Detection of prions in the urine of patients affected by sporadic <scp>Creutzfeldt–Jakob</scp> disease

Pritzkow, Sandra; Ramirez, Frank; Lyon, Adam; Schulz, Paul E.; Appleby, Brian; Moda, Fabio; Ramirez, Santiago; Notari, Silvio; Gambetti, Pierluigi; Soto, Claudio

doi:10.1002/acn3.51919

Cited by 3 publications

(1 citation statement)

References 23 publications

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“…Some annual visits were missed due to COVID-19. We did not collect emerging sample types such as nasal brushings 19 , urine 20 , or tears 21 . Additional pre-symptomatic natural history work across multiple sites 7,22,23 will be required to build confidence in our observations.…”

Section: Limitationsmentioning

confidence: 99%

Biomarker changes preceding symptom onset in genetic prion disease

Vallabh,

Mortberg,

Allen

et al. 2023

Preprint

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ImportanceGenetic prion disease is a universally fatal and rapidly progressive neurodegenerative disease for which genetically targeted therapies are currently under development. Preclinical proofs of concept indicate that treatment before symptoms will offer outsize benefit. Though early treatment paradigms will be informed by the longitudinal biomarker trajectory of mutation carriers, to date limited cases have been molecularly tracked from the presymptomatic phase through symptomatic onset.ObjectiveTo longitudinally characterize disease-relevant cerebrospinal fluid (CSF) and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion, alongside non-converters and healthy controls.Design, setting, and participantsThis single-center longitudinal cohort study has followed 41PRNPmutation carriers and 21 controls for up to 6 years. Participants spanned a range of known pathogenicPRNPvariants; all subjects were asymptomatic at first visit and returned roughly annually. Four at-risk individuals experienced prion disease onset during the study.Main outcomes and measuresRT-QuIC prion seeding activity, prion protein (PrP), neurofilament light chain (NfL) total tau (t-tau), and beta synuclein were measured in CSF. Glial fibrillary acidic protein (GFAP) and NfL were measured in plasma.ResultsWe observed RT-QuIC seeding activity in the CSF of three E200K carriers prior to symptom onset and death, while the CSF of one P102L carrier remained RT-QuIC negative through symptom conversion. The prodromal window of RT-QuIC positivity was one year long in an E200K individual homozygous (V/V) at PRNP codon 129 and was longer than two years in two codon 129 heterozygotes (M/V). Other neurodegenerative and neuroinflammatory markers gave less consistent signal prior to symptom onset, whether analyzed relative to age or individual baseline. CSF PrP was longitudinally stable (mean CV 10%) across all individuals over up to 6 years, including at RT-QuIC positive timepoints.Conclusion and relevanceIn this study, we demonstrate that at least for the E200K mutation, CSF prion seeding activity may represent the earliest detectable prodromal sign, and that its prognostic value may be modified by codon 129 genotype. 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.KEY POINTSQuestionWhat biofluid-based molecular changes precede symptom onset in genetic prion disease? For any observed changes, how consistently and by how long do they precede onset?FindingsIn this longitudinal study, presymptomatic CSF RT-QuIC prion seeding activity was observed in three E200K carriers who subsequently developed and died of prion disease, with changes in prodromal timing noted based onPRNPcodon 129 genotype. CSF PrP levels were longitudinally stable in all study participants up to 6 years, regardless of mutation status or presence of RT-QuIC seeding activity.MeaningThese findings suggest that CSF RT-QuIC may offer a brief, genotype-dependent prodromal signal prior to symptom onset in carriers of the E200K mutation. They further indicate that acrossPRNPmutations, CSF PrP levels are sufficiently stable to serve as a drug activity biomarker for PrP-lowering therapeutics and will not be confounded by disease-related molecular changes that precede symptom onset.

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Section: Limitationsmentioning

confidence: 99%

Biomarker changes preceding symptom onset in genetic prion disease

Vallabh,

Mortberg,

Allen

et al. 2023

Preprint

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Proteopathic seed amplification assays in easily accessible specimens for human synucleinopathies, tauopathies and prionopathies: a Scoping Review

Salciccia,

Costanzo,

Ruocco

et al. 2024

Neuroscience & Biobehavioral Reviews

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A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts

Jurcau,

Diaconu

et al. 2024

Neurology International

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Creutzfeldt-Jakob disease is a rare neurodegenerative and invariably fatal disease with a fulminant course once the first clinical symptoms emerge. Its incidence appears to be rising, although the increasing figures may be related to the improved diagnostic tools. Due to the highly variable clinical picture at onset, many specialty physicians should be aware of this disease and refer the patient to a neurologist for complete evaluation. The diagnostic criteria have been changed based on the considerable progress made in research on the pathogenesis and on the identification of reliable biomarkers. Moreover, accumulated knowledge on pathogenesis led to the identification of a series of possible therapeutic targets, although, given the low incidence and very rapid course, the evaluation of safety and efficacy of these therapeutic strategies is challenging.

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Detection of prions in the urine of patients affected by sporadic Creutzfeldt–Jakob disease

Cited by 3 publications

References 23 publications

Biomarker changes preceding symptom onset in genetic prion disease

Biomarker changes preceding symptom onset in genetic prion disease

Proteopathic seed amplification assays in easily accessible specimens for human synucleinopathies, tauopathies and prionopathies: a Scoping Review

A Systematic Review of Sporadic Creutzfeldt-Jakob Disease: Pathogenesis, Diagnosis, and Therapeutic Attempts

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