Biomarker changes preceding symptom onset in genetic prion disease

Abstract

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 returned roughly annually. Four at-risk individuals experienced prion disease onset during the study.

Main outcomes and measures: RT-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.

Results: We 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 relevance: In 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.

Figure 1.. Fluid biomarker changes in the cohort.

A) RT-QuIC kinetic curves, showing 6 positive CSF samples (each with 4/4 replicates positive) out of 149 tested (98 from carriers, 51 from controls). B) RT-QuIC endpoint titration of CSF, with codon 129 genotypes of converters indicated. C) CSF PrP concentrations represented as changes (Δ) relative to individual baseline, shown for the 4 converters plus all individuals (N=11) with at least 3 years between first and last available CSF sample. D-H) Biomarkers plasma GFAP (D), plasma NfL (E), CSF NfL (F), CSF T-tau (G), and CSF β-syn (H) are represented by two views each. Left: individual age vs. absolute concentration in pg/mL, with sequential samples from the same individual connected by thin lines, while thicker lines represent the separate log-linear best fit curves for controls and for non-converting carriers. Right: years from disease onset vs. change (Δ) relative to individual baseline in converters, with the same for controls and for non-converting carriers shown on a separate x-axis. Dashed lines connect timepoints before and after symptom onset.