New Insight Into the Impact of Battlefield Explosions on the Brain

Michael Vlessides

March 23, 2020

A series of novel biomarker signatures may help identify veterans exposed to battlefield explosions who will go on to develop behavioral, cognitive, and/or memory complaints, new research shows.

Conducted in humans and animals, the study uncovered an association between exposure to detonation of improvised explosive devices and an accumulation of tau protein in the brain, which may explain its presence in chronic traumatic encephalopathy (CTE).

The findings may open the door to more sensitive and objective estimation of brain degeneration among soldiers exposed to battlefield explosions and explain ensuing neuropsychiatric symptoms.

"We found that animals exhibited some sort of tauopathy after being exposed to repetitive blasts. In humans, on the other hand, imaging studies have shown there's a reason to be concerned that there may be some signal there as well," co-senior author Gregory Elder, MD, chief of neurology at the James J. Peters VA Medical Center in New York City, told Medscape Medical News.

The study was published online February 25 in Molecular Psychiatry.

Battlefield Fallout

Repetitive mild traumatic brain injury (mTBI) is a significant risk factor for subsequent development of neurodegenerative disease, including CTE. Following repetitive mTBI, CTE often presents as deterioration in behavior, cognition, and/or memory.

Perhaps not surprisingly, there is concern regarding the role of TBI in the chronic cognitive and behavioral symptoms that often develop during or after military service.

Research shows that as many as 1 in 5 veterans returning from service in Iraq and Afghanistan experience sustained mTBI after blast exposure, a rate that is likely even higher given that many blast-related injuries go undocumented.

"Over the years we've begun to see veterans coming back from conflicts in Iraq and Afghanistan who had a lot of postconcussive symptoms that we thought were related to blast-related mild traumatic brain injuries," said Elder.

To date, there have been several reports of pathologically confirmed cases of CTE among military veterans. Although previous research has described some of these pathologies, the prevalence of distinct pathological subtypes in veterans with chronic cognitive/behavioral syndromes following blast-related TBI has yet to be determined.

Given this knowledge gap, the researchers used a rat model of blast-induced mild traumatic brain injury to study the clinicopathology of tauopathy, while simultaneously investigating clinical biomarkers in human veterans exposed to blasts who subsequently suffered behavioral, cognitive, and/or memory problems.

As part of the two-pronged study, the investigators examined a rat model designed to mimic a blast exposure comparable to mTBI or subclinical blast exposure in humans.

The rats received a total of three such exposures delivered once daily for three consecutive days. Sham-exposed animals were treated identically, though not exposed to the blasts.

At 6 weeks following blast exposure, four control and five study animals were analyzed. Another five control and five blast-exposed animals were analyzed at 10 months.

In the human group of the trial, 10 male veterans (mean age 41.20 ± 9.42 years) and seven male healthy controls (mean age 47.33 ± 7.06 years) were enrolled. These individuals all had reported histories of repetitive blast exposure and mTBI, and also had behavioral and cognitive complaints.

All participants underwent a series of tests, including MRI and positron emission tomography (PET) imaging, as well as plasma and serum neurofilament (Nf-L) light chain quantification.

The investigators found several notable changes in the brains and blood of both animals and humans that were subjected to blasts.

Improved Diagnosis?

In the animal portion of the study, rats exposed to the experimental blast protocol exhibited a range of anxiety and behavioral traits that resembled posttraumatic stress disorder (PTSD).

Postmortem brain samples also revealed that the animals accumulated abnormal tau in nerve cells following blast exposure, as well as in perivascular astroglial processes. Interestingly, the study also showed that the pattern of p-tau distribution was altered following blast exposure.

On the human side, the researchers used PET scans and the [18F]AV1451 (flortaucipir) tau ligand, a molecule that produces a signal by binding to a site on the tau protein. They found that 5 of the 10 veterans exhibited excessive retention of [18F]AV1451 at the white/gray matter junction in frontal, parietal, and temporal brain regions. This, they explained, matches the anatomical distribution of tauopathy previously observed in postmortem studies of individuals with CTE.  

As an additional biomarker, the investigators measured blood levels of Nf-L, since elevated Nf-L levels have been reported in patients suffering from a variety of brain injuries. This part of the analysis revealed elevated levels of Nf-L
in the plasma of veterans displaying excess [18F]AV1451 retention.

These findings not only demonstrate the existence of a relationship between blast injuries and clinical neuropsychiatric syndromes in both rats and humans, but also identified biomarker signatures that characterize such disorders, said Elder.

As such, the findings may help improve understanding of the negative effects of blast-related injuries and human neurodegenerative diseases, including CTE.

These insights may prove vital in an age where suicide rates have jumped substantially among young military veterans. More objective, more sensitive, and earlier ways to detect brain damage among solders may reap untold benefits in this vulnerable population.

Nevertheless, the investigators acknowledge that more research is needed to determine whether clinical, neuroimaging, and/or fluid biomarker signatures can improve the diagnosis of long-term neuropsychiatric sequelae of mTBI.

"There are many veterans who have suffered blast-related mild traumatic brain injuries who either aren't getting better or are getting worse. We really don't know why, and we don't know how to identify those who are at greatest risk," said Elder.

"But if we could develop some sort of test that allows us to identify those who aren't going to do well, that may completely change the way we approach these individuals.

There are also a number of experimental therapies going on in tauopathy that may be potentially applicable in the future," he added.

New Perspective

Commenting on the findings for Medscape Medical News, David G. Cook, PhD, who was not involved in the study, said this is 'a very important paper', because it offers new perspective into the dysfunctions and changes in the brains of blast-exposed veterans and animals.

"But it's only a step in that direction," said Cook, research associate professor of medicine at the University of Washington School of Medicine in Seattle. "A whole lot more work needs to be done. But this is an important step in that pathway to trying to understand what's wrong, so we can begin to try to figure out what to fix."

There are still many questions related to the potential association between blast-related mTBI and the subsequent development of CTE, Cook noted.

"The field is now convinced that as an injury mechanism, blast-related injuries are different than chronic traumatic encephalopathy," he said.

"Nevertheless, even if it turns out that blast-related traumatic brain injuries don't push patients into a chronic traumatic encephalopathy diagnosis, they're still doing many things to the brain that are long, chronic, and debilitating, It's just that we understand far less about that."

Elder and Cook have disclosed no relevant financial relationships. The study was primarily supported by the Alzheimer's Drug Discovery Foundation and the Department of Veterans Affairs.

Mol Psychiatry. Published online February 25, 2020. Full text

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