Aitana Sogorb-Esteve, UCL Queen Square Institute of Neurology
Johanna Nilsson, Sahlgrenska Akademin
Imogen J. Swift, UCL Queen Square Institute of Neurology
Carolin Heller, UCL Queen Square Institute of Neurology
Martina Bocchetta, UCL Queen Square Institute of Neurology
Lucy L. Russell, UCL Queen Square Institute of Neurology
Georgia Peakman, UCL Queen Square Institute of Neurology
Rhian S. Convery, UCL Queen Square Institute of Neurology
John C. van Swieten, Erasmus MC
Harro Seelaar, Erasmus MC
Barbara Borroni, Università degli Studi di Brescia
Daniela Galimberti, Università degli Studi di Milano
Raquel Sanchez-Valle, Universitat de Barcelona
Robert Laforce, CHU de Québec - Université Laval
Fermin Moreno, Osakidetza, Donostia University Hospital
Matthis Synofzik, Hertie-Institut für klinische Hirnforschung
Caroline Graff, Care Sciences and Society
Mario Masellis, University of Toronto
Maria Carmela Tartaglia, Tanz Centre for Research in Neurodegenerative Diseases
James B. Rowe, Cambridge University Hospitals NHS Foundation Trust
Rik Vandenberghe, Departement Neurowetenschappen
Elizabeth Finger, Western UniversityFollow
Fabrizio Tagliavini, Foundation IRCCS Neurological Institute "C. Besta"
Isabel Santana, Universidade de Coimbra, Faculdade de Medicina
Chris R. Butler, University of Oxford Medical Sciences Division
Simon Ducharme, School of Medicine
Alexander Gerhard, The University of Manchester
Adrian Danek, Ludwig-Maximilians-Universität München
Johannes Levin, Ludwig-Maximilians-Universität München
Markus Otto, Universität Ulm

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Alzheimer's Research and Therapy





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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.