Neurofilament light chains in serum and cerebrospinal fluid and status of blood-CSF barrier in the selected neurological diseases

Czech version

Authors: L. Fialová ¹; A. Bartoš ^2,3; J. Švarcová ⁴
Authors‘ workplace: Ústav lékařské biochemie a laboratorní diagnostiky, 1. LF UK a VFN v Praze ¹; Národní ústav duševního zdraví, Klecany ²; Neurologická klinika 3. LF UK a FN Královské Vinohrady, Praha ³; Ústav lékařské chemie a klinické biochemie, 2. LF UK a FN Motol, Praha ⁴
Published in: Cesk Slov Neurol N 2018; 81(2): 185-192
Category: Original Paper
doi: https://doi.org/10.14735/amcsnn2018185

Overview

Aim:
The aim of this study was to assess the relationship between blood-CSF barrier permeability evaluated by the albumin quotient (Q_alb) and levels of neurofilament light chains (NFL) in serum and cerebrospinal fluid (CSF) in several groups of neurological patients with a different degree of the impairment of blood-CSF barrier.

Materials and methods:
The total number of 137 participants included 50 patients with multiple sclerosis with the inclusion of clinically isolated syndrome, 24 patients with Alzheimer’s disease, 17 patients with aseptic neuroinfections, 36 patients with various non-inflammatory neurological diseases and 10 symptomatic controls. Serum and CSF NFL levels were determined by the ELISA method. Serum and CSF albumin levels were tested by immunonephelometry. Q_alb was calculated as a ratio of CSF/ serum albumin levels.

Results:
No positive correlations between serum NFL levels and Q_alb values were found in the tested patients’ groups. CSF NFL levels were positively correlated with Q_alb values in patients with neuroinfections and in patients with non-inflammatory neurological diseases. A positive correlation between serum NFL levels and those in CSF was found in patients with aseptic neuroinfections even when patients were evaluated as a whole.

Conclusions:
Serum NFL levels do not seem to be directly influenced by blood-CSF barrier permeability assessed by Q_alb in neurodegenerative diseases and neuroinfections. On the contrary, the relationship between CSF NFL levels and Q_alb may be affected by the characteristics of the neuropathological changes in individual neurological diseases.

Key words:
albumin quotient – Alzheimer´s disease – cytoskeleton – blood-CSF barrier – multiple sclerosis – neuroinfection – neurofilaments

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE “uniform requirements” for biomedical papers.

Sources

1. Gotow T. Neurofilaments in health and disease. Med Electron Microsc 2000; 33(4): 173– 199.

2. Hjalmarsson C, Bjerke M, Andersson B et al. Neuronal and glia-related biomarkers in cerebrospinal fluid of patients with acute ischemic stroke. J Cent Nerv Syst Dis 2014; 6: 51– 58. doi: 10.4137/ JCNSD.S13821.

3. Fialova L, Malbohan I. Neuronal cytoskeleton components in cerebrospinal fluid in selected neurological diseases. In Slavik V, Dolezal T (eds). Cerebrospinal fluid: functions, composition and disorders. New York: Nova Science Publishers 2012; 65– 86.

4. Piťha J. Biomarkery roztroušené sklerózy – současné možnosti a perspektivy. Cesk Slov Neurol N 2015; 78/ 111(3): 269– 273.

5. Fialova L, Bartos A, Svarcova J et al. Serum and cerebrospinal fluid light neurofilaments and antibodies against them in clinically isolated syndrome and multiple sclerosis. J Neuroimmunol 2013; 262(1– 2): 113– 120. doi: 10.1016/ j.jneuroim.2013.06.010.

6. Teunissen CE, Iacobaeus E, Khademi M et al. Combination of CSF N-acetylaspartate and neurofilaments in multiple sclerosis. Neurology 2009; 72(15): 1322– 1329. doi: 10.1212/ WNL.0b013e3181a0fe3f.

7. Norgren N, Rosengren L, Stigbrand T. Elevated neurofilament levels in neurological diseases. Brain Res 2003; 987(1): 25– 31.

8. Disanto G, Adiutori R, Dobson R et al. Serum neurofilament light chain levels are increased in patients with a clinically isolated syndrome. J Neurol Neurosurg Psychiatry 2016; 87(2): 126– 129. doi: 10.1136/ jnnp-2014-309690.

9. Mattsson N, Andreasson U, Zetterberg H et al. Association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 2017; 74(5): 557– 566. doi: 10.1001/ jamaneurol.2016.6117.

10. Kuhle J, Barro C, Disanto 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(12): 1550– 1559.

11. Kuhle J, Barro C, Andreasson U 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(10): 1655– 1661. doi: 10.1515/ cclm-2015-1195.

12. Fialova L, Bartos A, Svarcova J. Neurofilaments and tau proteins in cerebrospinal fluid and serum in dementias and neuroinflammation. Biomed Pap MedFac Univ Palacky Olomouc Czech Repub 2017; 161(3): 286– 295. doi: 10.5507/ bp.2017.038.

13. Havrdová E. Roztroušená skleróza. Cesk Slov Neurol N 2008; 71/ 104(2): 121– 132.

14. Friese MA, Schattling B, Fugger L. Mechanisms of neurodegeneration and axonal dysfunction in multiple sclerosis. Nat Rev Neurol 2014; 10(4): 225– 238. doi: 10.1038/ nrneurol.2014.37.

15. Mareš J. Význam časné diagnostiky a terapie v životní perspektivě pacientů s roztroušenou sklerózou. Med praxi 2013; 10(4): 149– 153.

16. Disanto G, Barro C, Benkert P et al. Serum Neurofilament light: a biomarker of neuronal damage in multiple sclerosis. Ann Neurol 2017; 81(6): 857– 870. doi: 10.1002/ ana.24954.

17. Khalil M, Enzinger C, Langkammer C et al. CSF neurofilament and N-acetylaspartate related brain changes in clinically isolated syndrome. Mult Scler 2013; 19(4): 436– 442. doi: 10.1177/ 1352458512458010.

18. Rektorová I. Neurodegenerativní demence. Cesk Slov Neurol N 2009; 72/ 105(2): 97– 109.

19. Yuan A, Nixon RA. Specialized roles of neurofilament proteins in synapses: Relevance to neuropsychiatric disorders. Brain Res Bull 2016; 126(Pt 3): 334– 346. doi: 10.1016/ j.brainresbull.2016.09.002.

20. Bartoš A, Čechová L, Švarcová J et al. Likvorový triplet (tau proteiny a beta-amyloid) v diagnostice Alzheimerovy-Fischerovy nemoci. Cesk Slov Neurol N 2012; 75/ 108(5): 587– 594.

21. Olsson B, Lautner R, Andreasson U et al. CSF and blood biomarkers for the diagnosis of Alzheimer‘s disease: a systematic review and meta-analysis. Lancet Neurol 2016; 15(7): 673– 684. doi: 10.1016/ S1474-4422(16)00070-3.

22. Bacioglu M, Maia LF, Preische O et al. Neurofilament light chain in blood and CSF as marker of disease progression in mouse models and in neurodegenerative diseases. Neuron 2016; 91(2): 494– 496. doi: 10.1016/ j.neuron.2016.07.007.

23. Piťha J. Bariéry nervového systému za fyziologických a patologických stavů. Cesk Slov Neurol N 2014; 77/ 110(5): 553– 559.

24. Brettschneider J, Claus A, Kassubek J et al. Isolated blood-cerebrospinal fluid barrier dysfunction: prevalence and associated diseases. J Neurol 2005; 252(9): 1067– 1073.

25. Kalm M, Boström M, Sandelius A et al. Serum concentrations of the axonal injury marker neurofilament light protein are not influenced by blood-brain barrier permeability. Brain Res 2017; 1668: 12– 19. doi: 10.1016/ j.brainres.2017.05.011.

26. Polman CH, Reingold SC, Edan G et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the „McDonald Criteria“. Ann Neurol 2005; 58(6): 840– 846.

27. McKhann GM, Knopman DS, Chertkow H et al. The diagnosis of dementia due to Alzheimer‘s disease: recommendations from the National Institute on Aging-Alzheimer‘s Association workgroups on diagnostic guidelines for Alzheimer‘s disease. Alzheimers Dement 2011; 7(3): 263– 269. doi: 10.1016/ j.jalz.2011.03.005.

28. Mioshi E, Dawson K, Mitchell J et al. The Addenbrooke‘s Cognitive Examination Revised (ACE-R): a brief cognitive test battery for dementia screening. Int J Geriatr Psychiatry 2006; 21(11): 1078– 1085.

29. Bartoš A, Raisová M and Kopeček M. Amendment of the Czech Addenbrooke’s cognitive examination (ACE-CZ). Cesk Slov Neurol N 2011; 74/ 107(6): 681– 684.

30. Bartoš A, Raisová M and Kopeček M. Důvody a průběh novelizace české verze Addenbrookského kognitivního testu (ACE-CZ). Cesk Slov Neurol N 2011; 74/ 107(6): e1– e5.

31. Scheltens P, Leys D, Barkhof F et al. Atrophy of medial temporal lobes on MRI in „probable“ Alzheimer‘s disease and normal ageing: diagnostic value and neuropsychological correlates. J Neurol Neurosurg Psychiatry 1992; 55(10): 967– 972.

32. Bartoš A, Zach P, Diblíková F et al. Visual rating of medial temporal lobe atrophy on magnetic resonance imaging in Alzheimer’s disease. Psychiatrie 2007; 11 (Suppl 3): 49– 52.

33. Teunissen C, Menge T, Altintas A et al. Consensus definitions and application guidelines for control groups in cerebrospinal fluid biomarker studies in multiple sclerosis. Mult Scler 2013; 19(13): 1802–1809. doi: 10.1177/ 1352458513488232.

34. Zima T. Laboratorní diagnostika. 3. doplněné a přepracované vydání. Praha: Galén 2013.

35. Deisenhammer F, Bartos A, Egg R et al. Guidelines on routine cerebrospinal fluid analysis. Report from an EFNS task force. Eur J Neurol 2006; 13(9): 913– 922.

36. Teunissen CE, Petzold A, Bennett JL et al. A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 2009; 73(22): 1914– 1922. doi: 10.1212/ WNL.0b013e3181c47cc2.

37. LeVine SM. Albumin and multiple sclerosis. BMC Neurol 2016; 16: 47. doi: 10.1186/ s12883-016-0564-9.

38. Schenk GJ, de Vries HE. Altered blood-brain barrier transport in neuro-inflammatory disorders. Drug Discov Today Technol 2016; 20: 5– 11. doi: 10.1016/ j.ddtec.2016.07.002.

39. Uher T, Horakova D, Tyblova M et al. Increased albumin quotient (QAlb) in patients after first clinical event suggestive of multiple sclerosis is associated with development of brain atrophy and greater disability 48 months later. Mult Scler 2016; 22(6): 770– 781. doi: 10.1177/ 1352458515601903.

40. Bednarova J. Cerebrospinal-fluid profile in neuroborreliosis and its diagnostic significance. Folia Microbiol (Praha) 2006; 51(6): 599– 603.

41. Kawata K, Liu CY, Merkel SF et al. Blood biomarkers for brain injury: What are we measuring? Neurosci Biobehav Rev 2016; 68: 460– 473. doi: 10.1016/ j.neubiorev.2016.05.009.

42. Reiber H. Dynamics of brain-derived proteins in cerebrospinal fluid. Clin Chim Acta 2001; 310(2): 173– 186.

43. Reiber H. Proteins in cerebrospinal fluid and blood: barriers, CSF flow rate and source-related dynamics. Restor Neurol Neurosci 2003; 21(3– 4): 79– 96.

44. Shaw G. The use and potential of pNF-H as a general blood biomarker of axonal loss: an immediate application for CNS injury. In: Kobeissy FH. Brain neurotrauma: molecular, neuropsychological, and rehabilitation aspects. Boca Raton (FL): CRC Press/ Taylor & Francis, 2015.

45. Anesten B, Yilmaz A, Hagberg L et al. Blood-brain barrier integrity, intrathecal immunoactivation, and neuronal injury in HIV. Neurol Neuroimmunol Neuroinflamm 2016; 3(6): e300.

46. Sussmuth SD, Reiber H, Tumani H. Tau protein in cerebrospinal fluid (CSF): a blood-CSF barrier related evaluation in patients with various neurological diseases. Neurosci Lett 2001; 300(2): 95– 98.

47. Liguori C, Olivola E, Pierantozzi M et al. Cerebrospinal-fluid Alzheimer‘s disease biomarkers and blood-brain barrier integrity in a natural population of cognitive intact Parkinson‘s disease patients. CNS Neurol Disord Drug Targets 2017; 16(3): 339– 345. doi: 10.2174/ 1871527316666161205123123.

48. Kuhle J, Leppert D, Petzold A et al. Neurofilament heavy chain in CSF correlates with relapses and disability in multiple sclerosis. Neurology 2011; 76(14): 1206– 1213. doi: 10.1212/ WNL.0b013e31821432ff.

49. Gaiottino J, Norgren N, Dobson R et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One 2013; 8(9): e75091. doi: 10.1371/ journal.pone.0075091.