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Military veterans with a history of three or more concussions were more likely to have high levels of exosomal and plasma levels of neurofilament light (NfL) chain years after injury occurred, a cross-sectional study suggested.

Moreover, elevations of NfL, a measure of axonal damage, were highest in veterans with repetitive traumatic brain injury (TBI) who had symptoms of chronic post-concussive syndrome, post-traumatic stress disorder (PTSD), and depression, reported Kimbra Kenney, MD, of Walter Reed National Military Medical Center in Bethesda, Maryland, and colleagues, in

Blood tests that include exosomal and plasma NfL markers may one day help predict which people with mild TBIs will take longer to recover, Kenney noted.

"Our study found there's great potential for this protein to predict the problems people with concussions may experience years after their injuries," she said in a statement.

"While most people with mild concussions recover completely, some never get their lives back fully because of chronic disability," Kenney added. "These people may benefit greatly from a test that could predict those disabilities years ahead of time."

Most concussions are single and uncomplicated, but "a subset of individuals experience persistent post-concussive symptoms and substantial disability," noted Silvina Tonarelli, MD, of Texas Tech University in El Paso, and Davin Quinn, MD, of the University of New Mexico in Albuquerque, in an accompanying .

"There is a need for accurate and reliable biomarkers that are tied to the pathophysiologic mechanisms of mild TBI, and that track and predict neuropsychiatric outcomes," they wrote.

"A promising avenue of biomarker development is exosomes, a type of extracellular vesicle released by injured cells, whose contents can be informative about neuronal pathophysiology," Tonarelli and Quinn added.

Exosomes of other proteins like alpha synuclein are being studied as potential biomarkers in Parkinson's and other neurodegenerative diseases. In other disorders, including Alzheimer's disease and multiple sclerosis, blood levels of NfL have been shown to correspond with hallmarks of disease progression.

In this study, Kenney's research team studied 195 military veterans in the (CENC) cohort. Participants had a history of combat exposure during deployment; their median age was 38, and 85% were men.

Excluded from the study were people with moderate or severe TBI, and people who had coma that lasted more than 30 minutes, amnesia that lasted more than 24 hours, traumatic intracranial lesion on head CT, or a history of major neurologic or psychiatric disorder.

Besides exosomal and plasma levels of NfL, the researchers looked at other candidate biomarkers, including tumor necrosis factor (TNF)-α, interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF).

The researchers divided participants into three groups:

• 45 people had no history of mild TBI
• 94 people had one or two mild TBIs
• 56 people had three or more TBIs

People with one or two mild TBIs had their first concussion a median of 13.53 years ago and their last one 9.53 years ago. People with three or more mild TBIs had their first concussion a median of 22.11 years ago and their last one 6.83 years ago.

Exosomal and plasma levels of NfL were linked to repetitive mild TBIs and correlated with severity of post-concussive, PTSD, and depressive symptoms.

Plasma levels of TNF-α, an inflammatory marker, were tied to post-concussive and PTSD symptoms. The lifetime number of concussions correlated with exosomal and plasma NfL levels and with plasma IL-6, another inflammatory marker.

Moreover, an increased number of years since first concussion correlated with higher levels of exosomal and plasma NfL. Years since first concussion also was linked to plasma VEGF, which may modulate inflammatory responses, and plasma TNF-α.

"These are encouraging findings, suggesting that an ongoing neuroinflammatory process may be an important contributor to persistent post-concussion syndrome in a military population subjected to repetitive mild TBIs," Tonarelli and Quinn pointed out.

Strengths of the study include its "well-characterized cohort and rigorous mild TBI confirmation process," they observed, but "further confirmation of these relationships and clarification of confounding effects of comorbidities is required before these biomarkers can be of use."

The study had several limitations, Kenney and colleagues noted. The sample size was relatively small and there was substantial variability in the number of years in which injury occurred.

There also was variability in mechanisms of injury. "We included participants with deployment-associated TBI, which includes but it is not restricted to blast-related TBI, as well as TBIs sustained before military service," the researchers said.

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