Total-PrP Profiles in Blood and CSF: Insights into Pre-symptomatic and Symptomatic Prion Disease

Introduction:
Prion diseases are fatal neurodegenerative disorders driven by misfolded prion protein (PrP) accumulation. Diagnosis and treatment are hindered by clinical and genetic variability. Blood and cerebrospinal fluid (CSF) biomarkers are critical for early diagnosis and trial monitoring.

Objectives:
This study aimed to quantify total prion protein (t-PrP) in plasma and CSF from prion disease patients, genetic mutation carriers, and controls to identify mutation-specific biomarker signatures and evaluate diagnostic accuracy.

Methods:
A total of 136 plasma and 84 CSF samples were analyzed from healthy controls (HC), Alzheimer’s disease (AD) patients, sporadic (sCJD) and genetic Creutzfeldt-Jakob disease (gCJD), Gerstmann-Sträussler-Scheinker (GSS) syndrome, fatal familial insomnia (FFI), and asymptomatic PRNP mutation carriers. t-PrP was quantified using the BetaPrion ELISA. Statistical tests assessed group differences, correlations with demographics and PRNP codon 129 genotype, and receiver operating characteristic (ROC) curve performance.

Results and Discussion:
Plasma t-PrP was significantly lowered in sCJD, gCJD, FFI, and asymptomatic D178N carriers versus controls and Alzheimer’s patients, but unchanged in GSS and other asymptomatic mutations. CSF t-PrP was notably reduced only in FFI. Plasma t-PrP discriminated FFI and D178N carriers (AUC >0.90) and sCJD/gCJD (AUC≈0.8) from controls, outperforming CSF t-PrP. No association with age, sex, or disease onset was observed. Preanalytical variability remains a challenge. Concordant plasma and CSF patterns differ from prior compartmental dissociation reports.

Conclusion:
Plasma t-PrP offers mutation-specific biomarker profiles with superior diagnostic potential for some prion subtypes, especially D178N carriers. Longitudinal validation studies are needed to confirm its utility in clinical trials and risk prediction.