Validation of serum neurofilaments as prognostic and potential pharmacodynamic biomarkers for ALS.

Adult Aged Amyotrophic Lateral Sclerosis / blood Biomarkers / blood Female Humans Intermediate Filaments / metabolism Male Middle Aged Prognosis

Journal

Neurology
ISSN: 1526-632X
Titre abrégé: Neurology
Pays: United States
ID NLM: 0401060

Informations de publication

Date de publication:
07 07 2020
Historique:
received: 03 08 2019
accepted: 10 12 2019
pubmed: 10 5 2020
medline: 29 9 2020
entrez: 10 5 2020
Statut: ppublish

Résumé

To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%-5% and ∼2%-3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

Identifiants

DOI: 10.1212/WNL.0000000000009559 PMID: 32385188 PMC: PMC7371380
pubmed: 32385188
pii: WNL.0000000000009559
doi: 10.1212/WNL.0000000000009559
pmc: PMC7371380
doi:

Substances chimiques

Biomarkers 0

Types de publication

Journal Article Multicenter Study Observational Study Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Validation Study

Langues

eng

Sous-ensembles de citation

IM

Pagination

e59-e69

Subventions

Organisme : NINDS NIH HHS
ID : U01 NS107027
Pays : United States
Organisme : NINDS NIH HHS
ID : U54 NS092091
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR002366
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR000001
Pays : United States

Investigateurs

Sumaira Hussain (S)
Anne Cooley (A)
Yindi Li (Y)
Marielle Wallace (M)
Julie Steele (J)
Jessica P Hernandez (JP)
Jessica Medina (J)
Maria Elena Paredes (ME)
Ashley Manso (A)
Natalia Ravelo (N)
Wendy Levy (W)
Patrice Whitehead (P)
Stephan Zuchner (S)
Mamatha Pasnoor (M)
Omar Jawdat (O)
Duaa Jabari (D)
Constantine Farmakidis (C)
Melanie Glenn (M)
Mazen M Dimachkie (MM)
Laura Herbelin (L)
Hellen Tanui (H)
Sherri Anderson (S)
Michaela Walker (M)
Tina Liu (T)
Ayla McCally (A)
Andrew Heim (A)
Melissa Currence (M)
Yolanda Harness (Y)
Jeri Sieren (J)
Emilee Gibson (E)
Gil Gutierrez (G)
Danielle Bussey (D)
Rose Previte (R)
Pamella Kittrell (P)
Amruta Joshi (A)
Amy Conger (A)
Debbie Hastings (D)
Irys Caristo (I)
Mozhdeh Marandi (M)
Simon Carty (S)
J Paul Taylor (JP)
Gang Wu (G)
Evadnie Rampersaud (E)
Rebecca Schule (R)
Marka van Blitterswijk (MV)

Informations de copyright

© 2020 American Academy of Neurology.

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Auteurs

Michael Benatar (M)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD. mbenatar@med.miami.edu jwuu@med.miami.edu.
ORCID: 0000-0003-4241-5135

Lanyu Zhang (L)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Lily Wang (L)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Volkan Granit (V)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.
ORCID: 0000-0002-6519-7225

Jeffrey Statland (J)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.
ORCID: 0000-0003-0790-5315

Richard Barohn (R)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Andrea Swenson (A)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

John Ravits (J)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Carlayne Jackson (C)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Ted M Burns (TM)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Jaya Trivedi (J)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Erik P Pioro (EP)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.
ORCID: 0000-0002-0737-6065

James Caress (J)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.
ORCID: 0000-0002-5814-6083

Jonathan Katz (J)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Jacob L McCauley (JL)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.
ORCID: 0000-0002-1805-1733

Rosa Rademakers (R)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Andrea Malaspina (A)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Lyle W Ostrow (LW)

From Miller School of Medicine (M.B., L.Z., L.W., V.G., J.W.), University of Miami, FL; Kansas University Medical Center (J.S., R.B.), Kansas City; University of Iowa (A.S.), Iowa City; University of California San Diego (J.R.); University of Texas Health Science Center San Antonio (C.J.); University of Virginia (T.M.B.), Charlottesville; UT Southwestern Medical Center (J.T.), Dallas, TX; Cleveland Clinic (E.P.P.), OH; Wake Forest School of Medicine (J.C.), Winston-Salem, NC; California Pacific Medical Center (J.K.), San Francisco; John P Hussman Institute for Human Genomics (J.L.M.), Miami; Mayo Clinic Jacksonville (R.R.), FL; Blizard Institute (A.M.), Queen Mary University of London, UK; and Johns Hopkins University (L.W.O.), Baltimore, MD.

Joanne Wuu (J)

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Validation of serum neurofilaments as...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Validation of serum neurofilaments as...
questionsmedicales.fr › Maladies métaboliques et nutritionnelles › Maladies métaboliques › Troubles de l'homéostasie des protéines › Protéinopathies TDP-43 › Sclérose latérale amyotrophique › Validation of serum neurofilaments as...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Validation of serum neurofilaments as...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Validation of serum neurofilaments as...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Cytosquelette › Filaments intermédiaires › Validation of serum neurofilaments as...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Validation of serum neurofilaments as...
questionsmedicales.fr › Diagnostic › Pronostic › Validation of serum neurofilaments as...