Recent advancements in QuIC-based diagnostic assays for sporadic and inherited prion diseases: focusing on the emerging role of ES-QuIC

Prion diseases are a group of fatal neurological disorders characterized by the accumulation of misfolded prion protein, primarily concentrated in the brain. The development of a family of assays known as Quaking-Induced Conversion (QuIC), particularly Real Time (RT)-QuIC, has revolutionized prion disease diagnosis by detecting and amplifying minute quantities of misfolded prion protein into measurable signals. Despite these advancements, certain prion subtypes, such as rare inherited forms or atypical sporadic variants, can produce structural configurations that resist amplification. To address these limitations, we developed a modified QuIC-based assay to increase sensitivity across a wider spectrum of prion diseases. Through retrospective analysis of cerebrospinal fluid (CSF) and brain tissue samples from patients diagnosed with both sporadic Creutzfeldt–Jakob disease (sCJD) and inherited prion diseases (IPDs), many of them historically problematic for conventional QuIC testing, we benchmark this modified assay against its predecessors. The updated assay demonstrated more consistent detection of disease-associated prion protein, successfully identifying cases that had previously yielded negative, inconclusive or borderline results. Given the transmissible nature of prion diseases, early and accurate diagnostic detection carries considerable weight in guiding patient care and counseling, as well as in broader public health surveillance. Taken together, these results demonstrate the strong diagnostic potential of this enhanced assay and support further prospective and independent evaluation toward its incorporation into standard diagnostic workflows for patients with suspected prion disease.