TY - JOUR
T1 - Propagative α-synuclein seeds as serum biomarkers for synucleinopathies
AU - Okuzumi, Ayami
AU - Hatano, Taku
AU - Matsumoto, Gen
AU - Nojiri, Shuko
AU - Ueno, Shin ichi
AU - Imamichi-Tatano, Yoko
AU - Kimura, Haruka
AU - Kakuta, Soichiro
AU - Kondo, Akihide
AU - Fukuhara, Takeshi
AU - Li, Yuanzhe
AU - Funayama, Manabu
AU - Saiki, Shinji
AU - Taniguchi, Daisuke
AU - Tsunemi, Taiji
AU - McIntyre, Deborah
AU - Gérardy, Jean Jacques
AU - Mittelbronn, Michel
AU - Kruger, Rejko
AU - Uchiyama, Yasuo
AU - Nukina, Nobuyuki
AU - Hattori, Nobutaka
N1 - Funding Information:
This work was supported by the Japan Agency for Medical Research and Development (AMED) (20dm0107156 and 21wm0425015 to T.H. and A.O. and 21ak0101112 to T.H. and N.H.); the Multicenter Alliance for Brain Biomarkers (21dk0207055 to T.H., 21dm0207070 to N.H. and 20dm0107140 to N.N.); Grants-in-Aid for Scientific Research (21H04820 to N.H., 21K07424 to T.H., 19K16928 to A.O. and 20K22693 to S.U.) from the Japan Society for the Promotion of Science; the Visionary Council on the Moonshot Research and Development Program (JPMJMS2024-5 to N.H.); grants-in-aid from the Research Committee of CNS Degenerative Disease, Research on Policy Planning and Evaluation for Rare and Intractable Diseases, Health, Labor, and Welfare Sciences Research Grants; the Ministry of Health, Labour and Welfare, Japan, to N.H.; the Setsuro Fujii Memorial, Osaka Foundation for Promotion of Fundamental Medical Research, to T.H.; grants-in-aid from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan to G.M. (17K07098 and 20H05333) for Scientific Research on Innovative Areas ‘Multimode autophagy’; the National Centre of Excellence in Research on Parkinson’s Disease (NCER-PD) funded by the Luxembourg National Research Fund (FNR; NCER13/BM/11264123); and the PEARL program (PEARL /P13/6682797 to R.K. and PEARL P16/BM/11192868 to M.M.). We thank Editage and Edanz for editing drafts of this paper. We also would like to give special thanks to all participants in this study. Furthermore, we acknowledge the joint effort of the NCER-PD consortium members from the partner institutions—Luxembourg Centre for Systems Biomedicine, Luxembourg Institute of Health, Centre Hospitalier de Luxembourg and Laboratoire National de Santé—generally contributing to the Luxembourg Parkinson’s Study as listed below: G. Acharya, G. Aguayo, M. Alexandre, M. Ali, W. Ammerlann, R. Balling, M. Bassis, K. Beaumont, R. Becker, C. Bellora, G. Berchem, D. Berg, A Bisdorff, I. Boussaad, K. Brockmann, J. Calmes, L. Castillo, G. Contesotto, N. Diederich, R. Dondelinger, D. Esteves, G. Fagherazzi, J.-Y. Ferrand, M. Gantenbein, T. Gasser, P. Gawron, S. Ghosh, M. Giraitis, E. Glaab, C.P.C. Gomes, E. Gómez de Lope, J. Graas, M. Graziano, V. Groues, A. Grünewald, W. Gu, G. Hammot, A.-M. Hanff, L. Hansen, M. Hansen, M. Heneka, E. Henry, S. Herbrink, S. Herzinger, M. Heymann, M. Hu, A. Hundt, N. Jacoby, J. Jaroslaw Lebioda, Y. Jaroz, Q. Klopfenstein, J. Klucken, P. Lambert, Z. Landoulsi, R. Lentz, I. Liepelt, R. Liszka, L. Longhino, V. Lorentz, P.C. Lupu, C. Mackay, W. Maetzler, K. Marcus, T.M. Marques, P. Martins Conde, P. May, D. Mcintyre, C. Mediouni, F. Meisch, M. Menster, M. Minelli, M. Mittelbronn, B. Mollenhauer, F. Mühlschlegel, R. Nati, U. Nehrbass, S. Nickels, B. Nicolai, J.-P. Nicolay, W. Oertel, M. Ostaszewski, S. Pachchek, C. Pauly, L. Pauly, L. Pavelka, M. Perquin, R. Ramos Lima, A. Rauschenberger, R. Rawal, D. Reddy Bobbili, K. Roomp, E. Rosales, I. Rosety, E. Sandt, S. Sapienza, V. Satagopam, M. Schmitt, S. Schmitz, R. Schneider, J. Schwamborn, J.E. Schweitzer, A. Sharify, E. Soboleva, K. Sokolowska, O. Terwindt, H. Thien, E. Thiry, R.T.J. Loo, C. Trefois, J. Trouet, O. Tsurkalenko, M. Vaillant, M. Valenti, C. Vega, I. Vilas Boas, M. Vyas, R. Wade-Martins, P. Wilmes, E. Wollscheid-Lengeling, G. Zelimkhannov, N. Ramia and J.V. Fritz.
Publisher Copyright:
© 2023, The Author(s).
PY - 2023/6
Y1 - 2023/6
N2 - Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95–0.99)/AUC: 0.93 (95% CI 0.84–1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49–0.79)/AUC: 0.73 (95% CI 0.49–0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74–0.99)) and MSA (AUC: 0.80 (95% CI 0.65–0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.
AB - Abnormal α-synuclein aggregation is a key pathological feature of a group of neurodegenerative diseases known as synucleinopathies, which include Parkinson’s disease (PD), dementia with Lewy bodies and multiple system atrophy (MSA). The pathogenic β-sheet seed conformation of α-synuclein is found in various tissues, suggesting potential as a biomarker, but few studies have been able to reliably detect these seeds in serum samples. In this study, we developed a modified assay system, called immunoprecipitation-based real-time quaking-induced conversion (IP/RT-QuIC), which enables the detection of pathogenic α-synuclein seeds in the serum of individuals with synucleinopathies. In our internal first and second cohorts, IP/RT-QuIC showed high diagnostic performance for differentiating PD versus controls (area under the curve (AUC): 0.96 (95% confidence interval (CI) 0.95–0.99)/AUC: 0.93 (95% CI 0.84–1.00)) and MSA versus controls (AUC: 0.64 (95% CI 0.49–0.79)/AUC: 0.73 (95% CI 0.49–0.98)). IP/RT-QuIC also showed high diagnostic performance in differentiating individuals with PD (AUC: 0.86 (95% CI 0.74–0.99)) and MSA (AUC: 0.80 (95% CI 0.65–0.97)) from controls in a blinded external cohort. Notably, amplified seeds maintained disease-specific properties, allowing the differentiation of samples from individuals with PD versus MSA. In summary, here we present a novel platform that may allow the detection of individuals with synucleinopathies using serum samples.
UR - http://www.scopus.com/inward/record.url?scp=85160454113&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37248302
U2 - 10.1038/s41591-023-02358-9
DO - 10.1038/s41591-023-02358-9
M3 - Article
C2 - 37248302
AN - SCOPUS:85160454113
SN - 1078-8956
VL - 29
SP - 1448
EP - 1455
JO - Nature Medicine
JF - Nature Medicine
IS - 6
ER -