Post-traumatic stress disorder (PTSD) accounts for a substantial portion of the total mental health burden in Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) warfighters and veterans. The underlying biological pathology of PTSD is not yet known, and diagnosis is exclusively based on clinical behavioral features, which are often under- or over-reported. PTSD is associated with increased risk for serious medical illnesses and premature death, but the mechanisms underlying this risk are not known. Discovering biomarkers of PTSD would aid: in diagnosis; in redefining the illness along biologically homogeneous dimensions; in staging the course of the illness; and in highlighting potential targets for treatment. Research to date has highlighted several candidate biomarkers of PTSD, but none has sufficient sensitivity, specificity or prognostic significance for clinical practice. Evaluating promising biomarkers in tandem in the same subjects holds greater hope for identifying interactions among biomarkers that may be more helpful in diagnosing this condition. For example, uncovering the degree of dysregulation across multiple biological systems (e.g., allostatic load) in PTSD should help in furthering our understanding of the biological mechanisms underlying disease risk in PTSD.

The overall objective of the proposed research is to identify potential biomarkers of PTSD using an extensive biological protocol, including several novel biomarkers of great potential significance that have not been adequately studied in this disorder. We predict that OIF/OEF service members and veterans with PTSD will have greater allostatic load, lower ambient cortisol, greater cortisol suppression following dexamethasone administration, and smaller dentate gyrus/CA3 hippocampal subfield volume than controls. We also predict that APO E4 polymorphisms will be associated with decreased dentate/CA3 volume, and that service members and veterans with PTSD will have shorter white blood cell telomere length and diminished telomerase activity, suggesting an accelerated rate of cell aging in this disorder.

 We propose to recruit 40 OIF/OEF soldiers or veterans (20 PTSD positive; 20 PTSD negative controls). We will examine potential neuroendocrine, neurogenetic, allostatic load and neuroimaging biomarkers of PTSD in these service members, and combine the data with data collected as part of a separate UCSF-led, DOD-funded (via NCIRE) study (PI: Dr. Charles Marmar) that uses identical procedures. The combined sample size will be 100 and will yield power to detect clinically meaningful medium sized effects.

The research aims to identify biomarkers of PTSD, determining which of a number of promising biomarkers combined or individually best indexes PTSD severity and PTSD-related risk for subsequent morbidity. As such, the research will facilitate: the accurate diagnoses of PTSD; the identification of individuals who are most at risk for PTSD-related disability; and indicate promising directions for treatmentrelated research.