NCT04724941: Prodromal Alpha-Synuclein Screening

NCT04724941: Prodromal Alpha-Synuclein Screening

Overview

NCT04724941 (Prodromal Alpha-Synuclein Screening in Parkinson's Disease Study) is an observational clinical trial designed to identify individuals in the prodromal stage of Parkinson's disease using alpha-synuclein seed amplification assays. The study aims to characterize risk marker profiles in at-risk populations, enabling early detection and potential intervention before manifest motor symptoms develop [@nct].

This mechanistic page integrates the trial's approach with the underlying biology of alpha-synuclein pathology propagation, prodromal biomarkers, and the emerging role of seed amplification assays in early PD detection.

Clinical Trial Overview

| Attribute | Details |
|-----------|---------|
| Trial ID | NCT04724941 |
| Status | Recruiting |
| Enrollment | 2,000 participants (estimated) |
| Sponsor | University Hospital Schleswig-Holstein |
| Collaborators | UCB Biopharma SRL; University of Kiel |
| Location | Kiel, Germany |
| Start Date | June 2021 |
| Completion | December 2027 |
| Study Type | Observational |
| Primary Outcome | Risk marker profile |

The Rationale for Prodromal Screening

Why Detect PD Before Motor Symptoms?

Parkinson's disease is characterized by a long prodromal period during which pathological changes occur but clinical motor symptoms have not yet manifested. This window represents a critical opportunity for:

NCT04724941: Prodromal Alpha-Synuclein Screening

Overview

NCT04724941 (Prodromal Alpha-Synuclein Screening in Parkinson's Disease Study) is an observational clinical trial designed to identify individuals in the prodromal stage of Parkinson's disease using alpha-synuclein seed amplification assays. The study aims to characterize risk marker profiles in at-risk populations, enabling early detection and potential intervention before manifest motor symptoms develop [@nct].

This mechanistic page integrates the trial's approach with the underlying biology of alpha-synuclein pathology propagation, prodromal biomarkers, and the emerging role of seed amplification assays in early PD detection.

Clinical Trial Overview

| Attribute | Details |
|-----------|---------|
| Trial ID | NCT04724941 |
| Status | Recruiting |
| Enrollment | 2,000 participants (estimated) |
| Sponsor | University Hospital Schleswig-Holstein |
| Collaborators | UCB Biopharma SRL; University of Kiel |
| Location | Kiel, Germany |
| Start Date | June 2021 |
| Completion | December 2027 |
| Study Type | Observational |
| Primary Outcome | Risk marker profile |

The Rationale for Prodromal Screening

Why Detect PD Before Motor Symptoms?

Parkinson's disease is characterized by a long prodromal period during which pathological changes occur but clinical motor symptoms have not yet manifested. This window represents a critical opportunity for:

Prodromal Markers in PD

The prodromal phase of PD is characterized by several non-motor features that precede motor symptoms by years to decades:

Alpha-Synuclein Biology in Prodromal PD

Normal Alpha-Synuclein Function

Alpha-synuclein (α-syn) is a 140-amino acid protein encoded by the [SNCA gene](/genes/snca) that plays important roles in synaptic vesicle trafficking and neurotransmitter release. In its native state, α-syn exists as an intrinsically disordered monomer that transiently interacts with lipid membranes [@sato2023].

Pathological Conversion

In PD, α-syn undergoes a conformational change from native monomer to misfolded oligomers and fibrils that accumulate as [Lewy bodies](/mechanisms/lewy-body-formation-pathway) and [Lewy neurites](/mechanisms/alpha-synuclein-aggregation-pathway). This conversion is templated by pathological seeds—a process known as seeding [2](https://doi.org/10.1126/science.1220361).

The key steps in pathological α-syn conversion:

Prion-Like Propagation

The pathological α-syn species exhibit prion-like properties, able to template the conversion of normal endogenous α-syn in recipient cells. This template-directed misfolding drives the spread of pathology throughout the nervous system [3](https://doi.org/10.1084/jem.20112457).

Key propagation mechanisms:

• Intercellular transfer: Pathological α-syn can transfer between neurons via tunneling nanotubes, extracellular vesicles, and synaptic release
• Template-directed conversion: Seeds induce misfolding of native α-syn in recipient cells
• Strain diversity: Different conformational variants ("strains") may encode disease specificity

Seed Amplification Assays (SAA)

Technology Overview

Seed amplification assays are ultrasensitive detection methods that exploit the prion-like property of misfolded α-syn. These assays can detect pathological seeds at concentrations as low as 10⁻¹⁵ to 10⁻¹⁶ M [4](https://doi.org/10.1212/WNL.0000000000207291).

RT-QuIC (Real-Time Quaking-Induced Conversion)

RT-QuIC detects α-syn seeds by their ability to template the conversion of recombinant α-syn monomer into amyloid fibrils:

Performance characteristics:

• Sensitivity: 85-95% in manifest PD
• Specificity: >95% in healthy controls
• Sample types: CSF, blood, skin, olfactory mucosa
• Turnaround: 2-4 days

PMCA (Protein Misfolding Cyclic Amplification)

PMCA uses sonication cycles to amplify α-syn seeds in a manner analogous to PCR:

SAA vs. Traditional Biomarkers

| Method | Target | Sensitivity | Sample Type | Clinical Use |
|--------|--------|-------------|-------------|--------------|
| SAA | Pathological seeds | 85-95% | CSF, Blood | Diagnostic, Prodromal |
| Total α-syn | All α-syn | Variable | CSF, Blood | Research |
| pSer129 | Phosphorylated α-syn | ~90% | CSF, Blood | Pathological confirmation |
| Oligomers | Toxic oligomers | Moderate | CSF | Research |

Comparison: CSF vs. Blood Biomarkers

Cerebrospinal Fluid (CSF) Biomarkers

CSF provides direct access to the central nervous system and is the most validated sample type for α-syn detection:

Advantages:

• Direct reflection of CNS pathology
• Highest sensitivity for SAA
• Well-established collection protocols
• Rich in additional biomarkers (tau, amyloid)

• Invasive (lumbar puncture required)
• Variable collection protocols
• Lower throughput for screening

• Total α-syn: Reduced in PD vs. controls
• Phosphorylated α-syn (pSer129): Increased in PD
• Oligomeric α-syn: Elevated in PD
• Neurofilament light chain (NfL): Marker of neurodegeneration

Blood-Based Biomarkers

Blood-based testing offers significant advantages for population screening:

Advantages:

• Minimally invasive
• High-throughput screening feasible
• Lower cost than CSF
• Suitable for repeated sampling

• Peripheral α-syn may confound CNS signal
• Lower sensitivity than CSF in some assays
• Requires ultra-sensitive methods

• Blood-derived exosomes containing α-syn
• Plasma SAA with enhanced sensitivity
• Multiplexed protein panels
• Combined with genetic testing

NCT04724941's Screening Approach

The trial aims to leverage both CSF and blood-based SAA approaches to characterize the "risk marker profile" in prodromal individuals. This comprehensive approach will:

Clinical Significance of Prodromal Detection

Therapeutic Implications

Early detection through seed amplification enables several intervention strategies:

| Strategy | Approach | Timing |
|---------|----------|--------|
| Neuroprotection | Protect surviving neurons | Prodromal/Early |
| Disease modification | Halt seed propagation | Prodromal |
| Symptomatic | Dopaminergic therapy | Manifest |
| Preventive | Lifestyle modifications | At-risk |

Clinical Trial Enrichment

SAA-positive prodromal individuals represent ideal participants for disease-modifying therapy trials:

Advantages:

• Biologically confirmed pathology
• Likely to progress to manifest PD
• Earlier intervention window
• Smaller required sample sizes
• Clearer mechanism targeting

Cross-Links to Related Topics

Disease Pages

• [Parkinson's Disease](/diseases/parkinsons-disease) - Main disease page
• [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies) - Related α-synucleinopathy

Mechanism Pages

• [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-aggregation-pathway) - Aggregation mechanism
• [Alpha-Synuclein Propagation Models](/mechanisms/alpha-synuclein-propagation-models) - Spreading mechanisms
• [Lewy Body Formation Pathway](/mechanisms/lewy-body-formation-pathway) - Pathology formation

Gene/Protein Pages

• [SNCA Gene](/genes/snca) - Alpha-synuclein encoding gene
• [Alpha-Synuclein Protein](/proteins/alpha-synuclein) - Protein page

Biomarker Pages

• [Alpha-Synuclein Seed Kinetic Staging](/biomarkers/alpha-synuclein-seed-kinetics-pd) - SAA kinetics
• [CSF Biomarker Comparison](/biomarkers/csf-biomarker-comparison) - CSF markers

Cell Type Pages

• [Dopaminergic Neurons (SNpc)](/cell-types/dopaminergic-neurons-substantia-nigra) - Vulnerable neurons
• [Enteric Neurons](/cell-types/enteric-neurons) - Origin of pathology spread

Clinical Trials

• [Nouvneu001 PD Trial](/clinical-trials/nouvneu001-pd) - Other PD trial

See Also

• [SNCA gene](/genes/snca)
• [Lewy bodies](/mechanisms/lewy-body-formation-pathway)
• [Lewy neurites](/mechanisms/alpha-synuclein-aggregation-pathway)
• [Alpha-Synuclein Propagation Models](/mechanisms/alpha-synuclein-propagation-models)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies)
• [Alpha-Synuclein Aggregation Pathway](/mechanisms/alpha-synuclein-aggregation-pathway)
• [Lewy Body Formation Pathway](/mechanisms/lewy-body-formation-pathway)
• [SNCA Gene](/genes/snca)
• [Alpha-Synuclein Protein](/proteins/alpha-synuclein)

External Links

• [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
• [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)