TY - JOUR
T1 - Neurofilaments in pre-symptomatic ALS and the impact of genotype
AU - Benatar, Michael
AU - Wuu, Joanne
AU - Lombardi, Vittoria
AU - Jeromin, Andreas
AU - Bowser, Robert
AU - Andersen, Peter M.
AU - Malaspina, Andrea
N1 - Funding Information:
M. Benatar reports grant support from Muscular Dystrophy Association, ALS Association, ALS Recovery Fund, Kimmelman Estate, Target ALS, Eli Lilly & Company, and the National Institutes of Health (NIH) during the conduct of the study. He also reports grant support from FDA, CDC, and DOD; research support from Alexion Pharmaceuticals, UCB, Cytokinetics, Neuraltus, Biogen and Orphazyme A/S; and personal fees from NMD Pharma, Ra Pharmaceuticals, Mitsubishi-Tanabe, Avexis, UCB and Denali outside the submitted work.
Funding Information:
J. Wuu reports grant support from Muscular Dystrophy Association, ALS Association, ALS Recovery Fund, Kimmelman Estate, Eli Lilly & Company and the NIH during the conduct of the study; and grant support from FDA, CDC, and DOD, and from Target ALS Foundation outside the submitted work.
Funding Information:
R. Bowser reports grants from the ALS Association, the Muscular Dystrophy Association and Target ALS; and personal fees from Mitsubishi-Tanabe outside the submitted work. He has also received compensation and stock options from Iron Horse Diagnostics, Inc.
Funding Information:
P. M. Andersen reports grants from the Swedish Research Council, The Swedish Brain Research Foundation, the Knut and Alice Wallenberg Foundation; research support from Orphazyme A/S, Orion Pharma and Biogen; and personal fees from Biogen, Orphazyme A/S, and Hoffman la Roche/Genentech outside the submitted work.
PY - 2019/10/2
Y1 - 2019/10/2
N2 - Objective. To evaluate serum and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy (pNfH), and to compare these to levels of neurofilament light (NfL), as biomarkers of pre-symptomatic ALS. Design. The study population includes 34 controls, 79 individuals at-risk for ALS, 22 ALS patients, and 14 phenoconverters. At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation, but who demonstrate no clinical evidence of disease at the time of enrollment. pNfH and NfL in serum and CSF were quantified using established enzyme-linked immunosorbent assays. Results. There is a longitudinal increase in serum pNfH in advance of the emergence of clinically manifest ALS. A similar pattern is observed for NfL, but with the absolute levels also frequently exceeding a normative threshold. Although CSF data are more sparse, similar patterns are observed for both neurofilaments, with absolute levels exceeding a normative threshold prior to phenoconversion. In serum, these changes are observed in the 6–12 months prior to disease among SOD1 A4V mutation carriers, and as far back as 2 and 3.5 years, respectively, in individuals with a FUS c.521del6 mutation and a C9ORF72 hexanucleotide repeat expansion. Conclusions. Serum and CSF pNfH increase prior to phenoconversion. In CSF, the temporal course of these changes is similar to NfL. In serum, however, pNfH is less sensitive to pre-symptomatic disease than NfL. The duration of pre-symptomatic disease, as defined by changes in neurofilaments, may vary depending on underlying genotype.
AB - Objective. To evaluate serum and cerebrospinal fluid (CSF) levels of phosphorylated neurofilament heavy (pNfH), and to compare these to levels of neurofilament light (NfL), as biomarkers of pre-symptomatic ALS. Design. The study population includes 34 controls, 79 individuals at-risk for ALS, 22 ALS patients, and 14 phenoconverters. At-risk individuals are enrolled through Pre-Symptomatic Familial ALS (Pre-fALS), a longitudinal natural history and biomarker study of individuals who are carriers of any ALS-associated gene mutation, but who demonstrate no clinical evidence of disease at the time of enrollment. pNfH and NfL in serum and CSF were quantified using established enzyme-linked immunosorbent assays. Results. There is a longitudinal increase in serum pNfH in advance of the emergence of clinically manifest ALS. A similar pattern is observed for NfL, but with the absolute levels also frequently exceeding a normative threshold. Although CSF data are more sparse, similar patterns are observed for both neurofilaments, with absolute levels exceeding a normative threshold prior to phenoconversion. In serum, these changes are observed in the 6–12 months prior to disease among SOD1 A4V mutation carriers, and as far back as 2 and 3.5 years, respectively, in individuals with a FUS c.521del6 mutation and a C9ORF72 hexanucleotide repeat expansion. Conclusions. Serum and CSF pNfH increase prior to phenoconversion. In CSF, the temporal course of these changes is similar to NfL. In serum, however, pNfH is less sensitive to pre-symptomatic disease than NfL. The duration of pre-symptomatic disease, as defined by changes in neurofilaments, may vary depending on underlying genotype.
KW - Amyotrophic lateral sclerosis
KW - biomarkers
KW - disease prevention
KW - neurofilaments
KW - pre-symptomatic
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U2 - 10.1080/21678421.2019.1646769
DO - 10.1080/21678421.2019.1646769
M3 - Article
C2 - 31432691
AN - SCOPUS:85070993717
VL - 20
SP - 538
EP - 548
JO - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
JF - Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
SN - 2167-8421
IS - 7-8
ER -