Clinical laboratory tests used to aid in the diagnosis of human prion disease

Prion diseases are a group of rapidly progressive and always fatal neurodegenerative disorders caused by misfolded prion protein in the brain. Although autopsy remains the gold standard diagnostic tool, antemortem laboratory testing can be performed to aid in the diagnosis of prion disease. This review is meant to help laboratory directors and physicians in their interpretation of test results. Laboratory assays to detect both non-specific biomarkers of prion disease and prion-specific biomarkers can be used. The non-specific biomarkers in cerebrospinal fluid (CSF) are elevated when rapid neurodegeneration is occurring in the patient; and these markers include 14-3-3, tau, neuron specific enolase, S100B, and alpha synuclein. These markers have varying sensitivity and specificity but are overall limited as any of these analytes can be elevated in non-prion disease that is causing rapid damage of brain tissue. Prion-specific assays used in clinical laboratory testing are currently limited to two options. The first option is second-generation real time-quaking induced conversion (RT-QuIC) performed on CSF, and the second option is a western blot from a brain biopsy used to detect protease-resistant prion protein. Although both tests have exquisite specificity, RT-QuIC has a sensitivity of 92-97.2% in symptomatic individuals compared to the brain biopsy western blot sensitivity of 20-60%. RT-QuIC was added to the Center for Disease Control & Prevention9s diagnostic criteria for prion disease in 2018. Other caveats of laboratory testing need to be considered as sporadic, genetic, and acquired forms of prion disease have different clinical and laboratory presentations, and these caveats are discussed. Laboratory testing plays an important role in the diagnosis of prion disease, which is often challenging to diagnose.