Biomarker changes preceding symptom onset in genetic prion disease

Area of Science:

• Neurodegenerative diseases
• Prion diseases
• Biomarker discovery

Background:

• Genetic prion diseases are fatal and rapidly progressive, necessitating early therapeutic interventions.
• Preclinical studies suggest that early treatment before symptom onset offers significant benefits.
• Longitudinal tracking of biomarkers in presymptomatic mutation carriers is crucial for developing effective early treatment strategies.

Approach:

• This single-center longitudinal cohort study followed 41 PRNP mutation carriers and 21 controls for up to 6 years.
• Participants, all asymptomatic at enrollment, underwent annual monitoring.
• Key biomarkers including RT-QuIC prion seeding activity, prion protein (PrP), neurofilament light chain (NfL), total tau (t-tau), and beta synuclein were measured in CSF, alongside GFAP and NfL in plasma.

Key Points:

• RT-QuIC seeding activity was detected in the CSF of three E200K mutation carriers before symptom onset.
• The duration of RT-QuIC positivity before symptom onset varied based on PRNP codon 129 genotype.
• Other neurodegenerative markers showed limited sensitivity in the presymptomatic phase, while CSF PrP levels remained stable.

Conclusions:

• CSF prion seeding activity, particularly for the E200K mutation, may serve as the earliest detectable prodromal marker for genetic prion disease.
• The prognostic value of CSF prion seeding activity may be influenced by the individual's PRNP codon 129 genotype.
• Markers of neuronal damage and neuroinflammation have limited sensitivity in the prodromal stage of genetic prion disease.