title: Prion-specific and surrogate CSF biomarkers in Creutzfeldt-Jakob disease: diagnostic accuracy in relation to molecular subtypes and analysis of neuropathological correlates of p-tau and Aβ42 levels.
abstract: The differential diagnosis of Creutzfeldt-Jakob disease (CJD) from other, sometimes treatable, neurological disorders is challenging, owing to the wide phenotypic heterogeneity of the disease. Real-time quaking-induced prion conversion (RT-QuIC) is a novel ultrasensitive in vitro assay, which, at variance with surrogate neurodegenerative biomarker assays, specifically targets the pathological prion protein (PrPSc). In the studies conducted to date in CJD, cerebrospinal fluid (CSF) RT-QuIC showed good diagnostic sensitivity (82-96%) and virtually full specificity. In the present study, we investigated the diagnostic value of both prion RT-QuIC and surrogate protein markers in a large patient population with suspected CJD and then evaluated the influence on CSF findings of the CJD type, and the associated amyloid-β (Aβ) and tau neuropathology. RT-QuIC showed an overall diagnostic sensitivity of 82.1% and a specificity of 99.4%. However, sensitivity was lower in CJD types linked to abnormal prion protein (PrPSc) type 2 (VV2, MV2K and MM2C) than in typical CJD (MM1). Among surrogate proteins markers (14-3-3, total (t)-tau, and t-tau/phosphorylated (p)-tau ratio) t-tau performed best in terms of both specificity and sensitivity for all sCJD types. Sporadic CJD VV2 and MV2K types demonstrated higher CSF levels of p-tau when compared to other sCJD types and this positively correlated with the amount of tiny tau deposits in brain areas showing spongiform change. CJD patients showed moderately reduced median Aβ42 CSF levels, with 38% of cases having significantly decreased protein levels in the absence of Aβ brain deposits. Our results: (1) support the use of both RT-QuIC and t-tau assays as first line laboratory investigations for the clinical diagnosis of CJD; (2) demonstrate a secondary tauopathy in CJD subtypes VV2 and MV2K, correlating with increased p-tau levels in the CSF and (3) provide novel insight into the issue of the accuracy of CSF p-tau and Aβ42 as markers of brain tauopathy and β-amyloidosis.
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Lattanzio
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Samir
authors.initials: S
authors.lastname: Abu-Rumeileh
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Franceschini
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.|Department of Neurological Sciences, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Kai
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Giulia
authors.initials: G
authors.lastname: Amore
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Poggiolini
authors.affiliation: IRCCS, Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Marcello
authors.initials: M
authors.lastname: Rossi
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
authors.forename: Simone
authors.initials: S
authors.lastname: Baiardi
authors.affiliation: National CJD Research and Surveillance Unit, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Lynne
authors.initials: L
authors.lastname: McGuire
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Ladogana
authors.affiliation: Department of Neurosciences, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pocchiari
authors.affiliation: National CJD Research and Surveillance Unit, University of Edinburgh, Edinburgh, Scotland, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Green
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.|IRCCS, Institute of Neurological Sciences, Bologna, Italy.
authors.forename: Sabina
authors.initials: S
authors.lastname: Capellari
authors.affiliation: Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy. piero.parchi@unibo.it.|IRCCS, Institute of Neurological Sciences, Bologna, Italy. piero.parchi@unibo.it.
authors.forename: Piero
authors.identifier: 0000-0002-9444-9524
authors.initials: P
authors.lastname: Parchi
mesh_terms: D048948:14-3-3 Proteins / Q000134:cerebrospinal fluid; D000368:Aged; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000378:metabolism / Q000473:pathology; D007562:Creutzfeldt-Jakob Syndrome / Q000134:cerebrospinal fluid*; D003937:Diagnosis, Differential; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010766:Phosphorylation; D000072002:Prion Proteins / Q000134:cerebrospinal fluid; D012680:Sensitivity and Specificity; D013048:Specimen Handling; D013129:Spinal Puncture; D013997:Time Factors; D016875:tau Proteins / Q000134:cerebrospinal fluid*
chemical_list: D048948:14-3-3 Proteins; D016229:Amyloid beta-Peptides; D015415:Biomarkers; C054369:MAPT protein, human; D010446:Peptide Fragments; D000072002:Prion Proteins; C075222:amyloid beta-protein (1-42); D016875:tau Proteins
keywords: Alzheimer’s disease; Amyloid-beta; Biomarkers; Human prions; Protease-sensitive prionopathy; RT-QuIC; Tauopathy