Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration

ALLFTD and GENFI consortia, Julio C. Rojas, Ping Wang, Adam M. Staffaroni, Carolin Heller, Yann Cobigo, Amy Wolf, Sheng Yang M. Goh, Peter A. Ljubenkov, Hilary W. Heuer, Jamie C. Fong, Joanne B. Taylor, Eliseo Veras, Linan Song, Andreas Jeromin, David Hanlon, Lili Yu, Arvind Khinikar, Rajeev Sivasankaran, Agnieszka KielochMarie Anne Valentin, Anna M. Karydas, Laura L. Mitic, Rodney Pearlman, John Kornak, Joel H. Kramer, Bruce L. Miller, Kejal Kantarci, David S. Knopman, Neill Graff-Radford, Leonard Petrucelli, Rosa Rademakers, David J. Irwin, Murray Grossman, Eliana Marisa Ramos, Giovanni Coppola, Mario F. Mendez, Yvette Bordelon, Bradford C. Dickerson, Nupur Ghoshal, Edward D. Huey, Ian R. Mackenzie, Brian S. Appleby, Kimiko Domoto-Reilly, Ging Yuek R. Hsiung, Arthur W. Toga, Barbara Borroni, Daniela Galimberti, Fabrizio Tagliavini, Sandro Sorbi, Martina Bocchetta

Research output: Contribution to journalArticlepeer-review


OBJECTIVE: We 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. METHODS: Baseline 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. RESULTS: In 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. 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. TRIAL REGISTRATION INFORMATION: Identifier: NCT02372773 and NCT02365922. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.

Original languageEnglish
Pages (from-to)e2296-e2312
Issue number18
Publication statusPublished - May 4 2021

ASJC Scopus subject areas

  • Clinical Neurology


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