Seminar Friday, November 4, 2016

Speaker:

Denes Agoston, MD, PhD
Professor
Department of Anatomy, Physiology and Genetics
School of Medicine
Uniformed Services University of the Health Sciences

 

Title:

Physical-to-biological coupling in primary explosive blast; what biomarkers can tell us about the physical forces

 

Abstract:

Explosive blast is a highly complex physical event that triggers similarly complex biological response. Primary blast-induced traumatic brain injury (pbTBI) is unique to explosive blast and is caused by rapid transmission of the pressure wave through the skull and brain parenchyma. In contrast, the secondary, tertiary, etc. injury mechanisms, acceleration-deceleration, penetration of projectiles, etc. are also found in other types of TBI.

In response to the physical impact to the head, the structural integrity of the brain is altered, and damaged cells release neurons and glia specific proteins that are normally not present in the blood (or in the cerebrospinal fluid, CSF). Elevated blood (and CSF) levels of these biochemical makers can indicate the severity of the injury and help identifying the injury mechanism that varies by the type of physical forces causing the injury. Shockwaves (SWs) are the leading elements of pressure disturbance after explosive blast and they cause spalling, implosion and inertial effects [1, 2] but the biological injury process of pbTBI is influenced by several factors including peak overpressure, number of overpressure peaks, their frequency resonance differentially affecting biological structures with density differences and elasticity.

This lecture will discuss the pathobiological changes in the brain that appear to be specific to pbTBI. In summary: pbTBI triggers instantaneous, complex and dynamically changing pathologies. The pathological changes that appear to be specific to pbTBI are; selective damage to brain structures with different densities and damages to cell surfaces, cell adhesions and cell-cell junctions (spallation, inertial effects?) that lead to multiple pathologies including inflammation. These pathologies, the “molecular fingerprints” of pbTBI can be detected by monitoring serum and cerebrospinal fluid (CSF) levels of specific protein biomarkers [4]. Inflammation appears to be the key pathology linking early injury induced changes to delayed, chronic consequences of pbTBI [5]. Importantly, pbTBI frequently occurs along with injuries to other organs and concomitant peripheral injuries can exacerbate the inflammatory response and contribute to the development of long-term adverse effects following pbTBI. Critical but currently unsolved issues regarding pbTBI as specific disease entity include; lack of understanding and/or ignoring the physics of explosive blast by biologists. This serious disconnect results in using “blast models” that fail to generate the critical physical environment and consequently lead to inaccurate conclusions. Additional questions are: scalability, “dose response” and dissecting the physical components of blast causing specific pathologies in pbTBI. Answering these questions is crucial for designing effective and specific physical protections, developing diagnostics and evidence based pharmacotherapies in pbTBI.

 

References:

1. Cernak, I. and Noble-Haeusslein, L.J. (2010). Traumatic brain injury: an overview of pathobiology with emphasis on military populations. J Cereb Blood Flow Metab 30, 255-266.

2. Nakagawa, A., Manley, G.T., Gean, A.D., Ohtani, K., Armonda, R., Tsukamoto, A., Yamamoto, H., Takayama, K. and Tominaga, T. (2011). Mechanisms of primary blast-induced traumatic brain injury: insights from shock-wave research. J Neurotrauma 28, 1101-1119.

3. Agoston, D.V. and Kamnaksh, A. (2015). Frontiers in Neuroengineering 
Modeling the Neurobehavioral Consequences of Blast-Induced Traumatic Brain Injury Spectrum Disorder and Identifying Related Biomarkers. In: Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects. Kobeissy, F.H. (ed). CRC Press/Taylor & Francis (c) 2015 by Taylor & Francis Group, LLC.: Boca Raton (FL).

4. Agoston, D.V., Gyorgy, A., Eidelman, O. and Pollard, H.B. (2009). Proteomic biomarkers for blast neurotrauma: targeting cerebral edema, inflammation, and neuronal death cascades. J Neurotrauma 26, 901-911.

5. Kovesdi, E., Kamnaksh, A., Wingo, D., Ahmed, F., Grunberg, N.E., Long, J.B., Kasper, C.E. and Agoston, D.V. (2012). Acute minocycline treatment mitigates the symptoms of mild blast-induced traumatic brain injury. Front Neurol 3, 111.

 

Short Bio:

Denes V. Agoston, M.D., Ph.D. is a tenured Professor of Neuroscience at the Department of Anatomy, Physiology and Genetics, Uniformed Services University (USU), Bethesda Maryland and Guest Scientist at the Karolinska Institute Stockholm, Sweden. He earned his M.D. degree in Hungary and his Ph.D. for his work on cholinergic and peptidergic synaptic transmission in Gottingen, Germany. In 1988 he moved to the NIH and worked on transcriptional regulation of neuropeptide genes and on the molecular genetics of neuronal differentiation. Since joining USU in 1998, he has been working on various aspects of TBI, particularly on blast induced TBI. Dr. Agoston has been collaborating with numerous laboratories worldwide on the pathobiology of TBI through identification of diagnostic and prognostic protein biomarkers. Dr. Agoston is the author of more than 100 peer-reviewed articles, reviews and book chapters.