Posted February 26, 2014
Harvey B. Pollard, M.D., Ph.D.
Post-traumatic stress disorder (PTSD) is a condition that can affect both civilians and active duty military personnel, although the latter are at increased risk, especially after multiple combat tours. Dr. Harvey B. Pollard and his team at the Uniformed Services University of the Health Sciences received an FY07 PTSD Investigator-Initiated Research Award to uncover PTSD-specific proteins in cerebrospinal fluid (CSF) and plasma that can represent the causal, consequential, or compensating central mechanisms responsible for the pathological behavior typical in PTSD. Historically, efforts to develop biomarkers for PTSD have failed because the proteins of interest are expressed in very low abundance and their clinical relevance could not be established. Based on the more readily available samples of plasma from PTSD patients, Dr. Pollard has also conducted proteomics studies on plasma of PTSD patients compared to healthy controls and examined ratios of some proteins of interest. The team has uncovered an exciting relationship between a set of chemokines, Monocyte chemo-attractant protein (MCP-1) and Monocyte chemo-attractant protein 4 (MCP-4). Patients suffering from PTSD, but not healthy controls, have fluctuating ratios of MCP-4 to MCP-1 depending on the time of day. However, by determining the ratio of levels of MCP-4, which trend higher in PTSD patient plasma, to levels of MCP-1, which trend lower in PTSD plasma, a highly significant gender-independent metric can be generated for PTSD. The significance across circadian time ranges between p = 0.01 and p =0.001. These findings suggest that this differential chemokine ratio could serve as a biomarker for early PTSD diagnosis. In terms of gender-dependent markers, Dr. Pollard has also discovered that MIP-1β is a biomarker for female PTSD patients and TARC is a biomarker for male PTSD patients. However, these biomarkers are only significant at specific times during the circadian day.
In addition, Dr. Pollard's team has shown that there are small non-coding RNA molecules, called microRNAs (miRNAs), which are also differentially expressed in PTSD patients compared to healthy controls. In plasma, miR-518e is reduced at 2 a.m., but elevated at 9 a.m. By contrast, four miRNAs (miR-672, miR-29a, miR-130a and miR-29c) are elevated at 2 a.m., but not different from healthy controls at 9 a.m. Finally, by determining the ratio of the levels of miR-181a, a miR that is elevated at 9 a.m., to the levels of miR-337-5p, a miR that is reduced at 9 a.m., a scale-free biomarker can be generated that has a dynamic range of 2,230, P value = 0.0006, and an area under the curve for the receiver operating characteristic analysis of 0.98. These are gender-independent data and emphasize not only the variation over circadian time, but also how samples taken at a specific time, in this case 9 a.m., can be deployed operationally.
Previous scientific research has shown that miRNAs play a role in regulating the expression of genes by binding to specific messenger RNA sequences, thereby blocking the expression of those genes. A number of PTSD-affected miRNAs in CSF can be predicted to affect expression of at least six different proteins that are associated with various neurological defects, including amyotrophic lateral sclerosis, Alzheimer's disease, and other brain pathologies. Dr. Pollard plans to use these findings as a roadmap to uncover candidate protein targets for the early diagnosis and treatment of PTSD.