Biomarker changes preceding symptom onset in genetic prion disease
Authors: Vallabh Sonia M , Mortberg Meredith A , Allen Shona W. , Kupferschmid Ashley C , Kivisäkk Pia , Hammerschlag Bruno L , Bolling Anna , Trombetta Bianca A. , Devitte-McKee Kelli , Ford Abaigeal M. , Sather Lauren , Duffy Griffin , Rivera Ashley , Gerber Jessica , McManus Alison J , Minikel Eric Vallabh , Arnold Steven E 
Published: December 2023

ABSTRACTImportanceGenetic 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.ObjectiveTo 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 participantsThis single-center longitudinal cohort study has followed 41PRNPmutation carriers and 21 controls for up to 6 years. Participants spanned a range of known pathogenicPRNPvariants; all subjects were asymptomatic at first visit and returned roughly annually. Four at-risk individuals experienced prion disease onset during the study.Main outcomes and measuresRT-QuIC prion seeding activity, prion protein (PrP), neurofilament light chain (NfL) total tau (t-tau), and beta synuclein were measured in CSF. Glial fibrillary acidic protein (GFAP) and NfL were measured in plasma.ResultsWe observed RT-QuIC seeding activity in the CSF of three E200K carriers prior to symptom onset and death, while the CSF of one P102L carrier remained RT-QuIC negative through symptom conversion. The prodromal window of RT-QuIC positivity was one year long in an E200K individual homozygous (V/V) at PRNP codon 129 and was longer than two years in two codon 129 heterozygotes (M/V). Other neurodegenerative and neuroinflammatory markers gave less consistent signal prior to symptom onset, whether analyzed relative to age or individual baseline. CSF PrP was longitudinally stable (mean CV 10%) across all individuals over up to 6 years, including at RT-QuIC positive timepoints.Conclusion and relevanceIn this study, we demonstrate that at least for the E200K mutation, CSF prion seeding activity may represent the earliest detectable prodromal sign, and that its prognostic value may be modified by codon 129 genotype. Neuronal damage and neuroinflammation markers show limited sensitivity in the prodromal phase. CSF PrP levels remain stable even in the presence of RT-QuIC seeding activity.KEY POINTSQuestionWhat biofluid-based molecular changes precede symptom onset in genetic prion disease? For any observed changes, how consistently and by how long do they precede onset?FindingsIn this longitudinal study, presymptomatic CSF RT-QuIC prion seeding activity was observed in three E200K carriers who subsequently developed and died of prion disease, with changes in prodromal timing noted based onPRNPcodon 129 genotype. CSF PrP levels were longitudinally stable in all study participants up to 6 years, regardless of mutation status or presence of RT-QuIC seeding activity.MeaningThese findings suggest that CSF RT-QuIC may offer a brief, genotype-dependent prodromal signal prior to symptom onset in carriers of the E200K mutation. They further indicate that acrossPRNPmutations, CSF PrP levels are sufficiently stable to serve as a drug activity biomarker for PrP-lowering therapeutics and will not be confounded by disease-related molecular changes that precede symptom onset.