High diagnostic performance of independent alpha-synuclein seed amplification assays for detection of early Parkinson’s disease

Acta Neuropathologica Communications

Jennifer Mollon¹  Roland G. Heym¹  Simone Giaisi¹  Chelsea Caspell-Garcia²  Christopher S. Coffey²  David-Erick LaFontant²  Christina D. Orru³  Bradley R. Groveman³  Byron Caughey³  Andrew G. Hughson³  Samantha J. Hutten⁴  Kalpana Merchant⁵  Bret Holguin⁶  Carly M. Farris⁶  Luis Concha-Marambio⁶  Claudio Soto⁷  Un Jung Kang⁸  Marco J. Russo⁸ 

[1] AbbVie Deutschland GmbH & Co. KG, Ludwigshafen, Germany;Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA;Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT, USA;Michael J. Fox Foundation for Parkinson’s Research, New York, NY, USA;Northwestern University Feinberg School of Medicine, Chicago, IL, USA;R&D Unit, Amprion Inc., San Diego, CA, USA;R&D Unit, Amprion Inc., San Diego, CA, USA;Mitchell Center for Alzheimer’s Disease and Related Brain Disorders, Department of Neurology, University of Texas Houston Medical School, Houston, TX, USA;The Marlene and Paolo Fresco Institute for Parkinson’s & Movement Disorders, Department of Neurology, Department of Neuroscience and Physiology, Neuroscience Institute, The Parekh Center for Interdisciplinary Neurology, NYU Grossman School of Medicine, New York, NY, USA;

关键词: Seed amplification assay;    Alpha-synuclein;    Parkinson’s disease;    RT-QuIC;    PMCA;    Synucleinopathy;   

DOI  :  10.1186/s40478-021-01282-8

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY