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

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 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 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; Sandra Weintraub; Daniel I. Kaufer; Diana Kerwin; Irene Litvan; Chiadikaobi U. Onyike; Alexander Pantelyat; Erik D. Roberson; Maria C. Tartaglia; Tatiana Foroud; Weiping Chen; Julie Czerkowicz; Danielle L. Graham; John C. Van Swieten; Barbara Borroni; Raquel Sanchez-Valle; Fermin 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; Chris R. Butler; Alexander Gerhard; Johannes Levin; Adrian Danek; Markus Otto; Sandro Sorbi; David M. Cash; Rhian S. Convery; Martina Bocchetta; Martha Foiani; Caroline V. Greaves; Georgia Peakman; Lucy Russell; Imogen Swift; Emily Todd; Jonathan D. Rohrer; Bradley F. Boeve; Howard J. Rosen; Adam L. Boxer

doi:10.1212/WNL.0000000000011848

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

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 Kieloch, Marie Anne ValentinAnna 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, Sandra Weintraub, Daniel I. Kaufer, Diana Kerwin, Irene Litvan, Chiadikaobi U. Onyike, Alexander Pantelyat, Erik D. Roberson, Maria C. Tartaglia, Tatiana Foroud, Weiping Chen, Julie Czerkowicz, Danielle L. Graham, John C. Van Swieten, Barbara Borroni, Raquel Sanchez-Valle, Fermin 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, Chris R. Butler, Alexander Gerhard, Johannes Levin, Adrian Danek, Markus Otto, Sandro Sorbi, David M. Cash, Rhian S. Convery, Martina Bocchetta, Martha Foiani, Caroline V. Greaves, Georgia Peakman, Lucy Russell, Imogen Swift, Emily Todd, Jonathan D. Rohrer, Bradley F. Boeve, Howard J. Rosen, Adam L. Boxer

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Pages (from-to)	E2296-E2312
Journal	Neurology
Volume	96
Issue number	18
DOIs	https://doi.org/10.1212/WNL.0000000000011848
State	Published - May 4 2021

ASJC Scopus subject areas

Clinical Neurology

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Rojas, J. C., Wang, P., Staffaroni, A. M., Heller, C., Cobigo, Y., Wolf, A., Goh, S. Y. M., Ljubenkov, P. A., Heuer, H. W., Fong, J. C., Taylor, J. B., Veras, E., Song, L., Jeromin, A., Hanlon, D., Yu, L., Khinikar, A., Sivasankaran, R., Kieloch, A., ... Boxer, A. L. (2021). Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration. Neurology, 96(18), E2296-E2312. https://doi.org/10.1212/WNL.0000000000011848

Rojas, JC, Wang, P, Staffaroni, AM, Heller, C, Cobigo, Y, Wolf, A, Goh, SYM, Ljubenkov, PA, Heuer, HW, Fong, JC, Taylor, JB, Veras, E, Song, L, Jeromin, A, Hanlon, D, Yu, L, Khinikar, A, Sivasankaran, R, Kieloch, A, Valentin, MA, Karydas, AM, Mitic, LL, Pearlman, R, Kornak, J, Kramer, JH, Miller, BL, Kantarci, K , Knopman, DS , Graff-Radford, N , Petrucelli, L, Rademakers, R, Irwin, DJ, Grossman, M, Ramos, EM, Coppola, G, Mendez, MF, Bordelon, Y, Dickerson, BC, Ghoshal, N, Huey, ED, Mackenzie, IR, Appleby, BS, Domoto-Reilly, K, Hsiung, GYR, Toga, AW, Weintraub, S, Kaufer, DI, Kerwin, D, Litvan, I, Onyike, CU, Pantelyat, A, Roberson, ED, Tartaglia, MC, Foroud, T, Chen, W, Czerkowicz, J, Graham, DL, Van Swieten, JC, Borroni, B, Sanchez-Valle, R, Moreno, F, Laforce, R, Graff, C, Synofzik, M, Galimberti, D, Rowe, JB, Masellis, M, Finger, E, Vandenberghe, R, De Mendonça, A, Tagliavini, F, Santana, I, Ducharme, S, Butler, CR, Gerhard, A, Levin, J, Danek, A, Otto, M, Sorbi, S, Cash, DM, Convery, RS, Bocchetta, M, Foiani, M, Greaves, CV, Peakman, G, Russell, L, Swift, I, Todd, E, Rohrer, JD, Boeve, BF, Rosen, HJ & Boxer, AL 2021, 'Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration', Neurology, vol. 96, no. 18, pp. E2296-E2312. https://doi.org/10.1212/WNL.0000000000011848

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title = "Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration",

abstract = "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.",

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

note = "Publisher Copyright: {\textcopyright} 2021 American Academy of Neurology.",

year = "2021",

month = may,

day = "4",

doi = "10.1212/WNL.0000000000011848",

language = "English (US)",

volume = "96",

pages = "E2296--E2312",

journal = "Neurology",

issn = "0028-3878",

publisher = "Lippincott Williams and Wilkins",

number = "18",

}

TY - JOUR

T1 - Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration

AU - Rojas, Julio C.

AU - Wang, Ping

AU - Staffaroni, Adam M.

AU - Heller, Carolin

AU - Cobigo, Yann

AU - Wolf, Amy

AU - Goh, Sheng Yang M.

AU - Ljubenkov, Peter A.

AU - Heuer, Hilary W.

AU - Fong, Jamie C.

AU - Taylor, Joanne B.

AU - Veras, Eliseo

AU - Song, Linan

AU - Jeromin, Andreas

AU - Hanlon, David

AU - Yu, Lili

AU - Khinikar, Arvind

AU - Sivasankaran, Rajeev

AU - Kieloch, Agnieszka

AU - Valentin, Marie Anne

AU - Karydas, Anna M.

AU - Mitic, Laura L.

AU - Pearlman, Rodney

AU - Kornak, John

AU - Kramer, Joel H.

AU - Miller, Bruce L.

AU - Kantarci, Kejal

AU - Knopman, David S.

AU - Graff-Radford, Neill

AU - Petrucelli, Leonard

AU - Rademakers, Rosa

AU - Irwin, David J.

AU - Grossman, Murray

AU - Ramos, Eliana Marisa

AU - Coppola, Giovanni

AU - Mendez, Mario F.

AU - Bordelon, Yvette

AU - Dickerson, Bradford C.

AU - Ghoshal, Nupur

AU - Huey, Edward D.

AU - Mackenzie, Ian R.

AU - Appleby, Brian S.

AU - Domoto-Reilly, Kimiko

AU - Hsiung, Ging Yuek R.

AU - Toga, Arthur W.

AU - Weintraub, Sandra

AU - Kaufer, Daniel I.

AU - Kerwin, Diana

AU - Litvan, Irene

AU - Onyike, Chiadikaobi U.

AU - Pantelyat, Alexander

AU - Roberson, Erik D.

AU - Tartaglia, Maria C.

AU - Foroud, Tatiana

AU - Chen, Weiping

AU - Czerkowicz, Julie

AU - Graham, Danielle L.

AU - Van Swieten, John C.

AU - Borroni, Barbara

AU - Sanchez-Valle, Raquel

AU - Moreno, Fermin

AU - Laforce, Robert

AU - Graff, Caroline

AU - Synofzik, Matthis

AU - Galimberti, Daniela

AU - Rowe, James B.

AU - Masellis, Mario

AU - Finger, Elizabeth

AU - Vandenberghe, Rik

AU - De Mendonça, Alexandre

AU - Tagliavini, Fabrizio

AU - Santana, Isabel

AU - Ducharme, Simon

AU - Butler, Chris R.

AU - Gerhard, Alexander

AU - Levin, Johannes

AU - Danek, Adrian

AU - Otto, Markus

AU - Sorbi, Sandro

AU - Cash, David M.

AU - Convery, Rhian S.

AU - Bocchetta, Martina

AU - Foiani, Martha

AU - Greaves, Caroline V.

AU - Peakman, Georgia

AU - Russell, Lucy

AU - Swift, Imogen

AU - Todd, Emily

AU - Rohrer, Jonathan D.

AU - Boeve, Bradley F.

AU - Rosen, Howard J.

AU - Boxer, Adam L.

PY - 2021/5/4

Y1 - 2021/5/4

N2 - 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.

AB - 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.

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U2 - 10.1212/WNL.0000000000011848

DO - 10.1212/WNL.0000000000011848

M3 - Article

C2 - 33827960

AN - SCOPUS:85107091043

SN - 0028-3878

VL - 96

SP - E2296-E2312

JO - Neurology

JF - Neurology

IS - 18

ER -

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

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