title: Diagnostic and prognostic value of human prion detection in cerebrospinal fluid.
abstract: OBJECTIVE
  Several prion amplification systems have been proposed for detection of prions in cerebrospinal fluid (CSF), most recently, the measurements of prion seeding activity with second-generation real-time quaking-induced conversion (RT-QuIC). The objective of this study was to investigate the diagnostic performance of the RT-QuIC prion test in the broad phenotypic spectrum of prion diseases.
  
  
  METHODS
  We performed CSF RT-QuIC testing in 2,141 patients who had rapidly progressive neurological disorders, determined diagnostic sensitivity and specificity in 272 cases that were autopsied, and evaluated the impact of mutations and polymorphisms in the PRNP gene, and type 1 or type 2 human prions on diagnostic performance.
  
  
  RESULTS
  The 98.5% diagnostic specificity and 92% sensitivity of CSF RT-QuIC in a blinded retrospective analysis matched the 100% specificity and 95% sensitivity of a blind prospective study. The CSF RT-QuIC differentiated 94% of cases of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 from the sCJD MM2 phenotype, and 80% of sCJD VV2 from sCJD VV1. The mixed prion type 1-2 and cases heterozygous for codon 129 generated intermediate CSF RT-QuIC patterns, whereas genetic prion diseases revealed distinct profiles for each PRNP gene mutation.
  
  
  CONCLUSIONS
  The diagnostic performance of the improved CSF RT-QuIC is superior to surrogate marker tests for prion diseases such as 14-3-3 and tau proteins, and together with PRNP gene sequencing the test allows the major prion subtypes to be differentiated in vivo. This differentiation facilitates prediction of the clinicopathological phenotype and duration of the disease-two important considerations for envisioned therapeutic interventions. ANN NEUROL 2017;81:79-92.
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Aaron
authors.initials: A
authors.lastname: Foutz
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Psychiatry, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Appleby
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Clive
authors.initials: C
authors.lastname: Hamlin
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Sheng
authors.initials: S
authors.lastname: Yang
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Cohen
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Janis
authors.initials: J
authors.lastname: Blevins
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Cameron
authors.initials: C
authors.lastname: Fausett
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Han
authors.initials: H
authors.lastname: Wang
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Gambetti
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Shulin
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT.
authors.forename: Andrew
authors.initials: A
authors.lastname: Hughson
authors.affiliation: Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Curtis
authors.initials: C
authors.lastname: Tatsuoka
authors.affiliation: National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Schonberger
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Cohen
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT.
authors.forename: Byron
authors.initials: B
authors.lastname: Caughey
authors.affiliation: National Prion Disease Pathology Surveillance Center, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH.|Department of Neurology, Case Western Reserve University School of Medicine, Cleveland, OH.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
mesh_terms: D000368:Aged; D015415:Biomarkers; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011237:Predictive Value of Tests; D017096:Prion Diseases / Q000134:cerebrospinal fluid* / Q000175:diagnosis* / Q000235:genetics; D000072002:Prion Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics; D011379:Prognosis; D012680:Sensitivity and Specificity
chemical_list: D015415:Biomarkers; C512656:PRNP protein, human; D000072002:Prion Proteins