# Building translationally relevant relationships between neuropathology and abnormal neuroimaging in Veterans and mechanisms of blast-induced neurotrauma in mice

> **NIH VA I01** · VA PUGET SOUND HEALTHCARE SYSTEM · 2020 · —

## Abstract

Blast exposure is a common experience of Operation Iraqi Freedom/Operation Enduring Freedom/
Operation New Dawn (OIF/OEF/OND) Veterans. There is growing concern that repetitive blast exposure may
be a risk factor for neurological disorders, including chronic traumatic encephalopathy (CTE). The pathogenic
processes that link early-occurring, often transient brain injuries, to subsequent chronic behavioral and
cognitive impairments are not well understood. The pathology underlying these impairments is poorly
understood.
 A number of important knowledge gaps currently impede progress toward elucidating the patho-
physiology of repetitive blast-related mTBI that include, limited insight into the translational significance of the
pathology produced in blast-induced animal TBI models with reference to neuroimaging findings in Veterans
with blast-related mTBI. Moreover, the very limited neuropathological information from such Veterans
significantly limits our understanding of blast-related mTBI.
 Adding to the complexity of this issue numerous research groups have reported multiple forms of blast-
induced pathology in a number of animal blast TBI models including: aberrant tau expression, reactive
astrocytosis, microgliosis, axonal injury, myelin damage, and blood-brain barrier (BBB) disruption. Much
attention has been placed on tau because of its close association with sports-related CTE. Whether repetitive
blast-related mTBI follows that same pathogenic pathway to CTE, which is defined chiefly by specific tau
deposits, remains an open question.
 However, recent findings call attention to prominent glial pathology in Veterans with blast-related mTBI,
raising the possibility that this form of neurotrauma may represent a distinct class; or possibly a distinct
pathogenic process leading to chronic mTBI (which also may involve tau pathology).
 In repetitive blast exposed mice we have found microglial and astroglial pathology that, especially in
subcortical regions of the brain, is quite similar to the white matter-associated glial pathology recently reported
in Veterans with blast-related mTBI. We also have evidence that discrete microdomains of early-occurring BBB
disintegrity are closely associated with aberrant microglial responses that include myelin phagocytosis,
astrogliosis, and neuron loss. These data have prompted us test four closely related hypotheses:
Specific Aim 1: will test the hypothesis that in blast exposed mice, specific brain regions are vulnerable to
 early-occurring blood-brain barrier (BBB) disruption; and that these disruptions may trigger later persistent
 pathology associated with myelin disruption, as well as axonal and neuronal injury.
Specific Aim 2: will test the hypothesis that in mice, white matter pathology involving glial-mediated myelin
 phagocytosis and axonal injury will be closely associated with reduced fractional anisotropy.
Specific Aim 3: will test the hypothesis that specific brain regions with myelin, axonal inju...

## Key facts

- **NIH application ID:** 9859320
- **Project number:** 5I01BX002311-07
- **Recipient organization:** VA PUGET SOUND HEALTHCARE SYSTEM
- **Principal Investigator:** David G Cook
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2013-10-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9859320

## Citation

> US National Institutes of Health, RePORTER application 9859320, Building translationally relevant relationships between neuropathology and abnormal neuroimaging in Veterans and mechanisms of blast-induced neurotrauma in mice (5I01BX002311-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9859320. Licensed CC0.

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