UPenn Observational Research Repository on Neurodegenerative Disease (NCT04715399)
Overview
Mermaid diagram (expand to render)
This repository study at the University of Pennsylvania establishes a comprehensive biobank and longitudinal data repository for neurodegenerative disorders, collecting clinical data, biospecimens, and neuroimaging from patients with Alzheimer's disease, Parkinson's disease, PSP, FTD, ALS, CBS, and related conditions. The repository supports mechanistic research, biomarker discovery, and therapeutic development by providing well-characterized patient cohorts and standardized data collection protocols["@Boxer_2020"].
Study Details
| Parameter | Value |
|-----------|-------|
| NCT Number | NCT04715399 |
| Status | Recruiting |
| Study Type | Observational/Biobank |
| Conditions | PSP, PD, AD, FTD, ALS, CBS, CBD, MSA, PPA |
| Sites | University of Pennsylvania |
| Sponsor | University of Pennsylvania |
Scientific Background
Importance of Biobanking in Neurodegeneration
Neurodegenerative diseases represent a significant and growing health burden, affecting millions of individuals worldwide. The development of effective therapies requires a deep understanding of disease mechanisms, reliable biomarkers for diagnosis and progression tracking, and well-characterized patient cohorts for clinical trials[@Trojanowski_2010]. Biobanks play a critical role in enabling this research by:
Standardized Sample Collection: Biobanks establish standardized protocols for collecting, processing, and storing biospecimens, ensuring quality and comparability across studies.
Longitudinal Data: Repeated assessments over time enable understanding of disease progression and identification of prognostic biomarkers[@Irwin_2018].
Multi-Modal Integration: Combining clinical data, neuroimaging, genetics, and fluid biomarkers provides a comprehensive picture of disease[@Chen_2018].
Research Reproducibility: Well-annotated samples enable replication studies and validation of findings across independent cohorts.
Penn Neurodegeneration Research Program
The University of Pennsylvania has been a leader in neurodegenerative disease research for decades, with major contributions to:
Tau Biology: Understanding tau protein metabolism, phosphorylation, and aggregation mechanisms in PSP, CBD, and AD[@Boxer_2020]
Biomarker Development: Pioneering fluid biomarker development including amyloid and tau in CSF, and neuroimaging biomarkers[@Irwin_2018]
Genetics: Characterizing genotype-phenotype relationships in FTLD, MAPT mutations, GRN, and C9orf72 expansions[@Rohrer_2011]
Clinical Trials: Running landmark trials in AD, PD, PSP, and FTD[@Boxer_2023]
Objectives
Primary Objectives
Establish a Well-Characterized Cohort: Create a repository of patients with confirmed or suspected neurodegenerative disorders with detailed phenotypic characterization
Longitudinal Clinical Data Collection: Document disease progression through standardized clinical assessments at regular intervals
Build a Biospecimen Repository: Collect and bank DNA, plasma, serum, CSF, and tissue samples for future research
Support Mechanistic Research: Enable studies on disease mechanisms through access to patient samples and data
Accelerate Therapeutic Development: Facilitate clinical trial design and patient recruitment through well-characterized cohorts[@Boxer_2023]Secondary Objectives
- Establish standardized assessment protocols for clinical trials
- Enable development of cellular and animal models from patient samples
- Support biomarker discovery and validation studies
- Create reference standards for neuroimaging analysis
Data Collection Protocol
Clinical Assessments
Core Assessment Battery:
- Comprehensive neurological examination
- Detailed medical and family history
- Medication review
- Standardized rating scales specific to each diagnosis
Disease-Specific Scales:
| Disease | Primary Scale |
|---------|---------------|
| PSP | PSP Rating Scale (PSPRS) |
| PD | MDS-UPDRS |
| AD | ADAS-Cog, MMSE |
| FTD | Frontotemporal Behavioral Rating Scale |
| CBS | CBD Rating Scale |
| MSA | UMSARS |
Cognitive Testing:
- Montreal Cognitive Assessment (MoCA)
- Trail Making Test (Parts A and B)
- Stroop Test
- Wisconsin Card Sorting Test
- Domain-specific tests for language, memory, and executive function
Functional Measures:
- Clinical Dementia Rating (CDR)
- Functional Activities Questionnaire (FAQ)
- Modified Rankin Scale (mRS)
- Lawton-Brody Instrumental ADL Scale
Behavioral Assessment:
- Neuropsychiatric Inventory (NPI)
- Frontal Behavioral Inventory (FBI)
- Beck Depression Inventory
Neuroimaging Protocol
Magnetic Resonance Imaging (MRI):
- T1-weighted volumetric imaging (MPRAGE/SPGR)
- T2-weighted and FLAIR imaging
- Diffusion tensor imaging (DTI)
- Resting-state functional MRI
- Susceptibility-weighted imaging (SWI)
Positron Emission Tomography (PET):
- [18F]FDG-PET for glucose metabolism
- [11C]PiB or [18F]florbetapir for amyloid PET
- Tau PET ([18F]AV-1451, [18F]MK-6240)
- dopamine transporter imaging (DAT-PET)
Advanced Imaging:
- Arterial spin labeling (ASL) for cerebral blood flow
- Magnetic resonance spectroscopy (MRS)
- PET-MRI hybrid scanning
Genetic Testing
Targeted Sequencing:
- Known neurodegenerative disease genes (APP, PSEN1, PSEN2, MAPT, GRN, C9orf72, SNCA, LRRK2, GBA, VCP, TARDBP, FUS)
- APOE genotyping
- Known pathogenic variant screening
Genome-Wide Approaches:
- Whole exome sequencing
- Whole genome sequencing (selected cases)
- Genome-wide association studies (GWAS)
Longitudinal Follow-Up
Assessment Schedule:
- Baseline evaluation
- 12-month follow-up
- 24-month follow-up
- Annual thereafter
Data Collection Points:
- Clinical and cognitive assessments
- Sample collection
- Neuroimaging (where indicated)
- Outcome tracking
Biospecimen Collection
Sample Types and Processing
| Sample Type | Volume | Processing | Storage |
|-------------|--------|------------|---------|
| DNA (blood) | 10 ml EDTA | Extracted and quantified | -20°C |
| Plasma | 10 ml EDTA | Centrifugation, aliquot | -80°C |
| Serum | 10 ml SST | Centrifugation, aliquot | -80°C |
| CSF | 10-20 ml | Centrifugation, aliquot | -80°C |
| Skin fibroblast | 3mm biopsy | Culture expansion | Liquid N2 |
| Brain tissue | Autopsy | Dissection, flash freeze | -80°C |
Biomarker Analysis
The repository supports analysis of multiple biomarker classes[@Chen_2018]:
Fluid Biomarkers:
- Beta-amyloid (Aβ42, Aβ40, Aβ40/42 ratio)
- Total tau and phosphorylated tau (p-tau181, p-tau217, p-tau231)
- Neurofilament light chain (NfL)[@Benussi_2022]
- Alpha-synuclein and oligomers
- TDP-43 biomarkers
- YKL-40 (astrocytic marker)
- Neurogranin (synaptic marker)
Genetic Biomarkers:
- Known pathogenic variants
- Polygenic risk scores
- Epigenetic markers
Sample Quality Assurance
- Standardized collection protocols across sites
- Aliquoting to minimize freeze-thaw cycles
- Complete sample annotation in database
- Regular quality control assessments
Research Applications
Mechanistic Studies
The repository enables research into disease mechanisms:
Protein Aggregation Studies:
- Tau isoform analysis and post-translational modifications
- Alpha-synuclein strain characterization
- TDP-43 pathology patterns
Cellular Models:
- iPSC derivation from patient fibroblasts
- Neuronal differentiation protocols
- Drug screening platforms
Gene Expression:
- Transcriptomic profiling from blood and tissue
- Single-cell sequencing from brain tissue
- Expression quantitative trait loci (eQTL) analysis
Biomarker Discovery
The well-characterized samples support biomarker research:
Discovery Cohorts: Large numbers of patients with detailed phenotypes enable identification of candidate biomarkers
Validation Studies: Longitudinal samples allow validation of progression markers
Multi-Modal Integration: Combining fluid, imaging, and genetic biomarkers provides comprehensive profiling[@Irwin_2018]
Clinical Trial Support
The repository is essential for clinical trials[@Boxer_2023]:
Patient Recruitment: Well-characterized cohorts enable efficient recruitment
Natural History: Progression data informs trial design and endpoint selection
Biomarker Qualification: Repository samples enable biomarker development for trial enrichment and endpoint selection
Target Validation: Patient samples support mechanistic studies of therapeutic targets
Significance for Precision Medicine
Diagnostic Precision
The repository supports biomarker-driven diagnosis:
- Differentiation between neurodegenerative disease subtypes
- Identification of mimics and diagnostic mimics
- Detection of mixed pathologies
Prognostic Precision
Longitudinal data enables:
- Progression rate prediction
- Identification of rapid vs. slow progressors
- Prediction of specific clinical outcomes
Therapeutic Precision
The repository enables:
- Patient stratification by biomarker profile
- Target engagement studies
- Treatment response monitoring[@Boxer_2023]
Eligibility Criteria
Inclusion Criteria
Diagnosis: Confirmed or suspected diagnosis of:
- [Alzheimer's Disease](/diseases/alzheimers-disease) Parkinson's Disease
- Progressive Supranuclear Palsy
- Corticobasal Syndrome
- Frontotemporal Dementia
- Amyotrophic Lateral Sclerosis
- Multiple System Atrophy
- Related neurodegenerative conditions
Age: Any age (pediatric cases may be excluded for certain protocols)
Ability to Provide Informed Consent: Patient or legally authorized representative
Willingness to Donate Samples: Agreement to blood sampling and optional lumbar punctureExclusion Criteria
Significant medical conditions that may confound diagnosis
Active psychiatric conditions mimicking neurodegeneration
Inability to comply with study procedures
Other neurological disorders not under studyImpact on Neurodegeneration Research
Major Contributions
Penn's neurodegenerative repository has contributed to numerous major discoveries:
Tau Biology Advances: Understanding of tau phosphorylation, aggregation, and spread mechanisms[@Boxer_2020]
Biomarker Development: Validation of CSF and imaging biomarkers for diagnosis and progression[@Irwin_2018]
Genotype-Phenotype Relationships: Characterization of MAPT, GRN, and C9orf72 mutations[@Rohrer_2011]
Clinical Trial Design: Natural history data informing clinical trial endpoints[@Boxer_2023]
Collaborative Research Network
The repository supports:
- Multi-center consortium studies
- Industry partnerships for therapeutic development
- International collaborations for rare variants
- Patient advocacy group partnerships
Key Pathways
- [Tau Pathology Mechanisms](/mechanisms/tau-pathology)
- [Alpha-Synuclein Aggregation](/mechanisms/alpha-synuclein-aggregation)
- [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
- [Neurodegeneration Overview](/mechanisms/neurodegeneration-overview)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Progressive Supranuclear Palsy](/diseases/progressive-supranuclear-palsy)
- [Frontotemporal Disease](/diseases/frontotemporal-disease)
- [Corticobasal Degeneration](/diseases/corticobasal-degeneration)
Biomarkers
- [Neurofilament Light Chain](/biomarkers/neurofilament-light-chain-nfl)
- [Tau Biomarkers in CSF](/biomarkers/tau-csf)
- [Alpha-Synuclein Biomarkers](/biomarkers/alpha-synuclein-csf)
- [Fluid Biomarkers Overview](/biomarkers/fluid-biomarkers)
- [NIH CTSA PSP Biospecimen Repository](/clinical-trials/nih-ctsa-psp-biospecimen-nct05067192)
- [FTLD Diagnosis Study](/clinical-trials/diagnosing-ftld-nct02964637)
- [Synaptic Loss in MSA](/clinical-trials/synaptic-loss-msa-nct05121012)
See Also
- [Penn FTD Center](https://www.pennmedicine.org/departments-and-centers/department-of-neurology/programs-and-services/frontotemporal-dementia-center)
- [Penn Memory Center](https://www.pennmedicine.org/memorycenter)
- [Parkinson's Disease Research Center](/diseases/parkinsons-disease)
- [CurePSP Foundation](https://www.curepsp.org/)
External Links
- [ClinicalTrials.gov NCT04715399](https://clinicaltrials.gov/study/NCT04715399)
- [University of Pennsylvania Neurology](https://www.pennmedicine.org/departments-and-centers/department-of-neurology)
- [NIH neurodegenerative Disease Research](https://nih.gov)
References
[Boxer et al., FTD and related disorders (2020)](https://pubmed.ncbi.nlm.nih.gov/32092166/)[@Boxer_2020]
[Trojanowski et al., Biomarkers of Alzheimer disease (2010)](https://pubmed.ncbi.nlm.nih.gov/20161782/)[@Trojanowski_2010]
[Irwin et al., Neuroimaging biomarkers (2018)](https://pubmed.ncbi.nlm.nih.gov/29068454/)[@Irwin_2018]
[Chen et al., Fluid biomarkers in neurodegenerative disease (2018)](https://pubmed.ncbi.nlm.nih.gov/30148620/)[@Chen_2018]
[Rohrer et al., Clinical features of FTD (2011)](https://pubmed.ncbi.nlm.nih.gov/21047878/)[@Rohrer_2011]
[Benussi et al., Neurofilament light chain as biomarker (2022)](https://pubmed.ncbi.nlm.nih.gov/35499099/)[@Benussi_2022]
[Boxer et al., Clinical trials in FTD (2023)](https://pubmed.ncbi.nlm.nih.gov/37153892/)[@Boxer_2023]
[UPenn Neurodegenerative Repository - ClinicalTrials.gov](https://clinicaltrials.gov/study/NCT04715399)[@upenn]