Comparative study of cerebrospinal fluid α-synuclein seeding aggregation assays for diagnosis of Parkinson's disease.

Abstract

BACKGROUND:

PD diagnosis is based primarily on clinical criteria and can be inaccurate. Biological markers, such as α-synuclein aggregation, that reflect ongoing pathogenic processes may increase diagnosis accuracy and allow disease progression monitoring. Though α-synuclein aggregation assays have been published, reproducibility, standardization, and validation are key challenges for their development as clinical biomarkers.

OBJECTIVE:

To cross-validate two α-synuclein seeding aggregation assays developed to detect pathogenic oligomeric α-synuclein species in CSF using samples from the same PD patients and healthy controls from the BioFIND cohort.

METHODS:

CSF samples were tested by two independent laboratories in a blinded fashion. BioFIND features standardized biospecimen collection of clinically typical moderate PD patients and nondisease controls. α-synuclein aggregation was measured by protein misfolding cyclic amplification (Soto lab) and real-time quaking-induced conversion (Green lab). Results were analyzed by an independent statistician.

RESULTS:

Measuring 105 PD and 79 healthy control CSF samples, these assays showed 92% concordance. The areas under the curve from receiver operating characteristic curve analysis for the diagnosis of PD versus healthy controls were 0.93 for protein misfolding cyclic amplification, 0.89 for real-time quaking-induced conversion, and 0.95 when considering only concordant assay results. Clinical characteristics of false-positive and -negative subjects were not different from true-negative and -positive subjects, respectively.

CONCLUSIONS:

These α-synuclein seeding aggregation assays are reliable and reproducible for PD diagnosis. Assay parameters did not correlate with clinical parameters, including disease severity or duration. This assay is highly accurate for PD diagnosis and may impact clinical practice and clinical trials. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

• Authors: Un Jung Kang, Amelia K Boehme, Graham Fairfoul, Mohammad Shahnawaz, Thong Chi Ma, Samantha J Hutten, Alison Green, Claudio Soto
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 34 Issue 4 Pg. 536-544 (04 2019) ISSN: 1531-8257 [Electronic] United States
• PMID: 30840785 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Validation Study)
• Copyright: © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Chemical References

• Biomarkers
• alpha-Synuclein

Topics

• Aged
• Aged, 80 and over
• Biomarkers (cerebrospinal fluid)
• Female
• Humans
• Male
• Middle Aged
• Parkinson Disease (cerebrospinal fluid, diagnosis)
• Reproducibility of Results
• alpha-Synuclein (cerebrospinal fluid)