Neurotrauma Biomarker Levels and Adverse Symptoms Among Military and Law Enforcement Personnel Exposed to Occupational Overpressure Without Diagnosed Traumatic Brain Injury

Boutté, Angela M.; Thangavelu, Bharani; Nemes, Jeffrey; LaValle, Christina R.; Egnoto, Mike; Carr, Walter; Kamimori, Gary H.

doi:10.1001/jamanetworkopen.2021.6445

Cited by 31 publications

(25 citation statements)

References 44 publications

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“…Amyloid β peptide (Aβ) is also associated with progressions of CTE in military Veterans with TBI ( 124 ). Increased Aβ40 and Aβ42 serum levels were reported in military and law enforcement personnel exposed to LIB ( 13 ). It is known that the combined pathological presence of neurotoxic Aβ and tau may predict worsened long-term outcomes in blast-exposed patients, as they have been explained to exacerbate one another; for instance, with the help of tau, Aβ triggers neurodegeneration ( 125 ).…”

Section: Pathophysiology Of Blast-induced Mtbimentioning

confidence: 99%

“…Service members with blast-induced mTBI have significantly higher rates of physical and mental health problems compared to soldiers with other non-neurological injuries. Awareness of potential consequences of LIB exposures has been raised by studies reporting the capacity of various types of weaponry to generate injurious blast overpressures during military and law enforcement trainings (13)(14)(15). LIB-induced mTBI injuries in Service members and law enforcement personnel have been associated with chronic subclinical effects (16).…”

Section: Introductionmentioning

confidence: 99%

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Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

et al. 2022

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Most traumatic brain injuries (TBIs) during military deployment or training are clinically “mild” and frequently caused by non-impact blast exposures. Experimental models were developed to reproduce the biological consequences of high-intensity blasts causing moderate to severe brain injuries. However, the pathophysiological mechanisms of low-intensity blast (LIB)-induced neurological deficits have been understudied. This review provides perspectives on primary blast-induced mild TBI models and discusses translational aspects of LIB exposures as defined by standardized physical parameters including overpressure, impulse, and shock wave velocity. Our mouse LIB-exposure model, which reproduces deployment-related scenarios of open-field blast (OFB), caused neurobehavioral changes, including reduced exploratory activities, elevated anxiety-like levels, impaired nesting behavior, and compromised spatial reference learning and memory. These functional impairments associate with subcellular and ultrastructural neuropathological changes, such as myelinated axonal damage, synaptic alterations, and mitochondrial abnormalities occurring in the absence of gross- or cellular damage. Biochemically, we observed dysfunctional mitochondrial pathways that led to elevated oxidative stress, impaired fission-fusion dynamics, diminished mitophagy, decreased oxidative phosphorylation, and compensated cell respiration-relevant enzyme activity. LIB also induced increased levels of total tau, phosphorylated tau, and amyloid β peptide, suggesting initiation of signaling cascades leading to neurodegeneration. We also compare translational aspects of OFB findings to alternative blast injury models. By scoping relevant recent research findings, we provide recommendations for future preclinical studies to better reflect military-operational and clinical realities. Overall, better alignment of preclinical models with clinical observations and experience related to military injuries will facilitate development of more precise diagnosis, clinical evaluation, treatment, and rehabilitation.

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Section: Pathophysiology Of Blast-induced Mtbimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

et al. 2022

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“…3 LIB exposures experienced during combat operations and occupational training are a primary cause of military-obtained mTBIs. 4 , 5 …”

Section: Introductionmentioning

confidence: 99%

Long-Term Effects of Low-Intensity Blast Non-Inertial Brain Injury on Anxiety-Like Behaviors in Mice: Home-Cage Monitoring Assessments

Siedhoff

Chen

Balderrama

et al. 2022

Neurotrauma Reports

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Mild traumatic brain injury induced by low-intensity blast (LIB) exposure poses concerns in military personnel. Using an open-field, non-inertial blast model and assessments by conventional behavioral tests, our previous studies revealed early-phase anxiety-like behaviors in LIB-exposed mice. However, the impact of LIB upon long-term anxiety-like behaviors requires clarification. This study applied a highly sensitive automated home-cage monitoring (HCM) system, which minimized human intervention and environmental changes, to assess anxiety-like responses in mice 3 months after LIB exposure. Initial assessment of 72-h spontaneous activities in a natural cage condition over multiple light and dark phases showed altered sheltering behaviors. LIB-exposed mice exhibited a subtle, but significantly decreased, duration of short shelter visits as compared to sham controls. Other measured responses between LIB-exposed mice and sham controls were insignificant. When behavioral assessments were performed in a challenged condition using an aversive spotlight, LIB-exposed mice demonstrated a significantly higher frequency of movements of shorter distance and duration per movement. Taken together, these findings demonstrated the presence of chronic anxiety-like behaviors assessed by the HCM system under both natural and challenged conditions in mice occurring post-LIB exposure. This model thus provides a platform to test for screening and interventions on anxiety disorders occurring after LIB non-inertial brain injury.

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“…Three individual metabolites negatively correlated with Rivermead Post-Concussion Symptoms Questionnaire (acetic acid, creatine and methanol), while RAND Energy and Rivermead early and late symptoms predicted both MBRS status and the three metabolite parsimonious combinations. Our metabolite biomarkers appear to offer a promising complement or alternative to conventional protein biomarker assays for identifying/characterizing blast exposures ( 6 , 35 – 37 ).…”

Section: Discussionmentioning

confidence: 99%

A Distinct Metabolite Signature in Military Personnel Exposed to Repetitive Low-Level Blasts

et al. 2022

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Military Breachers and Range Staff (MBRS) are subjected to repeated sub-concussive blasts, and they often report symptoms that are consistent with a mild traumatic brain injury (mTBI). Biomarkers of blast injury would potentially aid blast injury diagnosis, surveillance and avoidance. Our objective was to identify plasma metabolite biomarkers in military personnel that were exposed to repeated low-level or sub-concussive blast overpressure. A total of 37 military members were enrolled (18 MBRS and 19 controls), with MBRS having participated in 8–20 breaching courses per year, with a maximum exposure of 6 blasts per day. The two cohorts were similar except that the number of blast exposures were significantly higher in the MBRS, and the MBRS cohort suffered significantly more post-concussive symptoms and poorer health on assessment. Metabolomics profiling demonstrated significant differences between groups with 74% MBRS classification accuracy (CA). Feature reduction identified 6 metabolites that resulted in a MBRS CA of 98%, and included acetic acid (23.7%), formate (22.6%), creatine (14.8%), acetone (14.2%), methanol (12,7%), and glutamic acid (12.0%). All 6 metabolites were examined with individual receiver operating characteristic (ROC) curve analyses and demonstrated areas-under-the-curve (AUCs) of 0.82–0.91 (P ≤ 0.001) for MBRS status. Several parsimonious combinations of three metabolites increased accuracy of ROC curve analyses to AUCs of 1.00 (P < 0.001), while a combination of volatile organic compounds (VOCs; acetic acid, acetone and methanol) yielded an AUC of 0.98 (P < 0.001). Candidate biomarkers for chronic blast exposure were identified, and if validated in a larger cohort, may aid surveillance and care of military personnel. Future point-of-care screening could be developed that measures VOCs from breath, with definitive diagnoses confirmed with plasma metabolomics profiling.

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Neurotrauma Biomarker Levels and Adverse Symptoms Among Military and Law Enforcement Personnel Exposed to Occupational Overpressure Without Diagnosed Traumatic Brain Injury

Abstract: This cohort study evaluates associations between exposure to low-level overpressure, elevated serum levels of neurotrauma biomarkers, and concussion-like symptoms in military and law enforcement personnel without a diagnosed traumatic brain injury.

Cited by 31 publications

References 44 publications

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Perspectives on Primary Blast Injury of the Brain: Translational Insights Into Non-inertial Low-Intensity Blast Injury

Long-Term Effects of Low-Intensity Blast Non-Inertial Brain Injury on Anxiety-Like Behaviors in Mice: Home-Cage Monitoring Assessments

A Distinct Metabolite Signature in Military Personnel Exposed to Repetitive Low-Level Blasts

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