This observational study investigates synaptic dysfunction in Multiple System Atrophy (MSA) and related alpha-synucleinopathies, including Progressive Supranuclear Palsy (PSP) and Parkinson's Disease (PD), using novel biomarkers and advanced neuroimaging techniques. The study addresses a critical need in neurodegenerative disease research: the development of reliable biomarkers that can detect synaptic loss in vivo, which is increasingly recognized as a key pathological feature underlying clinical deficits in these disorders 1.
- NCT Number: NCT05121012
- Status: Recruiting
- Study Type: Observational
- Conditions: Multiple System Atrophy (MSA), Progressive Supranuclear Palsy (PSP), Parkinson's Disease (PD)
- Sponsor: Major academic medical center with neurodegenerative disease research program
- Enrollment: Target 300 participants
¶ Background and Rationale
¶ Understanding Synaptic Dysfunction
Synaptic loss is now recognized as one of the earliest and most prominent features of neurodegenerative diseases, occurring well before neuronal cell death and clinical symptom onset 2. The synapse, where neuronal communication occurs, is particularly vulnerable to pathological insults in several ways:
Early Vulnerability: Synapses require constant maintenance and energy supply, making them susceptible to:
- Mitochondrial dysfunction
- Oxidative stress
- Impaired axonal transport
- Abnormal protein aggregation
Pathology Spread: Many neurodegenerative diseases feature prion-like propagation of pathological proteins across synaptic connections, leading to:
- Template-directed misfolding
- Trans-synaptic spread of pathology
- Network-level dysfunction
Clinical Correlation: Synaptic loss directly correlates with:
- Cognitive decline
- Motor dysfunction
- Disease progression rate
Multiple System Atrophy: MSA is characterized by glial cytoplasmic inclusions (GCIs) containing aggregated alpha-synuclein. Pathological studies reveal:
- Marked reduction in synaptic density in affected brain regions
- Loss of specific synaptic proteins (synaptophysin, SV2, PSD-95)
- Correlation between synaptic loss and disease severity
- More severe synaptic loss than in PD, correlating with poorer prognosis
Parkinson's Disease: Lewy bodies (neuronal inclusions) and Lewy neurites contain alpha-synuclein, leading to:
- Reduced synaptic markers in substantia nigra
- Cortical synaptic dysfunction even in early stages
- Relationship to cognitive impairment
Progressive Supranuclear Palsy: Although primarily a tauopathy, PSP shows:
- Synaptic dysfunction secondary to tau pathology
- Loss of excitatory synapses in affected circuits
- Correlation with motor and cognitive deficits
Current clinical measures have limitations:
- Clinical rating scales: Subjective, variable, insensitive to early changes
- Neuroimaging: Volume loss is a late marker
- Existing fluid biomarkers: NfL and tau reflect general neurodegeneration, not synaptic-specific changes
Synaptic biomarkers offer advantages:
- Direct measure of the functional substrate of symptoms
- Earlier detection than volume measures
- Potential for disease-specific patterns
- Surrogate endpoints for clinical trials
-
Characterize CSF Synaptic Biomarkers: Measure levels of novel synaptic proteins in cerebrospinal fluid including:
- Neurogranin (postsynaptic marker)
- Synaptic vesicle protein 2A (SV2A) ligands
- Beta-synuclein
- Alpha-synuclein oligomers
-
Quantify Synaptic Density with PET: Use SV2A PET imaging to measure synaptic density in vivo:
- [11C]UCB-J or [18F]UCB-J binding as proxy for synaptic density
- Compare regional patterns across MSA, PSP, and PD
- Correlate with clinical measures
-
Clinical Correlation: Establish relationships between synaptic biomarkers and:
- Disease severity (UMSARS, MDS-UPDRS, PSP Rating Scale)
- Disease duration and progression rate
- Specific symptom domains
- Cognitive function
-
Disease Staging: Assess how synaptic biomarkers vary across disease stages:
- Newly diagnosed vs. advanced disease
- Early vs. late phenotypic variants
- Rate of change over time
- Compare diagnostic accuracy of synaptic vs. general neurodegeneration biomarkers
- Develop composite scores integrating multiple biomarkers
- Establish reference values for clinical use
- Validate biomarkers against postmortem brain tissue
¶ Assessments and Biomarkers
Neurogranin:
- 78-amino acid postsynaptic protein enriched in dendritic spines
- Released during synaptic activity and synaptic loss
- Elevated in CSF correlates with synaptic dysfunction in AD and other dementias
- Measured via immunoassay (Mesoscale Discovery or SIMOA platforms)
- Specific for postsynaptic terminals
Synaptic Vesicle Protein 2A (SV2A):
- Integral membrane protein of synaptic vesicles
- Target for [11C]UCB-J and [18F]UCB-J PET tracers
- Levels in CSF may reflect synaptic turnover
- Novel assay under development
Beta-Synuclein:
- Normal synaptic protein that co-aggregates with alpha-synuclein
- Ratio of alpha- to beta-synuclein may indicate pathological burden
- Fragmentation patterns may distinguish disease subtypes
Alpha-Synuclein Oligomers:
- Toxic species thought to drive neurodegeneration
- Seeded aggregation assays (RT-QuIC, PMCA) detect pathological forms
- May appear before clinical symptoms
Total Tau and Phosphorylated Tau:
- General neurodegeneration markers for comparison
- p-tau181: differentiates AD from synucleinopathies
- Establish context for synaptic biomarkers
Neurofilament Light Chain (NfL):
- Marker of axonal degeneration
- Elevated in MSA, PSP, and PD
- Useful for disease progression monitoring
SV2A PET Tracers:
- [11C]UCB-J: First-generation, requires on-site cyclotron
- [18F]UCB-J: Second-generation, longer half-life enables broader use
- Binding correlates with synaptic density in postmortem validation
Imaging Protocol:
- 60-minute dynamic acquisition
- SUVr calculation using cerebellar cortex as reference region
- Regional analysis: caudate, putamen, thalamus, cortex, hippocampus
- Comparison with structural MRI for atrophy correction
Additional PET Ligands:
- [18F]FDG: Metabolic connectivity patterns
- [11C]PiB or [18F]florbetapir: Amyloid burden (exclude AD)
- Tau PET if clinically indicated
For MSA:
- Unified Multiple System Atrophy Rating Scale (UMSARS)
- Part I: Motor and autonomic symptoms (activities of daily living)
- Part II: Motor examination
- Part III: Orthostatic hypotension measurement
- Part IV: Composite scores
- Montreal Cognitive Assessment (MoCA)
- Semantic fluency and Stroop tests
For PSP:
- PSP Rating Scale (overall and subdomain scores)
- MDS-UPDRS Part III
- Frontal Assessment Battery
For PD:
- MDS-UPDRS Parts I-IV
- Hoehn and Yahr staging
- Montreal Cognitive Assessment
- Olfactory identification test
For All Participants:
- Medical history and neurological examination
- Vital signs including orthostatic measurements
- Pittsburgh Sleep Quality Index
- Beck Depression Inventory
- More severe SV2A reduction than PD in striatum
- Higher CSF neurogranin levels correlating with autonomic failure
- Distinct pattern of cortical vs. subcortical involvement
- Faster rate of synaptic marker decline
- Moderate reduction in cortical SV2A
- Prominent subcortical synaptic loss (brainstem, basal ganglia)
- Different neurogranin pattern than MSA
- Correlation with frontal lobe dysfunction
- Mild cortical synaptic loss, especially in early disease
- Prominent nigrostriatal synaptic dysfunction
- Neurogranin elevation predicts cognitive decline
- SV2A changes correlate with motor severity
- Clinical diagnosis of:
- MSA (parkinsonian or cerebellar variant)
- PSP (Richardson's syndrome or variants)
- Parkinson's Disease (classic or PD with dementia)
- Age 40-80 years
- Able to undergo lumbar puncture
- Able to undergo PET imaging
- Has reliable informant or caregiver for clinical correlation
- Informed consent obtained
- Significant medical comorbidities affecting survival
- Contraindication to MRI (pacemaker, metal implants)
- Active psychiatric illness requiring hospitalization
- History of stroke or traumatic brain injury with residual deficits
- Current enrollment in interventional clinical trial
- Inability to cooperate with study procedures
¶ Significance and Implications
Synaptic biomarkers could enable:
- Earlier Diagnosis: Synaptic changes may precede clinical diagnosis by years
- Differential Diagnosis: Distinct patterns may help distinguish:
- MSA from PD (more severe loss in MSA)
- PSP from other parkinsonisms (different regional pattern)
- Disease subtypes within each category
- Pathological Confirmation: Biomarkers may reflect specific protein pathology
Synaptic biomarkers offer unique monitoring capabilities:
- Progression Tracking: Objective measure of disease advancement
- Therapeutic Response: Could detect treatment effects on synaptic function
- Clinical Trial Endpoints: Surrogate markers for efficacy
These biomarkers are critical for:
- Patient Selection: Enrich trials with patients showing specific biomarker patterns
- Target Engagement: Demonstrate that treatments hit their intended synaptic targets
- Dose Selection: Optimal dosing based on biomarker response
- Mechanistic Proof: Confirm biological mechanism of action
SV2A PET Validation: Studies published in 2024-2025 have validated SV2A PET against postmortem synaptic density, confirming it as a reliable in vivo proxy 3.
Neurogranin in Synucleinopathies: Multi-center studies demonstrate elevated CSF neurogranin in MSA and PD, with higher levels predicting faster progression and cognitive decline 4.
Combination Biomarker Panels: Integration of synaptic markers with other fluid biomarkers improves diagnostic accuracy, achieving AUC >0.90 for differential diagnosis 5.
Longitudinal Changes: Recent longitudinal studies show progressive decline in synaptic biomarkers over 1-2 years, establishing the rate of change useful for clinical trials 6.
Ultrasensitive Assays: Single-molecule array (SIMOA) technology enables detection of synaptic proteins at sub-picogram levels, improving precision
Automated Analysis: Machine learning pipelines for PET image analysis reduce operator dependence and improve reproducibility
Multi-Analyte Platforms: New panels can measure multiple synaptic proteins from single CSF sample
This study contributes to:
- International MSA Research Consortium: Multi-center biomarker standardization
- Parkinson's Progression Markers Initiative (PPMI): Longitudinal PD biomarker study
- Progressive Supranuclear Palsy Genetics Consortium: GENetics of PSP
- Alzheimer's Disease Neuroimaging Initiative (ADNI) adapted for synucleinopathies