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

2021; Lippincott Williams & Wilkins; Volume: 96; Issue: 18 Linguagem: Inglês

10.1212/wnl.0000000000011848

1526-632X

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 Fong, Joanne Taylor, Eliseo Veras, Linan Song, Andreas Jeromin, David Hanlon, Lili Yu, Arvind Khinikar, Rajeev Sivasankaran, Agnieszka Kieloch, Marie‐Anne Valentin, Anna M. Karydas, Laura L. Mitic, Rodney Pearlman, John Kornak, Joel H. Kramer, Bruce L. Miller, Kejal Kantarci, David S. Knopman, Neill R. 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 Robin Hsiung, Arthur W. Toga, Sandra Weıntraub, Daniel Kaufer, Diana Kerwin, Irene Litvan, Chiadikaobi Onyike, Alexander Pantelyat, Erik D. Roberson, Maria Carmela Tartaglia, Tatiana Foroud, Weiping Chen, Julie Czerkowicz, Danielle Graham, John C. van Swieten, Barbara Borroni, Raquel Sánchez‐Valle, Fermín Moreno, Robert Laforce, Caroline Graff, Matthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Fabrizio Tagliavini, Isabel Santana, Simon Ducharme, Christopher Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Markus Otto, Sandro Sorbi, David M. Cash, Rhian S. Convery, Martina Bocchetta, Martha Foiani, Caroline Greaves, Georgia Peakman, Lucy L. Russell, Imogen J. Swift, Emily Todd, Jonathan D. Rohrer, Bradley F. Boeve, Howard J. Rosen, Adam L. Boxer,

Parkinson's Disease Mechanisms and Treatments

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.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.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.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.ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.