Swedish BioFINDER 2 Study: Biomarkers and Neurodegeneration (NCT03174938)

ClinicalTrials.gov Identifier: [NCT03174938](https://clinicaltrials.gov/study/NCT03174938)

Overview

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

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

Fluid Biomarker Platform

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:

PSP-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:

Biomarker Performance in PSP

| 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:

Clinical 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

Parkinson's Disease and Related Disorders

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:

Healthcare 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