ClinicalTrials.gov Identifier: NCT03174938
The Swedish BioFINDER 2 Study (NCT03174938) is a large-scale, longitudinal observational study investigating biomarkers for neurodegenerative diseases, including progressive supranuclear palsy (PSP). Led by Dr. Oskar Hansson at Lund University, BioFINDER 2 represents one of the most comprehensive biomarker research programs for atypical parkinsonian syndromes in Europe.
BioFINDER 2 builds upon the foundation established by the original BioFINDER study (2009-2017), which validated CSF biomarkers for Alzheimer's disease diagnosis. With expanded enrollment and novel biomarker platforms, BioFINDER 2 focuses onearlier detection, differential diagnosis, and disease progression monitoring in neurodegenerative disorders.
| Parameter |
Details |
| NCT Number |
NCT03174938 |
| Phase |
Observational |
| Status |
Recruiting |
| Sponsor |
Lund University (Sweden) |
| Study Type |
Longitudinal cohort |
| Enrollment |
1,000+ participants planned |
| Start Date |
2017 |
| Primary Outcome |
Biomarker validation |
| Follow-up Duration |
Up to 10 years |
| Attribute |
Value |
| NCT Number |
NCT03174938 |
| Phase |
Observational |
| Status |
Recruiting |
| Sponsor |
Lund University (Sweden) |
| Study Type |
Observational |
| Enrollment |
1,000+ participants planned |
| Start Date |
2017 |
| Primary Outcome |
Biomarker validation |
BioFINDER 2 enrolls participants across multiple diagnostic categories:
| Group |
Description |
Estimated N |
| Cognitively healthy controls |
No cognitive complaints, normal exams |
300 |
| Mild Cognitive Impairment (MCI) |
Subjective complaints, objective impairment |
200 |
| Alzheimer's Disease |
Dementia due to AD |
200 |
| Parkinson's Disease |
Classic PD |
100 |
| Progressive Supranuclear Palsy |
Richardson syndrome + variants |
100 |
| Corticobasal Syndrome |
CBS |
50 |
| Frontotemporal Dementia |
Behavioral variant + language variants |
50 |
| Multiple System Atrophy |
MSA |
50 |
| 血管性痴呆 |
Vascular dementia |
50 |
BioFINDER 2 specifically characterizes PSP clinical variants:
- Richardson's syndrome (PSP-RS): Classic ocular gaze palsy, postural instability, akinesia
- PSP-parkinsonism (PSP-P): Asymmetric onset, tremor, partial levodopa response
- PSP-pure akinesia with gait freezing (PSP-PAGF): Gait freezing, no ocular gaze palsy
- PSP-corticobasal syndrome (PSP-CBS): Apraxia, alien limb phenomena
- Progressive aphasia variants: Language dominant presentation
BioFINDER 2 employs state-of-the-art fluid biomarker assays:
| Biomarker |
Platform |
Clinical Utility |
| Total tau (t-tau) |
Simoa |
Neurodegeneration marker |
| p-tau181 |
Simoa |
AD diagnosis, ATN framework |
| p-tau217 |
Simoa, Lumipulse |
Highly specific for AD |
| p-tau231 |
Lumipulse |
Earlier detection |
| p-tau205 |
Experimental |
Research use only |
- Neurofilament light chain (NfL): General marker of axonal injury
- Neurofilament heavy chain (NfH): Complementary to NfL
- Tau oligomers: Research biomarker for toxic species
- YKL-40: Microglial activation, neuroinflammation
- sTREM2: Microglial activation, disease progression
Seed amplification assays (SAA) enable differential diagnosis:
- α-syn RT-QuIC: Detection of aggregated α-syn in CSF
- α-syn PMCA: Protein misfolding cyclic amplification
- Discrimination: Differentiates PD, MSA, DLB
| Sequence |
Clinical Utility |
| 3D T1 MPRAGE |
Volumetric analysis, cortical thickness |
| T2 FLAIR |
White matter hyperintensities |
| Susceptibility-weighted (SWI) |
Iron deposition, microbleeds |
| Diffusion tensor imaging (DTI) |
White matter integrity, tractography |
| Resting-state fMRI |
Functional connectivity |
| Arterial spin labeling (ASL) |
Cerebral blood flow |
| Target |
Tracer |
Clinical Application |
| Amyloid |
11C-PiB, 18F-flutemetamol |
AD diagnosis |
| Tau |
18F-Flortaucipir, 18F-RO948 |
Tau PET, differential diagnosis |
| Dopamine transporter |
123I-FP-CIT SPECT |
Parkinsonian differentiation |
| Monoamine oxidase B |
11C-L-deprenyl |
Microglial activation |
- PSP Rating Scale (PSPRS): Disease-specific severity (0-100)
- MDS-UPDRS: Unified Parkinson's Disease Rating Scale
- PSPRS: Progressive Supranuclear Palsy Rating Scale
- BIRD: Barcelona Instrument for Dementia in PSP
- Montreal Cognitive Assessment (MoCA): Global cognition screening
- MMSE: Folstein Mini-Mental State Examination
- FAB: Frontal Assessment Battery
- Trail Making Test: Executive function
- Stroop Test: Inhibition, cognitive flexibility
- BDI-II: Depression
- BAI: Anxiety
- Apathy Evaluation Scale: Apathy
- NPI: Neuropsychiatric inventory
BioFINDER 2 aims to:
- Validate CSF and plasma biomarkers for differential diagnosis of neurodegenerative diseases
- Characterize disease progression using fluid and imaging biomarkers
- Identify prognostic markers that predict clinical decline
- Support clinical trial enrichment by identifying biomarker-defined subgroups
- Establish reference ranges for biomarker cutoffs in clinical practice
Within BioFINDER 2, PSP patients undergo comprehensive assessments:
- Tau species: Total tau, phosphorylated tau (p-tau181, p-tau217, p-tau231)
- Neurofilament light chain (NfL): Marker of neuronal injury
- α-Synuclein: Seed amplification assays (SAA) for differential diagnosis
- Neuroinflammatory markers: YKL-40, GFAP
- MRI: Volumetric analysis, diffusion tensor imaging (DTI), susceptibility-weighted imaging
- PET: Tau PET (18F-flortaucipir, 18F-RO948), amyloid PET, monoamine PET
- DAT SPECT: Dopamine transporter imaging for parkinsonian differentiation
- PSP Rating Scale (PSPRS): Disease-specific severity measure
- Montreal Cognitive Assessment (MoCA): Global cognition
- MDS-UPDRS: Motor and non-motor symptoms
- Frontal Assessment Battery (FAB): Executive function
BioFINDER 2 has produced numerous landmark publications on PSP:
- Tau PET utility: Demonstrated that 18F-flortaucipir distinguishes PSP from PD and MSA with high specificity
- NfL as progression marker: Showed that plasma NfL correlates with disease severity and predicts decline in PSP
- p-tau217: Identified phosphorylated tau at threonine 217 as a sensitive marker for 4R-tauopathies
- Subtype stratification: Characterized biomarker profiles across PSP clinical variants (Richardson syndrome, PSP-P, PSP-PAGF, etc.)
- Biomarker trajectories: Established timeline of biomarker changes relative to clinical symptoms
- Diagnostic algorithms: Developed decision trees for differential diagnosis of parkinsonian syndromes
| Biomarker |
AUC for PSP vs. PD |
Utility |
| CSF p-tau181 |
0.82 |
Supports 4R-tauopathy |
| CSF p-tau217 |
0.88 |
High specificity |
| Plasma NfL |
0.91 |
Disease severity |
| Tau PET (putamen) |
0.85 |
Differential diagnosis |
BioFINDER 2 has developed integrated diagnostic algorithms:
- Step 1: Clinical examination and cognitive testing
- Step 2: Fluid biomarker panel (p-tau217, NfL, α-syn SAA)
- Step 3: Imaging biomarker confirmation (MRI, PET)
- Step 4: Integration for diagnosis
The biomarker panel developed in BioFINDER 2 has demonstrated:
- Earlier diagnosis: Median 2-3 years earlier than clinical diagnosis
- Differential diagnosis: 85-90% accuracy for atypical parkinsonism
- Prognostic information: NfL predicts progression rate
- Trial enrichment: Biomarker-defined cohorts improve trial power
The BioFINDER research infrastructure includes:
- Clinical sites: 10+ centers across Sweden
- Central laboratory: Lund University biomarker core
- Imaging core: Lund-PET center
- Data management: Centralized database with longitudinal follow-up
- Biobank: CSF, plasma, DNA repository
BioFINDER 2 maintains active collaborations:
- Alzheimer's Disease Neuroimaging Initiative (ADNI)
- International Parkinson's Disease Progression Marker Initiative (IPP-DI)
- Tau PET Open Analytics (TauRO)
- European Medicines Agency (EMA): Regulatory input for biomarker qualification
BioFINDER 2 serves as a critical resource for therapeutic development:
- Patient stratification: Identifies biomarker-positive candidates for clinical trials
- Endpoint validation: Correlates fluid biomarkers with clinical progression measures
- Natural history: Provides baseline progression data for power calculations
- Target engagement: Supports biomarker development for proof-of-concept studies
- Tau PET Tracers in PSP
- Molecular Anatomic Tau Imaging Study
- Anti-tau Immunotherapy Programs
The Swedish BioFINDER program involves multiple sites across Sweden:
- Primary: Lund University Hospital
- Additional: Malmö, Gothenburg, Stockholm, Uppsala
BioFINDER 2 provides unique insights into PSP:
- Biomarker characterization: First large-scale characterization of PSP biomarkers
- Subtype heterogeneity: Biomarker differences between clinical variants
- Progression modeling: NfL and p-tau track disease progression
- Clinical trial readiness: Biomarker-qualified endpoints for therapeutic trials
The biomarker framework translates to AD:
- ATN classification: Integrated biomarker approach
- Preclinical detection: Biomarker changes precede clinical symptoms
- Therapeutic monitoring: Target engagement readouts
- Combination biomarkers: Multi-marker panels improve specificity
BioFINDER 2 supports differential diagnosis:
- α-synuclein SAA: Detection of aggregate species
- NfL elevation: Indicates faster progression
- Imaging correlates: Structural and functional changes
Findings from BioFINDER 2 have influenced clinical practice:
- Clinical chemistry adoption: p-tau217 now available on Lumipulse platform
- Diagnostic algorithms: Updated guidelines for parkinsonian disorders
- Clinical trial design: Biomarker-based enrichment strategies
- Clinical guidelines: incorporation into diagnostic criteria
Biomarker-based diagnosis impacts healthcare:
- Earlier intervention: More effective treatment window
- Reduced diagnostic odyssey: 2-3 year缩短 in time to diagnosis
- Trial efficiency: Enriched cohorts reduce sample sizes and costs
- Personalized medicine: Biomarker-guided treatment selection
BioFINDER 2 continues to evolve:
- Digital biomarkers: Smartphone-based motor assessment
- Genetic stratification: Polygenic risk scores
- Multi-omic integration: Transcriptomics and proteomics
- International expansion: Multi-site replication studies
Next-generation biomarker platforms:
- Blood-based tau: Ultrasensitive Simoa assays
- Native conformation assays: Oligomer-specific detection
- AI-assisted imaging: Automated MRI analysis
- Wearable integration: Continuous monitoring biomarkers
The Swedish BioFINDER program involves multiple sites across Sweden: