Calsyntenin‐1 is a cerebrospinal fluid marker of frontotemporal dementia‐related synapse degeneration

Background Frontotemporal dementia (FTD) clinical diagnosis is challenged by the variable correspondence between the clinical syndrome and underlying neuropathological changes, the phenotypic overlap with Alzheimer's disease (AD) and the lack of pathophysiologic diagnostic biomarkers. As synapse degeneration is an early event in pathological frontotemporal lobar degeneration (FTLD), a surrogate marker of synapse loss could aid the early diagnosis of FTD. The aim of this study was to evaluate the diagnostic performance of a panel of 9 synaptic proteins in cerebrospinal fluid (CSF) for FTLD in a neuropathological cohort. Method We included cognitively normal controls (n=35, 69 years+/‐7) and patients with neuropathological confirmation of FTLD (n=49, mean age‐at‐CSF 67 years+/‐10) or AD (n=25, 73 years+/‐6) from the Penn FTD Center. Subsets of the FTLD group included FTLD‐TDP (n=25) and FTLD‐Tau (n=24) neuropathological subtypes and “pure FTLD” (neurofibrillary tangle score of B0/B1 according to the NIA‐AA classification; n=39). We quantified the synaptic panel by targeted mass spectrometry using isotopically‐labeled proteotypic peptides as internal standards. We used linear regression with Dunnett’s post‐hoc tests to compare group differences, receiver‐operating characteristic curves to assess diagnostic accuracy (AUC) and linear regression adjusting for age‐at‐death and sex to assess the association with tau burden. Result Of the 9 synaptic proteins, CSF Calsyntenin‐1 showed the strongest association with disease etiology ( r 2 =.12, p =.0006). Calsyntenin‐1 was lower in FTLD compared to controls ( p =.03) and AD ( p =.0008), particularly in “pure FTLD” ( p =.02 vs controls, p =.0004 vs AD). Calsyntenin‐1 levels were comparable between AD and controls ( p =.33) and between neuropathological FTLD subtypes ( p =.66). Calsyntenin‐1 did not correlate with age‐at‐CSF analysis in controls (p=.74), FTLD (p=.07) or AD (p=.40). Calsyntenin‐1 showed the best diagnostic accuracy for differentiating FTLD from AD (AUC=73.4%) and showed similar accuracy in “pure FTLD” (AUC=75.7%) and in FTLD‐TDP (AUC=76.0%) and FTLD‐Tau (AUC=70.4%). Calsyntenin‐1 directly correlated with global pathological tau burden in FTLD (r 2 =.22; p=0.005) and in “pure FTLD” (r 2 =.17; p =0.02). Conclusion Low CSF levels of the post‐synaptic modulator, Calsyntenin‐1, is specific to FTLD, particularly in cases with little or no tau pathology and could aid the early diagnosis of FTD and the differential diagnosis from AD and other tauopathies.