Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay

For the Systemic Synuclein Sampling Study

doi:10.1002/acn3.51753

Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay

For the Systemic Synuclein Sampling Study

Neurology

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Objectives: Detection of α-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α-synuclein measures, and investigate within-subject relationships. Methods: The Systemic Synuclein Sampling Study aimed to characterize α-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n = 59) and compared to healthy controls (n = 21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of α-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total α-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated α-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject α-synuclein measures were compared. Results: Sensitivity and specificity of α-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index = 83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α-synuclein positive. Interpretation: α-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α-synuclein measures, and within-subject relationships of central and peripheral α-synuclein measures emerged.

Original language	English (US)
Pages (from-to)	696-705
Number of pages	10
Journal	Annals of clinical and translational neurology
Volume	10
Issue number	5
DOIs	https://doi.org/10.1002/acn3.51753
State	Published - May 2023

Funding

S4 study authors (for group authorship): Kuldip Dave, Danna Jennings, John Seibyl, Vanessa Arnedo, Lindsey Riley, Carly Linder, Tatiana Foroud, Katherine Kopil, David Russell, Penelope Hogarth, Rizwan Akhtar, Amy Amara, Connie Marras, Naomi Visanji, David P. Breen, John Crary, Charles White, David Munoz, and Chelsea Caspell-Garcia. DaTscan doses were generously provided in-kind by GE Healthcare. The authors thank the study participants, the S4 Study's medical monitor Dr. Ergun Uc, and the following collaborators and contributors: Jan Hamer (Biorepository), Colleen Mitchell (Biorepository), Dixie Ecklund (Clinical and Statistics Core), Holly Riss (Clinical and Statistics Core), Lucia Sue (Pathology Core), Anthony Intorcia (Pathology Core), Michael Glass (Pathology Core), Jessica Walker (Pathology Core), Lindsey Guilmette (Imaging Core), Vikash Oza (Dermatology Collaborator), David Lott (ENT Collaborator), Ali Keshavarzian (GI Collaborator), Julie Schneider (Pathology Collaborator), Thomas Kremer (Industry Collaborator), Christian Schmauch (Industry Collaborator), Peggy Taylor (Industry Collaborator), Trevis Huff (Clinical and Statistics Core), Danielle Smith (Biorepository),Chaucer Noyes-Lloyd (Study Coordinator), Rachael Purri (Study Coordinator), Brandon Rothberg (Study Coordinator), Courtney Blair (Study Coordinator), K. Rose (Study Coordinator), Madeline Cresswell (Study Coordinator), Amy Duffy (Study Coordinator), and Madeline Potter (Study Coordinator). Michael J Fox Foundation. The following authors receive research funding support from the study sponsor (Michael J Fox Foundation): Lana M. Chahine, Thomas G Beach, Charles H. Adler, Monica Hepker, Anumantha Kanthasamy, Scott Appel, Sandra Pritzkow, Michelle Pinho, Sherri Mosovsky, Geidy E. Serrano, Christopher Coffey, Michael C. Brumm, Luis Oliveira, Jamie Eberling, and Brit Mollenhauer. The following authors are employed by the study sponsor (Michael J Fox Foundation): Luis Oliveira and Jamie Eberling.

ASJC Scopus subject areas

General Neuroscience
Clinical Neurology

Access to Document

10.1002/acn3.51753

Cite this

@article{b141758f4e9b46a190c60d40062c2343,

title = "Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay",

abstract = "Objectives: Detection of α-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α-synuclein measures, and investigate within-subject relationships. Methods: The Systemic Synuclein Sampling Study aimed to characterize α-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n = 59) and compared to healthy controls (n = 21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of α-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total α-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated α-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject α-synuclein measures were compared. Results: Sensitivity and specificity of α-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index = 83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α-synuclein positive. Interpretation: α-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α-synuclein measures, and within-subject relationships of central and peripheral α-synuclein measures emerged.",

author = "{For the Systemic Synuclein Sampling Study} and Chahine, {Lana M.} and Beach, {Thomas G.} and Adler, {Charles H.} and Monica Hepker and Anumantha Kanthasamy and Scott Appel and Sandra Pritzkow and Michelle Pinho and Sherri Mosovsky and Serrano, {Geidy E.} and Christopher Coffey and Brumm, {Michael C.} and Oliveira, {Luis M.A.} and Jamie Eberling and Brit Mollenhauer and Kuldip Dave and Danna Jennings and John Seibyl and Vanessa Arnedo and Lindsey Riley and Carly Linder and Tatiana Foroud and Katherine Kopil and David Russell and Penelope Hogarth and Rizwan Akhtar and Amy Amara and Connie Marras and Naomi Visanji and Breen, {David P.} and John Crary and Charles White and David Munoz and Chelsea Caspell-Garcia",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.",

year = "2023",

month = may,

doi = "10.1002/acn3.51753",

language = "English (US)",

volume = "10",

pages = "696--705",

journal = "Annals of clinical and translational neurology",

issn = "2328-9503",

publisher = "John Wiley and Sons Inc.",

number = "5",

}

TY - JOUR

T1 - Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay

AU - For the Systemic Synuclein Sampling Study

AU - Chahine, Lana M.

AU - Beach, Thomas G.

AU - Adler, Charles H.

AU - Hepker, Monica

AU - Kanthasamy, Anumantha

AU - Appel, Scott

AU - Pritzkow, Sandra

AU - Pinho, Michelle

AU - Mosovsky, Sherri

AU - Serrano, Geidy E.

AU - Coffey, Christopher

AU - Brumm, Michael C.

AU - Oliveira, Luis M.A.

AU - Eberling, Jamie

AU - Mollenhauer, Brit

AU - Dave, Kuldip

AU - Jennings, Danna

AU - Seibyl, John

AU - Arnedo, Vanessa

AU - Riley, Lindsey

AU - Linder, Carly

AU - Foroud, Tatiana

AU - Kopil, Katherine

AU - Russell, David

AU - Hogarth, Penelope

AU - Akhtar, Rizwan

AU - Amara, Amy

AU - Marras, Connie

AU - Visanji, Naomi

AU - Breen, David P.

AU - Crary, John

AU - White, Charles

AU - Munoz, David

AU - Caspell-Garcia, Chelsea

PY - 2023/5

Y1 - 2023/5

N2 - Objectives: Detection of α-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α-synuclein measures, and investigate within-subject relationships. Methods: The Systemic Synuclein Sampling Study aimed to characterize α-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n = 59) and compared to healthy controls (n = 21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of α-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total α-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated α-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject α-synuclein measures were compared. Results: Sensitivity and specificity of α-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index = 83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α-synuclein positive. Interpretation: α-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α-synuclein measures, and within-subject relationships of central and peripheral α-synuclein measures emerged.

AB - Objectives: Detection of α-synuclein aggregates by seed amplification is a promising Parkinson disease biomarker assay. Understanding intraindividual relationships of α-synuclein measures could inform optimal biomarker development. The objectives were to test accuracy of α-synuclein seed amplification assay in central (cerebrospinal fluid) and peripheral (submandibular gland) sources, compare to total α-synuclein measures, and investigate within-subject relationships. Methods: The Systemic Synuclein Sampling Study aimed to characterize α-synuclein in multiple tissues and biofluids within Parkinson disease subjects (n = 59) and compared to healthy controls (n = 21). Motor and non-motor measures and dopamine transporter scans were obtained. Four measures of α-synuclein were compared: seed amplification assay in cerebrospinal fluid and formalin-fixed paraffin-embedded submandibular gland, total α-synuclein quantified in biofluids using enzyme-linked immunoassay, and aggregated α-synuclein in submandibular gland detected by immunohistochemistry. Accuracy of seed amplification assay for Parkinson disease diagnosis was examined and within-subject α-synuclein measures were compared. Results: Sensitivity and specificity of α-synuclein seed amplification assay for Parkinson disease diagnosis was 92.6% and 90.5% in cerebrospinal fluid, and 73.2% and 78.6% in submandibular gland, respectively. 25/38 (65.8%) Parkinson disease participants were positive for both cerebrospinal fluid and submandibular gland seed amplification assay. Comparing accuracy for Parkinson disease diagnosis of different α-synuclein measures, cerebrospinal fluid seed amplification assay was the highest (Youden Index = 83.1%). 98.3% of all Parkinson disease cases had ≥1 measure of α-synuclein positive. Interpretation: α-synuclein seed amplification assay (cerebrospinal fluid>submandibular gland) had higher sensitivity and specificity compared to total α-synuclein measures, and within-subject relationships of central and peripheral α-synuclein measures emerged.

UR - http://www.scopus.com/inward/record.url?scp=85151287012&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85151287012&partnerID=8YFLogxK

U2 - 10.1002/acn3.51753

DO - 10.1002/acn3.51753

M3 - Article

C2 - 36972727

AN - SCOPUS:85151287012

SN - 2328-9503

VL - 10

SP - 696

EP - 705

JO - Annals of clinical and translational neurology

JF - Annals of clinical and translational neurology

IS - 5

ER -

Central and peripheral α-synuclein in Parkinson disease detected by seed amplification assay

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this