Exosomal and plasma NfL levels in military veterans linked to neurobehavioral symptoms

Repetitive mild traumatic brain injuries (mTBIs) were associated with elevated exosomal and plasma levels of neurofilament light (NfL) chain years after those injuries occurred, a cross-sectional study of military veterans found.

The greatest elevations were found in veterans with repetitive mild TBI who had symptoms of chronic post-concussive syndrome (PCS), posttraumatic stress disorder (PTSD), and depression, reported Kimbra Kenney, MD, of the Uniformed Services University of the Health Sciences in Bethesda, Maryland, and coauthors in Neurology.

“We evaluated peripherally circulating exosomal as well as soluble plasma levels of candidate protein biomarkers in veterans years after both their most recent and their initial mTBI,” Kenney and colleagues wrote.

“These findings contribute to the ongoing efforts to establish prognostic biomarkers for persistent neurobehavioral symptoms in chronic mTBI and shed light on potential mechanisms underlying these symptom complexes common after mTBI, especially after repetitive TBIs among active duty service members and veterans,” they added.

In an accompanying editorial, Silvina Tonarelli, MD, of Texas Tech University in El Paso, and Davin Quinn, MD, of the University of New Mexico in Albuquerque, wrote that “while the majority of mild traumatic brain injuries (mTBIs) are single and uncomplicated and complete recovery is expected, a subset of individuals experience persistent postconcussive symptoms (PCS) and substantial disability.”

“There is a need for accurate and reliable biomarkers that are tied to the pathophysiologic mechanisms of mTBI, and that track and predict neuropsychiatric outcomes,” they added. “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.”

Exosomes are snapshots of living cell interiors whose contents reflect ongoing processes at the time of their formation. Inclusion of NfL, a marker of axonal injury, in their contents may be informative in specific clinical contexts, including TBI, to predict outcomes and guide management.

In this study, Kenney and colleagues analyzed potential biomarkers, ongoing symptoms, and mTBI history for 195 participants in the Chronic Effects of Neurotrauma Consortium longitudinal study of service members who had experienced combat, and were 18 years of age or older. They excluded those with moderate or severe TBI, or who were unresponsive for more than 30 minutes, had acute findings on head CT, had posttraumatic amnesia > 24 hours, or had history of major neurologic or psychiatric disorder.

The researchers divided participants into three groups. Participants with 1-2 mTBIs (n=94) had a median time since last TBI of 9.53 years and a median time since first TBI of 13.53 years. Participants with 3 or more mTBIs (n=56) had a median time since last TBI of 6.83 years and a median time since first TBI 22.11 years. Controls had no mTBI (n=45).

Participants were 85% male with median age of 38 and similar education levels across tertiles. PCS symptoms were evaluated with the Neurobehavioral Symptom Inventory (NSI). PTSD symptoms were measured with the PTSD Checklist Military Version (PCL-M), and depression symptoms were assessed with Patient Health Questionnaire Depression Scale (PHQ-9).

In addition to exosomal and plasma levels of NfL, the researchers quantified tumor necrosis factor (TNF)–α, interleukin (IL)–6, IL-10, and vascular endothelial growth factor (VEGF). Their analysis showed:

  • Elevated exosomal and plasma levels of NfL were associated with repetitive mTBIs and with chronic PCS, PTSD, and depression symptoms.
  • Plasma TNF-α levels correlated with PCS and PTSD symptoms.
  • The total number of mTBIs correlated with exosomal and plasma NfL levels and with plasma IL-6.
  • An increased number of years since the most recent TBI correlated with higher exosomal NfL and lower plasma IL-6 levels.
  • An increased number of years since first TBI correlated with higher levels of exosomal and plasma NfL, as well as plasma TNF-α and VEGF.
“Our finding of persistently elevated neuronal and neuroinflammatory markers, including a dose-dependent relationship between mTBI totals and increasing symptom burden, may provide insight into the underlying pathogenesis of persistent symptom development after repetitive mTBI,” Kenney and co-authors wrote.
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“Elevated NfL levels have been linked to axonal injury or degeneration in TBI and several neurodegenerative disorders, suggesting that our findings reflect chronic, persistent axonal degeneration or dysregulation remotely after repetitive mTBIs,” they continued.

“These are encouraging findings, suggesting that an ongoing neuroinflammatory process may be an important contributor to persistent PCS in a military population subjected to repetitive mTBIs,” Tonarelli and Quinn observed. “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, including small sample size and lack of a depression-only control group, the editorialists added. Unknown confounders also might have influenced results.

  1. Repetitive mild traumatic brain injuries (mTBIs) were associated with elevated exosomal and plasma levels of neurofilament light (NfL) chain years after those injuries occurred, a cross-sectional study of military veterans found.

  2. Be aware that this is an early study and needs further confirmation and clarification before put into clinical practice, the editorialists note.

Paul Smyth, MD, Contributing Writer, BreakingMED™

The study was supported by the Department of Defense Chronic Effects of Neurotrauma Consortium, Department of Veterans Affairs, and the NIH National Institute of Nursing Research Intramural Research Program.

The researchers reported no disclosures. The editorialists reported no disclosures.

Cat ID: 474

Topic ID: 82,474,730,474,192,925