Project Title

Disentangling the Effects of PTSD from GWI for Improved Diagnostics and Treatments

Principal Investigator/Project Director

Travis Craddock

Colleges / Centers

College of Psychology

Funder

DOD - U.S. Army Medical Research Acquisition Activity

Start Date

9-30-2016

Abstract

Background: Studies conducted in military personnel afflicted with Gulf War Illness (GWI) suggest a comorbidity rate of over 1 in 3 to also suffer with Post Traumatic Stress Disorder (PTSD). As GWI and PTSD have been shown to exhibit similarities in the dysfunction of their immune profiles, and there is significant overlap in their symptoms, this suggests that a screen for probable PTSD diagnosis may delineate at least two phenotypes of GWI. Co-morbidity with PTSD brings into question how this condition may change the nature and severity of GWI. Specifically, understanding the role of systemic inflammatory mechanisms in GWI in the presence and absence of probable PTSD diagnosis is critical to define subtypes of GWI, and for the development of subtype specific treatments. Hypothesis: In this work we propose that GWI is at least in part supported by illness-specific inflammatory activity and that the extent and nature of the resulting inflammation is altered in the context of the co-morbid condition of PTSD, leading to a shift in treatment targets/strategies for each subtype. Objective: Perform a secondary systems biology analysis based on resources, methodology and results from our ongoing GWI research initiative to (1) isolate biobehavioral profiles that are specific to GWI alone, (2) evaluate how immune regulation in GWI is modified in the presence of probable PTSD diagnosis, and (3) use ongoing work in predictive modeling to assess possible changes to treatment of GWI in the context of probable PTSD diagnosis. Study Design: We will perform a secondary analysis of existing data obtained from our ongoing GWI research initiatives (VA Merit (Klimas PI), W81XWH-09-2-0071 (Klimas PI), GW140153 (Klimas PI)) for male veterans meeting the Fukuda et al. 1998 definition for GWI previously recruited from the Miami VA Medical Center. AIM 1: Review of cases to subtype groups and refine definition of GWI subjects with PTSD: The cases for all participants in our previous studies containing CIDI and DTS evaluations will be reviewed to determine the frequency and severity of PTSD. Participants that meet the DSM-IV and ICD-10 qualified symptoms for PTSD, as well as stringent DTS cutoff scores, will be taken as positive screens for a high probability of PTSD. Using this our cohort will be separated into three equally sized groups of 25 subjects each: 1) HC screened negative for PTSD symptoms, 2) GWI subjects screened negative for PTSD symptoms, and 3) GWI subjects screened positive for PTSD symptoms. Outcomes: This phase of work will support the case definition of two sub-types of GWI delineated by probable PTSD diagnosis. AIM 2: Identify and validate biobehavioral patterns that confirm diagnosis: Immune function in response to exercise at the cellular (Flow cytometry), and immune signaling (ELISA multiplex assay) levels as collected previously by our GWI research initiatives will be compared across AIM 1 defined groups via standard univariate, multivariate, and correlation analyses to test for differences in endocrine, immune, cardiovascular and psychometric status across illness subtypes. Outcomes: This phase of work will support the identification of exercise responsive markers and symptoms of GWI that differ with a probable PTSD diagnosis. AIM 3: Simulate optimal subtype specific treatments: Using the computational framework developed under our previous work (W81XWH-10-1-0774 Broderick PI) we will apply a combinatorial optimization scheme to a Monte Carlo simulation of a discrete ternary logic model that represents the combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and detailed immune system regulation to identify optimal treatment courses for GWI subjects with and without probably PTSD diagnosis based on the profiles identified in AIM 2. As we are estimating dynamic interaction between hormones, and cytokines as well as the population response in a number of individual cell types, therapies involving immune cell inoculation as well as cytokine and hormone replacement strategies will be examined. Outcome: This phase will result in a putative optimized GWI sub-type specific immune-endocrine intervention strategies that can be tested in clinic. Impact: This proposal is responsive to multiple components of the award mechanism. Specifically, this proposal is directly focused on secondary analysis to improve the diagnostic criteria for GWI. However the methodology used extends beyond conventional approaches by (i) formally exploring complex interactions between GWI and the co-morbid condition of PTSD, (ii) using a systems biology approach to harness the associations between molecular and cellular markers in order identify candidate diagnostic/treatment targets and (iii) promoting translational medicine by simulating validated biomarkers as potential candidate treatment targets for re-establishing healthy immune regulation. The deliverables of this project are highly focused and include validation of improved diagnostic criteria as well as the identification of interventions strategies targeting endocrine/immune mediators.

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