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medRxiv

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

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  • December 10, 2024
  • Edwin Jabbari, et al., UCL
Topic/Product:
CNS Disease Panel 120, Neurology
Disease Area:
Parkinson's Disease
Sample Type:
Plasma

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 1st January 2010 and 1st 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.

 
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Authors & Affiliations

Christina D. Orrú¹, David P. Vaughan²³, Nirosen Vijiaratnam²³, Raquel Real²³, Alejandro Martinez Carrasco²³, Riona Fumi²³, Marte Theilmann Jensen²³, Megan Hodgson²³, Christine Girges²³, Ana-Luisa Gil-Martinez²³, Eleanor J. Stafford²³, Lesley Wu²³, Bradley R. Groveman¹, Andrew G. Hughson¹, Olaf Ansorge⁴, Annelies Quaegebeur⁵⁶, Kieren S. J. Allinson⁵⁶, Thomas T. Warner⁷⁸, Zane Jaunmuktane⁷⁸, Anjum Misbahuddin⁹, P. Nigel Leigh¹¹⁰, Boyd C. P. Ghosh¹¹, Kailash P. Bhatia²³, Alistair Church¹², Christopher Kobylecki¹³, Michele T. M. Hu⁴, James B. Rowe⁵, Thomas Foltynie²³, Huw R. Morris²³, Byron Caughey¹, and Edwin Jabbari²³*

¹ Laboratory of Neurological Infections and Immunity, NIH/NIAID Rocky Mountain Laboratories, Hamilton, MT, USA
² Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
³ Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK
⁴ Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
⁵ Department of Clinical Neurosciences, Cambridge University Hospitals NHS Trust and MRC Cognition and Brain Sciences Unit, University of Cambridge, Cambridge, UK
⁶ Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
⁷ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
⁸ Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
⁹ Department of Neurology, Queen’s Hospital, Romford, UK
¹⁰ Department of Neuroscience, Brighton and Sussex Medical School, Brighton, UK
¹¹ Wessex Neurological Centre, University Hospitals Southampton NHS Foundation Trust, UK
¹² Department of Neurology, Royal Gwent Hospital, Newport, UK
¹³ Department of Neurology, Northern Care Alliance NHS Foundation Trust, Manchester Academic Health Science Centre, University of Manchester, Manchester, UK

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Steve Williams, MD, PhD

CSO

Dr. Willams serves as the company’s Chief Scientific Officer. He was previously Chief Medical Officer at Standard Biotools and at SomaLogic where he pioneered the discipline for discovery and validation of predictive, diagnostic and prognostic models using machine-learning applied to large-plex proteomics. 20 such tests were used for drug characterization, safety and efficacy when incorporated in clinical drug trials at Pharma/Biotech and 17 different multivariate tests were validated and translated into regulated healthcare uses. Prior to SomaLogic, Dr. Williams was at Pfizer in the UK and the USA as a clinical triallist in Translational Medicine, and subsequently as VP, Global Clinical Technology. He sat on the National Advisory Council for the National Institute of Biomedical Imaging and Bioengineering, the Executive Committee for the FNIH Biomarkers Consortium, and worked with FDA and PhRMA on developing evidentiary standards for biomarker qualification. Dr. William’s medical training was in London, at Charing Cross and Westminster Medical School, followed by a PhD in medicine/physiology at the same institution and training in Radiology at the University of Newcastle Upon Tyne. Steve is co-inventor on 26 proteomics patents and author/coauthor on multiple foundational proteomics manuscripts.

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Justin McAnear

CFO

Mr. McAnear serves as the company’s Chief Financial Officer. He brings over 25 years of operational and financial leadership experience across various sectors and was instrumental in taking 10x Genomics public in 2019, serving as its CFO for over five years. Mr. McAnear served for over 3 years as Tesla’s VP of Worldwide Finance and Operations, supporting landmark initiatives such as the Model X and Model 3 launches and Solar City acquisition.  He also held various roles at Apple and J&J earlier in his career and served as a naval officer and aviator for over 9 years.