CSF Tau proteins reduce misdiagnosis of sporadic Creutzfeldt–Jakob disease suspected cases with inconclusive 14-3-3 result

Abstract

Cerebrospinal fluid (CSF) 14-3-3 protein supports sporadic Creutzfeldt-Jakob (sCJD) diagnosis, but often leads to weak-positive results and lacks standardization. In this study, we explored the added diagnostic value of Total Tau (t-Tau) and phosphorylated Tau (p-Tau) in sCJD diagnosis, particularly in the cases with inconclusive 14-3-3 result. 95 definite sCJD and 287 patients without prion disease (non-CJD) were included in this study. CSF samples were collected in routine clinical diagnosis and analysed for 14-3-3 detection by Western blot (WB). CSF t-Tau and p-Tau were quantified by commercial ELISA kits and PRNP and APOE genotyping assessed by PCR-RFLP. In a regression analysis of the whole cohort, 14-3-3 protein revealed an overall accuracy of 82 % (sensitivity = 96.7 %; specificity = 75.6 %) for sCJD. Regarding 14-3-3 clear positive results, we observed no added value either of t-Tau alone or p-Tau/t-Tau ratio in the model. On the other hand, considering 14-3-3 weakpositive cases, t-Tau protein increased the overall accuracy of 14-3-3 alone from 91 to 94 % and specificity from 74 to 93 % (p \ 0.05), with no sensitivity improvement. However, inclusion of p-Tau/t-Tau ratio did not significantly improve the first model (p = 0.0595). Globally, t-Tau protein allowed a further discrimination of 65 % within 14-3-3 inconclusive results. Furthermore, PRNP MV genotype showed a trend to decrease 14-3-3 sensitivity (p = 0.051), but such effect was not seen on t-Tau protein.In light of these results, we suggest that t-Tau protein assay is of significant importance as a second marker in identifying 14-3-3 false-positive results among sCJD probable cases.

Does the Use of Antidepressants Accelerate the Disease Progress in Creutzfeldt–Jakob Disease Patients With Depression? A Case Report and A Systematic Review

“…Similarly, the cause of sCJD neuropathological changes has also proved to be a reversible process, such as synaptic or neuronal dysfunction (39). Interestingly, patients with sCJD also have higher concentrations of Aβ and tau proteins in their serum and CSF (40, 41). Aβ may be propagated in a prion-like manner (42, 43).…”

Role of Biomarkers for the Diagnosis of Prion Diseases: A Narrative Review

“…The gamma-isoform of the 14-3-3 protein (14-3-3 gamma) expressed in neurons could be a specific marker for neuronal damage and is useful for sCJD diagnosis [34][35][36]. The pathological mechanisms leading to the accumulation of 14-3-3 protein in CSF are not fully understood; however, neuronal loss followed by cell lysis is assumed to cause increase in 14-3-3 levels [37].…”

“…The diagnostic performance of quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3 is higher in comparison with western blotting (WB) [34,40]. Combination with other surrogate biomarkers, such as the determination of total tau (t-tau) and the ratio of t-tau/phosphorylated tau (p-tau), significantly increases the specificity [14,36,[41][42][43].…”

Role of Biomarkers for the Diagnosis of Prion Diseases

“…The gamma-isoform of the 14-3-3 protein (14-3-3 gamma) is expressed in neurons, could be a specific marker for neuronal damage and is useful for sCJD diagnosis [30][31][32]. The pathological mechanisms leading to the accumulation of 14-3-3 protein in CSF are not fully understood; however, neuronal loss followed by cell lysis is assumed to cause the increase in 14-3-3 levels [33].…”

“…The diagnostic performance of quantitative enzyme-linked immunosorbent (ELISA) assay for 14-3-3 is higher in comparison with western blotting (WB) [30,36]. Combination with other surrogate biomarkers such as the determination of total tau (t-tau) and the ratio of ttau/phosphorylated tau (p-tau) significantly increases the specificity [9,32,[37][38][39].…”