Overview
NCT05826457 (North American Prodromal Synucleinopathy Consortium Stage 2) is a multi-site observational clinical study designed to identify and characterize individuals in the prodromal stage of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Led by Washington University School of Medicine with collaborators across major North American institutions, NAPOS Stage 2 focuses on individuals with idiopathic REM sleep behavior disorder (RBD) — the strongest known prodromal marker of synucleinopathy [1](https://clinicaltrials.gov/study/NCT05826457).
This mechanistic page integrates the consortium's approach with the underlying biology of prodromal synucleinopathy, RBD as a clinical marker, biomarker development strategies, and the implications for early intervention in neurodegenerative disease.
Clinical Trial Overview
| Attribute | Details |
|-----------|---------|
| Trial ID | NCT05826457 |
| Status | Recruiting |
| Enrollment | 500 participants (estimated) |
| Sponsor | Washington University School of Medicine |
| Collaborators | Mayo Clinic; University of Minnesota; UCLA; McGill University; Emory University; Massachusetts General Hospital; Stanford University; Oregon Health and Science University; NINDS; NIA; NIH |
| Start Date | August 12, 2022 |
| Completion | May 1, 2025 |
| Study Type | Observational |
| Primary Outcome | Prodromal Synucleinopathy Rating Scale |
Scientific Rationale
Why Focus on REM Sleep Behavior Disorder?
...Overview
NCT05826457 (North American Prodromal Synucleinopathy Consortium Stage 2) is a multi-site observational clinical study designed to identify and characterize individuals in the prodromal stage of synucleinopathies, including Parkinson's disease (PD), dementia with Lewy bodies (DLB), and multiple system atrophy (MSA). Led by Washington University School of Medicine with collaborators across major North American institutions, NAPOS Stage 2 focuses on individuals with idiopathic REM sleep behavior disorder (RBD) — the strongest known prodromal marker of synucleinopathy [1](https://clinicaltrials.gov/study/NCT05826457).
This mechanistic page integrates the consortium's approach with the underlying biology of prodromal synucleinopathy, RBD as a clinical marker, biomarker development strategies, and the implications for early intervention in neurodegenerative disease.
Clinical Trial Overview
| Attribute | Details |
|-----------|---------|
| Trial ID | NCT05826457 |
| Status | Recruiting |
| Enrollment | 500 participants (estimated) |
| Sponsor | Washington University School of Medicine |
| Collaborators | Mayo Clinic; University of Minnesota; UCLA; McGill University; Emory University; Massachusetts General Hospital; Stanford University; Oregon Health and Science University; NINDS; NIA; NIH |
| Start Date | August 12, 2022 |
| Completion | May 1, 2025 |
| Study Type | Observational |
| Primary Outcome | Prodromal Synucleinopathy Rating Scale |
Scientific Rationale
Why Focus on REM Sleep Behavior Disorder?
Idiopathic REM sleep behavior disorder (iRBD) represents the strongest known clinical marker of prodromal synucleinopathy. Individuals with polysomnogram-confirmed iRBD have an estimated 80-90% likelihood of developing a manifest synucleinopathy (PD, DLB, or MSA) within 10-15 years of RBD diagnosis [2](https://doi.org/10.1212/WNL.0000000000000457). This makes RBD an ideal enrichment strategy for studies aiming to detect and characterize pre-symptomatic disease.
The biological basis for this relationship lies in the spreading pattern of [alpha-synuclein](/proteins/alpha-synuclein) pathology. According to the Braak staging hypothesis, pathological alpha-synuclein first appears in the lower brainstem and olfactory nuclei, progressively ascending to the midbrain and eventually the neocortex [3](https://doi.org/10.1016/s0197-4580(02)00065-9). The brainstem nuclei controlling REM sleep atonia (particularly the sublaterodorsal nucleus and coeruleus/subcoeruleus complex) are affected early in this cascade, explaining why REM sleep disruption precedes motor symptoms by years or decades.
The NAPOS Consortium
NAPOS represents a coordinated North American effort to establish a trial-ready cohort of prodromal synucleinopathy individuals. The consortium builds on earlier prodromal studies (including the NAPS1 study) and aims to:
Characterize biomarker profiles in prodromal individuals using multiple modalities
Develop a trial-ready registry for future disease-modifying therapy trials
Standardize assessments across sites to enable collaborative research
Create a biorepository of samples for biomarker validationMermaid diagram (expand to render)
Study Design
Participant Groups
RBD Group:
- Polysomnogram-confirmed RBD by ICSD-3 criteria
- No current diagnosis of PD, dementia, or MSA (except previous NAPS1 participants)
- Capable of providing informed consent
- Age > 18 years
Control Group:
- Age, sex, and race-matched healthy individuals
- No history of dream enactment behavior
- Normal performance on cognitive and motor assessments
- Willing to undergo all testing procedures
Assessment Battery
The comprehensive assessment protocol includes:
Clinical Evaluation
- Motor examination (MDS-UPDRS)
- Cognitive testing (neuropsychological battery)
- Autonomic function testing
- Olfactory assessment (UPSIT)
- Color vision testing
Sleep Studies
- Polysomnography (overnight sleep study)
- RBD group: two overnight studies
- Video-EEG monitoring
Neuroimaging
- MRI brain
- DaTscan (dopamine transporter imaging)
Biofluid Collection
- Serum and plasma
- Buffy coat
- PAXgene (for RNA)
- Cerebrospinal fluid (optional)
Biomarker Approaches
Alpha-Synuclein Seed Amplification Assays
The consortium leverages cutting-edge seed amplification assay (SAA) technology to detect pathological alpha-synuclein in biofluids. RT-QuIC (Real-Time Quaking-Induced Conversion) and PMCA (Protein Misfolding Cyclic Amplification) can detect misfolded alpha-synuclein seeds at concentrations as low as 10⁻¹⁵ to 10⁻¹⁶ M [4](https://doi.org/10.1212/WNL.0000000000207291).
In the prodromal setting, SAA positivity can identify individuals who have begun accumulating pathological alpha-synuclein but have not yet developed clinical symptoms. Studies have shown that approximately 50-60% of individuals with idiopathic RBD are SAA-positive in CSF, correlating with higher risk of progression to manifest disease [5](https://doi.org/10.1093/brain/awad018).
The Prodromal Synucleinopathy Rating Scale
The primary outcome measure — the Prodromal Synucleinopathy Rating Scale — combines multiple domains into a global score (0-3):
- Neurocognitive battery
- Motor function assessment
- Autonomic function
- Olfactory testing
- Color vision testing
A higher score indicates greater symptoms of synucleinopathy, enabling risk stratification within the prodromal cohort.
Neuroimaging Biomarkers
MRI:
- Assess for regional brain atrophy
- Evaluate neural network connectivity
- Detect incidental findings
DaTscan (SPECT):
- Measure dopamine transporter binding in the striatum
- Can detect subclinical dopaminergic deficits in prodromal individuals
Clinical Significance
Early Detection Enables Prevention
The identification of individuals in the prodromal phase of synucleinopathies opens several therapeutic windows:
| Stage | Key Features | Therapeutic Opportunity |
|-------|-------------|------------------------|
| Preclinical | SAA-positive, no symptoms | Primary prevention |
| Prodromal | Non-motor symptoms (RBD, hyposmia) | Disease modification |
| Early Manifest | Mild motor symptoms | Neuroprotection |
| Established | Moderate-severe PD | Symptomatic treatment |
Trial-Ready Cohort Development
NAPOS addresses a critical bottleneck in neurodegenerative disease clinical trials: the lack of biologically characterized, trial-ready participants. By establishing a registry of:
- Phenotypically characterized prodromal individuals
- With validated biomarker data
- Who have expressed willingness to participate in trials
The consortium enables faster enrollment for disease-modifying therapy studies, reducing the time and cost required to test new interventions.
Data Sharing and Collaboration
NAPOS is committed to open science, with de-identified subject-level data to be shared upon approved request through multiple NIH repositories:
- National Alzheimer's Coordinating Center (NACC)
- National Cell Repository for [Alzheimer's Disease](/diseases/alzheimers-disease) (NCRAD)
- NIAGADS
- Laboratory of NeuroImaging (LONI)
- National Sleep Research Resource (NSRR)
This data sharing approach maximizes the scientific value of the consortium's efforts and enables secondary analyses by the broader research community.
Disease Pages
- [Parkinson's Disease](/diseases/parkinsons-disease) — Main disease page
- [Dementia with Lewy Bodies](/diseases/dementia-with-lewy-bodies) — Related alpha-synucleinopathy
- [Multiple System Atrophy](/diseases/multiple-system-atrophy) — Related alpha-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
- [Gut-First Brain-First Alpha-Synuclein Propagation](/mechanisms/gut-first-brain-first-alpha-synuclein-propagation) — Propagation hypothesis
- [Prion-Like Spreading](/mechanisms/prion-like-spreading) — Template-directed misfolding
Biomarker Pages
- [Alpha-Synuclein Seed Kinetics PD](/biomarkers/alpha-synuclein-seed-kinetics-pd) — SAA kinetic staging
- [NCT04724941: Prodromal Alpha-Synuclein Screening](/mechanisms/nct04724941-prodromal-alpha-synuclein-screening) — Related German study
- [Blood-Based Biomarkers](/biomarkers/blood-based-biomarkers) — Blood biomarker approaches
Sleep and Prodromal Markers
- [Sleep Disorders and Neurodegeneration](/diseases/sleep-disorders-neurodegeneration) — Sleep as biomarker
- [REM Sleep Behavior Disorder Mechanism](/mechanisms/rem-sleep-behavior-disorder) — RBD biology
Clinical Trial Pages
- [NCT04724941 Prodromal Alpha-Synuclein Screening](/mechanisms/nct04724941-prodromal-alpha-synuclein-screening) — Related prodromal study
Institution Pages
- [Washington University School of Medicine](/institutions/washington-university) — Lead institution
- [Mayo Clinic](/institutions/mayo-clinic) — Collaborating institution
See Also
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
Unknown, NCT05826457: North American Prodromal Synucleinopathy Consortium Stage 2 (n.d.)
[Iranzo et al., Long-term duration of REM sleep behavior disorder (2013) (2013)](https://doi.org/10.1212/WNL.0000000000000457)
[Braak et al., Staging of brain pathology related to sporadic Parkinson's disease (2003) (2003)](https://doi.org/10.1016/s0197-4580(02)
[Baldwin et al., Real-time quaking-induced conversion in Parkinson's disease (2023) (2023)](https://doi.org/10.1212/WNL.0000000000207291)
[Shahnawaz et al., Discriminating alpha-synuclein strains in PD and MSA (2023) (2023)](https://doi.org/10.1093/brain/awad018)
[Postuma et al., Prodromal Parkinson disease subtypes (2019) (2019)](https://doi.org/10.1212/WNL.0000000000007919)
[Schenk et al., Sleep as a biomarker for neurodegenerative disease (2024) (2024)](https://doi.org/10.1016/j.neurobiolaging.2024.02.001)