Neurofilament light chain: a biomarker for genetic frontotemporal dementia

Abstract

Objective: To evaluate cerebrospinal fluid (CSF) and serum neurofilament light chain (NfL) levels in genetic frontotemporal dementia (FTD) as a potential biomarker in the presymptomatic stage and during the conversion into the symptomatic stage. Additionally, to correlate NfL levels to clinical and neuroimaging parameters.

Methods: In this multicenter case-control study, we investigated CSF NfL in 174 subjects (48 controls, 40 presymptomatic carriers and 86 patients with microtubule-associated protein tau (MAPT), progranulin (GRN), and chromosome 9 open reading frame 72 (C9orf72) mutations), and serum NfL in 118 subjects (39 controls, 44 presymptomatic carriers, 35 patients). In 55 subjects both CSF and serum was determined. In two subjects CSF was available before and after symptom onset (converters). Additionally, NfL levels were correlated with clinical parameters, survival, and regional brain atrophy.

Results: CSF NfL levels in patients (median 6762 pg/mL, interquartile range 3186-9309 pg/mL) were strongly elevated compared with presymptomatic carriers (804 pg/mL, 627-1173 pg/mL, P < 0.001), resulting in a good diagnostic performance to discriminate both groups. Serum NfL correlated highly with CSF NfL (r s = 0.87, P < 0.001) and was similarly elevated in patients. Longitudinal samples in the converters showed a three- to fourfold increase in CSF NfL after disease onset. Additionally, NfL levels in patients correlated with disease severity, brain atrophy, annualized brain atrophy rate and survival.

Interpretation: NfL in both serum and CSF has the potential to serve as a biomarker for clinical disease onset and has a prognostic value in genetic FTD.

Figure 1

Neurofilament light chain (NfL) levels in presymptomatic carriers and patients. NfL in (A) cerebrospinal fluid (CSF) and (C) serum by controls, presymptomatic carriers and patients; patients with concomitant amyotrophic lateral sclerosis are displayed as filled orange diamonds. Upper blue dashed lines represent the cut‐off line to separate presymptomatic carriers from patients at 2165 pg/mL for CSF (sensitivity 84%, specificity 100%) and at 18.0 pg/mL for serum (sensitivity 77%, specificity 98%). Lower green dashed lines represent the cut‐off line to separate controls from patients at 1190 pg/mL for CSF (sensitivity 97%, specificity 98%) and at 9.3 pg/mL for serum (sensitivity 91%, specificity 100%). NfL levels in (B) CSF and (D) serum specified by genetic group and clinical stage. Significances from the analysis of covariance analyses are displayed (corrected for age in all comparisons and additionally for disease duration in the comparisons between affected genes in patients). In Figure S3, graphs of the transformed data are shown. Ns, not significant; *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001.

Figure 2

Correlations between neurofilament light chain (NfL) levels and clinical or imaging data. (A) Correlation between serum and cerebrospinal fluid (CSF) NfL, circles represent controls, squares represent presymptomatic carriers and triangles represent patients; filled data points are collected on the same day; a log‐scale is used for display purposes, one sample had a serum NfL of 0 pg/mL and is thus excluded from the graph, but not from the analysis. (B) Correlation of CSF NfL with disease duration in patients (orange triangles). Correlations between CSF NfL and (C) whole‐brain volume and (D) insular annualized atrophy rate in presymptomatic carriers (blue squares) and patients (orange triangles). Kaplan–Meier curves of (E) all patients with CSF available and (F) all patients with serum available; NfL levels were stratified into tertiles: the blue upper lines represent the lowest tertiles, the green middle lines the middle tertiles and the orange lower lines the highest tertiles; information on survival was available in 72 out of 86 patients with CSF and all patients with serum (n = 35).