PTSD, major depression, and advanced transcriptomic age in brain tissue.

BACKGROUND: Psychiatric disorders have been associated with advanced epigenetic age in DNA methylation, yet this relationship has not been studied in the brain transcriptome. We examined transcriptomic age using an RNA-based algorithm recently developed by Ren and Kuan ("RNAAgeCalc") and the associations between posttraumatic stress disorder (PTSD), major depressive disorder (MDD), and alcohol use disorder with age-adjusted RNA age ("RNA age residuals") in three brain regions: dorsolateral prefrontal cortex, ventromedial prefrontal cortex (vmPFC), and motor cortex. METHODS: RNA sequencing was used to measure gene expression in postmortem brain tissue from the VA National PTSD Brain Bank (n = 94; 59% male). RESULTS: Linear models revealed that diagnoses of PTSD and/or MDD were positively associated with RNA age residuals in vmPFC only (p-adj = 0.012). Three genes in the RNAAgeCalc algorithm (KCNJ16, HYAL2, and CEBPB) were also differentially expressed in association with PTSD/MDD in vmPFC (p-adj = 6.45E-05 to 0.02). Enrichment analysis revealed that inflammatory and immune-related pathways were overrepresented (p-adj < 0.05) among the 43 genes in RNAAgeCalc that were also at least nominally associated with PTSD/MDD in vmPFC relative to the 448 RNAAgeCalc genes. Endothelial and mural cells were negatively associated with RNA age residuals in vmPFC (both p-adj = 0.028) and with PTSD/MDD (both p-adj = 0.017). CONCLUSIONS: Results highlight the importance of inflammation and immune system dysregulation in the link between psychopathology and accelerated cellular aging and raise the possibility that blood-brain barrier degradation may play an important role in stress-related accelerated brain aging.

A systematic review of gene-by-intervention studies of alcohol and other substance use.

Alcohol and other substance use problems are common, and the efficacy of current prevention and intervention programs is limited. Genetics may contribute to differential effectiveness of psychosocial prevention and intervention programs. This paper reviews gene-by-intervention (G×I) studies of alcohol and other substance use, and implications for integrating genetics into prevention science. Systematic review yielded 17 studies for inclusion. Most studies focused on youth substance prevention, alcohol was the most common outcome, and measures of genotype were heterogeneous. All studies reported at least one significant G×I interaction. We discuss these findings in the context of the history and current state of genetics, and provide recommendations for future G×I research. These include the integration of genome-wide polygenic scores into prevention studies, broad outcome measurement, recruitment of underrepresented populations, testing mediators of G×I effects, and addressing ethical implications. Integrating genetic research into prevention science, and training researchers to work fluidly across these fields, will enhance our ability to determine the best intervention for each individual across development. With growing public interest in obtaining personalized genetic information, we anticipate that the integration of genetics and prevention science will become increasingly important as we move into the era of precision medicine.

The Role of Social, Familial, and Individual-Level Factors on Multiple Alcohol Use Outcomes During the First Year of University.

BACKGROUND: The first year of university attendance represents a critical time frame for the development of alcohol use and misuse given changes in autonomy and increased access to alcohol. Prior studies have demonstrated that the establishment of drinking patterns during this period is impacted by an array of demographic, environmental, and familial factors. It is critical to consider such factors jointly, and to understand potentially differential effects on stages of alcohol use/misuse, in order to identify robust predictors that may be targeted in prevention and intervention programming. METHODS: As part of a longitudinal study, students at a large, public U.S. university were invited to complete online surveys that included questions related to alcohol use, emotional and behavioral health, environmental factors, sociodemographic factors, and familial environment. This study uses data from surveys administered in the fall and spring of the first year of university. We used univariate (maximum N = 7,291) and multivariate (maximum N = 4,788) logistic and linear regressions to evaluate the associations between potential risk and protective factors with 4 alcohol use outcomes: initiation, consumption, problems, and addiction resistance. RESULTS: In multivariate models, we observed associations between demographic, social/environmental, and personal-level predictors with all 4 alcohol outcomes, several of which were consistent across each stage of alcohol use. A deviant high school peer group was one of the strongest predictors of risk across outcomes. The influence of drinking motives and alcohol expectancies varied by alcohol use outcome. Externalizing characteristics were associated with increased risk across outcomes, while internalizing symptoms were associated with more problems and lower addiction resistance. CONCLUSIONS: These findings underscore the complex network of factors influencing stages of alcohol use during the first year of university. Importantly, these findings demonstrate that the impact of predictors changes across stages of alcohol use/misuse, which presents opportunities for targeted prevention efforts.

Subjective cognitive concerns, APOE ε4, PTSD symptoms, and risk for dementia among older veterans.

BACKGROUND: Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) are associated with self-reported problems with cognition as well as risk for Alzheimer's disease and related dementias (ADRD). Overlapping symptom profiles observed in cognitive disorders, psychiatric disorders, and environmental exposures (e.g., head injury) can complicate the detection of early signs of ADRD. The interplay between PTSD, head injury, subjective (self-reported) cognitive concerns and genetic risk for ADRD is also not well understood, particularly in diverse ancestry groups. METHODS: Using data from the U.S. Department of Veterans Affairs (VA) Million Veteran Program (MVP), we examined the relationship between dementia risk factors (APOE ε4, PTSD, TBI) and subjective cognitive concerns (SCC) measured in individuals of European (n = 140,921), African (n = 15,788), and Hispanic (n = 8,064) ancestry (EA, AA, and HA, respectively). We then used data from the VA electronic medical record to perform a retrospective survival analysis evaluating PTSD, TBI, APOE ε4, and SCC and their associations with risk of conversion to ADRD in Veterans aged 65 and older. RESULTS: PTSD symptoms (B = 0.50-0.52, p < 1E-250) and probable TBI (B = 0.05-0.19, p = 1.51E-07 - 0.002) were positively associated with SCC across all three ancestry groups. APOE ε4 was associated with greater SCC in EA Veterans aged 65 and older (B = 0.037, p = 1.88E-12). Results of Cox models indicated that PTSD symptoms (hazard ratio [HR] = 1.13-1.21), APOE ε4 (HR = 1.73-2.05) and SCC (HR = 1.18-1.37) were positively associated with risk for ADRD across all three ancestry groups. In the EA group, probable TBI also contributed to increased risk of ADRD (HR = 1.18). CONCLUSIONS: The findings underscore the value of SCC as an indicator of ADRD risk in Veterans 65 and older when considered in conjunction with other influential genetic, clinical, and demographic risk factors.

Program Evaluation of Group Transcending Self Therapy: An Integrative Modular Cognitive-Behavioral Therapy for Substance Use Disorders.

OBJECTIVES: Substance Use Disorders (SUDs) are increasingly prevalent among Veterans. Effective interventions for SUDs that also meet the clinical reality of open treatment groups are needed. Transcending Self Therapy: Group Integrative Cognitive Behavioral Treatment (Group TST-I-CBT) was developed to address this need. Group TST-I-CBT is a four-module, 20-session treatment designed so that a person can enter at any point in the treatment. We conducted a program evaluation of Group TST-I-CBT for veterans with SUDs. METHODS: Participants were N = 68 veterans enrolled in the 28-day Substance Abuse Residential Rehabilitation Treatment Program at an urban Veterans Administration Medical Center who received either Group TST-I-CBT (N = 34) or treatment-as-usual (TAU; N = 34). Medical records were reviewed and participant treatment outcome data was retrieved. Group TST-I-CBT clients completed a knowledge and feedback form at treatment completion. RESULTS: Compared to TAU participants, Group TST-I-CBT participants were significantly less likely to have a positive urine drug screen (UDS) during treatment (17.6% versus 0%; P = .01) and within one month post-discharge (50% versus 17.6%; P = .04). Among Group TST-I-CBT clients, Quality of Life Inventory scores significantly increased by an average of 14 points from pre- to post-treatment, t(15) = -3.31, P = .005, d = 0.83. Group TST-I-CBT clients displayed cognitive-behavioral therapy knowledge (mean correct answers ranged from 92%-100%) and rated Group TST-I-CBT as helpful, understandable, and useful (mean scores ranged from 9.3-9.6 out of 10). CONCLUSIONS: These preliminary data indicate that Group TST-I-CBT may be an effective group therapy as part of SUD treatment. A formal randomized controlled trial of Group TST-I-CBT may be warranted.

The Utility of a Brief Web-Based Prevention Intervention as a Universal Approach for Risky Alcohol Use in College Students: Evidence of Moderation by Family History.

Background: Alcohol use on college campuses is prevalent and contributes to problems that affect the health, emotional wellbeing, and academic success of college students. Risk factors, such as family history of alcohol problems, predict future alcohol problems, but less is known about their potential impact on intervention effectiveness. The purpose of this study was to examine the effect of an intervention implemented in a non-randomized sample of drinking and non-drinking college freshmen. Methods: Freshmen college students recruited for the intervention study (n = 153) completed a web-adaptation of the Brief Alcohol Screening and Intervention for College Students (BASICS) at the start of spring semester. We compared their 30-days post-intervention alcohol initiation, number of drinking days (DAYS), drinks per occasion (DRINKS), maximum drinks in 24 h (MAX24) and alcohol use disorder symptoms (AUDsx) to 151 comparison participants retrospectively matched on demographics and baseline alcohol use behaviors. We also tested baseline DRINKS, DAYS, AUDsx, MAX24, and parental family history (PFH) of alcohol problems as moderators of the effect of the intervention. Results: At follow-up, intervention participants had lower rates of AUDsx than comparison participants, especially among baseline drinkers. Among participants drinking 3+ days/month at baseline, intervention participants showed fewer DAYS at follow-up than the comparison group participants. BASICS was also associated with a decreased likelihood of initiation among baseline non-drinkers. PFH significantly interacted with treatment group, with positive PFH intervention participants reporting significantly fewer AUDsx at follow-up compared to positive PFH comparison participants. We found no evidence for an effect of the intervention on DRINKS or MAX24 in our analyses. Conclusions: Results suggest some indication that novel groups, such as non-drinkers, regular drinkers, and PFH positive students may experience benefits from BASICS. Although conclusions were limited by lack of randomization and short follow-up period, PFH positive and low to moderate drinking groups represent viable targets for future randomized studies.