The advent of effective antiretroviral medications (ARVs) has led to an aging of the HIV population with approximately 50% of people with HIV (PWH) being over the age of 50 years. Neurocognitive complications, typically known as HIV-associated neurocognitive disorders (HAND), persist in the era of ARVs and, in addition to risk of HAND, older PWH are also at risk for age-associated, neurodegenerative disorders including Alzheimer's disease (AD). It has been postulated that risk for AD may be greater among PWH due to potential compounding effects of HIV and aging on mechanisms of neural insult. We are now faced with the challenge of disentangling AD from HAND, which has important prognostic and treatment implications given the more rapidly debilitating trajectory of AD. Herein, we review the evidence to date demonstrating both parallels and differences in the profiles of HAND and AD. We specifically address similarities and difference of AD and HAND as it relates to (1) neuropsychological profiles (cross-sectional/longitudinal), (2) AD-associated neuropathological features as evidenced from neuropathological, cerebrospinal fluid and neuroimaging assessments, (3) biological mechanisms underlying cortical amyloid deposition, (4) parallels in mechanisms of neural insult, and (5) common risk factors. Our current understanding of the similarities and dissimilarities of AD and HAND should be further delineated and leveraged in the development of differential diagnostic methods that will allow for the early identification of AD and more suitable and effective treatment interventions among graying PWH.

Motivated by the Multicenter AIDS Cohort Study (MACS), we develop classification procedures for cognitive impairment based on longitudinal measures. To control family-wise error, we adapt the cross-sectional multivariate normative comparisons (MNC) method to the longitudinal setting. The cross-sectional MNC was proposed to control family-wise error by measuring the distance between multiple domain scores of a participant and the norms of healthy controls and specifically accounting for intercorrelations among all domain scores. However, in a longitudinal setting where domain scores are recorded multiple times, applying the cross-sectional MNC at each visit will still have inflated family-wise error rate due to multiple testing over repeated visits. Thus, we propose longitudinal MNC procedures that are constructed based on multivariate mixed effects models. A χ2 test procedure is adapted from the cross-sectional MNC to classify impairment on longitudinal multivariate normal data. Meanwhile, a permutation procedure is proposed to handle skewed data. Through simulations we show that our methods can effectively control family-wise error at a predetermined level. A dataset from a neuropsychological substudy of the MACS is used to illustrate the applications of our proposed classification procedures.

Background

Efavirenz is associated with side effects involving the central nervous system. However, it remains largely unknown whether switching off EFV improves neuropsychological performance.

Methods

We utilized data from the Multicenter AIDS Cohort Study (MACS). Participants were categorized by their use of EFV: never on EFV (No EFV), continuously on EFV (No Switch-OFF) and on EFV and then switched off (Switch-OFF). Baseline time points were defined as visits when first neuropsychological data were available. In Analysis 1, we compared neuropsychological and Center for Epidemiological Studies-Depression Scale (CES-D) scores before and after EFV switch in Switch-OFF group, aligning participants at the time of switch. Analysis 2 evaluated trajectory of neuropsychological/CES-D score among the three groups.

Results

This analysis included 1989 HIV-seropositive participants with neuropsychological data (1675 in No EFV, 44 in No Switch-OFF, and 270 in Switch-OFF group). At baseline, participants had a median age of 37 years, median CD4 cell count 442 cells/μl, and 22.9% viral suppression rate. In Analysis 1, neuropsychological and CES-D scores did not show clinically significant changes over 2 years prior to and 4 years after switch in Switch-OFF group. In Analysis 2, trends in neuropsychological and CES-D scores in the three different groups did not show significant differences during a median of 3.2 years of follow-up.

Conclusion

Discontinuation of EFV is not associated with changes in neuropsychological performance or severity of depression in men. Furthermore, we did not observe differences among participants who were never on EFV, continuously on EFV, and on EFV and then switched off.

Objective

The presentation of cognitive impairments in HIV-infected individuals has transformed since the introduction of antiretroviral therapies. Although the overall prevalence of cognitive impairments has not changed considerably, frank dementia is now infrequent, and milder forms of cognitive impairments predominate. Mechanistic insights to the underlying causes of these residual cognitive impairments have been elusive, in part due to the heterogenous etiology of cognitive dysfunction in this population. Here, we sought to categorize longitudinal change in HIV-infected patients based on the performance in specific cognitive domains.

Design

This study consisted of 193 participants from the CHARTER cohort with detailed demographic, clinical, and neuropsychological testing data obtained from 2 study visits interspersed by ∼6 months. Cognitive testing assessed executive function, learning and delayed recall, working memory, verbal fluency, speed of information processing, and motor skills. Change scores were calculated for each domain between the 2 study visits. Dimension reduction and clustering was accomplished by principal component analysis of change scores and k-means clustering to identify cognitive domains that group together and groups of subjects with similar patterns of change.

Results

We identified 4 distinct cognitive change phenotypes that included declines in: (1) verbal fluency, (2) executive function (3) learning and recall, and (4) motor function, with approximately equal numbers of participants in each phenotype.

Conclusions

Each of the 4 cognitive change phenotypes identify deficits that imply perturbations in specific neural networks. Future studies will need to validate if cognitive change phenotypes are associated with alterations in associated neural pathways.

Objective

We determined whether there are sex differences in the prevalence and profile of HIV-associated neurocognitive impairment, and whether sex moderates the effect of HIV-serostatus on neurocognitive impairment among HIV-positive and HIV-negative individuals. Secondarily, we assessed whether differences were explained by greater biopsychosocial risk factors in HIV-positive women.

Design

An observational cohort study.

Methods

Analyses included 1361 HIV-positive (204 women) and 702 HIV-negative (214 women) (ages = 18-79 years) participants from the UCSD HIV Neurobehavioral Research Program. Demographically corrected standardized T-scores from 15 neuropsychological tests were used to calculate domain-specific and global deficit scores (GDS). GDS at least 0.5 defined neurocognitive impairment. Biopsychosocial risk factors included low education, low reading level (education quality), lifetime substance use disorders, depressed mood (clinically significant depressive symptoms and/or current major depressive disorder) and a cumulative syndemic count (sum of biopsychosocial risk factors, range = 0-4). Race-stratified analyses were conducted. Analyses were adjusted for relevant demographic and clinical factors.

Results

HIV-associated neurocognitive impairment was more prevalent in women versus men; however, the difference was eliminated after adjustment for reading level. In sex-stratified logistic regressions, the association between HIV-seropositivity and higher likelihood of neurocognitive impairment was stronger in women versus men; however, the association was attenuated in women, but not men, after adjusting for reading level. These results in the overall sample were specific to blacks. Sex differences in the profile of HIV-associated neurocognitive impairment varied by race.

Conclusion

Women, particularly black women, were most at-risk for HIV-associated neurocognitive impairment. Higher rates of HIV-associated neurocognitive impairment in women versus men may reflect differences in educational quality.

Background

Prevalence estimates of cognitive impairment in HIV disease vary widely. Here we used multivariate normative comparison (MNC) with identify individuals with impaired cognition, and to compare the results with those using the Frascati and Gisslén criteria.

Methods

The current project used data collected before October 2014 from bisexual/gay men from the Multicenter AIDS Cohort Study. A total of 2904 men (mean age 39.7 years, 52.7% seropositive) had complete data in six cognitive domains at their first neuropsychological evaluation. T-scores were computed for each domain and the MNC was applied to detect impairment among seronegative and seropositive groups.

Results

The MNC classified 6.26% of seronegative men as being impaired using a predetermined 5% false discovery rate. By contrast, the Frascati and the Gisslén criteria identified 24.54 and 11.36% of seronegative men as impaired. For seropositive men, the percentage impairment was 7.45, 25.73, and 11.69%, respectively, by the MNC, Frascati and Gisslén criteria. When we used seronegative men without medical comorbidities as the control group, the MNC, the Frascati and the Gisslén criteria identified 5.05, 27.07, and 4.21% of the seronegative men, and 4.34, 30.95, and 4.48% of the seropositive men as having cognitive impairment. For each method, serostatus was not associated with cognitive impairment.

Conclusion

The MNC controls the false discovery rate and therefore avoids the low specificity that characterizes the Frascati and Gisslén criteria. More research is needed to evaluate the sensitivity of the MNC method in a seropositive population that may be sicker and older than the current study sample and that includes women.

In this fifth decade of the human immunodeficiency virus (HIV) epidemic, central nervous system (CNS) complications including cognitive impairment and mental health remain a burden for people with HIV (PWH) on antiretroviral therapy. Despite the persistence of these complications, which often co-occur, the underlying pathophysiology remains elusive and consequently treatments remain limited. To continue to grow our understanding of the underlying mechanisms of CNS complications among PWH, there is a need to reexamine our current approaches, which are now more than 2 decades old. At the 2021 National Institutes of Health-sponsored meeting on Biotypes of CNS Complications in PWH, the Neurobehavioral Working Group addressed the following: (1) challenges inherent to determining CNS complications; (2) heterogeneity in CNS complications; and (3) problems and solutions for examining integrated biotypes. The review below provides a summary of the main points presented and discussed by the Neurobehavioral Working Group at the meeting.

Cognitive impairment (CI) remains common despite access to combination antiretroviral therapy (cART); it has been linked to HIV-specific, HIV-related, and HIV-unrelated factors. Insulin resistance (IR) was associated with CI in the early cART era, when antiretroviral medications had greater mitochondrial and metabolic toxicity. We sought to examine these relationships in the current cART era of reduced antiretroviral toxicities. This study examined IR among non-diabetics in relation to a 1-h neuropsychological test battery among 994 women (659 HIV-infected and 335 HIV-uninfected controls) assessed between 2009 and 2011. The mean (standard deviation (SD)) age of the sample was 45.1 (9.3) years. The HIV-infected sample had a median interquartile range (IQR) cluster of differentiation 4 (CD4) T-lymphocyte count of 502 (310-727) cells/μL, and 54 % had undetectable plasma HIV RNA levels. Among all, the homeostasis model assessment (HOMA) of IR ranged from 0.25 to 37.14. In adjusted models, increasing HOMA was significantly associated with reduced performance on Letter-Number Sequencing (LNS) attention task (β = -0.10, p < 0.01) and on Hopkins Verbal Learning Test (HVLT) recognition (β = -0.10, p < 0.01) with weaker but statistically significant associations on phonemic fluency (β = -0.09, p = 0.01). An HIV*HOMA interaction effect was identified on the LNS attention task and Stroop trials 1 and 2, with worse performance in HIV-infected vs. HIV-uninfected women. In separate analyses, cohort members who had diabetes mellitus (DM) performed worse on the grooved pegboard test of psychomotor speed and manual dexterity. These findings confirm associations between both IR and DM on some neuropsychological tests and identify an interaction between HIV status and IR.

Objective

The risk of clinically significant depressive symptoms increases during perimenopause. With highly active antiretroviral treatment (HAART), more human immunodeficiency virus (HIV)-infected women survive to transition through menopause. In a cross-sectional analysis, we evaluated the association of menopausal stage and vasomotor symptoms with depressive symptoms in an ethnically diverse cohort of women with a high prevalence of HIV.

Methods

Participants included 835 HIV-infected women and 335 HIV-uninfected controls from the Women's Interagency HIV Study (63% African American). The Center for Epidemiologic Studies Depression Scale was used to screen for elevated depressive symptoms. Menopausal stages were defined according to standard definitions. Logistic regression analysis was used to identify predictors of elevated depressive symptoms.

Results

Compared with premenopausal women, early perimenopausal women (OR [odds ratio], 1.74; 95% CI, 1.17-2.60), but not late perimenopausal or postmenopausal women, were more likely to show elevated depressive symptoms in adjusted analyses. The odds were similar in HIV-infected and HIV-uninfected women. Persistent vasomotor symptoms also predicted elevated depressive symptoms in HIV-infected and HIV-uninfected women (OR, 1.45; 95% CI, 1.02-2.06). In HIV-infected women, menopausal stage interacted with antiretroviral use (P = 0.02); the likelihood of elevated depressive symptoms in early perimenopause compared with premenopause was especially high in HAART-untreated women (OR, 3.87; 95% CI, 1.57-9.55).

Conclusions

In HIV-infected and HIV-uninfected women, the odds of elevated depressive symptoms were significantly higher during early perimenopause. Elevated depressive symptoms were associated with nonadherence to HAART, underscoring the importance of screening and treating depressive symptoms in HIV-infected women who have experienced a change in the regularity of their menstrual cycles.

Objective

In the largest cohort study of neuropsychological outcomes among HIV-infected women to date, we examined the association between HIV status and cognition in relation to other determinants of cognitive function (aim 1) and the pattern and magnitude of impairment across cognitive outcomes (aim 2).

Methods

From 2009 to 2011, 1,521 (1,019 HIV-infected) participants from the Women's Interagency HIV Study (WIHS) completed a comprehensive neuropsychological test battery. We used multivariable regression on raw test scores for the first aim and normative regression-based analyses (t scores) for the second aim. The design was cross-sectional.

Results

The effect sizes for HIV status on cognition were very small, accounting for only 0.05 to 0.09 SD units. The effect of HIV status was smaller than that of years of education, age, race, income, and reading level. In adjusted analyses, HIV-infected women performed worse than uninfected women on verbal learning, delayed recall and recognition, and psychomotor speed and attention. The largest deficit was observed in delayed memory. The association of low reading level with cognition was greater in HIV-infected compared to HIV-uninfected women. HIV biomarkers (CD4 count, history of AIDS-defining illness, viral load) were associated with cognitive dysfunction.

Conclusions

The effect of HIV on cognition in women is very small except among women with low reading level or HIV-related comorbidities. Direct comparisons of rates of impairment in well-matched groups of HIV-infected men and women are needed to evaluate possible sex differences in cognition.