Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration.
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Rojas Julio C, Wang Ping, Staffaroni Adam M, Heller Carolin, Cobigo Yann, Wolf Amy, Goh Sheng-Yang M, Ljubenkov Peter A, Heuer Hilary W, Fong Jamie C, Taylor Joanne B, Veras Eliseo, Song Linan, Jeromin Andreas, Hanlon David, Yu Lili, Khinikar Arvind, Sivasankaran Rajeev, Kieloch Agnieszka, Valentin Marie-Anne, Karydas Anna M, Mitic Laura L, Pearlman Rodney, Kornak John, Kramer Joel H, Miller Bruce L, Kantarci Kejal, Knopman David S, Graff-Radford Neill, Petrucelli Leonard, Rademakers Rosa, Irwin David J, Grossman Murray, Ramos Eliana Marisa, Coppola Giovanni, Mendez Mario F, Bordelon Yvette, Dickerson Bradford C, Ghoshal Nupur, Huey Edward D, Mackenzie Ian R, Appleby Brian S, Domoto-Reilly Kimiko, Hsiung Ging-Yuek R, Toga Arthur W, Weintraub Sandra, Kaufer Daniel I, Kerwin Diana, Litvan Irene, Onyike Chiadikaobi U, Pantelyat Alexander, Roberson Erik D, Tartaglia Maria C, Foroud Tatiana, Chen Weiping, Czerkowicz Julie, Graham Danielle L, van Swieten John C, Borroni Barbara, Sanchez-Valle Raquel, Moreno Fermin, Laforce Robert, Graff Caroline, Synofzik Matthis, Galimberti Daniela, Rowe James B, Masellis Mario, Finger Elizabeth, Vandenberghe Rik, de Mendonça Alexandre, Tagliavini Fabrizio, Santana Isabel, Ducharme Simon, Butler Chris R, Gerhard Alexander, Levin Johannes, Danek Adrian, Otto Markus, Sorbi Sandro, Cash David M, Convery Rhian S, Bocchetta Martina, Foiani Martha, Greaves Caroline V, Peakman Georgia, Russell Lucy, Swift Imogen, Todd Emily, Rohrer Jonathan D, Boeve Bradley F, Rosen Howard J, Boxer Adam L, ALLFTD and GENFI consortia
Аннотация
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: ClinicalTrials.gov 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.