High diagnostic performance of plasma and cerebrospinal fluid beta‐synuclein in the differential diagnosis of sporadic Creutzfeldt‐Jakob disease

Abstract

AbstractBackgroundBeta‐synuclein (beta‐syn) is an emerging biofluid marker for synaptic damage in several neurological diseases. In particular, patients with prion disease showed significantly higher cerebrospinal fluid (CSF) and blood beta‐syn levels compared to controls and subjects with other neurodegenerative disorders. However, to date, no study explored the biomarker distribution and prognostic value across the heterogeneous spectrum of sporadic Creutzfeldt‐Jakob disease (sCJD) as well as its diagnostic performance in the real‐life setting of patients with rapidly progressive dementia (RPD).MethodUsing in house established immunoassays we measured CSF and/or plasma beta‐syn concentrations in 150 patients with sCJD, belonging to the most prevalent molecular subtypes [MM(V)1, VV2 and MV2K], and in 106 subjects with non‐prion RPD. In the same cohort, we assessed CSF levels of total tau (t‐tau) and protein 14‐3‐3. We compared the diagnostic performance of CSF/plasma beta‐syn with that of classic CSF markers and we tested the possible associations of CSF/plasma beta‐syn with survival in patients with sCJD.ResultsCJD patients showed higher CSF and plasma beta‐syn levels compared to non‐prion RPD subjects (p<0.001 for both) (Figure 1A, B). Different CSF and blood profiles of beta‐syn were observed for the most prevalent sCJD molecular subtypes (Figure 1C, D). Concerning the diagnostic value, CSF beta‐syn outperformed 14‐3‐3 (AUC 0.95 vs. 0.89, p = 0.028) but not t‐tau (AUC 0.92, p = 0.212). Further, the discriminative accuracy of plasma beta‐syn (AUC 0.91) was not inferior to that of classic CSF markers (t‐tau, p = 0.765 and 14‐3‐3, p = 0.447) and CSF beta‐syn (p = 0.135). In the whole sCJD cohort, CSF and plasma beta‐syn were significantly associated with survival at univariate analyses but not after accounting for codon 129 genotype or molecular subtype.ConclusionCSF beta‐syn performed similar or better compared to t‐tau and 14‐3‐3, respectively, thus, the marker might represent an alternative first‐level test in patients with suspected sCJD. Most interestingly, the high diagnostic value of beta‐syn in plasma, which was comparable to that of classic CSF surrogate markers, suggests that beta‐syn might be used as highly accurate blood surrogate marker in sCJD for patient screening and monitoring.