This is an observational biomarker study conducted by Xuanwu Hospital, Beijing (Capital Medical University) investigating the use of Real-Time Quaking-Induced Conversion (RT-QuIC) to detect pathological α-synuclein seeding activity in the plasma of patients with synucleinopathies including Parkinson's disease (PD), Multiple System Atrophy (MSA), and Progressive Supranuclear Palsy (PSP). The study enrolls 458 participants across four groups — healthy controls, PD, MSA, and PSP — and uses plasma-based RT-QuIC for the differential diagnosis of these overlapping neurodegenerative disorders. [1]
Despite the clinical overlap between synucleinopathies (PD, MSA, DLB) and tauopathies (PSP, CBS, CBD), α-synuclein pathology also occurs in some PSP cases, making differential diagnosis challenging. RT-QuIC offers a highly specific and sensitive approach to detecting misfolded proteins in peripheral tissues, enabling less invasive diagnosis compared to post-mortem analysis.
| Parameter | Detail |
|---|---|
| NCT ID | NCT07498686 |
| Status | Recruiting |
| Study Type | Observational (Cohort, Retrospective) |
| Enrollment | 458 participants (estimated) |
| Start Date | May 2023 (actual) |
| Primary Completion | November 2026 (estimated) |
| Completion Date | December 2026 (estimated) |
| Sponsor | Xuanwu Hospital, Beijing |
| PI | Weiwei Yang, Ph.D. |
| Contact | yangww_2010@163.com |
The study comprises four cohorts for comparative analysis:
| Arm | Description | Sample Size |
|---|---|---|
| Control | Healthy subjects | ~100 |
| PD | Parkinson's disease patients | ~221 |
| MSA | Multiple system atrophy patients | ~127 |
| PSP | Progressive supranuclear palsy patients | ~10 |
The PSP cohort size (~10 patients) is small compared to PD and MSA, reflecting the lower prevalence of PSP relative to PD. However, the inclusion of PSP patients enables assessment of RT-QuIC's ability to distinguish PSP from synucleinopathies.
Synucleinopathies are a class of neurodegenerative diseases characterized by the abnormal folding and aggregation of the alpha-synuclein (α-syn) protein. The principal synucleinopathies include:
The intracellular location and accumulation pattern of α-syn differ among these diseases, contributing to clinical overlap and diagnostic uncertainty. [2]
Real-Time Quaking-Induced Conversion (RT-QuIC) is a seed amplification assay that exploits the templating property of misfolded proteins:
The original RT-QuIC method was developed for prion disease diagnosis, achieving 95–98% sensitivity and 100% specificity in CSF for sporadic Creutzfeldt-Jakob disease. This approach has since been adapted for α-synuclein, TDP-43, and tau seeds. [3]
While PSP is classically considered a 4R-tauopathy, overlapping α-syn pathology has been documented in some PSP cases:
RT-QuIC can detect both synuclein and tau seeds depending on the substrate used. This study uses α-syn as the substrate, which may capture PSP cases with concurrent synucleinopathy but will miss pure PSP (without α-syn seeding activity).
The study evaluates RT-QuIC metrics as diagnostic and differential diagnostic biomarkers:
| Measure | Description | Timeframe |
|---|---|---|
| Slope | Rate of fluorescence increase during RT-QuIC reaction | From enrollment to 21 weeks |
| MAX (Maximum fluorescence) | Peak fluorescence intensity | From enrollment to 21 weeks |
These metrics serve as surrogate markers for the presence and burden of pathological α-syn seeds in plasma.
RT-QuIC diagnostic utility is assessed through the following kinetic parameters:
| Parameter | Description | Diagnostic Relevance |
|---|---|---|
| Maximum fluorescence (MAX) | Peak ThT fluorescence intensity | Reflects total seed burden |
| Peak time | Time to reach maximum fluorescence | Reflects seeding kinetics |
| K/2 | Slope at half-maximum fluorescence | Reflects rate of aggregation |
| Tmax/2 | Time to reach half-maximum fluorescence | Reflects lag phase duration |
These parameters can be used to construct ROC curves for distinguishing between synucleinopathies and PSP, and between different synucleinopathies.
PD Patients: Diagnosed according to 2015 International Movement Disorder Society (MDS) criteria for clinical PD. All patients are evaluated by movement disorder specialists at Xuanwu Hospital and assessed using:
MSA Patients: Diagnosed according to the 2008 European MSA Study Group (EMSA-SG) criteria.
PSP Patients: Clinical diagnosis of probable or possible PSP based on MDS-PSP criteria. The small PSP cohort (~10 patients) is used primarily for cross-disease comparison.
Controls: Healthy subjects without neurological disease, matched for age.
The plasma RT-QuIC assay follows established protocols for synucleinopathies:
Based on published literature for CSF and plasma RT-QuIC in synucleinopathies:
| Condition | Sensitivity | Specificity | Notes |
|---|---|---|---|
| PD vs. Controls | 70–85% | 90–100% | CSF RT-QuIC more sensitive than plasma |
| MSA vs. Controls | 80–95% | 90–100% | MSA shows high seeding activity |
| PSP (with synuclein) | Variable | Variable | Depends on comorbid synuclein pathology |
| PSP (without synuclein) | 0–10% | — | α-syn substrate won't detect tau seeds |
The primary clinical utility of plasma RT-QuIC would be distinguishing:
The inclusion of PSP patients in this study is particularly relevant because:
Yang W, et al. Plasma alpha-synuclein aggregation seeding activity as a novel biomarker for neurodegeneration disease. 2024. ↩︎
Spillantini MG, et al. Alpha-synuclein in Parkinson's disease and related synucleinopathies. Nature Reviews Neuroscience. 2020. ↩︎
Atarashi R, et al. Ultrasensitive detection of scrapie prion protein using seed amplification. Nature Medicine. 2011. ↩︎
Fairfoul G, et al. Alpha-synuclein RT-QuIC in the cerebrospinal fluid of Parkinson's disease. Acta Neuropathologica. 2016. ↩︎