Problems in diagnosis of prion diseases for the purpose of clinical trials and the use of biomarkers

Abstract

Prion diseases represent rapidly progressive, fatal neurodegenerative disorders with an exceptionally short clinical course, typically culminating in death within three months of symptom onset. While no effective therapeutic interventions currently exist, the imminent launch of an international investigator–initiated clinical trial within the next triennium underscores the urgent need for refined early diagnostic criteria. Previous investigations have demonstrated the diagnostic utility of diffusion–weighted magnetic resonance imaging (DW–MRI) combined with cerebrospinal fluid (CSF) biomarker analysis, particularly through our research group's development of the RT–QUIC assay, which has exhibited remarkable specificity.

Although these advances have facilitated novel biomarker–driven diagnostic criteria, the substantial reliance on biomarkers for early–stage diagnosis presents challenges, as certain markers may introduce diagnostic ambiguity. Current diagnostic frameworks, while incorporating clinical manifestations and biomarker profiles, remain suboptimal in their comprehensiveness.

This investigation aims to validate new diagnostic criteria through systematic evaluation of biomarkers in conjunction with clinical symptomatology, electroencephalographic patterns, neuroimaging findings, and CSF analyses. Our primary objective is enhancing differential diagnosis between prion diseases and other neurodegenerative disorders. We endeavor to optimize early diagnostic accuracy, thereby maximizing the potential efficacy of future therapeutic interventions. The development of a sophisticated multimodal diagnostic approach will be instrumental in establishing a comprehensive diagnostic and therapeutic framework for prion diseases, ultimately contributing to improved patient outcomes and effective treatment strategies.