CSF biomarkers for prion diseases

Abstract

Recently, clinical trials of human prion disease (HPD) treatments have begun in many countries, and the therapeutic window of these trials focuses mainly on the early stage of the disease. Furthermore, few studies have examined the role of biomarkers at the early stage. According to the World Health Organization, the clinical diagnostic criteria for HPDs include clinical findings, cerebrospinal fluid (CSF) protein markers, and electroencephalography (EEG). In contrast, the UK and European clinical diagnostic criteria include a combination of clinical findings, 14-3-3 protein in the CSF, magnetic resonance imaging-diffusion-weighted imaging (MRI-DWI), and EEG. Moreover, recent advancements in laboratory testing and MRI-DWI have improved the accuracy of diagnostics used for prion diseases. However, according to MRI-DWI data, patients with rapidly progressing dementia are sometimes misdiagnosed with HPD due to the high-intensity areas detected in their brains. Thus, analyzing the CSF biomarkers is critical to diagnose accurately different diseases. CSF biomarkers are investigated using a biochemical approach or the protein amplification methods that utilize the unique properties of prion proteins and the ability of PrP^Sc to induce a conformational change. The biochemical markers include the 14-3-3 and total tau proteins of the CSF. In contrast, the protein amplification methods include the protein misfolding cyclic amplification assay and real-time quaking-induced conversion (RT-QuIC) assay. The RT-QuIC analysis of the CSF has been proved to be a highly sensitive and specific test for identifying sporadic HPD forms; for this reason, it was included in the diagnostic criteria.

Keywords: Biomarker; CSF; PrP(Sc)-seeded aggregation assay; Prion disease; RT-QuIC assay; Therapeutic window.