Matthew S. Dawson

HIV-associated prospective memory impairment increases risk of dependence in everyday functioning.

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 HIV-associated ProM impairment and the successful management of instrumental 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 by 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 by deficits in 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.

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.).

Psychometric characteristics of the memory for intentions screening test.

The construct of prospective memory (ProM), or “remembering to remember,” is hypothesized to play a critical role in normal activities of daily living and has increasingly been the focus of clinical research over the past 10 years. However, the assessment of ProM as part of routine clinical care is presently hampered by the paucity of psychometrically sound, validated ProM tests available in the neuropsychological literature. The Memory for Intentions Screening Test (MIST; Raskin, 2004) is a user-friendly, comprehensive measure of ProM that demonstrates preliminary evidence of construct validity. Extending this research, this study evaluated the psychometric characteristics of the MIST in a sample of 67 healthy adults. Despite a mildly restricted range of scores, results revealed excellent inter-rater reliability, adequate split-half reliability, and satisfactory inter-relationships between the MIST summary score, subscales, and error types. Analysis of demographic correlates showed that the MIST was independently associated with both age and education, but not with sex or ethnicity. These findings broadly support the psychometric properties of the MIST, specifically its reliability and expected relationships with demographic characteristics. Recommendations are provided regarding future research to enhance the clinical usefulness of the MIST.

Efavirenz concentrations in CSF exceed IC50 for wild-type HIV

OBJECTIVES HIV-associated neurocognitive disorders remain common despite use of potent antiretroviral therapy (ART). Ongoing viral replication due to poor distribution of antivirals into the CNS may increase risk for HIV-associated neurocognitive disorders. This studys objective was to determine penetration of a commonly prescribed antiretroviral drug, efavirenz, into CSF. METHODS CHARTER is an ongoing, North American, multicentre, observational study to determine the effects of ART on HIV-associated neurological disease. Single random plasma and CSF samples were drawn within 1 h of each other from subjects taking efavirenz between September 2003 and July 2007. Samples were assayed by HPLC or HPLC/mass spectrometry with detection limits of 39 ng/mL (plasma) and <0.1 ng/mL (CSF). RESULTS Eighty participants (age 44 ± 8 years; 79 ± 15 kg; 20 females) had samples drawn 12.5 ± 5.4 h post-dose. The median efavirenz concentrations after a median of 7 months [interquartile range (IQR) 2-17] of therapy were 2145 ng/mL in plasma (IQR 1384-4423) and 13.9 ng/mL in CSF (IQR 4.1-21.2). The CSF/plasma concentration ratio from paired samples drawn within 1 h of each other was 0.005 (IQR 0.0026-0.0076; n = 69). The CSF/IC(50) ratio was 26 (IQR 8-41) using the published IC(50) for wild-type HIV (0.51 ng/mL). Two CSF samples had concentrations below the efavirenz IC(50) for wild-type HIV. CONCLUSIONS Efavirenz concentrations in the CSF are only 0.5% of plasma concentrations but exceed the wild-type IC(50) in nearly all individuals. Since CSF drug concentrations reflect those in brain interstitial fluids, efavirenz reaches therapeutic concentrations in brain tissue.

Human Immunodeficiency Virus Protease Inhibitors and Risk for Peripheral Neuropathy

Two recent analyses found that exposure to protease inhibitors (PIs) in the context of antiretroviral (ARV) therapy increased the risk for distal sensory polyneuropathy (DSPN) in subjects with human immunodeficiency virus (HIV) infection. These findings were supported by an in vitro model in which PI exposure produced neurite retraction and process loss in dorsal root ganglion sensory neurons. Confirmation of peripheral nerve toxicity with PIs could substantially limit their long‐term use in highly active ARV therapy.

Deficits in cue detection and intention retrieval underlie prospective memory impairment in schizophrenia.

Emerging evidence indicates that individuals with schizophrenia (SCZ) may exhibit deficits in prospective memory (ProM), a dissociable and ecologically important aspect of episodic memory entailing the formation, maintenance, and execution of future intentions. The present study aimed to elucidate the component processes of ProM impairment in 41 individuals with SCZ relative to 41 demographically similar healthy comparison (HC) participants. Results revealed that the SCZ group performed worse than HCs on overall ProM, with comparable deficits on time- and event-based ProM trials. In the SCZ cohort, better ProM performance was associated with younger age and less severe negative symptoms. Although a significantly greater number of Task Substitution and Loss of Time errors were evident in the SCZ group as compared to HCs, the most prevalent error type in SCZ was characterized by a complete failure to respond to the ProM cue. Importantly, the SCZ and HC groups did not differ on a post-test multiple-choice recognition trial, suggesting adequate formation and maintenance (i.e., retention) of the ProM cue-intention pairing when self-directed monitoring and retrieval demands were minimized. Findings indicate that SCZ is associated with impairment in the cue detection and self-initiated retrieval components of executing future intentions, which is consistent with a possible prefrontostriatal loop neuropathogenesis. Further studies are needed to explore the neurobiological mechanisms of SCZ-associated ProM impairment and the impact of such deficits on daily functioning (e.g., medication compliance).

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.

Action (Verb) Fluency Predicts Dependence in Instrumental Activities of Daily Living in Persons Infected With HIV-1

Inspired by the hypothesized neural dissociation between the retrieval of nouns and verbs, several studies now support the construct validity of Action (verb) Fluency as a measure of frontostriatal systems function. Relative to traditional noun- and letter-cued verbal fluency tests, Action Fluency is more sensitive to HIV-1-associated neuropsychological impairment, which may reflect inefficiencies engaging motor representations during action retrieval in this population. Accordingly, impaired Action Fluency might adversely impact instrumental activities of daily living (IADL) by disrupting the production and organization of script-based action schemas upon which successful IADL performance depends. The present study thus sought to evaluate the ecological validity of Action Fluency as a predictor of IADL among persons with HIV-1 infection. Action, Letter (FAS), and Noun (animal) fluency were compared in 21 HIV-1-infected participants with self-reported IADL dependence relative to 76 demographically comparable HIV-1-infected participants who reported no IADL declines. Results revealed significant between-group differences in Action and Letter Fluency, but not Noun Fluency. Action Fluency achieved an overall hit rate of 76% and was more sensitive than Letter Fluency in classifying IADL dependent participants. Individuals with impaired Action Fluency performance had a fivefold risk of concurrent IADL dependence as compared to those who performed within normal limits. Findings suggest that Action Fluency may possess incremental ecological validity in the identification of HIV-1-associated neurocognitive disorders. The HNRC is supported by Center award MH 62512 from the National Institute of Mental Health. The research described was also supported by grants DA12065 and MH59745 from the National Institutes of Health. Note that, the views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. The authors thank Jennifer Marquie Beck for her assistance with data coding.

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.