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CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis

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Abstract

Elevated cerebrospinal fluid (CSF), Neurofilament Light (NF-L) and phosphorylated Heavy (pNF-H) chain levels have been found in Amyotrophic Lateral Sclerosis (ALS), with studies reporting a correlation of both neurofilaments (NFs) with the disease progression. Here, we measured NF-L and pNF-H concentrations in the CSF of ALS patients from a single tertiary Center and investigated their relationship with disease-related variables. A total of 190 ALS patients (Bulbar, 29.9%; Spinal, 70.1%; M/F = 1.53) and 130 controls with mixed neurological diseases were recruited. Demographic and clinical variables were recorded, and ΔFS was used to rate the disease progression. Controls were divided into two cohorts: (1) patients with non-inflammatory neurological diseases (CTL-1); (2) patients with acute/subacute inflammatory diseases and tumors, expected to lead to significant axonal and tissue damage (CTL-2). For each patient and control, CSF was taken at the time of the diagnostic work-up and stored following the published guidelines. CSF NF-L and pNF-H were assayed with commercially available ELISA-based methods. Standard curves (from independent ELISA kits) were highly reproducible for both NFs, with a coefficient of variation < 20%. We found that CSF NF-L and pNF-H levels in ALS were significantly increased when compared to CTL-1 (NF-L: ALS, 4.7 ng/ml vs CTL-1, 0.61 ng/ml, p < 0.001; pNF-H: ALS, 1.7 ng/ml vs CTL-1, 0.03 ng/ml, p < 0.0001), but not to CTL-2. Analysis of different clinical and prognostic variables disclosed meaningful correlations with both NF-L and pNF-H levels. Our results, from a relatively large ALS cohort, confirm that CSF NF-L and pNF-H represent valuable diagnostic and prognostic biomarkers in ALS.

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References

  1. Lee MK, Cleveland DW (1996) Neuronal intermediate filaments. Annu Rev Neurosci 19:187–217

    Article  CAS  PubMed  Google Scholar 

  2. Petzold A (2005) neurofilament phosphoforms: surrogate markers of axonal injury, degeneration and loss. J Neurol Sci 233:183–198

    Article  CAS  PubMed  Google Scholar 

  3. Rosengren LE, Karlsson J-E, Karlsson J-O et al (1996) Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem 67:2013–2018

    Article  CAS  PubMed  Google Scholar 

  4. Hu YY, He SS, Wang XC et al (2002) Elevated levels of phosphorylated neurofilament proteins in cerebrospinal fluid of Alzheimer disease patients. Neurosci Lett 320:156–160

    Article  CAS  PubMed  Google Scholar 

  5. Pijnenburg YAL, Janssen JC, Schoonenboom NSM et al (2007) CSF neurofilaments in frontotemporal dementia compared to early onset Alzheimer’s disease and controls. Dement Geriatric Cogn Dis 23:225–230

    Article  Google Scholar 

  6. Mattsson N, Rüetschi U, Pijnenburg YAL et al (2008) Novel cerebrospinal fluid biomarkers of axonal degeneration in frontotemporal dementia. Mol Med Rep 1:757–761

    CAS  PubMed  Google Scholar 

  7. Ganesalingam J, An J, Bowser R et al (2013) pNfH is a promising biomarker in ALS. Amyotrophic Lat Scler Frontotemp Degen 14:146–149

    Article  CAS  Google Scholar 

  8. Landqvist Waldö M, Santillo AF, Passant U et al (2013) Cerebrospinal fluid neurofilament light chain protein levels in subtypes of frontotemporal dementia. BMC Neurology 13:54e1–54e8

    Article  Google Scholar 

  9. Scherling CS, Hall T, Berisha F et al (2014) Cerebrospinal fluid neurofilament concentration reflects disease severity in frontotemporal degeneration. Ann Neurol 75:116–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Abdelhak A, Junker A, Brettschneider J et al (2015) Brain-specific cytoskeletal markers in cerebrospinal fluid: is there a common pattern between amyotrophic lateral sclerosis and primary progressive multiple sclerosis? Int J Mol Sci 16:17565–17588

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Xu Z, Henderson RD, David M, McCombe PA (2016) Neurofilaments as biomarkers for amyotrophic lateral sclerosis: a systematic review and meta-analysis. PLoS ONE 11(e0164625):e1–e18

    Google Scholar 

  12. Meeter LH, Dopper EG, Jiskoot LC et al (2016) Neurofilament light chain: a biomarker for genetic frontotemporal dementia. Ann Clin Transl Neurol 3:623–626

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wilke C, Preische O, Deuschle C et al (2016) Neurofilament light chain in FTD is elevated not only in cerebrospinal fluid, but also in serum. J Neurol Neurosurg Psychiatry 87:1270–1272

    Article  PubMed  Google Scholar 

  14. Mattsson N, Andreasson U, Zettenberg H et al (2017) association of plasma neurofilament light with neurodegeneration in patients with Alzheimer disease. JAMA Neurol 74:557–566

    Article  PubMed  Google Scholar 

  15. Hu X, Yang Y, Gong D (2017) Cerebrospinal fluid levels of neurofilament light chain in multiple system atrophy relative to Parkinson’s disease: a meta-analysis. Neurol Sci 38:407–414

    Article  PubMed  Google Scholar 

  16. Hansson O, Janelidze S, Hall S et al (2017) Blood-based NfL. A biomarker for differential diagnosis of parkinsonian disorder. Neurology 88:930–937

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Krut JJ, Mellberg T, Price RW et al (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS ONE 9(e88951):e1–e7

    Google Scholar 

  18. Spataro R, Lo Re M, Piccoli T et al (2010) Causes and place of death in Italian patients with Amyotrophic Lateral Sclerosis. Acta Neurol Scand 122:217–223

    Article  CAS  PubMed  Google Scholar 

  19. Traynor BJ, Codd MB, Corr B et al (2000) Amyotrophic lateral sclerosis mimic syndromes: a population-based study. Arch Neurol 57:109–113

    Article  CAS  PubMed  Google Scholar 

  20. Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler 1:293–299

    CAS  Google Scholar 

  21. Cedarbaum JM, Stambler N, Malta E et al (1999) The ALSFRS-R: a revised ALS functional rating scale that incorporates assessments of respiratory function. BDNF ALS Study Group (Phase III). J Neurol Sci 169:13–21

    Article  CAS  PubMed  Google Scholar 

  22. Menke RAL, Gray E, Lu C-H et al (2015) CSF neurofilament light chain reflects corticospinal tract degeneration in ALS. Ann Clin Transl Neurol 2:748–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Reijn TS, Abdo WF, Schelhaas HJ, Verbeek MM (2009) CSF neurofilament protein analysis in the differential diagnosis of ALS. J Neurol 256:615–619

    Article  CAS  PubMed  Google Scholar 

  24. Tortelli R, Ruggieri M, Cortese R et al (2012) Elevated cerebrospinal fluid neurofilament light levels in patients with amyotrophic lateral sclerosis: a possible marker of disease severity and progression. Eur J Neurol 19:1561–1567

    Article  CAS  PubMed  Google Scholar 

  25. Boylan KB, Glass JD, Crook JE et al (2013) Phosphorylated neurofilament heavy subunit (pNF-H) in peripheral blood and CSF as potential prognostic biomarker in amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 84:467–472

    Article  PubMed  Google Scholar 

  26. Gaiottino J, Norgren N, Dobson R et al (2013) Increased neurofilament light chain blood levels in neurodegenerative neurological disease. PLoS ONE 8(e75091):e1–e9

    Google Scholar 

  27. Gonçalves M, Tillack L, de Carvalho M et al (2014) Phosphoneurofilament heravy chain and N-glycomics from the cerebrospinal fluid in amyotrophic lateral sclerosis. Clin Chim Acta 438:342–349

    Article  PubMed  Google Scholar 

  28. Lu C-H, Petzold A, Topping J et al (2015) plasma neurofilament heavy chain levels and disease progression in amyotrophic lateral sclerosis: insights from a longitudinal study. J Neurol Neurosurg Psychiatry 86:565–573

    Article  PubMed  Google Scholar 

  29. Lu C-H, Macdonald-Wallis C, Gray E et al (2015) Neurofilament light chain. A prognostic biomarker in amyotrophic lateral sclerosis. Neurology 84:2247–2257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Weydt P, Oeckl P, Huss A et al (2016) Neurofilament levels as biomarkers in asymptomatic and symptomatic familial amyotrophic lateral sclerosis. Ann Neurol 79:152–158

    Article  CAS  PubMed  Google Scholar 

  31. Steinacker P, Feneberg E, Weishaupt J et al (2016) Neurofilaments in the diagnosis of motoneuron diseases: a prospective study of 455 patients. J Neurol Neurosurg Psychiatry 87:12–20

    PubMed  Google Scholar 

  32. Oeckl P, Jardel C, Salachas F et al (2016) Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS. Amyotr Lat Scler Frontotemp Degen 17:404–413

    Article  CAS  Google Scholar 

  33. Steinacker P, Huss A, Mayer B et al (2017) diagnostic and prognostic significance of neurofilament light chain NF-L, but not progranulin and S100B, in the course of amyotrophic lateral sclerosis: data from the German MND-net. Amyotr Lat Scler Frontotemp Degen 18:112–119

    Article  CAS  Google Scholar 

  34. Gaiani A, Martinelli I, Bello L et al (2017) Diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis. Neurofilament light chain levels in definite subtypes of disease. JAMA Neurol 74:525–532

    Article  PubMed  Google Scholar 

  35. Poesen K, De Schaepdryver M, Stubendorff B et al (2017) neurofilaments markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 88:2302–2309

    Article  CAS  PubMed  Google Scholar 

  36. Turner MR, Gray E (2015) Are neurofilaments heading for the ALS clinic? J Neurol Neurosurg Psychiatry 87:3–4

    PubMed  Google Scholar 

  37. De Carvaho M, Dengler R, Eisen A et al (2008) Electrodiagnosis criteria for diagnosis of ALS. Clin Neurophysiol 119:497–503

    Article  Google Scholar 

  38. Neary D, Snowden JS, Gustafson L et al (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546–1554

    Article  CAS  PubMed  Google Scholar 

  39. Bang J, Spina S, Miller BL (2015) Frontotemporal dementia. Lancet 386:1672–1682

    Article  PubMed  Google Scholar 

  40. Kimura F, Fujimura C, Ishida S et al (2006) Progression rate of ALSFRS-R at the time of diagnosis predicts survival time in ALS. Neurology 66:265–267

    Article  CAS  PubMed  Google Scholar 

  41. Cellura E, Spataro R, Taiello AC, La Bella V (2012) Factors affecting the diagnostic delay in amyotrophic lateral sclerosis. Clin Neurol Neurosurg 114:550–554

    Article  PubMed  Google Scholar 

  42. Robinson KM, Lacey SC, Grugan P, Glosser G, Grossman M, McCluskey LF (2006) Cognitive functioning in sporadic amyotrophic lateral sclerosis: a six month longitudinal study. J Neurol Neurosurg Psychiatry 77:668–670

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Phukan J, Pender NP, Hardiman O (2007) Cognitive impairment in amyotrophic lateral sclerosis. Lancet Neurol 6:994–1003

    Article  CAS  PubMed  Google Scholar 

  44. Kasper E, Zydatiss K, Schuster C, Machts J, Bittner D, Kaufmann J et al (2016) No change in executive performance in ALS patients: a longitudinal neuropsychological study. Neurodegener Dis 16:184–191

    Article  PubMed  Google Scholar 

  45. Burkhardt C, Neuwirth C, Weber M (2017) Longitudinal assessment of the Edinburgh Cognitive and Behavioural Amyotrophic Lateral Sclerosis Screen (ECAS): lack of practice effect in ALS patients. Amyotroph Lateral Sclerosis Frontotemp Degener 18:202–209

    Article  Google Scholar 

  46. Teunissen CE, Petzold A, Bennett JL et al (2009) A consensus protocol for the standardization of cerebrospinal fluid collection and biobanking. Neurology 73:1914–1922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Abdoa FW, Bloema BR, Van Geel WJ et al (2007) CSF neurofilament light chain and tau differentiate multiple system atrophy from Parkinson’s disease. Neurobiol Aging 28:742–747

    Article  Google Scholar 

  48. Steinacker P, Blennow K, Halbgebauer S et al (2016) Neurofilaments in blood and CSF for diagnosis and prediction of onset in Creutzfeldt-Jakob disease. Sci Rep 6:38737 e1–38737 e6

    Article  Google Scholar 

  49. Kang DX, Fan DS (1995) The electrophysiological study of differential diagnosis between amyotrophic lateral sclerosis and cervical spondylotic myelopathy. Electromyogr Clin Neurophysiol 35:231–238

    CAS  PubMed  Google Scholar 

  50. Andersen PM, Abrahams S, Borasio GD et al (2012) EFNS guidelines on the Clinical Management of Amyotrophic Lateral Sclerosis (MALS) – revised report of an EFNS task force. Eur J Neurol 19:360–375

    Article  PubMed  Google Scholar 

  51. Swinnen B, Robberecht W (2014) The phenotypic variability of amyotrophic lateral sclerosis. Nature Rev Neurol 10:661–670

    Article  Google Scholar 

  52. Appel V, Stewart SS, Smith RG, Appel SH (1987) A rating scale for amyotrophic lateral sclerosis: description and preliminary experience. Ann Neurol 22:328–333

    Article  CAS  PubMed  Google Scholar 

  53. Mitsumoto H, Brooks BR, Silani V (2014) Clinical trials in amyotrophic lateral sclerosis: why so many negative trials and how can trials be improved? Lancet Neurol 13:1127–1138

    Article  PubMed  Google Scholar 

  54. Bensimon G, Lacomblez L, Meininger V, for the ALS/Riluzole study group (1994) A controlled trial of riluzole in amyotrophic lateral sclerosis. New Engl J Med 330:585–591

    Article  CAS  PubMed  Google Scholar 

  55. Elia AE, Lalli S, Monsurrò MR et al (2015) Tauroursodeoxycholic acid in the treatment of patients with amyotrophic lateral sclerosis. Eur J Neurol 23:45–52

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by funds from the Italian Ministry of Health for the Ricerca Corrente to IRCCS Istituti Clinici Scientifici Maugeri SpA SB.

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Author notes

  1. Daniela Rossi and Paolo Volanti contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Research on Neurodegenerative Disorders, ICS Maugeri, 27100, Pavia, Italy

    Daniela Rossi & Liliana Brambilla

  2. ALS Center and Neurorehabilitation Unit, ICS Maugeri, 98073, Mistretta, Italy

    Paolo Volanti

  3. Department of Experimental BioMedicine and Clinical Neurosciences, ALS Clinical Research Center, University of Palermo, Via G La Loggia, 1, 90129, Palermo, Italy

    Tiziana Colletti, Rossella Spataro & Vincenzo La Bella

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  1. Daniela Rossi
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Correspondence to Vincenzo La Bella.

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Rossi, D., Volanti, P., Brambilla, L. et al. CSF neurofilament proteins as diagnostic and prognostic biomarkers for amyotrophic lateral sclerosis. J Neurol 265, 510–521 (2018). https://doi.org/10.1007/s00415-017-8730-6

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  • DOI: https://doi.org/10.1007/s00415-017-8730-6

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