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Stratifying the Presymptomatic Phase of Genetic Frontotemporal Dementia by Serum NfL and pNfH : A Longitudinal Multicentre Study
Author(s) -
Wilke Carlo,
Reich Selina,
Swieten John C.,
Borroni Barbara,
SanchezValle Raquel,
Moreno Fermin,
Laforce Robert,
Graff Caroline,
Galimberti Daniela,
Rowe James B.,
Masellis Mario,
Tartaglia Maria C.,
Finger Elizabeth,
Vandenberghe Rik,
Mendonça Alexandre,
Tagliavini Fabrizio,
Santana Isabel,
Ducharme Simon,
Butler Chris R.,
Gerhard Alexander,
Levin Johannes,
Danek Adrian,
Otto Markus,
Frisoni Giovanni,
Ghidoni Roberta,
Sorbi Sandro,
Bocchetta Martina,
Todd Emily,
Kuhle Jens,
Barro Christian,
Rohrer Jonathan D.,
Synofzik Matthis
Publication year - 2022
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.26265
Subject(s) - frontotemporal dementia , biomarker , c9orf72 , oncology , dementia , medicine , cohort , neurodegeneration , disease , genetics , biology
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