Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study

Christina D Orrú¹, David P Vaughan², Nirosen Vijiaratnam², Raquel Real², Alejandro Martinez-Carrasco², Riona Fumi², Marte Theilmann Jensen², Megan Hodgson², Christine Girges², Ana-Luisa Gil-Martinez², Eleanor J Stafford², Lesley Wu², Stefanie Lerche³, Isabel Wurster³, Bradley R Groveman¹, Andrew G Hughson¹, Olaf Ansorge⁴, Annelies Quaegebeur⁵, Kieren S J Allinson⁵, Thomas T Warner⁶, Zane Jaunmuktane⁶, Anjum Misbahuddin⁷, P Nigel Leigh⁸, Boyd C P Ghosh⁹, Kailash P Bhatia², Alistair Church¹⁰, Christopher Kobylecki¹¹, Michele T M Hu⁴, James B Rowe¹², Piero Parchi¹³, Kathrin Brockmann³, Thomas Foltynie², Huw R Morris², Byron Caughey¹, Edwin Jabbari¹⁴

Affiliations

¹ Laboratory of Neurological Infections and Immunity, Division of Intramural Research, NIH/NIAID Rocky Mountain Laboratories, Hamilton, MT, USA.
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
³ Hertie Institute for Clinical Brain Research and Department of Neurodegeneration, University of Tübingen, Tübingen, Germany.
⁴ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁵ Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁶ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK; Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.
⁷ Department of Neurology, Queen's Hospital, Romford, UK.
⁸ Department of Neuroscience, Brighton and Sussex Medical School, Brighton BN1 9PX, UK.
⁹ Wessex Neurological Centre, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
¹⁰ Department of Neurology, Royal Gwent Hospital, Newport, UK.
¹¹ Department of Neurology, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
¹² Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust and MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
¹³ Department of Biomedical and Neuromotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
¹⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK. Electronic address: e.jabbari@ucl.ac.uk.

PMID: 40541208
DOI: 10.1016/S1474-4422(25)00157-7

Free article

Observational Study

Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study

Christina D Orrú et al. Lancet Neurol. 2025 Jul.

Free article

. 2025 Jul;24(7):580-590.

doi: 10.1016/S1474-4422(25)00157-7.

Authors

Affiliations

¹ Laboratory of Neurological Infections and Immunity, Division of Intramural Research, NIH/NIAID Rocky Mountain Laboratories, Hamilton, MT, USA.
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK.
³ Hertie Institute for Clinical Brain Research and Department of Neurodegeneration, University of Tübingen, Tübingen, Germany.
⁴ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
⁵ Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
⁶ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK; Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK.
⁷ Department of Neurology, Queen's Hospital, Romford, UK.
⁸ Department of Neuroscience, Brighton and Sussex Medical School, Brighton BN1 9PX, UK.
⁹ Wessex Neurological Centre, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
¹⁰ Department of Neurology, Royal Gwent Hospital, Newport, UK.
¹¹ Department of Neurology, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK.
¹² Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust and MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK.
¹³ Department of Biomedical and Neuromotor Sciences (DiBiNeM), University of Bologna, Bologna, Italy; IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy.
¹⁴ Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK; Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK. Electronic address: e.jabbari@ucl.ac.uk.

PMID: 40541208
DOI: 10.1016/S1474-4422(25)00157-7

Abstract

Background: α-synuclein seed amplification assay (SAA) positivity has been proposed as a diagnostic biomarker for Parkinson's disease. However, studies of the prognostic value of this biomarker have been limited to small, single-centre studies over short follow-up periods. We aimed to assess the diagnostic and prognostic value of quantitative CSF α-synuclein SAA kinetic measures in Parkinson's disease.

Methods: In this longitudinal cohort study, we collected and analysed data from participants with Parkinson's disease, progressive supranuclear palsy, and healthy controls enrolled in three cohorts: the UK parkinsonism cohort, the Parkinson's Progression Markers Initiative (PPMI) international observational study, and the Tübingen Parkinson's disease cohort. Baseline CSF α-synuclein SAA data and longitudinal clinical data were collected between Jan 1, 2005, and Nov 1, 2023. The following seeding kinetic measures were calculated from the α-synuclein SAA curve for each SAA-positive sample: time to threshold (TTT) for a positive SAA result; maximum Thioflavin T fluorescence during the reaction time (MaxThT); and area under the fluorescence curve during the reaction time (AUC). We compared seeding kinetic measures between sporadic Parkinson's disease and progressive supranuclear palsy, and between sporadic Parkinson's disease and monogenic Parkinson's disease. We used time-to-event analyses to assess the ability of α-synuclein SAA kinetic measures to predict an unfavourable outcome in Parkinson's disease, adjusting for sex, age, and disease duration at SAA testing.

Findings: We analysed data from 1631 participants: newly generated data from the UK parkinsonism cohort (Parkinson's disease, n=66; progressive supranuclear palsy, n=52; controls, n=9) and previously generated data from the PPMI (Parkinson's disease, n=1036; controls, n=239) and Tübingen (Parkinson's disease, n=229) cohorts. In the UK parkinsonism cohort, α-synuclein SAA was positive in 63 (96%) of 66 Parkinson's disease samples and eight (15%) of 52 progressive supranuclear palsy samples, with six (75%) of eight positive progressive supranuclear palsy samples having distinct low and slow seeding kinetics (low MaxThT and high TTT) as a marker of Lewy body co-pathology. TTT was faster in GBA1-associated Parkinson's disease compared with sporadic Parkinson's disease in both the PPMI (p=0·04) and Tübingen (p=0·01) cohorts. In the PPMI cohort, after excluding individuals who had an unfavourable outcome at the time of baseline SAA testing, an unfavourable outcome was observed in 593 (73%) of 810 participants with α-synuclein SAA-positive Parkinson's disease during a median follow-up period of 4·5 years (IQR 2-9). TTT at baseline predicted only cognitive decline (Montreal Cognitive Assessment score ≤21) as a component of an unfavourable outcome in Parkinson's disease in both the PPMI (n=824, hazard ratio [HR] 2·36 [95% CI 1·60-3·46], p=0·001) and Tübingen (n=135, 2·17 [1·07-4·41], p=0·03) cohorts. TTT also predicted cognitive decline in a subgroup of participants with Parkinson's disease in the PPMI cohort who were Alzheimer's disease biomarker negative (n=355, HR 1·80 [95% CI 1·03-3·18], p=0·04).

Interpretation: Assessing α-synuclein SAA kinetic measures might aid in the diagnostic differentiation of Parkinson's disease from progressive supranuclear palsy with Lewy body co-pathology. Furthermore, faster seeding kinetics are found in GBA1-Parkinson's disease and predict cognitive decline in Parkinson's disease independently of Alzheimer's disease co-pathology.

Funding: Medical Research Council, PSP Association.

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Conflict of interest statement

Declaration of interests BCPG's salary is paid by University Hospital Southampton. In the past 12 months BCPG has received honoraria from the neurology masterclass and GEC, grants from the PSP Association, and paid consultancy from ImmunoBrain. BCPG serves as a trustee and is on the research committee for the PSP Association. CK is employed by Northern Care Alliance NHS Foundation Trust. In the past 12 months CK has received speaker honoraria from Neurology Academy, Ipsen, and Britannia Pharmaceuticals. JBR is employed by Cambridge University with academic grants from AstraZeneca, Lilly, GSK, and Janssen, and paid consultancy for Asceneuron, Astex, Astronautx, Alector, Booster Therapeutics, Clinical Ink, Curasen, CumulusNeuro, Eisai, Ferrer, ICG, Invicro, Prevail, in the past 12 months unrelated to the current work. HRM is employed by UCL. In the past 12 months HRM reports paid consultancy from Roche, Aprinoia, AI Therapeutics and Amylyx; lecture fees or honoraria from BMJ, Kyowa Kirin, and the Movement Disorders Society. TF has served on advisory boards for Peptron, Treefrog, AbbVie, Bluerock, Bayer, and Bial, and has received honoraria for talks sponsored by Bayer, Bial, Profile Pharma, Boston Scientific, and Novo Nordisk. HRM is a co-applicant on a patent application related to C9ORF72 (Method for diagnosing a neurodegenerative disease; PCT/GB2012/052140). BC, CDO, BRG, and AGH are inventors on a patent pertaining the RML α-synuclein SAA (RT-QuIC) technology. All other authors declare no competing interests.

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Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study

Affiliations

Diagnostic and prognostic value of α-synuclein seed amplification assay kinetic measures in Parkinson's disease: a longitudinal cohort study

Authors

Affiliations

Abstract

Conflict of interest statement

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Medical

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