Koen Poesen1, Maxim De Schaepdryver2, Beatrice Stubendorff2, Benjamin Gille2, Petra Muckova2, Sindy Wendler2, Tino Prell2, Thomas M Ringer2, Heidrun Rhode2, Olivier Stevens2, Kristl G Claeys2, Goedele Couwelier2, Ann D'Hondt2, Nikita Lamaire2, Petra Tilkin2, Dimphna Van Reijen2, Sarah Gourmaud2, Nadin Fedtke2, Bianka Heiling2, Matthias Rumpel2, Annekathrin Rödiger2, Anne Gunkel2, Otto W Witte2, Claire Paquet2, Rik Vandenberghe2, Julian Grosskreutz2, Philip Van Damme2. 1. From the Laboratory for Molecular Neurobiomarker Research (K.P., M.D.S., B.G.), Laboratory for Cognitive Neurology (R.V.) and Laboratory of Neurobiology (Center for Brain & Disease Research, VIB, Leuven) (P.V.D.), Department of Neurosciences, KU Leuven (University of Leuven); Laboratory Medicine (K.P., M.D.S.) and Department of Neurology (O.S., K.G.C., G.C., A.D., N.L., P.T., D.V.R., R.V., P.V.D.), University Hospitals Leuven, Belgium; Hans Berger Department of Neurology (B.S., T.P., T.M.R., N.F., B.H., M.R., A.R., A.G., O.W.W., J.G.) and Institute for Biochemistry (P.M., S.W., H.R.), Jena University Hospital, Germany; INSERM, U942 (S.G., C.P.), Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, CMRR Paris Nord AP-HP, Université Paris Diderot, France. koen.poesen@uzleuven.be. 2. From the Laboratory for Molecular Neurobiomarker Research (K.P., M.D.S., B.G.), Laboratory for Cognitive Neurology (R.V.) and Laboratory of Neurobiology (Center for Brain & Disease Research, VIB, Leuven) (P.V.D.), Department of Neurosciences, KU Leuven (University of Leuven); Laboratory Medicine (K.P., M.D.S.) and Department of Neurology (O.S., K.G.C., G.C., A.D., N.L., P.T., D.V.R., R.V., P.V.D.), University Hospitals Leuven, Belgium; Hans Berger Department of Neurology (B.S., T.P., T.M.R., N.F., B.H., M.R., A.R., A.G., O.W.W., J.G.) and Institute for Biochemistry (P.M., S.W., H.R.), Jena University Hospital, Germany; INSERM, U942 (S.G., C.P.), Groupe Hospitalier Lariboisière Fernand-Widal Saint-Louis, CMRR Paris Nord AP-HP, Université Paris Diderot, France.
Abstract
OBJECTIVE: To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase. METHODS: We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters. RESULTS: pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement. CONCLUSIONS: In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.
OBJECTIVE: To determine the diagnostic performance and prognostic value of phosphorylated neurofilament heavy chain (pNfH) and neurofilament light chain (NfL) in CSF as possible biomarkers for amyotrophic lateral sclerosis (ALS) at the diagnostic phase. METHODS: We measured CSF pNfH and NfL concentrations in 220 patients with ALS, 316 neurologic disease controls (DC), and 50 genuine disease mimics (DM) to determine and assess the accuracy of the diagnostic cutoff value for pNfH and NfL and to correlate with other clinical parameters. RESULTS: pNfH was most specific for motor neuron disease (specificity 88.2% [confidence interval (CI) 83.0%-92.3%]). pNfH had the best performance to differentially diagnose patients with ALS from DM with a sensitivity of 90.7% (CI 84.9%-94.8%), a specificity of 88.0% (CI 75.7%-95.5%) and a likelihood ratio of 7.6 (CI 3.6-16.0) at a cutoff of 768 pg/mL. CSF pNfH and NfL levels were significantly lower in slow disease progressors, however, with a poor prognostic performance with respect to the disease progression rate. CSF pNfH and NfL levels increased significantly as function of the number of regions with both upper and lower motor involvement. CONCLUSIONS: In particular, CSF pNfH concentrations show an added value as diagnostic biomarkers for ALS, whereas the prognostic value of pNfH and NfL warrants further investigation. Both pNfH and NfL correlated with the extent of motor neuron degeneration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that elevated concentrations of CSF pNfH and NfL can accurately identify patients with ALS.
Authors: Michael Benatar; Joanne Wuu; Vittoria Lombardi; Andreas Jeromin; Robert Bowser; Peter M Andersen; Andrea Malaspina Journal: Amyotroph Lateral Scler Frontotemporal Degener Date: 2019-08-21 Impact factor: 4.092
Authors: Hiroshi Mitsumoto; Diana C Garofalo; Regina M Santella; Eric J Sorenson; Björn Oskarsson; J Americo M Fernandes; Howard Andrews; Jonathan Hupf; Madison Gilmore; Daragh Heitzman; Richard S Bedlack; Jonathan S Katz; Richard J Barohn; Edward J Kasarskis; Catherine Lomen-Hoerth; Tahseen Mozaffar; Sharon P Nations; Andrea J Swenson; Pam Factor-Litvak Journal: Amyotroph Lateral Scler Frontotemporal Degener Date: 2020-04-10 Impact factor: 4.092