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Cited by 191Parkinson's Disease Mechanisms and TreatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

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Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies

Open access
Poggiolini, Ilaria, Gupta, Vandana, Lawton, Michael, Lee, Seoyun, El-Turabi, Aadil, Querejeta-Coma, Agustin, Trenkwalder, Claudia, Sixel-Döring, Friederike, Foubert-Samier, Alexandra, Pavy-Le Traon, Anne, Plazzi, Giuseppe, Biscarini, Francesco, Montplaisir, Jacques, Gagnon, Jean-François, Postuma, Ronald B, Antelmi, Elena, Meissner, Wassilios G, Mollenhauer, Brit, Ben-Shlomo, Yoav, Hu, Michele T, Parkkinen, Laura·2022·Brain
DOI 10.1093/brain/awab431PMC PMC9014737
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Abstract

Several studies have confirmed the α-synuclein real-time quaking-induced conversion (RT-QuIC) assay to have high sensitivity and specificity for Parkinson’s disease. However, whether the assay can be used as a robust, quantitative measure to monitor disease progression, stratify different synucleinopathies and predict disease conversion in patients with idiopathic REM sleep behaviour disorder remains undetermined. The aim of this study was to assess the diagnostic value of CSF α-synuclein RT-QuIC quantitative parameters in regard to disease progression, stratification and conversion in synucleinopathies. We performed α-synuclein RT-QuIC in the CSF samples from 74 Parkinson’s disease, 24 multiple system atrophy and 45 idiopathic REM sleep behaviour disorder patients alongside 55 healthy controls, analysing quantitative assay parameters in relation to clinical data. α-Synuclein RT-QuIC showed 89% sensitivity and 96% specificity for Parkinson’s disease. There was no correlation between RT-QuIC quantitative parameters and Parkinson’s disease clinical scores (e.g. Unified Parkinson’s Disease Rating Scale motor), but RT-QuIC positivity and some quantitative parameters (e.g. Vmax) differed across the different phenotype clusters. RT-QuIC parameters also added value alongside standard clinical data in diagnosing Parkinson’s disease. The sensitivity in multiple system atrophy was 75%, and CSF samples showed longer T50 and lower Vmax compared to Parkinson’s disease. All RT-QuIC parameters correlated with worse clinical progression of multiple system atrophy (e.g. change in Unified Multiple System Atrophy Rating Scale). The overall sensitivity in idiopathic REM sleep behaviour disorder was 64%. In three of the four longitudinally followed idiopathic REM sleep behaviour disorder cohorts, we found around 90% sensitivity, but in one sample (DeNoPa) diagnosing idiopathic REM sleep behaviour disorder earlier from the community cases, this was much lower at 39%. During follow-up, 14 of 45 (31%) idiopathic REM sleep behaviour disorder patients converted to synucleinopathy with 9/14 (64%) of convertors showing baseline RT-QuIC positivity. In summary, our results showed that α-synuclein RT-QuIC adds value in diagnosing Parkinson’s disease and may provide a way to distinguish variations within Parkinson’s disease phenotype. However, the quantitative parameters did not correlate with disease severity in Parkinson’s disease. The assay distinguished multiple system atrophy patients from Parkinson’s disease patients and in contrast to Parkinson’s disease, the quantitative parameters correlated with disease progression of multiple system atrophy. Our results also provided further evidence for α-synuclein RT-QuIC having potential as an early biomarker detecting synucleinopathy in idiopathic REM sleep behaviour disorder patients prior to conversion. Further analysis of longitudinally followed idiopathic REM sleep behaviour disorder patients is needed to better understand the relationship between α-synuclein RT-QuIC signature and the progression from prodromal to different synucleinopathies.

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Figures

Figure 1 RT-QuIC parameters and other CSF biomarkers in different patient cohorts. (A) The lag phase (Tlag) = time each positive reaction exceeds the threshold (RFU > 5 SD); (B) the maximum fluorescence value (Fmax) = highest mean fluorescence value achieved; (C) T50 = time latency to reach 50% of the Fmax; (D) the maximum slope (Vmax) = maximum increase per unit of time; and (E) the area under curve (AUC). Bars show the average ± SD. (F) Levels of total αSyn and (G) phospho-tau in the Discovery cohort. Bars show the average ± SD. (H) No correlation detected between total αSyn levels and T50 values in the Discovery cohort including all Parkinson’s disease, iRBD and heathy controls (same cases showed in G). (I) Kinetic curves of αSyn seeding activity measured by RT-QuIC in Parkinson’s disease (red line, n = 74) and MSA (purple line, n = 24) clinical cases. Each curve depicts the average percentage of ThT fluorescence from duplicate reactions of each group. Each dot depicts average RFU value at 10-h interval. Vertical bars represent the mean ± SD.
Figure 1 RT-QuIC parameters and other CSF biomarkers in different patient cohorts. (A) The lag phase (Tlag) = time each positive reaction exceeds the threshold (RFU > 5 SD); (B) the maximum fluorescence value (Fmax) = highest mean fluorescence value achieved; (C) T50 = time latency to reach 50% of the Fmax; (D) the maximum slope (Vmax) = maximum increase per unit of time; and (E) the area under curve (AUC). Bars show the average ± SD. (F) Levels of total αSyn and (G) phospho-tau in the Discovery cohort. Bars show the average ± SD. (H) No correlation detected between total αSyn levels and T50 values in the Discovery cohort including all Parkinson’s disease, iRBD and heathy controls (same cases showed in G). (I) Kinetic curves of αSyn seeding activity measured by RT-QuIC in Parkinson’s disease (red line, n = 74) and MSA (purple line, n = 24) clinical cases. Each curve depicts the average percentage of ThT fluorescence from duplicate reactions of each group. Each dot depicts average RFU value at 10-h interval. Vertical bars represent the mean ± SD.CC BY-NC · PubMed Central
Figure 2 RT-QuIC parameters (A–E) and ELISA biomarkers (F–I) in the Discovery cohort against validated Parkinson’s disease clinical clusters. Data are mean ± SD (range) unless otherwise stated. No other changes were detected except (D) Vmax was different across the clusters (P = 0.02), with cluster 1 having higher Vmax than clusters 2 (P = 0.02) and 3 (P = 0.03) and cluster 4 having higher Vmax than clusters 2 and 3 (P = 0.05).
Figure 2 RT-QuIC parameters (A–E) and ELISA biomarkers (F–I) in the Discovery cohort against validated Parkinson’s disease clinical clusters. Data are mean ± SD (range) unless otherwise stated. No other changes were detected except (D) Vmax was different across the clusters (P = 0.02), with cluster 1 having higher Vmax than clusters 2 (P = 0.02) and 3 (P = 0.03) and cluster 4 having higher Vmax than clusters 2 and 3 (P = 0.05).CC BY-NC · PubMed Central
Figure 3 Kaplan–Meier analysis of iRBD patients showing rates of neurological disease-free survival according to time from baseline lumbar puncture. No evidence was seen that RT-QuIC positive iRBD patients had a higher risk of conversion than RT-QuIC negative counterparts.
Figure 3 Kaplan–Meier analysis of iRBD patients showing rates of neurological disease-free survival according to time from baseline lumbar puncture. No evidence was seen that RT-QuIC positive iRBD patients had a higher risk of conversion than RT-QuIC negative counterparts.CC BY-NC · PubMed Central

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Authors
Poggiolini, I., Gupta, V., Lawton, M., Lee, S., El-Turabi, A., Querejeta-Coma, A., Trenkwalder, C., Sixel-Döring, F., Foubert-Samier, A., Pavy-Le Traon, A., Plazzi, G., Biscarini, F., Montplaisir, J., Gagnon, J.-F., Postuma, R. B., Antelmi, E., Meissner, W. G., Mollenhauer, B., Ben-Shlomo, Y., Hu, M. T., & Parkkinen, L.
Affiliations
  • University of Oxford (GB)
  • University of Bristol (GB)
  • Nuffield Department of Clinical Neurosciences, Oxford Parkinson’s Disease Centre, University of Oxford, UK
  • Universitätsmedizin Göttingen (DE)
  • Paracelsus Elena Klinik, Centre for Movement Disorders, Kassel, Germany
  • French Reference Centre for MSA, University Hospital Bordeaux, Bordeaux, France
  • French Reference Centre for MSA, University Hospital of Toulouse, Toulouse, France
  • University of Modena and Reggio Emilia (IT)
  • University of Bologna (IT)
  • Hôpital du Sacré-Cœur de Montréal (CA)
  • Université du Québec à Montréal (CA)
  • Montreal General Hospital (CA)
  • University of Verona (IT)
  • Centre National de la Recherche Scientifique (FR)
  • School of Social and Community Medicine, Bristol Medical School, University of Bristol, UK
Corresponding author
Parkkinen, Laura
ORCID
Venue
Brain
Publisher
Oxford University Press (OUP)
Published
2021-12-11
Volume
145
Issue
2
Pages
584-595
ISSN
  • 0006-8950 (ISSN-L)
  • 1460-2156
DOI
10.1093/brain/awab431
PMC
PMC9014737
OpenAlex
W4200520313
Cited by
191
References
57
Citations by year
2026: 33 · 2025: 50 · 2024: 48 · 2023: 35 · 2022: 25
FWCI
12.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Brain (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • Explore Bristol Research (publishedVersion, cc-by-nc)
  • HAL (submittedVersion, cc-by-nc)
  • Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion, cc-by-nc)
  • IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
  • Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion, cc-by-nc)
Funders
  • Biogen
  • Teva Pharmaceutical Industries
  • Jazz Pharmaceuticals
  • Parkinson's Foundation
  • UK Research and Innovation
  • National Institute for Health and Care Research
  • Parkinson's UK (J-1403, G‐1806, J-0901, J-2101)
  • Deutsche Forschungsgemeinschaft
  • Eisai
  • Servier
  • H. Lundbeck A/S
  • Deutsche Parkinson Vereinigung
  • Idorsia Pharmaceuticals
  • Otsuka Pharmaceutical Development and Commercialization
  • Canadian Institutes of Health Research
  • Medical Research Council (MR/T046287/1)
  • Engineering and Physical Sciences Research Council (EP/R013756/1)
  • NIHR Oxford Biomedical Research Centre
Topics
  • Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
alpha-synuclein, cerebrospinal fluid, RT-QuIC, synucleinopathies, Parkinson's disease, multiple system atrophy, idiopathic REM sleep behavior disorder, disease progression, disease transformation, sensitivity and specificity, Vmax, T50, biomarkers, Unified Parkinson's Disease Rating Scale
MeSH terms
Synucleinopathies, Humans, Parkinson Disease, Disease Progression, Multiple System Atrophy, REM Sleep Behavior Disorder, alpha-Synuclein

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