High diagnostic performance of plasma and cerebrospinal fluid beta‐synuclein for sporadic <scp>Creutzfeldt–Jakob</scp> disease

Abu‐Rumeileh, Samir; Halbgebauer, Steffen; Bentivenga, Giuseppe Mario; Barba, Lorenzo; Baiardi, Simone; Mastrángelo, Andrea; Oeckl, Patrick; Steinacker, Petra; Mammana, Angela; Capellari, Sabina; Otto, Markus; Parchi, Piero

doi:10.1002/acn3.51873

Cited by 3 publications

(4 citation statements)

References 32 publications

(97 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Neither when normalized to age nor to individual baseline did any of these markers consistently provide distinctive signal in all 4 of our converting individuals relative to nonconverters and controls. Despite the excellent diagnostic utility of β-syn in discriminating prion disease from other rapidly progressive dementias, 2 it was not more consistently elevated than CSF T-tau or CSF NfL in individuals proximate to conversion. While these markers may be useful as an adjunct, none is likely to provide the prognostic specificity of RT-QuIC.…”

Section: Discussionmentioning

confidence: 87%

“…Prion disease exhibits striking biomarker signatures at the symptomatic stage, 1-4 but data about presymptomatic changes are limited (Supplementary Background, eAppendix 1). Neurodegeneration and neuroinflammation markers may rise 2 years before onset in slowly progressive subtypes such as P102L, but only months before onset in rapidly progressive subtypes D178N and E200K, 3,5 mirroring disease duration.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion

Vallabh,

Mortberg,

Allen

et al. 2024

Neurology

View full text Add to dashboard Cite

ObjectivesTo longitudinally characterize disease-relevant CSF and plasma biomarkers in individuals at risk for genetic prion disease up to disease conversion. MethodsThis 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 betasynuclein in CSF. ResultsAmong 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. DiscussionCSF 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.

show abstract

Section: Discussionmentioning

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion

Vallabh,

Mortberg,

Allen

et al. 2024

Neurology

View full text Add to dashboard Cite

show abstract

“…In summary, despite the fair diagnostic performance, our results indicate that pl-GFAP has no added value compared to traditional CSF and plasma surrogate markers of neurodegeneration. Moreover, the recent discovery of blood markers with comparable accuracy to CSF 14-3-3 and t-tau (e.g., β-synuclein) further reduces the potential applications and usefulness of pl-GFAP for diagnostic/screening purposes [21].…”

Section: Discussionmentioning

confidence: 99%

“…This peculiar behaviour, already observed with other plasma biomarkers, such as tau, NfL, and β-synuclein, could be related to the different regional lesion profiles between the two sCJD subtypes. Specifically, the early cortical involvement (also in terms of astrogliosis), which characterises MM(V)1 (but not VV2) subjects, may lead to a higher spillover of these molecules in the blood compared to that from subcortical regions [2,17,18,21].…”

Section: Discussionmentioning

confidence: 99%

Diagnostic and Prognostic Value of Plasma GFAP in Sporadic Creutzfeldt–Jakob Disease in the Clinical Setting of Rapidly Progressive Dementia

Bentivenga,

Baiardi,

Mastrangelo

et al. 2024

IJMS

Self Cite

View full text Add to dashboard Cite

The diagnostic and prognostic value of plasma glial fibrillary acidic protein (pl-GFAP) in sporadic Creutzfeldt–Jakob disease (sCJD) has never been assessed in the clinical setting of rapidly progressive dementia (RPD). Using commercially available immunoassays, we assayed the plasma levels of GFAP, tau (pl-tau), and neurofilament light chain (pl-NfL) and the CSF total tau (t-tau), 14-3-3, NfL, phospho-tau181 (p-tau), and amyloid-beta isoforms 42 (Aβ42) and 40 (Aβ40) in sCJD (n = 132) and non-prion RPD (np-RPD) (n = 94) patients, and healthy controls (HC) (n = 54). We also measured the CSF GFAP in 67 sCJD patients. Pl-GFAP was significantly elevated in the sCJD compared to the np-RPD and HC groups and affected by the sCJD subtype. Its diagnostic accuracy (area under the curve (AUC) 0.760) in discriminating sCJD from np-RPD was higher than the plasma and CSF NfL (AUCs of 0.596 and 0.663) but inferior to the 14-3-3, t-tau, and pl-tau (AUCs of 0.875, 0.918, and 0.805). Pl-GFAP showed no association with sCJD survival after adjusting for known prognostic factors. Additionally, pl-GFAP levels were associated with 14-3-3, pl-tau, and pl-NfL but not with CSF GFAP, Aβ42/Aβ40, and p-tau. The diagnostic and prognostic value of pl-GFAP is inferior to established neurodegeneration biomarkers. Nonetheless, pl-GFAP noninvasively detects neuroinflammation and neurodegeneration in sCJD, warranting potential applications in disease monitoring.

show abstract

Biomarker changes preceding symptom onset in genetic prion disease

Vallabh,

Mortberg,

Allen

et al. 2023

Preprint

View full text Add to dashboard Cite

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.

show abstract

High diagnostic performance of plasma and cerebrospinal fluid beta‐synuclein for sporadic Creutzfeldt–Jakob disease

Cited by 3 publications

References 32 publications

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion

Fluid Biomarkers in Individuals at Risk for Genetic Prion Disease up to Disease Conversion

Diagnostic and Prognostic Value of Plasma GFAP in Sporadic Creutzfeldt–Jakob Disease in the Clinical Setting of Rapidly Progressive Dementia

Biomarker changes preceding symptom onset in genetic prion disease

Contact Info

Product

Resources

About