TY - JOUR
T1 - Neuronal pentraxin 2: A synapse-derived CSF biomarker in genetic frontotemporal dementia
T2 - A synapse-derived CSF biomarker in genetic frontotemporal dementia
AU - van der Ende, Emma L.
AU - Xiao, Meifang
AU - Xu, Desheng
AU - Poos, Jackie M.
AU - Panman, Jessica L.
AU - Panman, Jessica L.
AU - Jiskoot, Lize C.
AU - Jiskoot, Lize C.
AU - Meeter, Lieke H.
AU - Dopper, Elise G. P.
AU - Papma, Janne M.
AU - Heller, Carolin
AU - Convery, Rhian
AU - Moore, Katrina
AU - Bocchetta, Martina
AU - Neason, Mollie
AU - Peakman, Georgia
AU - Cash, David M.
AU - Teunissen, Charlotte E.
AU - Graff, Caroline
AU - Graff, Caroline
AU - Synofzik, Matthis
AU - Synofzik, Matthis
AU - Moreno, Fermin
AU - Finger, Elizabeth
AU - Sánchez-Valle, Raquel
AU - Vandenberghe, Rik
AU - Laforce Jr, Robert
AU - Masellis, Mario
AU - Tartaglia, Maria Carmela
AU - Rowe, James B.
AU - Butler, Christopher R.
AU - Ducharme, Simon
AU - Gerhard, Alex
AU - Gerhard, Alex
AU - Danek, Adrian
AU - Levin, Johannes
AU - Levin, Johannes
AU - Levin, Johannes
AU - Pijnenburg, Yolande A. L.
AU - Otto, Markus
AU - Borroni, Barbara
AU - Tagliavini, Fabrizio
AU - de Mendonca, Alexandre
AU - Santana, Isabel
AU - Galimberti, Daniela
AU - Galimberti, Daniela
AU - Seelaar, Harro
AU - Rohrer, Jonathan D.
AU - Worley, Paul F.
AU - Worley, Paul F.
AU - van Swieten, John C.
N1 - Funding Information: Funding This study was supported in the netherlands by two Memorabel grants from Deltaplan Dementie (The netherlands Organisation for health research and Development and alzheimer nederland; grant numbers 733050813 and 733050103), the Bluefield Project to cure Frontotemporal Dementia, the Dioraphte foundation (grant number 1402 1300) and the european Joint Programme— neurodegenerative Disease research and the netherlands Organisation for health research and Development (PreFrontals: 733051042, riMod-FTD: 733051024); in Belgium by the Mady Browaeys Fonds voor Onderzoek naar Frontotemporale Degeneratie; in the UK by the Mrc UK genFi grant (Mr/M023664/1); Jr 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); KM is supported by an alzheimer’s society PhD studentship (as-PhD-2015-005); JBr is supported by the Wellcome Trust (103838); in spain by the Fundació Marató de TV3 (20143810 to rsV); in germany by the Deutsche Forschungsgemeinschaft (DFg, german research Foundation) under germany’s excellence strategy within the framework of the Munich cluster for systems neurology (eXc 2145 synergy—iD 390857198) and by grant 779357 ’solve-rD’ from the horizon 2020 research and innovation Programme (to Ms); in sweden by grants from the swedish FTD initiative funded by the schörling Foundation, grants from JPnD PreFrontals swedish research council (Vr) 529-2014-7504, swedish research council (Vr) 2015-02926, swedish research council (Vr) 2018-02754, swedish Brain Foundation, swedish alzheimer Foundation, stockholm county council alF, swedish Demensfonden, stohnes foundation, gamla Tjänarinnor, Karolinska institutet Doctoral Funding, and stratneuro. Competing interests none declared. Patient consent for publication Obtained. Publisher Copyright: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. Copyright: Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/6/1
Y1 - 2020/6/1
N2 - Introduction Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. Methods We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. Results Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301-872)) than presymptomatic carriers (1003 pg/mL (624-1358), p<0.001) and non-carriers (990 pg/mL (597-1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. Discussion We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.
AB - Introduction Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD. Methods We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses. Results Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301-872)) than presymptomatic carriers (1003 pg/mL (624-1358), p<0.001) and non-carriers (990 pg/mL (597-1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage. Discussion We conclude that NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.
UR - http://www.scopus.com/inward/record.url?scp=85083204915&partnerID=8YFLogxK
U2 - https://doi.org/10.1136/jnnp-2019-322493
DO - https://doi.org/10.1136/jnnp-2019-322493
M3 - Article
C2 - 32273328
SN - 0022-3050
VL - 91
SP - 612
EP - 621
JO - Journal of Neurology, Neurosurgery and Psychiatry
JF - Journal of Neurology, Neurosurgery and Psychiatry
IS - 6
ER -