Real-Time Quaking-Induced Conversion Assays for Prions: Applying a Sensitive but Imperfect Test in Clinical Practice.

BACKGROUND: Real-time quaking-induced conversion (RT-QuIC) assays offer a sensitive and specific means for detection of prions, although false negative results are recognized in clinical practice. We profile the clinical, laboratory, and pathologic features associated with false negative RT-QuIC assays and extend these to frame the diagnostic approach to patients with suspected prion disease.

METHODS: 113 patients with probable or definite prion disease were assessed at Mayo Clinic (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) or Washington University School of Medicine (St. Louis, MO) from 2013-2021. RT-QuIC testing for prions was performed in CSF at the National Prion Disease Pathology Surveillance Center (Cleveland, OH).

RESULTS: Initial RT-QuIC testing was negative in 13/113 patients (sensitivity 88.5%). RT-QuIC negative patients were younger (median 52.0 years vs 66.1 years, p<0.001). Other demographic and presenting features, and CSF cell count, protein, and glucose levels were similar in RT-QuIC negative and positive patients. Frequency of 14-3-3 positivity (4/13 vs 77/94, p<0.001) and median CSF total tau levels were lower in RT-QuIC negative patients (2517 vs 4001 pg/mL, p=0.020), while time from symptom onset to first presentation (153 vs 47 days, p=0.001) and symptomatic duration (710 vs 148 days, p=0.001) were longer.

CONCLUSIONS: RT-QuIC is a sensitive yet imperfect measure necessitating incorporation of other test results when evaluating patients with suspected prion disease. Patients with negative RT-QuIC had lower markers of neuronal damage (CSF total-tau and protein 14-3-3) and longer symptomatic duration of disease suggesting that false negative RT-QuIC testing associates with a more indolent course.