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- Vallabh, S. M., et al.
(author)
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Cerebrospinal fluid and plasma biomarkers in individuals at risk for genetic prion disease
- 2020
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In: Bmc Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- 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 inN = 29 participants and over 10-20 months inN = 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. Conclusions CSF PrP will be interpretable as a pharmacodynamic readout for PrP-lowering therapeutics in pre-symptomatic individuals and may serve as an informative surrogate biomarker in this population. In contrast, markers of prion seeding activity and neuronal damage do not reliably cross-sectionally distinguish mutation carriers from controls. Thus, as PrP-lowering therapeutics for prion disease advance, "secondary prevention" based on prodromal pathology may prove challenging; instead, "primary prevention" trials appear to offer a tractable paradigm for trials in pre-symptomatic individuals.
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- Preston, Markus, et al.
(author)
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Methodology for Multiparameter Evaluation of Barriers Against Proliferation of Minor Actinides
- 2024
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In: Nuclear Technology. - 0029-5450 .- 1943-7471.
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Journal article (peer-reviewed)abstract
- There exist elements apart from uranium and plutonium that could potentially be used to construct the core of a nuclear explosive device. These belong to the so-called minor actinides (MAs), which exist in nonnegligible amounts in spent nuclear fuel (SNF) and are in nearly all cases not covered by international safeguards. Future reprocessing of SNF could result in significant separation of these elements, potentially leading to new proliferation concerns. In this work, a methodology for a transparent assessment of the barriers against proliferation of MAs has been developed and applied to the case of neptunium, americium, and curium separated from spent fuel from pressurized water reactors. In this methodology, openly available data and Monte Carlo simulations have been used to assess the barriers posed by a number of parameters relevant to the production of a nuclear explosive device from SNF. The evaluation shows that the properties of neptunium present low barriers to proliferation and that it should be discussed within the context of future nonproliferation treaties and possibly be placed under international safeguards. The properties of americium and curium present higher barriers to proliferation, meaning that these elements require less focus in the nonproliferation context.
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