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Multicenter Study
. 2022 Jan;91(1):33-47.
doi: 10.1002/ana.26265. Epub 2021 Nov 29.

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

Carlo Wilke  1   2 , Selina Reich  1   2 , John C van Swieten  3 , Barbara Borroni  4 , Raquel Sanchez-Valle  5 , Fermin Moreno  6   7 , Robert Laforce  8 , Caroline Graff  9   10 , Daniela Galimberti  11   12 , James B Rowe  13 , Mario Masellis  14 , Maria C Tartaglia  15 , Elizabeth Finger  16 , Rik Vandenberghe  17   18   19 , Alexandre de Mendonça  20 , Fabrizio Tagliavini  21 , Isabel Santana  22   23 , Simon Ducharme  24   25 , Chris R Butler  26   27 , Alexander Gerhard  28   29 , Johannes Levin  30   31   32 , Adrian Danek  30 , Markus Otto  33   34 , Giovanni Frisoni  35 , Roberta Ghidoni  36 , Sandro Sorbi  37   38 , Martina Bocchetta  39 , Emily Todd  39 , Jens Kuhle  40 , Christian Barro  40   41 ; Genetic Frontotemporal dementia Initiative (GENFI); Jonathan D Rohrer  39 , Matthis Synofzik  1   2
Collaborators, Affiliations
Free article
Multicenter Study

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

Carlo Wilke et al. Ann Neurol. 2022 Jan.
Free article

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.

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