To study the association of plasma neurofilament light chain (pNfL) levels and their annualized rate of change (ARC) with clinical and prognostic variables in frontotemporal dementia (FTD) due to C9orf72 and GRN mutations, and with markers of phenoconversion in presymptomatic carriers.

C9orf72 and GRN mutations are the main genetic causes of FTD and, for C9orf72, amyotrophic lateral sclerosis (ALS). pNfL levels are elevated during the clinical phase and show the highest increase before phenoconversion, with remarkable heterogeneity among individual trajectories. In order to correctly interpret their values for clinical practice and therapeutic trials, more information about expected pNfL trajectories according to causal gene and clinical profiles is needed.

Our study cohort consisted of 372 individuals, including 112 C9orf72 expansion carriers (63 symptomatic, 49 presymptomatic), 93 GRN mutation carriers (52 symptomatic, 41 presymptomatic), and 167 controls. Participants were recruited through PREV-DEMALS and Predict-PGRN protocols, and the national research network on FTD/ALS. They underwent repeated plasma samplings during a mean follow-up of 4 years. Longitudinal neuroimaging studies were performed in presymptomatic carriers. pNfL were analyzed with SIMOA.

In controls, pNfL increased with aging and their ARC was +4% on average.

The causal gene markedly influenced pNfL in patients, with higher levels (p=0.014) and more sustained annualized increases in GRN than C9orf72 carriers (30% vs 25%, p=0.016). In GRN disease, the effect of aging on pNfL was completely overshadowed; additionally, patients with extensive white matter hyperintensities had higher pNfL.

Among C9orf72 carriers, pNfL mirrored phenotype severity, with highest levels in ALS patients (p=0.008). Notably, a lower ARC predicted slowly progressive disease course.

In presymptomatic carriers, remarkable pNfL increases were associated with progressive frontotemporal involvement.

pNfL levels prove their usefulness in tracking the degenerative process in C9orf72 and GRN mutations since its presymptomatic stage. Their trajectories reflect disease severity and progression rate.