| 2. |
- Mok, T. H., et al.
(författare)
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Seed amplification and neurodegeneration marker trajectories in individuals at risk of prion disease
- 2023
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 146:6
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 3. |
- Moon, R. J., et al.
(författare)
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Setting priorities in CNF particle size measurement : What is needed vs. what is feasible
- 2023
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Ingår i: TAPPI Journal. - : Technical Assoc. of the Pulp and Paper Industry Press. - 0734-1415. ; 22:2, s. 116-137
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Tidskriftsartikel (refereegranskat)abstract
- Measuring the size of cellulose nanomaterials can be challenging, especially in the case of branched and entangled cellulose nanofibrils (CNFs). The International Organization for Standardization, Technical Committee 6, Task Group 1—Cellulosic Nanomaterials, is exploring opportunities to develop standard methods for the measurement of CNF particle size and particle size distribution. This paper presents a summary of the available measuring techniques, responses from a survey on the measurement needs of CNF companies and researchers, and outcomes from an international workshop on cellulose nanofibril measurement and standardization. Standardization needs differed among groups, with Japanese companies mostly requiring measurements for product specification and production control, and other companies mostly needing measurements for safety/regula-tory purposes and for grade definitions in patents. Among all the companies, average length and width with percen-tiles (D(10), D(50), D(90)) were the most desired measurands. Workshop participants concurred that defining the location(s) on the CNF at which to measure the width and the length is an urgent and complex question. They also agreed that methods are needed for rapid particle size measurement at the nanoscale. Our recommendation within ISO is to start work to revise the definition of CNFs and develop sample preparation and measurement guidelines. It was also recommended that further research be done to reproducibly prepare hierarchical branched CNF structures and characterize them, develop automated image analysis for hierarchical branched CNF structures, and develop a classification system encompassing measurements at multiple size ranges from micro-to nanoscale to fully characterize and distinguish CNF samples. 00327-2022
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