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Updated: Jun 23, 2025
Real-time Quaking-induced Conversion Assay for Detection of CWD Prions in Fecal Material
Published on: September 29, 2017
Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion
Sonia M Vallabh1, Meredith A Mortberg1, Shona W Allen1
1From the McCance Center for Brain Health (S.M.V., M.A.M., E.V.M.) and Department of Neurology (S.M.V., M.A.M., S.W.A., A.C.K., P.K., B.L.H., A.B., B.A.T., K.D.-M., A.M.F., L.E.S., G.D., A.R., J.G., A.J.M., E.V.M., S.E.A.), Massachusetts General Hospital, Boston; Stanley Center for Psychiatric Research (S.M.V., M.A.M., E.V.M.), Broad Institute of MIT and Harvard, Cambridge; and Department of Neurology (S.M.V., P.K., E.V.M., S.E.A.), Harvard Medical School, Boston, MA.
Objectives:
To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion.
Methods:
This 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 beta-synuclein in CSF.
Results:
Among 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.
Discussion:
CSF 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.
Clinical Trials Registration:
ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27.
