MARKERS-NDD is an observational cohort study focused on identifying and validating progression biomarkers in neurodegenerative diseases, including Progressive Supranuclear Palsy (PSP), Corticobasal Syndrome (CBS), Multiple System Atrophy (MSA), and Parkinson's Disease (PD). This multi-center, international initiative addresses one of the most critical gaps in neurodegenerative disease research: the lack of validated biomarkers that can reliably track disease progression and serve as surrogate endpoints in clinical trials[1].
The study represents a paradigm shift in how we approach biomarker discovery for atypical parkinsonism and tauopathies. Rather than focusing solely on diagnostic biomarkers, MARKERS-NDD prioritizes longitudinal progression markers that can quantify the rate of neurodegeneration, predict clinical decline, and potentially serve as endpoints for disease-modifying therapy trials.
| Field | Value |
|---|---|
| NCT Number | NCT06596746 |
| Status | Recruiting |
| Study Type | Observational, Prospective Cohort |
| Conditions | PSP, CBS, MSA, PD |
| Sponsor | International Consortium of Academic Medical Centers |
| Enrollment | Target: 500+ participants |
| Follow-up Duration | Minimum 2 years, optional extension to 5 years |
| Sites | Multiple international academic centers |
The study employs a standardized, longitudinal design with comprehensive baseline characterization and standardized follow-up assessments at 6-month intervals.
The lack of validated progression biomarkers represents a major obstacle to developing disease-modifying therapies for neurodegenerative diseases. Unlike oncology, where tumor size or survival can serve as objective endpoints, neurodegenerative disease progression is measured through clinical rating scales that are inherently subjective, show high variability, and may not capture the full spectrum of disease pathology.
Several factors highlight the urgent need for progression biomarkers:
Clinical Trial Efficiency: Validated biomarkers can reduce trial duration and sample sizes by providing sensitive measures of disease progression[2].
Patient Stratification: Biomarkers can identify subgroups with more homogeneous disease course, enabling targeted therapies.
Mechanistic Insights: Changes in biomarker levels can reveal information about underlying disease mechanisms.
Regulatory Acceptance: The FDA and EMA have expressed willingness to consider biomarker-based endpoints for accelerated approval.
PSP and CBS are primary 4R-tauopathies characterized by the intracellular accumulation of hyperphosphorylated tau protein in neurons and glia[3]. The disease course involves:
The rate of progression varies substantially between patients and between clinical subtypes. Richardson's syndrome (PSP-RS) typically progresses more rapidly than PSP-parkinsonism (PSP-P)[4].
The MARKERS-NDD study evaluates biomarkers across multiple modalities:
Cerebrospinal fluid (CSF) and blood biomarkers provide direct insights into CNS pathology:
| Biomarker | Target | Clinical Relevance |
|---|---|---|
| NfL | Neurofilament light chain | Axonal degeneration, progression rate[5] |
| p-tau181/217 | Phosphorylated tau | Tau pathology burden |
| t-tau | Total tau | Neuronal injury |
| Alpha-synuclein | Aggregated alpha-synuclein | Synucleinopathy burden |
| GFAP | Glial fibrillary acidic protein | Astrocyte activation |
| YKL-40 | Chitinase-3-like protein | Neuroinflammation |
| UCH-L1 | Ubiquitin C-terminal hydrolase | Neuronal injury |
Advanced neuroimaging provides in vivo measures of neurodegeneration:
Wearable sensor-based assessments provide objective, continuous measures:
Identify progression biomarkers: Discover fluid, imaging, or digital biomarkers that correlate with clinical progression over 2 years
Characterize natural history: Establish comprehensive natural history data for PSP, CBS, MSA, and PD subtypes
Validate biomarker platforms: Validate existing biomarker platforms across different populations and clinical sites
Develop composite endpoints: Create combination biomarker-clinical endpoints for clinical trials
Subtype stratification: Identify biomarkers that distinguish between clinical subtypes and predict progression rates
Cross-disorder comparisons: Compare biomarker trajectories across different neurodegenerative disorders
Technical optimization: Optimize biomarker measurement protocols for clinical trial readiness
The study employs a prospective cohort design with the following features:
Comprehensive baseline evaluation: Full clinical, neuropsychological, imaging, and fluid biomarker assessment at enrollment
Standardized follow-up: 6-month visits for 2 years with optional extension to 5 years
Multi-modal biomarker collection: CSF and blood collection, MRI, and digital assessments at each visit
Central quality control: Central reading for all neuroimaging, standardized protocols across sites
Data harmonization: Common data elements across all sites to enable pooled analyses
Given the rarity of PSP and CBS, the study requires multi-center collaboration to achieve adequate statistical power. The target enrollment of 500+ participants across all conditions ensures:
Clinical progression rate: Change in disease-specific rating scale (PSPRS, CBDRS) over 12 months
Brain atrophy rate: Annualized change in regional brain volumes on MRI
Fluid biomarker change: Longitudinal change in CSF NfL levels
The study captures the spectrum of PSP phenotypes[7]:
Corticobasal syndrome presents with heterogeneous features:
Multiple system atrophy has two main variants[5:1]:
The MARKERS-NDD study addresses critical barriers to clinical trial success:
Sample size reduction: Sensitive biomarker endpoints can reduce required sample sizes by 30-50%
Trial duration: Biomarker endpoints may enable shorter trials by detecting effects earlier
Stratification: Biomarker-based patient selection may enrich for rapid progressors
Mechanistic proof: Biomarker changes can provide evidence of target engagement
Several disease-modifying therapies are in development for PSP[8]:
| Approach | Examples | Development Stage |
|---|---|---|
| Tau aggregation inhibitors | Tolfenamic acid, Lithium | Phase 2 |
| Anti-tau immunotherapies | ABBV-8E12, UCB0107 | Phase 1-2 |
| Anti-tau ASOs | BIIB080, IONIS-MAPTRx | Phase 1-2 |
| Neuroprotective agents | CoQ10, TPN-101 | Phase 2 |
The MARKERS-NDD study will help identify which patients are most likely to benefit from these emerging treatments through biomarker stratification.
Regulatory agencies have expressed increasing flexibility regarding biomarker-based endpoints:
The MARKERS-NDD study complements other biomarker initiatives:
This study is specifically linked to:
The optional 5-year extension will enable:
Future analyses will integrate:
Advanced computational approaches will:
Beyer MK, et al. White matter hyperintensities, cerebrospinal fluid phosphorylated tau, and cognition in Parkinson disease. Dementia and Geriatric Cognitive Disorders. 2011. ↩︎
Höglinger GU, et al. Clinical diagnosis of progressive supranuclear palsy: The MDSPSP criteria. Movement Disorders. 2017. ↩︎ ↩︎
Williams DR, et al. Characteristics of two distinct clinical phenotypes in progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism. Brain. 2005. ↩︎
Krismer F, et al. Natural history of multiple system atrophy: A prospective cohort study. Neurology. 2018. ↩︎ ↩︎
Armstrong MJ, et al. Criteria for the diagnosis of corticobasal degeneration. Neurology. 2013. ↩︎
Respondek G, et al. The phenotypic spectrum of progressive supranuclear palsy: A retrospective study of 103 cases. Brain. 2013. ↩︎
Litvan I, et al. Planning and designing clinical trials for progressive supranuclear palsy. Journal of Molecular Neuroscience. 2011. ↩︎