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BackgroundIn order to detect HIV-associated neurocognitive decline, it is important to accurately estimate individuals' premorbid levels of cognitive functioning. Although previous studies have operated under the assumption that word reading tests are valid and stable indicators of premorbid abilities in HIV infection, studies of other populations have found that this is not always the case. Therefore, it is important to empirically examine the validity of word reading tests as estimates of premorbid functioning specifically within the HIV population.MethodThe Wide Range Achievement Test-4 Reading subtest (WRAT-4 Reading) was administered along with comprehensive neurocognitive assessments to 150 HIV seropositive (HIV+) and 76 HIV seronegative (HIV-) age-, education-, and sex-matched participants; a subset of 48 HIV+ individuals completed a second study visit (M = 14.4 months), in which the alternate version of the WRAT-4 was administered.ResultsAlthough HIV+ individuals evidenced worse current neurocognitive functioning than HIV- participants, WRAT-4 Reading performance was comparable between groups. Longitudinally, HIV+ participants evidenced improved disease and neuropsychological functioning, yet WRAT-4 Reading demonstrated strong test-retest reliability and no practice effect, and did not differ between the initial and follow-up assessments. Test-retest differences in reading performance were minor and were not associated with changes in neurocognitive performance or changes in HIV disease.ConclusionsWe found no evidence of WRAT-4 Reading performance decline in HIV infection, despite HIV+/HIV- group differences in neurocognitive functioning. Additionally, reading performances among HIV+ individuals demonstrated consistency across study visits. These results begin to support the validity of the WRAT-4 Reading subtest as an indicator of premorbid cognitive functioning in HIV+ individuals.

This article examines the longitudinal relation between positive affect (PA) and sleep in 126 spousal Alzheimer's disease caregivers. Caregivers underwent 4 yearly assessments for the Positive and Negative Affect Schedule, the self-rated Pittsburgh Sleep Quality Index, and actigraphy to objectify nighttime total sleep time, wake after sleep onset, and percentage of sleep. Increased levels of PA and a greater positivity (i.e., positive-to-negative affect) ratio were significantly associated with better subjective sleep over the entire study period. Yearly increases in PA-even when controlling for negative affect (NA)-and in the positivity ratio were also associated with better subjective sleep. PA and actigraphy measures showed no significant relations. Increased PA is longitudinally associated with better sleep in dementia caregivers largely independent of NA.

ObjectiveWhile HIV-associated neurocognitive disorders (HAND) remain prevalent despite combination antiretroviral therapy (CART), the clinical relevance of asymptomatic neurocognitive impairment (ANI), the most common HAND diagnosis, remains unclear. We investigated whether HIV-infected persons with ANI were more likely than those who were neurocognitively normal (NCN) to experience a decline in everyday functioning (symptomatic decline).MethodsA total of 347 human participants from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort were NCN (n = 226) or had ANI (n = 121) at baseline. Neurocognitive assessments occurred approximately every 6 months, with median (interquartile range) follow-up of 45.2 (28.7-63.7) months. Symptomatic decline was based on self-report (SR) or objective, performance-based (PB) problems in everyday functioning. Proportional hazards modeling was used to generate risk ratios for progression to symptomatic HAND after adjusting for baseline and time-dependent covariates, including CD4+ T-lymphocyte count (CD4), virologic suppression, CART, and mood.ResultsThe ANI group had a shorter time to symptomatic HAND than the NCN after adjusting for baseline predictors: adjusted risk ratios for symptomatic HAND were 2.0 (confidence interval [CI] 1.1-3.6; p = 0.02) for SR, 5.8 (CI 3.2-10.7; p < 0.0001) for PB, and 3.2 (CI 2.0-5.0; p < 0.0001) for either SR or PB. Current CD4 and depression were significant time-dependent covariates, but antiretroviral regimen, virologic suppression, and substance abuse or dependence were not.ConclusionsThis longitudinal study demonstrates that ANI conveys a 2-fold to 6-fold increase in risk for earlier development of symptomatic HAND, supporting the prognostic value of the ANI diagnosis in clinical settings. Identifying those at highest risk for symptomatic decline may offer an opportunity to modify treatment to delay progression.

Despite modern antiretroviral therapy, HIV-associated sensory neuropathy affects over 50 % of HIV patients. The clinical expression of HIV neuropathy is highly variable: many individuals report few symptoms, but about half report distal neuropathic pain (DNP), making it one of the most prevalent, disabling, and treatment-resistant complications of HIV disease. The presence and intensity of pain is not fully explained by the degree of peripheral nerve damage, making it unclear why some patients do, and others do not, report pain. To better understand central nervous system contributions to HIV DNP, we performed a cross-sectional analysis of structural magnetic resonance imaging volumes in 241 HIV-infected participants from an observational multi-site cohort study at five US sites (CNS HIV Anti-Retroviral Treatment Effects Research Study, CHARTER). The association between DNP and the structural imaging outcomes was investigated using both linear and nonlinear (Gaussian Kernel support vector) multivariable regression, controlling for key demographic and clinical variables. Severity of DNP symptoms was correlated with smaller total cerebral cortical gray matter volume (r = -0.24; p = 0.004). Understanding the mechanisms for this association between smaller total cortical volumes and DNP may provide insight into HIV DNP chronicity and treatment-resistance.

ObjectiveHIV-associated neurocognitive disorders (HANDs) remain prevalent in patients who receive HAART and may be associated with cumulative exposure to antiretroviral medications and other factors. We proposed that chronic toxic effects of antiretroviral drugs could contribute to cerebral small vessel disease (CSVD), which might be one of the key underpinnings of HAND.DesignClinicopathological cross-sectional study of HIV-infected adults in the California NeuroAIDS Tissue Network.MethodsWe employed multivariable logistic regression methods to determine associations between HAART exposure (protease inhibitor-based, nonprotease inhibitor-based, or no HAART) and CSVD occurrence (standard histopathology: moderate/severe, mild, or absent). We also associated HAND (relative to normal cognition) with CSVD, HIV-related neuropathologic changes, older age at death (≥50 years), sex, or hepatitis C virus infection.ResultsWe found that both mild and moderate/severe CSVD were associated with protease inhibitor-based HAART exposure after adjusting for diabetes mellitus [odds ratio (OR) 2.8 (95% confidence interval, CI 1.03-7.9) and 2.6 (95% CI 1.03-6.7), respectively, n = 134]. Moderate/severe CSVD was associated with diabetes after adjusting for HAART exposure [OR 7.4 (95% CI 1.6-70.7), n = 134]. Notably, HAND was associated with mild CSVD [OR 4.8 (95% CI 1.1-21.2), n = 63], which remained statistically significant after adjusting for vessel mineralization, HIV encephalitis, microglial nodular lesions, white matter lesions, or older age.ConclusionProtease inhibitor-based HAART exposure may increase the risk of CSVD and thereby neurocognitive impairment in HIV-infected adults. Apart from the possible direct toxicity to cerebral small vessels, protease inhibitor-based HAART may contribute indirectly to CSVD by inducing metabolic abnormalities.

Neurocognitive impairments commonly occur and adversely impact everyday functioning in older adults infected with HIV, but little is known about successful cognitive aging (SCA) and its health-related quality of life (HRQoL) correlates. Seventy younger (≤40 years) and 107 older (≥50 years) HIV+ adults, as well as age-matched seronegative comparison groups of younger (N = 48) and older (N = 77) subjects completed a comprehensive battery of neuropsychological, psychiatric, medical, and HRQoL assessments. SCA was operationalized as the absence of both performance-based neurocognitive deficits and self-reported symptoms (SCA-ANDS) as determined by published normative standards. A stair-step decline in SCA-ANDS was observed in accordance with increasing age and HIV serostatus, with the lowest rates of SCA-ANDS found in the older HIV+ group (19 %). In both younger and older HIV+ adults, SCA-ANDS was strongly related to better mental HRQoL. HIV infection has additive adverse effects on SCA, which may play a unique role in mental well-being among HIV-infected persons across the lifespan.

Studies of healthy adults show that engagement in physical, social, and mental activities is associated with better cognitive outcomes, suggesting that these activities may increase cognitive reserve. Given the prevalence and real-world impact of HIV-associated neurocognitive disorders (HAND), the present study examined the association between neurocognitive outcomes and self-reported proxies for physical exercise, social activity, and mental activity (employment was used as a proxy for mental activity) among 139 HIV-infected adults (M age = 48.7; 48 % age 50+). Participants completed a neuromedical and neuropsychological battery and were classified based on the number of self-reported active lifestyle factors (ALFs; 0 to 3), including physical exercise, social activity, and current employment. The association between ALFs and both demographically adjusted average neuropsychological T-scores and HAND diagnoses was examined. Results revealed that an increased number of ALFs were associated with better global neurocognitive performance as well as a lower prevalence of HAND. These cross-sectional findings suggest that an active engagement in life may bolster neurocognitive functioning, perhaps by enhancing cognitive and/or brain reserve. However, an alternative explanation might be that persons with better neurocognitive functioning are more inclined and able to engage in these life activities. Future studies should utilize neuroimaging methodology, longitudinal data, and interventional approaches to establish cause-effect relationships and uncover the neural mechanisms whereby physical, social, and mental stimulation may protect neurocognition via cognitive reserve among those living with HIV.

ObjectivesThis study aimed to further elucidate the biobehavioral mechanisms linking dementia caregiving with an increased cardiovascular disease risk. We hypothesized that both elevated depressive symptoms and a behavioral correlate of depression, low leisure satisfaction, are associated with systemic inflammation.MethodWe studied 121 elderly Alzheimer's disease caregivers who underwent 4 annual assessments for depressive symptoms, leisure satisfaction, and circulating levels of inflammatory markers. We used mixed-regression analyses controlling for sociodemographic and health-relevant covariates to examine longitudinal relationships between constructs of interest.ResultsThere were inverse relationships between total leisure satisfaction and tumor necrosis factor-α (TNF-α; p = .047), interleukin-8 (IL-8; p < .001), and interferon-γ (IFG; p = .020) but not with IL-6 (p = .21) and C-reactive protein (p = .65). Lower enjoyment from leisure activities was related to higher levels of TNF-α (p = .045), IL-8 (p < .001), and IFG (p = .002), whereas lower frequency of leisure activities was related only to higher IL-8 levels (p = .023). Depressive symptoms were not associated with any inflammatory marker (all p values > .17). Depressive symptoms did not mediate the relationship between leisure satisfaction and inflammation.DiscussionLower satisfaction with leisure activities is related to higher low-grade systemic inflammation. This knowledge may provide a promising way of improving cardiovascular health in dementia caregivers through behavioral activation treatments targeting low leisure satisfaction.

Aging and HIV are both risk factors for memory deficits and declines in real-world functioning. However, we know little about the profile of memory deficits driving instrumental activities of daily living (IADL) declines across the lifespan in HIV. This study examined 145 younger (

Studies have shown reduced Stroop interference in bilinguals compared to monolinguals defined dichotomously, but no study has explored how varying degrees of second language fluency, might affect linguistic inhibitory control in the first language. We examined effects of relative English fluency on the ability to inhibit the automatic reading response on the Golden version of the Stroop Test administered in Spanish. Participants were 141 (49% male) adult native Spanish speakers from the U.S.-Mexico border region (education range = 8-20 and age range = 20-63). A language dominance index was calculated as the ratio of English words to total words produced in both languages using the Controlled Oral Word Association Test with letters PMR in Spanish and FAS in English. Greater degree of English fluency as measured by the dominance index predicted better speed on the Stroop incongruent trial independent of education effects. On the other hand, neither the dominance index nor education predicted performance on the word reading and color-naming trials. These results suggest an advantage in inhibitory control among those with greater second-language ability.

ObjectiveThe Veterans Aging Cohort Study (VACS) Index is predictive of mortality and combines age, traditional HIV biomarkers (HIV-1 plasma RNA and current CD4 count), and non-HIV biomarkers (indicators of renal and liver function, anemia, and hepatitis C coinfection). We examined the association between the VACS Index and HIV-associated neurocognitive impairment (NCI).Design and methodsParticipants included 601 HIV-infected adults enrolled in cohort studies at the University of California, San Diego, HIV Neurobehavioral Research Program (ages: 18-76 years; 88% male; 63% white; median current CD4 = 364 cells/mm; 63% on antiretroviral therapy; AIDS = 64%). Biomarkers used in calculating the VACS Index were measured in prospectively collected blood samples using conventional laboratory methods. NCI was defined using global and seven domain deficit scores.ResultsHigher VACS Index scores were associated with concurrent risk for global NCI [P < 0.001; odds ratio = 1.21, confidence interval (CI): 1.12 to 1.32], even when adjusting for psychiatric comorbidities. This relation was statistically significant for most cognitive domains in adjusted models. Furthermore, the VACS Index predicted concurrent NCI beyond nadir CD4 and estimated duration of infection. Older age, lower hemoglobin, and lower CD4 counts were the VACS components most strongly linked to NCI.ConclusionsThe findings extend previous research on the potential usefulness of the VACS Index in predicting HIV-associated outcomes to include NCI. Although the effect size was relatively small, our findings suggest that demographic information, HIV-disease factors, and common comorbidities might each play important roles in the clinical manifestation of cognitive impairment among HIV-infected individuals. Additional research is needed to determine if a more sensitive and specific index can be developed.

Caregiving for individuals with Alzheimer's disease is associated with chronic stress and elevated symptoms of depression. Placement of the care receiver (CR) into a long-term care setting may be associated with improved caregiver well-being; however, the psychological mechanisms underlying this relationship are unclear. This study evaluated whether decreases in activity restriction and increases in personal mastery mediated placement-related reductions in caregiver depressive symptoms. In a 5-year longitudinal study of 126 spousal Alzheimer's disease caregivers, we used multilevel models to evaluate placement-related changes in depressive symptoms (short form of the Center for Epidemiologic Studies Depression scale), activity restriction (Activity Restriction Scale), and personal mastery (Pearlin Mastery Scale) in 44 caregivers who placed their spouses into long-term care relative to caregivers who never placed their CRs. The Monte Carlo method for assessing mediation was used to evaluate the significance of the indirect effect of activity restriction and personal mastery on postplacement changes in depressive symptoms. Placement of the CR was associated with significant reductions in depressive symptoms and activity restriction and was also associated with increased personal mastery. Lower activity restriction and higher personal mastery were associated with reduced depressive symptoms. Furthermore, both variables significantly mediated the effect of placement on depressive symptoms. Placement-related reductions in activity restriction and increases in personal mastery are important psychological factors that help explain postplacement reductions in depressive symptoms. The implications for clinical care provided to caregivers are discussed. (PsycINFO Database Record © 2014 APA, all rights reserved).

HIV involvement of the CNS continues to be a significant problem despite successful use of combination antiretroviral therapy (cART). Drugs of abuse can act in concert with HIV proteins to damage glia and neurons, worsening the neurotoxicity caused by HIV alone. Methamphetamine (METH) is a highly addictive psychostimulant drug, abuse of which has reached epidemic proportions and is associated with high-risk sexual behavior, increased HIV transmission, and development of drug resistance. HIV infection and METH dependence can have synergistic pathological effects, with preferential involvement of frontostriatal circuits. At the molecular level, epigenetic alterations have been reported for both HIV-1 infection and drug abuse, but the neuropathological pathways triggered by their combined effects are less known. We investigated epigenetic changes in the brain associated with HIV and METH. We analyzed postmortem frontal cortex tissue from 27 HIV seropositive individuals, 13 of which had a history of METH dependence, in comparison to 14 cases who never used METH. We detected changes in the expression of DNMT1, at mRNA and protein levels, that resulted in the increase of global DNA methylation. Genome-wide profiling of DNA methylation in a subset of cases, showed differential methylation on genes related to neurodegeneration; dopamine metabolism and transport; and oxidative phosphorylation. We provide evidence for the synergy of HIV and METH dependence on the patterns of DNA methylation on the host brain, which results in a distinctive landscape for the comorbid condition. Importantly, we identified new epigenetic targets that might aid in understanding the aggravated neurodegenerative, cognitive, motor and behavioral symptoms observed in persons living with HIV and addictions.

HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP. Genotype-DNP associations were explored by logistic regression and permutation-based analytical methods. Among 559 evaluable subjects, 331 (59%) developed HIV-SN, and 168 (30%) reported DNP. Fifteen polymorphisms in 8 genes (p

Genetic elements in HIV-1 subtype B tat and env are associated with neurotoxicity yet less is known about other subtypes. HIV-1 subtype C tat and env sequences were analyzed to determine viral genetic elements associated with neurocognitive impairment in a large Indian cohort. Population-based sequences of HIV-1 tat (exon 1) and env (C2-V3 coding region) were generated from blood plasma of HIV-infected patients in Pune, India. Participants were classified as cognitively normal or impaired based on neuropsychological assessment. Tests for signature residues, positive and negative selection, entropy, and ambiguous bases were performed using tools available through Los Alamos National Laboratory (http://www.hiv.lanl.gov) and Datamonkey (http://www.datamonkey.org). HIV-1 subtype C tat and env sequences were analyzed for 155 and 160 participants, of which 34-36% were impaired. Two signature residues were unique to impaired participants in exon 1 of tat at codons 29 (arginine) and 68 (proline). Positive selection was noted at codon 29 among normal participants and at codon 68 in both groups. The signature at codon 29 was also a signature for low CD4+ (

BackgroundRisky decision-making is commonly observed in persons at risk for and infected with HIV and is associated with executive dysfunction. Yet it is currently unknown whether HIV alters brain processing of risk-taking decision-making.MethodsThis study examined the neural substrate of a risky decision-making task in 21 HIV seropositive (HIV+) and 19 seronegative (HIV-) comparison participants. Functional magnetic resonance imaging was conducted while participants performed the risky-gains task, which involves choosing among safe (20 cents) and risky (40/80 cent win or loss) choices. Linear mixed effects analyses examining group and decision type were conducted. Robust regressions were performed to examine the relationship between nadir CD4 count and Kalichman sexual compulsivity and brain activation in the HIV+ group. The overlap between the task effects and robust regressions was explored.ResultsAlthough there were no serostatus effects in behavioral performance on the risky-gains task, HIV+ individuals exhibited greater activation for risky choices in the basal ganglia, i.e. the caudate nucleus, but also in the anterior cingulate, dorsolateral prefrontal cortex, and insula relative to the HIV- group. The HIV+ group also demonstrated reduced functional responses to safe choices in the anterior cingulate and dorsolateral prefrontal cortex relative to the HIV- group. HIV+ individuals with higher nadir CD4 count and greater sexual compulsivity displayed lower differential responses to safe versus risky choices in many of these regions.ConclusionsThis study demonstrated fronto-striatal loop dysfunction associated with HIV infection during risky decision-making. Combined with similar between-group task behavior, this suggests an adaptive functional response in regions critical to reward and behavioral control in the HIV+ group. HIV-infected individuals with higher CD4 nadirs demonstrated activation patterns more similar to seronegative individuals. This suggests that the severity of past immunosuppression (CD4 nadir) may exert a legacy effect on processing of risky choices in the HIV-infected brain.

Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4 + T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p < 0.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (p < 0.001) and more NCI (p < 0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value > 13 were independently associated with GDS and NCI (p < 0.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but present in multivariable analyses, raising the possibility of specific SNVs in EIF2AK3 as an important component of genetic vulnerability to neurocognitive complications in PWH. [ABSTRACT FROM AUTHOR]

The acute and early period of HIV-1 infection (AEH) is characterized by neuroinflammatory and immunopathogenic processes that can alter the integrity of neural systems and neurocognitive functions. However, the extent to which central nervous system changes in AEH confer increased risk of real-world functioning (RWF) problems is not known. In the present study, 34 individuals with AEH and 39 seronegative comparison participants completed standardized neuromedical, psychiatric, and neurocognitive research evaluations, alongside a comprehensive assessment of RWF that included cognitive symptoms in daily life, basic and instrumental activities of daily living, clinician-rated global functioning, and employment. Results showed that AEH was associated with a significantly increased risk of dependence in RWF, which was particularly elevated among AEH persons with global neurocognitive impairment (NCI). Among those with AEH, NCI (i.e., deficits in learning and information processing speed), mood disorders (i.e., Bipolar Disorder), and substance dependence (e.g., methamphetamine dependence) were all independently predictive of RWF dependence. Findings suggest that neurocognitively impaired individuals with AEH are at notably elevated risk of clinically significant challenges in normal daily functioning. Screening for neurocognitive, mood, and substance use disorders in AEH may facilitate identification of individuals at high risk of functional dependence who may benefit from psychological and medical strategies to manage their neuropsychiatric conditions.

CONTEXT: Dementia care giving can lead to increased stress, physical and psychosocial morbidity, and mortality. Anecdotal evidence suggests that hospice care provided to people with dementia and their caregivers may buffer caregivers from some of the adverse outcomes associated with family caregiving in Alzheimers Disease (AD). OBJECTIVES: This pilot study examined psychological and physical outcomes among 32 spousal caregivers of patients with AD. It was hypothesized that caregivers who utilized hospice services would demonstrate better outcomes after the death of their spouse than caregivers who did not utilize hospice. METHODS: The charts of all spousal caregivers enrolled in a larger longitudinal study from 2001 to 2006 (N=120) were reviewed, and participants whose spouse had died were identified. Of these, those who received hospice care (n=10) were compared to those who did not (n=22) for various physiological and psychological measures of stress, both before and after the death of the care recipient. An Analysis of Covariance (ANCOVA), with postdeath scores as the dependent variable and pre-death scores as covariates, was used for all variables. RESULTS: Significant group differences were found in postdeath depressive symptoms (HAM-D; F(1,29)=6.10, p0.5 between groups. CONCLUSIONS: These data suggest that hospice enrollment may ameliorate the detrimental psychological effects in caregivers who have lost a spouse with Alzheimers Disease. Based on these pilot data, further prospective investigation is warranted.

BackgroundMethamphetamine (METH) use and human immunodeficiency virus (HIV) infection are highly comorbid, and both are associated with increased prevalence of affective distress. Delineating the trajectory of affective distress in the context of METH dependence and HIV infection is important given the implications for everyday functional impairment, adverse health behaviors, and increased risk for adverse health outcomes.MethodsWe conducted a five-year longitudinal investigation involving 133 METH-dependent (74 HIV seropositive) and 163 non-METH-dependent (90 HIV seropositive) persons to examine both long-standing patterns and transient changes in affective distress. Mixed-effect regression models with random subject-specific slopes and intercepts evaluated the effect of METH dependence, HIV serostatus, and related variables on affective distress, as measured by the Profile of Mood States.ResultsTransient changes in affective distress were found to be greater among those with a diagnosis of current MDD, briefer durations of abstinence from METH, and higher quantity of METH consumed. Weak associations were observed among static (time-independent predictors) covariates and long-standing patterns in affective distress.LimitationsStudy lacked data pertaining to the participants' involvement in METH treatment and relied on respondent-driven sampling.ConclusionsOur longitudinal investigation of the trajectory of affective distress indicated that specific and dynamic indices of current METH use were associated with greater transient changes in mood. In the evaluation and treatment of affective distress, recency and quantity of current METH use are important to consider given their association with heightened affective distress and mood instability over time.

Dementia caregiving is associated with elevations in depressive symptoms and increased risk for cardiovascular diseases (CVD). This study evaluated the efficacy of the Pleasant Events Program (PEP), a 6-week Behavioral Activation intervention designed to reduce CVD risk and depressive symptoms in caregivers. One hundred dementia family caregivers were randomized to either the 6-week PEP intervention (N = 49) or a time-equivalent Information-Support (IS) control condition (N = 51). Assessments were completed pre- and post-intervention and at 1-year follow-up. Biological assessments included CVD risk markers Interleukin-6 (IL-6) and D-dimer. Psychosocial outcomes included depressive symptoms, positive affect, and negative affect. Participants receiving the PEP intervention had significantly greater reductions in IL-6 (p = .040), depressive symptoms (p = .039), and negative affect (p = .021) from pre- to post-treatment. For IL-6, clinically significant improvement was observed in 20.0% of PEP participants and 6.5% of IS participants. For depressive symptoms, clinically significant improvement was found for 32.7% of PEP vs 11.8% of IS participants. Group differences in change from baseline to 1-year follow-up were non-significant for all outcomes. The PEP program decreased depression and improved a measure of physiological health in older dementia caregivers. Future research should examine the efficacy of PEP for improving other CVD biomarkers and seek to sustain the intervention's effects.

Neurocognitive impairment (NCI) remains prevalent in HIV infection. Randomized trials have shown that physical exercise improves NCI in non-HIV-infected adults, but data on HIV-infected populations are limited. Community-dwelling HIV-infected participants (n = 335) completed a comprehensive neurocognitive battery that was utilized to define both global and domain-specific NCI. Participants were divided into "exercise" (n = 83) and "no exercise" (n = 252) groups based on whether they self-reported engaging in any activity that increased heart rate in the last 72 h or not. We also measured and evaluated a series of potential confounding factors, including demographics, HIV disease characteristics, substance use and psychiatric comorbidities, and physical functioning. Lower rates of global NCI were observed among the exercise group (15.7 %) as compared to those in the no exercise group (31.0 %; p

HIV coreceptor usage of CXCR4 (X4) is associated with decreased CD4+ T-cell counts and accelerated disease progression, but the role of X4 tropism in HIV-associated neurocognitive disorders (HAND) has not previously been described. This longitudinal study evaluated data on 197 visits from 72 recently HIV-infected persons who had undergone up to four sequential neurocognitive assessments over a median of 160 days (IQR, 138–192). Phenotypic tropism testing (Trofile ES, Monogram, Biosciences) was performed on stored blood samples. Multivariable mixed model repeated measures regression was used to determine the association between HAND and dual-mixed (DM) viral tropism, estimated duration of infection (EDI), HIV RNA, CD4 count, and problematic methamphetamine use. Six subjects (8.3 %) had DM at their first neurocognitive assessment and four converted to DM in subsequent sampling (for total of 10 DM) at a median EDI of 10.1 months (IQR, 7.2–12.2). There were 44 (61.1 %) subjects who demonstrated HAND on at least one study visit. HAND was associated with DM tropism (odds ratio, 4.4; 95 % CI, 0.9–20.5) and shorter EDI (odds ratio 1.1 per month earlier; 95 % CI, 1.0–1.2). This study found that recency of HIV-1 infection and the development of DM tropism may be associated with HAND in the relatively early stage of infection. Together, these data suggest that viral interaction with cellular receptors may play an important role in the early manifestation of HAND.

MRI alterations in the cerebral white (WM) and gray matter (GM) are common in HIV infection, even during successful combination antiretroviral therapy (CART), and their pathophysiology and clinical significance are unclear. We evaluated the association of these alterations with recovery of CD4+ T cells. Seventy-five HIV-infected (HIV+) volunteers in the CNS HIV Anti-Retroviral Therapy Effects Research study underwent brain MRI at two visits. Multi-channel morphometry yielded volumes of total cerebral WM, abnormal WM, cortical and subcortical GM, and ventricular and sulcal CSF. Multivariable linear regressions were used to predict volumetric changes with change in current CD4 and detectable HIV RNA. On average, the cohort (79 % initially on CART) demonstrated loss of total cerebral WM alongside increases in abnormal WM and ventricular volumes. A greater extent of CD4 recovery was associated with increases in abnormal WM and subcortical GM volumes. Virologic suppression was associated with increased subcortical GM volume, independent of CD4 recovery. These findings suggest a possible link between brain alterations and immune recovery, distinct from the influence of virologic suppression. The association of increasing abnormal WM and subcortical GM volumes with CD4+ T cell recovery suggests that neuroinflammation may be one mechanism in CNS pathogenesis.

ObjectivesDisability among long-term methamphetamine (MA) users is multifactorial. This study examined the additive adverse impact of human immunodeficiency virus (HIV) infection, a common comorbidity in MA users, on functional dependence.MethodsA large cohort of participants (N = 798) stratified by lifetime MA-dependence diagnoses (ie, MA+ or MA-) and HIV serostatus (ie, HIV+ or HIV-) underwent comprehensive baseline neuromedical, neuropsychiatric, and functional research evaluations, including assessment of neurocognitive symptoms in daily life, instrumental and basic activities of daily living, and employment status.ResultsIndependent, additive effects of MA and HIV were observed across all measures of functional dependence, independent of other demographic, psychiatric, and substance-use factors. The prevalence of global functional dependence increased in the expected stepwise fashion across the cohort, with the lowest rates in the MA-/HIV- group (29%) and the highest rates in the MA+/HIV+ sample (69%). The impact of HIV on MA-associated functional dependence was moderated by nadir CD4 count, such that polysubstance use was associated with greater disability among those HIV-infected persons with higher but not lower nadir CD4 count. Within the MA+/HIV+ cohort, functional dependence was reliably associated with neurocognitive impairment, lower cognitive reserve, polysubstance use, and major depressive disorder.ConclusionsHIV infection confers an increased concurrent risk of MA-associated disability, particularly among HIV-infected persons without histories of immune compromise. Directed referrals, earlier HIV treatment, and compensatory strategies aimed at counteracting the effects of low cognitive reserve, neurocognitive impairment, and psychiatric comorbidities on functional dependence in MA+/HIV+ individuals may be warranted.

ObjectiveThere is a growing public health interest in the aging human immunodeficiency virus (HIV)-infected (HIV+) population, although there is a dearth of research on successful aging with HIV. This study aimed to understand the risk and protective factors associated with self-rated successful aging (SRSA) with HIV.DesignCross-sectional, case-controlled.SettingHIV Neurobehavioral Research Program and the Stein Institute for Research on Aging at University of California, San Diego.ParticipantsEighty-three community-dwelling HIV+ and 83 demographically matched HIV-uninfected (HIV-) individuals, enrolled between December 1, 2011, and May 10, 2012, mean age of 59 years, primarily white men, 69% with acquired immune deficiency syndrome (AIDS), who had been living with an HIV diagnosis for 16 years. Diagnostic criteria for HIV/AIDS were obtained through a blood analysis.MeasurementsParticipants provided ratings of SRSA, the primary outcome measure, as part of a comprehensive survey that included measures of physical and emotional functioning and positive psychological traits. Relationships between how the different variables related to SRSA were explored.ResultsWhile SRSA was lower in the HIV+ individuals than their HIV- counterparts, 66% of adults with HIV reported scores of 5 or higher on a 10-point scale of SRSA. Despite worse physical and mental functioning and greater psychosocial stress among the HIV+ participants, the 2 groups had comparable levels of optimism, personal mastery, and social support. Higher SRSA in HIV+ individuals was associated with better physical and emotional functioning and positive psychological factors, but not HIV disease status or negative life events.ConclusionsSuccessful psychosocial aging is possible in older HIV+ individuals. Positive psychological traits such as resilience, optimism, and sense of personal mastery have stronger relationship with SRSA than duration or severity of HIV disease. Research on interventions to enhance these positive traits in HIV+ adults is warranted.

ObjectiveReplicating HIV-1 in the brain is present in HIV encephalitis (HIVE) and microglial nodule encephalitis (MGNE) and is putatively linked with HIV-associated neurocognitive disorders (HAND). A cliniconeurovirological correlation was conducted to elucidate the relationship between brain viral load and clinical phenotype. SUBJECTS AND ASSAYS: HIV gag/pol RNA and DNA copies were quantified with reverse transcriptase-polymerase chain reaction or polymerase chain reaction in 148 HAART-era brain specimens. Comparison with HAND, HIVE, and MGNE and correlation with neuropsychological (NP) test scores were done using one-way ANOVA with Tukey-Kramer and Spearman tests, respectively.ResultsBrain HIV RNA was higher in subjects with HAND plus HIVE versus without HAND (delta = 2.48 log10 units, n = 27 versus 36, P < 0.001). In HAND without HIVE or MGNE, brain HIV RNA was not significantly different versus without HAND (P = 0.314). Worse NP scores correlated significantly with higher HIV RNA and interferon responses in brain specimens (P < 0.001) but not with HIV RNA levels in premortem blood plasma (n = 114) or cerebrospinal fluid (n = 104). In subjects with MGNE, brain HIV RNA was slightly higher versus without MGNE (P < 0.01) and much lower versus with HIVE (P < 0.001).ConclusionsBrain HIV RNA and to a lesser extent HIV DNA are correlated with worse NP performance in the 6 months before death. Linkage occurs primarily in patients with HIVE and MGNE, and these patients could obtain added NP improvement by further reducing brain HIV while on HAART. Patients not in those groups are less certain to obtain added NP benefit.

Abstract Background Human Immunodeficiency Virus-1 (HIV) infection frequently results in neurocognitive impairment. While the cause remains unclear, recent gene expression studies have identified genes whose transcription is dysregulated in individuals with HIV-association neurocognitive disorder (HAND). However, the methods for interpretation of such data have lagged behind the technical advances allowing the decoding genetic material. Here, we employ systems biology methods novel to the field of NeuroAIDS to further interrogate extant transcriptome data derived from brains of HIV + patients in order to further elucidate the neuropathogenesis of HAND. Additionally, we compare these data to those derived from brains of individuals with Alzheimer’s disease (AD) in order to identify common pathways of neuropathogenesis. Methods In Study 1, using data from three brain regions in 6 HIV-seronegative and 15 HIV + cases, we first employed weighted gene co-expression network analysis (WGCNA) to further explore transcriptome networks specific to HAND with HIV-encephalitis (HIVE) and HAND without HIVE. We then used a symptomatic approach, employing standard expression analysis and WGCNA to identify networks associated with neurocognitive impairment (NCI), regardless of HIVE or HAND diagnosis. Finally, we examined the association between the CNS penetration effectiveness (CPE) of antiretroviral regimens and brain transcriptome. In Study 2, we identified common gene networks associated with NCI in both HIV and AD by correlating gene expression with pre-mortem neurocognitive functioning. Results Study 1: WGCNA largely corroborated findings from standard differential gene expression analyses, but also identified possible meta-networks composed of multiple gene ontology categories and oligodendrocyte dysfunction. Differential expression analysis identified hub genes highly correlated with NCI, including genes implicated in gliosis, inflammation, and dopaminergic tone. Enrichment analysis identified gene ontology categories that varied across the three brain regions, the most notable being downregulation of genes involved in mitochondrial functioning. Finally, WGCNA identified dysregulated networks associated with NCI, including oligodendrocyte and mitochondrial functioning. Study 2: Common gene networks dysregulated in relation to NCI in AD and HIV included mitochondrial genes, whereas upregulation of various cancer-related genes was found. Conclusions While under-powered, this study identified possible biologically-relevant networks correlated with NCI in HIV, and common networks shared with AD, opening new avenues for inquiry in the investigation of HAND neuropathogenesis. These results suggest that further interrogation of existing transcriptome data using systems biology methods can yield important information.

The acute and early stages of HIV infection (AEH) are characterized by substantial viral replication, immune activation, and alterations in brain metabolism. However, little is known about the prevalence and predictors of neurocognitive deficits and neuropsychiatric disturbances during this period. The present study examined the impact of demographic, HIV disease, and substance use factors on HIV-associated neurocognitive impairment and self-reported neuropsychiatric distress among 46 antiretroviral-naive adults with median duration of infection of 75 days relative to a sample of 21 HIV seronegative (HIV-) adults with comparable demographics and risk factors. Participants were administered a brief neurocognitive battery that was adjusted for demographics and assessed executive functions, memory, psychomotor speed, and verbal fluency, as well as the Profile of Mood States, a self-report measure of neuropsychiatric distress. Odds ratios revealed that AEH participants were nearly four times more likely than their seronegative counterparts to experience neurocognitive impairment, particularly in the areas of learning and information processing speed. Similarly, AEH was associated with a nearly fivefold increase in the odds of neuropsychiatric distress, most notably in anxiety and depression. Within the AEH sample, HIV-associated neurocognitive impairment was associated with problematic methamphetamine use and higher plasma HIV RNA levels, whereas neuropsychiatric distress was solely associated with high-risk alcohol use. Extending prior neuroimaging findings, the results from this study indicate that HIV-associated neurocognitive impairment and neuropsychiatric distress are highly prevalent during AEH and are associated with high-risk substance use.

Using multi-process framework by McDaniel and Einstein (2000), the current study examined whether the length of prospective memory (PM) delay intervals as measured by the 2- and 15-min subscales of the Memory for Intentions Screening Test (MIST) have differential predictive value for antiretroviral (ARV) adherence. Participants included 74 HIV-infected individuals whose ARV adherence was tracked with an electronic monitoring system. Participants were classified as "adherent" (n = 49) or "non-adherent" (n = 25) based on recorded pill bottle openings of ≥90% of prescribed doses over 30 days. An adherence group by MIST delay interval interaction was observed, such that non-adherent participants had worse performance on the 15-min, but not 2-min delay PM MIST subscales. The observed MIST 15-min delay effects were significantly more pronounced on time- versus event-cued PM trials. Long-delay time-based PM was predictive of non-adherence independent of demographics, mood state, self-reported adherence, and general cognitive functioning. Findings from this clinical study indicate that ARV non-adherence may be particularly associated with deficits in strategic cue monitoring over longer PM delays, which may inform interventions to improve adherence among persons living with HIV infection.

In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.

Aged (>50 years old) human immunodeficiency virus (HIV) patients are the fastest-growing segment of the HIV-infected population in the USA and despite antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group. Autophagy is an intracellular clearance pathway for aggregated proteins and aged organelles; dysregulation of autophagy is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and HAND. Here, we hypothesized that dysregulated autophagy may contribute to aging-related neuropathology in HIV-infected individuals. To explore this possibility, we surveyed autophagy marker levels in postmortem brain samples from a cohort of well-characterized 50 years old (aged) HIV+ and HIV encephalitis (HIVE) patients. Detailed clinical and neuropathological data showed the young and aged HIVE patients had higher viral load, increased neuroinflammation and elevated neurodegeneration; however, aged HIVE postmortem brain tissues showed the most severe neurodegenerative pathology. Interestingly, young HIVE patients displayed an increase in beclin-1, cathepsin-D and light chain (LC)3, but these autophagy markers were reduced in aged HIVE cases compared to age-matched HIV+ donors. Similar alterations in autophagy markers were observed in aged gp120 transgenic (tg) mice; beclin-1 and LC3 were decreased in aged gp120 tg mice while mTor levels were increased. Lentivirus-mediated beclin-1 gene transfer, that is known to activate autophagy pathways, increased beclin-1, LC3, and microtubule-associated protein 2 expression while reducing glial fibrillary acidic protein and Iba1 expression in aged gp120 tg mice. These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients.

The present study assesses the impact of methamphetamine (METH) on antiretroviral therapy (ART) adherence among HIV+ persons, as well as examines the contribution of neurocognitive impairment and other neuropsychiatric factors [i.e., major depressive disorder (MDD), antisocial personality disorder (ASPD), and attention deficit disorder (ADHD)] for ART non-adherence. We examined HIV+ persons with DSM-IV-diagnosed lifetime history of METH abuse/dependence (HIV+ /METH+ ; n=67) as compared to HIV+ participants with no history of METH abuse/dependence (HIV+ /METH - ; n=50). Ancillary analyses compared these groups with a small group of HIV+ /METH+ persons with current METH abuse/dependence (HIV+ /CU METH+ ; n=8). Non-adherence was defined as self-report of any skipped ART dose in the last four days. Neurocognitive functioning was assessed with a comprehensive battery, covering seven neuropsychological domains. Lifetime METH diagnosis was associated with higher rates of detectable levels of plasma and CSF HIV RNA. When combing groups (i.e., METH+ and METH- participants), univariate analyses indicated co-occurring ADHD, ASPD, and MDD predicted ART non-adherence (p's < 0.10; not lifetime METH status or neurocognitive impairment). A significant multivariable model including these variables indicated that only MDD uniquely predicted ART non-adherence after controlling for the other variables (p

ObjectiveThe apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer's disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition.DesignClinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium.MethodsWe used multivariable logistic regressions to model outcomes [Aβ plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE ε4 (allelic discrimination assay), older age (≥50 years), Aβ plaques, and their two-way interactions] and comorbid factors.ResultsIsocortical Aβ deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00, 95% CI 1.41-638.63, P = 0.029, n = 15), but not in non-ε4 carriers (n = 57).ConclusionThe APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally, Aβ plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimer's disease brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND patients who could benefit from Aβ-targeted therapies.

Standard methods used to estimate HIV-1 population diversity are often resource intensive (e.g., single genome amplification, clonal amplification and pyrosequencing) and not well suited for large study cohorts. Additional approaches are needed to address the relationships between intraindividual HIV-1 genetic diversity and 2 disease. With a small cohort of individuals, we validated three methods for measuring diversity: Shannon entropy and average pairwise distance (APD) using single genome sequences, and counts of mixed bases (i.e. ambiguous nucleotides) from population based sequences. In a large cohort, we then used the mixed base approach to determine associations between measure HIV-1 diversity and HIV associated disease. Normalized counts of mixed bases correlated with Shannon Entropy at both the nucleotide (rho=0.72, p=0.002) and amino acid level (rho=0.59, p=0.015), and APD (rho=0.75, p=0.001). Among participants who underwent neuropsychological and clinical assessments (n=187), increased HIV-1 population diversity was associated with both a diagnosis of AIDS and neuropsychological impairment.

The contribution of bipolar disorder (BD), a prevalent serious mental illness characterized by impulsivity and mood instability, to antiretroviral (ART) and psychiatric medication adherence among HIV-infected (HIV+) individuals is unknown. We examined medication adherence among 44 HIV+/BD+ persons as compared to 33 demographically- and medically-comparable HIV+/BD- persons. Classification of adherent (≥ 90%) or non-adherent (

ObjectiveThe apolipoprotein E (APOE) ε4 allele enhances cerebral accumulation of β-amyloid (Aβ) and is a major risk factor for sporadic Alzheimer's disease. We hypothesized that HIV-associated neurocognitive disorders (HAND) would be associated with the APOE ε4 genotype and cerebral Aβ deposition.DesignClinicopathological study of HIV-infected adults from four prospective cohorts in the US National NeuroAIDS Tissue Consortium.MethodsWe used multivariable logistic regressions to model outcomes [Aβ plaques (immunohistochemistry) and HAND (standard criteria)] on predictors [APOE ε4 (allelic discrimination assay), older age (≥50 years), Aβ plaques, and their two-way interactions] and comorbid factors.ResultsIsocortical Aβ deposits generally occurred as diffuse plaques and mild-to-moderate amyloid angiopathy. Isocortical phospho-Tau-immunoreactive neurofibrillary lesions were sparse. The APOE ε4 and older age were independently associated with the presence of Aβ plaques [adjusted odds ratio (OR) 10.16 and 5.77, 95% confidence interval (CI) 2.89 - 35.76 and 1.91-17.48, P = 0.0003 and 0.0019, respectively, n = 96]. The probability of HAND was increased in the presence of Aβ plaques among APOE ε4 carriers (adjusted OR 30.00, 95% CI 1.41-638.63, P = 0.029, n = 15), but not in non-ε4 carriers (n = 57).ConclusionThe APOE ε4 and older age increased the likelihood of cerebral Aβ plaque deposition in HIV-infected adults. Generally, Aβ plaques in HIV brains were immunohistologically different from those in symptomatic Alzheimer's disease brains. Nonetheless, Aβ plaques were associated with HAND among APOE ε4 carriers. The detection of APOE ε4 genotype and cerebral Aβ deposition biomarkers may be useful in identifying living HAND patients who could benefit from Aβ-targeted therapies.

Sestrin-2 is involved in p53-dependent antioxidant defenses and in the maintenance of metabolic homeostasis. We hypothesize that sestrin-2 expression is altered in the brains of subjects diagnosed with human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) due to neuronal oxidative stress. We studied sestrin-2 immunoreactivity in 42 isocortex sections from HIV-1-infected subjects compared to 18 age-matched non-HIV controls and 19 advanced Alzheimer's disease (AD) cases. With HIV infection, the sestrin-2 immunoreactivity pattern shifted from neuropil predominance (N) to neuropil and neuronal-soma co-dominance (NS) and neuronal-soma predominance (S; P

BackgroundUnemployment rates are high among chronic methamphetamine (MA) users and carry a significant economic burden, yet little is known about the neurocognitive and psychiatric predictors of employment in this vulnerable population.MethodsThe present study examined this issue in 63 participants with recent MA dependence and 47 comparison subjects without histories of MA use disorders. All participants completed a comprehensive neurocognitive, psychiatric and neuromedical evaluation. Individuals with HIV infection, severe neuropsychological or psychiatric conditions that might affect cognition (e.g., seizure disorder, schizophrenia), or a positive Breathalyzer or urine toxicology screen on the day of testing were excluded.ResultsConsistent with previous research, a logistic regression revealed MA dependence as a significant, independent predictor of full-time unemployment status. Within the MA-dependent sample, greater impairment in global neurocognitive functioning and history of injection drug use emerged as significant independent predictors of unemployment status. The association between worse global cognitive functioning and unemployment was primarily driven by deficits in executive functions, learning, verbal fluency, and working memory.ConclusionThese findings indicate that neurocognitive deficits play a significant role in the higher unemployment rates of MA-dependent individuals, and highlight the need for vocational rehabilitation and supported employment programs that assess and bolster cognitive skills in this population.