David P. Sheppard

Does Older Age Confer an Increased Risk of Incident Neurocognitive Disorders Among Persons Living with HIV Disease

Objective: This study aimed to determine the combined effects of age and HIV infection on the risk of incident neurocognitive disorders. Method: A total of 146 neurocognitively normal participants were enrolled at baseline into one of four groups based on age (≤40 years and ≥50 years) and HIV serostatus resulting in 24 younger HIV−, 27 younger HIV+, 39 older HIV−, and 56 older HIV+ individuals. All participants were administered a standardized clinical neuropsychological battery at baseline and 14.3 ± .2 months later. Results: A logistic regression predicting incident neurocognitive disorders from HIV, age group, and their interaction was significant (χ2[4] = 13.56, p = .009), with a significant main effect of HIV serostatus (χ2[1] = 5.01, p = .025), but no main effect of age or age by HIV interaction (ps > .10). Specifically, 15.7% of the HIV+ individuals had an incident neurocognitive disorder as compared to 3.2% of the HIV− group (odds ratio = 4.8 [1.2, 32.6]). Among older HIV+ adults, lower baseline cognitive reserve, prospective memory, and verbal fluency each predicted incident neurocognitive disorders at follow-up. Conclusions: Independent of age, HIV infection confers a nearly fivefold risk for developing a neurocognitive disorder over approximately one year. Individuals with lower cognitive reserve and mild weaknesses in higher-order neurocognitive functions may be targeted for closer clinical monitoring and preventative measures.

The effects of HIV disease and older age on laboratory-based, naturalistic, and self-perceived symptoms of prospective memory: does retrieval cue type and delay interval matter?

ABSTRACT There is a rising prevalence of older HIV+ adults who are at risk of deficits in higher order neurocognitive functions and associated problems in everyday functioning. The current study applied multiprocess theory to examine the effects of HIV and aging on measures of laboratory-based, naturalistic, and self-perceived symptoms of prospective memory (PM). Participants included 125 Younger (48 with HIV, age = 32 ± 4.6 years) and 189 Older (112 with HIV, age = 56 ± 4.9 years) adults. Controlling for global neurocognitive functioning, mood, and other demographics, older age and HIV had independent effects on long-delay time-based PM in the laboratory, whereas on a naturalistic PM task older HIV− adults performed better than older HIV+ adults and younger persons. In line with the naturalistic findings, older age, but not HIV, was associated with a relative sparing of self-perceived PM failures in daily life across longer delay self-cued intervals. Findings suggest that, even in relatively younger aging cohorts, the effects of HIV and older age on PM can vary across PM delay intervals by the strategic demands of the retrieval cue type, are expressed differently in the laboratory and in daily life, and are independent of other higher order neurocognitive functions (e.g., retrospective memory).

A systematic review of prospective memory in HIV disease: from the laboratory to daily life

Abstract Objective: Prospective memory (PM) is described as the capacity to form and maintain an intention that is executed in response to a specific cue. Neural injury and associated neurocognitive disorders are common among persons living with HIV disease, who might therefore be susceptible to impairment in PM. Method: This literature review utilized a structured qualitative approach to summarize and evaluate our current understanding of PM functioning in people living with HIV disease. 33 studies of PM in HIV+ persons met criteria for inclusion. Results: Findings showed that HIV is associated with moderate deficits in PM, which appear to be largely independent of commonly observed comorbid factors. The pattern of PM deficits reveals dysregulation of strategic processes that is consistent with the frontal systems pathology and associated executive dysfunction that characterizes HIV-associated neural injury. The literature also suggests that HIV-associated PM deficits present a strong risk of concurrent problems in a wide range of health behaviors (e.g. medication non-adherence) and activities of daily living (e.g. employment). Early attempts to improve PM in HIV disease have revealed that supporting strategic processes might be effective for some individuals. Conclusions: HIV-associated PM deficits are common and exert a significant adverse effect on the daily lives and health of infected persons. Much work remains to be done to understand the cognitive architecture of HIV-associated PM deficits and the most efficient means to enhance PM functioning and improve health outcomes in persons living with HIV.

Pattern Separation: A Key Processing Deficit Associated with Aging?

Age-related memory impairment has been well documented in older adults and may serve as an early indicator of mild cognitive impairment or Alzheimer’s disease in some individuals. The work of Dr. Raymond Kesner has shown that pattern separation is a critical mechanism, supported by the dentate gyrus and CA3 hippocampal subregions, for reducing potential interference among similar memory representations to enhance memory accuracy. A growing literature indicates that pattern separation becomes less efficient with normal aging as a result of age-related changes in the hippocampus and its perforant path input. Researchers have hypothesized that decreased pattern separation efficiency may be a key processing deficit that could contribute to memory impairment associated with aging. In this chapter, we will review studies that have examined age-related changes in pattern separation in humans and rodents. In addition, we will discuss the potential basic science, translational, and clinical implications from these studies to illustrate the need to further examine the relationship between the brain changes associated with aging and pattern separation. The innovative behavioral studies to examine pattern separation conducted in the laboratory of Dr. Raymond Kesner have contributed greatly to our understanding of this mnemonic process and have set the foundation for the behavioral investigation of age-related changes in pattern separation.

Does age influence the frequency of anxiety symptoms and disorders in HIV disease

ABSTRACT The current study examined the individual and combined effects of age and HIV serostatus on anxiety symptoms and diagnoses among a community sample. Participants included 163 Older (50+ years) HIV+ persons, 113 Younger (<40) HIV+ persons, 95 Older HIV- persons, and 75 Younger HIV- persons who completed the Profile of Mood States and the Composite International Diagnostic Interview as part of a baseline neuroAIDS research assessment. Results showed that HIV infection was associated with significantly higher rates of anxiety symptoms as well as 12-month and lifetime diagnoses of Generalized Anxiety Disorder (GAD) and Panic Disorder (PD). There was no significant effect of age and no significant interaction between HIV serostatus and age; however, Older HIV+ participants were significantly older at onset of anxiety diagnoses as compared to their Younger HIV+ counterparts. Among both Older and Younger HIV+ participants, there were high rates of comorbidity between anxiety disorders and Major Depressive and methamphetamine use disorders. Across the lifespan, HIV-associated neurocognitive disorders interacted with 12-month anxiety disorders to increase risk of poorer everyday functioning outcomes. Overall, these data suggest that HIV disease and its comorbidities are related to elevated anxiety symptoms and diagnoses in both younger and older adults.

Construct validity of the UCSD performance-based skills assessment-brief version (UPSA-B) in HIV disease

ABSTRACT Among individuals living with HIV disease, approximately 60% experience problems with everyday functioning. The present study investigated the utility of the UCSD Performance-based Skills Assessment-Brief Version (UPSA-B) as a measure of functional capacity in HIV. We utilized a cross-sectional three-group design comparing individuals with HIV– associated neurocognitive disorder (HAND) (HIV + HAND+; n = 27), HIV+ neurocognitively normal individuals (HIV + HAND−; n = 51), and an HIV– comparison group (HIV−; n = 28) with broadly comparable demographics and non-HIV comorbidities. Participants were administered the UPSA-B, the Medication Management Test-Revised (MMT-R), and were assessed for manifest everyday functioning and quality of life, as part of a standardized clinical neurocognitive research battery. Results indicated that the HIV + HAND+ group had significantly lower UPSA-B scores than the HIV + HAND–group, but did not differ from the HIV– group. Among HIV+ individuals, UPSA-B scores were significantly related to MMT-R scores, all neurocognitive domains assessed, and education, but the UPSA-B was not related to manifest everyday functioning (e.g., unemployment), health-related quality of life, or HIV disease variables. Findings provide mixed support for the construct validity of the UPSA-B in HIV. Individuals impaired on the UPSA-B may be at increased risk for HAND, but the extent to which it detects general manifest everyday functioning problems is uncertain.

Effect of Retrieval Practice on Short-Term and Long-Term Retention in HIV+ Individuals

OBJECTIVES Episodic memory deficits are both common and impactful among persons infected with HIV; however, we know little about how to improve such deficits in the laboratory or in real life. Retrieval practice, by which retrieval of newly learned material improves subsequent recall more than simple restudy, is a robust memory boosting strategy that is effective in both healthy and clinical populations. In this study, we investigated the benefits of retrieval practice in 52 people living with HIV and 21 seronegatives. METHODS In a within-subjects design, all participants studied 48 verbal paired associates in 3 learning conditions: Massed-Restudy, Spaced-Restudy, and Spaced-Testing. Retention of verbal paired associates was assessed after short- (30 min) and long- (30 days) delay intervals. RESULTS After a short delay, both HIV+ persons and seronegatives benefited from retrieval practice more so than massed and spaced restudy. The same pattern of results was observed specifically for HIV+ persons with clinical levels of memory impairment. The long-term retention interval data evidenced a floor effect that precluded further analysis. CONCLUSIONS This study provides evidence that retrieval practice improves verbal episodic memory more than some other mnemonic strategies among HIV+ persons. (JINS, 2017, 23, 214-222).

Pill Burden Influences the Association Between Time-Based Prospective Memory and Antiretroviral Therapy Adherence in Younger But Not Older HIV-Infected Adults

&NA; Prospective memory (PM) is associated with antiretroviral (ARV) adherence in HIV, but little is known about how pill burden and age might affect this association. One hundred seventeen older (≥50 years) and 82 younger (<50 years) HIV‐infected adults were administered a measure of PM in the laboratory and subsequently were monitored for ARV adherence for 30 days using the Medication Event Monitoring System. In the older group, better time‐based PM performance was associated with higher likelihood of adherence, irrespective of pill burden. Within the younger sample, time‐based PM was positively related to adherence only in participants with lower pill burdens. Younger HIV‐infected individuals with higher pill burdens may overcome the normal effects of time‐based PM on adherence through compensatory medication‐taking strategies, whereas suboptimal use of these strategies by younger HIV‐infected individuals with lower pill burdens may heighten their risk of ARV nonadherence secondary to deficits in time‐based PM.

Does intra-individual neurocognitive variability relate to neuroinvasive disease and quality of life in West Nile Virus?

West Nile Virus (WNV) can be a neuroinvasive pathogen that may produce persistent mild-to-moderate neurocognitive impairments in some infected persons. Intra-individual variability (IIV) is an index of a person’s performance across a neuropsychological test or battery, which is an indicator of neurocognitive control and integrity of prefrontal systems. The present study examined possible associations of IIV to neurological health and well-being in WNV infection. Participants included 84 adults with a range of clinical WNV disease (31 West Nile Encephalitis, 16 West Nile Meningitis, 37 West Nile Fever) who completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). IIV was operationalized as covariance of variation (CoV), or the intra-individual standard deviation across 5 age-adjusted RBANS standard scores divided by the mean of standard scores. Participants were assessed for health-related quality of life (QoL) using the RAND 36-item short form health survey (SF-36). Analyses revealed that the West Nile Encephalitis group had higher neurocognitive CoV compared to the West Nile Fever group, and this difference was associated with a medium effect size (Cohen’s d = .52). Mixed linear models controlling for estimated IQ, activities of daily living, depression, neuroinvasive disease groups, and fatigue showed that higher RBANS CoV was associated with lower physical, but not mental health QoL. In persons with WNV infection, there is a modest association between elevations in IIV and encephalitis, and even subtle disruptions in neuropsychological functioning show relationships with important self-reported functioning as measured by physical health quality of life. Future studies should examine whether IIV predicts long-term health outcomes (e.g., mortality) in individuals infected with WNV.

Frequency and Correlates of Subjective Cognitive Impairment in HIV Disease

The increasing prevalence of older adults living with HIV has raised growing concerns about a possible rise in the incidence of neurocognitive disorders due to HIV and other age-related factors. In typical aging, subjective cognitive impairment (SCI) among individuals with normal neurocognitive functioning may be an early manifestation of an incipient neurocognitive disorder. The current study examined the frequency and correlates of SCI in 188 HIV-infected adults without performance-based neurocognitive deficits or a current psychiatric disorder and 133 HIV seronegative comparison participants. All participants completed the Prospective and Retrospective Memory Questionnaire and Profile of Mood States Confusion/Bewilderment scale. Consistent with the diagnostic criteria proposed by Jessen et al. (Alzheimers Dement 10(6):844–852, 2014), participants were classified with SCI if their scores on either of the self-reported measures was greater than 1.5 SD above the normative mean. A logistic regression controlling for current mood complaints and lifetime history of substance use disorders revealed that HIV infection increased the odds of SCI (odds ratio= 4.5 [1.6, 15.4], p = 0.004). Among HIV+ individuals, SCI was associated with lower performance-based learning and delayed memory scores (Cohen’s d range 0.41–0.42.) and poorer global everyday functioning (odds ratio= 8.5 [2.6, 15.9]), but not HIV disease severity (ps > 0.10). In a sample of individuals without neurocognitive impairment or elevated mood symptoms, HIV disease was associated with a nearly fivefold increased odds of SCI compared to seronegative individuals, which may indicate an increased risk for developing major neurocognitive disorders as these HIV+ individuals age.