Military Blast Exposure and Chronic Neurodegeneration: Summary of Working Groups and Expert Panel Findings and Recommendations

Brix, Kelley A.; Brody, David L.; Grimes, Jamie; Yitzhak, Avraham; Agoston, Denes V.; Aldag, Matt; Armstrong, Regina C.; Arun, Peethambaran; Audette, Michel; Babcock, Debra; Balaban, Carey D.; Banton, Rohan; Bellgowan, Patrick S.F.; Borkholder, David A.; Broglio, Steven P.; Brokaw, Elizabeth B.; Cantu, Robert C.; Carr, Walter; Chapman, Sandi; Cmarik, Joan L.; Colder, Brian; Colombe, Jeff B.; Cook, David G.; Cozzarelli, Tara; Silva, Uade Olaghere da; Daphalapurkar, Nitin; Dardzinski, Bernard J.; Degraba, Tom; DeMar, James C.; DeWitt, Douglas S.; Dickstein, Dara L.; Duckworth, Josh; Elder, Gregory A.; Fazel-Rezai, Reza; Fine, Michael; Fiskum, Gary; Fournier, A.J.; Ganpule, Shaleish; Gill, Jessica; Glenn, John F.; Greene, Colin; Greig, Nigel H.; Haering, Chad; Harrington, Jason; Hein, Amy M.; Helmick, Kathy; Hicks, Ramona; Hinds, Sidney; Hoffman, Stuart W.; Horkayne‐Szakaly, Iren; Iacono, Diego; Ishii, Erick K.; Jones, Robert; Karami, G.; Krawczyk, Daniél C.; Labutta, Robert J.; Latta, Robert C.; Lattimore, Theresa; Leggieri, Michael J.; Leonessa, Fabio; Lin, Alexander P.; Ling, Geoffrey; Long, Matt; Lu, Kun Ping; Panker, Stephanie Maxfield; McCabe, Joseph T.; Merkle, Andrew C.; Montenigro, Philip H.; Mueller, Gary P.; Ng, Laurel J.; Nigam, Savita; O‘Donnell, John C.; Okonkwo, David O.; Pauli, Ingrid; Perl, Daniel P.; Peskind, Elaine R.; Pfister, Bryan J.; Philippens, M.M.G.M.; Piehler, Thuvan; Proctor, Julie L.; Przekwas, Andrzej; Qashu, Felicia; Raskind, Murray A.; Razumovsky, Alexander Y.; Reifman, Jaques; Reyes, Patricio F.; Rigby, Paul; Risling, Mårten; Robinson, Meghan E.; Rooks, Tyler; Rosen, Charles L.; Rosseau, Gail; Sammons-Jackson, Wendy; Santago, Anthony C.; Shoge, Richard; Sours, Chandler; Stone, James L.; Templin, Mike V.; Tepe, Victoria; Thielen, Peter; Thomas, M. A.; Timmes, Thomas C.; Tortella, Frank C.; Tucker, Laura B.; Tweedie, David; Hamm, Dale Vander; Vu, B. Christie; Wang, Ying; West, Therese; Wilde, Elisabeth A.; Willis, Adam M.; Wu, John; Zai, Laila; Zander, Nikki; Zheng, James; Ziejewski, Mariusz

doi:10.1089/neu.2017.5222

Cited by 13 publications

(6 citation statements)

References 11 publications

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“…Incidence rates of mTBI among military personnel are much higher than those reported for civilians (4). Low intensity blast (LIB) exposures are among the principle causes of mTBIs during military training or combat, and less frequent in industrial disasters/incidents (5)(6)(7)(8)(9)(10)(11)(12). Service members with blast-induced mTBI have significantly higher rates of physical and mental health problems compared to soldiers with other non-neurological injuries.…”

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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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: 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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“…Related to the need for proper design of shock studies, there has been a recent convergence of views regarding a critical aspect of blast research progress with the paramount need for standardization of results reporting for blast studies (23,206,208,210,216,(223)(224)(225)(226)(227). Clear description of static, dynamic, stagnation, and reflected pressure and how these properties are measured and interpreted are critical.…”

Section: Research Guidelines and Standards For Results Reportingmentioning

confidence: 99%

Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury

McCabe

Tucker

2020

Front. Neurol.

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Approaches to furthering our understanding of the bioeffects, behavioral changes, and treatment options following exposure to blast are a worldwide priority. Of particular need is a more concerted effort to employ animal models to determine possible sex differences, which have been reported in the clinical literature. In this review, clinical and preclinical reports concerning blast injury effects are summarized in relation to sex as a biological variable (SABV). The review outlines approaches that explore the pertinent role of sex chromosomes and gonadal steroids for delineating sex as a biological independent variable. Next, underlying biological factors that need exploration for blast effects in light of SABV are outlined, including pituitary, autonomic, vascular, and inflammation factors that all have evidence as having important SABV relevance. A major second consideration for the study of SABV and preclinical blast effects is the notable lack of consistent model design-a wide range of devices have been employed with questionable relevance to real-life scenarios-as well as poor standardization for reporting of blast parameters. Hence, the review also provides current views regarding optimal design of shock tubes for approaching the problem of primary blast effects and sex differences and outlines a plan for the regularization of reporting. Standardization and clear description of blast parameters will provide greater comparability across models, as well as unify consensus for important sex difference bioeffects.

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“…Other research studies report discrepant findings that young adults are disproportionately affected by blast-related mTBIs. A growing body of literature suggests strong evidence from experimental and human studies that there is an association of an early life blast-related mTBI with late-onset neurodegenerative conditions and neuropathologic findings as a result of dynamic and persistent pathobiological processes and microstructural changes in the brain triggered by the injury (155)(156)(157)(158)(159)(160). This will be a critical avenue for future investigation since such work would enhance our understanding of the long-term effects of blast-related concussion and encourage better management, strategic health service plans, and more effective preventive and therapeutic interventions to improve the quality of life of those serving in military conflicts.…”

Section: Discussionmentioning

confidence: 99%

Characteristics and Impact of U.S. Military Blast-Related Mild Traumatic Brain Injury: A Systematic Review

et al. 2020

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As a result of armed conflict, head trauma from exposure to blasts is an increasing critical health issue, particularly among military service members. Whilst numerous studies examined the burden of blast-related brain injuries on service members', few systematic reviews have been published. This work provides a comprehensive summary of the evidence on blast-related mild traumatic brain injury (mTBI) burden in active U.S. military service members and inactive Veterans, describing characteristics and outcomes. Records published up to April 2017 were identified through a search of PubMed, Web of Science, Scopus, Ovid MEDLINE, and Cochrane Library. Records-based and original research reporting on U.S. military service members and Veterans with mild blast TBI were included. Data on subject characteristics, exposure, diagnostic criterion, and outcomes were extracted from included studies using a standardized extraction form and were presented narratively. Of the 2,290 references identified by the search, 106 studies with a total of 37,515 participants met inclusion criteria for blast-related mTBI. All but nine studies were based out of military or Veteran medical facilities. Unsurprisingly, men were over-represented (75-100%). The criteria used to define blast-related mTBI were consistent; however, the methodology used to ascertain whether individuals met those criteria for diagnosis were inconsistent. The diagnosis, most prevalent among the Army, heavily relied on self-reported histories. Commonly reported adverse outcomes included hearing disturbances and headaches. The most frequently associated comorbidities were post-traumatic stress disorder, depression, anxiety, sleep disorders, attention disorders, and cognitive disorders. The primary objective of this review was to provide a summary of descriptive data on blast-related mTBI in a U.S. military population. Low standardization of the methods for reaching diagnosis and problems in the study reporting emphasize the importance to collect high-quality data to fill knowledge gaps pertaining to blast-related mTBI.

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Military Blast Exposure and Chronic Neurodegeneration: Summary of Working Groups and Expert Panel Findings and Recommendations

Cited by 13 publications

References 11 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

Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury

Characteristics and Impact of U.S. Military Blast-Related Mild Traumatic Brain Injury: A Systematic Review

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