Translational Biomarker Research for Militarily Relevant Populations in Neurocognitive Diseases

Emmerich, Tanja (2017). Translational Biomarker Research for Militarily Relevant Populations in Neurocognitive Diseases. PhD thesis The Open University.



In recent decades more soldiers are being mobilized to conflict areas, such as the over 2 million service members, who have been deployed to Iraq and Afghanistan since October 2001, which includes but is not limited to Operation Enduring Freedom (OEF) and Operation Iraqi Freedom (OIF); or the 700,000 service veterans deployed to the Persian Gulf War in 1990-91 in the US. The UK mobilized over 46,000 military personnel to Iraq, 9,500 British troops to Afghanistan and 50,000 troops to the Gulf War. Soldiers are being exposed to traumatic events such as physical and psychological trauma, as well as chemical exposure and therefore service members are at risk of postdeployment health-related issues, associated commonly with post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) among OEF/OIF veterans, as well as Gulf War Illness (GWI) among the Persian Gulf War Veteran population.

Although progress has been made in identifying underlying pathology for TBI and PTSD and acute as well as sub-acute biomarkers have been identified, with commercially available tests on the horizon, the work presented here addresses a critical but underinvestigated issue, the need for chronic biomarkers for these conditions, as they can go undetected for an extended period of time. Additionally, more evidence has surfaced that discusses how symptoms related to mild TBI (mTBI) can last for years after the insult, emphasizing the importance of investigatjng biomarkers at a late timepoint after injury as, owing to the mild nature of the injury, the condition was often undiagnosed at the time. PTSD itself still lacks an objective measure that can capture its complexity, whereas co-morbidity of PTSD with TBI further complicates the issue. The other mentioned militarily relevant condition, termed GWI, faces similar issues. Veterans deployed to the Persian Gulf War in 1991 suffer from a disease that has shown to exhibit persistent multisymptom complexity. No biomarker has been identified for this particular population thus making objective diagnosis difficult.

Besides the identification of clinical biomarkers, much research has been done in preclinical models, yet there is still a need to verify and validate such animal models in order to demonstrate their utility. Once the validity of a preclinical model has been confirmed, investigation of pathogenic mechanisms in those models has the potential to reveal therapeutic targets of relevance to the human condition.

Chapter 1 will discuss epidemiology, current clinical diagnosis and pathophysiology of TBI, PTSD and GWI as well as the status of biomarker research in each of these three areas. The thesis then focuses on the identification of plasma biomarkers in human patient populations, specifically in military populations suffering from TBI, PTSD or both at chronic time points post traumatic exposure (Chapters 2 & 3). In Chapter 4, we then explore whether or not such changes are present in our established animal model of TBI. In Chapter 5 we investigate peripheral biomarkers in plasma samples from Gulf War veterans and in two animal models of GWI. Given the complexity of TBI, PTSD and GWI clinical presentation and pathogenesis and their heterogeneity in human populations, it is anticipated that a valid biomarker for broad application will in fact require assessment of many markers to create a panel that can support diagnosis. The lipidomic and proteomic analyses I employed in this work are approaches with the required breadth and lack of bias to be successful in such an undertaking, and I hope that the work described in this thesis provides a foundation for future development of such biomarker panels.

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