JOURNAL OF NEUROLOGY, NEUROSURGERY, AND PSYCHIATRY

van der Ende EL, Xiao M, Xu D, Poos JM, Panman JL, Jiskoot LC, Meeter LH, Dopper EG, Papma JM, Heller C, Convery R, Moore K, Bocchetta M, Neason M, Peakman G, Cash DM, Teunissen CE, Graff C, Synofzik M, Moreno F, Finger E, Sanchez-Valle R, Vandenberghe R, Laforce R, Jr., Masellis M, Tartaglia MC, Rowe JB, Butler CR, Ducharme S, Gerhard A, Danek A, Levin J, Pijnenburg YA, Otto M, Borroni B, Tagliavini F, de Mendonca A, Santana I, Galimberti D, Seelaar H, Rohrer JD, Worley PF and van Swieten JC

J Neurol Neurosurg Psychiatry. 2020 Apr 9

DOI: http://dx.doi.org/10.1136/jnnp-2019-322493

Abstract

Introduction Synapse dysfunction is emerging as an early pathological event in frontotemporal dementia (FTD), however biomarkers are lacking. We aimed to investigate the value of cerebrospinal fluid (CSF) neuronal pentraxins (NPTXs), a family of proteins involved in homeostatic synapse plasticity, as novel biomarkers in genetic FTD.

Methods We included 106 presymptomatic and 54 symptomatic carriers of a pathogenic mutation in GRN, C9orf72 or MAPT, and 70 healthy non-carriers participating in the Genetic Frontotemporal dementia Initiative (GENFI), all of whom had at least one CSF sample. We measured CSF concentrations of NPTX2 using an in-house ELISA, and NPTX1 and NPTX receptor (NPTXR) by Western blot. We correlated NPTX2 with corresponding clinical and neuroimaging datasets as well as with CSF neurofilament light chain (NfL) using linear regression analyses.

Results Symptomatic mutation carriers had lower NPTX2 concentrations (median 643 pg/mL, IQR (301–872)) than presymptomatic carriers (1003 pg/mL (624–1358), p<0.001) and non-carriers (990 pg/mL (597–1373), p<0.001) (corrected for age). Similar results were found for NPTX1 and NPTXR. Among mutation carriers, NPTX2 concentration correlated with several clinical disease severity measures, NfL and grey matter volume of the frontal, temporal and parietal lobes, insula and whole brain. NPTX2 predicted subsequent decline in phonemic verbal fluency and Clinical Dementia Rating scale plus FTD modules. In longitudinal CSF samples, available in 13 subjects, NPTX2 decreased around symptom onset and in the symptomatic stage.

Discussion We conclude that N