Biomarker changes preceding symptom onset in genetic prion disease
Importance. Genetic prion disease is a universally fatal and rapidly progressive neurodegenerative disease for which genetically targeted therapies are currently under development. Preclinical proofs of concept indicate that treatment before symptoms will offer outsize benefit. Though early treatment paradigms will be informed by the longitudinal biomarker trajectory of mutation carriers, to date limited cases have been molecularly tracked from the presymptomatic phase through symptomatic onset. Objective. To longitudinally characterize disease-relevant cerebrospinal fluid (CSF) and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion, alongside non-converters and healthy controls. Design, setting, and participants. This single-center longitudinal cohort study has followed 41 PRNP mutation carriers and 21 controls for up to 6 years. Participants spanned a range of known pathogenic PRNP variants; all subjects were asymptomatic at first visit and re