Linda Abadjian

A randomized controlled trial of telephone motivational interviewing to enhance mental health treatment engagement in Iraq and Afghanistan veterans.

OBJECTIVE To test the efficacy of telephone-administered motivational interviewing (MI) to enhance treatment engagement in Iraq and Afghanistan veterans with mental health (MH) problems. METHOD Between April 23, 2008, and February 25, 2011, 73 Iraq and Afghanistan veterans who screened positive for ≥1 MH problem(s) on telephone-administered psychometric assessment, but were not engaged in treatment, were randomized to either personalized referral for MH services and four sessions of telephone MI or standard referral and four neutral telephone check-in sessions (control) at baseline, 2, 4 and 8 weeks. Blinded assessment occurred at 8 and 16 weeks. RESULTS In intent-to-treat analyses, 62% assigned to telephone MI engaged in MH treatment compared to 26% of controls [relative risk (RR)=2.41, 95% confidence interval (CI)=1.33-4.37, P=.004], which represented a large effect size (Cohens h=0.74). Participants in the MI group also demonstrated significantly greater retention in MH treatment than controls [MI mean visits (S.D.)=1.68 (2.73) and control mean visits (S.D.)=0.38 (0.81), incidence rate ratio (IRR)=4.36, 95% CI=1.96-9.68, P<.001], as well as significant reductions in stigma and marijuana use at 8 weeks (P<.05). CONCLUSIONS Telephone MI enhances MH treatment engagement in Iraq and Afghanistan veterans with MH problems.

Differential cognitive impairment in HCV coinfected men with controlled HIV compared to HCV monoinfection

Background:Individuals infected with both HIV and hepatitis C virus (HCV) have shown impaired performance on different neuropsychological (NP) tests; however, whether coinfected individuals with controlled HIV and minimal liver damage in the era of antiretroviral therapy have impairment is understudied. Methods:Nineteen HCV monoinfected, 17 HIV/HCV coinfected, and 17 control male participants were evaluated for depression, attention, executive function, information processing, fine motor speed, and verbal/visual learning/memory. Eleven controls and 14 HIV monoinfected participants with controlled viral load from a previous study were also included for comparison. At time of testing, participants were not using drugs or alcohol and did not have cirrhosis. A global deficit score (GDS) was calculated from 7 domains of NP tests and alterations in specific domains were determined. Results:HIV/HCV subjects had a higher depression score (11.1 ± 7.5) than controls (5.4 ± 4.1, P = 0.010) and a higher GDS score (0.77 ± 0.47) than HCV (0.46 ± 0.34, P = 0.036), HIV (0.45 ± 0.36, P = 0.008), and controls (0.30 ± 0.29, P = 0.001). Coinfection was associated with worse scores in attention working memory (P =0.007), executive function (P = 0.01), fine motor function (P = 0.011), verbal learning/memory (P < 0.001), and visual learning/memory (P < 0.001) compared to controls. Within the HCV group, viral load was associated with lower attention, executive function, and information processing speed and positively with GDS. Conclusions:Coinfection significantly increased the risk of cognitive impairment in subjects with controlled HIV viral loads. In HCV monoinfected but not coinfected subjects, HCV viral load correlated with worsening GDS, suggesting different pathways for NP impairment.

Peripheral biomarkers do not correlate with cognitive impairment in highly active antiretroviral therapy–treated subjects with human immunodeficiency virus type 1 infection

Neuropsychological (NP) impairments in human immunodeficiency virus (HIV)-infected individuals remain high despite the introduction of highly active antiretroviral therapy (HAART). We sought to determine whether or not a monocyte gene expression profile along with other peripheral factors would correlate with neuropsychological impairment among HIV-infected individuals. Forty-four HIV-1-seropositive subjects (HIV+) on HAART and 11 HIV-1-seronegative controls (HIV−) had NP testing and blood drawn for monocyte gene expression analysis. All HIV+ subjects were assessed for CD4 counts, apolipoprotein E (ApoE) genotype, viral load, and plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14). NP scores were normalized to age, gender, and education. Twenty-five percent of HIV+ individuals showed abnormal NP testing results (>1.5 SD below normal in two domains). HIV+ individuals had deficits in attention/working memory, verbal learning, and information processing speed compared to HIV− controls. There was no correlation between overall NP impairment and plasma viral load, level of education, age, ethnic diversity, sCD14, plasma LPS, CD4 cell count, ApoE genotype, or years of infection. However, greater years of infection had worse visual learning performance. sCD14 and CD4 nadir positively correlated with information processing speed and fine motor skills, respectively. LPS correlated with viral load but not cognitive impairment. Monocyte gene expression confirmed a chronic inflammatory profile that correlated with viral load but not cognition. No blood index or profile was associated with overall NP impairment.

A peripheral monocyte interferon phenotype in HIV infection correlates with a decrease in magnetic resonance spectroscopy metabolite concentrations

Objective:In spite of effective antiretroviral therapy (ART), cognition is impaired in upwards of 35% of the HIV-infected population. We investigated a possible link between peripheral immune activation and brain metabolite concentrations. Design and methods:Thirty-five HIV-seropositive (HIV+) and eight HIV-seronegative adults were recruited to this cross-sectional study. All HIV-positive patients were on ART or a treatment interruption. Participants were evaluated for monocyte gene expression, cognitive status, and brain metabolite concentrations using 4-Tesla short echo-time proton magnetic resonance spectroscopy. Absolute concentrations of brain metabolites in the frontal white matter (FWM), anterior cingulate cortex (ACC), and basal ganglia were derived and related to monocyte gene expression and global deficit scores. Results:Analysis of monocyte gene arrays revealed an interferon (IFN)-&agr;-induced activation phenotype. Fourteen genes having the greatest fold increase in response to HIV were IFN genes. Monocyte activation as measured by gene expression profiles strongly correlated with lower N-acetylaspartate (NAA) in FWM. The IFN response gene Interferon-gamma inducible protein-10 (IP-10) was activated in monocytes from HIV individuals and strongly correlated with plasma protein levels. Plasma IP-10 correlated significantly and inversely with ACC NAA, which was lower in HIV-positive patients with mild compared to no cognitive impairment. Conclusion:Chronic peripheral immune activation driven by a type 1 IFN correlates with neuronal injury in FWM and ACC and cognitive dysfunction. Easily measured IFN-induced blood markers may be clinically significant in following early neural cell damage.

Monocyte Activation in HIV/HCV Coinfection Correlates with Cognitive Impairment

Coinfection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) challenges the immune system with two viruses that elicit distinct immune responses. Chronic immune activation is a hallmark of HIV infection and an accurate indicator of disease progression. Suppressing HIV viremia by antiretroviral therapy (ART) effectively prolongs life and significantly improves immune function. HIV/HCV coinfected individuals have peripheral immune activation despite effective ART control of HIV viral load. Here we examined freshly isolated CD14 monocytes for gene expression using high-density cDNA microarrays and analyzed T cell subsets, CD4 and CD8, by flow cytometry to characterize immune activation in monoinfected HCV and HIV, and HIV-suppressed coinfected subjects. To determine the impact of coinfection on cognition, subjects were evaluated in 7 domains for neuropsychological performance, which were summarized as a global deficit score (GDS). Monocyte gene expression analysis in HIV-suppressed coinfected subjects identified 43 genes that were elevated greater than 2.5 fold. Correlative analysis of subjects’ GDS and gene expression found eight genes with significance after adjusting for multiple comparisons. Correlative expression of six genes was confirmed by qPCR, five of which were categorized as type 1 IFN response genes. Global deficit scores were not related to plasma lipopolysaccharide levels. In the T cell compartment, coinfection significantly increased expression of activation markers CD38 and HLADR on both CD4 and CD8 T cells but did not correlate with GDS. These findings indicate that coinfection is associated with a type 1 IFN monocyte activation profile which was further found to correlate with cognitive impairment, even in subjects with controlled HIV infection. HIV-suppressed coinfected subjects with controlled HIV viral load experiencing immune activation could benefit significantly from successful anti-HCV therapy and may be considered as preferential candidates.

Blood neuron-derived exosomes as biomarkers of cognitive impairment in HIV

Objective: To investigate proteins associated with neuronal damage in plasma neuron-derived exosomes (NDE) of HIV-infected study participants as a liquid biomarker for cognitive impairment. Methods: Plasma NDE were isolated using precipitation and immunoadsorption with antibody to a cell surface-specific neuronal marker. Total exosomes and NDE were enumerated, characterized, and proteins extracted and targets quantified by ELISA. Results: Plasma NDE from 23 HIV seropositive individuals of which 11 had mild cognitive impairment, and 12 HIV seronegative controls of which three had cognitive impairment were isolated. NDE were enriched for the neuronal markers neurofilament light (NF-L) and synaptophysin (SYP). Neuropsychologically impaired individuals had fewer NDE compared with neuropsychologically normal study participants. NDE from neuropsychologically impaired study participants had significantly higher levels of high-mobility group box 1 (HMGB1), NF-L, and amyloid &bgr; proteins compared with neuropsychologically normal individuals. NDE HMGB1 protein significantly decreased with age in HIV-infected individuals. Conclusion: Plasma NDE were altered in several ways in HIV infection. Elevated HMGB1, NF-L, and amyloid &bgr; proteins could distinguish cognitive impairment. NDE contents reflect neuronal health in ‘real time’ and may be useful for following cognitive impairment and response to therapy in HIV infection.

The Association Between PTSD and Functional Outcome Is Mediated by Perception of Cognitive Problems Rather Than Objective Neurological Test Performance

Posttraumatic stress disorder (PTSD) has been consistently linked to poorer functional outcomes, including quality of life, health problems, and social and occupational functioning. Less is known about the potential mechanisms by which PTSD leads to poorer functional outcomes. We hypothesized that neurocognitive functioning and perception of cognitive problems would both mediate the relationship between PTSD diagnosis and functioning. In a sample of 140 veterans of the recent wars and conflicts in Iraq and Afghanistan, we assessed PTSD symptoms, history of traumatic brain injury (TBI), depression, self-report measures of quality of life, social and occupational functioning, and reintegration to civilian life, as well as perception of cognitive problems. Veterans also completed a comprehensive neuropsychological battery of tests. Structural equation modeling revealed that perception of cognitive problems, but not objective neuropsychological performance, mediated the relationship between PTSD diagnosis and functional outcomes after controlling for TBI, depression, education, and a premorbid IQ estimate, b = -6.29, 95% bias-corrected bootstrapped confidence interval [-11.03, -2.88], showing a large effect size. These results highlight the importance of addressing appraisals of posttrauma cognitive functioning in treatment as a means of improving functional outcomes.

Evidence of Hippocampal Structural Alterations in Gulf War Veterans With Predicted Exposure to the Khamisiyah Plume

Objectives: To replicate and expand our previous findings of smaller hippocampal volumes in Gulf War (GW) veterans with predicted exposure to the Khamisiyah plume. Methods: Total hippocampal and hippocampal subfield volumes were quantified from 3 Tesla magnetic resonance images in 113 GW veterans, 62 of whom had predicted exposure as per the Department of Defense exposure models. Results: Veterans with predicted exposure had smaller total hippocampal and CA3/dentate gyrus volumes compared with unexposed veterans, even after accounting for potentially confounding genetic and clinical variables. Among veterans with predicted exposure, memory performance was positively correlated with hippocampal volume and negatively correlated with estimated exposure levels and self-reported memory difficulties. Conclusions: These results replicate and extend our previous finding that low-level exposure to chemical nerve agents from the Khamisiyah pit demolition has detrimental, lasting effects on brain structure and function.

Insomnia Severity, Subjective Sleep Quality, and Risk for Obstructive Sleep Apnea in Veterans With Gulf War Illness

Despite the fact that sleep disturbances are common in veterans with Gulf War Illness (GWI), there has been a paucity of published sleep studies in this veteran population to date. Therefore, the present study examined subjective sleep quality (assessed with the Pittsburgh Sleep Quality Index), insomnia severity (assessed with the Insomnia Severity Index), and risk for obstructive sleep apnea (assessed with the STOP questionnaire) in 98 Gulf War veterans. Veterans with GWI, defined either by the Kansas or Centers for Disease Control and Prevention criteria, had greater risk for obstructive sleep apnea (i.e., higher STOP scores) than veterans without GWI. This difference persisted even after accounting for potentially confounding demographic (e.g., age, gender) and clinical variables. Veterans with GWI, defined by either the Kansas or Centers for Disease Control and Prevention criteria, also had significantly greater insomnia severity and poorer sleep quality than veterans without GWI (p < 0.05), even after accounting for potentially confounding variables. Furthermore, there were significant, positive correlations between insomnia severity, subjective sleep quality, and GWI symptom severity (p ≤ 0.01). In stepwise linear regression models, insomnia severity significantly predicted GWI status over and above demographic and clinical variables. Together these findings provide good rationale for treating sleep disturbances in the management of GWI.

118. HIV-1-infected subjects with neuropsychological impairment have a unique gene expression profile

Poor self-rated health (SRH) is associated with overweight, as well as higher levels of IL-6 and TNF-alpha in women. IL-6 and TNF-alpha can be produced but also by adipocytes. To investigate the relation between adipose tissue, inflammation and SRH, leptin (a marker of adipose tissue amount) and haptoglobin were used. A random selection of the Stockholm County population with 90 men and 100 women, 20–75 years, attended a health control, provided blood samples and rated SRH. Two years later, they responded to questions about SRH and chronic disease. Cross-sectional and prospective relations between leptin, haptoglobin and SRH were analysed with ordinal logistic regressions. Dependent variables were SRH from the first or the second assessment. Independent variables were leptin, haptoglobin, BMI, presence of chronic disease and age. In men, high leptin was associated with poor SRH (p = 0.01) while low leptin was associated with poor SRH in women (p = 0.01). Prospectively, a relation was found in women between low leptin and poor SRH two years later (p = 0.04). In men, chronic disease was associated with poor SRH at both time points (p = 0.01 and p = 0.006). In women, higher BMI was associated with poor SRH (p’s < 0.05). Haptoglobin and age were not related to SRH at either occassion. Surprisingly, the results suggest that high levels of leptin are associated with poor SRH in men and good SRH in women. The finding in women could possibly be explained by the fact that leptin not only marks cytokine-producing adipose tissue but also displays partly dissimilar features compared to TNF-alpha and IL-6.