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Original Investigation
December 2016

Diagnosing Sporadic Creutzfeldt-Jakob Disease by the Detection of Abnormal Prion Protein in Patient Urine

Author Affiliations
  • 1MRC Prion Unit, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England
  • 2Dementia Research Centre, Department of Neurodegenerative Disease, University College London Institute of Neurology, London, England
  • 3National Prion Clinic, National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, England
JAMA Neurol. 2016;73(12):1454-1460. doi:10.1001/jamaneurol.2016.3733
Key Points

Question  Is abnormal prion protein present in the urine of patients with sporadic Creutzfeldt-Jakob disease?

Findings  In this cross-sectional study, 40% of patients with sporadic Creutzfeldt-Jakob disease excreted abnormal prion protein in their urine, an indication absent in healthy and neurological disease control individuals.

Meaning  Sporadic Creutzfeldt-Jakob disease can be diagnosed using urine-based testing and the screening of urine used for the production of pharmaceuticals may be possible.


Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.