Faculty Bibliography

Depression has been linked to Alzheimer's disease as either an increased risk factor for its development or as a prodromal symptom. The neurobiological basis for such an association, however, remains poorly understood. Numerous studies have examined whether changes in amyloid beta (Abeta) metabolism, which are implicated in the pathogenesis of Alzheimer's disease, are also found in depression. In this paper, we investigated the relationship between depressive symptoms and cerebrospinal fluid (CSF) Abeta indices in otherwise healthy, cognitively normal elderly with late-life major depression (LLMD) and controls using a longitudinal approach, which is a novel contribution toward the literature. Significantly lower levels of CSF Abeta42 were observed in the LLMD group at baseline and were associated with more severe depressive symptoms. During longitudinal follow-up, the depressed group remained cognitively unchanged, but was significantly less depressed than at baseline. A greater improvement in depressive symptoms was associated with increases in CSF Abeta42 levels in both groups. Increases in CSF Abeta42 and Abeta40 were also associated with increased CSF total-tau levels. Our results suggest that LLMD may be associated with state-dependent effects of CSF Abeta42 levels. Future studies should determine whether the association reflects state-dependent changes in neuronal activity and/or brain amyloid burden in depression.

Charles Marmar will present data from a prospective longitudinal cohort study of active-duty military. The total sample size of this ongoing study is n = 1800 and currently there are pre-and post deployment data available for over 600 individuals. Outcome trajectories were modeled and four primary outcome groups were identified. Pre-deployment inflammatory markers predicted progressive symptomatology following deployment

Posttraumatic Stress Disorder (PTSD) is associated with maladaptive changes in self-identity, including impoverished perceived self-efficacy. This study examined if enhancing perceptions of self-efficacy in combat veterans with and without symptoms of PTSD promotes cognitive strategies associated with positive mental health outcomes. Prior to completing a future thinking and social problem-solving task, sixty-two OEF/OIF veterans with and without symptoms of PTSD were randomized to either a high self-efficacy (HSE) induction in which they were asked to recall three autobiographical memories demonstrating self-efficacy or a control condition in which they recalled any three autobiographical events. An interaction between HSE and PTSD revealed that individuals with symptoms of PTSD in the HSE condition generated future events with more self-efficacious statements than those with PTSD in the control condition, whereas those without PTSD did not differ in self-efficacy content across the conditions. In addition, individuals in the HSE condition exhibited better social problem solving than those in the control condition. Increasing perceptions of self-efficacy may promote future thinking and problem solving in ways that are relevant to overcoming trauma and adversity.

INTRODUCTION: Post-traumatic stress disorder (PTSD) has been associated with immune disturbances, including a higher incidence of infections and autoimmune diseases as well as a net pro-inflammatory state. Natural killer (NK) cells, a key component of the innate immune system, have been less well-studied in PTSD despite their importance in immunity. METHODS: We studied two independent samples of combat-exposed male war veterans with or without PTSD, the first ("Discovery Sample") to generate hypotheses, and the second ("Validation Sample") to replicate the findings. The Discovery Sample was comprised of 42 PTSD subjects and 42 controls. The Validation Sample was comprised of 25 PTSD subjects and 30 controls. Participants had fasting, morning blood samples collected for examination of the frequency of NK cell subsets, determined by flow cytometry. The current and lifetime Clinician Administered PTSD Scale (CAPS) was used to assess symptom severity. Statistical analyses were adjusted for age and BMI. RESULTS: PTSD subjects compared to controls had (i) a significantly higher relative frequency of atypical CD56(-)CD16(+) NK cells in the Discovery Sample (p=0.027), which was replicated in the Validation Sample (p=0.004) and the combined sample (p<0.001), and (ii) a non-significantly lower relative frequency of CD56(bright)CD16(-) NK cells in the two samples (p=0.082; p=0.118), which became statistically significant in the combined sample (p=0.020). Further, within subjects with PTSD of both samples, the relative frequency of atypical CD56(-)CD16(+) NK cells was near significantly positively correlated with lifetime PTSD severity (p=0.074). DISCUSSION: This study is the first to characterize NK cell subsets in individuals with PTSD. The results suggest that combat-exposed men with PTSD exhibit an aberrant profile of NK cells with significantly higher frequencies of an atypical population of CD56(-)CD16(+) cells and possibly lower frequencies of the functional CD56(bright)CD16(-) NK cell subsets. Higher proportions of dysfunctional CD56(-)CD16(+) cells have been reported in certain chronic viral infections and in senescent individuals. It is possible that this could contribute to immune dysfunctions and prematurely senescent phenotypes seen in PTSD.

OBJECTIVE: The primary goal of this analysis was to assess whether recent use of outpatient services for general medical concerns by Vietnam veterans varies according to level of posttraumatic stress disorder (PTSD) symptomatology over time. Another goal was to determine whether PTSD symptomatology was associated with veterans' reports of discussing behavioral health issues as part of a general medical visit. METHODS: Self-reported service use data and measures of PTSD were from a nationally representative sample of 848 male and female Vietnam theater veterans (individuals who were deployed to the Vietnam theater of operations) who participated in the National Vietnam Veterans Longitudinal Study, a 25-year follow-up of a cohort of veterans originally interviewed from 1984-1988 as part of the National Vietnam Veterans Readjustment Study. Four categories of PTSD symptomatology course over 25 years were defined, and logistic regression models were used to assess their relationship with recent use of outpatient general medical services. RESULTS: Male and female theater veterans with high or increasing PTSD symptomatology over the period were more likely than those with low symptomatology to report recent VA outpatient visits. Males in the increasing and high categories were also more likely to discuss behavioral health issues at general medical visits. CONCLUSIONS: Vietnam veterans with high and increasing PTSD symptomatology over time were likely to use VA outpatient general health services. Attention to stressors of the aging process and to persistence of PTSD symptoms is important for Vietnam veterans, as is addressing PTSD with other psychiatric and medical comorbidities within the context of outpatient general medical care.

Background: Delineating the molecular basis of individual differences in the stress response is critical to understanding the pathophysiology of post-traumatic-stress-disorder (PTSD), with the ultimate goal of identifying biomarkers that can be associated with treatment response. Methods: We analyzed blood genome-wide expression, functional neuroendocrinology and immunology from a cross-sectional biomarker study with and without PTSD (n=68/group). In addition, gene expression in blood and brain (amygdala and hippocampus) and neuronal morphology were analyzed from a PTSD rat model, in which vulnerable and resilient phenotypes are identified according to the behavioral response to predator scent stress (PSS). Analyses of the human and animal data were performed separately, and then compared and integrated with the use of gene co-expression network analyses. Results: Differentially expressed (DE) genes were identified in association with PTSD. These DE genes were consistent with downregulation of glucocorticoid receptor (GR) signaling and upregulation of pro-inflammatory cytokine signaling. These findings were replicated by the DE-signatures identified in rat blood and brain, in association with exposure-related individual differences. Interestingly, even though the across-tissue overlap in rat DE-signatures was small at the individual gene level (6%), there was a high conservation at the upstream transcription factor level (36%) with GR and its signaling as the most convergent. Gene co-expression networks were also identified. Among the most promising networks, there was a large (>100 genes) PTSD co-expression module showing a high level of dysregulation (modular differential connectivity >50, compared to veterans without PTSD) and conservation in the blood and brain of PTSD-like rats. Functionally, this module is enriched with the genes related to innate immune response (p<0.001), and its eigengene expression associates with the lymphocyte lysozyme inhibition by dexamethasone (p<0.05) and plasma cortisol decline in the dexamethasone suppression test (p<0.001). Finally, GR-agonist administration in rats shortly after PSS prevented PTSD-like phenotypes by reversing the vulnerability-associated cytokine signaling in the amygdala and neuronal morphology patterns in the limbic brain. Conclusions: We identified genes, pathways and gene co-expression networks in the blood of combat veterans with PTSD. GR-dependent immune pathways and networks are associated with trauma-related individual differences in blood and brain, and can be the basis of treatment for PTSD

Management of post-traumatic stress disorder (PTSD) is complicated by the overlapping symptoms of its co morbidities and the diagnostic reliance on self-report and time consuming psychological evaluation. A more comprehensive understanding of molecular pathophysiology of PTSD could facilitate an unbiased biomarker-driven next-generation intervention strategy. Herein, we cast light on the epigenomic consequences of combat elicited PTSD. In this study, hypermethylated genes were investigated as to the implications for behavior, immune response, nervous system development, and relevant PTSD co-morbidities such as cardiac health and diabetes. 52 PTSD-positive male veterans of US Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF) were matched to 52 controls by age and ethnicity. PTSD diagnosis was determined by a clinician-administered PTSD scale (CAPS), score >40, while the control group demonstrated a CAPS <10. Methylation status of DNA extracted from whole blood was assayed using high density arrays (Agilent, Inc.). 5,000 probes were statistically differentially methylated (FDR < 0.1), representing approximately 3,600 unique genes. Chromosome 4 and 18 imprints a significantly large portion of the methylated probes, including those which control emotional and cognition process, and glucocorticoid deficiency. Interestingly, a significant number of genes facilitating telomere maintenance and insulin reception were hypermethylated at both promoter and gene body sites; therefore the DNA methylation status in these genes could be prevailing. Nearly 85% of the differentially methylatedprobes were hypermethylated in PTSD patients. The majority of these probes encode the candidate proteins responsible for transcription regulation and enzymaticactions. Genes involved in memory consolidation, emotion/aggressive behavior, and perturbed circadian rhythm were preferentially hypermethylated. PTSD epigenetically perturbed both the cellular and humoral immune system; in addition the morphologies of two brain regions known to control PTSD symptoms, namely cerebral cortex and hippocampus were perturbed. Genes involved in several PTSD comorbidities, such as cardiomyopathy and poor insulin management, were also hypermethylated. Integration of the epigenomic observations with other omics outcomes is underway, as well as validation of these findings in an independent cohort

Major depressive disorder (MDD), common in the elderly, is a risk factor for dementia. Abnormalities in glutamatergic neurotransmission via the N-methyl-d-aspartate receptor (NMDA-R) have a key role in the pathophysiology of depression. This study examined whether depression was associated with cerebrospinal fluid (CSF) levels of NMDA-R neurotransmission-associated amino acids in cognitively intact elderly individuals with MDD and age- and gender-matched healthy controls. CSF was obtained from 47 volunteers (MDD group, N=28; age- and gender-matched comparison group, N=19) at baseline and 3-year follow-up (MDD group, N=19; comparison group, N=17). CSF levels of glutamine, glutamate, glycine, l-serine and d-serine were measured by high-performance liquid chromatography. CSF levels of amino acids did not differ across MDD and comparison groups. However, the ratio of glutamine to glutamate was significantly higher at baseline in subjects with MDD than in controls. The ratio decreased in individuals with MDD over the 3-year follow-up, and this decrease correlated with a decrease in the severity of depression. No correlations between absolute amino-acid levels and clinical variables were observed, nor were correlations between amino acids and other biomarkers (for example, amyloid-beta42, amyloid-beta40, and total and phosphorylated tau protein) detected. These results suggest that abnormalities in the glutamine-glutamate cycle in the communication between glia and neurons may have a role in the pathophysiology of depression in the elderly. Furthermore, the glutamine/glutamate ratio in CSF may be a state biomarker for depression.

Object/UNASSIGNED:The purpose of the current study is to determine the sensitivity and specificity of an eye tracking method as a classifier for identifying concussion. Methods/UNASSIGNED:Brain injured and control subjects prospectively underwent both eye tracking and Sport Concussion Assessment Tool 3. The results of eye tracking biomarker based classifier models were then validated against a dataset of individuals not used in building a model. The area under the curve (AUC) of receiver operating characteristics was examined. Results/UNASSIGNED:An optimal classifier based on best subset had an AUC of 0.878, and a cross-validated AUC of 0.852 in CT- subjects and an AUC of 0.831 in a validation dataset. The optimal misclassification rate in an external dataset (n = 254) was 13%. Conclusion/UNASSIGNED:If one defines concussion based on history, examination, radiographic and Sport Concussion Assessment Tool 3 criteria, it is possible to generate an eye tracking based biomarker that enables detection of concussion with reasonably high sensitivity and specificity.