Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion

Abstract

ObjectivesTo longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. MethodsThis single-center longitudinal cohort study has followed known carriers of PRNP pathogenic variants at risk for prion disease, individuals with a close relative who died of genetic prion disease but who have not undergone predictive genetic testing, and controls. All participants were asymptomatic at first visit and returned roughly annually. We determined PRNP genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and betasynuclein in CSF. ResultsAmong 41 carriers and 21 controls enrolled, 28 (68%) and 15 (71%) were female, and mean ages were 47.5 and 46.1. At baseline, all individuals were asymptomatic. We observed RT-QuIC seeding activity in the CSF of 3 asymptomatic E200K carriers who subsequently converted to symptomatic and died of prion disease. 1 P102L carrier remained RT-QuIC negative through symptom conversion. No other individuals developed symptoms. The prodromal window from detection of RT-QuIC positivity to disease onset was 1 year long in an E200K individual homozygous (V/V) at PRNP codon 129 and 2.5 and 3.1 years in 2 codon 129 heterozygotes (M/V). Changes in neurodegenerative and neuroinflammatory markers were variably observed prior to onset, with increases observed for plasma NfL in 4/4 converters, and plasma GFAP, CSF NfL, CSF T-tau, and CSF beta-synuclein each in 2/4 converters, although values relative to age and fold changes relative to individual baseline were not remarkable for any of these markers. CSF PrP was longitudinally stable with mean coefficient of variation 9.0% across all individuals over up to 6 years, including data from converting individuals at RT-QuIC-positive timepoints. DiscussionCSF prion seeding activity may represent the earliest detectable prodromal sign in E200K carriers. 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.

Predicting Symptom Onset of Genetic Prion Diseases Using Fluid Biomarkers

“…There are several limitations of the Vallabh et al 4 study. The small sample size precludes any conclusive results from the study.…”

“…6 These findings are congruent with previously published studies, suggesting that RT-QuIC positivity can precede clinical onset, especially in E200K carriers. 7,8 There are several limitations of the Vallabh et al 4 study. The small sample size precludes any conclusive results from the study.…”

“…One of the most important findings of the Vallabh et al 4 study is that it suggests that total PrP can be accurately measured throughout progressive disease stages. Given the challenges of using conventional approaches to preventive clinical trials in prion disease, demonstrating a reduction in a surrogate biomarker may be the most efficient and reliable initial approach to such a study.…”

“…In this issue of Neurology ® , Vallabh et al 4 present the results of a single-site longitudinal natural history study of asymptomatic individuals at risk of genetic prion disease. This study focused on identifying fluid biomarkers that precede clinical onset.…”

“…Over the course of 4 years, 4 participants in the study of Vallabh et al 4 developed symptomatic prion disease. Three participants carried the most common sequence variant that causes genetic Creutzfeldt-Jakob disease (gCJD) (E200K), and one carried the most common sequence variant seen in Gerstmann-Sträussler-Scheinker syndrome (P102L).…”