Disparities in Metabolic Syndrome and Neurocognitive Function Among Older Hispanics/Latinos with Human Immunodeficiency Virus.

Neurocognitive impairment and metabolic syndrome (MetS) are prevalent in persons with HIV (PWH). We examined disparities in HIV-associated neurocognitive function between Hispanic and non-Hispanic White older PWH, and the role of MetS in explaining these disparities. Participants included 116 community-dwelling PWH aged 50-75 years enrolled in a cohort study in southern California [58 Hispanic (53% Spanish speaking) and 58 age-comparable non-Hispanic White; overall group: age: M = 57.9, standard deviation (SD) = 5.7; education (years): M = 13, SD = 3.4; 83% male, 58% AIDS, 94% on antiretroviral therapy]. Global neurocognition was derived from T-scores adjusted for demographics (age, education, sex, ethnicity, language) on a battery of 10 cognitive tests. MetS was ascertained via standard criteria that considered central obesity, and fasting elevated triglycerides, low high-density lipoprotein cholesterol and elevated glucose, or medical treatment for these conditions. Covariates examined included sociodemographic, psychiatric, substance use and HIV disease characteristics. Compared with non-Hispanic Whites, Hispanics showed worse global neurocognitive function (Cohen's d = 0.56, p < 0.05) and had higher rates of MetS (38% vs. 56%, p < 0.05). A stepwise regression model including ethnicity and significant covariates showed Hispanic ethnicity was the sole significant predictor of worse global neurocognition (B = -3.82, SE = 1.27, p < 0.01). A model also including MetS showed that both Hispanic ethnicity (B = -3.39, SE = 1.31, p = 0.01) and MetS (B = -2.73, SE = 1.31, p = 0.04) were independently associated with worse neurocognition. In conclusion, findings indicate that increased MetS is associated with worse neurocognitive function in both Hispanic and non-Hispanic White older PWH, but does not explain neurocognitive disparities. MetS remains an important target for intervention efforts to ameliorate neurocognitive dysfunction among diverse older PWH.

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.

Longitudinal analysis of CSF HIV RNA in untreated people with HIV: Identification of CSF controllers.

Interindividual variation of human immunodeficiency virus (HIV) RNA setpoint in cerebrospinal fluid (CSF) and its determinants are poorly understood, but relevant for HIV neuropathology, brain reservoirs, viral escape, and reseeding after antiretroviral interruptions. Longitudinal multicentric study on demographic, clinical, and laboratory correlates of CSF HIV RNA in 2000 follow-up visits from 597 people with HIV (PWH) off antiretroviral therapy (ART) and with plasma HIV RNA > the lower limit of quantification (LLQ). Factors associated with CSF control (CSFC; CSF HIV RNA < LLQ while plasma HIV RNA > LLQ) and with CSF/plasma discordance (CSF > plasma HIV RNA > LLQ) were also assessed through mixed-effects models. Posthoc and sensitivity analyses were performed for persistent CSFC and ART-naïve participants, respectively. Over a median follow-up of 2.1 years, CSF HIV RNA was associated with CD4+ and CD8+ T cells, CSF leukocytes, blood-brain barrier (BBB) integrity, biomarkers of iron and lipid metabolism, serum globulins, past exposure to lamivudine, and plasma HIV RNA (model p < 0.0001). CSFC (persistent in 7.7% over 3 years) and CSF/plasma discordance (persistent in <0.01% over 1 year) were variably associated with the same parameters (model p < 0.001). Sensitivity analyses confirmed most of the previous associations in participants never exposed to ART. Persistent CSFC was associated with higher CD4+ T-cell count nadir (p < 0.001), lower serum globulins (p = 0.003), and lower CSF leukocytes (p < 0.001). Without ART, one in 13 PWH had persistently undetectable CSF HIV RNA, while persistent CSF/plasma discordance was extremely rare over years. Immune responses, inflammation, BBB permeability, and iron and lipid metabolism were all associated with HIV replication in CSF.

Physical dose validation of dynamic treatment for Gamma Knife radiosurgery.

BACKGROUND: Dynamic treatment in Gamma Knife (GK) radiosurgery systems delivers radiation continuously with couch movement, as opposed to stationary step-and-shoot treatment where radiation is paused when moving between isocenters. Previous studies have shown the potential for dynamic GK treatment to give faster treatment times and improved dose conformity and homogeneity. However, these studies focused only on computational simulations and lack physical validation. PURPOSE: This study aims conduct dynamic treatment dosimetric validation with physical experimental measurements. The experiments aim to (1) address assumptions made with computational studies, such as the validity of treating a continuous path as discretised points, (2) investigate uncertainties in translating computed plans to actual treatment, and (3) determine ideal treatment planning parameters, such as interval distance for the path discretization, collimator change limitations, and minimum isocenter treatment times. METHODS: This study uses a GK ICON treatment delivery machine, and a motion phantom custom-made to attach to the machine's mask adapter and move in 1D superior-inferior motion. Phantom positioning is first verified through comparisons against couch motion and computed doses. For dynamic treatment experiments, the phantom is moved through a program that first reads the desired treatment plan isocenters' position, time, and collimator sizes, then carries out the motion continuously while the treatment machine delivers radiation. Measurements are done with increasing levels of complexity: varying speed, varying collimator sizes, varying both speed and collimator sizes, then extends the same measurements to simulated 2D motion by combining phantom and couch motion. Dose comparisons between phantom motion radiation measurements and either couch motion measurements or dose calculations are analyzed with 2 mm/2% and 1 mm/2% gamma indices, using both local and global gamma index calculations. RESULTS: Phantom positional experiments show a high accuracy, with global gamma indices for all dose comparisons ≥ $\ge $ 99%. Discretization level to approximate continuous path as discrete points show the good dose matches with dose calculations when using 1 and 2-mm gaps. Complex 1D motion, including varying speed, collimator sizes, or both, as well as 2D motion with the same complexities, all show good dose matches with dose calculations: the scores are ≥ $\ge $ 92.0% for the strictest 1 mm/2% local gamma index calculation, ≥ $\ge $ 99.8% for 2 mm/2% local gamma index, and ≥ $\ge $ 97.0% for all global gamma indices. Five simulated 2D treatments with optimized plans scored highly as well, with all gamma index scores ≥ $\ge $ 95.3% when compared to stationary treatment, and scores ≥ $\ge $ 97.9% when compared to plan calculated dose. CONCLUSIONS: Dynamic treatment computational studies are validated, with dynamic treatment shown to be physically feasible and deliverable with high accuracy. A 2-mm discretization level in treatment planning is proposed as the best option for shorter dose calculation times while maintaining dose accuracy. Our experimental method enables dynamic treatment measurements using the existing clinical workflow, which may be replicated in other centers, and future studies may include 2D or 3D motion experiments, or planning studies to further quantify potential indication-specific benefits.

Effects of Opioid Withdrawal on Psychobiology in People Living with HIV.

OBJECTIVE: Many persons with opioid use disorders (OUDs) have HIV disease and experience clinically significant stress after they enroll in abstinence-based treatment and undergo medically assisted withdrawal. We examined whether opioid withdrawal affects virologic control, inflammatory markers, cognition, and mood in persons with an OUD and HIV, and explored whether measures of withdrawal stress, such as activation of the HPA axis, contribute to alterations in immune function, cognition, and mood. METHOD AND PARTICIPANTS: Study participants were 53 persons with HIV who were admitted for OUD treatment at the City Addiction Hospital in Saint Petersburg, Russian Federation. Participants were examined at admission, at the anticipated peak of withdrawal 3 to 7 days after the last day of a clonidine-based withdrawal process lasting 7 to 14 days, and 3 to 4 weeks after completing withdrawal. At these times, participants received medical exams and were evaluated for symptoms of withdrawal, as well as cognition and mood. Viral load, plasma cortisol, DHEA sulfate ester (DHEA-S), interleukin-6 (IL-6), and soluble CD14 (sCD14) were determined. Multivariable models examined the relationships between markers of HPA activation and the other parameters over time. RESULTS: HPA activation as indexed by cortisol/DHEA-S ratio increased during withdrawal, as did markers of immune activation, IL-6 and sCD14. There were no significant associations between viral load and indicators of HPA activation. In longitudinal analyses, higher cortisol/DHEA sulfate was related to worse cognition overall, and more mood disturbance. Increase in IL-6 was associated with worse cognitive performance on a learning task. There were no significant associations with sCD14. CONCLUSIONS: Worsening of cognition and measures of mood disturbance during withdrawal were associated with activation of the HPA axis and some measures of inflammation. Whether repeated episodes of opioid withdrawal have a cumulative impact on long-term HIV outcomes and neurocognition is a topic for further investigation.

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.

Reactivity of Health-Related Quality of Life to Perceived Stress: The Buffering Role of Psychosocial Resources in a Longitudinal Study of Adults with and Without HIV.

People with HIV now have increased longevity; however, their health-related quality of life (HRQoL) still lags significantly compared to people without HIV. Perceived stress negatively impacts HRQoL, whereas psychosocial resources are linked to better HRQoL. This longitudinal analysis aims to explore the buffering role of psychosocial resources on the relationship between HRQoL and perceived stress. Participants (N = 240) included 142 persons with HIV (PwH) and 98 without HIV, M(SD) = 50.9(8.1) years. Multilevel models over four study years examined longitudinal relationships between HRQoL (outcome) and perceived stress (predictor) and potential moderation by psychosocial resources (personal mastery, social support, and resilience) by HIV serostatus. Among PwH only, personal mastery (p = 0.001), social support (p = 0.015), and resilience (p = 0.029) were associated with an attenuated effect of perceived stress (less negative slopes) for physical HRQoL over time. Bolstering personal mastery, social support, and resilience may have relevance for improving physical well-being among 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.

Mitochondrial DNA mutation pathogenicity score and neurocognitive performance in persons with HIV.

BACKGROUND: Mitochondrial DNA (mtDNA) genetic variation is associated with neurocognitive (NC) impairment (NCI) in people with HIV (PWH). Other approaches use sequence conservation and protein structure to predict the impact of mtDNA variants on protein function. We examined predicted mtDNA variant pathogenicity in the CHARTER study using MutPred scores, hypothesizing that persons with higher scores (greater predicted pathogenicity) have more NCI. METHODS: CHARTER included NC testing in PWH from 2003 to 2007. MutPred scores were assigned to CHARTER participants with mtDNA sequence; any score > 0.5 was considered potentially deleterious. Outcomes at cohort entry were NCI, defined by global and seven NC domain deficit scores, and by mean global and domain NC performance T-scores. Univariate and multivariable regression analyses assessed associations between having a deleterious variant and NCI. Additional models included estimated peripheral blood cell mtDNA copy number. RESULTS: Data were available for 744 PWH (357 African ancestry; 317 European; 70 Hispanic). In the overall cohort, PWH having any potentially deleterious variant were less likely to have motor impairment (16 vs. 25 %, p = 0.001). In multivariable analysis, having a deleterious variant remained associated with lower likelihood of motor impairment (adjusted odds ratio 0.59 [95 % CI 0.41-0.88]; p = 0.009), and better motor performance by T-score (ß 1.71 [0.31-3.10], p = 0.02). Associations persisted after adjustment for estimated mtDNA quantity. CONCLUSIONS: In these PWH, having a potentially deleterious mtDNA variant was associated with less motor impairment. These unexpected findings suggest that potentially deleterious mtDNA variations may confer protection against impaired motor function by as yet unknown mechanisms.

Identifying and distinguishing cognitive profiles among virally suppressed people with HIV.

OBJECTIVE: Cognitive deficits are common among people with HIV (PWH), even when virally suppressed. We identified cognitive profiles among virally suppressed PWH and determined how sociodemographic, clinical/behavioral, and HIV disease characteristics distinguish profile membership. METHOD: Participants included 704 virally suppressed PWH (Mage = 43.9 [SD = 10.2], 88% male, 58.9% non-Hispanic White) from the HIV Neurobehavioral Research Program. Demographically adjusted T scores were derived from a neuropsychological evaluation comprised of 13 tests. We implemented a pipeline involving dimension reduction and clustering to identify profiles of cognitive performance. Random forest models on a 70/30 training/testing set with internal cross-validation were used to identify sociodemographic, clinical/behavioral, and HIV disease correlates of profile membership. RESULTS: Six cognitive profiles were identified: (a) "unimpaired" (19.9%); (b) weakness in verbal learning and memory (15.5%); (c) weakness in executive function and learning (25.8%); (d) weakness in motor, processing speed, and executive function (8.1%); (e) impaired learning and recall with weak-to-impaired motor, processing speed, and executive function (13.1%); (f) global deficits (17.6%). The most discriminative sociodemographic, clinical/behavioral, and HIV disease characteristics varied by profile with self-reported mood symptoms and cognitive/functional difficulties (e.g., language/communication, memory, and overall everyday function complaints) most consistently associated with profile membership. CONCLUSIONS: Cognitive profiles and their associated factors among PWH are heterogeneous, but learning/memory deficits were most common and self-reported mood, and cognitive/functional difficulties were most consistently related to profile membership. This heterogeneity in cognitive profiles and their correlates in PWH suggests that differing mechanisms contribute to cognitive deficits and, thus, underscores the need for personalized risk reduction and therapeutic strategies among PWH. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

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.

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.

Elevated Plasma Protein Carbonyl Concentration Is Associated with More Abnormal White Matter in People with HIV.

Structural brain abnormalities, including those in white matter (WM), remain common in people with HIV (PWH). Their pathogenesis is uncertain and may reflect multiple etiologies. Oxidative stress is associated with inflammation, HIV, and its comorbidities. The post-translational carbonylation of proteins results from oxidative stress, and circulating protein carbonyls may reflect this. In this cross-sectional analysis, we evaluated the associations between protein carbonyls and a panel of soluble biomarkers of neuronal injury and inflammation in plasma (N = 45) and cerebrospinal fluid (CSF, n = 32) with structural brain MRI. The volume of abnormal WM was normalized for the total WM volume (nAWM). In this multisite project, all regression models were adjusted for the scanner. The candidate covariates included demographics, HIV disease characteristics, and comorbidities. Participants were PWH on virally suppressive antiretroviral therapy (ART) and were mostly white (64.4%) men (88.9%), with a mean age of 56.8 years. In unadjusted analyses, more nAWM was associated with higher plasma protein carbonyls (p = 0.002) and higher CCL2 (p = 0.045). In the adjusted regression models for nAWM, the association with plasma protein carbonyls remained significant (FDR p = 0.018). Protein carbonyls in plasma may be a valuable biomarker of oxidative stress and its associated adverse health effects, including within the central nervous system. If confirmed, these findings would support the hypothesis that reducing oxidative stress could treat or prevent WM injury in PWH.

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 [...].

Combined effects of loneliness and inflammation on depression in people with HIV.

OBJECTIVE: Loneliness is prevalent in people with HIV (PWH) and associated with adverse health-related consequences, including depression. Chronic inflammation has been linked to depression in PWH, though its association with loneliness is less well established. Simultaneous examination of inflammation, loneliness and depression is needed to clarify these relationships. This study investigated the relationship between loneliness and inflammation, and the effects of loneliness and inflammation on depression in PWH. METHODS: 82 PWH who were on suppressive ART (mean age [SD] = 53.2 [9.0]) completed the UCLA Loneliness Scale-Version 3 and the Center for Epidemiologic Studies Depression Scale as part of a comprehensive evaluation. Biomarkers of systemic inflammation (CRP, IL-6, CCL2/MCP-1, sCD14) and coagulation (D-dimer) were measured in blood using commercial immunoassays. RESULTS: Multivariable linear regression analyses revealed that higher D-dimer, CCL2/MCP-1, and sCD14 were significant predictors of loneliness (ps < .05) while accounting for relevant covariates. Stepwise multiple linear regression models that included loneliness, biomarkers, and their interactions as predictors of depressive symptoms revealed significant main effects of loneliness and CCL2/MCP-1 levels (ps < .05), and a significant loneliness by D-dimer interaction (p < .05) whereby higher D-dimer was associated with increased depressive symptoms only at higher levels of loneliness. CONCLUSIONS: Increased coagulation activity is associated with loneliness, and in the context of loneliness, may increase risk for depression. Increased inflammation was associated with depression suggesting potentially dissociable underlying biological processes. To the extent that these processes are modifiable, such findings could have important implications in the treatment of loneliness and depression in PWH.

A longitudinal study of cannabis use and risk for cognitive and functional decline among older adults with HIV.

Cannabis use is rapidly increasing among older adults in the United States, in part to treat symptoms of common health conditions (e.g., chronic pain, sleep problems). Longitudinal studies of cannabis use and cognitive decline in aging populations living with chronic disease are lacking. We examined different levels of cannabis use and cognitive and everyday function over time among 297 older adults with HIV (ages 50-84 at baseline). Participants were classified based on average cannabis use: frequent (> weekly) (n = 23), occasional (≤ weekly) (n = 83), and non-cannabis users (n=191) and were followed longitudinally for up to 10 years (average years of follow-up = 3.9). Multi-level models examined the effects of average and recent cannabis use on global cognition, global cognitive decline, and functional independence. Occasional cannabis users showed better global cognitive performance overall compared to non-cannabis users. Rates of cognitive decline and functional problems did not vary by average cannabis use. Recent cannabis use was linked to worse cognition at study visits when participants had THC+ urine toxicology-this short-term decrement in cognition was driven by worse memory and did not extend to reports of functional declines. Occasional (≤ weekly) cannabis use was associated with better global cognition over time in older adults with HIV, a group vulnerable to chronic inflammation and cognitive impairment. Recent THC exposure may have a temporary adverse impact on memory. To inform safe and efficacious medical cannabis use, the effects of specific cannabinoid doses on cognition and biological mechanisms must be investigated in older adults.

RESUMEN: El consumo de cannabis está aumentando rápidamente entre los adultos mayores en los Estados Unidos, en parte para tratar síntomas de afecciones de salud comunes (p. ej. dolor crónico, problemas de dormir). Actualmente, hay pocos estudios longitudinales sobre el consumo de cannabis y el deterioro cognitivo en poblaciones que envejecen y viven con enfermedades crónicas. Examinamos diferentes niveles del consumo de cannabis y funciones cognitivas a lo largo del tiempo entre 297 adultos mayores con VIH (de 50 a 84 años al principio de la investigación). Los participantes se clasificaron según el consumo promedio de cannabis: consumidores de cannabis frecuentes (> semanal) (n = 23) ocasionales (≤ semanal) (n = 83), y no consumidores de cannabis (n=191) fueron seguidos longitudinalmente hasta por 10 años (promedio = 3,9 años). Los modelos multinivel investigaron los efectos del consumo promedio y reciente de cannabis en la cognición global, el deterioro cognitivo global, y la independencia funcional. Los consumidores ocasionales de cannabis mostraron un mejor rendimiento cognitivo global en comparación con los no consumidores. El nivel de deterioro cognitivo y problemas funcionales no estuvieron asociado con el uso de cannabis. El consumo reciente de cannabis se vinculó con una peor cognición en las visitas del estudio cuando los participantes tenían toxicología de orina de THC positivo­esta disminución a corto plazo de la cognición se debió a una peor memoria, pero no se extendió a los informes de deterioros funcionales. El consumo ocasional (≤ semanal) de cannabis se asoció con una mejor cognición global a lo largo del tiempo en adultos mayores con VIH, un grupo susceptible a la inflamación crónica y la disfunción cognitiva. La exposición reciente al THC puede tener un impacto negativo temporal en la memoria. Los efectos de dosis específicas de cannabinoides en la cognición y sus mecanismos de acción biológicos deben ser investigados en personas mayores con el fin de informar el uso seguro y eficaz del cannabis medicinal.

Neuropsychiatric predictors of cognitive functioning over a one-year follow-up period in HIV.

BACKGROUND: Neuropsychiatric symptoms (NPS) and cognitive impairment are highly prevalent among persons with HIV (PWH). We examined the effect of the most common NPS, depression and anxiety, on cognitive change among PWH and compared these associations to those among persons without HIV (PWoH). METHODS: Participants included 168 PWH and 91 PWoH who completed baseline self-report measures of depression (Beck Depression Inventory-II) and anxiety (Profile of Mood States [POMS] - Tension-anxiety subscale) and completed a comprehensive neurocognitive evaluation at baseline and at 1-year follow-up. Demographically-corrected scores from 15 neurocognitive tests were used to calculate global and domain-specific T-scores. Linear mixed-effects models examined the effect of depression and anxiety and their interaction with HIV-serostatus and time on global T-scores. RESULTS: There were significant depression-by-HIV and anxiety-by-HIV interactions on global T-scores such that, among PWH only, greater depressive and anxiety symptoms at baseline related to worse global T-scores across visits. Non-significant interactions with time suggest stability in these relationships across visits. Follow-up analyses examining cognitive domains revealed that both the depression-by-HIV and the anxiety-by-HIV interactions were driven by learning and recall. LIMITATIONS: Follow-up was limited to one-year and there were fewer PWoH than PWH, creating a differential in statistical power. CONCLUSION: Findings suggest that anxiety and depression have stronger links to worse cognitive functioning in PWH than PWoH, particularly learning and memory, and that these associations seem to persist for at least one-year.

Signatures of HIV and Major Depressive Disorder in the Plasma Microbiome.

Inter-individual differences in the gut microbiome are linked to alterations in inflammation and blood-brain barrier permeability, which may increase the risk of depression in people with HIV (PWH). The microbiome profile of blood, which is considered by many to be typically sterile, remains largely unexplored. We aimed to characterize the blood plasma microbiome composition and assess its association with major depressive disorder (MDD) in PWH and people without HIV (PWoH). In this cross-sectional, observational cohort, we used shallow-shotgun metagenomic sequencing to characterize the plasma microbiome of 151 participants (84 PWH and 67 PWoH), all of whom underwent a comprehensive neuropsychiatric assessment. The microbial composition did not differ between PWH and PWoH or between participants with MDD and those without it. Using the songbird model, we computed the log ratio of the highest and lowest 30% of the ranked classes associated with HIV and MDD. We found that HIV infection and lifetime MDD were enriched in a set of differentially abundant inflammatory classes, such as Flavobacteria and Nitrospira. Our results suggest that the circulating plasma microbiome may increase the risk of MDD related to dysbiosis-induced inflammation in PWH. If confirmed, these findings may indicate new biological mechanisms that could be targeted to improve treatment of MDD in PWH.

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.