Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
02
11
2021
received:
16
06
2021
accepted:
03
11
2021
pubmed:
8
11
2021
medline:
15
1
2022
entrez:
7
11
2021
Statut:
ppublish
Résumé
Although the presymptomatic stages of frontotemporal dementia (FTD) provide a unique chance to delay or even prevent neurodegeneration by early intervention, they remain poorly defined. Leveraging a large multicenter cohort of genetic FTD mutation carriers, we provide a biomarker-based stratification and biomarker cascade of the likely most treatment-relevant stage within the presymptomatic phase: the conversion stage. We longitudinally assessed serum levels of neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) in the Genetic FTD Initiative (GENFI) cohort (n = 444), using single-molecule array technique. Subjects comprised 91 symptomatic and 179 presymptomatic subjects with mutations in the FTD genes C9orf72, GRN, or MAPT, and 174 mutation-negative within-family controls. In a biomarker cascade, NfL increase preceded the hypothetical clinical onset by 15 years and concurred with brain atrophy onset, whereas pNfH increase started close to clinical onset. The conversion stage was marked by increased NfL, but still normal pNfH levels, while both were increased at the symptomatic stage. Intra-individual change rates were increased for NfL at the conversion stage and for pNfH at the symptomatic stage, highlighting their respective potential as stage-dependent dynamic biomarkers within the biomarker cascade. Increased NfL levels and NfL change rates allowed identification of presymptomatic subjects converting to symptomatic disease and capture of proximity-to-onset. We estimate stage-dependent sample sizes for trials aiming to decrease neurofilament levels or change rates. Blood NfL and pNfH provide dynamic stage-dependent stratification and, potentially, treatment response biomarkers in presymptomatic FTD, allowing demarcation of the conversion stage. The proposed biomarker cascade might pave the way towards a biomarker-based precision medicine approach to genetic FTD. ANN NEUROL 2022;91:33-47.
Substances chimiques
Biomarkers
0
Neurofilament Proteins
0
neurofilament protein L
0
neurofilament protein H
108688-71-7
Types de publication
Journal Article
Multicenter Study
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
33-47Subventions
Organisme : European Reference Network for Rare Neurological Diseases
ID : 739510
Organisme : Memorabel grants from Deltaplan Dementie
ID : 733050103
Organisme : Medical Research Council
ID : MC_UU_00024/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M008525/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100464
Pays : United Kingdom
Organisme : NIHR Cambridge Biomedical Research Centre
ID : BRC-1215-20014
Organisme : Medical Research Council
ID : SUAG/051 G101400
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/J009482/1
Pays : United Kingdom
Organisme : NIHR Rare Disease Translational Research Collaboration
ID : BRC149/NS/MH
Organisme : Schweizerischer Nationalfonds zur Forderung der Wissenschaftlichen Forschung
ID : P400PM_191077
Organisme : EU Joint Programme - Neurodegenerative Disease Research
ID : 2019-02248
Organisme : Horizon 2020 research and innovation programme
ID : 643417
Organisme : Memorabel grants from Deltaplan Dementie
ID : 733050813
Organisme : Medical Research Council
ID : MR/M023664/1
Pays : United Kingdom
Organisme : MRC Clinician Scientist Fellowship
ID : MR/M008525/1
Organisme : Horizon 2020 research and innovation programme
ID : 779257
Organisme : Medical Research Council
ID : MR/T046015/1
Pays : United Kingdom
Investigateurs
Sónia Afonso
(S)
Maria Rosario Almeida
(MR)
Sarah Anderl-Straub
(S)
Christin Andersson
(C)
Anna Antonell
(A)
Silvana Archetti
(S)
Andrea Arighi
(A)
Mircea Balasa
(M)
Myriam Barandiaran
(M)
Nuria Bargalló
(N)
Robart Bartha
(R)
Benjamin Bender
(B)
Alberto Benussi
(A)
Luisa Benussi
(L)
Valentina Bessi
(V)
Giuliano Binetti
(G)
Sandra Black
(S)
Sergi Borrego-Ecija
(S)
Jose Bras
(J)
Rose Bruffaerts
(R)
Marta Cañada
(M)
Valentina Cantoni
(V)
Paola Caroppo
(P)
David Cash
(D)
Miguel Castelo-Branco
(M)
Rhian Convery
(R)
Thomas Cope
(T)
Giuseppe Di Fede
(G)
Alina Díez
(A)
Diana Duro
(D)
Chiara Fenoglio
(C)
Camilla Ferrari
(C)
Catarina B Ferreira
(CB)
Nick Fox
(N)
Morris Freedman
(M)
Giorgio Fumagalli
(G)
Alazne Gabilondo
(A)
Roberto Gasparotti
(R)
Serge Gauthier
(S)
Stefano Gazzina
(S)
Giorgio Giaccone
(G)
Ana Gorostidi
(A)
Caroline Greaves
(C)
Rita Guerreiro
(R)
Carolin Heller
(C)
Tobias Hoegen
(T)
Begoña Indakoetxea
(B)
Vesna Jelic
(V)
Lize Jiskoot
(L)
Hans-Otto Karnath
(HO)
Ron Keren
(R)
Tobias Langheinrich
(T)
Maria João Leitão
(MJ)
Albert Lladó
(A)
Gemma Lombardi
(G)
Sandra Loosli
(S)
Carolina Maruta
(C)
Simon Mead
(S)
Lieke Meeter
(L)
Gabriel Miltenberger
(G)
Rick van Minkelen
(R)
Sara Mitchell
(S)
Katrina Moore
(K)
Benedetta Nacmias
(B)
Jennifer Nicholas
(J)
Linn Öijerstedt
(L)
Jaume Olives
(J)
Sebastien Ourselin
(S)
Alessandro Padovani
(A)
Jessica Panman
(J)
Janne M Papma
(JM)
Georgia Peakman
(G)
Michela Pievani
(M)
Yolande Pijnenburg
(Y)
Cristina Polito
(C)
Enrico Premi
(E)
Sara Prioni
(S)
Catharina Prix
(C)
Rosa Rademakers
(R)
Veronica Redaelli
(V)
Tim Rittman
(T)
Ekaterina Rogaeva
(E)
Pedro Rosa-Neto
(P)
Giacomina Rossi
(G)
Martin Rosser
(M)
Beatriz Santiago
(B)
Elio Scarpini
(E)
Sonja Schönecker
(S)
Harro Seelaar
(H)
Elisa Semler
(E)
Rachelle Shafei
(R)
Christen Shoesmith
(C)
Miguel Tábuas-Pereira
(M)
Mikel Tainta
(M)
Ricardo Taipa
(R)
David Tang-Wai
(D)
David L Thomas
(DL)
Paul Thompson
(P)
Hakan Thonberg
(H)
Carolyn Timberlake
(C)
Pietro Tiraboschi
(P)
Philip Van Damme
(P)
Mathieu Vandenbulcke
(M)
Michele Veldsman
(M)
Ana Verdelho
(A)
Jorge Villanua
(J)
Jason Warren
(J)
Ione Woollacott
(I)
Elisabeth Wlasich
(E)
Henrik Zetterberg
(H)
Miren Zulaica
(M)
Informations de copyright
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Références
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain 2011;134:2456-2477.
Gorno-Tempini ML, Hillis AE, Weintraub S, et al. Classification of primary progressive aphasia and its variants. Neurology 2011;76:1006-1014.
Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol 2019;266:2075-2086.
Hutton M, Lendon CL, Rizzu P, et al. Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702-705.
Baker M, Mackenzie IR, Pickering-Brown SM, et al. Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17. Nature 2006;442:916-919.
Cruts M, Gijselinck I, van der Zee J, et al. Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21. Nature 2006;442:920-924.
Renton AE, Majounie E, Waite A, et al. A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD. Neuron 2011;72:257-268.
DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 2011;72:245-256.
Panza F, Lozupone M, Seripa D, et al. Development of disease-modifying drugs for frontotemporal dementia spectrum disorders. Nat Rev Neurol 2020;16:213-228.
Liscic RM, Alberici A, Cairns NJ, et al. From basic research to the clinic: innovative therapies for ALS and FTD in the pipeline. Mol Neurodegener 2020;15:31.
Benussi A, Alberici A, Samra K, et al. Revising the definition of preclinical and prodromal frontotemporal dementia. in preparation.
Khalil M, Teunissen CE, Otto M, Piehl Fredrik, et al. Neurofilaments as biomarkers in neurological disorders. Nat Rev Neurol. 2018;14:577-589. https://doi.org/10.1038/s41582-018-0058-z
Kuhle J, Barro C, Andreasson U, et al. 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;54:1655-1661.
Wilke C, Pujol-Calderon F, Barro C, et al. Correlations between serum and CSF pNfH levels in ALS, FTD and controls: a comparison of three analytical approaches. Clin Chem Lab Med 2019;57:1556-1564.
Wilke C, Preische O, Deuschle C, et al. Neurofilament light chain in FTD is elevated not only in cerebrospinal fluid, but also in serum. J Neurol Neurosurg Psychiatry 2016;87:1270-1272.
van der Ende EL, Meeter LH, Poos JM, et al. Serum neurofilament light chain in genetic frontotemporal dementia: a longitudinal, multicentre cohort study. Lancet Neurol 2019;18:1103-1111.
Rohrer JD, Nicholas JM, Cash DM, et al. Presymptomatic cognitive and neuroanatomical changes in genetic frontotemporal dementia in the Genetic Frontotemporal dementia Initiative (GENFI) study: a cross-sectional analysis. Lancet Neurol 2015;14:253-262.
Brooks BR, Miller RG, Swash M, et al. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-299.
Miyagawa T, Brushaber D, Syrjanen J, et al. Use of the CDR® plus NACC FTLD in mild FTLD: Data from the ARTFL/LEFFTDS consortium. Alzheimers Dement 2020;16:79-90.
Khalil M, Pirpamer L, Hofer E, et al. Serum neurofilament light levels in normal aging and their association with morphologic brain changes. Nat Commun 2020;11:812.
Wilke C, Haas E, Reetz K, et al. Neurofilaments in spinocerebellar ataxia type 3: blood biomarkers at the preataxic and ataxic stage in humans and mice. EMBO Mol Med 2020 Jun 8;n/a(n/a);12:e11803.
Wilke C, Dos Santos MCT, Schulte C, et al. Intraindividual neurofilament dynamics in serum mark the conversion to sporadic parkinson's disease. Mov Disord 2020;35:1233-1238.
Bateman RJ, Xiong C, Benzinger TLS, et al. Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease. N Engl J Med 2012;367:795-804.
Preische O, Schultz SA, Apel A, et al. Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nat Med 2019 2019/02/01;25:277-283.
Byrne LM, Rodrigues FB, Johnson EB, et al. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington's disease. Sci Transl Med 2018;10:458.
Jacobi H, du Montcel ST, Bauer P, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol 2015;14:1101-1108.
Panman JL, Venkatraghavan V, van der Ende EL, et al. Modelling the cascade of biomarker changes in GRN-related frontotemporal dementia. J Neurol Neurosurg Psychiatry 2021;15:494-501.
Barro C, Chitnis T, Weiner HL. Blood neurofilament light: a critical review of its application to neurologic disease. Ann Clin Transl Neurol 2020;7:2508-2523.
Bridel C, van Wieringen WN, Zetterberg H, et al. Diagnostic value of cerebrospinal fluid neurofilament light protein in neurology: a systematic review and meta-analysis. JAMA Neurol 2019;76:1035-1048.
Wilke C, Bender F, Hayer SN, et al. Serum neurofilament light is increased in multiple system atrophy of cerebellar type and in repeat-expansion spinocerebellar ataxias: a pilot study. J Neurol 2018;265:1618-1624.
Wilke C, Rattay TW, Hengel H, et al. Serum neurofilament light chain is increased in hereditary spastic paraplegias. Ann Clin Transl Neurol 2018;5:876-882.
Ghidoni R, Benussi L, Glionna M, et al. Low plasma progranulin levels predict progranulin mutations in frontotemporal lobar degeneration. Neurology 2008;71:1235-1239.
Finch N, Baker M, Crook R, et al. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members. Brain 2009;132:583-591.
Gendron TF, Chew J, Stankowski JN, et al. Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med 2017;9:9.
Moore KM, Nicholas J, Grossman M, et al. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study. Lancet Neurol 2020;19:145-156.
Rohrer JD, Woollacott IO, Dick KM, et al. Serum neurofilament light chain protein is a measure of disease intensity in frontotemporal dementia. Neurology 2016;87:1329-1336.
Poesen K, de Schaepdryver M, Stubendorff B, et al. Neurofilament markers for ALS correlate with extent of upper and lower motor neuron disease. Neurology 2017;88:2302-2309.
Gille B, de Schaepdryver M, Goossens J, et al. Serum neurofilament light chain levels as a marker of upper motor neuron degeneration in patients with Amyotrophic Lateral Sclerosis. Neuropathol Appl Neurobiol 2019;45:291-304.
Poesen K, Van Damme P. Diagnostic and Prognostic Performance of Neurofilaments in ALS. Front Neurol 2018;9:1167.
de Vivo DC, Topaloglu H, Swoboda KJ, et al. Nusinersen in Infants Who Initiate Treatment in a Presymptomatic Stage of Spinal Muscular Atrophy (SMA): Interim Efficacy and Safety Results From the Phase 2 NURTURE Study (S25.001). Neurology 2019;92:S25.001.
Winter B, Guenther R, Ludolph AC, et al. Neurofilaments and tau in CSF in an infant with SMA type 1 treated with nusinersen. J Neurol Neurosurg Psychiatry 2019;10:1068.2-1068.101069.
Zucchi E, Lu CH, Cho Y, et al. A motor neuron strategy to save time and energy in neurodegeneration: adaptive protein stoichiometry. J Neurochem 2018;146:631-641.
Rosen HJ, Boeve BF, Boxer AL. Tracking disease progression in familial and sporadic frontotemporal lobar degeneration: recent findings from ARTFL and LEFFTDS. Alzheimers Dement 2020;16:71-78.
Andreasson U, Perret-Liaudet A, van Waalwijk van Doorn LJ, et al. A practical guide to immunoassay method validation. Front Neurol 2015;6:179.