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Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease
Tze How Mok (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), Akın Nihat (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), Nour K. Majbour (MRC Prion Unit, University College London), Danielle Sequeira (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), Leah Holm-Mercer (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), Thomas Coysh (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), Lee Darwent (MRC Prion Unit, University College London), Mark Batchelor (MRC Prion Unit, University College London), Bradley R. Groveman (National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories), Christina D Orr (National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories), Andrew G. Hughson (National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories), Amanda Heslegrave (UK Dementia Research Institute, National Hospital for Neurology and Neurosurgery), Rhiannon Laban (UK Dementia Research Institute, University College London), Elena Veleva (UK Dementia Research Institute, University College London), Ross W. Paterson (UK Dementia Research Institute, UCL Queen Square Institute of Neurology), Ashvini Keshavan (UK Dementia Research Institute, UCL Queen Square Institute of Neurology), Jonathan M. Schott (UK Dementia Research Institute, UCL Queen Square Institute of Neurology), Imogen J. Swift (UK Dementia Research Institute, UCL Queen Square Institute of Neurology), Carolin Heller (UK Dementia Research Institute, UCL Queen Square Institute of Neurology), Jonathan Daniel Rohrer (UK Dementia Research Institute, UCL Queen Square Institute of Neurology), Alexander Gerhard (University of Manchester, Stiftung Universitätsmedizin Essen), Christopher Butler (University of Oxford), James Benedict Rowe (MRC Cognition and Brain Sciences Unit, University of Cambridge), Mario Masellis (Sunnybrook Health Science Centre, University of Toronto), Miles D. Chapman (University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery), Michael Peter Lunn (University College London Hospitals NHS Foundation Trust, National Hospital for Neurology and Neurosurgery), Jan Bieschke (MRC Prion Unit, University College London), Graham S. Jackson (MRC Prion Unit, University College London), Henrik Zetterberg (University of Wisconsin–Madison, UK Dementia Research Institute), Byron W. Caughey (National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories), Peter Rudge (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), John Collinge (University College London Hospitals NHS Foundation Trust, MRC Prion Unit), Simon Mead (University College London Hospitals NHS Foundation Trust, MRC Prion Unit)
Résumé : Human prion diseases are remarkable for long incubation times followed typically by rapid clinical decline. Seed amplification assays and neurodegeneration biofluid biomarkers are remarkably useful in the clinical phase, but their potential to predict clinical onset in healthy people remains unclear. This is relevant not only to the design of preventive strategies in those at-risk of prion diseases, but more broadly, because prion-like mechanisms are thought to underpin many neurodegenerative disorders. Here, we report the accrual of a longitudinal biofluid resource in patients, controls and healthy people at risk of prion diseases, to which ultrasensitive techniques such as real-time quaking-induced conversion (RT-QuIC) and single molecule array (Simoa) digital immunoassays were applied for preclinical biomarker discovery. We studied 648 CSF and plasma samples, including 16 people who had samples taken when healthy but later developed inherited prion disease (IPD) ('converters'; range from 9.9 prior to, and 7.4 years after onset). Symptomatic IPD CSF samples were screened by RT-QuIC assay variations, before testing the entire collection of at-risk samples using the most sensitive assay. Glial fibrillary acidic protein (GFAP), neurofilament light (NfL), tau and UCH-L1 levels were measured in plasma and CSF. Second generation (IQ-CSF) RT-QuIC proved 100% sensitive and specific for sporadic Creutzfeldt-Jakob disease (CJD), iatrogenic and familial CJD phenotypes, and subsequently detected seeding activity in four presymptomatic CSF samples from three E200K carriers; one converted in under 2 months while two remain asymptomatic after at least 3 years' follow-up. A bespoke HuPrP P102L RT-QuIC showed partial sensitivity for P102L disease. No compatible RT-QuIC assay was discovered for classical 6-OPRI, A117V and D178N, and these at-risk samples tested negative with bank vole RT-QuIC. Plasma GFAP and NfL, and CSF NfL levels emerged as proximity markers of neurodegeneration in the typically slow IPDs (e.g. P102L), with significant differences in mean values segregating healthy control from IPD carriers (within 2 years to onset) and symptomatic IPD cohorts; plasma GFAP appears to change before NfL, and before clinical conversion. In conclusion, we show distinct biomarker trajectories in fast and slow IPDs. Specifically, we identify several years of presymptomatic seeding positivity in E200K, a new proximity marker (plasma GFAP) and sequential neurodegenerative marker evolution (plasma GFAP followed by NfL) in slow IPDs. We suggest a new preclinical staging system featuring clinical, seeding and neurodegeneration aspects, for validation with larger prion at-risk cohorts, and with potential application to other neurodegenerative proteopathies.