title: Diagnosing Sporadic Creutzfeldt-Jakob Disease by the Detection of Abnormal Prion Protein in Patient Urine.
abstract: OBJECTIVE
  Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disorder associated with the accumulation of infectious abnormal prion protein through a mechanism of templated misfolding. A recent report has described the detection of abnormal prion protein in the urine of patients with variant CJD (vCJD) using protein misfolding by cyclic amplification, which was apparently absent in the more common sporadic form of CJD (sCJD). A noninvasive diagnostic test could improve early diagnosis of sCJD and, by screening donations, mitigate the potential risks of prion transmission through human urine-derived pharmaceuticals. Here, we describe the adaptation of the direct detection assay, developed originally as a blood test for vCJD, for the detection of disease-associated prion protein in urine samples from patients with sCJD.
  
  
  OBJECTIVE
  To determine the feasibility of sCJD diagnosis by adaptation of an established vCJD diagnostic blood test to urine.
  
  
  METHODS
  This retrospective, cross-sectional study included anonymized urine samples from healthy nonneurological control individuals (n = 91), patients with non-prion neurodegenerative diseases (n = 34), and patients with prion disease (n = 37) of which 20 had sCJD. Urine samples obtained during the Medical Research Council PRION-1 Trial, the National Prion Monitoring Cohort Study, and/or referred to the National Prion Clinic or Dementia Research Centre at the National Hospital for Neurology and Neurosurgery in the United Kingdom.
  
  
  METHODS
  Presence of sCJD infection determined by an assay that captures, enriches, and detects disease-associated prion protein isoforms.
  
  
  RESULTS
  A total of 162 samples were analyzed, composed of 91 normal control individuals (51 male, 33 female, and 7 not recorded), 34 neurological disease control individuals (19 male and 15 female), and 37 with prion disease (22 male and 15 female). The assay's specificity for prion disease was 100% (95% CI, 97%-100%), with no false-positive reactions from 125 control individuals, including 34 from a range of neurodegenerative diseases. In contrast to a previous study, which used a different method, sensitivity to vCJD infection was low (7.7%; 95% CI, 0.2%-36%), with only 1 of 13 patients with positive test results, while sensitivity to sCJD was unexpectedly high at 40% (95% CI, 19%-64%).
  
  
  CONCLUSIONS
  We determined 40% of sCJD urine sample results as positive. To our knowledge, this is the first demonstration of an assay that can detect sCJD infection in urine or any target analyte outside of the central nervous system. Urine detection could allow the development of rapid, molecular diagnostics for sCJD and has implications for other neurodegenerative diseases where disease-related assemblies of misfolded proteins might also be present in urine.
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Connie
authors.initials: C
authors.lastname: Luk
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Samantha
authors.initials: S
authors.lastname: Jones
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Claire
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Nick C
authors.initials: NC
authors.lastname: Fox
authors.affiliation: National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, England.
authors.forename: Tze H
authors.initials: TH
authors.lastname: Mok
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England3National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, England.
authors.forename: Simon
authors.initials: S
authors.lastname: Mead
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England3National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, England.
authors.forename: John
authors.initials: J
authors.lastname: Collinge
authors.affiliation: MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England.
authors.forename: Graham S
authors.initials: GS
authors.lastname: Jackson
mesh_terms: D000328:Adult; D001681:Biological Assay / Q000379:methods / Q000592:standards*; D007562:Creutzfeldt-Jakob Syndrome / Q000652:urine*; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D008297:Male; D000072002:Prion Proteins / Q000652:urine*; D012680:Sensitivity and Specificity; D016482:Urinalysis / Q000379:methods / Q000592:standards*
chemical_list: D000072002:Prion Proteins