Primary objective: Excessive accumulation of amyloid beta (Aβ) and tau have been observed in older individuals with chronic neurological symptoms related to a traumatic brain injury (TBI), yet little is known about the possible role of Aβ in younger active duty service members following a TBI. The purpose of the study was to determine if Aβ 40 or 42 related to sustaining a TBI or to chronic neurological symptoms in a young cohort of military personnel.
Blunt and blast traumatic brain injuries (TBI) are devastating medical conditions that are prevalent in civilian and military populations, respectively. While these injuries can be mild, moderate, or severe, long-term physical, cognitive, and psychiatric sequelae are suffered across all levels of severity and significantly impact quality of life. Extensive research has been conducted on biomarkers in peripheral blood after TBI, in an effort to identify and ultimately manage medical care by prophylactically treating patients at-risk for developing chronic deficits following TBI. We recently investigated another potential peripheral biomarker for TBI and found that chronic symptoms of TBI were linked to elevated concentrations of tau, one of the two hallmark proteins in Alzheimer's disease (AD). This similar pathology between TBI and AD led us to question the role of amyloid beta (Aβ), the other hallmark protein in AD, in the development of chronic symptoms following TBI. This study assessed 71 U.S. military personnel, all of whom had been recently deployed. Blood samples were collected and analyzed for concentrations of Aβ40 and Aβ42 using Simoa, an ultrasensitive, single-molecule immunoassay. Symptomatology of depression, post-traumatic stress disorder (PTSD), and post-concussive disorder (PCD) were assessed by the Quick Inventory of Depressive Symptomatology, the PTSD Checklist Military Version, and the Neurobehavioral Symptom Inventory, respectively. Subjects with a history of TBI (TBI+) were compared to those without a history of TBI (TBI-). TBI+ subjects (n=53) were identified by either self-reporting a TBI on the Warrior Administered Retrospective Casualty Assessment Tool or by having a documented TBI in their medical record, while TBI- subjects (n=18) were classified as controls.
Posttraumatic stress disorder (PTSD) affects many returning combat veterans, but underlying biological mechanisms remain unclear. In order to compare circulating micro RNA (miRNA) of combat veterans with and without PTSD, peripheral blood from 24 subjects was collected following deployment, and isolated miRNA was sequenced. PTSD was associated with 8 differentially expressed miRNA. Pathway analysis shows that PTSD is related to the axon guidance and Wnt signaling pathways, which work together to support neuronal development through regulation of growth cones. PTSD is associated with miRNAs that regulate biological functions including neuronal activities, suggesting that they play a role in PTSD symptomatology.
Military personnel experience posttraumatic stress disorder (PTSD), which is associated with differential DNA methylation across the whole genome. However, the relationship between these DNA methylation patterns and clinically relevant increases in PTSD severity is not yet clearly understood. The purpose of this study was to identify differences in DNA methylation associated with PTSD symptoms and investigate DNA methylation changes related to increases in the severity of PTSD in military personnel. In this pilot study, a cross-sectional comparison was made between military personnel with PTSD (n = 8) and combat-matched controls without PTSD (n = 6). Symptom measures were obtained, and genome-wide DNA methylation was measured using methylated DNA immunoprecipitation (MeDIP-seq) from whole blood samples at baseline and 3 months later. A longitudinal comparison measured DNA methylation changes in military personnel with clinically relevant increases in PTSD symptoms between time points (PTSD onset) and compared methylation patterns to controls with no clinical changes in PTSD. In military personnel with elevated PTSD symptoms 3 months following baseline, 119 genes exhibited reduced methylation and 8 genes exhibited increased methylation. Genes with reduced methylation in the PTSD-onset group relate to the canonical pathways of netrin signaling, Wnt/Ca(+) pathway, and axonal guidance signaling. These gene pathways relate to neurological disorders, and the current findings suggest that these epigenetic changes potentially relate to PTSD symptomology. This study provides some novel insights into the role of epigenetic changes in PTSD symptoms and the progression of PTSD symptoms in military personnel.
Repetitive low-level blast exposure is one of the major occupational health concerns among US military service members and law enforcement. This study seeks to identify gene expression using microRNA and RNA sequencing in whole-blood samples from experienced breachers and unexposed controls. We performed experimental RNA sequencing using Illumina's HiSeq 2500 Sequencing System, and microRNA analysis using NanoString Technology nCounter miRNA expression panel in whole-blood total RNA samples from 15 experienced breachers and 14 age-, sex-, and race-matched unexposed controls. We identified 10 significantly dysregulated genes between experienced breachers and unexposed controls, with FDR corrected <0.05: One upregulated gene, LINC00996 (long intergenic non-protein coding RNA 996); and nine downregulated genes, IGLV3-16 (immunoglobulin lambda variable 3-16), CD200 (CD200 molecule), LILRB5 (leukocyte immunoglobulin-like receptor B5), ZNF667-AS1 (ZNF667 antisense RNA 1), LMOD1 (leiomodin 1), CNTNAP2 (contactin-associated protein 2), EVPL (envoplakin), DPF3 (double PHD fingers 3), and IGHV4-34 (immunoglobulin heavy variable 4-34). The dysregulated gene expressions reported here have been associated with chronic inflammation and immune response, suggesting that these pathways may relate to the risk of lasting neurological symptoms following high exposures to blast over a career.
