# TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism

> **NIH NIH U54** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $339,372

## Abstract

Multiple pathologies can contribute to cognitive impairment, dementia and parkinsonism, particularly in the
setting of advanced age. A history of chronic traumatic brain injury (cTBI) or repetitive head impacts (RHI)
increases the risk for dementia, although the relative contributions of chronic traumatic encephalopathy (CTE),
Alzheimer disease (AD), Lewy body disease (LBD), frontotemporal lobar degeneration, amyotrophic lateral
sclerosis (ALS) and other pathologies to post-traumatic dementia are unknown. In this project we will use the 8
cohorts of the Brain Bank Core that are separately focused on RHI, TBI, AD, ADRD, ALS, PTSD, and community-
aging to systematically evaluate the precise neuropathology of RHI and TBI-related neurodegeneration. These
combined brain banks contain over 2500 cases, and include the largest neuropathologically-confirmed autopsy
cohort of CTE subjects (n= 361) as well as >50 cases of remote, moderately-severe TBI with a chronic cavitary
lesion (cTBI). We and others have reported the clinical, neuroimaging, and neuropathologic characteristics of
subjects who developed early onset dementia after sustaining a single moderate-severe TBI many years earlier
and developed multiple unique pathologies. Furthermore, our preliminary data examining the pathology in
hundreds of participants with and without RHI demonstrate that the type and distribution of beta-amyloid plaques
are altered in CTE; neocortical LBD is common in CTE and associated with RHI, and 50% of participants with a
history of cTBI had CTE in an ALS cohort. In addition, we show that RHI is associated with altered microglial and
astrocyte phenotypes that are differentially associated with comorbid pathology in CTE. Our hypothesis, based
on our preliminary data, is that RHI and cTBI are associated with increased frequency of multiple
neurodegenerative pathologies and that the distribution of pathology is altered to reflect the pattern of injury. We
further hypothesize that these multiple RHI and cTBI-related pathologies, including CTE, contribute to the
development of dementia and parkinsonism in various brain bank cohorts. Our long-term goal is to uncover the
relative risk, heterogeneity, and cellular mechanisms of cTBI-related neurodegeneration that underlie the
development of dementia and parkinsonism. The immediate goal of this research project is to determine the
prevalence and pathological distribution of RHI and cTBI-related disease in a variety of neurodegenerative brain
banks. This research is critical to understanding how trauma triggers or accelerates multiple neuropathologies.
Overall, we aim to determine prevalence and heterogeneity of multiple pathologies in subjects exposed to RHI
and cTBI and to determine the relative contributions of these pathologies to cognitive decline and parkinsonism.

## Key facts

- **NIH application ID:** 10021469
- **Project number:** 5U54NS115266-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Thor Stein
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $339,372
- **Award type:** 5
- **Project period:** 2019-09-30 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10021469

## Citation

> US National Institutes of Health, RePORTER application 10021469, TBI-related polyproteinopathy and the role of multiple neurodegenerations in cognitive decline and parkinsonism (5U54NS115266-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10021469. Licensed CC0.

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