Gaiani A, Martinelli I, Bello L, Querin G, Puthenparampil M, Ruggero S, Toffanin E, Cagnin A, Briani C, Pegoraro E, Sorarù G. Diagnostic and Prognostic Biomarkers in Amyotrophic Lateral Sclerosis: Neurofilament Light Chain Levels in Definite Subtypes of Disease. JAMA Neurol. 2017 May 1;74(5):525-532. PubMed.
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University of Ulm
This is a nice confirmation of earlier prospective studies of neurofilaments in motor neuron diseases (Lu et al., 2015; Steinacker et al. 2016). The measurement of the light chain in CSF is often a bit tricky because of assay variations. We could observe this in our round robin on neurofilaments (Oeckl et al., 2016). Therefore, in our clinical routine we use both neurofilament light chain and phosphorylated heavy chain. For ALS and other motor neuron diseases, such as primary lateral sclerosis (PLS), this might not make a big difference (see Steinacker et al. 2016). However, it allows a direct confirmation of the quality of the measurements. Interestingly, for primary progressive aphasias (PPA), one can subtype specific differences in neurofilament light chain and phosphorylated heavy chain measurements (Steinacker et al., 2017).
References:
Lu CH, Macdonald-Wallis C, Gray E, Pearce N, Petzold A, Norgren N, Giovannoni G, Fratta P, Sidle K, Fish M, Orrell R, Howard R, Talbot K, Greensmith L, Kuhle J, Turner MR, Malaspina A. Neurofilament light chain: A prognostic biomarker in amyotrophic lateral sclerosis. Neurology. 2015 Jun 2;84(22):2247-57. Epub 2015 May 1 PubMed.
Steinacker P, Feneberg E, Weishaupt J, Brettschneider J, Tumani H, Andersen PM, von Arnim CA, Böhm S, Kassubek J, Kubisch C, Lulé D, Müller HP, Muche R, Pinkhardt E, Oeckl P, Rosenbohm A, Anderl-Straub S, Volk AE, Weydt P, Ludolph AC, Otto M. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J Neurol Neurosurg Psychiatry. 2016 Jan;87(1):12-20. Epub 2015 Aug 21 PubMed.
Oeckl P Phd, Jardel C PharmD PhD, Salachas F Md, Lamari F Md, Andersen PM Md PhD, Bowser R PhD, de Carvalho M PhD, Costa J PhD, van Damme P Md PhD, Gray E PhD, Grosskreutz J Md, Hernández-Barral M Md, Herukka SK PhD Md, Huss A MSc, Jeromin A PhD, Kirby J PhD, Kuzma-Kozakiewicz M Md PhD, Amador Md Md, Mora JS Md, Morelli C Md, Muckova P PhD, Petri S Md, Poesen K PharmD PhD, Rhode H Md, Rikardsson AK, Robberecht W Md PhD, Rodríguez Mahillo AI PhD, Shaw P Md, Silani V Md, Steinacker P PhD, Turner MR PhD, Tüzün E Md PhD, Yetimler B MSc, Ludolph AC Md, Otto M Md. Multicenter validation of CSF neurofilaments as diagnostic biomarkers for ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2016 Jul-Aug;17(5-6):404-13. Epub 2016 Apr 11 PubMed.
Steinacker P, Semler E, Anderl-Straub S, Diehl-Schmid J, Schroeter ML, Uttner I, Foerstl H, Landwehrmeyer B, von Arnim CA, Kassubek J, Oeckl P, Huppertz HJ, Fassbender K, Fliessbach K, Prudlo J, Roßmeier C, Kornhuber J, Schneider A, Volk AE, Lauer M, Danek A, Ludolph AC, Otto M, FTLDc Study Group. Neurofilament as a blood marker for diagnosis and monitoring of primary progressive aphasias. Neurology. 2017 Mar 7;88(10):961-969. Epub 2017 Feb 8 PubMed.
View all comments by Markus OttoUniversity of Goteborg, Sahlgrenska University Hospital
This is a nice confirmation of the 1996 Rosengren et al. study that reported that patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF.
In agreement with that paper, Gaiani and colleagues also found higher NfL levels in ALS subtypes with upper motor neuron involvement as compared with lower motor neuron disease. Thus, this paper further supports the use of CSF biomarkers in the evaluation of patients in clinical neurology.
Interestingly, for this specific biomarker, technical developments have given the possibility to accurately analyze NfL also in blood samples (Gisslén et al., 2015), with plasma levels showing a tight correlation with CSF levels (Gisslén et al., 2015; Kuhle et al., 2016).
The first studies show increased blood levels of NfL in both ALS (Gaiottino et al., 2013) and FTD (Rohrer et al., 2016), similar to the findings in CSF in the Gaiani study.
References:
Rosengren LE, Karlsson JE, Karlsson JO, Persson LI, Wikkelsø C. Patients with amyotrophic lateral sclerosis and other neurodegenerative diseases have increased levels of neurofilament protein in CSF. J Neurochem. 1996 Nov;67(5):2013-8. PubMed.
Gisslén M, Price RW, Andreasson U, Norgren N, Nilsson S, Hagberg L, Fuchs D, Spudich S, Blennow K, Zetterberg H. Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study. EBioMedicine. 2016 Jan;3:135-40. Epub 2015 Nov 22 PubMed.
Kuhle J, Barro C, Andreasson U, Derfuss T, Lindberg R, Sandelius Å, Liman V, Norgren N, Blennow K, Zetterberg H. 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 Oct 1;54(10):1655-61. PubMed.
Gaiottino J, Norgren N, Dobson R, Topping J, Nissim A, Malaspina A, Bestwick JP, Monsch AU, Regeniter A, Lindberg RL, Kappos L, Leppert D, Petzold A, Giovannoni G, Kuhle J. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS One. 2013;8(9):e75091. PubMed.
Rohrer JD, Woollacott IO, Dick KM, Brotherhood E, Gordon E, Fellows A, Toombs J, Druyeh R, Cardoso MJ, Ourselin S, Nicholas JM, Norgren N, Mead S, Andreasson U, Blennow K, Schott JM, Fox NC, Warren JD, Zetterberg H. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology. 2016 Sep 27;87(13):1329-36. Epub 2016 Aug 31 PubMed.
View all comments by Kaj BlennowOxford University
This study adds further weight to CSF NfL as the leading prognostic biomarker in ALS. The extension of the analysis to consider clinical upper and lower motor neuron involvement, regional phenotypes, and the clinical disease stage is interesting, and the correlations seem likely to largely reflect the underlying rate of disease progression in each sub-group.
CSF NfL should now be a standard part of all future therapeutic trials, to understand its practicality and performance in this landscape, compared to standard disability measures. A routine diagnostic role for CSF NfL is still uncertain. It is not a biomarker specific to ALS, and true mimic disorders are relatively uncommon for the experienced ALS neurologist, for whom clinical history and examination are still the most accurate. Blood-based NfL assay development is also anticipated, which would remove a significant practical barrier to wider implementation.
View all comments by Martin R. TurnerMake a Comment
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