ClinicalTrials.gov Identifier: [NCT03174938](https://clinicaltrials.gov/study/NCT03174938)
Overview
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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.
...ClinicalTrials.gov Identifier: [NCT03174938](https://clinicaltrials.gov/study/NCT03174938)
Overview
Mermaid diagram (expand to render)
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.
Study Characteristics
| 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 |
Trial Details
| 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 |
Study Population
Diagnostic Groups
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 |
PSP Subtypes Enrolled
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
Biomarker Methodologies
BioFINDER 2 employs state-of-the-art fluid biomarker assays:
Tau Species
| 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 |
Neurodegeneration Markers
- 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
Alpha-Synuclein Assays
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
Imaging Biomarker Protocols
MRI Sequences
| 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 |
PET Tracers
| 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 |
Clinical Assessment Battery
Motor Assessments
- 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
Cognitive Assessments
- 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
neuropsychiatric Assessments
- BDI-II: Depression
- BAI: Anxiety
- Apathy Evaluation Scale: Apathy
- NPI: Neuropsychiatric inventory
Study Objectives
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 practicePSP-Specific Assessments
Within BioFINDER 2, PSP patients undergo comprehensive assessments:
Fluid Biomarkers
- 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
Imaging Biomarkers
- 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
Clinical Assessments
- 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
Key Findings Contributing to PSP Research
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 |
Clinical Implementation
Diagnostic Algorithm Development
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 diagnosisClinical Utility Studies
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
Research Infrastructure
BioFINDER Network
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
Collaborations
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
Connection to Therapeutic Trials
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
Connected Trials
- Tau PET Tracers in PSP
- Molecular Anatomic Tau Imaging Study
- Anti-tau Immunotherapy Programs
Participating Centers
The Swedish BioFINDER program involves multiple sites across Sweden:
- Primary: Lund University Hospital
- Additional: Malmö, Gothenburg, Stockholm, Uppsala
Disease-Specific Impact
Progressive Supranuclear Palsy
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
Alzheimer's Disease
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
Impact on Clinical Practice
Biomarker Translation
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 criteriaHealthcare Economics
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
Future Directions
Ongoing Extensions
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
Technology Development
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
Participating Centers
The Swedish BioFINDER program involves multiple sites across Sweden:
- Primary: Lund University Hospital
- Additional: Malmö, Gothenburg, Stockholm, Uppsala
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/genes/ar)
External Links
- [PubMed](https://pubmed.ncbi.nlm.nih.gov/)
- [KEGG Pathways](https://www.genome.jp/kegg/pathway.html)
References
Unknown, NCT03174938 - Swedish BioFINDER 2 Study (n.d.)
[Hansson O, et al., Swedish BioFINDER: biomarkers for neurodegenerative diseases. J Intern Med. 2022 (2022)](https://doi.org/10.1111/joim.13569)
[Pichet Binette A, et al., Tau PET in atypical parkinsonisms. Brain. 2023 (2023)](https://doi.org/10.1093/brain/awad123)
[Karikari TK, et al., Blood p-tau217 in PSP. Nat Med. 2022 (2022)](https://doi.org/10.1038/s41591-022-01875-3)
Unknown, CBS/PSP Clinical Trials Guide (n.d.)
Unknown, Progressive Supranuclear Palsy Biomarkers (n.d.)