RT-QuIC Nasal Brushing
(2014)Objective
To evaluate the diagnostic accuracy of real-time quaking-induced conversion (RT-QuIC) testing on nasal brushings for detecting sporadic Creutzfeldt–Jakob disease (sCJD) in living patients.
Study Summary
• More sensitive and faster than CSF RT-QuIC.
• Non-invasive sampling approach suitable for living patients.
Intervention
Nasal brushing samples from 31 patients with sCJD (definite, probable, or inherited) and 43 controls (neurologic and non-neurologic) were tested using RT-QuIC. Fluorescent amyloid formation kinetics were compared to CSF-based testing.
Inclusion Criteria
Patients with suspected rapidly progressive dementia, referred for diagnostic evaluation. Controls included patients with other neurologic diseases (Alzheimer’s, Parkinson’s, etc.) and healthy individuals.
Study Design
Arms: sCJD vs. Controls
Patients per Arm: CJD: 31; Controls: 43
Outcome
• Specificity (nasal RT-QuIC): 100% (43/43; 95% CI: 90–100)
• CSF RT-QuIC sensitivity: 77%; specificity: 100%
• Nasal RT-QuIC produced stronger and faster signals than CSF (P<0.001)
• Prion seeding activity in nasal mucosa was 3–4 log10 SD50/μL, higher than CSF levels
• One patient with probable CJD tested negative by both methods
Bottom Line
RT-QuIC testing of nasal brushings demonstrated 97% sensitivity and 100% specificity for diagnosing CJD, outperforming CSF-based RT-QuIC (77% sensitivity) in the same patients. This minimally invasive approach detects substantial prion seeding activity in the olfactory epithelium and offers a promising method for definitive antemortem diagnosis of CJD.
Major Points
- RT-QuIC of nasal brushings positive in 30/31 CJD patients (15/15 definite sCJD, 13/14 probable sCJD, 2/2 inherited E200K CJD)
- All 43 non-CJD controls were RT-QuIC negative on nasal brushings
- Olfactory mucosa samples gave significantly stronger and faster RT-QuIC responses than CSF (P<0.001)
- Individual brushings contained approximately 10⁵ to 10⁷ prion seeds, several logs₁₀ greater concentration than in CSF
- Nasal brushing is a safe, minimally invasive procedure requiring only local vasoconstrictor and fiberoptic rhinoscope
- Method detected all CJD molecular subtypes (MM, MV, VV genotypes; types 1 and 2 PrPᶜᴶᴰ)
- One false negative case (Patient 29) had typical tau and 14-3-3 levels but negative RT-QuIC on both OM and CSF
- The presence of substantial prion seeds in the nasal vault raises biosafety considerations for medical instruments contacting this area
Study Design
- Study Type
- Prospective diagnostic accuracy study
- Randomization
- No
- Blinding
- Blinded analysis; RT-QuIC testing performed on blinded sample sets
- Sample Size
- 74
- Follow-up
- Not applicable (diagnostic study)
- Centers
- 2
- Countries
- Italy, United States
Primary Outcome
Definition: Diagnostic accuracy of RT-QuIC assay on olfactory mucosa samples for detecting CJD
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| - | - | - |
Limitations & Criticisms
- Relatively small sample size (31 CJD patients, 43 controls); larger validation studies needed
- Single-center sampling (Italy) for CJD patients limits generalizability
- One false negative case suggests method may not detect all CJD cases
- Time between symptom onset and OM brushing varied widely (0.5-28 months); effect of disease stage on test performance unclear
- Control population had significantly different age distribution than CJD patients
- Biosafety implications of prion-contaminated medical instruments not fully addressed
- Study did not compare performance to brain biopsy (true gold standard in living patients)
- Only sporadic and E200K inherited CJD tested; performance in other inherited forms unknown
- Requires specialized laboratory expertise and equipment for RT-QuIC assay
Citation
N Engl J Med 2014;371:519-29