Cerebrospinal Fluid Prion Disease Biomarkers in Pre-clinical and Clinical Naturally Occurring Scrapie

Llorens, Franc; Barrio, Tomás; Correia, Ângela; Villar‐Piqué, Anna; Thüne, Katrin; Lange, Peter; Badiola, Juan José; Schmitz, Matthias; Lachmann, Ingolf; Bolea, Rosa; Zerr, Inga

doi:10.1007/s12035-018-1014-z

Cited by 15 publications

(18 citation statements)

References 27 publications

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“…Across the candidate disease markers measured, most carriers could not be distinguished from non-carrier controls. Put differently, the present data do not support analogies between the disease state of most adult carriers and the clinically silent incubation phase in prioninfected animals [55][56][57][58][59]. Previous cohort studies and case reports have largely found imaging and physiological changes to coincide with onset [14][15][16][60][61][62][63]; reports of suggestive MRI and biochemical changes in single individuals have been confined to the 1 to 2 years before symptom onset [14,[17][18][19].…”

Section: Discussioncontrasting

confidence: 77%

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Vallabh

Minikel

Williams

et al. 2020

BMC Med

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Background: Prion disease is neurodegenerative disease that is typically fatal within months of first symptoms. Clinical trials in this rapidly declining symptomatic patient population have proven challenging. Individuals at high lifetime risk for genetic prion disease can be identified decades before symptom onset and provide an opportunity for early therapeutic intervention. However, randomizing pre-symptomatic carriers to a clinical endpoint is not numerically feasible. We therefore launched a cohort study in pre-symptomatic genetic prion disease mutation carriers and controls with the goal of evaluating biomarker endpoints that may enable informative trials in this population. Methods: We collected cerebrospinal fluid (CSF) and blood from pre-symptomatic individuals with prion protein gene (PRNP) mutations (N = 27) and matched controls (N = 16), in a cohort study at Massachusetts General Hospital. We quantified total prion protein (PrP) and real-time quaking-induced conversion (RT-QuIC) prion seeding activity in CSF and neuronal damage markers total tau (T-tau) and neurofilament light chain (NfL) in CSF and plasma. We compared these markers cross-sectionally, evaluated short-term test-retest reliability over 2-4 months, and conducted a pilot longitudinal study over 10-20 months. Results: CSF PrP levels were stable on test-retest with a mean coefficient of variation of 7% for both over 2-4 months in N = 29 participants and over 10-20 months in N = 10 participants. RT-QuIC was negative in 22/23 mutation carriers. The sole individual with positive RT-QuIC seeding activity at two study visits had steady CSF PrP levels and slightly increased tau and NfL concentrations compared with the others, though still within the normal range, and remained asymptomatic 1 year later. T-tau and NfL showed no significant differences between mutation carriers and controls in either CSF or plasma.

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Section: Discussioncontrasting

confidence: 77%

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Vallabh

Minikel

Williams

et al. 2020

BMC Med

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“…Therefore, we cannot exclude t-PrP as a potential pre-clinical biomarker for other mutation types or prion disease types. Second, despite the absence of studies addressing the quantification of t-PrP levels in pre-symptomatic cases, we recently detected lower t-PrP concentrations in the CSF of pre-clinical and clinical naturally occurring scrapie [42], which would support the idea that reduced t-PrP concentrations may happen at pre-clinical and early prion disease stages.…”

Section: Discussionmentioning

confidence: 60%

Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases

Villar‐Piqué

Schmitz

Lachmann³

et al. 2018

Mol Neurobiol

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Cerebrospinal fluid (CSF) total prion protein (t-PrP) is decreased in sporadic Creutzfeldt-Jakob disease (sCJD). However, data on the comparative signatures of t-PrP across the spectrum of prion diseases, longitudinal changes during disease progression, and levels in pre-clinical cases are scarce. T-PrP was quantified in neurological diseases (ND, n = 147) and in prion diseases from different aetiologies including sporadic (sCJD, n = 193), iatrogenic (iCJD, n = 12) and genetic (n = 209) forms. T-PrP was also measured in serial lumbar punctures obtained from sCJD cases at different symptomatic disease stages, and in asymptomatic prion protein gene (PRNP) mutation carriers. Compared to ND, t-PrP concentrations were significantly decreased in sCJD, iCJD and in genetic prion diseases associated with the three most common mutations E200K, V210I (associated with genetic CJD) and D178N-129M (associated with fatal familial insomnia). In contrast, t-PrP concentrations in P102L mutants (associated with the Gerstmann-Sträussler-Scheinker syndrome) remained unaltered. In serial lumbar punctures obtained at different disease stages of sCJD patients, t-PrP concentrations inversely correlated with disease progression. Decreased mean t-PrP values were detected in asymptomatic D178-129M mutant carriers, but not in E200K and P102L carriers. The presence of low CSF t-PrP is common to all types of prion diseases regardless of their aetiology albeit with mutation-specific exceptions in a minority of genetic cases. In some genetic prion disease, decreased levels are already detected at pre-clinical stages and diminish in parallel with disease progression. Our data indicate that CSF t-PrP concentrations may have a role as a pre-clinical or early symptomatic diagnostic biomarker in prion diseases as well as in the evaluation of therapeutic interventions.

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“…Results from studies involving neuronal exosomes have been demonstrated to be reproducible for αsynuclein (Shi et al, 2014;Dutta et al, 2018;Zhao et al, 2019) and for different forms of Aβ and tau (Fiandaca et al, 2015;Goetzl et al, 2016;Winston et al, 2016;Jia et al, 2019), and the acquired data in the neuronal exosomes correlated to those obtained from CSF samples (Jia et al, 2019). Increased CSF levels of tau and 14-3-3 proteins and decreased concentration levels of total PrP were found to be potential biomarkers for prion diseases (Otto et al, 1997;Llorens et al, 2018). NfL and phosphorylated forms of the neurofilament heavy chain have been shown consistently to be increased in the CSF, plasma, and serum of patients with ALS in several single-and multicenter studies (Boylan et al, 2013;Lehnert et al, 2014;Lu et al, 2015;Oeckl et al, 2016).…”

Section: Current Challenges and Future Perspectivesmentioning

confidence: 92%

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

Hornung

Dutta

Bitan

2020

Front. Mol. Neurosci.

170

159

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Eukaryotic cells release different types of extracellular vesicles (EVs) including exosomes, ectosomes, and microvesicles. Exosomes are nanovesicles, 30-200 nm in diameter, that carry cell-and cell-state-specific cargo of proteins, lipids, and nucleic acids, including mRNA and miRNA. Recent studies have shown that central nervous system (CNS)-derived exosomes may carry amyloidogenic proteins and facilitate their cell-to-cell transfer, thus playing a critical role in the progression of neurodegenerative diseases, such as tauopathies and synucleinopathies. CNS-derived exosomes also have been shown to cross the blood-brain-barrier into the bloodstream and therefore have drawn substantial attention as a source of biomarkers for various neurodegenerative diseases as they can be isolated via a minimally invasive blood draw and report on the biochemical status of the CNS. However, although isolating specific brain-cell-derived exosomes from the blood is theoretically simple and the approach has great promise, practical details are of crucial importance and may compromise the reproducibility and utility of this approach, especially when different laboratories use different protocols. In this review we discuss the role of exosomes in neurodegenerative diseases, the usefulness of CNS-derived blood exosomes as a source of biomarkers for these diseases, and practical challenges associated with the methodology of CNS-derived blood exosomes and subsequent biomarker analysis.

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Cerebrospinal Fluid Prion Disease Biomarkers in Pre-clinical and Clinical Naturally Occurring Scrapie

Cited by 15 publications

References 27 publications

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease

Cerebrospinal Fluid Total Prion Protein in the Spectrum of Prion Diseases

CNS-Derived Blood Exosomes as a Promising Source of Biomarkers: Opportunities and Challenges

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