ApoE2 Exaggerates PTSD-Related Behavioral, Cognitive, and Neuroendocrine Alterations.
ABSTRACT: Apolipoprotein E (apoE) is an essential component of lipoprotein particles in both the brain and periphery, and exists in three isoforms in the human population: E2, E3, and E4. ApoE has numerous, well-established roles in neurobiology. Most notably, E4 is associated with earlier onset and increased risk of Alzheimer's disease (AD). Although possession of E2 is protective in the context of AD, E2 appears to confer an increased incidence and severity of posttraumatic stress disorder (PTSD). However, the biological processes underlying this link remain unclear. In this study, we began to elucidate these associations by examining the effects of apoE on PTSD severity in combat veterans, and on PTSD-like behavior in mice with human apoE. In a group of 92 veterans with PTSD, we observed significantly higher Clinician-Administered PTSD Scale and PTSD Checklist scores in E2+ individuals, as well as alterations in salivary cortisol levels. Furthermore, we measured behavioral and biological outcomes in mice expressing human apoE after a single stressful event as well as following a period of chronic variable stress, a model of combat-related trauma. Mice with E2 showed impairments in fear extinction, and behavioral, cognitive, and neuroendocrine alterations following trauma. To the best of our knowledge, these data constitute the first translational demonstration of PTSD severity in men and PTSD-like symptoms in mice with E2, and point to apoE as a novel biomarker of susceptibility, and potential therapeutic target, for PTSD.
Project description:The apolipoprotein E (APOE) ?4 allele has been implicated in a range of neuropsychiatric conditions. The present research examined if the ?4 allele of the APOE gene moderated the effect of combat exposure on posttraumatic stress disorder (PTSD) among Iraq/Afghanistan-era veterans.Participants included 765 non-Hispanic White (NHW) and 859 non-Hispanic Black (NHB) Iraq/Afghanistan-era veterans. A structured interview established psychiatric diagnoses. Combat exposure and PTSD symptom severity were assessed via self-report.The most common lifetime diagnoses were depression (39.2%), PTSD (38.4%), and alcohol dependence (24.38%). After correcting for multiple comparisons, no significant effects were observed on any of the outcomes among the NHW sample; however, within the NHB sample, significant gene × environment (G × E) interactions were observed for lifetime PTSD (P = .0029) and PTSD symptom severity (P = .0009). In each case, the APOE ?4 allele had no effect on the outcomes when combat exposure was low; however, when combat exposure was high, an additive effect was observed such that ?4 homozygotes exposed to high levels of combat reported the highest rates of PTSD (92%) and the worst symptom severity scores on the Davidson Trauma Scale (M = 79.5).Although preliminary, these findings suggest that the APOE ?4 allele, in conjunction with exposure to high levels of combat exposure, may increase veterans' risk for developing PTSD.
Project description:BACKGROUND:Previous research examining the association between apolipoprotein E (APOE) gene polymorphism and risk for posttraumatic stress disorder (PTSD) has been inconsistent due to the use of small and select samples. This study examined the relation between APOE genotype and PTSD symptoms in two nationally representative samples of U.S. military veterans. The potential effect of cumulative trauma burden and social support in moderating this association was also evaluated. METHODS:The main sample consisted of 1,386 trauma-exposed European American (EA) veterans (mean age: 62-63 years) who participated in the National Health and Resilience in Veterans Study (NHRVS) in 2011. The independent replication sample consisted of 509 trauma-exposed EA veterans from the 2013 NHRVS. RESULTS:APOE ?4 allele carriers reported significantly greater severity of PTSD symptoms than noncarriers in the main, but not the replication, sample. In both samples, the interaction of APOE ?4 carrier status and cumulative trauma burden was associated with greater severity of PTSD symptoms (F range = 2.53-8.09, all P's < .01), particularly re-experiencing/intrusion symptoms (F range = 3.59-4.24, P's < .001). Greater social support was associated with lower severity of PTSD symptoms among APOE ?4 allele carriers with greater cumulative trauma burden (? range -.27 to -.60, P's < .05). CONCLUSION:U.S. military veterans who are APOE ?4 allele carriers and exposed to a high number of traumas may be at increased risk for developing PTSD symptoms than ?4 noncarriers. Greater social support may moderate this association, thereby highlighting the potential importance of social support promoting interventions in mitigating the effect of ?4 × cumulative trauma burden on PTSD risk.
Project description:Neuroimaging studies have revealed functional abnormalities in the anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal of this study was to determine whether hyperresponsivity of the dorsal anterior cingulate in PTSD is an acquired characteristic or a familial risk factor.Using a case-control twin design, the authors studied combat-exposed veterans with PTSD (N=12) and their identical combat-unexposed co-twins (N=12), as well as combat-exposed veterans without PTSD (N=14) and their identical combat-unexposed co-twins (N=14). Participants underwent functional MRI during completion of the Multi-Source Interference Task, which reliably activates the dorsal anterior cingulate.Combat-exposed veterans with PTSD and their unexposed co-twins had significantly greater activation in the dorsal anterior cingulate and tended to have larger response time difference scores, as compared to combat-exposed veterans without PTSD and their co-twins. Dorsal anterior cingulate activation in the exposed twins was positively correlated with their PTSD symptom severity. Dorsal anterior cingulate activation in the unexposed twins was positively correlated with their combat-exposed co-twins' PTSD symptom severity, but not with depression or alcohol use severity in the combat-exposed co-twins.Hyperresponsivity in the dorsal anterior cingulate appears to be a familial risk factor for the development of PTSD following psychological trauma.
Project description:Background:Previously we reported a genetic risk score significantly improved PTSD prediction among a trauma-exposed civilian population. In the current study, we sought to assess this prediction among a trauma-exposed military population. Methods:We examined current PTSD diagnosis and PTSD symptom severity among a random sample of 1042 community-based US military veterans. Main effects and interaction effects were assessed for PTSD genetic risk by trauma exposure using cross-product terms for PTSD x trauma exposures, including combat, lifetime trauma, and adverse childhood exposures. The PTSD risk variants studied were within genetic loci previously associated with PTSD, including CRHR1, CHRNA5, RORA, and FKBP5 genetic variants, which were used to calculate a total PTSD genetic risk score (range=0-8, mean=3.6, SD=1.4). Results:Based on DSM-5 PTSD criteria, 7.1% of veterans (95% CI=5.6-8.8) met criteria for current PTSD. The PTSD genetic risk count was significantly higher among PTSD cases vs non-cases (3.92 vs 3.55, p=0.027). Since the PTSD genetic risk score was not significant in the PTSD diagnosis model, we assessed this association using PTSD symptom severity. Because these symptom data were skewed (mean=9.54, SD=12.71, range=0-76), we used negative binomial regression to assess this outcome. This symptom model included a PTSD genetic risk score, demographic factors, trauma exposures, current insomnia, current depression, concussion history, and attention-deficit disorder, expressed as incident rate ratios (IRR), which is an estimate of one-unit increase in PTSD severity, given other variables are held constant. Variables in the final model included age and sex (both p<0.001), PTSD genetic risk (IRR=1.02, p=0.028), warzone tours (IRR=0.94, p=0.003), childhood abuse (IRR=1.50, p<0.0001), current depression (IRR=1.89, p<0.0001), current insomnia (IRR=2.58, p<0.0001), low social support (IRR=1.19, p<0.0001), attention-deficit disorder (IRR=1.51, p<0.0001), agreeable personality (IRR=0.77, p<0.0001), and concussion (IRR=1.38, p<0.0001). Significant interactions were detected for combat and lifetime trauma exposure by PTSD genetic risk (both p<0.0001), suggesting that the impact of trauma exposures on PTSD severity was lower when the PTSD genetic risk was higher. Conclusion:Both warzone and non-warzone factors predicted current PTSD symptoms among veterans, including a PTSD genetic risk score. Interaction effects were detected for combat exposure and lifetime trauma by genetic risk score for PTSD symptoms, suggesting that PTSD symptom manifestation was more dependent on PTSD risk variants than the level of trauma or combat exposure. This suggests that controlling for other factors, the absence of genetic risk variants may confer PTSD resilience. Further research is planned.
Project description:Objective/Background: Despite a well-established role of guilt cognitions in the maintenance and treatment of posttraumatic stress disorder (PTSD), relationships of guilt cognitions to nightmares are not well understood. This study investigated the ways in which guilt cognitions, related to traumatic events, influenced the relationship between combat exposure and trauma-related sleep disturbance in military Veterans with PTSD. Participants: We recruited a sample of 50 Veterans with PTSD who completed study measures at a screening session. Methods: Participants completed self-report measures of exposure to potentially traumatic events, trauma-related guilt (hindsight bias, wrongdoing, and lack of justification) and trauma-related sleep disturbance as measured by a self-report scale and clinician ratings of nightmare severity. Results: Bivariate regression analyses established a relationship of combat exposure to wrongdoing (? = .31, p = .031), and a relationship of wrongdoing with self-reported trauma-related sleep disturbance (? = .27, p = .049) and clinician-rated nightmare severity (? = .36, p = .009). Bootstrapping analysis that included years of education as a covariate found a significant overall indirect effect of combat exposure on clinician-rated nightmare severity exerted through wrongdoing (? = .10, 95% CI [.004, .246]). Conclusions: Results suggest the association of combat exposure with trauma-related sleep disturbance is significantly influenced by perceived wrongdoing related to a traumatic event. Targeting cognitions related to wrongdoing and moral injury during a traumatic event in PTSD treatment may help ameliorate trauma-related sleep disturbance.
Project description:Combat-exposed Veterans are at increased risk for developing psychological distress, mood disorders, and trauma and stressor-related disorders. Trauma and mood disorders have been linked to alterations in brain volume, function, and connectivity. However, far less is known about the effects of combat exposure on brain health. The present study examined the relationship between severity of combat exposure and cortical thickness. Post-9/11 Veterans (N?=?337; 80% male) were assessed with structural neuroimaging and clinically for combat exposure, depressive symptoms, prior head injury, and posttraumatic stress disorder (PTSD). Vertex-wide cortical thickness was estimated using FreeSurfer autosegmentation. FreeSurfer's Qdec was used to examine relationship between combat exposure, PTSD, and prior head injuries on cortical thickness (Monte Carlo corrected for multiple comparisons, vertex-wise cluster threshold of 1.3, p?<?0.01). Covariates included age, sex, education, depressive symptoms, nonmilitary trauma, alcohol use, and prior head injury. Higher combat exposure uniquely related to lower cortical thickness in the left prefrontal lobe and increased cortical thickness in the left middle and inferior temporal lobe; whereas PTSD negatively related to cortical thickness in the right fusiform. Head injuries related to increased cortical thickness in the bilateral medial prefrontal cortex. Combat exposure uniquely contributes to lower cortical thickness in regions implicated in executive functioning, attention, and memory after accounting for the effects of PTSD and prior head injury. Our results highlight the importance of examining effects of stress and trauma exposure on neural health in addition to the circumscribed effects of specific syndromal pathology.
Project description:<h4>Background</h4>Mild traumatic brain injury (mTBI) is a common injury among military personnel serving in Iraq or Afghanistan. The impact of repeated episodes of combat mTBI is unknown.<h4>Objective</h4>To evaluate relationships among mTBI, post-traumatic stress disorder (PTSD) and neurological deficits (NDs) in US veterans who served in Iraq or Afghanistan.<h4>Methods</h4>This was a case-control study. From 2091 veterans screened for traumatic brain injury, the authors studied 126 who sustained mTBI with one or more episodes of loss of consciousness (LOC) in combat. Comparison groups: 21 combat veterans who had definite or possible episodes of mTBI without LOC and 21 veterans who sustained mTBI with LOC as civilians.<h4>Results</h4>Among combat veterans with mTBI, 52% had NDs, 66% had PTSD and 50% had PTSD and an ND. Impaired olfaction was the most common ND, found in 65 veterans. The prevalence of an ND or PTSD correlated with the number of mTBI exposures with LOC. The prevalence of an ND or PTSD was >90% for more than five episodes of LOC. Severity of PTSD and impairment of olfaction increased with number of LOC episodes. The prevalence of an ND for the 34 combat veterans with one episode of LOC (4/34=11.8%) was similar to that of the 21 veterans of similar age and educational background who sustained civilian mTBI with one episode of LOC (2/21=9.5%, p-NS).<h4>Conclusions</h4>Impaired olfaction was the most frequently recognised ND. Repeated episodes of combat mTBI were associated with increased likelihood of PTSD and an ND. Combat setting may not increase the likelihood of an ND. Two possible connections between mTBI and PTSD are (1) that circumstances leading to combat mTBI likely involve severe psychological trauma and (2) that altered cerebral functioning following mTBI may increase the likelihood that a traumatic event results in PTSD.
Project description:<h4>Background</h4>Complicated grief (CG) is a bereavement-specific syndrome distinct from but commonly comorbid with posttraumatic stress disorder (PTSD). While bereavement is common among military personnel (Simon et al., 2018), there is little research on the impact of CG comorbidity on PTSD treatment outcomes.<h4>Methods</h4>To evaluate the impact of comorbid CG on PTSD treatment outcomes we analyzed data from a randomized trial comparing prolonged exposure, sertraline, and their combination in veterans with a primary diagnosis of combat-related PTSD (n?=?194). Assessment of PTSD, trauma-related guilt, functional impairment, and suicidal ideation and behavior occurred at baseline and weeks 6, 12, and 24 during the 24-week trial.<h4>Results</h4>CG was associated with lower PTSD treatment response (odds ratio (OR)?=?0.29, 95% confidence interval (CI) [0.12, 0.69], p?=?0.005) and remission (OR?=?0.28, 95% CI [0.11, 0.71], p?=?0.007). Those with CG had greater severity of PTSD (p?=?0.005) and trauma-related guilt (<0.001) at baseline and endpoint. In addition, those with CG were more likely to experience suicidal ideation during the study (CG: 35%, 14/40 vs. no CG 15%, 20/130; OR?=?3.01, 95% CI [1.29, 7.02], p?=?0.011).<h4>Conclusions</h4>Comorbid CG is associated with elevated PTSD severity and independently associated with poorer endpoint treatment outcomes in veterans with combat-related PTSD, suggesting that screening and additional intervention for CG may be needed.
Project description:<h4>Objective</h4>To examine the association between the 5-HTTLPR polymorphism of the serotonin transporter (SLC6A4) gene, combat exposure, and posttraumatic stress disorder (PTSD) diagnosis and among two samples of combat-exposed veterans.<h4>Method</h4>The first sample included 550 non-Hispanic Black (NHB) combat-exposed veterans. The second sample included 555 non-Hispanic White (NHW) combat-exposed veterans. Participants were genotyped for the 5-HTTLPR/rs25531 variants of the SLC6A4 gene. A structured clinical interview was used to diagnose PTSD. Combat and civilian trauma exposure were assessed with validated self-report instruments. Logistic regression was used to test for main effects of 5-HTTLPR on PTSD diagnosis as well as gene x environment (GxE) interactions after adjusting for sex, ancestry proportion scores, civilian trauma exposure, and combat exposure.<h4>Results</h4>Within the NHB sample, a significant additive effect was observed for 5-HTTLPR (OR = 1.502, p = .0025), such that the odds of having a current diagnosis of PTSD increased by 1.502 for each additional S' allele. No evidence for an association between 5-HTTLPR and PTSD was observed in the NHW sample. In addition, no evidence for combat x 5-HTTLPR effects were observed in either sample.<h4>Conclusion</h4>The present study suggests that there may be an association between 5-HTTLPR genotype and PTSD diagnosis among NHB veterans; however, no evidence for the hypothesized 5-HTTLPR x combat interaction was found.
Project description:We investigated the extent of cortical thinning in U.S. Veterans exposed to combat who varied in the severity of their posttraumatic stress disorder (PTSD) symptoms. In addition, we explored the neural correlates of PTSD symptom dimensions and the interactive effects of combat exposure and PTSD upon cortical thickness. Sixty-nine combat exposed Veterans completed high-resolution magnetic resonance imaging (MRI) scans to estimate cortical thickness. The Clinician Administered PTSD Scale (CAPS) and Combat Exposure Scale (CES) assessments were completed to measure current PTSD and historical combat severity, respectively. PTSD symptom dimensions (numbing, avoidance, reexperiencing, anxious arousal, and dysphoric arousal) were studied. Vertex-wise whole cerebrum analyses were conducted. We found widespread negative correlations between CAPS severity and cortical thickness, particularly within the prefrontal cortex. This prefrontal correlation remained significant after controlling for depression severity, medication status, and other potential confounds. PTSD dimensions, except anxious arousal, negatively correlated with cortical thickness in various unique brain regions. CES negatively correlated with cortical thickness in the left lateral prefrontal, regardless of PTSD diagnosis. A significant interaction between CES and PTSD diagnosis was found, such that CES negatively correlated with cortical thickness in the non-PTSD, but not in the PTSD, participants. The results underscore the severity of cortical thinning in U.S. Veterans suffering from high level of PTSD symptoms, as well as in Veterans with no PTSD diagnosis but severe combat exposure. The latter finding raises considerable concerns about a concealed injury potentially related to combat exposure in the post-9/11 era.