title: 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 weak-positive 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.
authors.affiliation: Neurochemistry Laboratory, Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal. jajao86@gmail.com.|CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal. jajao86@gmail.com.
authors.forename: M J
authors.identifier: http://orcid.org/0000-0002-8950-1439
authors.initials: MJ
authors.lastname: Leitão
authors.affiliation: Neurochemistry Laboratory, Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Faculdade de Medicina, Pólo III, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal.
authors.forename: I
authors.initials: I
authors.lastname: Baldeiras
authors.affiliation: CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal.
authors.forename: M R
authors.initials: MR
authors.lastname: Almeida
authors.affiliation: Neurochemistry Laboratory, Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Faculdade de Medicina, Pólo III, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.
authors.forename: M H
authors.initials: MH
authors.lastname: Ribeiro
authors.affiliation: CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal.
authors.forename: A C
authors.initials: AC
authors.lastname: Santos
authors.affiliation: CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal.
authors.forename: M
authors.initials: M
authors.lastname: Ribeiro
authors.affiliation: Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.
authors.forename: J
authors.initials: J
authors.lastname: Tomás
authors.affiliation: Neurology Department, St Marcos Hospital, Sete Fontes, São Victor, 4710-243, Braga, Portugal.
authors.forename: S
authors.initials: S
authors.lastname: Rocha
authors.affiliation: Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Faculdade de Medicina, Pólo III, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal.
authors.forename: I
authors.initials: I
authors.lastname: Santana
authors.affiliation: Neurochemistry Laboratory, Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.|Neurology Department, University Hospital Coimbra, Centro Hospitalar e Universitário de Coimbra, Praceta Mota Pinto, 3000-075, Coimbra, Portugal.|Faculty of Medicine, University of Coimbra, Faculdade de Medicina, Pólo III, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|CNC.IBILI-Center for Neuroscience and Cell Biology, University of Coimbra, Rua Larga, 1st floor, 3004-504, Coimbra, Portugal.
authors.forename: C R
authors.initials: CR
authors.lastname: Oliveira
mesh_terms: D048948:14-3-3 Proteins / Q000134:cerebrospinal fluid*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001057:Apolipoproteins E / Q000235:genetics; D015415:Biomarkers / Q000134:cerebrospinal fluid; D015153:Blotting, Western; D015331:Cohort Studies; D007562:Creutzfeldt-Jakob Syndrome / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000235:genetics; D003951:Diagnostic Errors / Q000517:prevention & control*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D060005:Genotyping Techniques; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D000072002:Prion Proteins / Q000235:genetics; D012044:Regression Analysis; D012680:Sensitivity and Specificity; D055815:Young Adult; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D048948:14-3-3 Proteins; D001057:Apolipoproteins E; D015415:Biomarkers; C054369:MAPT protein, human; C512656:PRNP protein, human; D000072002:Prion Proteins; D016875:tau Proteins
keywords: 14-3-3 protein; Biomarkers; CSF; Phosphorylated Tau protein; Tau protein; sCJD