Differences in metabolic biomarkers in people with schizophrenia who are of Mexican descent compared to non-Hispanic whites.

Metabolic dysfunction is highly prevalent and contributes to premature mortality among people with schizophrenia (PwS), especially in Hispanic/Latino/a/x/e PwS, compared to non-Hispanic White (NHW) PwS. This study evaluated the relative contributions of Mexican descent and schizophrenia diagnosis to metabolic biomarker levels. This cross-sectional study included 115 PwS and 102 non-psychiatric comparison (NC) participants - English-speakers aged 26-66 years, 27% Mexican descent, and 52% women across both groups. Assessments included evaluations of BMI, psychopathology, and fasting metabolic biomarkers. We used ANOVA analyses to compare metabolic outcomes between diagnostic and ethnic subgroups, linear regression models to examine associations between Mexican descent and metabolic outcomes, and Spearman's correlations to examine relationships between metabolic outcomes and illness-related variables in PwS. Mexican PwS had higher hemoglobin A1c levels, insulin resistance, and body mass index than NHW PwS. Mexican descent was associated with higher hemoglobin A1c levels, insulin resistance, body mass index, and leptin levels, controlling for age, sex, depression, education, and smoking. Among Mexican PwS, worse negative symptoms were associated with greater insulin resistance. These findings support the possibility of ethnicity-based differences in metabolic dysregulation, though further investigation is warranted to create targeted health interventions for Hispanic PwS.

Mechanisms underlying HIV-associated cognitive impairment and emerging therapies for its management.

People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers.

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.

Characterization of HIV-Associated Neurocognitive Impairment in Middle-Aged and Older Persons With HIV in Lima, Peru.

Background: With widespread use of antiretroviral medications, people living with HIV (PWH) are living longer worldwide, increasing their risk of developing neurocognitive impairment (NCI). The proportion of Peruvians over age 60 is expected to increase to 25% of the population by 2050, including PWH. Therefore, the problem of aging and NCI, especially in the setting of HIV infection, is uniquely pressing. We sought to study the rates of and risk factors associated with NCI among middle-aged and older PWH in Lima, Peru. Materials and Methods: Sociodemographic, medical (infectious and non-infectious), and psychiatric comorbidity and laboratory data were collected. We administered a brief neuropsychological battery evaluating seven cognitive domains affected in HIV-associated NCI and a depression screening. Cognitive test raw scores were converted to T-scores that were demographically adjusted. Descriptive statistics were performed together with regression (unadjusted and adjusted) analyses to determine potential risk factors for NCI among PWH. Results: This was a cross-sectional study in which 144 PWH aged ≥40 years attending a large HIV clinic in Lima, Peru, were recruited from September 2019 to March 2020. Mean age was 51.6 ± 7.7 years, and mean years of education were 14.0 ± 3.1 with 15% females. Median [interquartile range (IQR)] current CD4 and nadir CD4 were 554 (371, 723) and 179 (83, 291), respectively, and 10% currently had AIDS. The prevalence of NCI was 28.5%, and many demonstrated difficulty with attention and working memory (70%). One-quarter of PWH had mild depression or worse on Patient Health Questionnaire 9 (PHQ-9 ≥ 5). In bivariate analyses, neither a depression history nor a higher PHQ-9 score correlated with NCI. No other non-communicable medical or psychiatric comorbidity nor HIV characteristic was predictive of NCI. Having a positive lifetime history of hepatitis B infection, pulmonary tuberculosis, or syphilis increased risk of NCI (PR 1.72; 95% CI 1.04-2.86) in unadjusted analyses, but not in adjusted analyses. Conclusions: NCI among older Peruvians with HIV was found to be highly prevalent with levels consistent with prior reports of HIV-associated NCI worldwide. Common latent HIV-associated co-infections, including latent syphilis, hepatitis B infection, or pulmonary tuberculosis, may increase the risk of NCI among middle-aged and older PWH in Peru.

Neurocognitive impairment in Spanish-speaking Latinos living with HIV in the US: Application of the neuropsychological norms for the US-Mexico border region in Spanish (NP-NUMBRS).

Objective Latinos in the US are at increased risk for HIV-associated neurocognitive impairment (NCI). Most studies of US Latinos living with HIV have included primarily English-speakers only. We investigated the rate, pattern, and correlates of HIV-associated NCI in native Spanish-speaking Latinos living in the US near the Mexican border. Methods Participants included 407 native Spanish-speaking Latinos (Age: M = 37.65, SD = 10.0; Education: M = 10.75, SD = 4.1; 53% male): 153 persons living with HIV (PLWH; 56% AIDS) and 254 healthy controls. All participants completed comprehensive neuropsychological assessments in Spanish. Raw neuropsychological test scores from seven domains were converted to demographically-adjusted T-scores using norms developed with healthy controls. Global and domain NCI were defined per established criteria. Among PLWH we applied norms developed for non-Hispanic (NH) Whites and Blacks, and investigated correlates of global NCI, including HIV disease characteristics and psychiatric comorbidities. Results Utilizing population specific norms, rates of global NCI were significantly higher among PLWH (39%) than healthy controls (17%), comparable to previously published rates. In contrast, rates of global NCI in the same group of PLWH were significantly different when NH White norms (63%, p < 0.0001) and NH Black norms were used (18%, p < 0.0001). Among PLWH without a history of lifetime substance use disorder, more years of antiretroviral exposure were significantly associated with decreased rates of global NCI. Conclusions Present findings lend support to the validity of newly developed norms for native Spanish-speakers living near the US-Mexico border, and underscore the importance of utilizing appropriate norms to accurately identify HIV-associated NCI.

Frailty and Neurocognitive Impairment: Impacts on Quality of Life in HIV.

Little is known about the effects of aging-related conditions on health-related quality of life (HRQOL) among people living with HIV (PLWH). The purpose of our study was to examine the independent effects of neurocognitive impairment (NCI) and frailty and the interactive effects with HIV serostatus on HRQOL. Our sample consisted of 121 adults (63 PLWH and 58 HIV-uninfected) participating in the Multi-Dimensional Successful Aging among HIV-Infected Adults study at the University of California, San Diego. HRQOL was measured with the Medical Outcome Study 36-Item Short Form Health Survey scale. We found that frailty was significantly associated with HRQOL (p < .001) in the overall sample, and this effect was significantly stronger for PLWH than HIV-uninfected adults. NCI was not significantly associated with HRQOL in our sample. Frailty may be a particularly important factor in HRQOL for PLWH, highlighting the need for prevention and intervention strategies to mitigate the risks for frailty.

COMT Val158Met Polymorphism, Cardiometabolic Risk, and Nadir CD4 Synergistically Increase Risk of Neurocognitive Impairment in Men Living With HIV.

OBJECTIVE: The Val allele of the Val158Met single-nucleotide polymorphism of the catechol-o-methyltransferase gene (COMT) results in faster metabolism and reduced bioavailability of dopamine (DA). Among persons living with HIV, Val carriers display neurocognitive deficits relative to Met carriers, presumably due to exacerbation of HIV-related depletion of DA. COMT may also impact neurocognition by modulating cardiometabolic function, which is often dysregulated among persons living with HIV. We examined the interaction of COMT, cardiometabolic risk, and nadir CD4 on neurocognitive impairment (NCI) among HIV+ men. METHODS: Three hundred twenty-nine HIV+ men underwent COMT genotyping and neurocognitive and neuromedical assessments. Cohort-standardized z scores for body mass index, systolic blood pressure, glucose, triglycerides, and high-density lipoprotein cholesterol were averaged to derive a cardiometabolic risk score (CMRS). NCI was defined as demographically adjusted global deficit score of ≥0.5. Logistic regression modeled NCI as a function of COMT, CMRS, and their interaction, covarying for estimated premorbid function, race/ethnicity, and HIV-specific characteristics. Follow-up analysis included the 3-way interaction of COMT, CMRS, and nadir CD4. RESULTS: Genotypes were 81 (24.6%) Met/Met, 147 (44.7%) Val/Met, and 101 (30.7%) Val/Val. COMT interacted with CMRS (P = 0.02) such that higher CMRS increased risk of NCI among Val/Val [odds ratio (OR) = 2.13, P < 0.01], but not Val/Met (OR = 0.93, P > 0.05) or Met/Met (OR = 0.92, P > 0.05) carriers. Among Val/Val, nadir CD4 moderated the effect of CMRS (P < 0.01) such that higher CMRS increased likelihood of NCI only when nadir CD4 <180. DISCUSSION: Results suggest a tripartite model by which genetically driven low DA reserve, cardiometabolic dysfunction, and historical immunosuppression synergistically enhance risk of NCI among HIV+ men, possibly due to neuroinflammation and oxidative stress.

Alterations in brain TREM2 and Amyloid-ß levels are associated with neurocognitive impairment in HIV-infected persons on antiretroviral therapy.

Neuroinflammation is a common pathological correlate of HIV-associated neurocognitive disorders (HAND) in individuals on antiretroviral therapy (ART). Triggering receptor expressed on myeloid cells 2 (TREM2) regulates neuroinflammation, clears extracellular Amyloid (A)-ß, surveys for damaged neurons, and orchestrates microglial differentiation. TREM2 has not been studied in HIV+ brain tissues. In this retrospective study, we investigated TREM2 expression levels and localization to microglia, Aß protein levels, and tumor necrosis factor (TNF)-α transcript levels in the frontal cortices of 52 HIV+ decedents. All donors had been on ART; 14 were cognitively normal (CN), 17 had an asymptomatic neurocognitive impairment (ANI), and 21 had a minor neurocognitive disorder (MND). Total TREM2 protein levels were increased in the soluble and decreased in the membrane-enriched fractions of MND brain tissues compared to CN; however, brains from MND Hispanics showed the most robust alterations in TREM2 as well as significantly increased TNF-α mRNA and Aß levels when compared to CN Hispanics. Significant alterations in the expression of total TREM2 protein and transcripts for TNF-α were not observed in non-Hispanics, despite higher levels of Aß in the non-Hispanic CN group compared to the non-Hispanic MND groups. These findings show that decreased and increased TREM2 in membrane-bound fractions and in soluble-enriched fractions, respectively, is associated with increased Aß and neuroinflammation in this cohort of HIV+ brains, particularly those identifying as Hispanics. These findings suggest a role for TREM2 in the brain of HIV+ individuals may deserve more investigation as a biomarker for HAND and as a possible therapeutic target. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

A composite of multisystem injury and neurocognitive impairment in HIV infection: association with everyday functioning.

The Veterans Aging Cohort Study (VACS) Index is a composite marker of multisystem injury among HIV-infected persons. We aimed to examine its cross-sectional association with functional outcomes, after considering neurocognitive impairment (NCI) and other well-established correlates of everyday functioning among HIV-infected persons. Participants included 670 HIV-infected adults (ages 18-76; 88% male; 63% non-Hispanic White; median current CD4 = 404 cells/mm3; 67% on antiretroviral therapy; AIDS = 63%) enrolled in observational studies at the University of California San Diego HIV Neurobehavioral Research Program. Functional outcomes were assessed via self-report measures of declines in activities of daily living, perceived cognitive symptoms in daily life, and employment status. NCI was assessed via a comprehensive neurocognitive test battery and defined based on established methods. Covariates examined included demographics, HIV disease characteristics not included in the VACS Index, and psychiatric comorbidities. The VACS Index was computed via standard methods and categorized based on its distribution. Results from multivariable regression models showed that both higher VACS Index scores (indicative of worse health) and the presence of NCI were independently associated with declines in activities of daily living, increased cognitive symptoms in daily life, and unemployment. These independent effects remained after adjusting for significant covariates. In conclusion, the VACS Index may be a useful tool for identifying HIV-infected patients at high risk for everyday functioning problems. Considering factors such as NCI, historical HIV disease characteristics, and current mood might be particularly important to enhance the predictive power of the VACS Index for functional status among HIV-infected persons.

Differences in Neurocognitive Impairment Among HIV-Infected Latinos in the United States.

OBJECTIVES: Human immunodeficiency virus (HIV) disproportionately affects Hispanics/Latinos in the United States, yet little is known about neurocognitive impairment (NCI) in this group. We compared the rates of NCI in large well-characterized samples of HIV-infected (HIV+) Latinos and (non-Latino) Whites, and examined HIV-associated NCI among subgroups of Latinos. METHODS: Participants included English-speaking HIV+ adults assessed at six U.S. medical centers (194 Latinos, 600 Whites). For overall group, age: M=42.65 years, SD=8.93; 86% male; education: M=13.17, SD=2.73; 54% had acquired immunodeficiency syndrome. NCI was assessed with a comprehensive test battery with normative corrections for age, education and gender. Covariates examined included HIV-disease characteristics, comorbidities, and genetic ancestry. RESULTS: Compared with Whites, Latinos had higher rates of global NCI (42% vs. 54%), and domain NCI in executive function, learning, recall, working memory, and processing speed. Latinos also fared worse than Whites on current and historical HIV-disease characteristics, and nadir CD4 partially mediated ethnic differences in NCI. Yet, Latinos continued to have more global NCI [odds ratio (OR)=1.59; 95% confidence interval (CI)=1.13-2.23; p<.01] after adjusting for significant covariates. Higher rates of global NCI were observed with Puerto Rican (n=60; 71%) versus Mexican (n=79, 44%) origin/descent; this disparity persisted in models adjusting for significant covariates (OR=2.40; CI=1.11-5.29; p=.03). CONCLUSIONS: HIV+ Latinos, especially of Puerto Rican (vs. Mexican) origin/descent had increased rates of NCI compared with Whites. Differences in rates of NCI were not completely explained by worse HIV-disease characteristics, neurocognitive comorbidities, or genetic ancestry. Future studies should explore culturally relevant psychosocial, biomedical, and genetic factors that might explain these disparities and inform the development of targeted interventions. (JINS, 2018, 24, 163-175).

Performance of Hispanics and Non-Hispanic Whites on the NIH Toolbox Cognition Battery: the roles of ethnicity and language backgrounds.

OBJECTIVE: This study examined the influence of Hispanic ethnicity and language/cultural background on performance on the NIH Toolbox Cognition Battery (NIHTB-CB). METHOD: Participants included healthy, primarily English-speaking Hispanic (n = 93; Hispanic-English), primarily Spanish-speaking Hispanic (n = 93; Hispanic-Spanish), and English speaking Non-Hispanic white (n = 93; NH white) adults matched on age, sex, and education levels. All participants were in the NIH Toolbox national norming project and completed the Fluid and Crystallized components of the NIHTB-CB. T-scores (demographically-unadjusted) were developed based on the current sample and were used in analyses. RESULTS: Spanish-speaking Hispanics performed worse than English-speaking Hispanics and NH whites on demographically unadjusted NIHTB-CB Fluid Composite scores (ps < .01). Results on individual measures comprising the Fluid Composite showed significant group differences on tests of executive inhibitory control (p = .001), processing speed (p = .003), and working memory (p < .001), but not on tests of cognitive flexibility or episodic memory. Test performances were associated with language/cultural backgrounds in the Hispanic-Spanish group: better vocabularies and reading were predicted by being born outside the U.S., having Spanish as a first language, attending school outside the U.S., and speaking more Spanish at home. However, many of these same background factors were associated with worse Fluid Composites within the Hispanic-Spanish group. CONCLUSIONS: On tests of Fluid cognition, the Hispanic-Spanish group performed the poorest of all groups. Socio-demographic and linguistic factors were associated with those differences. These findings highlight the importance of considering language/cultural backgrounds when interpreting neuropsychological test performances. Importantly, after applying previously published NIHTB-CB norms with demographic corrections, these language/ethnic group differences are eliminated.

The Veterans Aging Cohort Study (VACS) Index and Neurocognitive Change: A Longitudinal Study.

BACKGROUND: The Veterans Aging Cohort Study (VACS) Index, a composite marker of disease severity among human immunodeficiency virus (HIV)-infected persons, has been associated with concurrent risk for neurocognitive impairment (NCI). The present study examined whether the VACS Index predicts longitudinal neurocognitive change. METHODS: Participants included 655 HIV-infected persons followed for up to 6 years in cohort studies at the University of California, San Diego, HIV Neurobehavioral Research Program (mean age at baseline, 42.5 years; 83% male; 60% white; AIDS in 67%; median current CD4(+) T-cell count, 346/µL; 61% receiving antiretroviral therapy). The VACS Index was calculated through standard methods. Participants completed a comprehensive neurocognitive battery. Neurocognitive status was plotted over time using demographically and practice-adjusted global and domain T scores. NCI was defined by global deficit scores derived from T scores. RESULTS: Baseline VACS Index scores were not predictive of changes in global T scores during the follow-up period (P = .14). However, in time-dependent analyses adjusting for covariates, higher VACS Index scores were significantly associated with worse global and domain neurocognitive performance (Ps < .01), as well as increased risk for developing NCI in a subgroup of persons who were neurocognitively normal at baseline (hazard ratio [HR], 1.17; P < .001). We categorized VACS Index scores by quartiles and found that the upper-quartile group was significantly more likely to develop NCI than the lower quartile (HR, 2.16; P < .01) and middle groups (HR, 1.76; P < .01). CONCLUSIONS: Changes in VACS Index scores correspond to changes in neurocognitive function. HIV-infected persons with high VACS Index scores are at increased risk for decline and incident NCI. The VACS Index shows promise as a tool for identifying HIV-infected persons at risk for NCI.

Physical Activity is Associated with Better Neurocognitive and Everyday Functioning Among Older Adults with HIV Disease.

We examined the association between physical activity (PA), neurocognitive impairment (NCI), and instrumental activities of daily living (IADLs) among older HIV+ persons. One hundred older HIV+ adults completed the International Physical Activity Questionnaire, a neurocognitive battery, and IADL scale. Higher levels of moderate PA were associated with lower odds of NCI (p = 0.01), even when covariates were modeled. The association between moderate PA and NCI was driven by executive function (p = 0.04). Higher levels of moderate PA were also associated with lower odds of IADL Dependence (p = 0.03), although this fell to a trend (p = 0.08) when including covariates. Follow-up analysis showed those with both NCI and IADL Dependence had lower moderate PA than those with neither (p = 0.03). While these cross-sectional findings suggest PA is associated with better neurocognitive and everyday functioning in older HIV+ adults, longitudinal studies utilizing objective PA methods are needed to evaluate directionality and mechanisms.

The veterans aging cohort study index is associated with concurrent risk for neurocognitive impairment.

OBJECTIVE: The Veterans Aging Cohort Study (VACS) Index is predictive of mortality and combines age, traditional HIV biomarkers (HIV-1 plasma RNA and current CD4 count), and non-HIV biomarkers (indicators of renal and liver function, anemia, and hepatitis C coinfection). We examined the association between the VACS Index and HIV-associated neurocognitive impairment (NCI). DESIGN AND METHODS: Participants included 601 HIV-infected adults enrolled in cohort studies at the University of California, San Diego, HIV Neurobehavioral Research Program (ages: 18-76 years; 88% male; 63% white; median current CD4 = 364 cells/mm; 63% on antiretroviral therapy; AIDS = 64%). Biomarkers used in calculating the VACS Index were measured in prospectively collected blood samples using conventional laboratory methods. NCI was defined using global and seven domain deficit scores. RESULTS: Higher VACS Index scores were associated with concurrent risk for global NCI [P < 0.001; odds ratio = 1.21, confidence interval (CI): 1.12 to 1.32], even when adjusting for psychiatric comorbidities. This relation was statistically significant for most cognitive domains in adjusted models. Furthermore, the VACS Index predicted concurrent NCI beyond nadir CD4 and estimated duration of infection. Older age, lower hemoglobin, and lower CD4 counts were the VACS components most strongly linked to NCI. CONCLUSIONS: The findings extend previous research on the potential usefulness of the VACS Index in predicting HIV-associated outcomes to include NCI. Although the effect size was relatively small, our findings suggest that demographic information, HIV-disease factors, and common comorbidities might each play important roles in the clinical manifestation of cognitive impairment among HIV-infected individuals. Additional research is needed to determine if a more sensitive and specific index can be developed.

Physical exercise is associated with less neurocognitive impairment among HIV-infected adults.

Neurocognitive impairment (NCI) remains prevalent in HIV infection. Randomized trials have shown that physical exercise improves NCI in non-HIV-infected adults, but data on HIV-infected populations are limited. Community-dwelling HIV-infected participants (n = 335) completed a comprehensive neurocognitive battery that was utilized to define both global and domain-specific NCI. Participants were divided into "exercise" (n = 83) and "no exercise" (n = 252) groups based on whether they self-reported engaging in any activity that increased heart rate in the last 72 h or not. We also measured and evaluated a series of potential confounding factors, including demographics, HIV disease characteristics, substance use and psychiatric comorbidities, and physical functioning. Lower rates of global NCI were observed among the exercise group (15.7 %) as compared to those in the no exercise group (31.0 %; p < 0.01). A multivariable logistic regression controlling for potential confounds (i.e., education, AIDS status, current CD4+ lymphocyte count, self-reported physical function, current depression) showed that being in the exercise group remained significantly associated with lower global NCI (odds ratio = 2.63, p < 0.05). Similar models of domain-specific NCI showed that exercise was associated with reduced impairment in working memory (p < 0.05) and speed of information processing (p < 0.05). The present findings suggest that HIV-infected adults who exercise are approximately half as likely to show NCI as compared to those who do not. Future longitudinal studies might be best suited to address causality, and intervention trials in HIV-infected individuals will determine whether exercise can prevent or ameliorate NCI in this population.