Blood reference materials from macaques infected with variant <scp>C</scp>reutzfeldt‐<scp>J</scp>akob disease agent

McDowell, Kristy L.; Nag, Nabanita; Franco, Zulmarie; Bu, Ming; Piccardo, Pedro; Cervenak, Juraj; Deslys, Jean‐Philippe; Comoy, Emmanuel; Asher, David M.; Gregori, Luisa

doi:10.1111/trf.12841

Cited by 17 publications

(13 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…17,25 The PMCA technique and some modified versions using shaking to fragment aggregates (realtime quaking-induced conversion), 41 addition of prion-binding compounds, 42,43 or more sophisticated detection techniques (eg, surround optical fiber immunoassay) 44 have been successfully applied to detect prions in biological fluids, such as CSF, blood, and urine of animals and humans, even at the preclinical stage of the disease. [20][21][22][23][24][45][46][47][48][49][50] The principles behind PMCA have been extended to reach high-efficiency detection of misfolded Aβ oligomers in the CSF of patients affected by AD. 27 In this study we implemented PMCA for specific and sensitive detection of αSyn aggregates in the CSF of people affected by PD.…”

Section: Discussionmentioning

confidence: 99%

Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid

Shahnawaz¹,

et al. 2017

View full text Add to dashboard Cite

IMPORTANCE Parkinson disease (PD) is a highly prevalent and incurable neurodegenerative disease associated with the accumulation of misfolded α-synuclein (αSyn) aggregates. An important problem in this disease is the lack of a sensitive, specific, and noninvasive biochemical diagnosis to help in clinical evaluation, monitoring of disease progression, and early differential diagnosis from related neurodegenerative diseases. OBJECTIVE To develop a novel assay with high sensitivity and specificity to detect small quantities of αSyn aggregates circulating in cerebrospinal fluid (CSF) of patients affected by PD and related synucleinopathies. DESIGN, SETTING, AND PARTICIPANTS The strategy evaluated in this proof-of-concept study uses the protein misfolding cyclic amplification (PMCA) technology that detects minute amounts of misfolded oligomers by taking advantage of their ability to nucleate further aggregation, enabling a very high amplification of the signal. The technology was first adapted with synthetic αSyn oligomers prepared in vitro and used to screen in 2 blinded cohorts of CSF samples from German and Japanese patients with PD (n = 76) and individuals serving as controls affected by other neurologic disorders (n = 65), neurodegenerative diseases (n = 18), and Alzheimer disease (n = 14). The kinetics of αSyn aggregation were measured by αSyn-PMCA in the presence of CSF samples from the participants to detect αSyn oligomeric seeds present in this biological fluid. The assays were conducted from November 15, 2013, to August 28, 2015. MAIN OUTCOMES AND MEASURES Kinetic parameters correlated with disease severity at the time of sample collection, measured by the Hoehn and Yahr scale, with the lowest grade indicating unilateral involvement with minimal or no functional impairment, and the highest grade defining patients with complete confinement to wheelchair or bed. RESULTS Studies with synthetic αSyn aggregates showed that αSyn-PMCA enabled to detect as little as 0.1 pg/mL of αSyn oligomers. The αSyn-PMCA signal was directly proportional to the amount of αSyn oligomers added to the reaction. A blinded study of CSF samples correctly identified patients affected by PD with an overall sensitivity of 88.5% (95% CI, 79.2%-94.6%) and specificity of 96.9% (95% CI, 89.3%-99.6%). The αSyn-PMCA results for different patients correlated with the severity of the clinical symptoms of PD (Japanese cohort: r s = −0.54, P = .006; German cohort: r s = −0.36, P = .02). CONCLUSIONS AND RELEVANCE The findings suggest that detection of αSyn oligomers by αSyn-PMCA in the CSF of patients affected by PD may offer a good opportunity for a sensitive and specific biochemical diagnosis of the disease. Further studies are needed to investigate the usefulness of αSyn-PMCA to monitor disease progression and for preclinical identification of patients who may develop PD.

show abstract

Section: Discussionmentioning

confidence: 99%

Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid

Shahnawaz¹,

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Except for variant CJD prions, 17,27 human prions have not been efficiently amplified by PMCA, 27 whereas some animal prions such as those derived from hamster scrapie, 28,29,30 bovine spongiform encephalopathy, 31 or chronic wasting disease 32,33 can be efficiently amplified. The compatibility of the genotype at codon 129 between the seed and substrate is one of the most important factors for the efficient amplification of human prions.…”

Section: Discussionmentioning

confidence: 99%

Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt–Jakob disease in cell-protein misfolding cyclic amplification

Takeuchi

Kobayashi

Parchi

et al. 2016

Laboratory Investigation

View full text Add to dashboard Cite

There are two distinct subtypes of dura mater graft-associated Creutzfeldt-Jakob disease (dCJD) with methionine homozygosity at codon 129 of the PRNP gene. The majority of cases is represented by a non-plaque-type (np-dCJD) resembling sporadic CJD (sCJD)-MM1 or -MV1, while the minority by a plaque-type (p-dCJD). p-dCJD shows distinctive phenotypic features, namely numerous kuru plaques and an abnormal isoform of prion protein (PrP Sc ) intermediate in size between types 1 and 2. Transmission studies have shown that the unusual phenotypic features of p-dCJD are linked to the V2 prion strain that is associated with sCJD subtypes VV2 or -MV2. In this study, we applied protein misfolding cyclic amplification (PMCA) using recombinant human prion protein as a substrate and demonstrated that p-dCJD prions show amplification features that are distinct from those of np-dCJD. Although no amplification of np-dCJD prions was observed with either 129 M or 129 V substrate, p-dCJD prions were drastically amplified with the 129 V substrates, despite the PRNP codon 129 incompatibility between seed and substrate. Moreover, by using a type 2 PrP Sc -specific antibody not recognizing PrP Sc in p-dCJD, we found that type 2 products are generated de novo from p-dCJD prions during PMCA with the 129 V substrates. These findings suggest that our cell-PMCA is a useful tool for easily and rapidly identifying acquired CJD associated with the transmission of the V2 CJD strain to codon 129 methionine homozygotes, based on the preference for the 129 V substrate and the type of the amplified products.

show abstract

“…Such syndromes were never previously described in conventional mice and macaques, but it should also be noted that reports on experimental transmission of prions through the intravenous route within these models are very limited [21,22]. Even if none of our control animals exhibited any of these unexpected pictures, our first reaction was to seek an alternative, nonprion etiology to these atypical profiles.…”

Section: Confirmation Of the Prion Nature Of These Unexpected Phenotypesmentioning

confidence: 78%

Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?

Comoy

Mikol

Deslys

2018

Prion

Self Cite

View full text Add to dashboard Cite

The recently reevaluated high prevalence of healthy carriers (1/2,000 in UK) of variant Creutzfeldt-Jakob Disease (v-CJD), whose blood might be infectious, suggests that the evolution of this prion disease might not be under full control as expected. After experimental transfusion of macaques and conventional mice with blood derived from v-CJD exposed (human and animal) individuals, we confirmed in these both models the transmissibility of v-CJD, but we also observed unexpected neurological syndromes transmissible by transfusion: despite their prion etiology confirmed through transmission experiments, these original cases would escape classical prion diagnosis, notably in the absence of detectable abnormal PrP with current techniques. It is noteworthy that macaques developed an original, yet undescribed myelopathic syndrome associating demyelination and pseudo-necrotic lesions of spinal cord, brainstem and optical tract without affecting encephalon, which is rather evocative of spinal cord disease than prion disease in human medicine. These observations strongly suggest that the spectrum of human prion diseases may extend the current field restricted to the phenotypes associated to protease-resistant PrP, and may notably include spinal cord diseases.

show abstract

Blood reference materials from macaques infected with variant Creutzfeldt‐Jakob disease agent

Abstract: The macaque vCJD blood panels generated in this study provide a unique resource to support vCJD assay development and to characterize vCJD infectivity in blood.

Cited by 17 publications

References 29 publications

Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid

Development of a Biochemical Diagnosis of Parkinson Disease by Detection of α-Synuclein Misfolded Aggregates in Cerebrospinal Fluid

Distinctive properties of plaque-type dura mater graft-associated Creutzfeldt–Jakob disease in cell-protein misfolding cyclic amplification

Unexpected prion phenotypes in experimentally transfused animals: predictive models for humans?

Contact Info

Product

Resources

About