TY - JOUR
T1 - A panel of CSF proteins separates genetic frontotemporal dementia from presymptomatic mutation carriers
T2 - a GENFI study
AU - on behalf of the Genetic Frontotemporal Dementia Initiative (GENFI)
AU - Bergström, Sofia
AU - Öijerstedt, Linn
AU - Remnestål, Julia
AU - Olofsson, Jennie
AU - Ullgren, Abbe
AU - Seelaar, Harro
AU - van Swieten, John C.
AU - Synofzik, Matthis
AU - Sanchez-Valle, Raquel
AU - Moreno, Fermin
AU - Finger, Elizabeth
AU - Masellis, Mario
AU - Tartaglia, Carmela
AU - Vandenberghe, Rik
AU - Laforce, Robert
AU - Galimberti, Daniela
AU - Borroni, Barbara
AU - Butler, Chris R.
AU - Gerhard, Alexander
AU - Ducharme, Simon
AU - Rohrer, Jonathan D.
AU - Månberg, Anna
AU - Graff, Caroline
AU - Nilsson, Peter
AU - Jiskoot, Lize
AU - Rowe, James B.
AU - de Mendonça, Alexandre
AU - Tagliavini, Fabrizio
AU - Santana, Isabel
AU - Le Ber, Isabelle
AU - Levin, Johannes
AU - Danek, Adrian
AU - Otto, Markus
AU - Frisoni, Giovanni
AU - Ghidoni, Roberta
AU - Sorbi, Sandro
AU - Pasquier, Florence
AU - Jelic, Vesna
AU - Andersson, Christin
AU - Afonso, Sónia
AU - Almeida, Maria Rosario
AU - Anderl-Straub, Sarah
AU - Antonell, Anna
AU - Archetti, Silvana
AU - Arighi, Andrea
AU - Balasa, Mircea
AU - Barandiaran, Myriam
AU - Bargalló, Nuria
AU - Bartha, Robart
AU - Maruta, Carolina
N1 - Funding Information:
This study has received support from the Swedish FTD initiative funded by the Schörling Family Foundation. This work was also funded by KTH Center for Applied Precision Medicine (KCAP) funded by the Erling-Persson Family Foundation, grants from Vetenskapsrådet Dnr 529-2014-7504, VR 2015-02926 and 2018-02754, Swedish Alzheimer Foundation, Swedish Brain Foundation, Åhlén foundation, Demensfonden, Stohnes foundation, Gamla Tjänarinnor and Stockholm County Council ALF. Furthermore, support was received by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, the JPND GENFI-PROX grant (2019-02248), the Dioraphte Foundation [grant numbers 09-02-00]; the Association for Frontotemporal Dementias Research Grant 2009; The Netherlands Organization for Scientific Research (NWO) (grant HCMI 056-13-018); ZonMw Memorabel (Deltaplan Dementie), (project numbers 733 050 103 and 733 050 813); JPND PreFrontAls consortium (project number 733051042). JDR 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). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases - Project ID No 739510. M.S. was supported by the JPND grant “GENFI-prox” (by DLR/BMBF to M. S, joint with JDR., J.vS., M.O., B.B. and C.G.). Open Access funding provided by Royal Institute of Technology.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
AB - Background: A detailed understanding of the pathological processes involved in genetic frontotemporal dementia is critical in order to provide the patients with an optimal future treatment. Protein levels in CSF have the potential to reflect different pathophysiological processes in the brain. We aimed to identify and evaluate panels of CSF proteins with potential to separate symptomatic individuals from individuals without clinical symptoms (unaffected), as well as presymptomatic individuals from mutation non-carriers. Methods: A multiplexed antibody-based suspension bead array was used to analyse levels of 111 proteins in CSF samples from 221 individuals from families with genetic frontotemporal dementia. The data was explored using LASSO and Random forest. Results: When comparing affected individuals with unaffected individuals, 14 proteins were identified as potentially important for the separation. Among these, four were identified as most important, namely neurofilament medium polypeptide (NEFM), neuronal pentraxin 2 (NPTX2), neurosecretory protein VGF (VGF) and aquaporin 4 (AQP4). The combined profile of these four proteins successfully separated the two groups, with higher levels of NEFM and AQP4 and lower levels of NPTX2 in affected compared to unaffected individuals. VGF contributed to the models, but the levels were not significantly lower in affected individuals. Next, when comparing presymptomatic GRN and C9orf72 mutation carriers in proximity to symptom onset with mutation non-carriers, six proteins were identified with a potential to contribute to a separation, including progranulin (GRN). Conclusion: In conclusion, we have identified several proteins with the combined potential to separate affected individuals from unaffected individuals, as well as proteins with potential to contribute to the separation between presymptomatic individuals and mutation non-carriers. Further studies are needed to continue the investigation of these proteins and their potential association to the pathophysiological mechanisms in genetic FTD.
KW - Aquaporin 4 (AQP4)
KW - Cerebrospinal fluid
KW - LASSO
KW - Neurofilament medium polypeptide (NEFM)
KW - Neuronal pentraxin 2 (NPTX2)
KW - Neurosecretory protein VGF (VGF)
KW - Random forest
KW - Suspension bead array
UR - http://www.scopus.com/inward/record.url?scp=85125455228&partnerID=8YFLogxK
U2 - 10.1186/s13024-021-00499-4
DO - 10.1186/s13024-021-00499-4
M3 - Article
C2 - 34838088
AN - SCOPUS:85125455228
SN - 1750-1326
VL - 16
JO - Molecular Neurodegeneration
JF - Molecular Neurodegeneration
IS - 1
M1 - 79
ER -