Alpha‐synuclein <scp>RT</scp>‐Qu<scp>IC</scp> in the <scp>CSF</scp> of patients with alpha‐synucleinopathies

Fairfoul, Graham; McGuire, Lynne; Pal, Suvankar; Ironside, James; Neumann, Juliane; Christie, Sharon; Joachim, C; Esiri, Margaret M.; Evetts, Samuel; Rolinski, Michal; Baig, Fahd; Ruffmann, Claudio; Wade‐Martins, Richard; Hu, Michele T.M.; Parkkinen, Laura; Green, Alison J E

doi:10.1002/acn3.338

Cited by 398 publications

(260 citation statements)

References 20 publications

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“…There are reports of increased CSF concentrations of α-synuclein oligomers in CSF of PD patients [132, 233, 364], and recent publications on sensitive assays that appear to detect the minute amounts of putative seeds of α-synuclein oligomers in CSF [86, 325]. …”

Section: α-Synuclein Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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Section: α-Synuclein Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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“…Importantly, because ThT affects the Raman signal, 48 all RT-QuIC reactions were prepared without adding ThT. Indeed, it has been recently demonstrated by different groups 43,49,50 that PD-derived α-synuclein possesses the ability to amplify recombinant α-synuclein when tested by RT-QuIC. Moreover, morphological studies conducted by AFM and TEM showed that DLB-seeded reactions may generate rod-shaped amyloid-fibrils of different sizes differing from other α-synuclein aggregates and exhibiting a more circular and compact appearance.…”

Section: Seeding Variability Of α-Synuclein and Potential Strain Diffmentioning

confidence: 99%

Seeding variability of different alpha synuclein strains in synucleinopathies

Candelise

Schmitz

Llorens

et al. 2019

Annals of Neurology

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Objectives: Currently, the exact reasons why different α-synucleinopathies exhibit variable pathologies and phenotypes are still unknown. A potential explanation may be the existence of distinctive α-synuclein conformers or strains. Here, we intend to analyze the seeding activity of dementia with Lewy bodies (DLB) and Parkinson's disease (PD) brain-derived α-synuclein seeds by real-time quaking-induced conversion (RT-QuIC) and to investigate the structure and morphology of the α-synuclein aggregates generated by RT-QuIC. Methods: A misfolded α-synuclein-enriched brain fraction from frontal cortex and substantia nigra pars compacta tissue, isolated by several filtration and centrifugation steps, was subjected to α-synuclein/RT-QuIC analysis. Our study included neuropathologically well-characterized cases with DLB, PD, and controls (Ctrl). Biochemical and morphological analyses of RT-QuIC products were conducted by western blot, dot blot analysis, Raman spectroscopy, atomic force microscopy, and transmission electron microscopy. Results: Independently from the brain region, we observed different seeding kinetics of α-synuclein in the RT-QuIC in patients with DLB compared to PD and Ctrl. Biochemical characterization of the RT-QuIC product indicated the generation of a proteinase K-resistant and fibrillary α-synuclein species in DLB-seeded reactions, whereas PD and control seeds failed in the conversion of wild-type α-synuclein substrate. Interpretation: Structural variances of α-synuclein seeding kinetics and products in DLB and PD indicated, for the first time, the existence of different α-synuclein strains in these groups. Therefore, our study contributes to a better understanding of the clinical heterogeneity among α-synucleinopathies, offers an opportunity for a specific diagnosis, and opens new avenues for the future development of strain-specific therapies. ANN NEUROL 2019;85:691-703 S ynucleinopathies, such as Parkinson's disease (PD) and dementia with Lewy bodies (DLB), are a class of neurodegenerative diseases characterized by the presence of insoluble intraneural deposits consisting of fibrillary α-synuclein, 1,2 referred to as Lewy bodies. A PD with dementia (PDD) diagnosis is appropriate when the cognitive symptoms View this article online at wileyonlinelibrary.com.

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“…The QuIC paradigm has recently been applied to α-synuclein (Fairfoul et al 2016; Hughson et al 2016). One implementation of the assay demonstrated sufficient sensitivity to detect seeding from the cerebrospinal fluid of patients with PD or DLB (Fairfoul et al 2016).…”

Section: Bioassays For Non-prp Prionsmentioning

confidence: 99%

“…One implementation of the assay demonstrated sufficient sensitivity to detect seeding from the cerebrospinal fluid of patients with PD or DLB (Fairfoul et al 2016). Additionally, the QuIC assay has also been applied to measuring the seeding of tau prions (Hughson et al 2016).…”

Section: Bioassays For Non-prp Prionsmentioning

confidence: 99%

Bioassays and Inactivation of Prions

Giles

Woerman

Berry

et al. 2017

Cold Spring Harb Perspect Biol

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The experimental study of prions requires a model for their propagation. However, because prions lack nucleic acids, the simple techniques used to replicate the propagation of bacteria and viruses are not applicable. For much of the history of prion research, time-consuming bioassays in animals were the only option for measuring infectivity. Although cell models and other in vitro tools for the propagation of prions have been developed, they all suffer limitations, and animal bioassays remain the gold standard for measuring infectivity. A wealth of recent data suggests that β-amyloid (Aβ) and tau proteins, which aggregate in Alzheimer’s disease, and α-synuclein, which aggregates in Parkinson’s disease, also become prions. Cell and animal models that recapitulate some of the key features of cell-to-cell spreading of these additional prions have been developed. The unusual resistance of prions to inactivation was an early indication that they represented a different class of infectious agents to bacteria or viruses. Incomplete inactivation of prions has led to medically induced, or iatrogenic, Creutzfeldt–Jakob disease (CJD). Worldwide, the number of elderly individuals who undergo surgery has increased, and due to the unusually long asymptomatic phase of CJD, there are a growing number of cases in which surgical instruments are used on an asymptomatic patient and then reused repeatedly before a CJD diagnosis is confirmed. Recent data suggesting the potential for iatrogenic transmission of Aβ amyloidosis has raised renewed interest in the field of prion inactivation.

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Alpha‐synuclein RT‐QuIC in the CSF of patients with alpha‐synucleinopathies

Cited by 398 publications

References 20 publications

Current state of Alzheimer’s fluid biomarkers

Current state of Alzheimer’s fluid biomarkers

Seeding variability of different alpha synuclein strains in synucleinopathies

Bioassays and Inactivation of Prions

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