Multimarker synaptic protein cerebrospinal fluid panels reflect TDP-43 pathology and cognitive performance in a pathological cohort of frontotemporal lobar degeneration

Abstract

Background: Synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD). Consequently, a surrogate marker of synapse loss could be used to monitor early pathologic changes in patients with underlying FTLD. The aim of this study was to evaluate the relationship of antemortem cerebrospinal fluid (CSF) levels of 8 synaptic proteins with postmortem global tau and TDP-43 burden and cognitive performance and to assess their diagnostic capacity in a neuropathological FTLD cohort.

Methods: We included patients with a neuropathological confirmation of FTLD-Tau (n = 24, mean age-at-CSF 67 years ± 11), FTLD-TDP (n = 25, 66 years ± 9) or AD (n = 25, 73 years ± 6) as well as cognitively normal controls (n = 35, 69 years ± 7) from the Penn FTD Center and ADRC. We used a semi-quantitative measure of tau and TDP-43 inclusions to quantify pathological burden across 16 brain regions. Statistical methods included Spearman rank correlations, one-way analysis of covariance, ordinal regression, step-wise multiple linear regression and receiver-operating characteristic curves.

Result: CSF calsyntenin-1 and neurexin-2a were correlated in all patient groups (r_s = .55 to .88). In FTLD-TDP, we observed low antemortem CSF levels of calsyntenin-1 and neurexin-2a compared to AD (.72-fold, p = .001, .77-fold, p = .04, respectively) and controls (.80-fold, p = .02, .78-fold, p = .02, respectively), which were inversely associated with post-mortem global TDP-43 burden (regression r² = .56, p = .007 and r² = .57, p = .006, respectively). A multimarker panel including calsyntenin-1 was associated with TDP-43 burden (r² = .69, p = .003) and MMSE score (r² = .19, p = .03) in FTLD. A second multimarker synaptic panel, also including calsyntenin-1, was associated with MMSE score in FTLD-tau (r² = .49, p = .04) and improved diagnostic performance to discriminate FTLD-Tau and FTLD-TDP neuropathologic subtypes (AUC = .83).

Conclusion: These synaptic panels have potential in the differential diagnosis of FTLD neuropathologic subtypes and as surrogate markers of cognitive performance in future clinical trials targeting TDP-43 or tau.

Keywords: Biomarker; Calsyntenin-1; Cerebrospinal fluid; Frontotemporal dementia; Frontotemporal lobar degeneration; TDP-43; Tau.

Fig. 1

Pair-wise correlation of antemortem CSF levels of 8 synaptic proteins in FTLD, AD and controls. Pair-wise r_s coefficients resulting from statistical tests performed in (a) FTLD-Tau, (b) FTLD-TDP, (c) AD and (d) controls are shown. Degree of shading is relative to size of Spearman r_s coefficients, which are shown in bold where p < .05. A set of 3 proteins that correlated in all groups are highlighted by a black box

Fig. 2

Antemortem CSF SRM intensities of the synaptic panel across patient groups. Violin plots show the distribution of SRM intensities for each synaptic protein quantified in CSF for patients with neuropathological confirmation of FTLD-Tau (Tau), FTLD-TDP (TDP) or AD and cognitively normal subjects (Control). Solid horizontal lines show the mean value for each and boxes represent the standard error of the mean. The horizontal dotted line represents the mean value in the control group for each protein. Summary statistics for ANCOVA including sex and age-at-CSF performed on square root transformed data are shown at the top of each plot. ANCOVA p-values are adjusted for multiple testing (9 proteins). *p < .05, **p < .01 for Dunnet’s post-hoc tests

Fig. 3

Association of antemortem CSF levels of synaptic proteins with postmortem TDP-43 burden. Scatter plots show the antemortem SRM intensities for selected synaptic proteins quantified in CSF and post-mortem TDP-43 burden for patients with neuropathological confirmation of FTLD. Linear regression lines and standard error (shaded region) are shown for each plot. Adj.r², p-values and t-statistics for the synaptic protein (syn t), time from CSF to autopsy (aut t), age-at-death (age t) and biological sex (sex t) are shown for each linear regression. P-values were adjusted for multiple testing (9 proteins)