CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease
- 1MRC Prion Unit at UCL
Abstract
Silent proteopathic seed propagation is hypothesised to precede neurodegenerative disease, but direct evidence that it signals near-term clinical conversion in humans is lacking. In prion disease, a prototypic disorder of proteopathic seeding, cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) offers a direct measure of prion protein amyloid seeding activity. We analysed longitudinal CSF RT-QuIC data from 94 PRNP E200K mutation carriers across international natural history cohorts to determine whether seeding status predicts clinical conversion. Eleven carriers developed inherited prion disease; all showed at least one positive RT-QuIC result before onset. First positivity appeared a median of 2.0 years prior to symptoms (IQR 1.3-3.3; range 0.2-4.8). Landmark analyses showed RT-QuIC positivity identified a markedly increased short-term conversion risk, whereas persistently asymptomatic carriers remained negative throughout follow-up. These findings establish CSF RT-QuIC positivity as a biomarker-defined state of incipient conversion in E200K carriers, informing risk stratification and preventive trial design.
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BibTeX
@misc{mok2026prpamyloid,
title = {{CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease}},
author = {T. H. Mok and A. Nihat and S. M. Vallabh and B. Noa and N. Omer and M. Geschwind and S. E. Arnold and E. V. Minikel and J. Collinge and S. Mead},
howpublished = {medRxiv},
year = {2026},
month = nov,
doi = {10.64898/2026.11.03.26367164},
url = {https://www.medrxiv.org/content/10.64898/2026.11.03.26367164v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - CSF PrP-amyloid seeding predicts clinical onset in inherited prion disease
AU - T. H. Mok
AU - A. Nihat
AU - S. M. Vallabh
AU - B. Noa
AU - N. Omer
AU - M. Geschwind
AU - S. E. Arnold
AU - E. V. Minikel
AU - J. Collinge
AU - S. Mead
PY - 2026
DA - 2026/11/03
PB - medRxiv
DO - 10.64898/2026.11.03.26367164
UR - https://www.medrxiv.org/content/10.64898/2026.11.03.26367164v1
AB - Silent proteopathic seed propagation is hypothesised to precede neurodegenerative disease, but direct evidence that it signals near-term clinical conversion in humans is lacking. In prion disease, a prototypic disorder of proteopathic seeding, cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) offers a direct measure of prion protein amyloid seeding activity. We analysed longitudinal CSF RT-QuIC data from 94 PRNP E200K mutation carriers across international natural history cohorts to determine whether seeding status predicts clinical conversion. Eleven carriers developed inherited prion disease; all showed at least one positive RT-QuIC result before onset. First positivity appeared a median of 2.0 years prior to symptoms (IQR 1.3-3.3; range 0.2-4.8). Landmark analyses showed RT-QuIC positivity identified a markedly increased short-term conversion risk, whereas persistently asymptomatic carriers remained negative throughout follow-up. These findings establish CSF RT-QuIC positivity as a biomarker-defined state of incipient conversion in E200K carriers, informing risk stratification and preventive trial design.
ER -