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

Abstract

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 (r2 =.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 (r2=.22; p=0.005) and in “pure FTLD” (r2=.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.

Temporal proteomics of human cerebrospinal fluid after severe traumatic brain injury

“…CLSTN1, a synaptic protein, is decreased in the CSF of preclinical Alzheimer’s patients before the onset of clinical symptoms and the appearance of neurodegenerative markers [ 62 ]. In addition, lower CLSTN1 CSF levels have been linked to frontotemporal dementia-related synapse degeneration [ 63 ]. Finally NPTX1, a protein involved in synaptic plasticity, was found in lower concentrations in the CSF of patients with Alzheimer’s disease [ 64 ], as well as in patients with symptomatic genetic frontotemporal dementia [ 65 ].…”

Identification of Candidate Protein Biomarkers Associated with Domoic Acid Toxicosis in Cerebrospinal Fluid of California Sea Lions (Zalophus californianus)

“…Two immunoglobulin light chains (IGKV2D-28 and IGKV2-29) were of the highest performing classifiers (AUC > 0.88) and have similar expression profiles where CSLs with acute DAT have on average two-fold higher levels than chronic DAT animals. The elevation in light chains in the acute group may reflect intrathecal production of immunoglobulins as described in human patients with epilepsy[43], or impairment in the blood brain barrier[44]; whereas the reduction in light chains in the chronic group relative to the acute group could be due to the course of antiseizure therapy[45], or resolution of inflammatory changes in the more chronic cases as observed on histology, or both.…”

Identification of Candidate Protein Biomarkers Associated with Domoic Acid Toxicosis in Cerebrospinal Fluid of California Sea Lions (Zalophus californianus)

“…The downregulation of calsyntenin-1 has also been observed in patients with frontotemporal dementia, and this protein has been identified as a potential biomarker in CSF for neurodegenerative disorders. 41 − 43 …”

“…The downregulation of calsyntenin-1 leads to a disruption of axonal transport, which occurs during Alzheimer’s disease. The downregulation of calsyntenin-1 has also been observed in patients with frontotemporal dementia, and this protein has been identified as a potential biomarker in CSF for neurodegenerative disorders. − …”