# Developing Gyrencephalic Models of TBI-Induced ADRD Neuropathology

> **NIH NIH RF1** · UNIVERSITY OF PENNSYLVANIA · 2024 · $3,102,638

## Abstract

PROJECT SUMMARY / ABSTRACT
There has been considerable concern regarding the long-term effects of traumatic brain injury (TBI), largely
driven by reports of neurodegenerative proteinopathies associated with participation in contact sports. In
addition, increasing epidemiological data indicates that even a single moderate or severe TBI can increase the
risk of dementia. While there has been a particular focus on the role of tauopathies following TBI, our group and
others have demonstrated often complex and diverse neuropathologies with late survival post-injury in some
individuals. However, the mechanisms driving these pathologies are poorly understood. In addition, to date there
has been limited success in attempts to model both the neuropathological and clinical features of post-TBI
neurodegeneration. As such, in order to permit mechanistic and translational studies of TBI-related
neurodegeneration, there is a pressing need to develop preclinical models that recapitulate the complex
pathologies and clinical phenotypes in the chronic phase post-injury.
To address this critical knowledge gap, we propose an iterative design to develop novel gyrencephalic models
of post-TBI ADRD. Three novel and distinct injury paradigms are proposed to represent repetitive mild
exposures, as well as diffuse and focal TBI. We propose carefully considered biomechanical inputs relevant to
real-world scenarios, with rigorous characterization of the nature and progression of neuropathological outcomes
up to 1 year post-injury. The clinical relevance of pathologies will be determined via parallel and standardized
comparisons with well-characterized human tissue samples from the CONNECT-TBI archive. Face validation
will be determined through novel cognitive assessments, with additional validation attained via measurement of
advanced neuroimaging and blood biomarker outcomes. Critically, reproducibility will be assessed at a second
site. If successful, the development of a model with validated clinical relevance will provide a vital platform to
study TBI-related neurodegeneration, including the assessment of novel diagnostics, and potential therapeutic
interventions. Moreover, studying the evolution of pathology following the initiating injury may offer critical
insights to the pathogenesis of TBI-related neurodegeneration.

## Key facts

- **NIH application ID:** 10933868
- **Project number:** 1RF1NS138030-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Victoria Eleanor Johnson
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $3,102,638
- **Award type:** 1
- **Project period:** 2024-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933868

## Citation

> US National Institutes of Health, RePORTER application 10933868, Developing Gyrencephalic Models of TBI-Induced ADRD Neuropathology (1RF1NS138030-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10933868. Licensed CC0.

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