Differential impairment of cerebrospinal fluid synaptic biomarkers in the genetic forms of frontotemporal dementia.
Creators: name: Sogorb-Esteve, Aitana
name: Nilsson, Johanna
name: Swift, Imogen J
name: Heller, Carolin
name: Bocchetta, Martina
name: Russell, Lucy L
name: Peakman, Georgia
name: Convery, Rhian S
name: Van Swieten, John C
name: Seelaar, Harro
name: Borroni, Barbara
name: Galimberti, Daniela
name: Sanchez-Valle, Raquel
name: Laforce, Robert
name: Moreno, Fermin
name: Synofzik, Matthis
name: Graff, Caroline
name: Masellis, Mario
name: Tartaglia, Maria Carmela
name: Rowe, James B
name: Vandenberghe, Rik
name: Finger, Elizabeth
name: Tagliavini, Fabrizio
name: Santana, Isabel
name: Butler, Chris R
name: Ducharme, Simon
name: Gerhard, Alexander
name: Danek, Adrian
name: Levin, Johannes
name: Otto, Markus
name: Sorbi, Sandro
name: Le Ber, Isabelle
name: Pasquier, Florence
name: Gobom, Johan
name: Brinkmalm, Ann
name: Blennow, Kaj
name: Zetterberg, Henrik
name: Rohrer, Jonathan D
name: GENetic FTD Initiative
Publisher: name: Apollo - University of Cambridge Repository
Year: 2022
Subjects: Research
Frontotemporal dementia
Synaptic dysfunction
Biomarkers

description: 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.