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

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

Comprehensive cross-sectional and longitudinal analyses of plasma neurofilament light across FTD spectrum disorders

“…We show that, compared to measures in controls or presymptomatic mutation carriers who did not phenoconvert, baseline plasma NfL and rates of NfL change were higher in presymptomatic carriers before phenoconversion. These data validate and extend prior cross-sectional 24 and longitudinal 20 , 25 , 26 studies. For example, Rojas et al.…”

“…Fortunately, findings suggest that blood NfL increases as presymptomatic FTD mutation carriers approach prodromal and disease stages. 20 , 24 , 25 , 26 However, because the number of phenoconverters in each study was small, additional investigations are crucial if we are to establish whether NfL represents a viable phenoconversion biomarker.…”

How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases

“…Among the fluid-based biomarkers investigated for this purpose, neurofilaments turned out to be particularly useful [77][78][79][80]. Neurofilaments are structural proteins highly expressed in axons, composed of three main subunits, heavy (NfH), medium and light chain (NfL).…”

“…With the development of the highly sensitive Simoa technique, neurofilament dosage can be easily performed in plasma or serum, whose levels are extremely correlated to CSF ones, thus allowing less invasive, repeatable dosages [84,85]. NfL levels in preclinical C9orf72 carriers are comparable to controls at a group level [77,84], with steady, low-amplitude increases over the years [79,80]. NfL levels and their annualized rates of change increase during or just before the prodromal phase [47,77,79], thus allowing to identify those who are at risk of short-term progression to clinical disease, in the subsequent 2 to 5 years [78].…”

Plasma Neurofilament Light Chain in memory clinic practice: evidence from a real-life study

“…Third, patients with FTD showed the highest plasma NfL concentration, which differed signi cantly from individuals diagnosed with LBD, NC and NND, but not from those with OND or AD. In a recent publication, Wilke et al reported that plasma NfL progressively increased in conversion stages of genetic forms of FTD (19). The absence of difference between patients with FTD and AD might be explained by the inclusion of early-stage FTD subjects in our sample (20).…”