TY - JOUR
T1 - Stratifying the presymptomatic phase of genetic frontotemporal dementia by serum NfL and pNfH
T2 - a longitudinal multicentre study
AU - Genetic Frontotemporal dementia Initiative (GENFI)
AU - Wilke, Carlo
AU - Reich, Selina
AU - van Swieten, John C.
AU - Borroni, Barbara
AU - Sanchez-Valle, Raquel
AU - Moreno, Fermin
AU - Laforce, Robert
AU - Graff, Caroline
AU - Galimberti, Daniela
AU - Rowe, James B.
AU - Masellis, Mario
AU - Tartaglia, Maria C.
AU - Finger, Elizabeth
AU - Vandenberghe, Rik
AU - de Mendonça, Alexandre
AU - Tagliavini, Fabrizio
AU - Santana, Isabel
AU - Ducharme, Simon
AU - Butler, Chris R.
AU - Gerhard, Alexander
AU - Levin, Johannes
AU - Danek, Adrian
AU - Otto, Markus
AU - Frisoni, Giovanni
AU - Ghidoni, Roberta
AU - Sorbi, Sandro
AU - Bocchetta, Martina
AU - Todd, Emily
AU - Kuhle, Jens
AU - Barro, Christian
AU - Afonso, Sónia
AU - Almeida, Maria Rosario
AU - Anderl-Straub, Sarah
AU - Andersson, Christin
AU - Antonell, Anna
AU - Archetti, Silvana
AU - Arighi, Andrea
AU - Balasa, Mircea
AU - Barandiaran, Myriam
AU - Bargalló, Nuria
AU - Bartha, Robart
AU - Bender, Benjamin
AU - Benussi, Alberto
AU - Benussi, Luisa
AU - Bessi, Valentina
AU - Binetti, Giuliano
AU - Black, Sandra
AU - Borrego-Ecija, Sergi
AU - Bras, Jose
AU - Maruta, Carolina
N1 - Funding Information:
The authors thank all participants and their families for their contribution to the GENFI study. C.W. and M.S. are members of the European Reference Network for Rare Neurological Diseases Project ID No. 739510. This work was supported by the Horizon 2020 research and innovation program (grant 779257 Solve‐RD to M.S.), the National Ataxia Foundation (grant to C.W. and M.S.), the Wilhelm Vaillant Stiftung (grant to C.W.), the EU Joint Programme – Neurodegenerative Disease Research (JPND) “GENFI‐prox” through participating national funding agencies (by DLR/BMBF to M.S., J.D.R., B.B., C.G., and M.O.), and the European Union's Horizon 2020 research and innovation programme under grant agreement No. 643417. J.C.S. and H.S. received funding by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813 and 733050103) in the Netherlands and the Bluefield Project to Cure Frontotemporal Dementia. J.B.R. was supported by the NIHR Cambridge Biomedical Research Centre (BRC‐1215‐20014) and the Medical Research Council (SUAG/051 G101400). C.B. is supported by a postdoctoral fellowship from the Swiss National Science Foundation (P400PM_191077). J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI‐PROX grant (2019‐02248). The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.
Funding Information:
The authors thank all participants and their families for their contribution to the GENFI study. C.W. and M.S. are members of the European Reference Network for Rare Neurological Diseases Project ID No. 739510. This work was supported by the Horizon 2020 research and innovation program (grant 779257 Solve-RD to M.S.), the National Ataxia Foundation (grant to C.W. and M.S.), the Wilhelm Vaillant Stiftung (grant to C.W.), the EU Joint Programme ? Neurodegenerative Disease Research (JPND) ?GENFI-prox? through participating national funding agencies (by DLR/BMBF to M.S., J.D.R., B.B., C.G., and M.O.), and the European Union's Horizon 2020 research and innovation programme under grant agreement No. 643417. J.C.S. and H.S. received funding by two Memorabel grants from Deltaplan Dementie (The Netherlands Organisation for Health Research and Development and Alzheimer Nederland; grant numbers 733050813 and 733050103) in the Netherlands and the Bluefield Project to Cure Frontotemporal Dementia. J.B.R. was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014) and the Medical Research Council (SUAG/051 G101400). C.B. is supported by a postdoctoral fellowship from the Swiss National Science Foundation (P400PM_191077). J.D.R. is supported by the Miriam Marks Brain Research UK Senior Fellowship and has received funding from an MRC Clinician Scientist Fellowship (MR/M008525/1) and the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project and the JPND GENFI-PROX grant (2019-02248). The funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the manuscript.
Publisher Copyright:
© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
PY - 2022/1
Y1 - 2022/1
N2 - Objective: 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. Methods: 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. Results: 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. Interpretation: 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.
AB - Objective: 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. Methods: 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. Results: 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. Interpretation: 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.
UR - http://www.scopus.com/inward/record.url?scp=85120051874&partnerID=8YFLogxK
U2 - 10.1002/ana.26265
DO - 10.1002/ana.26265
M3 - Article
C2 - 34743360
AN - SCOPUS:85120051874
SN - 0364-5134
VL - 91
SP - 33
EP - 47
JO - Annals of Neurology
JF - Annals of Neurology
IS - 1
ER -