Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia

Aitana Sogorb-Esteve, Johanna Nilsson, on behalf of the GENetic FTD Initiative, Imogen J. Swift, Carolin Heller, Martina Bocchetta, Lucy L. Russell, Georgia Peakman, Rhian S. Convery, John C. van Swieten, Harro Seelaar, Barbara Borroni, Daniela Galimberti, Raquel Sanchez-Valle, Robert Laforce, Fermin Moreno, Matthis Synofzik, Caroline Graff, Mario Masellis, Maria Carmela TartagliaJames B. Rowe, Rik Vandenberghe, Elizabeth Finger, Fabrizio Tagliavini, Isabel Santana, Chris R. Butler, Simon Ducharme, Alexander Gerhard, Adrian Danek, Johannes Levin, Markus Otto, Sandro Sorbi, Isabelle Le Ber, Florence Pasquier, Johan Gobom, Ann Brinkmalm, Kaj Blennow, Henrik Zetterberg, Jonathan D. Rohrer*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: Approximately a third of frontotemporal dementia (FTD) is genetic with mutations in three genes accounting for most of the inheritance: C9orf72, GRN, and MAPT. Impaired synaptic health is a common mechanism in all three genetic variants, so developing fluid biomarkers of this process could be useful as a readout of cellular dysfunction within therapeutic trials. Methods: A total of 193 cerebrospinal fluid (CSF) samples from the GENetic FTD Initiative including 77 presymptomatic (31 C9orf72, 23 GRN, 23 MAPT) and 55 symptomatic (26 C9orf72, 17 GRN, 12 MAPT) mutation carriers as well as 61 mutation-negative controls were measured using a microflow LC PRM-MS set-up targeting 15 synaptic proteins: AP-2 complex subunit beta, complexin-2, beta-synuclein, gamma-synuclein, 14–3-3 proteins (eta, epsilon, zeta/delta), neurogranin, Rab GDP dissociation inhibitor alpha (Rab GDI alpha), syntaxin-1B, syntaxin-7, phosphatidylethanolamine-binding protein 1 (PEBP-1), neuronal pentraxin receptor (NPTXR), neuronal pentraxin 1 (NPTX1), and neuronal pentraxin 2 (NPTX2). Mutation carrier groups were compared to each other and to controls using a bootstrapped linear regression model, adjusting for age and sex. Results: CSF levels of eight proteins were increased only in symptomatic MAPT mutation carriers (compared with controls) and not in symptomatic C9orf72 or GRN mutation carriers: beta-synuclein, gamma-synuclein, 14–3-3-eta, neurogranin, Rab GDI alpha, syntaxin-1B, syntaxin-7, and PEBP-1, with three other proteins increased in MAPT mutation carriers compared with the other genetic groups (AP-2 complex subunit beta, complexin-2, and 14–3-3 zeta/delta). In contrast, CSF NPTX1 and NPTX2 levels were affected in all three genetic groups (decreased compared with controls), with NPTXR concentrations being affected in C9orf72 and GRN mutation carriers only (decreased compared with controls). No changes were seen in the CSF levels of these proteins in presymptomatic mutation carriers. Concentrations of the neuronal pentraxins were correlated with brain volumes in the presymptomatic period for the C9orf72 and GRN groups, suggesting that they become abnormal in proximity to symptom onset. Conclusions: Differential synaptic impairment is seen in the genetic forms of FTD, with abnormalities in multiple measures in those with MAPT mutations, but only changes in neuronal pentraxins within the GRN and C9orf72 mutation groups. Such markers may be useful in future trials as measures of synaptic dysfunction, but further work is needed to understand how these markers change throughout the course of the disease.

Original languageEnglish
Article number118
JournalAlzheimer's Research and Therapy
Volume14
Issue number1
DOIs
Publication statusPublished - 31 Aug 2022

Bibliographical note

Funding Information:
The Dementia Research Centre is supported by Alzheimer’s Research UK, Alzheimer’s Society, Brain Research UK, and The Wolfson Foundation. This work was supported by the NIHR UCL/H Biomedical Research Centre, the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research Facility, and the UK Dementia Research Institute, which receives its funding from UK DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. 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). This work was also supported by the MRC UK GENFI grant (MR/M023664/1), the Bluefield Project, and the JPND GENFI-PROX grant (2019–02248). Several authors of this publication are members of the European Reference Network for Rare Neurological Diseases—Project ID No 739510. ASE is supported by Race Against Dementia Fellowship by Alzheimer’s Research UK (ARUK-RADF2021A-003). ASE’s work is also supported by the UK Dementia Research Institute which receives its funding from DRI Ltd., funded by the UK Medical Research Council, Alzheimer’s Society, and Alzheimer’s Research UK. IS is supported by funding from the Alzheimer’s Society, UK. RC is supported by a Frontotemporal Dementia Research Studentships in Memory of David Blechner funded through The National Brain Appeal (RCN 290173). JCVS was supported by the Dioraphte Foundation grant 09–02-03–00, 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 number 733 051 042), Alzheimer Nederland, and the Bluefield project. FM received funding from the Tau Consortium and the Center for Networked Biomedical Research on Neurodegenerative Disease (CIBERNED). RS-V is supported by an Alzheimer’s Research UK Clinical Research Training Fellowship (ARUK-CRF2017B-2) and has received funding from Fundació Marató de TV3, Spain (grant no. 20143810). CG received funding from JPND-Prefrontals VR Dnr 529–2014-7504, VR 2015–02926, and 2018–02754; the Swedish FTD Inititative-Schörling Foundation; Alzheimer Foundation; Brain Foundation; and Stockholm County Council ALF. MM has received funding from a Canadian Institute of Health Research operating grant and the Weston Brain Institute and the Ontario Brain Institute. JBR has received funding from the Welcome Trust (220258), the Cambridge University Centre for Frontotemporal Dementia, the Medical Research Council (SUAG/051 G101400), and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre (BRC-1215–20014). EF has received funding from a CIHR grant #327387. DG received support from the EU Joint Programme – Neurodegenerative Disease Research (JPND) and the Italian Ministry of Health (PreFrontALS) grant 733051042. RV has received funding from the Mady Browaeys Fund for Research into Frontotemporal Dementia. MO has received funding from BMBF (FTLDc). HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532); the European Research Council (#681712); Swedish State Support for Clinical Research (#ALFGBG-720931); the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862); the AD Strategic Fund and the Alzheimer’s Association (#ADSF-21–831376-C, #ADSF-21–831381-C and #ADSF-21–831377-C); the Olav Thon Foundation; the Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019-0228); the European Union’s Horizon 2020 research; and innovation programme under the Marie Skłodowska-Curie grant agreement No 860197 (MIRIADE), European Union Joint Program for Neurodegenerative Disorders (JPND2021-00694), and the UK Dementia Research Institute at UCL.

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© 2022, The Author(s).

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