Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study

Wilke, C.; Reich, S.; van Swieten, J. C.; Borroni, B.; Sanchez-Valle, R.; Moreno, F.; Laforce, R.; Graff, C.; Galimberti, D.; Rowe, J. B.; Masellis, M.; Tartaglia, M. C.; Finger, E.; Vandenberghe, R.; de Mendonca, A.; Tagliavini, F.; Santana, I.; Ducharme, S.; Butler, C. R.; Gerhard, A.; Levin, J.; Danek, A.; Otto, M.; Frisoni, G.; Ghidoni, R.; Sorbi, S.; Bocchetta, M.; Todd, E.; Kuhle, J.; Barro, C.; Afonso, S.; Almeida, M. R.; Anderl-Straub, S.; Andersson, C.; Antonell, A.; Archetti, S.; Arighi, A.; Balasa, M.; Barandiaran, M.; Bargallo, N.; Bartha, R.; Bender, B.; Benussi, A.; Benussi, L.; Bessi, V.; Binetti, G.; Black, S.; Borrego-Ecija, S.; Bras, J.; Bruffaerts, R.; Canada, M.; Cantoni, V.; Caroppo, P.; Cash, D.; Castelo-Branco, M.; Convery, R.; Cope, T.; Di Fede, G.; Diez, A.; Duro, D.; Fenoglio, C.; Ferrari, C.; Ferreira, C. B.; Fox, N.; Freedman, M.; Fumagalli, G.; Gabilondo, A.; Gasparotti, R.; Gauthier, S.; Gazzina, S.; Giaccone, G.; Gorostidi, A.; Greaves, C.; Guerreiro, R.; Heller, C.; Hoegen, T.; Indakoetxea, B.; Jelic, V.; Jiskoot, L.; Karnath, H. -O.; Keren, R.; Langheinrich, T.; Leitao, M. J.; Llado, A.; Lombardi, G.; Loosli, S.; Maruta, C.; Mead, S.; Meeter, L.; Miltenberger, G.; van Minkelen, R.; Mitchell, S.; Moore, K.; Nacmias, B.; Nicholas, J.; Oijerstedt, L.; Olives, J.; Ourselin, S.; Padovani, A.; Panman, J.; Papma, J. M.; Peakman, G.; Pievani, M.; Pijnenburg, Y.; Polito, C.; Premi, E.; Prioni, S.; Prix, C.; Rademakers, R.; Redaelli, V.; Rittman, T.; Rogaeva, E.; Rosa-Neto, P.; Rossi, G.; Rosser, M.; Santiago, B.; Scarpini, E.; Schonecker, S.; Seelaar, H.; Semler, E.; Shafei, R.; Shoesmith, C.; Tabuas-Pereira, M.; Tainta, M.; Taipa, R.; Tang-Wai, D.; Thomas, D. L.; Thompson, P.; Thonberg, H.; Timberlake, C.; Tiraboschi, P.; Van Damme, P.; Vandenbulcke, M.; Veldsman, M.; Verdelho, A.; Villanua, J.; Warren, J.; Woollacott, I.; Wlasich, E.; Zetterberg, H.; Zulaica, M.; Rohrer, J. D.; Synofzik, M.

doi:10.1002/ana.26265

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.

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study / Wilke, C.; Reich, S.; van Swieten, J. C.; Borroni, B.; Sanchez-Valle, R.; Moreno, F.; Laforce, R.; Graff, C.; Galimberti, D.; Rowe, J. B.; Masellis, M.; Tartaglia, M. C.; Finger, E.; Vandenberghe, R.; de Mendonca, A.; Tagliavini, F.; Santana, I.; Ducharme, S.; Butler, C. R.; Gerhard, A.; Levin, J.; Danek, A.; Otto, M.; Frisoni, G.; Ghidoni, R.; Sorbi, S.; Bocchetta, M.; Todd, E.; Kuhle, J.; Barro, C.; Afonso, S.; Almeida, M. R.; Anderl-Straub, S.; Andersson, C.; Antonell, A.; Archetti, S.; Arighi, A.; Balasa, M.; Barandiaran, M.; Bargallo, N.; Bartha, R.; Bender, B.; Benussi, A.; Benussi, L.; Bessi, V.; Binetti, G.; Black, S.; Borrego-Ecija, S.; Bras, J.; Bruffaerts, R.; Canada, M.; Cantoni, V.; Caroppo, P.; Cash, D.; Castelo-Branco, M.; Convery, R.; Cope, T.; Di Fede, G.; Diez, A.; Duro, D.; Fenoglio, C.; Ferrari, C.; Ferreira, C. B.; Fox, N.; Freedman, M.; Fumagalli, G.; Gabilondo, A.; Gasparotti, R.; Gauthier, S.; Gazzina, S.; Giaccone, G.; Gorostidi, A.; Greaves, C.; Guerreiro, R.; Heller, C.; Hoegen, T.; Indakoetxea, B.; Jelic, V.; Jiskoot, L.; Karnath, H. -O.; Keren, R.; Langheinrich, T.; Leitao, M. J.; Llado, A.; Lombardi, G.; Loosli, S.; Maruta, C.; Mead, S.; Meeter, L.; Miltenberger, G.; van Minkelen, R.; Mitchell, S.; Moore, K.; Nacmias, B.; Nicholas, J.; Oijerstedt, L.; Olives, J.; Ourselin, S.; Padovani, A.; Panman, J.; Papma, J. M.; Peakman, G.; Pievani, M.; Pijnenburg, Y.; Polito, C.; Premi, E.; Prioni, S.; Prix, C.; Rademakers, R.; Redaelli, V.; Rittman, T.; Rogaeva, E.; Rosa-Neto, P.; Rossi, G.; Rosser, M.; Santiago, B.; Scarpini, E.; Schonecker, S.; Seelaar, H.; Semler, E.; Shafei, R.; Shoesmith, C.; Tabuas-Pereira, M.; Tainta, M.; Taipa, R.; Tang-Wai, D.; Thomas, D. L.; Thompson, P.; Thonberg, H.; Timberlake, C.; Tiraboschi, P.; Van Damme, P.; Vandenbulcke, M.; Veldsman, M.; Verdelho, A.; Villanua, J.; Warren, J.; Woollacott, I.; Wlasich, E.; Zetterberg, H.; Zulaica, M.; Rohrer, J. D.; Synofzik, M.. - In: ANNALS OF NEUROLOGY. - ISSN 0364-5134. - 91:1(2022), pp. 33-47. [10.1002/ana.26265]

Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study

Wilke C.;Reich S.;van Swieten J. C.;Borroni B.;Sanchez-Valle R.;Moreno F.;Laforce R.;Graff C.;Galimberti D.;Rowe J. B.;Masellis M.;Tartaglia M. C.;Finger E.;Vandenberghe R.;de Mendonca A.;Tagliavini F.;Santana I.;Ducharme S.;Butler C. R.;Gerhard A.;Levin J.;Danek A.;Otto M.;Frisoni G.;Ghidoni R.;Sorbi S.;Bocchetta M.;Todd E.;Kuhle J.;Barro C.;Afonso S.;Almeida M. R.;Anderl-Straub S.;Andersson C.;Antonell A.;Archetti S.;Arighi A.;Balasa M.;Barandiaran M.;Bargallo N.;Bartha R.;Bender B.;Benussi A.;Benussi L.;Bessi V.;Binetti G.;Black S.;Borrego-Ecija S.;Bras J.;Bruffaerts R.;Canada M.;Cantoni V.;Caroppo P.;Cash D.;Castelo-Branco M.;Convery R.;Cope T.;Di Fede G.;Diez A.;Duro D.;Fenoglio C.;Ferrari C.;Ferreira C. B.;Fox N.;Freedman M.;Fumagalli G.;Gabilondo A.;Gasparotti R.;Gauthier S.;Gazzina S.;Giaccone G.;Gorostidi A.;Greaves C.;Guerreiro R.;Heller C.;Hoegen T.;Indakoetxea B.;Jelic V.;Jiskoot L.;Karnath H. -O.;Keren R.;Langheinrich T.;Leitao M. J.;Llado A.;Lombardi G.;Loosli S.;Maruta C.;Mead S.;Meeter L.;Miltenberger G.;van Minkelen R.;Mitchell S.;Moore K.;Nacmias B.;Nicholas J.;Oijerstedt L.;Olives J.;Ourselin S.;Padovani A.;Panman J.;Papma J. M.;Peakman G.;Pievani M.;Pijnenburg Y.;Polito C.;Premi E.;Prioni S.;Prix C.;Rademakers R.;Redaelli V.;Rittman T.;Rogaeva E.;Rosa-Neto P.;Rossi G.;Rosser M.;Santiago B.;Scarpini E.;Schonecker S.;Seelaar H.;Semler E.;Shafei R.;Shoesmith C.;Tabuas-Pereira M.;Tainta M.;Taipa R.;Tang-Wai D.;Thomas D. L.;Thompson P.;Thonberg H.;Timberlake C.;Tiraboschi P.;Van Damme P.;Vandenbulcke M.;Veldsman M.;Verdelho A.;Villanua J.;Warren J.;Woollacott I.;Wlasich E.;Zetterberg H.;Zulaica M.;Rohrer J. D.;Synofzik M.

2022-01-01

Abstract

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.

Scheda breve

Scheda completa

Scheda completa (DC)

	Anno di pubblicazione (Date of publication)
	
				2022
			
	Titolo del periodico (Journal title)
	
				ANNALS OF NEUROLOGY
			
	Numero e parte del fascicolo (Issue number and part)
	
				1
			
	DOI
	
				https://dx.doi.org/10.1002/ana.26265
			
	Codice PubMed (PubMed Identifier)
	
				34743360
			
	Codice Scopus (Scopus identifier)
	
				2-s2.0-85120051874
			
	Codice WOS (WOS identifier)
	
				WOS:000723188500001
			
	Tutti gli autori
	
						Wilke, C.; Reich, S.; van Swieten, J. C.; Borroni, B.; Sanchez-Valle, R.; Moreno, F.; Laforce, R.; Graff, C.; Galimberti, D.; Rowe, J. B.; Masellis, M...espandi
						
	Citazione
	
				Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH: A Longitudinal Multicentre Study / Wilke, C.; Reich, S.; van Swieten, J. C.; Borroni, B.; Sanchez-Valle, R.; Moreno, F.; Laforce, R.; Graff, C.; Galimberti, D.; Rowe, J. B.; Masellis, M.; Tartaglia, M. C.; Finger, E.; Vandenberghe, R.; de Mendonca, A.; Tagliavini, F.; Santana, I.; Ducharme, S.; Butler, C. R.; Gerhard, A.; Levin, J.; Danek, A.; Otto, M.; Frisoni, G.; Ghidoni, R.; Sorbi, S.; Bocchetta, M.; Todd, E.; Kuhle, J.; Barro, C.; Afonso, S.; Almeida, M. R.; Anderl-Straub, S.; Andersson, C.; Antonell, A.; Archetti, S.; Arighi, A.; Balasa, M.; Barandiaran, M.; Bargallo, N.; Bartha, R.; Bender, B.; Benussi, A.; Benussi, L.; Bessi, V.; Binetti, G.; Black, S.; Borrego-Ecija, S.; Bras, J.; Bruffaerts, R.; Canada, M.; Cantoni, V.; Caroppo, P.; Cash, D.; Castelo-Branco, M.; Convery, R.; Cope, T.; Di Fede, G.; Diez, A.; Duro, D.; Fenoglio, C.; Ferrari, C.; Ferreira, C. B.; Fox, N.; Freedman, M.; Fumagalli, G.; Gabilondo, A.; Gasparotti, R.; Gauthier, S.; Gazzina, S.; Giaccone, G.; Gorostidi, A.; Greaves, C.; Guerreiro, R.; Heller, C.; Hoegen, T.; Indakoetxea, B.; Jelic, V.; Jiskoot, L.; Karnath, H. -O.; Keren, R.; Langheinrich, T.; Leitao, M. J.; Llado, A.; Lombardi, G.; Loosli, S.; Maruta, C.; Mead, S.; Meeter, L.; Miltenberger, G.; van Minkelen, R.; Mitchell, S.; Moore, K.; Nacmias, B.; Nicholas, J.; Oijerstedt, L.; Olives, J.; Ourselin, S.; Padovani, A.; Panman, J.; Papma, J. M.; Peakman, G.; Pievani, M.; Pijnenburg, Y.; Polito, C.; Premi, E.; Prioni, S.; Prix, C.; Rademakers, R.; Redaelli, V.; Rittman, T.; Rogaeva, E.; Rosa-Neto, P.; Rossi, G.; Rosser, M.; Santiago, B.; Scarpini, E.; Schonecker, S.; Seelaar, H.; Semler, E.; Shafei, R.; Shoesmith, C.; Tabuas-Pereira, M.; Tainta, M.; Taipa, R.; Tang-Wai, D.; Thomas, D. L.; Thompson, P.; Thonberg, H.; Timberlake, C.; Tiraboschi, P.; Van Damme, P.; Vandenbulcke, M.; Veldsman, M.; Verdelho, A.; Villanua, J.; Warren, J.; Woollacott, I.; Wlasich, E.; Zetterberg, H.; Zulaica, M.; Rohrer, J. D.; Synofzik, M.. - In: ANNALS OF NEUROLOGY. - ISSN 0364-5134. - 91:1(2022), pp. 33-47. [10.1002/ana.26265]
			
	Appare nelle tipologie:
	
				03.1 Articolo su rivista (Journal article)

File in questo prodotto:

File	Dimensione	Formato
2021 Wilke AnnalsNeurology.pdf accesso aperto Descrizione: first online Tipologia: Versione editoriale (Publisher’s layout) Licenza: Creative commons Dimensione 2.29 MB Formato Adobe PDF Visualizza/Apri	2.29 MB	Adobe PDF	Visualizza/Apri
Annals of Neurology - 2021 - Wilke - Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL.pdf accesso aperto Tipologia: Versione editoriale (Publisher’s layout) Licenza: Creative commons Dimensione 2.3 MB Formato Adobe PDF Visualizza/Apri	2.3 MB	Adobe PDF	Visualizza/Apri