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High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease
Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other sy...
Autores principales: | , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572469/ https://www.ncbi.nlm.nih.gov/pubmed/34742348 http://dx.doi.org/10.1186/s40478-021-01282-8 |
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author | Russo, Marco J. Orru, Christina D. Concha-Marambio, Luis Giaisi, Simone Groveman, Bradley R. Farris, Carly M. Holguin, Bret Hughson, Andrew G. LaFontant, David-Erick Caspell-Garcia, Chelsea Coffey, Christopher S. Mollon, Jennifer Hutten, Samantha J. Merchant, Kalpana Heym, Roland G. Soto, Claudio Caughey, Byron Kang, Un Jung |
author_facet | Russo, Marco J. Orru, Christina D. Concha-Marambio, Luis Giaisi, Simone Groveman, Bradley R. Farris, Carly M. Holguin, Bret Hughson, Andrew G. LaFontant, David-Erick Caspell-Garcia, Chelsea Coffey, Christopher S. Mollon, Jennifer Hutten, Samantha J. Merchant, Kalpana Heym, Roland G. Soto, Claudio Caughey, Byron Kang, Un Jung |
author_sort | Russo, Marco J. |
collection | PubMed |
description | Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01282-8. |
format | Online Article Text |
id | pubmed-8572469 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-85724692021-11-08 High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease Russo, Marco J. Orru, Christina D. Concha-Marambio, Luis Giaisi, Simone Groveman, Bradley R. Farris, Carly M. Holguin, Bret Hughson, Andrew G. LaFontant, David-Erick Caspell-Garcia, Chelsea Coffey, Christopher S. Mollon, Jennifer Hutten, Samantha J. Merchant, Kalpana Heym, Roland G. Soto, Claudio Caughey, Byron Kang, Un Jung Acta Neuropathol Commun Research Alpha-synuclein seed amplification assays (αSyn-SAAs) are promising diagnostic tools for Parkinson’s disease (PD) and related synucleinopathies. They enable detection of seeding-competent alpha-synuclein aggregates in living patients and have shown high diagnostic accuracy in several PD and other synucleinopathy patient cohorts. However, there has been confusion about αSyn-SAAs for their methodology, nomenclature, and relative accuracies when performed by various laboratories. We compared αSyn-SAA results obtained from three independent laboratories to evaluate reproducibility across methodological variations. We utilized the Parkinson’s Progression Markers Initiative (PPMI) cohort, with DATSCAN data available for comparison, since clinical diagnosis of early de novo PD is critical for neuroprotective trials, which often use dopamine transporter imaging to enrich their cohorts. Blinded cerebrospinal fluid (CSF) samples for a randomly selected subset of PPMI subjects (30 PD, 30 HC, and 20 SWEDD), from both baseline and year 3 collections for the PD and HC groups (140 total CSF samples) were analyzed in parallel by each lab according to their own established and optimized αSyn-SAA protocols. The αSyn-SAA results were remarkably similar across laboratories, displaying high diagnostic performance (sensitivity ranging from 86 to 96% and specificity from 93 to 100%). The assays were also concordant for samples with results that differed from clinical diagnosis, including 2 PD patients determined to be clinically inconsistent with PD at later time points. All three assays also detected 2 SWEDD subjects as αSyn-SAA positive who later developed PD with abnormal DAT-SPECT. These multi-laboratory results confirm the reproducibility and value of αSyn-SAA as diagnostic tools, illustrate reproducibility of the assay in expert hands, and suggest that αSyn-SAA has potential to provide earlier diagnosis with comparable or superior accuracy to existing methods. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s40478-021-01282-8. BioMed Central 2021-11-06 /pmc/articles/PMC8572469/ /pubmed/34742348 http://dx.doi.org/10.1186/s40478-021-01282-8 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, 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/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Russo, Marco J. Orru, Christina D. Concha-Marambio, Luis Giaisi, Simone Groveman, Bradley R. Farris, Carly M. Holguin, Bret Hughson, Andrew G. LaFontant, David-Erick Caspell-Garcia, Chelsea Coffey, Christopher S. Mollon, Jennifer Hutten, Samantha J. Merchant, Kalpana Heym, Roland G. Soto, Claudio Caughey, Byron Kang, Un Jung High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease |
title | High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease |
title_full | High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease |
title_fullStr | High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease |
title_full_unstemmed | High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease |
title_short | High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease |
title_sort | high diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early parkinson’s disease |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8572469/ https://www.ncbi.nlm.nih.gov/pubmed/34742348 http://dx.doi.org/10.1186/s40478-021-01282-8 |
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