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.
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.
| 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 |
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. 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 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. 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.
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:
RBD Group:
Control Group:
The comprehensive assessment protocol includes:
Clinical Evaluation
Sleep Studies
Neuroimaging
Biofluid Collection
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.
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.
The primary outcome measure — the Prodromal Synucleinopathy Rating Scale — combines multiple domains into a global score (0-3):
A higher score indicates greater symptoms of synucleinopathy, enabling risk stratification within the prodromal cohort.
MRI:
DaTscan (SPECT):
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 |
NAPOS addresses a critical bottleneck in neurodegenerative disease clinical trials: the lack of biologically characterized, trial-ready participants. By establishing a registry of:
The consortium enables faster enrollment for disease-modifying therapy studies, reducing the time and cost required to test new interventions.
NAPOS is committed to open science, with de-identified subject-level data to be shared upon approved request through multiple NIH repositories:
This data sharing approach maximizes the scientific value of the consortium's efforts and enables secondary analyses by the broader research community.