used the Simoa and ECL assays only to measure blood NfL concentration. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies that used the Simoa digital immunoassay to measure both CSF and blood NfL concentrations. (B) Forest plot of the pooled correlation coefficients for studies using Simoa to measure blood NfL. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies that used the Simoa digital immunoassay to measure blood NfL. (C) Forest plot of the pooled correlation coefficients for studies using the ECL assay to measure blood NfL. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies that used the electrochemiluminescence assay to measure blood NfL. (D) Forest plot of the pooled correlation coefficients for studies using the ELISA assay to measure blood NfL. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies that used the ELISA to measure blood NfL. (E) Forest plot of the pooled correlation coefficients for CSF and blood neurofilament light protein for studies using the Simoa assay to measure both CSF and blood NfL concentrations. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies that used the Simoa digital immunoassay to measure both CSF and blood NfL concentrations. (F) Forest plot of the pooled correlation coefficients for studies using the ELISA or ECL assays to measure CSF NfL and Simoa assay to measure blood NfL. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies that used the ELISA or ECL assays to measure CSF NfL concentrations and the Simoa digital immunoassay to measure blood NfL concentrations.(G) Forest plot of the pooled correlation coefficients for studies that measured serum NfL. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies which measured serum NfL. (H) Forest plot of the pooled correlation coefficients for studies that measured plasma NfL. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies which measured plasma NfL. CSF, cerebrospinal fluid; NfL, neurofilament light chain protein; ECL, electrochemiluminescence.
Figure 4
Figure 4
(A) Forest plot of the pooled correlation coefficients for studies involving CNS-only disorders. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies including participants with neurological disorders that only affect the central nervous system only. (B) Forest plot of the pooled correlation coefficients for studies involving CNS and PNS disorders. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies including participants with neurological disorders that affect both the CNS and PNS. (C) Forest plot of the pooled correlation coefficients from control participants. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from control participants. (D) Forest plot of the pooled correlation coefficients from studies reporting Spearman’s rank correlation coefficient. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies reporting Spearman’s rank correlation coefficient. (E) Forest plot of the pooled correlation coefficients from studies reporting Pearson’s correlation coefficient. Forest plot of the summary correlation coefficients with corresponding 95% CIs for the correlation between CSF and blood neurofilament light protein from studies reporting Pearson’s correlation coefficient. CNS, central nervous system;CSF, cerebrospinal fluid; NfL, neurofilament light chain protein; PNS, peripheral nervous system.
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