African ancestry GWAS of dementia in a large military cohort identifies significant risk loci.

While genome wide association studies (GWASs) of Alzheimer's Disease (AD) in European (EUR) ancestry cohorts have identified approximately 83 potentially independent AD risk loci, progress in non-European populations has lagged. In this study, data from the Million Veteran Program (MVP), a biobank which includes genetic data from more than 650,000 US Veteran participants, was used to examine dementia genetics in an African descent (AFR) cohort. A GWAS of Alzheimer's disease and related dementias (ADRD), an expanded AD phenotype including dementias such as vascular and non-specific dementia that included 4012 cases and 18,435 controls age 60+ in AFR MVP participants was performed. A proxy dementia GWAS based on survey-reported parental AD or dementia (n = 4385 maternal cases, 2256 paternal cases, and 45,970 controls) was also performed. These two GWASs were meta-analyzed, and then subsequently compared and meta-analyzed with the results from a previous AFR AD GWAS from the Alzheimer's Disease Genetics Consortium (ADGC). A meta-analysis of common variants across the MVP ADRD and proxy GWASs yielded GWAS significant associations in the region of APOE (p = 2.48 × 10-101), in ROBO1 (rs11919682, p = 1.63 × 10-8), and RNA RP11-340A13.2 (rs148433063, p = 8.56 × 10-9). The MVP/ADGC meta-analysis yielded additional significant SNPs near known AD risk genes TREM2 (rs73427293, p = 2.95 × 10-9), CD2AP (rs7738720, p = 1.14 × 10-9), and ABCA7 (rs73505251, p = 3.26 × 10-10), although the peak variants observed in these genes differed from those previously reported in EUR and AFR cohorts. Of the genes in or near suggestive or genome-wide significant associated variants, nine (CDA, SH2D5, DCBLD1, EML6, GOPC, ABCA7, ROS1, TMCO4, and TREM2) were differentially expressed in the brains of AD cases and controls. This represents the largest AFR GWAS of AD and dementia, finding non-APOE GWAS-significant common SNPs associated with dementia. Increasing representation of AFR participants is an important priority in genetic studies and may lead to increased insight into AD pathophysiology and reduce health disparities.

Association of mild traumatic brain injury, post-traumatic stress disorder, and other comorbidities on photosensitivity.

SIGNIFICANCE: Photosensitivity is common after mild traumatic brain injury. However, this study demonstrates that photosensitivity is also impacted by common comorbidities that often occur with mild traumatic brain injury. Understanding how physical and psychological traumas impact photosensitivity can help improve provider care to trauma survivors and guide novel therapeutic interventions. PURPOSE: This study aimed to characterize the association between mild traumatic brain injury and common comorbidities on photosensitivity in post-9/11 veterans. METHODS: Existing data from the Translational Research Center for TBI and Stress Disorders cohort study were analyzed including traumatic brain injury history and post-traumatic stress disorder clinical diagnostic interviews; sleep quality, anxiety, and depression symptoms self-report questionnaires; and photosensitivity severity self-report from the Neurobehavioral Symptom Inventory. Analysis of covariance and multiple ordinal regression models were used to assess associations between mild traumatic brain injury and common comorbidities with photosensitivity severity. RESULTS: Six hundred forty-one post-9/11 veterans were included in this study. An initial analysis showed that both mild traumatic brain injury and current post-traumatic stress disorder diagnosis were independently associated with higher photosensitivity ratings compared with veterans without either condition, with no interaction observed between these two conditions. Results of the ordinal regression models demonstrated positive associations between degree of photosensitivity and the number of mild traumatic brain injuries during military service and current post-traumatic stress disorder symptom severity, particularly hyperarousal symptoms, even when controlling for other factors. In addition, the degree of sleep disturbances and current anxiety symptoms were both positively associated with photosensitivity ratings, whereas depression symptoms, age, and sex were not. CONCLUSIONS: Repetitive mild traumatic brain injury, post-traumatic stress disorder, anxiety, and sleep disturbances were all found to significantly impact photosensitivity severity and are therefore important clinical factors that eye care providers should consider when managing veterans with a history of deployment-related trauma reporting photosensitivity symptoms.

Early onset adolescent binge drinking is associated with reduced white matter integrity in post-9/11 adult veterans.

Adolescence represents a critical period of neural development during which binge drinking (BD) is prevalent. Though prior work has shown that white matter (WM) integrity is susceptible to damage from excessive alcohol intake in adults, the effect of early adolescent BD on WM health in adulthood remains unknown. Veterans with a history of BD onset before age 15 [n = 49; mean age = 31.8 years; early-onset adolescent binge drinkers (EBD)] and after age 15 [n = 290; mean age = 32.2 years; late-onset adolescent binge drinkers (LBD)] were studied with diffusion tensor imaging. Group differences in fractional anisotropy (FA; movement of water molecules along the WM) and mean diffusivity (MD; average movement of water molecules) were examined as indices of WM integrity using FreeSurfer and FMRIB Software Library (FSL) processing streams. Lower FA and higher MD are thought to represent degradations in WM integrity. A reference group (RG) of social drinkers with no history of BD (n = 31) was used to provide comparative normative data. We observed widespread decreased FA and increased MD in EBDs, compared to LBDs, as well as decreased FA in the pars triangularis, lateral orbitofrontal cortex, superior frontal cortex, isthmus cingulate, and genu and splenium of the corpus callosum EBDs also had lower WM integrity compared to the RG. Adults who initiated BD during early adolescence demonstrated decreased FA and increased MD throughout the frontostriatal circuits that mediate inhibitory control and thus may result in impulsive behavior and a predisposition for developing alcohol use disorder during adulthood.

The Impact of Blast Exposure-With or Without Traumatic Brain Injury-on Metabolic Abnormalities in Post-9/11 Veterans.

OBJECTIVE: The primary aim included explorations of: (1) the associations between the history of blast exposure (BE), close blast exposure (CBE), and blast-related traumatic brain injury (bTBI) and metabolic abnormality; and (2) the potential mediating effect of comorbid psychological and somatic conditions on these associations. The secondary aim explored the association of dose-response impact of BE, CBE, and bTBI and metabolic abnormality. SETTING: Data were collected by the Translational Research Center for TBI and Stress Disorders (TRACTS). PARTICIPANTS: Post-9/11 veterans from the TRACTS baseline sample who had conflict-zone deployment experience ( N = 734). DESIGN: Cross-sectional secondary data analysis. We computed relative risks (RRs) and 95% CI using modified Poisson regression. We quantified the impact of co-occurring psychological and somatic conditions on this association using mediation analyses. MAIN MEASURES: Exposures included BE (<100 m), CBE (<10 m), and bTBI. Metabolic abnormality outcomes included (1) overweight/obesity (defined by abnormal waist-hip ratio [WHR] and abnormal waist circumference [WC]); (2) glucose dysregulation; and (3) meeting criteria for cardiometabolic syndrome (defined by guidelines). RESULTS: The sample was majority male (91%) and White (68%), with a mean age of 34.6 years (SD = 8.99). Most participants had 1 or more BE (83%); 48% experienced 1 or more CBE. Overweight/obesity was highly prevalent in the sample (51% had abnormal WHR and 60% abnormal WC). There was no significant direct or indirect association between BE, CBE, and bTBI and metabolic abnormalities (RRs: 0.70-1.51; P 's > .05). CONCLUSION: Future research is needed to investigate the association of BE with metabolic abnormalities with larger, more targeted sample selection, and longer follow-up. Effective and sustainable weight management and metabolic health prevention interventions for this veteran cohort are needed.

Alzheimer's disease and related dementias among aging veterans: Examining gene-by-environment interactions with post-traumatic stress disorder and traumatic brain injury.

INTRODUCTION: Post-traumatic stress disorder (PTSD) and traumatic brain injury (TBI) confer risk for Alzheimer's disease and related dementias (ADRD). METHODS: This study from the Million Veteran Program (MVP) evaluated the impact of apolipoprotein E (APOE) ε4, PTSD, and TBI on ADRD prevalence in veteran cohorts of European ancestry (EA; n = 11,112 ADRD cases, 170,361 controls) and African ancestry (AA; n = 1443 ADRD cases, 16,191 controls). Additive-scale interactions were estimated using the relative excess risk due to interaction (RERI) statistic. RESULTS: PTSD, TBI, and APOE ε4 showed strong main-effect associations with ADRD. RERI analysis revealed significant additive APOE ε4 interactions with PTSD and TBI in the EA cohort and TBI in the AA cohort. These additive interactions indicate that ADRD prevalence associated with PTSD and TBI increased with the number of inherited APOE ε4 alleles. DISCUSSION: PTSD and TBI history will be an important part of interpreting the results of ADRD genetic testing and doing accurate ADRD risk assessment.

The Boston Assessment of Traumatic Brain Injury-Lifetime Semistructured Interview for Assessment of TBI and Subconcussive Injury Among Female Survivors of Intimate Partner Violence: Evidence of Research Utility and Validity.

OBJECTIVE: To adapt the Boston Assessment of TBI-Lifetime (BAT-L) interview specifically for female survivors of intimate partner violence (IPV), validate the adapted BAT-L/IPV, and report the prevalence of head injury. SETTING: The BAT-L is the first validated instrument to diagnose traumatic brain injuries (TBIs) throughout the life span for post-9/11 veterans. The BAT-L/IPV was adapted to target diagnostic issues belonging exclusively to IPV while maintaining its life span approach. PARTICIPANTS: Community-dwelling convenience sample of 51 female survivors of IPV with subthreshold (n = 10) or full diagnostic criteria (n = 41) of posttraumatic stress disorder. DESIGN: Standard TBI criteria were evaluated using a semistructured clinical interview. MAIN MEASURES: The BAT-L/IPV is compared with the Ohio State University TBI Identification Method (OSU-TBI-ID) scoring approach as the criterion standard. RESULTS: Correspondence between the BAT-L/IPV and the OSU-TBI-ID score was excellent (Cohen κ = 0.86; Kendall τ-b = 0.89). Sensitivity = 89.3% (95% CI, 81.2-97.4); specificity = 98.3% (95% CI, 95.0-100); positive predictive value = 98.0% (95% CI, 94.2-100); and negative predictive value = 90.6% (95% CI, 83.5-97.7). On the BAT-L/IPV, more than one-third (35.3%) of IPV survivors reported TBI secondary to an IPV-related assault, 76.5% reported IPV subconcussive head injury, 31.4% reported attempted strangulation, and 37.3% reported non-IPV TBI. CONCLUSIONS: The BAT-L/IPV performed well in diagnosing TBI in female IPV survivors as compared with the criterion standard. The prevalence of TBI was frequent; subconcussive head injury was pervasive. Greater awareness for head injury risk and increased diagnostic specificity of TBI in IPV survivors is needed.

Research utility of a CAPS-IV and CAPS-5 hybrid interview: Posttraumatic stress symptom and diagnostic concordance in recent-era U.S. veterans.

The Clinician-Administered PTSD Scale (CAPS) is used to measure posttraumatic stress symptoms (PTSS) and diagnose posttraumatic stress disorder (PTSD). However, its use, particularly in settings involving longitudinal assessment, has been complicated by changes in the diagnostic criteria between the fourth and fifth editions of the Diagnostic and Statistical Manual of Mental Disorders (i.e., DSM-IV and DSM-5, respectively). The current sample included trauma-exposed U.S. veterans who were deployed in support of military operations following the September 11, 2001, terrorist attacks (N = 371) and were enrolled in a longitudinal study focused on deployment-related stress and traumatic brain injury. A hybrid clinical interview using item wording from the CAPS for DSM-IV (CAPS-IV) with the addition of items unique to the CAPS for DSM-5 (CAPS-5) was used to assess both DSM-IV and DSM-5 PTSD diagnostic criteria, allowing for the calculation of separate total scores and diagnoses. Diagnostic agreement, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and interrater reliability between CAPS-IV and CAPS-5 were evaluated for the entire sample and stratified by gender. We found high diagnostic agreement (92.9%-95.4%), sensitivity (94.4%-98.2%), specificity (91.7%-92.8%), PPV (89.5%-93.0%), NPV (95.7%-98.1%), and interrater reliability,κ = 0.86-0.91,) for both men and women. The current study supports the use of a hybrid PTSD diagnostic interview assessing both DSM-IV and DSM-5 diagnostic criteria, particularly in situations such as longitudinal studies that may require a feasible method of incorporating changes in diagnostic criteria from the DSM-IV to the DSM-5.

Network analysis of mild traumatic brain injury, persistent neurobehavioral and psychiatric symptoms, and functional disability among recent-era United States veterans.

Recent-era U.S. veterans are clinically complex, with a high prevalence of co-occurring mild traumatic brain injury (mTBI), psychiatric conditions, and behavioral dysfunction. The current study examined the direct and indirect associations between mTBI and persistent neurobehavioral, psychiatric, and functional disability symptoms among recent-era U.S. veterans and service members (n = 648). We evaluated the postconcussive syndrome (PCS) potential causal model with two network analysis modeling approaches. Separate analyses were conducted for military mTBI and lifetime mTBI. An exploratory factor analysis was conducted to limit topological overlap in the network analysis. The most influential symptoms (i.e., the unique variables most strongly associated with the rest of the network) in the military mTBI network were behavioral disengagement, expected influence (EI) = 1.10; cognitive difficulties, EI = 1.08; agitation/irritability, EI = 1.05; and PTSD-related reexperiencing and avoidance symptoms, EI = 0.98. After accounting for other symptoms, mTBI was only minimally informative, EI = 0.34. Additionally, military mTBI did not moderate the association between symptoms or the overall connectivity of the network. The results for lifetime mTBI were consistent with those for military mTBI. The present analyses identified a variety of behavioral, cognitive, and emotional symptoms that play an important role in understanding comorbidity and daily functioning among recent-era U.S. veterans. Associations between cumulative mTBI that occurred in civilian or military settings were indirect and relatively small in magnitude. The current results add to a growing literature raising doubts about the PCS model.

Associations between changes in somatic and psychiatric symptoms and disability alterations in recent-era U.S. veterans.

Cross-sectional work suggests that deployment-related posttraumatic sequelae are associated with increased disability in U.S. veterans deployed following the September 11, 2001 (9/11), terrorist attacks. However, few studies have examined the psychiatric and somatic variables associated with changes in functional disability over time. A total of 237 post-9/11 veterans completed comprehensive assessments of psychiatric and cognitive functioning, as well as a disability questionnaire, at baseline and 2-year follow-up. At baseline, higher levels of PTSD, depressive, and pain-related symptoms were associated with baseline global functional disability, semipartial r2 = .036-.044. Changes in symptoms of PTSD, depression, pain, and sleep, but not anxiety or alcohol use, were independently associated with changes in functional disability, semipartial r2 = .017-.068. Baseline symptoms of these conditions were unrelated to changes in disability, and cognitive performance was unrelated to disability at any assessment point. Together, this suggests that changes in psychiatric and somatic symptoms are tightly linked with changes in functional disability and should be frequently monitored, and even subclinical symptoms may be a target of intervention.

Associations among clinical variables and anger differ by early life adversity among post-9/11 veterans.

Maladaptive anger and aggression are common in US military veterans and increase risk for impaired social relationships and functioning, justice-involvement and violence. Early life (before age 18) adversity predisposes veterans to later life psychopathology, though the link to increased later life anger is unclear. We analysed cross-sectional data of 158 post-9/11 veterans from the Translational Research Center for Traumatic Brain Injury and Stress Disorders study with and without a history of early life adversity (ns = 109 and 49, respectively). We explored the relationship among major clinical variables and current veteran anger (Dimensions of Anger Reactions) and whether the associations with these variables differed among participants with and without a history of retrospective self-reported early life adversity (Childhood Trauma Questionnaire). In the overall sample, posttraumatic stress disorder (PTSD) and depression severities had the strongest associations with current veteran anger (ßs = 0.261 and 0.263; p-values = 0.0022 and 0.0103, respectively). In the subsample without early life adversity, only PTSD severity was significantly associated with anger (ß = 0.577, p = 0.0004). In the early life adversity subsample, this strong association weakened and was no longer significant (ß = 0.168, p = 0.1007); instead, anxiety and depression severities showed moderate associations with anger (ßs = 0.243 and 0.287, p-values = 0.0274 and 0.0130, respectively). Findings suggest that clinicians should screen veterans with history of early life adversity for depression and anxiety when anger is present.

Childhood trauma differentially impacts depression and stress associations with reintegration challenges among post-9/11 U.S. veterans.

BACKGROUND: Post-9/11 veterans exhibit high prevalence of deployment stress, psychological conditions, and traumatic brain injury (TBI) which impact reintegration, especially among those with a history of interpersonal early life trauma (I-ELT). The relative importance of each risk factor is unclear. PURPOSE: We examined major deployment and clinical exposures of reintegration challenges among veterans with and without I-ELT. METHOD: We analyzed cross-sectional data of 155 post-9/11 veterans from the Translational Research Center for TBI and Stress Disorders study. FINDINGS: Depression severity had the strongest association with reintegration challenges, followed by posttraumatic stress disorder (PTSD) severity, post-deployment stress, and deployment safety concerns. Deployment safety concerns had a stronger, significant association among veterans with I-ELT. In nearly every model, PTSD and depression severities were weaker for veterans with I-ELT, compared to those without. DISCUSSION: Clinicians should consider the relative risk of concurrent clinical conditions and trauma histories when considering veterans' reintegration needs.

Impaired executive function exacerbates neural markers of posttraumatic stress disorder.

BACKGROUND: A major obstacle in understanding and treating posttraumatic stress disorder (PTSD) is its clinical and neurobiological heterogeneity. To address this barrier, the field has become increasingly interested in identifying subtypes of PTSD based on dysfunction in neural networks alongside cognitive impairments that may underlie the development and maintenance of symptoms. The current study aimed to determine if subtypes of PTSD, based on normative-based cognitive dysfunction across multiple domains, have unique neural network signatures. METHODS: In a sample of 271 veterans (90% male) that completed both neuropsychological testing and resting-state fMRI, two complementary, whole-brain functional connectivity analyses explored the link between brain functioning, PTSD symptoms, and cognition. RESULTS: At the network level, PTSD symptom severity was associated with reduced negative coupling between the limbic network (LN) and frontal-parietal control network (FPCN), driven specifically by the dorsolateral prefrontal cortex and amygdala Hubs of Dysfunction. Further, this relationship was uniquely moderated by executive function (EF). Specifically, those with PTSD and impaired EF had the strongest marker of LN-FPCN dysregulation, while those with above-average EF did not exhibit PTSD-related dysregulation of these networks. CONCLUSION: These results suggest that poor executive functioning, alongside LN-FPCN dysregulation, may represent a neurocognitive subtype of PTSD.

Apolipoprotein E (APOE) ε4 moderates the relationship between c-reactive protein, cognitive functioning, and white matter integrity.

Elevated serum C-reactive protein (CRP) and possessing an APOE ε4 allele are two of the most prominent risk factors for cognitive and neurological dysfunction in older adults, but little is known about the unique or cumulative effects of these risk factors in young-to-middle-aged adults. To further characterize these potential relationships, measures of cognition and microstructural white matter integrity were examined using data from a sample of 329 post-9/11 war veterans that was collected as part of a comprehensive evaluation that included assessment of neuropsychological functioning, MRI scanning, psychiatric diagnoses, health screening, markers of inflammation, and APOE genotypes. Hierarchical linear regression analyses revealed the CRP and APOE ε4 interaction was associated with global cognition (ß = -0.633), executive functioning (ß = -0.566), and global fractional anisotropy (ß = -0.470), such that elevated CRP was associated with worse cognition and white matter integrity in APOE ε4 carriers. Diffusion tensor imaging (DTI) was used to determine if CRP × APOE ε4 presence was associated with regionally specific fractional anisotropy in white matter tracts. Tract-based spatial statistics revealed CRP × APOE ε4 presence was associated with fractional anisotropy in the corpus callosum, right superior longitudinal fasciculus, right posterior corona radiata, as well as the bilateral anterior and superior corona radiatas. This suggests that APOE ε4 carriers may be uniquely vulnerable to the potentially negative impact of elevated systematic inflammation to cognition and microstructural white matter integrity.

Age of onset of adolescent binge drinking is differentially associated with cortical thickness in post-9/11 adult Veterans.

BACKGROUND: Adolescence is a critical period for neural development and has been associated with high rates of alcohol abuse. This research examined potential long-term brain and behavioral effects of early versus late-onset adolescent binge drinking in an adult sample of post-9/11 Veterans. METHODS: We compared cortical thickness measures in Veterans with a history of binge drinking that began before the age of 15 (n = 50; mean age = 32.1 years) to those with a history of binge drinking with onset after the age of 15 (n = 300; mean age = 32.1 years). Data processing was conducted with FreeSurfer. A targeted neuropsychological battery (Digit Span test, Delis-Kaplan Executive Function System Color-Word Interference Test, California Verbal Learning Test-II) was used to examine the relationships between cortical thickness and attention, memory, and inhibition. A reference group of social drinkers with no history of early binge drinking (n = 31) was used to provide normative data. RESULTS: Early-onset adolescent binge drinkers (EBD) had greater cortical thickness in several regions than late-onset adolescent binge drinkers (LBD); both binge-drinking groups had greater cortical thickness than the reference group. There was a stronger negative association between cortical thickness and age in EBDs than LBDs in the (i) lateral orbitofrontal cortex, (ii) supramarginal gyrus, (iii) paracentral lobule, and (iv) anterior caudal cingulate. Poorer performance on the attention and inhibition tasks in the EBDs was also associated with thicker cortices. CONCLUSIONS: This study demonstrates greater cortical thickness across frontoparietal regions in adults who began binge drinking in early versus late adolescence. A stronger negative association between cortical thickness and age in the EBDs suggests that early-onset adolescent binge drinking may be associated with accelerated cortical thinning. Thicker cortex in these regions, which are known to mediate inhibitory control, may increase impulsive behavior and contribute to the risk of alcohol addiction.

Apolipoprotein E (APOE) ε4 Status Moderates the Relationship Between Close-Range Blast Exposure and Cognitive Functioning.

OBJECTIVES: Recent studies suggest that close-range blast exposure (CBE), regardless of acute concussive symptoms, may have negative long-term effects on brain health and cognition; however, these effects are highly variable across individuals. One potential genetic risk factor that may impact recovery and explain the heterogeneity of blast injury's long-term cognitive outcomes is the inheritance of an apolipoprotein (APOE) ε4 allele, a well-known genetic risk factor for Alzheimer's disease. We hypothesized that APOE ε4 carrier status would moderate the impact of CBE on long-term cognitive outcomes. METHODS: To test this hypothesis, we examined 488 post-9/11 veterans who completed assessments of neuropsychological functioning, psychiatric diagnoses, history of blast exposure, military and non-military mild traumatic brain injuries (mTBIs), and available APOE genotypes. We separately examined the effects of CBE on attention, memory, and executive functioning in individuals with and without the APOE ε4 allele. RESULTS: As predicted, we observed a differential impact of CBE status on cognition as a function of APOE ε4 status, in which CBE ε4 carriers displayed significantly worse neuropsychological performance, specifically in the domain of memory. These results persisted after adjusting for clinical, demographic, and genetic factors and were not observed when examining other neurotrauma variables (i.e., lifetime or military mTBI, distant blast exposure), though these variables displayed similar trends. CONCLUSIONS: These results suggest APOE ε4 carriers are more vulnerable to the impact of CBE on cognition and highlight the importance of considering genetic risk when studying cognitive effects of neurotrauma.

Early Adolescent Binge Drinking Increases Risk of Psychopathology in Post-9/11 Veterans and Mild Traumatic Brain Injury Exacerbates Symptom Severity.

AIMS: To demonstrate that early adolescent binge drinking (BD) increases the risk for and/or severity of psychopathology in post-9/11 Veterans and determine if mild traumatic brain injury (mTBI) modifies risk. METHODS: Post-9/11 Veterans (n = 375) were classified into two groups: 57 Veterans with a history of early adolescent BD (E-BD; age of onset <15) and 318 who did not BD until age 15 or older (late-BD or L-BD; age of onset ≥15). History of military mTBI and mental health disorders were also assessed following military service. RESULTS: Logistic regression and analysis of variance (ANOVA) analyses revealed that the E-BD's had significantly higher prevalence of alcohol use disorders (AUDs) and more severe symptoms of AUD, substance use disorder (SUD), depression and stress. Two-way ANOVAs showed that history of military mTBI was differentially associated with posttraumatic stress disorder (PTSD) incidence and severity among Veterans who had engaged in early adolescent BD. Specifically, Veterans with a history of both early adolescent BD and military mTBI were at greater risk for a PTSD diagnosis and had more severe symptoms of PTSD than those with only a history of adolescent BD. The greater PTSD symptom severity in the comorbid group was driven by hyperarousal symptoms. CONCLUSIONS: A history of BD during early adolescence is prevalent among Veterans and is related to higher risk for AUD and more severe AUD, SUD, mood and stress symptoms later in life. Veterans with early BD and military mTBI showed greater incidence and severity of PTSD, indicating that mTBI, a common comorbidity among post-9/11 Veterans, exacerbates risk.

Traumatic Brain Injury and Opioid Overdose Among Post-9/11 Veterans With Long-Term Opioid Treatment of Chronic Pain.

OBJECTIVE: To evaluate the association between traumatic brain injury (TBI) and nonfatal opioid overdose, and the role of psychiatric conditions as mediators of this association. SETTING: Post-9/11 veterans receiving care at national Department of Veterans Affairs (VA) facilities from 2007 to 2012. PARTICIPANTS: In total, 49 014 veterans aged 18 to 40 years receiving long-term opioid treatment of chronic noncancer pain. DESIGN: Longitudinal cohort study using VA registry data. MAIN MEASURES: TBI was defined as a confirmed diagnosis (28%) according to VA comprehensive TBI evaluation; no TBI was defined as a negative primary VA TBI screen (ie, no head injury). Nonfatal opioid overdose was defined using ICD-9 (International Classification of Diseases, Ninth Revision) codes. We performed demographic-adjusted Cox proportional hazards regression. We quantified the impact of co-occurring and individual psychiatric conditions (mood, anxiety, substance use, and posttraumatic stress disorder) on this association using mediation analyses. RESULTS: Veterans with TBI had more than a 3-fold increased risk of opioid overdose compared with those without (adjusted hazards ratio [aHR] = 3.22; 95% confidence interval [CI], 2.13-4.89). This association was attenuated in mediation analyses of any co-occurring psychiatric condition (aHR = 1.77; 95% CI, 1.25-2.52) and individual conditions (aHR range, 1.52-2.95). CONCLUSION: TBI status, especially in the context of comorbid conditions, should be considered in clinical decisions regarding long-term use of opioids in patients with chronic pain.

The Impact of Common Psychiatric and Behavioral Comorbidities on Functional Disability Across Time and Individuals in Post-9/11 Veterans.

Returning veterans often face multiple concurrent psychiatric and behavioral conditions that negatively impact reintegration into civilian life and are associated with functional disability. Understanding how conditions interact to negatively impact functioning is an important step toward developing holistic treatment approaches optimized for this population. This study utilized a cross-sectional and prospective longitudinal cohort design, applying regression algorithms to understand the relative contribution of common clinical issues to functional disability in U.S. veterans who served after the September 11, 2001 (9/11), terror attacks. Community-dwelling post-9/11 veterans (N = 397) completed detailed assessments, including common clinical condition diagnoses, combat experience, and demographics, which were used to predict functional disability (World Health Organization Disability Assessment Schedule); 205 participants were reassessed approximately 1-2 years after enrollment. Regression analyses showed a strong association between the predictor variables and functional disability, f 2 = 1.488. Validation analyses showed a high prediction ability of functional disability to independent samples, r = .719, and across time in the same individuals, r = .780. The strongest predictors included current posttraumatic stress disorder, depressive disorder, sleep disturbance, and pain diagnoses. These results demonstrate the importance of considering multiple common co-occurring conditions when assessing functional disability in post-9/11 veterans and suggest that certain syndromes contribute the most unique information to predicting functional disability with high confidence. As most U.S. veterans utilize private healthcare systems, these results have clinical utility for both Veterans Affairs and civilian healthcare practitioners in assessing and monitoring functional disability in post-9/11 veterans over time.

The Deployment Trauma Phenotype and Employment Status in Veterans of the Wars in Iraq and Afghanistan.

OBJECTIVES: To determine the prevalence of comorbid mild traumatic brain injury (mTBI), posttraumatic stress disorder (PTSD), and depression, termed the deployment trauma phenotype (DTP), and its constituent diagnoses' impact on unemployment status in a national cohort of veterans. SETTING: Retrospective analysis of the comprehensive TBI evaluation, a Veterans Affairs-wide protocol for assessing TBI, employment status, and psychiatric impressions. PARTICIPANTS: The final data set consisted of 48 821 veterans. MAIN OUTCOMES AND MEASURES: Frequency of mTBI, PTSD, and depression in isolation and combinations and their association with unemployment status. RESULTS: Age- and education-adjusted risk ratios (RRs) showed that the mTBI-only group was the least likely to be unemployed, RR = 0.65 (0.59-0.71). By contrast, the greatest likelihood of unemployment was associated with membership in the DTP group, RR = 1.45 (1.36-1.56), and the comorbid PTSD and depression group, RR = 1.39 (1.27-1.52). Furthermore, the DTP was nearly 3 times more prevalent (16.4%) in this sample compared with comorbid PTSD and depression (5.7%), indicating that the DTP conveys risk for unemployment to a significantly greater number of individuals. CONCLUSIONS AND RELEVANCE: The comorbid and interactive conditions of PTSD, depression, and mTBI, rather than mTBI in isolation, were linked to significant risk for unemployment in this veteran cohort. These findings suggest that multifaceted assessments and interventions to improve postdeployment reintegration are needed.

Traumatic Brain Injury and Attempted Suicide Among Veterans of the Wars in Iraq and Afghanistan.

Studies of the association between traumatic brain injury (TBI) and suicide attempt have yielded conflicting results. Furthermore, no studies have examined the possible mediating role of common comorbid psychiatric conditions in this association. This study used Veterans Affairs registry data to evaluate the associations between deployment-related TBI, psychiatric diagnoses, and attempted suicide among 273,591 veterans deployed in support of Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn, and who received care from the Department of Veterans Affairs during 2007-2012. We performed Cox proportional hazards regression analyses, adjusting for demographic characteristics. Mediation analyses were conducted to quantify the impact of psychiatric conditions (posttraumatic stress disorder, depression, anxiety, and substance abuse) on this association. The sample was predominantly male (84%); mean age = 28.7 years. Veterans with TBI (16%) were more likely to attempt suicide than those without (0.54% vs. 0.14%): adjusted hazards ratio = 3.76, 95% confidence interval: 3.15, 4.49. This association was attenuated in mediation analyses (adjusted hazards ratio = 1.25, 95% confidence interval: 1.07, 1.46), with 83% of the association of TBI with attempted suicide mediated by co-occurring psychiatric conditions and with posttraumatic stress disorder having the largest impact. These results suggest that veterans with these conditions should be closely monitored for suicidal behavior.