Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion
To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. This single-center longitudinal cohort study has followed known carriers of pathogenic variants at risk for prion disease, individuals with a close rel...
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| Published in: | Neurology Vol. 103; no. 2; p. e209506 |
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| Main Authors: | , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
United States
Lippincott Williams & Wilkins
23-07-2024
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| Subjects: | |
| Online Access: | Get full text |
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| Summary: | To longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion.
This single-center longitudinal cohort study has followed known carriers of
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
genotypes, measured NfL and GFAP in plasma, and RT-QuIC, total PrP, NfL, T-tau, and beta-synuclein in CSF.
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.
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.
ClinicalTrials.gov NCT05124392 posted 2017-12-01, updated 2023-01-27. |
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| Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The Article Processing Charge was funded by NIH. Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. Submitted and externally peer reviewed. The handling editor was Associate Editor Linda Hershey, MD, PhD, FAAN. Previously published in MedRxiv (https://doi.org/10.1101/2023.12.18.23300042). |
| ISSN: | 0028-3878 1526-632X 1526-632X |
| DOI: | 10.1212/WNL.0000000000209506 |