Diagnostic and prognostic value of alpha-synuclein seed amplification assay in Parkinson’s disease: a longitudinal cohort study

  1. Christina D Orrú
  2. David P Vaughan
  3. Nirosen Vijiaratnam
  4. Raquel Real
  5. Alejandro Martinez Carrasco
  6. Riona Fumi
  7. Marte Theilmann Jensen
  8. Megan Hodgson
  9. Christine Girges
  10. Ana-Luisa Gil-Martinez
  11. Eleanor J. Stafford
  12. Lesley Wu
  13. Bradley R Groveman
  14. Andrew G Hughson
  15. Olaf Ansorge
  16. Annelies Quaegebeur
  17. Kieren SJ Allinson
  18. Thomas T Warner
  19. Zane Jaunmuktane
  20. Anjum Misbahuddin
  21. P Nigel Leigh
  22. Boyd CP Ghosh
  23. Kailash P Bhatia
  24. Alistair Church
  25. Christopher Kobylecki
  26. Michele TM Hu
  27. James B Rowe
  28. Thomas Foltynie
  29. Huw R Morris
  30. Byron Caughey
  31. Edwin Jabbari
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Abstract

Background

Alpha-synuclein seed amplification assay (a-syn SAA) has been proposed to be a diagnostic biomarker for Parkinson’s disease (PD). Here, we have explored the diagnostic and prognostic value of cerebrospinal fluid (CSF) a-syn SAA status and seeding kinetics in PD.

Methods

Baseline CSF a-syn SAA data and longitudinal clinical data were collected and analysed between 1 st January 2010 and 1 st April 2022 for the Parkinson’s Progression Markers Initiative (PPMI) and UK parkinsonism cohorts respectively. We calculated the sensitivity and specificity of a-syn SAA in PD and controls, used linear regression to analyse a-syn SAA positive vs. negative group comparisons, and used time-to-event analyses to assess the ability of a-syn SAA seeding kinetic measures to predict clinical decline in PD.

Findings

We studied 1,402 participants: publicly available data from the PPMI cohort, n=1275 (PD, n=1,036; controls, n=239); newly generated data from the UK parkinsonism cohort, n=127 (PD, n=66; progressive supranuclear palsy (PSP), n=52; controls n=9). Over 2-5 years of follow-up, the sensitivity of a-syn SAA in PD was 87.7% and the specificity in controls was 91.9%. A-syn SAA was positive in 8/52 (15.4%) PSP samples with distinct ‘low and slow’ kinetics. A-syn SAA negative LRRK2-PD participants (n=57) had an older mean (SD) age at symptom onset (63.0 (7.6) vs. 55.4 (9.9) years) and higher mean (SD) baseline serum neurofilament light chain levels (20.4 (13.2) vs. 13.8 (8.6) pg/ml), p<0.05, vs. a-syn SAA positive LRRK2-PD participants (n=110). The baseline seeding kinetic measure, time to threshold, predicted cognitive decline in PD, defined as MoCA ≤21 (HR 2.51, 95% CI 1.50-4.20, p=0.001).

Interpretation

In PD, a-syn SAA may have value as a diagnostic and prognostic biomarker in clinical practice and as a stratification tool in clinical trials. Furthermore, we have highlighted the presence of pathological heterogeneity in LRRK2-PD.

Funding

Medical Research Council, PSP Association.

Article activity feed

  1. Version published to 10.1101/2024.12.03.24318422v2 on medRxiv
  2. Version published to 10.1101/2024.12.03.24318422v1 on medRxiv