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Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies
The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliabl...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Berlin Heidelberg
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299922/ https://www.ncbi.nlm.nih.gov/pubmed/32342188 http://dx.doi.org/10.1007/s00401-020-02160-8 |
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author | Rossi, Marcello Candelise, Niccolò Baiardi, Simone Capellari, Sabina Giannini, Giulia Orrù, Christina D. Antelmi, Elena Mammana, Angela Hughson, Andrew G. Calandra-Buonaura, Giovanna Ladogana, Anna Plazzi, Giuseppe Cortelli, Pietro Caughey, Byron Parchi, Piero |
author_facet | Rossi, Marcello Candelise, Niccolò Baiardi, Simone Capellari, Sabina Giannini, Giulia Orrù, Christina D. Antelmi, Elena Mammana, Angela Hughson, Andrew G. Calandra-Buonaura, Giovanna Ladogana, Anna Plazzi, Giuseppe Cortelli, Pietro Caughey, Byron Parchi, Piero |
author_sort | Rossi, Marcello |
collection | PubMed |
description | The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-020-02160-8) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-7299922 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Springer Berlin Heidelberg |
record_format | MEDLINE/PubMed |
spelling | pubmed-72999222020-06-22 Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies Rossi, Marcello Candelise, Niccolò Baiardi, Simone Capellari, Sabina Giannini, Giulia Orrù, Christina D. Antelmi, Elena Mammana, Angela Hughson, Andrew G. Calandra-Buonaura, Giovanna Ladogana, Anna Plazzi, Giuseppe Cortelli, Pietro Caughey, Byron Parchi, Piero Acta Neuropathol Original Paper The clinical diagnosis of synucleinopathies, including Parkinson’s disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA), is challenging, especially at an early disease stage, due to the heterogeneous and often non-specific clinical manifestations. The discovery of reliable specific markers for synucleinopathies would consequently be of great aid to the diagnosis and management of these disorders. Real-Time Quaking-Induced Conversion (RT-QuIC) is an ultrasensitive technique that has been previously used to detect self-templating amyloidogenic proteins in the cerebrospinal fluid (CSF) and other biospecimens in prion disease and synucleinopathies. Using a wild-type recombinant α-synuclein as a substrate, we applied RT-QuIC to a large cohort of 439 CSF samples from clinically well-characterized, or post-mortem verified patients with parkinsonism or dementia. Of significance, we also studied patients with isolated REM sleep behavior disorder (iRBD) (n = 18) and pure autonomic failure (PAF) (n = 28), representing clinical syndromes that are often caused by a synucleinopathy, and may precede the appearance of parkinsonism or cognitive decline. The results show that our RT-QuIC assay can accurately detect α-synuclein seeding activity across the spectrum of Lewy Body (LB)-related disorders (LBD), including DLB, PD, iRBD, and PAF, with an overall sensitivity of 95.3%. In contrast, all but two patients with MSA showed no α-synuclein seeding activity in the applied experimental setting. The analysis of the fluorescence response reflecting the amount of α-synuclein seeds revealed no significant differences between the clinical syndromes associated with LB pathology. Finally, the assay demonstrated 98% specificity in a neuropathological cohort of 101 cases lacking LB pathology. In conclusion, α-synuclein RT-QuIC provides an accurate marker of synucleinopathies linked to LB pathology and may have a pivotal role in the early discrimination and management of affected patients. The finding of no α-synuclein seeding activity in MSA seems to support the current view that MSA and LBD are associated with different conformational strains of α-synuclein. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00401-020-02160-8) contains supplementary material, which is available to authorized users. Springer Berlin Heidelberg 2020-04-27 2020 /pmc/articles/PMC7299922/ /pubmed/32342188 http://dx.doi.org/10.1007/s00401-020-02160-8 Text en © The Author(s) 2020, Corrected Publication May 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Original Paper Rossi, Marcello Candelise, Niccolò Baiardi, Simone Capellari, Sabina Giannini, Giulia Orrù, Christina D. Antelmi, Elena Mammana, Angela Hughson, Andrew G. Calandra-Buonaura, Giovanna Ladogana, Anna Plazzi, Giuseppe Cortelli, Pietro Caughey, Byron Parchi, Piero Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies |
title | Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies |
title_full | Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies |
title_fullStr | Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies |
title_full_unstemmed | Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies |
title_short | Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies |
title_sort | ultrasensitive rt-quic assay with high sensitivity and specificity for lewy body-associated synucleinopathies |
topic | Original Paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299922/ https://www.ncbi.nlm.nih.gov/pubmed/32342188 http://dx.doi.org/10.1007/s00401-020-02160-8 |
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