@article{779aecfffcfb45998b0699f7eeee3d5d,
title = "Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers",
abstract = "Objective: To evaluate poly(GP), a dipeptide repeat protein, and neurofilament light chain (NfL) as biomarkers in presymptomatic C9orf72 repeat expansion carriers and patients with C9orf72-associated frontotemporal dementia. Additionally, to investigate the relationship of poly(GP) with indicators of neurodegeneration as measured by NfL and grey matter volume. Methods: We measured poly(GP) and NfL levels in cerebrospinal fluid (CSF) from 25 presymptomatic C9orf72 expansion carriers, 64 symptomatic expansion carriers with dementia, and 12 noncarriers. We explored associations with grey matter volumes using region of interest and voxel-wise analyses. Results: Poly(GP) was present in C9orf72 expansion carriers and absent in noncarriers (specificity 100%, sensitivity 97%). Presymptomatic carriers had lower poly(GP) levels than symptomatic carriers. NfL levels were higher in symptomatic carriers than in presymptomatic carriers and healthy noncarriers. NfL was highest in patients with concomitant motor neuron disease, and correlated with disease severity and survival. Associations between poly(GP) levels and small grey matter regions emerged but did not survive multiple comparison correction, while higher NfL levels were associated with atrophy in frontotemporoparietal cortices and the thalamus. Interpretation: This study of C9orf72 expansion carriers reveals that: (1) poly(GP) levels discriminate presymptomatic and symptomatic expansion carriers from noncarriers, but are not associated with indicators of neurodegeneration; and (2) NfL levels are associated with grey matter atrophy, disease severity, and shorter survival. Together, poly(GP) and NfL show promise as complementary biomarkers for clinical trials for C9orf72-associated frontotemporal dementia, with poly(GP) as a potential marker for target engagement and NfL as a marker of disease activity and progression.",
author = "Meeter, {Lieke H.H.} and Gendron, {Tania F.} and Sias, {Ana C.} and Jiskoot, {Lize C.} and Russo, {Silvia P.} and {Donker Kaat}, Laura and Papma, {Janne M.} and Panman, {Jessica L.} and {van der Ende}, {Emma L.} and Dopper, {Elise G.} and Sanne Franzen and Caroline Graff and Boxer, {Adam L.} and Rosen, {Howard J.} and Raquel Sanchez-Valle and Daniela Galimberti and Pijnenburg, {Yolande A.L.} and Luisa Benussi and Roberta Ghidoni and Barbara Borroni and Robert Laforce and {del Campo}, Marta and Teunissen, {Charlotte E.} and {van Minkelen}, Rick and Rojas, {Julio C.} and Giovanni Coppola and Geschwind, {Dan H.} and Rosa Rademakers and Karydas, {Anna M.} and Linn {\"O}ijerstedt and Elio Scarpini and Giuliano Binetti and Alessandro Padovani and Cash, {David M.} and Dick, {Katrina M.} and Martina Bocchetta and Miller, {Bruce L.} and Rohrer, {Jonathan D.} and Leonard Petrucelli and {van Swieten}, {John C.} and Lee, {Suzee E.}",
note = "Funding Information: We thank all participants of this study, and the local research coordinators for the help in collecting the samples, clinical and imaging data. This study was supported by Deltaplan Dementie (The Netherlands Organisation for Health Research and Development, and Alzheimer Nederland, grant number 733050103), the European Joint Programme - Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD 733051024), Alzheimer Nederland [L.H.M. (WE.09-2014-04) and C.T.], the Dioraphte Foundation, The Bluefield Project, the National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS089979 (T.F.G.), R35NS097273 (L.P.), P01NS099114 (T.F.G, L.P.), U54NS092089 (A.L.B.), R35NS097261 (R.R.)], the Amyotrophic Lateral Sclerosis Association (T.F.G., L.P.), Robert Packard Center for ALS Research (L.P.), Target ALS Foundation (T.F.G., L.P.), Association for Frontotemporal Degeneration (L.P.), Muscular Dystrophy Association (T.F.G.), National Institute on Aging [P01AG019724 (B.L.M.); P50AG23501 (B.L.M.); AG032306 (H.J.R); K23AG039414 (S.E.L)], the Italian Ministry of Health [Ricerca Corrente (R.G., L.B., G.B.)], Spanish National Institute of Health Carlos III (ISCIII) under the aegis of the EU Joint Programme – Neurodegenerative Disease Research (JPND) [AC14/00013 (R.S.V.)] and Fundacio Marato de TV3 [20143810 (R.S.V.)], the Swedish Medical Research Council (C.G., L.O.), ALF Stockholm county council (C.G., L.O.), Swedish Brain Foundation (C.G., L.O.), Swedish Alzheimer Foundation (C.G., L.O.), Karolinska Institutet doctoral funding & Stratneuro (C.G., L.O.), Swedish Brain Power (C.G., L.O.), the association of Frontotemporal Dementia (C.T.) the Dutch Research Council (ZonMW, C.T.), Weston Brain Institute (C.T.) and Alzheimer{\textquoteright}s Drug Discovery Foundation (C.T.). The Dementia Research Centre at UCL is supported by Alzheimer{\textquoteright}s Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCLH Biomedical Research Centre, and the MRC UK GENFI grant (MR/ M023664/1). J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). K.D. is supported by an Alzheimer{\textquoteright}s Society PhD Studentship (AS-PhD-2015-005). Funding Information: Funding Information See Acknowledgment section for funding information. We thank all participants of this study, and the local research coordinators for the help in collecting the samples, clinical and imaging data. This study was supported by Deltaplan Dementie (The Netherlands Organisation for Health Research and Development, and Alzheimer Nederland, grant number 733050103), the European Joint Programme - Neurodegenerative Disease Research and the Netherlands Organisation for Health Research and Development (PreFrontALS: 733051042, RiMod-FTD 733051024), Alzheimer Nederland [L.H.M. (WE.09-2014-04) and C.T.], the Dioraphte Foundation, The Bluefield Project, the National Institutes of Health/National Institute of Neurological Disorders and Stroke [R21NS089979 (T.F.G.), R35NS097273 (L.P.), P01NS099114 (T.F.G, L.P.), U54NS092089 (A.L.B.), R35NS097261 (R.R.)], the Amyotrophic Lateral Sclerosis Association (T.F.G., L.P.), Robert Packard Center for ALS Research (L.P.), Target ALS Foundation (T.F.G., L.P.), Association for Frontotemporal Degeneration (L.P.), Muscular Dystrophy Association (T.F.G.), National Institute on Aging [P01AG019724 (B.L.M.); P50AG23501 (B.L.M.); AG032306 (H.J.R); K23AG039414 (S.E.L)], the Italian Ministry of Health [Ricerca Corrente (R.G., L.B., G.B.)], Spanish National Institute of Health Carlos III (ISCIII) under the aegis of the EU Joint Programme – Neurodegenerative Disease Research (JPND) [AC14/00013 (R.S.V.)] and Fundacio Marato de TV3 [20143810 (R.S.V.)], the Swedish Medical Research Council (C.G., L.O.), ALF Stockholm county council (C.G., L.O.), Swedish Brain Foundation (C.G., L.O.), Swedish Alzheimer Foundation (C.G., L.O.), Karolinska Institutet doctoral funding & Stratneuro (C.G., L.O.), Swedish Brain Power (C.G., L.O.), the association of Frontotemporal Dementia (C.T.) the Dutch Research Council (ZonMW, C.T.), Weston Brain Institute (C.T.) and Alzheimer's Drug Discovery Foundation (C.T.). The Dementia Research Centre at UCL is supported by Alzheimer's Research UK, Brain Research Trust, and The Wolfson Foundation. This work was supported by the NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCLH Biomedical Research Centre, and the MRC UK GENFI grant (MR/M023664/1). J.D.R. is supported by an MRC Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). K.D. is supported by an Alzheimer's Society PhD Studentship (AS-PhD-2015-005). Publisher Copyright: {\textcopyright} 2018 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.",
year = "2018",
month = may,
doi = "10.1002/acn3.559",
language = "English (US)",
volume = "5",
pages = "583--597",
journal = "Annals of Clinical and Translational Neurology",
issn = "2328-9503",
publisher = "John Wiley and Sons Inc.",
number = "5",
}