Abstract
ObjectiveWe tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)–causing mutations at risk of disease progression.MethodsBaseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers 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.ResultsIn both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (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 those with 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.ConclusionsPlasma 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.Trial Registration InformationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of EvidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
Highlights
Linear mixedeffect models related neurofilament light chain (NfL) to clinical variables. In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors
Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease
Higher baseline NfL correlated with worse longitudinal CDR+NACC-frontotemporal lobar degeneration (FTLD) sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers
Summary
The primary research question was the following: do plasma NfL concentrations identify f-FTLD mutation carriers at risk of clinical progression (Class I level of evidence)?. GENFI involves 25 research centers across Europe and Canada and enrolls symptomatic carriers of mutations in the 3 major FTLD genes with frontotemporal dementia and those at risk of carrying a mutation because a first-degree relative is a known symptomatic carrier Both cohorts consisted of participants with available baseline NfL concentrations, known genotype, and CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer’s Disease Coordinating Center FTLD module (CDR+NACC-FTLD) global and sum of boxes (sb) scores.. The samples analyzed by the 2 centers had comparable means and SDs (Quanterix 21.8 ± 35 pg/mL and Novartis 20.2 ± 34 pg/mL), and there were no differences in the median plasma NfL concentrations in 2 groups of age-matched asymptomatic noncarrier controls measured separately (Quanterix 6.9 ± 4 pg/mL, n = 38 vs Novartis 6.4 ± 6 pg/mL, n = 50, p = 0.6). Data Availability Joint ARTFL and LEFFTDS data and biospecimens and GENFI data are available to qualified investigators for replication of the present study results or further projects
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