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Original Investigation
February 2017

Diagnosis of Human Prion Disease Using Real-Time Quaking-Induced Conversion Testing of Olfactory Mucosa and Cerebrospinal Fluid Samples

Author Affiliations
  • 1Department of Neurosciences, Biomedicine, and Movement Sciences, University of Verona, Policlinico G. B. Rossi, Verona, Italy
  • 2Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana
  • 3Department of Surgical Sciences, Dentistry, Gynecology, and Pediatrics, University of Verona, Verona, Italy
  • 4Struttura Complessa di Otorinolaringoiatria, Ospedale Santa Maria della Misericordia, Rovigo, Italy
  • 5Copan Italia SpA, Brescia, Italy
  • 6Biocrystallography Laboratory, Department of Biotechnology, University of Verona, Italy
  • 7Department of Neuroscience, University of Padova, Padova, Italy
  • 8Istituto di Ricovero e Cura a Carattere Scientifico San Camillo Hospital, Venice, Italy
  • 9Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Rome, Italy
  • 10Neurology Unit, Ospedale Maria Vittoria, Torino, Italy
  • 11Neurology Unit, Ospedale Cattinara, Trieste, Italy
JAMA Neurol. 2017;74(2):155-162. doi:10.1001/jamaneurol.2016.4614
Key Points

Question  How can diagnosis of Creutzfeldt-Jakob disease be optimized using cerebrospinal fluid and nasal swabbing samples?

Findings  In this case-control laboratory analysis, a diagnostic algorithm had 100% sensitivity and 100% specificity for 61 cases of sporadic Creutzfeldt-Jakob disease relative to 71 non–prion disease cases using real-time quaking-induced conversion analysis of cerebrospinal fluid and/or olfactory mucosa samples. The sensitivity for genetic prion diseases was 75%, and gentler nasal swabs worked as well as cytobrushes for olfactory mucosa sampling.

Meaning  Real-time quaking-induced conversion testing can provide rapid and accurate intra vitam diagnosis of Creutzfeldt-Jakob disease.


Importance  Early and accurate in vivo diagnosis of Creutzfeldt-Jakob disease (CJD) is necessary for quickly distinguishing treatable from untreatable rapidly progressive dementias and for future therapeutic trials. This early diagnosis is becoming possible using the real-time quaking-induced conversion (RT-QuIC) seeding assay, which detects minute amounts of the disease-specific pathologic prion protein in cerebrospinal fluid (CSF) or olfactory mucosa (OM) samples.

Objective  To develop an algorithm for accurate and early diagnosis of CJD by using the RT-QuIC assay on CSF samples, OM samples, or both.

Design, Setting, and Participants  In this case-control study, samples of CSF and OM were collected from 86 patients with a clinical diagnosis of probable (n = 51), possible (n = 24), or suspected (n = 11) CJD and 104 negative control samples (54 CSF and 50 OM). The CSF and OM samples were analyzed using conventional RT-QuIC. The CSF samples underwent further testing using improved RT-QuIC conditions. In addition, the diagnostic performance of a novel, easy-to-use, gentle flocked swab for sampling of OM was evaluated. Data were collected from January 1 to June 30, 2015.

Main Outcome and Measures  Correlations between RT-QuIC results and the final diagnosis of recruited patients.

Results  Among the 86 patients (37 men [43%] and 49 women [57%]; mean [SD] age, 65.7 [11.5] years) included for analysis, all 61 patients with sporadic CJD had positive RT-QuIC findings using OM or CSF samples or both for an overall RT-QuIC diagnostic sensitivity of 100% (95% CI, 93%-100%). All patients with a final diagnosis of non–prion disease (71 CSF and 67 OM samples) had negative RT-QuIC findings for 100% specificity (95% CI, 94%-100%). Of 8 symptomatic patients with various mutations causing CJD or Gerstmann-Sträussler-Scheinker syndrome, 6 had positive and 2 had negative RT-QuIC findings for a sensitivity of 75% (95% CI, 36%-96%).

Conclusions and Relevance  A proposed diagnostic algorithm for sporadic CJD combines CSF and OM RT-QuIC testing to provide virtually 100% diagnostic sensitivity and specificity in the clinical phase of the disease.