Neuronal pentraxin 2: a synapse-derived CSF biomarker in genetic frontotemporal dementia

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 NPTX2 is a promising synapse-derived disease progression biomarker in genetic FTD.

Figure 1

NPTX2 levels (A) in presymptomatic (n=106) and symptomatic mutation carriers (n=54) and non-carriers (n=70) and (B) separated by genetic group. Whiskers indicate minimum and maximum values. Orange squares indicate subjects who converted to the symptomatic stage during follow-up (n=3); grey asterisks indicate subjects with amyotrophic lateral sclerosis (ALS) without frontotemporal dementia (FTD) (n=3); grey crosses indicate subjects with both FTD and ALS (n=4). P values are from analyses of covariance (ANCOVAs) with age as a covariate and Bonferroni correction for multiple comparisons. *p<0.05; **p<0.01; ***p<0.001. CSF, cerebrospinal fluid; NPTX, neuronal pentraxin; PRE, presymptomatic mutation carrier; SYM: symptomatic mutation carrier.

Figure 2

Relationship between NPTX2 and (A) frontal lobe volume (n=126), (B) insular volume (n=126), (C) Mini Mental State Examination (MMSE) (n=145) and (D) Clinical Dementia Rating scale (CDR) plus FTD modules (n=120) among mutation carriers. b and p were obtained through multiple linear regression with square-root transformed NPTX2 as the dependent variable, adjusting for age, gender and study site; for MMSE, we also included years of education as a covariate. CSF, cerebrospinal fluid; FTD, frontotemporal dementia; NPTX, neuronal pentraxin; TIV, total intracranial volume.

Figure 3

Correlation between NPTX2 and NfL levels in presymptomatic (n=106) and symptomatic (n=50) mutation carriers. NfL is plotted on a log-scale for visualisation purposes. b and p were obtained through multiple linear regression with square-root transformed NPTX2 as the dependent variable, adjusting for age, gender and study site. CSF, cerebrospinal fluid; NfL, neurofilament light chain; NPTX, neuronal pentraxin.

Figure 4

Longitudinal NPTX2 levels plotted against age in 13 subjects with multiple CSF samples. A line is drawn between NPTX2 levels of follow-up samples. Presymptomatic samples are shown as green squares, symptomatic samples as red triangles and the non-carrier as blue circles. GRN mutation carriers are shown as open symbols, C9orf72 mutation carriers as filled symbols and the MAPT mutation carrier as half-filled symbols. Dotted horizontal line indicates median NPTX2 level in presymptomatic mutation carriers (1003 pg/mL); dashed horizontal line indicates median in symptomatic mutation carriers (644 pg/mL). For blinding purposes, a jitter of ±2 years was applied to all subjects. CSF, cerebrospinal fluid; NPTX, neuronal pentraxin.

Figure 5

NPTX1 and NPTXR levels as measured by Western blot. (A) Representative (cropped) Western blots of NPTX1 and NPTXR (n=230); (B, C) NPTX1 and NPTXR levels across groups, expressed as a percentage of band intensity compared with non-carriers. Whiskers indicate minimum and maximum values. Displayed significance levels are from analysis of covariance (ANCOVA) on square-root transformed relative band intensities of NPTX1 and NPTXR with age as a covariate. *p<0.05; **p<0.01. CSF, cerebrospinal fluid; NPTX, neuronal pentraxin; PRE, presymptomatic mutation carrier; SYM, symptomatic mutation carrier.