This study sought to determine the synergistic effects of age and HIV infection on medical co-morbidity burden, along with its clinical correlates and impact on health-related quality of life (HRQoL) across the lifespan in HIV. Participants included 262 individuals across four groups stratified by age (£ 40 and ‡ 50 years) and HIV serostatus. Medical co-morbidity burden was assessed using a modified version of the Charlson Co-morbidity Index (CCI). Multiple regression accounting for potentially confounding demographic, psychiatric, and medical factors revealed an interaction between age and HIV infection on the CCI, with the highest medical co-morbidity burden in the older HIV + cohort. Nearly half of the older HIV + group had at least one major medical comorbidity, with the most prevalent being diabetes (17.8%), syndromic neurocognitive impairment (15.4%), and malignancy (12.2%). Affective distress and detectable plasma viral load were significantly associated with the CCI in the younger and older HIV-infected groups, respectively. Greater co-morbidity burden was uniquely associated with lower physical HRQoL across the lifespan. These findings highlight the prevalence and clinical impact of co-morbidities in older HIV-infected adults and underscore the importance of early detection and treatment efforts that might enhance HIV disease outcomes.

Prefrontal cortical dopamine (DA) regulates various executive cognitive functions, including attention and working memory. Efforts to enhance prefrontal-related cognition, which have focused on catecholaminergic stimulant drugs, have been unsatisfactory. Recently, the demonstration that a functional polymorphism in the catecholamine-O-methyltransferase (COMT) gene impacts prefrontal cognition raises the possibility of a novel pharmacological approach for the treatment of prefrontal lobe executive dysfunction. To explore in a proof of concept study the effects of tolcapone, a CNS penetrant specific COMT inhibitor, we performed a randomized, double blind, placebo controlled, and crossover design of this drug in normal subjects stratified by COMT (val158met) genotype. COMT enzyme activity was determined in peripheral blood. Forty-seven normal volunteers with no family history of psychiatric disorders underwent neuropsychological testing and 34 of those subjects underwent physiological measurement of prefrontal information processing assessed by blood oxygen level-dependent functional magnetic resonance imaging (fMRI). We found significant drug effects on measures of executive function and verbal episodic memory and a significant drug by genotype interaction on the latter, such that individuals with val/ val genotypes improved, whereas individuals with met/met genotypes worsened on tolcapone. fMRI revealed a significant tolcaponeinduced improvement in the efficiency of information processing in prefrontal cortex during a working memory test. This study demonstrates enhancement of prefrontal cortical function in normal human subjects with a nonstimulant drug having COMT inhibitory activity. Our results are consistent with data from animal studies and from computational models of the effects of selective enhancement of DA signaling in the prefrontal cortex.

HIV infection is associated with impairments in prospective memory (ProM), an aspect of episodic memory that refers to the ability to execute a future intention, such as remembering to take a medication at a specific time. The current study sought to examine the relationship between HIVassociated ProM impairment and the successful management of independent activities of daily living (IADLs). In a cohort of 66 HIV-infected individuals, ProM accounted for a significant proportion of variance in self-reported IADL dependence over and above that which was explained by retrospective memory and current affective distress. Analysis of component cognitive processes revealed that the relationship between HIV-associated ProM deficits and IADL dependence was driven by impaired cue detection and self-initiated intention retrieval. Results were not better explained by demographic factors, HIV disease severity, psychiatric comorbidity, or substance use. Collectively, these data support the potential incremental ecological validity of ProM as a predictor of dependence in IADLs among persons living with HIV infection. KeywordsHuman immunodeficiency virus; neuropsychological assessment; episodic memory; activities of daily living HIV-associated Prospective Memory Impairment Increases Risk of Dependence in Everyday FunctioningThe human immunodeficiency virus (HIV) crosses the blood-brain barrier and often leads to neuropathological changes (e.g., syncytia and synaptodendritic injury), which primarily affect the basal ganglia, frontal neocortex, hippocampus, and cerebral white matter (González-Scarano, & Martín-García, 2005 has improved systemic disease outcomes and diminished the incidence of frank dementia among persons infected with HIV, the prevalence of milder forms of HIV-associated neurocognitive impairment remains a significant public health problem (McArthur, 2004). The neurobehavioral syndrome of HIV infection is most consistent with dysregulation of frontostriato-thalamo-cortical circuits and is typically marked by mild-to-moderate bradyphrenia, bradykinesia, executive dysfunction, and deficits in episodic memory (e.g., Reger, Welsh, Razani, Martin, & Boone, 2002). As many as one-half of individuals with HIV-associated neurocognitive impairment experience problems independently managing their instrumental activities of daily living (IADLs; Heaton et al., 2004). Neuropsychological impairment contributes to decrements in medication management (e.g., Albert et al., 1999), automobile driving (Marcotte et al., 1999), and vocational functioning (e.g., van Gorp, Baerwald, Ferrando, McElhiney, & Rabkin, 1999), even after considering the effects of HIV disease severity and psychiatric distress (e.g., depression).Deficits in episodic memory are among the strongest neuropsychological predictors of IADL declines in HIV (e.g., Andrade et al., 2005;Benedict, Mezhir, Walsh, & Hewitt, 2000;Heaton et al., 1994;van Gorp et al., 2007). Episodic memory impairment is evident in approximately 50% of individuals infected with HIV (e.g...

Objective To determine whether HIV infection and aging act synergistically to disrupt everyday functioning. Design Cross-sectional, factorial study of everyday functioning in the context of HIV serostatus and age (≤ 40 years vs ≥ 50 years). Methods 103 HIV+ and 87 HIV− participants were administered several measures of everyday functioning, including self-report indices of health-related quality of life (HRQoL) and instrumental and basic activities of daily living (IADLs and BADLs), and objective measures of functioning including employment and Karnofsky Performance Scale (KPS) ratings. Results Significant interaction effects of HIV and aging were observed for IADL and BADL declines, as well as KPS ratings (ps<.05), independent of potentially confounding factors. Follow-up contrasts revealed significantly worse functioning in the older HIV+ group for all functional outcome measures relative to the other study groups (ps<.05). A significant interaction effect was also observed on the emotional functioning HRQoL subscale, and additive effects of both age and HIV were observed for the physical functioning and general health perceptions HRQoL subscales (ps<.05). Significant predictors of poorer functioning in the older HIV+ group included current major depressive disorder for all outcomes, and comorbid medical conditions, lower estimated premorbid functioning, neurocognitive impairment, and nadir CD4 count for selected outcomes. Conclusion Findings suggest that older age may exacerbate the adverse effects of HIV on daily functioning, which highlights the importance of evaluating and monitoring the functional status of older HIV-infected adults. Early detection of functional difficulties could facilitate delivery of compensatory strategies (e.g., cognitive remediation) or assistive services.

Optimal adherence to antiretroviral medications is critical to the effective long-term management of HIV infection. Although prospective memory (ProM; i.e., "remembering to remember") has long been theorized to play an important role in medication adherence, no prior studies have evaluated whether HIV-associated ProM impairment possesses unique predictive value in this regard. Results from this study demonstrate a robust association between ProM impairment and self-reported medication management in 87 HIV-infected persons currently prescribed antiretroviral medications. Specifically, more frequent ProM complaints and performance deficits on both laboratory and semi-naturalistic ProM tasks were all independently related to poorer self-reported medication management. A series of hierarchical regression analyses revealed that HIV-associated ProM impairment accounted for a significant amount of variance in self-reported medication management beyond that which was explained by other factors known to predict nonadherence, including mood disorders, psychosocial variables, environmental structure, and deficits on a traditional battery of neuropsychological tests. Overall, these findings support the hypothesis that ProM captures a unique and largely untapped aspect of cognition that is germane to optimal medication adherence. The potential benefits of individualized remediation strategies that are informed by conceptual models of ProM and specifically target medication adherence warrant further exploration.

Chronic use of methamphetamine (MA) is associated with neuropsychological dysfunction and affective distress. Some normalization of function has been reported after abstinence, but little data is available on the possible added benefits of long-term sobriety. To address this, we performed detailed neuropsychological and affective evaluations in 83 MA-dependent individuals at a baseline visit and following an average one-year interval period. Among the 83 MAdependent participants, 25 remained abstinent and 58 used MA at least once during the interval period. Thirty-eight non-MA-addicted, demographically matched healthy comparison (i.e., HC) participants were also examined. At baseline, both MA-dependent participants who were able to maintain abstinence and those who were not performed significantly worse than the healthy comparison subjects on global neuropsychological functioning and were significantly more distressed. At the one-year follow-up, both the long term abstainers and healthy comparison groups showed comparable global neuropsychological performance and affective distress levels, whereas the MA-dependent group who continued to use were worse than the comparison participants in terms of global neuropsychological functioning and affective distress. An interaction was observed between neuropsychological impairment at baseline, MA abstinence, and cognitive improvement, with abstinent MA-dependent participants who were neuropsychologically impaired at baseline demonstrating significantly and disproportionately greater improvement in processing speed and slightly greater improvement in motor abilities relative to the other participants. These results suggest partial recovery of neuropsychological functioning and improvement in affective distress upon sustained abstinence from MA that may extend beyond a year or more.

This study evaluated the effects of HIV-associated Neurocognitive Disorders (HAND) on 2 Internet-based tests of healthcare management. Study participants included 46 individuals with HIV infection, 19 of whom were diagnosed with HAND, and 21 seronegatives. Participants were administered Internet-based tests of online pharmacy and health records navigation skills in which they used mock credentials to log in to an experimenter-controlled website and independently perform a series of typical online health-related behaviors (e.g., refill a prescription, read and interpret an electronic chart note). HAND was associated with significantly lower accuracy on both the online pharmacy and health records navigation tasks. Among the HIV+ participants, poorer performance on the online healthcare navigation tasks was associated with fewer years of education, higher plasma viral load, less frequent Internet use, and lower health literacy. Findings indicate that individuals with HAND may have marked difficulties navigating the Internet to complete important health-related behaviors.

Accumulating evidence from non-human primates and computational modeling suggests that dopaminergic signals arising from the midbrain (substantia nigra/ventral tegmental area) mediate striatal gating of the prefrontal cortex during the selective updating of working memory. Using event-related functional magnetic resonance imaging, we explored the neural mechanisms underlying the selective updating of information stored in working memory. Participants were scanned during a novel working memory task that parses the neurophysiology underlying working memory maintenance, overwriting, and selective updating. Analyses revealed a functionally coupled network consisting of a midbrain region encompassing the substantia nigra/ventral tegmental area, caudate, and dorsolateral prefrontal cortex that was selectively engaged during working memory updating compared to the overwriting and maintenance of working memory content. Further analysis revealed differential midbrain-dorsolateral prefrontal interactions during selective updating between low-performing and high-performing individuals. These findings highlight the role of this meso-cortico-striatal circuitry during the selective updating of working memory in humans, which complements previous research in behavioral neuroscience and computational modelin