Erica Weber

Timing is everything: antiretroviral nonadherence is associated with impairment in time-based prospective memory.

Nonadherence to combination antiretroviral (ARV) therapies (cART) is highly prevalent and significantly increases the risk of adverse human immunodeficiency virus (HIV) disease outcomes. The current study evaluated the hypothesis that prospective memory-a dissociable aspect of episodic memory describing the ability to execute a future intention-plays an important role in successful cART adherence. Seventy-nine individuals with HIV infection who were prescribed at least one ARV medication underwent a comprehensive neuropsychological and neuromedical evaluation prior to completing a 1-month observation of their cART adherence as measured by electronic medication monitoring. Nonadherent individuals (n = 31) demonstrated significantly poorer prospective memory functioning as compared to adherent persons (n = 48), particularly on an index of time-based ProM (i.e., elevated loss of time errors). Deficits in time-based prospective memory were independently predictive of cART nonadherence, even after considering the possible influence of established predictors of adherence, such as general cognitive impairment (e.g., retrospective learning and memory) and psychiatric comorbidity (e.g., depression). These findings extend a nascent literature showing that impairment in time-based prospective memory significantly increases the risk of medication nonadherence and therefore may guide the development of novel strategies for intervention. (JINS, 2009, 15, 42-52.).

Synergistic effects of HIV infection and older age on daily functioning.

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:One hundred three 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 ratings. Results:Significant interaction effects of HIV and aging were observed for IADL and BADL declines, and for Karnofsky Performance Scale ratings (Ps < 0.05), independent of potentially confounding factors. Follow-up contrasts revealed significantly worse functioning in the older HIV+ group for most functional outcome measures relative to the other study groups (Ps < 0.05). 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 < 0.05). 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 (eg, cognitive remediation) or assistive services.

The semantic relatedness of cue–intention pairings influences event-based prospective memory failures in older adults with HIV infection

HIV infection and aging are each independently associated with prospective memory (ProM) impairment, which increases the risk of poor functional outcomes, including medication non-adherence. The incidence and prevalence of HIV infection among older adults has increased in recent years, thereby raising questions about the combined effects of these risk factors on ProM. In the present study, 118 participants were classified into four groups on the basis of HIV serostatus and age (i.e., ≤40 years and ≥50 years). Results showed significant additive effects of HIV and aging on event-based ProM, with the greatest deficits evident in the older HIV+ group, even after controlling for other demographic factors and potential medical and psychiatric confounds. Event-based ProM impairment was particularly apparent in the older HIV+ group on trials for which the retrieval cue and intention were not semantically related. Worse performance on the semantically unrelated cue–intention trials was associated with executive dysfunction, older age, and histories of immunocompromise in the older HIV+ cohort. These data suggest that older HIV-infected adults are significantly less proficient at engaging the strategic encoding and retrieval processes required to a execute a future intention when the cue is unrelated to the intended action, perhaps secondary to greater neuropathological burden in the prefrontostriatal systems critical to optimal ProM functioning.

The effects of memantine on prepulse inhibition.

Reduced prepulse inhibition (PPI) of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. The role of NMDA neurotransmission in the regulation of PPI is unclear, due to cross-species differences in the effects of NMDA antagonists on PPI. Recent reports suggest that drug effects on PPI differ in subgroups of normal humans that differ in the levels of baseline PPI or specific personality domains; here, we tested the effects of these variables on the sensitivity of PPI to the NMDA antagonist, memantine. PPI was measured in male Sprague–Dawley rats, after treatment with memantine (0, 10 or 20 mg/kg, s.c.). Baseline PPI was then measured in 37 healthy adult men. Next, subjects were tested twice, in a double-blind crossover design, comparing either (1) placebo vs 20 mg of the NMDA antagonist memantine (n=19) or (2) placebo vs 30 mg memantine (n=18). Tests included measures of acoustic startle amplitude, PPI, autonomic indices and subjective self-rating scales. Memantine had dose- and interval-dependent effects on PPI in rats. Compared with vehicle, 10 mg/kg increased short-interval (10–20 ms) PPI, and 20 mg/kg decreased long-interval (120 ms) PPI. In humans, memantine caused dose-dependent effects on psychological and somatic measures: 20 mg was associated with increased ratings of happiness, and 30 mg was associated with increased ratings of dizziness. PPI at the 120 ms prepulse interval was increased by 20 mg, but not 30 mg of memantine. Subgroups most sensitive to the PPI-enhancing effects of memantine were those with low baseline PPI, or with personality scale scores suggestive of high novelty seeking, high sensation seeking, or high disinhibition. NMDA blockade with memantine appears to have dose- and interval-dependent effects on sensorimotor gating in rats and humans, particularly among specific subgroups of normal human subjects. These findings are discussed as they relate to consistencies across other studies in humans, as well as apparent inconsistencies in the NMDA regulation of PPI across species.

Lower Cognitive Reserve Among Individuals with Syndromic HIV-Associated Neurocognitive Disorders (HAND)

HIV-seropositive individuals with low cognitive reserve are at high risk for developing HIV-associated neurocognitive disorders (HAND). The present study evaluated the hypothesis that cognitive reserve would also play a unique role in the expression of everyday functioning complications among those with HAND (i.e., syndromic versus subsyndromic impairment). Eighty-six individuals with HIV infection were evaluated; 53 individuals evidenced normal neurocognitive performance, 16 had subsyndromic HAND (i.e., asymptomatic neurocognitive impairment), and 17 were diagnosed with syndromic HAND based on a comprehensive neurobehavioral evaluation. Cognitive reserve represented a combined score including years of education, estimated verbal IQ, and highest occupational attainment. The groups were comparable (e.g. demographics), and the HAND groups had similar rates of global neurocognitive impairment. The syndromic HAND group evidenced lower reserve scores relative to both other groups, suggesting that individuals with lower reserve may be less able to effectively counteract their neurocognitive impairment to maintain independence in daily living activities than HIV-infected individuals with high cognitive reserve.

Planning deficits in HIV-associated neurocognitive disorders: Component processes, cognitive correlates, and implications for everyday functioning

Executive dysfunction remains among the most prevalent cognitive domains impaired in persons with HIV-associated neurocognitive disorders (HAND). However, little is known specifically about the cognitive architecture or everyday functioning implications of planning, which is an aspect of executive functions involving the identification, organization, and completion of sequential behaviours toward the accomplishment of a goal. The current study examined these issues using the Tower of LondonDX in 53 individuals with HAND, 109 HIV-infected persons without HAND, and 82 seronegative participants. The HAND+ group performed significantly more poorly than HIV-infected individuals without HAND on number of correct moves, total moves, execution time, time violations, and rule violations. Within the HIV+ group as a whole, greater total move scores and rule violations were most strongly associated with executive dysfunction. Of clinical relevance, elevated total moves and rule violations were significant, independent predictors of self-reported declines in instrumental activities of daily living and unemployment status in HIV. These results suggest that planning accuracy, efficiency, and rule-bound control are impaired in HAND and may meaningfully affect more cognitively complex aspects of everyday living.

Human immunodeficiency virus infection heightens concurrent risk of functional dependence in persons with long-term methamphetamine use

Objectives:Disability 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. Methods:A 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. Results:Independent, 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. Conclusions:HIV 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.

Cognitive Mechanisms of Switching in HIV-Associated Category Fluency Deficits

HIV infection is associated with deficits in category fluency, but the underlying cognitive mechanisms of such impairments have not been determined. Considering the preferential disruption of the structure and function of frontostriatal circuits in HIV disease, the present study evaluated the hypothesis that HIV-associated category fluency deficits are driven by impaired switching. Study participants were 96 HIV-infected individuals and 43 demographically comparable healthy comparison volunteers who were administered a standard measure of animal fluency and an alternating category fluency task (i.e., fruits and furniture) in a randomized order. Consistent with prior research on letter fluency, HIV infection was associated with greater impairments in switching, but not semantic clustering within the animal fluency task. Moreover, a significant interaction was observed whereby the HIV-associated deficits in switching were exacerbated by the explicit demands of the alternating fluency task. Across both fluency tasks, switching demonstrated generally small correlations with standard clinical measures of executive functions, working memory, and semantic memory. Collectively, these findings suggest that HIV-associated category fluency deficits are driven by switching impairments and related cognitive abilities (e.g., mental flexibility), perhaps reflecting underlying neuropathology within prefrontostriatal networks.

Is prospective memory a dissociable cognitive function in HIV infection

An emerging literature indicates that HIV infection is associated with deficits in prospective memory (ProM), or the ability to execute a future intention. This literature offers evidence of neurobiological dissociability of ProM from other cognitive abilities and its incremental ecological validity as a predictor of poorer everyday functioning outcomes (e.g., medication nonadherence). The present study evaluated the hypothesis that ProM represents a unique cognitive construct in HIV disease. A confirmatory 4-factor structural equation model was tested on data derived from 162 participants with HIV. The model posited that measures of ProM comprise a unique factor, apart from standard clinical tests of retrospective memory, executive functions, and motor skills. The fit of the model was evaluated using the Bollen–Stine bootstrap method and indicated that a 4-factor model with measures of ProM loading on a unique factor fit the data well, and better than a model with a single common factor hypothesized to drive cognitive performance. The results of this study lend further evidence to the dissociability of ProM in HIV infection, are consistent with prior studies in healthy adults, and contribute to a growing literature on the construct validity of ProM in HIV disease.

HIV-associated Prospective Memory Impairment in the Laboratory Predicts Failures on a Semi-naturalistic Measure of Health Care Compliance

HIV-associated neurocognitive impairment, particularly in the domain of prospective memory (ProM), increases the risk of poor everyday functioning outcomes, including medication non-adherence. However, whether ProM plays a role in health care compliance outside of the realm of medication adherence remains to be determined. This study evaluated the hypothesis that ProM is an independent predictor of failure to comply with non-medication-related instructions akin to those commonly given by health care providers. Participants were 139 HIV-infected adults who underwent medical, psychiatric, and neuropsychological assessments, including a laboratory-based measure of ProM. To assess real-world compliance, participants were instructed to call the examiner 24 hours after the evaluation and report how many hours they had slept. Individuals who failed to correctly comply with these instructions (n = 104) demonstrated significantly lower performance on both time- and event-based ProM at baseline than the compliant group (n = 35), an effect that was primarily driven by errors of omission. ProM remained a significant predictor of noncompliance after controlling for potential confounders, including demographics (e.g., education), traditional cognitive measures of retrospective memory and executive functions, and psychiatric factors (e.g., depression). Results support the hypothesis that ProM plays a unique role in compliance with health care instructions for HIV disease management and may inform interventions designed to improve treatment outcomes.