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

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.

Keywords: Biomarkers; Frontotemporal dementia; Synaptic dysfunction.

Fig. 1

Diagrammatic representation of the synapse and the role of the different synaptic proteins included within the mass spectrometry panel. Adapted from Nilsson et al. [14]

Fig. 2

Cerebrospinal fluid (CSF) concentrations of the synaptic panel proteins in the GENFI cohort including 23 presymptomatic MAPT (PS MAPT), 31 C9orf72 (PS C9), and 23 GRN (PS GRN) mutation carriers and 12 symptomatic MAPT (S MAPT), 26 C9orf72 (S C9), and 17 GRN (S GRN) mutation carriers and 61 non-carriers. The results are shown in fmol/μL. p-values: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001, and ****p ≤ 0.0001. The bars indicate the median and the IQR. Only one peptide per protein is shown as discussed in the “Methods” section. Specific means, IC, and p-values are shown in Additional file 1: Table S2