Prion real-time quaking-induced conversion (RT-QuIC) is emerging as the most potent assay for the in vivo diagnosis of Creutzfeldt–Jakob disease (CJD), but its full application, especially as a screening test, is limited by suboptimal substrate availability, reagent costs, and incomplete assay standardization. Therefore, the search for the most informative cerebrospinal fluid (CSF) surrogate biomarker is still of primary importance. We compared the diagnostic accuracy of CSF protein 14-3-3, measured with both western blot (WB) and enzyme-linked immunosorbent assay (ELISA), total (t)-tau and neurofilament light chain protein (NfL) alone or in combination with RT-QuIC in 212 subjects with rapidly progressive dementia in which we reached a highly probable clinical diagnosis at follow-up or a definite neuropathological diagnosis. T-tau performed best as surrogate CSF biomarker for the diagnosis of CJD (91.3% sensitivity and 78.9% specificity). The 14-3-3 ELISA assay demonstrated a slightly higher diagnostic value compared to the WB analysis (76.9% vs. 72.2%), but both methods performed worse than the t-tau assay. NfL was the most sensitive biomarker for all sCJD subtypes (> 95%), including those with low values of t-tau or 14-3-3, but showed the lowest specificity (43.1%). When ELISA-based biomarkers were adopted as screening tests followed by RT-QuIC, t-tau correctly excluded a higher number of non-CJD cases compared to NfL and 14-3-3 ELISA. Our study showed that among the CSF surrogate biomarkers of potential application for the clinical diagnosis of CJD, t-tau performs best either alone or as screening test followed by RT-QuIC as a second-level confirmatory test.
Prion disease Dementia Total tau 14-3-3 Neurofilament light chain
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We sincerely thank Dr. Byron Caughey for providing the substrate for IQ-CSF RT-QuIC. This work was supported by the Italian Ministry of Health (“Ricerca Corrente”).
Conceptualization: SA-R and PP; methodology, formal analysis and investigation: all authors; writing—original draft preparation: SA-R and PP; writing—review and editing: PP based on the critical revision of all authors—supervision: PP.
Compliance with ethical standards
Conflicts of interest
The authors declare that they have no conflict of interest.
The study was conducted according to the revised Declaration of Helsinki and Good Clinical Practice guidelines and approved by the “Area Vasta Emilia Centro” ethics committee (CE-AVEC: 18025, 113/2018/OSS/AUSLBO). Informed consent was given by study participants or the next of kin.
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