Abstract
Background
Neurofilament light chain (NfL) is a neuron-specific biomarker with prognostic ability in several types of central nervous system injuries. This study investigates if plasma NfL (pNfL) is elevated early after spontaneous intracerebral hemorrhage (ICH) and whether such elevation reflects disease severity and day-30 outcome.
Methods
pNfL was quantified by single molecule array analysis in 103 reference subjects (RS) and in samples from 37 patients with ICH obtained on admission to hospital and at 24-h follow-up. The primary outcome was day-30 mortality. Clinical status on admission was evaluated by standardized scoring systems.
Results
Median pNfL among RS was 9.6 (interquartile range [IQR] 6.2) pg/mL. Upon admission, ICH patients had pNfL of 19.8 (IQR 30.7) pg/mL increasing to 35.9 (IQR 44.5) pg/mL at 24 h (all, p < 0.001). On admission, pNfL was higher among ICH non-survivors than survivors (119.2 [IQR 152.6] pg/mL vs. 15.7 [IQR 19.6] pg/mL, p < 0.01) and this difference was observed also on 24 h follow-up (195.1 [IQR 73.9] pg/mL vs. 31.3 [IQR 27.8] pg/mL, p < 0.01). The area under the receiver operating characteristic curve (ROC AUC) for discrimination of day-30 mortality was significant on admission (AUC = 0.83, 95% confidence interval [CI]: 0.56–1.0) and increased on 24-h follow-up (AUC = 0.93, 95% CI: 0.84–1.0). The odds ratio (OR) for death, by each quartile increase in pNfL was significant both on admission (OR = 4.52, 95% CI: 1.32–15.48) and after 24-h follow-up (OR = 9.52, 95% CI: 1.26–71.74).
Conclusions
PNfL is associated with day-30 mortality after spontaneous ICH when early after the ictus.
Author contributions: Conception and design of the study: CVBH, AMH, TP. Acquisition and analysis of data: CVBH, TG, SVL, NH, TP, AMH, TP. All authors drafted/revised the manuscript for its intellectual content, approved the final version, and agreed to be accountable for all aspects of the work. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: The study was funded by Laege Sofus Carl Emil Friis og Hustru Olga Doris Friis Legat; Grosserer L.F. Foghts Foundation and the AP Moller Foundation. Claus VB Hviid received a scholarship from the Health Research Fund of Central Denmark Region.
Employment or leadership: None declared.
Honorarium: None declared.
Disclosure statement: None of the authors have any conflicts of interest regarding the present paper, but have the following general conflicts of interest: Anne-Mette Hvas has received a speaker’s fee from Astellas, CSL Behring, Bayer, Bristol-Myers Squibb and Leo Pharma, and unrestricted research support from Octapharma, CSL Behring and Leo Pharma.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2003;2:43–53.10.1016/S1474-4422(03)00266-7Search in Google Scholar
2. van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol 2010;9:167–76.10.1016/S1474-4422(09)70340-0Search in Google Scholar
3. Poon MT, Fonville AF, Al-Shahi Salman R. Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2014;85:660–7.10.1136/jnnp-2013-306476Search in Google Scholar PubMed
4. Sreekrishnan A, Dearborn JL, Greer DM, Shi FD, Hwang DY, Leasure AC, et al. Intracerebral hemorrhage location and functional outcomes of patients: a systematic literature review and meta-analysis. Neurocrit Care 2016;25:384–91.10.1007/s12028-016-0276-4Search in Google Scholar PubMed
5. Hemphill 3rd JC, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2015;46:2032–60.10.1161/STR.0000000000000069Search in Google Scholar PubMed
6. Yuan A, Rao MV, Veeranna, Nixon RA. Neurofilaments at a glance. J Cell Sci 2012;125:3257–63.10.1242/jcs.104729Search in Google Scholar PubMed PubMed Central
7. Lycke JN, Karlsson JE, Andersen O, Rosengren LE. Neurofilament protein in cerebrospinal fluid: a potential marker of activity in multiple sclerosis. J Neurol Neurosurg Psychiatry 1998;64:402–4.10.1136/jnnp.64.3.402Search in Google Scholar PubMed PubMed Central
8. Scherling CS, Hall T, Berisha F, Klepac K, Karydas A, Coppola G, et al. Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann Neurol 2014;75:116–26.10.1002/ana.24052Search in Google Scholar PubMed PubMed Central
9. Shahim P, Gren M, Liman V, Andreasson U, Norgren N, Tegner Y, et al. Serum neurofilament light protein predicts clinical outcome in traumatic brain injury. Sci Rep 2016;6:36791.10.1038/srep36791Search in Google Scholar PubMed PubMed Central
10. Lu CH, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N, et al. Neurofilament light chain: a prognostic biomarker in amyotrophic lateral sclerosis. Neurology 2015;84:2247–57.10.1212/WNL.0000000000001642Search in Google Scholar PubMed PubMed Central
11. Moseby-Knappe M, Mattsson N, Nielsen N, Zetterberg H, Blennow K, Dankiewicz J, et al. Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol 2019;76:64–71.10.1001/jamaneurol.2018.3223Search in Google Scholar PubMed PubMed Central
12. De Marchis GM, Katan M, Barro C, Fladt J, Traenka C, Seiffge DJ, et al. Serum neurofilament light chain in patients with acute cerebrovascular events. Eur J Neurol 2018;25:562–8.10.1111/ene.13554Search in Google Scholar PubMed
13. Gattringer T, Pinter D, Enzinger C, Seifert-Held T, Kneihsl M, Fandler S, et al. Serum neurofilament light is sensitive to active cerebral small vessel disease. Neurology 2017;89:2108–14.10.1212/WNL.0000000000004645Search in Google Scholar PubMed PubMed Central
14. Korley FK, Goldstick J, Mastali M, Van Eyk JE, Barsan W, Meurer WJ, et al. Serum NfL (neurofilament light chain) levels and incident stroke in adults with diabetes mellitus. Stroke 2019;50:1669–75.10.1161/STROKEAHA.119.024941Search in Google Scholar PubMed PubMed Central
15. Onatsu J, Vanninen R, Jakala P, Mustonen P, Pulkki K, Korhonen M, et al. Serum neurofilament light chain concentration correlates with infarct volume but not prognosis in acute ischemic stroke. J Stroke Cerebrovasc Dis 2019;28:2242–9.10.1016/j.jstrokecerebrovasdis.2019.05.008Search in Google Scholar PubMed
16. Pedersen A, Stanne TM, Nilsson S, Klasson S, Rosengren L, Holmegaard L, et al. Circulating neurofilament light in ischemic stroke: temporal profile and outcome prediction. J Neurol 2019; DOI: 10.1007/s00415-019-09477-9.Search in Google Scholar PubMed PubMed Central
17. Pujol-Calderon F, Portelius E, Zetterberg H, Blennow K, Rosengren LE, Hoglund K. Neurofilament changes in serum and cerebrospinal fluid after acute ischemic stroke. Neurosci Lett 2019;698:58–63.10.1016/j.neulet.2018.12.042Search in Google Scholar PubMed
18. Traenka C, Disanto G, Seiffge DJ, Gensicke H, Hert L, Grond-Ginsbach C, et al. Serum neurofilament light chain levels are associated with clinical characteristics and outcome in patients with cervical artery dissection. Cerebrovasc Dis 2015;40:222–7.10.1159/000440774Search in Google Scholar PubMed
19. Cai JY, Lu C, Chen MH, Ba HJ, Chen XD, Lin JH, et al. Predictive value of phosphorylated axonal neurofilament subunit H for clinical outcome in patients with acute intracerebral hemorrhage. Clin Chim Acta 2013;424:182–6.10.1016/j.cca.2013.06.019Search in Google Scholar PubMed
20. Lewis SB, Wolper RA, Miralia L, Yang C, Shaw G. Detection of phosphorylated NF-H in the cerebrospinal fluid and blood of aneurysmal subarachnoid hemorrhage patients. J Cereb Blood Flow Metab 2008;28:1261–71.10.1038/jcbfm.2008.12Search in Google Scholar PubMed
21. Nylen K, Csajbok LZ, Ost M, Rashid A, Karlsson JE, Blennow K, et al. CSF – neurofilament correlates with outcome after aneurysmal subarachnoid hemorrhage. Neurosci Lett 2006;404: 132–6.10.1016/j.neulet.2006.05.029Search in Google Scholar PubMed
22. Petzold A, Keir G, Kay A, Kerr M, Thompson EJ. Axonal damage and outcome in subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2006;77:753–9.10.1136/jnnp.2005.085175Search in Google Scholar PubMed PubMed Central
23. Petzold A, Rejdak K, Belli A, Sen J, Keir G, Kitchen N, et al. Axonal pathology in subarachnoid and intracerebral hemorrhage. J Neurotrauma 2005;22:407–14.10.1089/neu.2005.22.407Search in Google Scholar PubMed
24. Sellner J, Patel A, Dassan P, Brown MM, Petzold A. Hyperacute detection of neurofilament heavy chain in serum following stroke: a transient sign. Neurochem Res 2011;36:2287–91.10.1007/s11064-011-0553-8Search in Google Scholar PubMed
25. Zanier ER, Refai D, Zipfel GJ, Zoerle T, Longhi L, Esparza TJ, et al. Neurofilament light chain levels in ventricular cerebrospinal fluid after acute aneurysmal subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry 2011;82:157–9.10.1136/jnnp.2009.177667Search in Google Scholar PubMed PubMed Central
26. Gisslen M, Price RW, Andreasson U, Norgren N, Nilsson S, Hagberg L, et al. Plasma concentration of the neurofilament light protein (NFL) is a biomarker of CNS injury in HIV infection: a cross-sectional study. EBioMedicine 2015;3:135–40.10.1016/j.ebiom.2015.11.036Search in Google Scholar PubMed PubMed Central
27. Rissin DM, Kan CW, Campbell TG, Howes SC, Fournier DR, Song L, et al. Single-molecule enzyme-linked immunosorbent assay detects serum proteins at subfemtomolar concentrations. Nat Biotechnol 2010;28:595–9.10.1038/nbt.1641Search in Google Scholar PubMed PubMed Central
28. Disanto G, Barro C, Benkert P, Naegelin Y, Schadelin S, Giardiello A, et al. Serum neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol 2017;81:857–70.10.1002/ana.24954Search in Google Scholar PubMed PubMed Central
29. Lauridsen SV, Hvas AM, Sandgaard E, Gyldenholm T, Rahbek C, Hjort N, et al. Coagulation profile after spontaneous intracerebral hemorrhage: a cohort study. J Stroke Cerebrovasc Dis 2018;27:2951–61.10.1016/j.jstrokecerebrovasdis.2018.06.022Search in Google Scholar PubMed
30. Sandgaard E, Troldborg A, Lauridsen SV, Gyldenholm T, Thiel S, Hvas AM. Changes in the lectin pathway following intracerebral or spontaneous subarachnoid hemorrhage. Mol Neurobiol 2019;56:78–87.10.1007/s12035-018-1066-0Search in Google Scholar PubMed
31. Kwak R, Kadoya S, Suzuki T. Factors affecting the prognosis in thalamic hemorrhage. Stroke 1983;14:493–500.10.1161/01.STR.14.4.493Search in Google Scholar
32. Kuhle J, Barro C, Andreasson U, Derfuss T, Lindberg R, Sandelius A, et al. Comparison of three analytical platforms for quantification of the neurofilament light chain in blood samples: ELISA, electrochemiluminescence immunoassay and Simoa. Clin Chem Lab Med 2016;54:1655–61.10.1515/cclm-2015-1195Search in Google Scholar PubMed
33. DeLong ER, DeLong DM, Clarke-Pearson DL. Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach. Biometrics 1988;44:837–45.10.2307/2531595Search in Google Scholar
34. Tukey JW. Exploratory data analysis. Reading, MA: Addiosn-Wesley, 1977.Search in Google Scholar
35. Poesen K, De Schaepdryver M, Stubendorff B, Gille B, Muckova P, Wendler S, et al. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 2017;88:2302–9.10.1212/WNL.0000000000004029Search in Google Scholar PubMed
36. Kuhle J, Barro C, Disanto G, Mathias A, Soneson C, Bonnier G, et al. 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;22:1550–9.10.1177/1352458515623365Search in Google Scholar PubMed
37. Meeter LH, Dopper EG, Jiskoot LC, Sanchez-Valle R, Graff C, Benussi L, et al. Neurofilament light chain: a biomarker for genetic frontotemporal dementia. Ann Clin Transl Neurol 2016;3:623–36.10.1002/acn3.325Search in Google Scholar PubMed PubMed Central
38. Zetterberg H, Skillback T, Mattsson N, Trojanowski JQ, Portelius E, Shaw LM, et al. Association of cerebrospinal fluid neurofilament light concentration with Alzheimer disease progression. JAMA Neurol 2016;73:60–7.10.1001/jamaneurol.2015.3037Search in Google Scholar PubMed PubMed Central
39. Hemphill 3rd JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemorrhage. Stroke 2001;32:891–7.10.1161/01.STR.32.4.891Search in Google Scholar PubMed
40. Rost NS, Smith EE, Chang Y, Snider RW, Chanderraj R, Schwab K, et al. Prediction of functional outcome in patients with primary intracerebral hemorrhage: the FUNC score. Stroke 2008;39:2304–9.10.1161/STROKEAHA.107.512202Search in Google Scholar PubMed
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