Neurocognition and its predictors in a linguistically and culturally diverse cohort of people with HIV.

Objective: HIV/AIDS disproportionately affects Black and Latino people in the United States, yet there is a lack of research on predictors of neurocognitive outcomes in these groups. We examined neurocognitive performance and its key predictors across White, Black, and Latino people with HIV (PWH). Method: Participants included 586 PWH of White, Black, and Latino (English- and Spanish-speaking) background. Neurocognition was assessed via demographically-adjusted Fluid Cognition Composite T-scores from the NIH-Toolbox cognition battery, and individual tests comprising this composite. Predictors examined included sociodemographic and HIV disease characteristics, and medical, psychiatric and substance comorbidities. Results: Compared to White PWH, English-speaking Latino PWH had lower T-scores on the Fluid Cognition Composite, as well as Flanker Inhibition and Picture Sequence Memory tests. While there were no other significant group differences on Fluid Cognition, both Latino PWH language groups performed worse than Black PWH on Flanker Inhibition, and Black PWH performed worse than White PWH on List Sorting. Separate multivariable linear regression models by ethnic/racial/language group showed that significant correlates of worse Fluid Cognition included depressive symptoms among White PWH; hepatitis C co-infection among Black PWH; hypertension among English-speaking Latino PWH; and higher estimated duration of HIV disease and depressive symptoms in Spanish-speaking Latino PWH. Conclusions: Findings suggest worse neurocognition among English-speaking Latino PWH compared to Whites. Predictors of neurocognitive function among PWH differ across ethnic/racial and language groups. Consideration of these HIV disease characteristics and comorbidities may be valuable in developing targeted culturally-relevant interventions aimed at ameliorating neurocognitive dysfunction among diverse PWH.

Emotional health and its association with neurocognition in Hispanic and non-Hispanic White people with HIV.

OBJECTIVE: Emotional functioning is linked to HIV-associated neurocognitive impairment, yet research on this association among diverse people with HIV (PWH) is scant. We examined emotional health and its association with neurocognition in Hispanic and White PWH. METHODS: Participants included 107 Hispanic (41% primarily Spanish-speakers; 80% Mexican heritage/origin) and 216 White PWH (Overall age: M = 53.62, SD = 12.19; 86% male; 63% AIDS; 92% on antiretroviral therapy). Emotional health was assessed via the National Institute of Health Toolbox (NIHTB)-Emotion Battery, which yields T-scores for three factor-based summary scores (negative affect, social satisfaction, and psychological well-being) and 13 individual component scales. Neurocognition was measured via demographically adjusted fluid cognition T-scores from the NIHTB-cognition battery. RESULTS: 27%-39% of the sample had problematic socioemotional summary scores. Hispanic PWH showed less loneliness, better social satisfaction, higher meaning and purpose, and better psychological well-being than Whites (ps <.05). Within Hispanics, Spanish-speakers showed better meaning and purpose, higher psychological well-being summary score, less anger hostility, but greater fear affect than English speakers. Only in Whites, worse negative affect (fear affect, perceived stress, and sadness) was associated with worse neurocognition (p <.05); and in both groups, worse social satisfaction (emotional support, friendship, and perceived rejection) was linked with worse neurocognition (p <.05). CONCLUSION: Adverse emotional health is common among PWH, with subgroups of Hispanics showing relative strengths in some domains. Aspects of emotional health differentially relate to neurocogntition among PWH and cross-culturally. Understanding these varying associations is an important step towards the development of culturally relevant interventions that promote neurocognitive health among Hispanic PWH.

Cannabis use may attenuate neurocognitive performance deficits resulting from methamphetamine use disorder.

OBJECTIVE: Methamphetamine and cannabis are two widely used, and frequently co-used, substances with possibly opposing effects on the central nervous system. Evidence of neurocognitive deficits related to use is robust for methamphetamine and mixed for cannabis. Findings regarding their combined use are inconclusive. We aimed to compare neurocognitive performance in people with lifetime cannabis or methamphetamine use disorder diagnoses, or both, relative to people without substance use disorders. METHOD: 423 (71.9% male, aged 44.6 ± 14.2 years) participants, stratified by presence or absence of lifetime methamphetamine (M-/M+) and/or cannabis (C-/C+) DSM-IV abuse/dependence, completed a comprehensive neuropsychological, substance use, and psychiatric assessment. Neurocognitive domain T-scores and impairment rates were examined using multiple linear and binomial regression, respectively, controlling for covariates that may impact cognition. RESULTS: Globally, M+C+ performed worse than M-C- but better than M+C-. M+C+ outperformed M+C- on measures of verbal fluency, information processing speed, learning, memory, and working memory. M-C+ did not display lower performance than M-C- globally or on any domain measures, and M-C+ even performed better than M-C- on measures of learning, memory, and working memory. CONCLUSIONS: Our findings are consistent with prior work showing that methamphetamine use confers risk for worse neurocognitive outcomes, and that cannabis use does not appear to exacerbate and may even reduce this risk. People with a history of cannabis use disorders performed similarly to our nonsubstance using comparison group and outperformed them in some domains. These findings warrant further investigation as to whether cannabis use may ameliorate methamphetamine neurotoxicity.

Distinct effects of SSRIs and SNRIs on Soluble Biomarkers in Blood and Cerebrospinal Fluid of people with HIV.

BACKGROUND: Persistent inflammation affects people with HIV (PWH) despite antiretroviral therapy (ART). Selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs, SNRIs), HMG-CoA reductase-inhibitors (statins), and angiotensin-converting enzyme inhibitors (ACEIs) have immuno-modulant properties. We evaluated the potential impact of these drugs on inflammation and neurodegeneration in PWH. METHODS: Cross-sectional single-center (U.S.) analysis in 184 PWH on ART with plasma HIV RNA < 200 cp/mL. All participants had 10 biomarkers measured in blood and cerebrospinal fluid (CSF). To reduce dimensionality, hierarchical clustering and principal components (PCs) analysis were employed. The analyses were adjusted for duration of the drugs and and clinical conditions. RESULTS: Participants were mostly middle-aged men, with median CD4+ T-cells of 620/µL. In adjusted models, SSRI use was associated with three PCs: higher CSF and plasma Aß42 and CSF CCL2 (aß=0.14, p = 0.040); lower CSF 8-oxo-dG, total tau, and sCD14 (aß=-0.12, p = 0.042); higher plasma sCD14 with lower sCD40L (aß=0.15, p = 0.042). SNRI use was associated with higher values of CSF and plasma neopterin and CSF sTNFR-II (aß=0.22, p = 0.004). Statins and ACEIs showed no association. CONCLUSIONS: SSRIs and SNRIs had distinct biomarker signatures. SSRIs were associated with reduced neurodegeneration, immune activation and oxidative stress in CSF, suggesting a role of SSRIs as adjunctive therapy in PWH.

Automated procedure for demographic adjustments on cognitive test scores.

Performances of normal people on cognitive tests are known to vary by demographic characteristics, such as age, education, and sex. Thus, cognitive test scores should be corrected for demographic influences when they are used to detect below-expected results due to disease or injury involving the central nervous system (CNS). Normative corrections, if estimated from a large, diverse, and well-characterized cohort of controls, help to remove expected differences in cognitive performance associated with normal demographic characteristics and associated socio-economic disadvantages. In this paper, we (1) describe in detail the process of generating regression-based normative standards, and its advantages and limitations, (2) provide recommendations for applying these normative standards to data from individuals and populations at risk for CNS dysfunction, and (3) introduce an R package, test2norm, that contains functions for producing and applying normative formulas to generate demographically corrected scores for measuring deviations from expected, normal cognitive performances.

Reply to Augello, P.A.; Wu, J. Comment on "Rogers et al. The Combined Effects of Cannabis, Methamphetamine, and HIV on Neurocognition. Viruses 2023, 15, 674".

We thank Augello and Wu [...].

MRP8/14 Is a Molecular Signature Triggered by Dopamine in HIV Latent Myeloid Targets That Increases HIV Transcription and Distinguishes HIV+ Methamphetamine Users with Detectable CSF Viral Load and Brain Pathology.

There is a significant overlap between HIV infection and substance-use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are the targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 h, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic rate compared to DRD1. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase in p24 levels following DA stimulation. Conversely, DA increased the expression of these genes' transcripts at the protein level, MRP8 and MRP14, respectively, which form a complex also known as calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding of the complex to the receptor for an advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface, in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanism for the delayed effect via DRD4 on the p24 increase. To cross-validate MRP8/14 as a DA signature with a biomarker value, we tested its expression in HIV+ Meth users' postmortem brain specimens and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as the basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in specimens from participants with a detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.

The Evolution of Assessing Central Nervous System Complications in Human Immunodeficiency Virus: Where Do We Go From Here?

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.

Neuropsychological Test Norms for the Assessment of HIV-Associated Neurocognitive Impairment Among South African Adults.

Reliable and valid neurocognitive (NC) test batteries that assess multiple domains of cognitive functioning are vital tools in the early detection of HIV-associated NC impairment. The HIV Neurobehavioral Research Center's International Neurobehavioral Battery (HNRC Battery) is one such diagnostic tool and has shown cultural validity in several international neuroHIV studies. However, no published norms are currently available for the full HNRC Battery in South Africa. To accurately interpret NC test results, appropriate reference norms are required. In light of this challenge, data were collected from 500 healthy, HIV-uninfected participants to develop demographically corrected South African norms. When demographically corrected United States of America (U.S.) norms were applied to the performance scores of our neurologically intact, HIV-negative sample, an impairment rate of 62.2% was observed compared to a 15.0% impairment rate when the newly generated South African norms were applied. These results reiterate the findings of other low- and middle-income countries, highlighting the need for localized, country-specific norms when interpreting NC performance.

The Combined Effects of Cannabis, Methamphetamine, and HIV on Neurocognition.

OBJECTIVE: Methamphetamine and cannabis are two widely used substances among people living with HIV (PLWH). Whereas methamphetamine use has been found to worsen HIV-associated neurocognitive impairment, the effects of combined cannabis and methamphetamine use disorder on neurocognition in PLWH are not understood. In the present study, we aimed to determine the influence of these substance use disorders on neurocognition in PLWH and to explore if methamphetamine-cannabis effects interacted with HIV status. METHOD AND PARTICIPANTS: After completing a comprehensive neurobehavioral assessment, PLWH (n = 472) were stratified by lifetime methamphetamine (M-/M+) and cannabis (C-/C+) DSM-IV abuse/dependence disorder into four groups: M-C- (n = 187), M-C+ (n = 68), M+C-, (n = 82), and M+C+ (n = 135). Group differences in global and domain neurocognitive performances and impairment were examined using multiple linear and logistic regression, respectively, while holding constant other covariates that were associated with study groups and/or cognition. Data from participants without HIV (n = 423) were added, and mixed-effect models were used to examine possible interactions between HIV and substance use disorders on neurocognition. RESULTS: Compared with M+C+, M+C- performed worse on measures of executive functions, learning, memory, and working memory and were more likely to be classified as impaired in those domains. M-C- performed better than M+C+ on measures of learning and memory but worse than M-C+ on measures of executive functions, learning, memory, and working memory. Detectable plasma HIV RNA and nadir CD4 < 200 were associated with lower overall neurocognitive performance, and these effects were greater for M+C+ compared with M-C-. CONCLUSIONS: In PLWH, lifetime methamphetamine use disorder and both current and legacy markers of HIV disease severity are associated with worse neurocognitive outcomes. There was no evidence of an HIV × M+ interaction across groups, but neurocognition was most impacted by HIV among those with polysubstance use disorder (M+C+). Better performance by C+ groups is consistent with findings from preclinical studies that cannabis use may protect against methamphetamine's deleterious effects.

Plasma biomarkers of vascular dysfunction uniquely relate to a vascular-risk profile of neurocognitive deficits in virally-suppressed adults with HIV.

Objective: Chronic inflammation and vascular dysfunction (e.g., chronic endothelial activation) are related yet dissociable mechanisms of HIV-associated neurocognitive impairment (NCI), even among those on antiretroviral therapy (ART). However, how these mechanisms differentially contribute to domain-specific deficits in people with and without HIV (PWH, PWoH) is unclear. We empirically-derived profiles of NCI and examined relationships with peripheral inflammatory and vascular biomarkers. Methods: Participants were 84 virally-suppressed PWH and 126 PWoH who underwent neuropsychological testing and blood draw. Cluster analysis identified subgroups based on domain deficit scores. ANOVAs examined HIV serostatus and cluster group differences in composite plasma biomarker z-scores of inflammation (IL-6, CXCL10/IP-10, CCL2/MCP-1) and vascular injury (VCAM-1, ICAM-1, uPAR). Confirmatory regressions examined the interaction of HIV and biomarker z-scores on domain-specific T-scores, controlling for cardiovascular disease (CVD) risk and psychosocial factors. Results: Cluster analysis identified three groups: Unimpaired (n = 129), Learning/Recall (n = 52, isolated learning/recall deficits), Dysexecutive/Slow (n = 29, executive function, working memory, processing speed, and motor deficits). PWH had higher odds of Dysexecutive/Slow membership, which related to CVD risk and higher vascular dysfunction, but not inflammation, in PWH. Vascular biomarkers moderated adverse HIV effects on executive function, processing speed, and working memory such that PWH had lower T-scores only when vascular dysfunction was high. Conclusions: In PWH with controlled disease, peripheral markers of endothelial dysfunction and vascular permeability are selectively associated with an empirically-derived subgroup that exhibits domain deficits commonly impacted by cerebrovascular disease. Findings support the presence of a vascular NCI subgroup of PWH who may benefit from interventions that directly target the neurovascular unit.

HIV Antiretroviral Medication Neuropenetrance and Neurocognitive Outcomes in HIV+ Adults: A Review of the Literature Examining the Central Nervous System Penetration Effectiveness Score.

This literature review summarizes the existing research examining the CNS penetration effectiveness (CPE) score and neurocognitive outcomes (i.e., neuropsychological assessment and neurocognitive screening) in HIV+ individuals. Despite the effectiveness of Combined Antiretroviral Therapy (CART) in reducing mortality and morbidity in HIV and controlling viral replication, HIV often persists in the Central Nervous System (CNS), and rates of neurocognitive impairment remain higher than predicted in the post-CART era. The CPE score was developed to rank antiretroviral regimens on their ability to penetrate the CNS and potency in inhibiting the virus, and it has been examined in relation to neurocognitive functioning for over a decade. Based on the results of 23 studies, we conclude that CPE is not as strongly associated with neurocognitive outcomes as initially hypothesized, although higher CPE ARV regimens may be associated with modest, improved outcomes in global neurocognitive functioning, and to a lesser extent attention/working memory and learning/memory. Conclusions, however, are limited by the heterogeneity in study design and methods, and the lack of a more recent CPE metric update. It is recommended that future research in this area employ comprehensive, standardized neuropsychological test batteries and examine domain-level performance, and use the newer 2010 CPE metric, although an updated CPE ranking is urgently needed.

Cognitive and Physiologic Reserve Independently Relate to Superior Neurocognitive Abilities in Adults Aging With HIV.

BACKGROUND: To investigate joint contributions of cognitive and physiologic reserve to neurocognitive SuperAging in older persons with HIV (PWH). METHODS: Participants included 396 older PWH (age range: 50-69 years) who completed cross-sectional neuropsychological and neuromedical evaluations. Using published criteria, participants exhibiting global neurocognition within normative expectations of healthy 25-year-olds were classified as SuperAgers (SA; n = 57). Cognitively normal (CN; n = 172) and impaired (n = 167) participants were classified with chronological age-based norms. Cognitive reserve was operationalized with an estimate of premorbid verbal intelligence, and physiologic reserve was operationalized with a cumulative index of 39 general and HIV-specific health variables. Analysis of variance with confirmatory multinomial logistic regression examined linear and quadratic effects of cognitive and physiologic reserve on SA status, adjusting for chronological age, depression, and race/ethnicity. RESULTS: Univariably, SA exhibited significantly higher cognitive and physiologic reserve compared with CN and cognitively impaired ( d s ≥ 0.38, p s < 0.05). Both reserve factors independently predicted SA status in multinomial logistic regression; higher physiologic reserve predicted linear increases in odds of SA, and higher cognitive reserve predicted a quadratic "J-shaped" change in odds of SA compared with CN (ie, odds of SA > CN only above 35th percentile of cognitive reserve). CONCLUSIONS: Each reserve factor uniquely related to SA status, which supports the construct validity of our SA criteria and suggests cognitive and physiologic reserve reflect nonoverlapping pathways of neuroprotection in HIV. Incorporation of proxy markers of reserve in clinical practice may improve characterization of age-related cognitive risk and resilience among older PWH, even among PWH without overt neurocognitive impairment.

The association between benzodiazepine use and greater risk of neurocognitive impairment is moderated by medical burden in people with HIV.

Benzodiazepine use is linked to neurocognitive impairment (NCI) in the general population and people with HIV (PWH); however, this relationship may depend on age-related factors such as medical comorbidities, which occur at an elevated rate and manifest earlier in PWH. We retrospectively examined whether chronological age or medical burden, a clinical marker for aging, moderated the relationship between benzodiazepine use and NCI in PWH. Participants were 435 PWH on antiretroviral therapy who underwent neurocognitive and medical evaluations, including self-reported current benzodiazepine use. A medical burden index score (proportion of accumulated multisystem deficits) was calculated from 28 medical deficits. Demographically corrected cognitive deficit scores from 15 neuropsychological tests were used to calculate global and domain-specific NCI based on established cut-offs. Logistic regressions separately modeled global and domain-specific NCI as a function of benzodiazepine x age and benzodiazepine x medical burden interactions, adjusting for current affective symptoms and HIV disease characteristics. A statistically significant benzodiazepine x medical burden interaction (p = .006) revealed that current benzodiazepine use increased odds of global NCI only among those who had a high medical burden (index score > 0.3 as indicated by the Johnson-Neyman analysis), which was driven by the domains of processing speed, motor, and verbal fluency. No age x benzodiazepine interactive effects on NCI were present. Findings suggest that the relationship between BZD use and NCI among PWH is specific to those with greater medical burden, which may be a greater risk factor for BZD-related NCI than chronological age.

Polygenic networks in peripheral leukocytes indicate patterns associated with HIV infection and context-dependent effects of cannabis use.

In spite of suppressive antiretroviral therapies (ART), Human Immunodeficiency Virus (HIV)-infected subjects still experience the consequences of viral persistence and chronic inflammation. In the brain, where most HIV-1 targets are of innate immune origin, neurological and cognitive impairments are detectable and enhanced by highly prevalent substance use disorders. Cannabis is one of the most prevalent substances among HIV+ â€‹subjects, compared to non-infected populations, either prescribed for improving various symptoms or used recreationally, as well as a component of polysubstance use. The mechanisms by which addictive substances and HIV interact are multifactorial and poorly understood. Importantly, the HIV brain target cells, macrophages and microglia, express receptors to neurotransmitters elevated by such drugs, and express receptors to cannabinoids, particularly CB2R. We have tested a panel of 784 transcripts associated with neurological disorders, digitally multiplexed and detectable in peripheral blood cells from a small cohort (n â€‹= â€‹102) of HIV-positive (HIV+) and HIV-negative (HIV-) specimens, stratified based on criteria of lifetime (LT) dependence of cannabis (CAN+) or not (CAN-). Demographic homogeneity and low incidence of co-morbidities helped increase power and allowed the identification of key differences consistent with HIV infection, cannabis exposure, or their interactions. A small percentage of these subjects used cannabis as well as other drugs. The data was analyzed using robust systems and visualization strategies to detect orchestrated patterns in gene networks connected based on molecular interfaces with higher power than in single genes. We found that the effects of cannabis differed drastically between HIV- and HIV+ â€‹groups, particularly in gene networks playing a role in inflammation, neurodegeneration, apoptosis and leukocyte adhesion and transmigration. At the level of individual genes, we identified detrimental effects that were associated with polysubstance use as a covariate, particularly methamphetamine. Transcription factor usage predictions suggest that the effects of cannabis are associated with transcriptional co-regulation at the gene promoters by multiple factors that vary by context. Overall, we have found that the effects of cannabis may be context-dependent, with potential benefits in the context of HIV reflected by improvements in cognition, but in the absence of the polysubstance use component.

Relationship of the balloon analog risk task to neurocognitive impairment differs by HIV serostatus and history of major depressive disorder.

HIV and major depressive disorder (MDD) commonly co-occur and are both linked to greater risk-taking behavior, possibly due to neurocognitive impairment (NCI). The present study examined the concordance of the Balloon Analog Risk Task (BART), a gold standard measure of risk-taking propensity, with NCI and real-world sexual risk behaviors in PWH with comorbid MDD. Participants included 259 adults, stratified by HIV serostatus (HIV + /HIV -) and lifetime MDD (MDD + /MDD -), who completed neuropsychological testing, the BART, and sexual risk behavior questionnaires. Logistic regression, stratified by HIV serostatus, examined joint effects of MDD and BART (linear and quadratic) on NCI. Follow-up linear regressions examined sexual risk behavior and neurocognitive domain T-scores as correlates of the BART. NCI prevalence was lowest in HIV - /MDD - , but BART scores did not differ by HIV/MDD status. In the HIV + group, BART performance predicted NCI such that high and low BART scores related to greater odds of NCI, but only in dual-risk HIV + /MDD + individuals. HIV + /MDD + individuals with both low and high BART scores exhibited poorer learning and recall, whereas processing speed and executive function were only poor in low BART risk-taking HIV + /MDD + . Higher BART scores linearly related to higher sexual risk behaviors only in MDD + individuals, independent of HIV serostatus. Low and high risk-taking on the BART may reflect discrete neurocognitive profiles in HIV + /MDD + individuals, with differential implications for real-world sexual risk behavior. HIV and comorbid MDD may disturb corticostriatal circuits responsible for integrating affective and neurocognitive components of decision-making, thereby contributing to risk-averse and risk-taking phenotypes.

Higher Cerebrospinal Fluid Soluble Urokinase-type Plasminogen Activator Receptor, But Not Interferon γ-inducible Protein 10, Correlate With Higher Working Memory Deficits.

BACKGROUND: We hypothesized that the induction of monocyte activation biomarkers, especially soluble urokinase-type plasminogen activator receptor (suPAR) and interferon γ-inducible protein 10 (IP-10), is lower in HIV-1C than HIV-1B, owing to a defective Tat cysteine dimotif (C30S). METHODS: A total of 68 paired cerebrospinal fluid (CSF) and blood samples from people with HIV (PWH), free of CNS opportunistic infections, from a Southern Brazil outpatient HIV clinic were evaluated such as HIV-1B subtype (n = 27), HIV-1C (n = 26), other (n = 15), and 19 HIV-negative controls. The levels of suPAR, IP-10, neopterin, and ß2 microglobulin (ß2m) in the CSF and serum were quantified using different immunoassays. RESULTS: Overall, in PWH, increases in CSF suPAR, CSF/serum suPAR, and CSF/serum ß2m correlated with worse working memory deficits (r = 0.303, 0.353, and 0.289, respectively, all P < 0.05). The medians of IP-10, suPAR, neopterin, and ß2m in CSF and serum and the CSF/serum ratio and suPAR index were comparable between the HIV-1B and HIV-1C subtypes. CSF IP-10 and neopterin and serum IP-10 and suPAR levels were higher in PWH than the HIV-negative controls (P = 0.015, P = 0.001, P < 0.0001, and P < 0.001, respectively). The serum ß2m level was higher in HIV-associated dementia than neuropsychologically normal or asymptomatic (P = 0.024). DISCUSSION: We observed that higher levels of CSF suPAR and the suPAR quotient correlated with worse working memory deficit. Elevated levels of monocyte activation were similar in both HIV-1 B and C subtypes, providing no evidence of reduced neuropathogenicity of HIV-1 subtype C Tat compared with subtype B.

Ethnic/Racial Disparities in Longitudinal Neurocognitive Decline in People With HIV.

BACKGROUND: To examine longitudinal neurocognitive decline among Latino, non-Latino Black, and non-Latino White people with HIV (PWH) and factors that may explain ethnic/racial disparities in neurocognitive decline. METHODS: Four hundred ninety nine PWH (13.8% Latino, 42.7% Black, 43.5% White; baseline age: M = 43.5) from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study completed neurocognitive, neuromedical, and laboratory assessments every 6-12 months with up to 5 years of follow-up. Longitudinal neurocognitive change was determined via published regression-based norms. Survival analyses investigated the relationship between ethnicity/race and neurocognitive change, and baseline and time-dependent variables that may explain ethnic/racial disparities in neurocognitive decline, including socio-demographic, HIV-disease, medical, psychiatric, and substance use characteristics. RESULTS: In Cox proportional hazard models, hazard ratios for neurocognitive decline were increased for Latino compared with White PWH (HR = 2.25, 95% CI = 1.35 to 3.73, P = 0.002), and Latino compared with Black PWH (HR = 1.86, 95% CI = 1.14 to 3.04, P = 0.013), with no significant differences between Black and White PWH (P = 0.40). Comorbidities, including cardiometabolic factors and more severe neurocognitive comorbidity classification, accounted for 33.6% of the excess hazard for Latino compared with White PWH, decreasing the hazard ratio associated with Latino ethnicity (HR = 1.83, 95% CI = 1.06 to 3.16, P = 0.03), but did not fully account for elevated risk of decline. CONCLUSIONS: Latino PWH may be at higher risk of early neurocognitive decline compared with Black and White PWH. Comorbidities accounted for some, but not all, of this increased risk among Latino PWH. Future research examining institutional, sociocultural, and biomedical factors, including structural discrimination and age-related biomarkers, may further explain the observed disparities.

Identification of Youthful Neurocognitive Trajectories in Adults Aging with HIV: A Latent Growth Mixture Model.

Despite the neurocognitive risks of aging with HIV, initial cross-sectional data suggest a subpopulation of older people with HIV (PWH) possess youthful neurocognition (NC) characteristic of SuperAgers (SA). Here we characterize longitudinal NC trajectories of older PWH and their convergent validity with baseline SA status, per established SuperAging criteria in PWH, and baseline biopsychosocial factors. Growth mixture modeling (GMM) identified longitudinal NC classes in 184 older (age ≥ 50-years) PWH with 1-5 years of follow-up. Classes were defined using 'peak-age' global T-scores, which compare performance to a normative sample of 25-year-olds. 3-classes were identified: Class 1Stable Elite (n = 31 [16.8%], high baseline peak-age T-scores with flat trajectory); Class 2Quadratic Average (n = 100 [54.3%], intermediate baseline peak-age T-scores with u-shaped trajectory); Class 3Quadratic Low (n = 53 [28.8%], low baseline peak-age T-scores with u-shaped trajectory). Baseline predictors of Class 1Stable Elite included SA status, younger age, higher cognitive and physiologic reserve, and fewer subjective cognitive difficulties. This GMM analysis supports the construct validity of SuperAging in older PWH through identification of a subgroup with longitudinally-stable, youthful neurocognition and robust biopsychosocial health.

RESUMEN: A pesar de los riesgos neurocognitivos de envejecer con VIH, datos transversales iniciales sugieren que una subpoblación de personas con VIH (PCV) de edad mayor posee neurocognición (NC) juvenil, característica de los Súper-Ancianos (SA). Aquí nosotros caracterizamos trayectorias longitudinales de NC en PCV mayores y su validez convergente con su status de referencia de SA, según los criterios establecidos en PCV, y factores biopsicosociales en la base de referencia. El modelo de mezclas Gaussianas (GMM) identificó clases longitudinales de NC en 184 PCV mayores (edad ≥ 50-años) con 1­5 años de seguimiento. Las clases fueron definidas utilizando puntuaciones-T (T-scores) globales de "edad pico", que comparan el desempeño con una muestra normativa de personas de 25 años de edad. 3-clases fueron identificadas: Clase 1Élite Estable (n = 31 [16.8%], puntuaciones-T de edad pico de referencia altas con trayectoria plana; Clase 2Promedio Cuadrático (n = 100 [54.3%], puntuaciones-T de edad pico de referencia intermedias con trayectoria en forma de u); Clase 3Cuadrática Baja (n = 53 [28.8%], %], puntuaciones-T de edad pico de referencia bajas con trayectoria en forma de u). Los predictores de referencia de la Clase 1Élite Estable incluyen estatus de SA, edad mas joven, reserva cognitiva y fisiológica superior, y menos dificultades cognitivas subjetivas. Este análisis GMM apoya la validez del constructo de Súper-Envejecimiento en PCV mayores mediante la identificación de un subgrupo longitudinalmente estable, neurocognición juvenil y una robusta salud biopsicosocial.

Objective and subjective sleep measures are associated with neurocognition in aging adults with and without HIV.

Objective: Poor sleep quality is related to worse neurocognition in older adults and in people with HIV (PWH); however, many previous studies have relied only on self-report sleep questionnaires, which are inconsistently correlated with objective sleep measures. We examined relationships between objective and subjective sleep quality and neurocognition in persons with and without HIV, aged 50 and older. Method: Eighty-five adults (PWH n = 52, HIV-negative n = 32) completed comprehensive neuropsychological testing to assess global and domain-specific neurocognition. Objective sleep quality was assessed with wrist actigraphy (total sleep time, efficiency, sleep fragmentation) for five to 14 nights. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index. Results: Objective and subjective sleep measures were unrelated (p's > 0.30). Compared to HIV-negative participants, PWH had greater sleep efficiency (80% vs. 75%, p = 0.05) and were more likely to be using prescription and/or over the counter sleep medication (p = 0.04). In the whole sample, better sleep efficiency (p < 0.01) and greater total sleep time (p = 0.05) were associated with better learning. Less sleep fragmentation was associated with better learning (p < 0.01) and recall (p = 0.04). While PWH had slightly stronger relationships between total sleep time and sleep fragmentation, it is not clear if these differences are clinically meaningful. Better subjective sleep quality was associated with better executive function (p < 0.01) and working memory (p = 0.05); this relationship was primarily driven by the HIV-negative group. Conclusions: Objective sleep quality was associated with learning and recall whereas subjective sleep quality was associated with executive function and working memory. Therefore, assessing objective and subjective sleep quality could be clinically useful, as they are both related to important domains of cognition frequently impacted in HIV-associated neurocognitive disorders as well as neurodegenerative disorders associated with aging. Future studies should evaluate if behavioral sleep interventions can improve neurocognition.