Correlation Between CSF and Blood Neurofilament Light Chain Protein: a Systematic Review and Meta-analysis

Overview

Journal BMJ Neurol Open

Specialty Neurology

Date 2021 Jul 5

PMID 34223154

Citations 40

Authors

Jasmini Alagaratnam

Sophia Von Widekind

Davide De Francesco

Jonathan Underwood

Paul Edison

Alan Winston

Henrik Zetterberg

Sarah Fidler

Affiliations

Soon will be listed here.

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 I 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: I=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.

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References

Lewczuk P, Ermann N, Andreasson U, Schultheis C, Podhorna J, Spitzer P . Plasma neurofilament light as a potential biomarker of neurodegeneration in Alzheimer's disease. Alzheimers Res Ther. 2018; 10(1):71. PMC: 6064615. DOI: 10.1186/s13195-018-0404-9. View

Steinacker P, Anderl-Straub S, Diehl-Schmid J, Semler E, Uttner I, von Arnim C . Serum neurofilament light chain in behavioral variant frontotemporal dementia. Neurology. 2018; 91(15):e1390-e1401. DOI: 10.1212/WNL.0000000000006318. View

Chan Y . Biostatistics 104: correlational analysis. Singapore Med J. 2004; 44(12):614-9. View

Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M . Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015; 350:g7647. DOI: 10.1136/bmj.g7647. View

Meregalli C, Fumagalli G, Alberti P, Canta A, Chiorazzi A, Monza L . Neurofilament light chain: a specific serum biomarker of axonal damage severity in rat models of Chemotherapy-Induced Peripheral Neurotoxicity. Arch Toxicol. 2020; 94(7):2517-2522. DOI: 10.1007/s00204-020-02755-w. View

Fortea J, Carmona-Iragui M, Benejam B, Fernandez S, Videla L, Barroeta I . Plasma and CSF biomarkers for the diagnosis of Alzheimer's disease in adults with Down syndrome: a cross-sectional study. Lancet Neurol. 2018; 17(10):860-869. DOI: 10.1016/S1474-4422(18)30285-0. View

Olsson B, Portelius E, Cullen N, Sandelius A, Zetterberg H, Andreasson U . Association of Cerebrospinal Fluid Neurofilament Light Protein Levels With Cognition in Patients With Dementia, Motor Neuron Disease, and Movement Disorders. JAMA Neurol. 2018; 76(3):318-325. PMC: 6440232. DOI: 10.1001/jamaneurol.2018.3746. View

Benatar M, Wuu J, Andersen P, Lombardi V, Malaspina A . Neurofilament light: A candidate biomarker of presymptomatic amyotrophic lateral sclerosis and phenoconversion. Ann Neurol. 2018; 84(1):130-139. PMC: 11348288. DOI: 10.1002/ana.25276. View

Kuhle J, Plattner K, Bestwick J, Lindberg R, Ramagopalan S, Norgren N . A comparative study of CSF neurofilament light and heavy chain protein in MS. Mult Scler. 2013; 19(12):1597-603. DOI: 10.1177/1352458513482374. View

10.

Kuhle J, Barro C, Disanto G, Mathias A, Soneson C, Bonnier G . Serum neurofilament light chain in early relapsing remitting MS is increased and correlates with CSF levels and with MRI measures of disease severity. Mult Scler. 2016; 22(12):1550-1559. DOI: 10.1177/1352458515623365. View

11.

Abdelhak A, Huss A, Kassubek J, Tumani H, Otto M . Serum GFAP as a biomarker for disease severity in multiple sclerosis. Sci Rep. 2018; 8(1):14798. PMC: 6172254. DOI: 10.1038/s41598-018-33158-8. View

12.

Mattsson N, Andreasson U, Zetterberg H, Blennow K . Association of Plasma Neurofilament Light With Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 2017; 74(5):557-566. PMC: 5822204. DOI: 10.1001/jamaneurol.2016.6117. View

13.

Korley F, Goldstick J, Mastali M, Van Eyk J, Barsan W, Meurer W . Serum NfL (Neurofilament Light Chain) Levels and Incident Stroke in Adults With Diabetes Mellitus. Stroke. 2019; 50(7):1669-1675. PMC: 6591022. DOI: 10.1161/STROKEAHA.119.024941. View

14.

OConnell G, Alder M, Webel A, Moore S . Neuro biomarker levels measured with high-sensitivity digital ELISA differ between serum and plasma. Bioanalysis. 2019; 11(22):2087-2094. PMC: 7132632. DOI: 10.4155/bio-2019-0213. View

15.

Tyrberg T, Nilsson S, Blennow K, Zetterberg H, Grahn A . Serum and cerebrospinal fluid neurofilament light chain in patients with central nervous system infections caused by varicella-zoster virus. J Neurovirol. 2020; 26(5):719-726. PMC: 7532135. DOI: 10.1007/s13365-020-00889-2. View

16.

Moher D, Liberati A, Tetzlaff J, Altman D . Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009; 6(7):e1000097. PMC: 2707599. DOI: 10.1371/journal.pmed.1000097. View

17.

Booth A, Clarke M, Dooley G, Ghersi D, Moher D, Petticrew M . The nuts and bolts of PROSPERO: an international prospective register of systematic reviews. Syst Rev. 2012; 1:2. PMC: 3348673. DOI: 10.1186/2046-4053-1-2. View

18.

Rojas J, Bang J, Lobach I, Tsai R, Rabinovici G, Miller B . CSF neurofilament light chain and phosphorylated tau 181 predict disease progression in PSP. Neurology. 2017; 90(4):e273-e281. PMC: 5798651. DOI: 10.1212/WNL.0000000000004859. View

19.

Lu C, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N . Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015; 84(22):2247-57. PMC: 4456658. DOI: 10.1212/WNL.0000000000001642. View

20.

Hansson O, Janelidze S, Hall S, Magdalinou N, Lees A, Andreasson U . Blood-based NfL: A biomarker for differential diagnosis of parkinsonian disorder. Neurology. 2017; 88(10):930-937. PMC: 5333515. DOI: 10.1212/WNL.0000000000003680. View