Kaitlin B. Casaletto

Neurocognitive Change in the Era of HIV Combination Antiretroviral Therapy: The Longitudinal CHARTER Study

BACKGROUND Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) can show variable clinical trajectories. Previous longitudinal studies of HAND typically have been brief, did not use adequate normative standards, or were conducted in the context of a clinical trial, thereby limiting our understanding of incident neurocognitive (NC) decline and recovery. METHODS We investigated the incidence and predictors of NC change over 16-72 (mean, 35) months in 436 HIV-infected participants in the CNS HIV Anti-Retroviral Therapy Effects Research cohort. Comprehensive laboratory, neuromedical, and NC assessments were obtained every 6 months. Published, regression-based norms for NC change were used to generate overall change status (decline vs stable vs improved) at each study visit. Survival analysis was used to examine the predictors of time to NC change. RESULTS Ninety-nine participants (22.7%) declined, 265 (60.8%) remained stable, and 72 (16.5%) improved. In multivariable analyses, predictors of NC improvements or declines included time-dependent treatment status and indicators of disease severity (current hematocrit, albumin, total protein, aspartate aminotransferase), and baseline demographics and estimated premorbid intelligence quotient, non-HIV-related comorbidities, current depressive symptoms, and lifetime psychiatric diagnoses (overall model P < .0001). CONCLUSIONS NC change is common in HIV infection and appears to be driven by a complex set of risk factors involving HIV disease, its treatment, and comorbid conditions.

Demographically Corrected Normative Standards for the English Version of the NIH Toolbox Cognition Battery

Demographic factors impact neuropsychological test performances and accounting for them may help to better elucidate current brain functioning. The NIH Toolbox Cognition Battery (NIHTB-CB) is a novel neuropsychological tool, yet the original norms developed for the battery did not adequately account for important demographic/cultural factors known to impact test performances. We developed norms fully adjusting for all demographic variables within each language group (English and Spanish) separately. The current study describes the standards for individuals tested in English. Neurologically healthy adults (n=1038) and children (n=2917) who completed the NIH Toolbox norming project in English were included. We created uncorrected scores weighted to the 2010 Census demographics, and applied polynomial regression models to develop age-corrected and fully demographically adjusted (age, education, sex, race/ethnicity) scores for each NIHTB-CB test and composite (i.e., Fluid, Crystallized, and Total Composites). On uncorrected NIHTB-CB scores, age and education demonstrated significant, medium-to-large associations, while sex showed smaller, but statistically significant effects. In terms of race/ethnicity, a significant stair-step effect on uncorrected NIHTB-CB scores was observed (African American<Hispanic<White). After applying normative corrections, NIHTB-CB no longer demonstrated any significant associations with demographic factors. The previously developed norms still maintained significant associations with demographic factors, and demonstrated more variable impairment rates in segments of the healthy normative sample. Similar to other neuropsychological tests, demographic factors demonstrated significant associations with unadjusted NIHTB-CB scores. Application of fully corrected scores will help account for unwanted variance that is associated with non-clinical factors to more accurately reflect effects of disease-related changes in brain function.

The Wide Range Achievement Test–4 Reading subtest “holds” in HIV-infected individuals

Background: In 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. Method: The 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. Results: Although 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. Conclusions: We 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.

Depression and executive dysfunction contribute to a metamemory deficit among individuals with methamphetamine use disorders.

OBJECTIVE Chronic methamphetamine (MA) use is associated with moderate deficits in learning and memory, but the extend to which MA users are aware of such memory deficits (i.e., metamemory) is not known. METHODS In the current study, 195 participants with lifetime MA use diagnoses (MA +) and 195 non-MA-using comparison subjects (MA -) underwent comprehensive neuropsychiatry research assessments, including performance-based and self-report measures of episodic memory. RESULTS MA use disorders, major depressive disorder (MDD), and their interaction were uniquely associated with metamemory functioning, such that MDD increased the likelihood of a metamemory deficit among MA + participants. Within the MA group, individuals who over-estimated their memory abilities demonstrated greater executive dysfunction and lower cognitive reserve. CONCLUSIONS Chronic MA use is associated with reduced awareness of objective deficits in memory acquisition and recall, which is particularly exacerbated by the presence of major depression. Efforts to enhance metamemory accuracy and deployment of compensatory mnemonic strategies may benefit substance abuse treatment outcomes.

Allowing brief delays in responding improves event-based prospective memory for young adults living with HIV disease

Event-based prospective memory (PM) tasks require individuals to remember to perform an action when they encounter a specific cue in the environment, and they have clear relevance for daily functioning for individuals with HIV. In many everyday tasks, not only must the individual maintain the intent to perform the PM task, but the PM task response also competes with the alternative and more habitual task response. The current study examined whether event-based PM can be improved by slowing down the pace of the task environment. Fifty-seven young adults living with HIV performed an ongoing lexical decision task while simultaneously performing a PM task of monitoring for a specific word (which was focal to the ongoing task of making lexical decisions) or syllable contained in a word (which was nonfocal). Participants were instructed to refrain from making task responses until after a tone was presented, which occurred at varying onsets (0–1600 ms) after each stimulus appeared. Improvements in focal and nonfocal PM accuracy were observed with response delays of 600 ms. Furthermore, the difference in PM accuracy between the low-demand focal PM task and the resource-demanding nonfocal PM task was reduced by half across increasingly longer delays, falling from 31% at 0-ms delay to only 14% at 1600-ms delay. The degree of ongoing task response slowing for the PM conditions, relative to a control condition that did not have a PM task and made lexical decisions only, also decreased with increased delay. Overall, the evidence indicates that delaying the task responses of younger HIV-infected adults increased the probability that the PM relevant features of task stimuli were adequately assessed prior to the ongoing task response, and by implication that younger HIV infected adults can more adequately achieve PM goals when the pace of the task environment is slowed down.

Abbreviated Goal Management Training Shows Preliminary Evidence as a Neurorehabilitation Tool for HIV-associated Neurocognitive Disorders among Substance Users.

Objective: Substance use disorders are highly comorbid with and contribute to the increased prevalence of neurocognitive dysfunction observed in HIV infection. Despite their adverse impact on everyday functioning, there are currently no compensatory-based neurorehabilitation interventions validated for use among HIV+ substance users (HIV/SUD). This study examined the effectiveness of goal management training (GMT) alone or GMT as part of a metacognitive training among HIV/SUD individuals with executive dysfunction. Methods: Ninety HIV/SUD individuals were randomized to a single 15-min session: (1) GMT (n = 30); (2) GMT plus metacognitive training (neurocognitive awareness; GMT + Meta; n = 30); or (3) active control (n = 30). Following a brief neurocognitive battery and study condition, participants performed a complex laboratory-based function task, Everyday Multitasking Test (Everyday MT), during which metacognition (awareness) was evaluated. Results: There was an increasing, but non-significant tendency for better Everyday MT performances across study conditions (Control ≤ GMT ≤ GMT + Meta; ps < .08). Post hoc analyses showed that GMT and GMT + Meta groups demonstrated small benefits (d = .20–.27) compared to the control arm but did not differ from one another (ds < .10). When GMT groups were combined, there were significant medium effect size benefits in Everyday MT performance and metacognitive task appraisals as compared to the control condition. Among participants who underwent GMT, benefits were most prominent in persons with poorer pre-training dual-tasking ability, depression, and methamphetamine use disorders (ds = .35–1.04). Conclusions: A brief compensatory strategy has benefits for everyday multitasking and metacognition among HIV+ substance users with executive dysfunction. Future work exploring more intensive trainings, potentially complimentary to other restorative approaches and/or pharmacological treatments, is warranted.

Shallow Encoding and Forgetting Are Associated with Dependence in Instrumental Activities of Daily Living Among Older Adults Living with HIV Infection

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 (<50 years) and 119 older (≥50 years) adults with HIV who completed the California Verbal Learning Test-Second Edition (CVLT-II), the Wechsler Memory Scale-Third Edition Logical Memory subtest (WMS-III LM), and a modified Lawton and Brody ADL questionnaire. No memory predictors of IADL dependence emerged in the younger cohort. In the older group, IADL dependence was uniquely associated with worse performance on all primary CVLT-II variables, as well as elevated recency effects. Poorer immediate and delayed recall of the WMS-III LM was also associated with IADL dependence, although recognition was intact. Findings suggest older HIV-infected adults with shallow encoding and forgetting are at risk for IADL dependence.

Retinal thinning is uniquely associated with medial temporal lobe atrophy in neurologically normal older adults.

Given the converging pathologic and epidemiologic data indicating a relationship between retinal integrity and neurodegeneration, including Alzheimers disease (AD), we aimed to determine if retinal structure correlates with medial temporal lobe (MTL) structure and function in neurologically normal older adults. Spectral-domain optical coherence tomography, verbal and visual memory testing, and 3T-magnetic resonance imaging of the brain were performed in 79 neurologically normal adults enrolled in a healthy aging cohort study. Retinal nerve fiber thinning and reduced total macular and macular ganglion cell volumes were each associated with smaller MTL volumes (ps < 0.04). Notably, these markers of retinal structure were not associated with primary motor cortex or basal ganglia volumes (regions relatively unaffected in AD) (ps > 0.70), or frontal, precuneus, or temporoparietal volumes (regions affected in later AD Braak staging ps > 0.20). Retinal structure was not significantly associated with verbal or visual memory consolidation performances (ps > 0.14). Retinal structure was associated with MTL volumes, but not memory performances, in otherwise neurologically normal older adults. Given that MTL atrophy is a neuropathological hallmark of AD, retinal integrity may be an early marker of ongoing AD-related brain health.

Antiretroviral Non-Adherence is Associated With a Retrieval Profile of Deficits in Verbal Episodic Memory.

HIV-associated deficits in verbal episodic memory are commonly associated with antiretroviral non-adherence; however, the specific aspects of memory functioning (e.g., encoding, consolidation, or retrieval) that underlie this established relationship are not well understood. This study evaluated verbal memory profiles of 202 HIV+ participants who underwent a 30-day electronic monitoring of antiretroviral adherence. At the group level, non-adherence was significantly associated with lower scores on immediate and delayed passage recall and word list learning. Retention and recognition of passages and word lists were not related to adherence. Participants were then classified as having either a normal verbal memory profile, a “subcortical” retrieval profile (i.e., impaired free recall with relatively spared recognition), or a “cortical” encoding profile (e.g., cued recall intrusions) based on the Massman et al. (1990) algorithm for the California Verbal Learning Test. HIV+ participants with a classic retrieval deficit had significantly greater odds of being non-adherent than participants with a normal or encoding profile. These findings suggest that adherence to prescribed antiretroviral regimens may be particularly vulnerable to disruption in HIV+ individuals due to deficits in the complex process of efficiently accessing verbal episodic information with minimal cues. A stronger relationship between non-adherence and passage (vs. word list) recall was also found and may reflect the importance of contextual features in remembering to take medications. Targeted interventions for enhancing and supporting episodic memory retrieval processes may improve antiretroviral adherence and overall health outcomes among persons living with HIV.

Visualisation of future task performance improves naturalistic prospective memory for some younger adults living with HIV disease

ABSTRACT Human immunodeficiency virus (HIV) disease is commonly associated with deficits in prospective memory (PM), which increase the risk of suboptimal health behaviours, like medication non-adherence. This study examined the potential benefits of a brief future visualisation exercise during the encoding stage of a naturalistic PM task in 60 young adults (aged 19–24 years) with HIV disease. Participants were administered a brief clinical neuropsychological assessment, which included a standardised performance-based measure of time- and event-based PM. All participants were also given a naturalistic PM task in which they were asked to complete a mock medication management task when the examiner showed them the Grooved Pegboard Test during their neuropsychological evaluation. Participants were randomised into: (1) a visualisation condition in which they spent 30 sec imagining successfully completing the naturalistic PM task; or (2) a control condition in which they repeated the task instructions. Logistic regression analyses revealed significant interactions between clinical neurocognitive functions and visualisation. HIV positive (HIV+) participants with intact retrospective learning and/or low time-based PM demonstrated observable gains from the visualisation technique, while HIV+ participants with impaired learning and/or intact time-based PM did not evidence gains. Findings indicate that individual differences in neurocognitive ability moderate the response to visualisation in HIV+ young adults. The extent to which such cognitive supports improve health-related PM outcomes (e.g., medication adherence) remains to be determined.