Plasma neurofilament light for prediction of disease progression in familial frontotemporal lobar degeneration

Objective: We tested the hypothesis that plasma neurofilament light chain
(NfL) concentrations identify asymptomatic carriers of familial
frontotemporal lobar degeneration (FTLD)-causing mutations at risk of
disease progression. Methods: Baseline plasma NfL concentrations were
measured with Simoa in original (n = 277) and validation (n = 297)
cohorts. C9orf72, GRN and MAPT mutation carriers and non-carriers from the
same families were classified by disease severity [asymptomatic, prodromal
and full phenotype] using the CDR® Dementia Staging Instrument plus
behavior and language domains from the National Alzheimer’s Disease
Coordinating Center FTLD module (CDR®+NACC-FTLD). Linear mixed effect
models related NfL to clinical variables. Results: In both cohorts,
baseline NfL was higher in asymptomatic mutation carriers who showed
phenoconversion or subsequent disease progression compared to
non-progressors (original: 11.4 ± 7 pg/mL vs. 6.7 ± 5 pg/mL, p = 0.002;
validation: 14.1 ± 12 pg/mL vs. 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL
discriminated symptomatic from asymptomatic mutation carriers or prodromal
disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7%
specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3%
specificity). Higher baseline NfL correlated with worse longitudinal
CDR®+NACC-FTLD sum of boxes scores, neuropsychological function and
atrophy, regardless of genotype or disease severity, including
asymptomatic mutation carriers. Conclusions: Plasma NfL identifies
asymptomatic carriers of FTLD-causing mutations at short-term risk of
disease progression, and is a potential tool to select participants for
prevention clinical trials. Classification of evidence: This study
provides Class I evidence that in familial FTLD, elevation of plasma NfL
predicts short-term risk of clinical progression.