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Background: This study examined the effects of human immunodeficiency virus (HIV) on resting state functional connectivity (RSFC) in a large cohort of people with HIV (PWH) and healthy controls without HIV (PWoH). Within PWH analyses focused on the effects of viral suppression and cognitive impairment on RSFC., Methods: A total of 316 PWH on stable combination antiretroviral therapy and 209 demographically matched PWoH were scanned at a single institution. Effects of the virus were examined by grouping PWH by detectable (viral load > 20 copies/mL; VLD) and undetectable (VLU) viral loads and as being cognitively impaired (CI) (Global Deficit Score ≥ 0.5) or cognitively normal (CN). Regression analysis, object oriented data analysis, and spring embedded graph models were applied to RSFC measures from 298 established brain regions of interest comprising 13 brain networks to examine group differences., Results: No significant RSFC differences were observed between PWH and PWoH. Within PWH, there were no significant differences in RSFC between VLD and VLU subgroups and CI and CN subgroups., Conclusions: There were no significant effects of HIV on RSFC in our relatively large cohort of PWH and PWoH. Future studies could increase the sample size and combine with other imaging modalities., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: As people with human immunodeficiency virus (HIV) (PWH) age, it remains unclear whether they are at higher risk for age-related neurodegenerative disorders-for example, Alzheimer disease (AD)-and, if so, how to differentiate HIV-associated neurocognitive impairment from AD. We examined a clinically available blood biomarker test for AD (plasma amyloid-β [Aβ] 42/Aβ40 ratio) in PWH who were cognitively normal (PWH&#95;CN) or cognitively impaired (PWH&#95;CI) and people without HIV (PWoH) who were cognitively normal (PWoH&#95;CN) or had symptomatic AD (PWoH&#95;AD)., Methods: A total of 66 PWH (age >40 years) (HIV RNA <50 copies/mL) and 195 PWoH provided blood samples, underwent magnetic resonance imaging, and completed a neuropsychological battery or clinical dementia rating scale. Participants were categorized by impairment (PWH&#95;CN, n = 43; PWH&#95;CI, n = 23; PWoH&#95;CN, n = 138; PWoH&#95;AD, n = 57). Plasma Aβ42 and Aβ40 concentrations were obtained using a liquid chromatography-tandem mass spectrometry method to calculate the PrecivityAD amyloid probability score (APS). The APS incorporates age and apolipoprotein E proteotype into a risk score for brain amyloidosis. Plasma Aβ42/Aβ40 ratios and APSs were compared between groups and assessed for relationships with hippocampal volumes or cognition and HIV clinical characteristics (PWH only)., Results: The plasma Aβ42/Aβ40 ratio was significantly lower, and the APS higher, in PWoH&#95;AD than in other groups. A lower Aβ42/Aβ40 ratio and higher APS was associated with smaller hippocampal volumes for PWoH&#95;AD. The Aβ42/Aβ40 ratio and APS were not associated with cognition or HIV clinical measures for PWH., Conclusions: The plasma Aβ42/Aβ40 ratio can serve as a screening tool for AD and may help differentiate effects of HIV from AD within PWH, but larger studies with older PWH are needed., Competing Interests: Potential conflicts of interest. K. E. Y., K. M. K., M. R. M. are full-time employees of and have equity interest in C2N Diagnostics. The PrecivityAD test is licensed by C2N Diagnostics, and Washington University will receive royalties from this test. K. E. Y. and M. R. M. also report royalties or licenses from C2N Diagnostics (equity shares); payment for travel, lodging, and meal expenses to attend scientific meetings as employees of C2N Diagnostics; and a patent planned, issued, or pending for methods for measuring concentrations of biomolecules in biofluids (C2N Diagnostics: US 10,976,323 B2). S. E. S. receives funding from the Barnes-Jewish Hospital Foundation to evaluate the clinical utility of Alzheimer disease blood tests and is an unpaid board member for the Greater Missouri Alzheimer's Association. S. E. S. reports personal honoraria from the University of Wisconsin, St Luke's Hospital, and Houston Methodist Medical Center for presenting lectures, from the University of Washington for serving on the Alzheimer Disease Center Clinical Task Force, and from the University of Indiana for serving on the biospecimen review committee of the National Centralized Repository for Alzheimer's Disease and reports travel support from the National Institute on Aging (grant R01AG070941). S. E. S. also reports that plasma amyloid-β (Aβ) 42/Aβ40 data was provided to Washington University by C2N Diagnostics at no cost. (No payment or research funding were provided by C2N Diagnostics, nor any gifts of financial incentives of any kind to S. E. S.) J. C. M. consults for the Barcelona Brain Research Center and the Native Alzheimer Disease-Related Resource Center in Minority Aging Research (external advisory board); receives honoraria for the Tetra-Institutional Alzheimer Disease Research Center seminar series and Montefiore Grand Rounds; and participates on the data safety monitoring board for the Cure Alzheimer's Fund (strategy council), observational study monitoring board for Diverse VCID (Vascular Contributions to Cognitive Impairment and Dementia), and the Longitudinal early-onset Alzheimer's Disease Study advisory board for Indiana University. J. C. M. also reports National Institutes of Health support, unrelated to the current work (grants P30 AG066444, P01AG003991, P01AG026276, and U19AG032438). A. F. is a member of scientific advisory boards for Roche Diagnostics, Genentech, and DiademRes and consults for DiamiR and Siemens Healthcare Diagnostics. A. F. also reports travel support for in-person attendance at Alzheimer's Association International Conference premeetings in San Diego, California, and travel support/honorarium for in-person attendance at the Scientific Advisory Board meeting for the South Texas Alzheimer's Disease Research Center. B. M. A. is on the data safety monitoring board for Diverse VCID. J. O. H. has received funding from Janssen Scientific for investigator-initiated research, paid to the institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Neurological involvement in HIV is often associated with cognitive impairment. Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy, most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. In this Review, we describe the manifestations of HIV-associated neurocognitive disorder in the era of effective HIV therapy, outline diagnosis and treatment recommendations, and explore the research questions that remain. Although comorbid disorders, such as hepatitis C infection or epilepsy, might cause some impairment, their prevalence is insufficient to explain the frequency with which it is encountered. HIV disease markers, such as viral load and CD4 cell counts, are not strongly associated with ongoing impairment on treatment, whereas cardiovascular disease markers and inflammatory markers are. New cerebrospinal fluid and neuroimaging biomarkers are needed to detect and follow impairment. Ongoing research efforts to optimise HIV therapy within the CNS, and potentially to intervene in downstream mechanisms of neurotoxicity, remain important avenues for future investigation. Ultimately, the full control of virus in the brain is a necessary step in the goal of HIV eradication., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The human immunodeficiency virus (HIV) has multiple genetic clades with varying prevalence throughout the world. Both HIV clade C (HIV-C) and HIV clade B (HIV-B) can cause cognitive impairment, but it is unclear if these clades are characterized by similar patterns of brain dysfunction. We examined brain volumetrics and neuropsychological performance among highly active antiretroviral therapy (HAART)-naïve HIV-B and HIV-C participants. Thirty-four HAART-naïve HIV-infected (HIV+) participants [17 HIV-B (USA); 17 HIV-C (South Africa)] and 34 age- and education-matched HIV-uninfected (HIV−) participants were evaluated. All participants underwent similar laboratory, neuropsychological, and neuroimaging studies. Brain volume measures were assessed within the caudate, putamen, amygdala, thalamus, hippocampus, corpus callosum, and cortical (gray and white matter) structures. A linear model that included HIV status, region, and their interaction assessed the effects of the virus on brain volumetrics. HIV− and HIV+ individuals were similar in age. On laboratory examination, HIV-C participants had lower CD4 cell counts and higher plasma HIV viral loads than HIV-B individuals. In general, HIV+ participants performed significantly worse on neuropsychological measures of processing speed and memory and had significantly smaller relative volumetrics within the thalamus, hippocampus, corpus callosum, and cortical gray and white matter compared to the respective HIV− controls. Both HIV-B and HIV-C are associated with similar volumetric declines when compared to matched HIV− controls. HIV-B and HIV-C were associated with significant reductions in brain volumetrics and poorer neuropsychological performance; however, no specific effect of HIV clade subtype was evident. These findings suggest that HIV-B and HIV-C both detrimentally affect brain integrity.

Previous studies have reported cognitive deficits among HIV-positive individuals infected with clade C virus. However, no study has examined whether individuals predominately infected with clade C virus exhibit brain atrophy relative to healthy controls. This study examined volumetric differences between 28 HIV+ individuals and 23 HIV- controls from South Africa. Volumetric measures were obtained from six regions of interest -- caudate, thalamus, corpus callosum, total cortex, total gray matter, and total white matter. HIV+ participants had significantly lower volumes in the total white matter (p<0.01), thalamus (p<0.01) and total gray matter (inclusive of cortical and subcortical regions, p<0.01). This study is the first to provide evidence of brain atrophy among HIV+ individuals in South Africa, where HIV clade C predominates. Additional research that integrates neuroimaging, comprehensive neuropsychological testing, genetic variance in clade-specific proteins, and the impact of treatment with Antiretrovirals (ARV) are necessary to understand the development of HIV-related neurocognitive disorders in South Africa.

BackgroundPersons with human immunodeficiency virus (PWH) are characterized by altered brain structure and function. As they attain normal lifespans, it has become crucial to understand potential interactions between human immunodeficiency virus (HIV) and aging. However, it remains unclear how brain aging varies with viral load (VL).MethodsIn this study, we compare magnetic resonance imaging (MRI) biomarkers among PWH with undetectable VL (UVL; ≤50 genomic copies/mL; n = 230), PWH with detectable VL (DVL; >50 copies/mL; n = 93), and HIV-uninfected (HIV-) controls (n = 206). To quantify gray matter cerebral blood flow (CBF), we utilized arterial spin labeling. To measure structural aging, we used a publicly available deep learning algorithm to estimate brain age from T1-weighted MRI. Cognitive performance was measured using a neuropsychological battery covering 5 domains.ResultsAssociations between age and CBF varied with VL. Older PWH with DVL had reduced CBF vs PWH with UVL (P = .02). Structurally predicted brain aging was accelerated in PWH vs HIV- controls regardless of VL (P < .001). Overall, PWH had impaired learning, executive function, psychomotor speed, and language compared to HIV- controls. Structural brain aging was associated with reduced psychomotor speed (P < .001).ConclusionsBrain aging in HIV is multifaceted. CBF depends on age and current VL and is improved by medication adherence. By contrast, structural aging is an indicator of cognitive function and reflects serostatus rather than current VL.

ObjectiveDespite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH.DesignTwenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding.Methods[C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV.ResultsAnalyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH.ConclusionsOur results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.

We evaluated the relationship between neighborhood disadvantage (measured by the Area Deprivation Index [ADI]) and frailty. We performed a secondary analysis, pooling cross-sectional data collected from 209 people with HIV (PWH) aged ≥50 years enrolled in studies in Colorado (CO) and Missouri (MO). MO participants (N = 137) had a higher ADI (µ= 70, ơ2 = 25) compared to CO (µ= 32, ơ2 = 15; p <.001). No significant differences in ADI were observed between frailty categories when cohorts were examined either separately or combined; however, when comparing individual frailty criteria, the most apparent differences by neighborhood disadvantage were seen among those with limited physical activity (μ = 67, ơ2 = 28) compared to those without (μ = 55, ơ2 = 29, p =.03). Neighborhood disadvantage was associated with low physical activity but not with overall frailty status. Future research should examine how access to physical activity spaces varies based on ADI, as this could be crucial in preventing frailty. [ABSTRACT FROM AUTHOR]

Inflammation occurs after HIV infection and persists, despite highly active antiretroviral therapy (HAART). Diffusion tensor imaging (DTI) measures HIV-associated white matter changes, but can be confounded by inflammation. Currently, the influence of inflammation on white matter integrity in well-controlled HIV+ patients remains unknown. We used diffusion basis spectral imaging (DBSI)-derived cellularity to isolate restricted water diffusion associated with inflammation separated from the anisotropic diffusion associated with axonal integrity. Ninety-two virologically suppressed HIV+ patients on HAART and 66 HIV uninfected (HIV-) controls underwent neuropsychological performance (NP) testing and neuroimaging. NP tests assessed multiple domains (memory, psychomotor speed, and executive functioning). DTI- and DBSI-derived fractional anisotropy (FA) maps were processed with tract-based spatial statistics for comparison between both groups. Cellularity was assessed regarding age, HIV status, and NP. Within the HIV+ cohort, cellularity was compared with clinical (HAART duration) and laboratory measures of disease (eg, CD4 cell current and nadir). NP was similar for both groups. DTI-derived FA was lower in HIV+ compared with HIV- individuals. By contrast, DBSI-derived FA was similar for both groups. Instead, diffuse increases in cellularity were present in HIV+ individuals. Observed changes in cellularity were significantly associated with age, but not NP, in HIV+ individuals. A trend level association was seen between cellularity and HAART duration. Elevated inflammation, measured by cellularity, persists in virologically well-controlled HIV+ individuals. Widespread cellularity changes occur in younger HIV+ individuals and diminish with aging and duration of HAART.

The expression of cognitive symptoms associated with HIV varies over time and across individuals. This pattern may reflect transient contextual factors, including the degree of effort exerted by individuals undergoing cognitive testing. The present study examined whether effort corresponds to the expression of persistent HIV-related cognitive impairment among individuals receiving combination antiretroviral therapy (cART). HIV+ individuals (n = 111) averaged 48.2 (14.9) years of age and 13.0 (2.7) years of education and HIV- individuals (n = 92) averaged 34.9 (17.2) years of age and 13.5 (1.9) years of education. Participants completed a neuropsychological battery and a clinically validated measure of effort (Test of Memory Malingering, trial 1). Results revealed that the vast majority of HIV+ (85%) and HIV- (89%) individuals performed above published guidelines for adequate effort. Furthermore, the expression of cognitive impairment in HIV was not related to effort performance. The results were unchanged when examining HIV+ individuals with and without viral suppression. Finally, disability and disability-seeking status, and a proxy measure of apathy did not correspond to effort levels in HIV+ individuals. These findings suggest that variability in the expression of cognitive impairment in the cART era is unlikely to represent overt effort failures or other confounds unrelated to the disease. Persistent cognitive impairment in HIV likely represents historical and/or ongoing disease mechanisms despite otherwise successful treatment.

Prior research has suggested benefits of aerobic physical activity (PA) on cognition and brain volumes in HIV uninfected (HIV-) individuals, however, few studies have explored the relationships between PA and brain integrity (cognition and structural brain volumes) in HIV-infected (HIV+) individuals. Seventy HIV+ individuals underwent neuropsychological testing, structural neuroimaging, laboratory tests, and completed a PA questionnaire, recalling participation in walking, running, and jogging activities over the last year. A PA engagement score of weekly metabolic equivalent (MET) hr of activity was calculated using a compendium of PAs. HIV+ individuals were classified as physically active (any energy expended above resting expenditure, n=22) or sedentary (n=48). Comparisons of neuropsychological performance, grouped by executive and motor domains, and brain volumes were completed between groups. Physically active and sedentary HIV+ individuals had similar demographic and laboratory values, but the active group had higher education (14.0 vs. 12.6 years, p=.034). Physically active HIV+ individuals performed better on executive (p=.040, unadjusted; p=.043, adjusted) but not motor function (p=.17). In addition, among the physically active group the amount of physical activity (METs) positively correlated with executive (Pearson's r=0.45, p=0.035) but not motor (r=0.21; p=.35) performance. In adjusted analyses the physically active HIV+ individuals had larger putamen volumes (p=.019). A positive relationship exists between PA and brain integrity in HIV+ individuals. Results from the present study emphasize the importance to conduct longitudinal interventional investigation to determine if PA improves brain integrity in HIV+ individuals.

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. [ABSTRACT FROM AUTHOR]

Background While antiretroviral therapy (ART) has improved outcomes for people with HIV (PWH), brain dysfunction is still evident. Immune activation and inflammation remain elevated in PWH receiving ART, thereby contributing to morbidity and mortality. Previous studies demonstrated reduced functional and structural changes in PWH; however, underlying mechanisms remain elusive. Methods Our cohort consisted of PWH with ART adherence and viral suppression (< 50 copies/mL; N = 173). Measurements included immune cell markers of overall immune health (CD4/CD8 T-cell ratio) and myeloid inflammation (CD16+ monocytes), plasma markers of inflammatory status (soluble CD163 and CD14), and structural and functional neuroimaging (volume and cerebral blood flow [CBF], respectively). Results Decreased CD4/CD8 ratios correlated with reduced brain volume, and higher levels of inflammatory CD16+ monocytes were associated with reduced brain volume in total cortex and gray matter. An increase in plasma soluble CD14—a marker of acute peripheral inflammation attributed to circulating microbial products—was associated with reduced CBF within the frontal, parietal, temporal, and occipital cortices and total gray matter. Conclusions CD4/CD8 ratio and number of CD16+ monocytes, which are chronic immune cell markers, are associated with volumetric loss in the brain. Additionally, this study shows a potential new association between plasma soluble CD14 and CBF. [ABSTRACT FROM AUTHOR]

Before the introduction of antiretroviral therapy, human immunodeficiency virus (HIV) infection was often accompanied by central nervous system (CNS) opportunistic infections and HIV encephalopathy marked by profound structural and functional alterations detectable with neuroimaging. Treatment with antiretroviral therapy nearly eliminated CNS opportunistic infections, while neuropsychiatric impairment and peripheral nerve and organ damage have persisted among virally suppressed people with HIV (PWH), suggesting ongoing brain injury. Neuroimaging research must use methods sensitive for detecting subtle HIV-associated brain structural and functional abnormalities, while allowing for adjustments for potential confounders, such as age, sex, substance use, hepatitis C coinfection, cardiovascular risk, and others. Here, we review existing and emerging neuroimaging tools that demonstrated promise in detecting markers of HIV-associated brain pathology and explore strategies to study the impact of potential confounding factors on these brain measures. We emphasize neuroimaging approaches that may be used in parallel to gather complementary information, allowing efficient detection and interpretation of altered brain structure and function associated with suboptimal clinical outcomes among virally suppressed PWH. We examine the advantages of each imaging modality and systematic approaches in study design and analysis. We also consider advantages of combining experimental and statistical control techniques to improve sensitivity and specificity of biotype identification and explore the costs and benefits of aggregating data from multiple studies to achieve larger sample sizes, enabling use of emerging methods for combining and analyzing large, multifaceted data sets. Many of the topics addressed in this article were discussed at the National Institute of Mental Health meeting "Biotypes of CNS Complications in People Living with HIV," held in October 2021, and are part of ongoing research initiatives to define the role of neuroimaging in emerging alternative approaches to identifying biotypes of CNS complications in PWH. An outcome of these considerations may be the development of a common neuroimaging protocol available for researchers to use in future studies examining neurological changes in the brains of PWH. [ABSTRACT FROM AUTHOR]

Background With implementation of combination antiretroviral therapy (cART), changes to brain integrity in people with HIV (PWH) are subtle compared to those observed in the pre-cART era. T1-weighted/T2-weighted (T1w/T2w) ratio has been proposed as a measure of cortical myelin. This study examines T1w/T2w values between virologically controlled PWH and persons without HIV (PWoH). Methods Virologically well-controlled PWH (n = 164) and PWoH (n = 120) were compared on global and regional T1w/T2w values. T1w/T2w values were associated with HIV disease variables (nadir and current CD4 T-cell count, and CNS penetration effectiveness of cART regimen) in PWH, and as a function of age for both PWoH and PWH. Results PWH had reduced global and regional T1w/T2w values compared to PWoH in the posterior cingulate cortex, caudal anterior cingulate cortex, and insula. T1w/T2w values did not correlate with HIV variables except for a negative relationship with CNS penetration effectiveness. Greater cardiovascular disease risk and older age were associated with lower T1w/T2w values only for PWH. Conclusions T1w/T2w values obtained from commonly acquired MRI protocols differentiates virologically well-controlled PWH from PWoH. Changes in T1w/T2w ratio do not correlate with typical HIV measures. Future studies are needed to determine the biological mechanisms underlying this measure. [ABSTRACT FROM AUTHOR]

Background: Persons with HIV (PWH) undergo white matter changes, which can be quantified using the brain-age gap (BAG), the difference between chronological age and neuroimaging-based brain-predicted age. Accumulation of microstructural damage may be accelerated in PWH, especially with detectable viral load (VL).Methods: In total, 290 PWH (85% with undetectable VL) and 165 HIV-negative controls participated in neuroimaging and cognitive testing. BAG was measured using a Gaussian process regression model trained to predict age from diffusion magnetic resonance imaging in publicly available normative controls. To test for accelerated aging, BAG was modeled as an age × VL interaction. The relationship between BAG and global neuropsychological performance was examined. Other potential predictors of pathological aging were investigated in an exploratory analysis.Results: Age and detectable VL had a significant interactive effect: PWH with detectable VL accumulated +1.5 years BAG/decade versus HIV-negative controls (P = .018). PWH with undetectable VL accumulated +0.86 years BAG/decade, although this did not reach statistical significance (P = .052). BAG was associated with poorer global cognition only in PWH with detectable VL (P < .001). Exploratory analysis identified Framingham cardiovascular risk as an additional predictor of pathological aging (P = .027).Conclusions: Aging with detectable HIV and cardiovascular disease may lead to white matter pathology and contribute to cognitive impairment. [ABSTRACT FROM AUTHOR]

Objective: To examine whether the revised Veterans Aging Cohort Study (VACS2.0) index [including serum albumin, body mass index, and white blood cell count] had stronger correlations with cognitive function, brain volume, and frailty in persons with HIV (PWHs) $50 years compared with the VACS1.0. Design and methods: Neuropsychological performance (NP) Z-scores (learning, retention, executive functioning, psychomotor function/processing speed, language, and global cognition), and neuroimaging measures (brain volumetrics) were analyzed in PWHs (n = 162). A subset of the sample (n = 159) was defined as either frail (n = 18) or nonfrail (n = 141) according to the Fried phenotype criteria. Brain volumes, NP scores, and frailty subgroups were analyzed with VACS scores, albumin, body mass index, and white blood cell count using Pearson significance tests and independent T tests. Results: Higher VACS scores significantly correlated with lower brain volumes. Higher VACS2.0 scores were associated with lower NP in the executive functioning and psychomotor function/ processing speed domains and were primarily driven by albumin. VACS1.0 scores did not correlate with cognition Z-scores. There was no relationship between frailty status and VACS1.0. PWHs who were frail had significantly greater VACS2.0 scores than nonfrail PWHs. Conclusions: The addition of albumin to the VACS index improved its correlations with NP and frailty in PWHs. While low albumin levels may contribute to cognitive decline or frailty, the reverse causality should also be considered. These findings suggest that the VACS2.0 index (especially albumin) is a valuable measure for clinicians to improve outcomes in PWHs. [ABSTRACT FROM AUTHOR]

Keywords: HIV; central nervous system; cognition; mental health EN HIV central nervous system cognition mental health S1 S2 2 03/27/23 20230316 NES 230316 Central nervous system (CNS) complications are highly prevalent, heterogeneous conditions among people with human immunodeficiency virus (HIV) (PWH) receiving modern suppressive antiretroviral therapy. I B Supplement sponsorship. b i This article appears as part of the supplement "State of the Science of Central Nervous System Complications in People With HIV", sponsored by the National Institutes of Health, National Institute of Mental Health. [Extracted from the article]

Human immunodeficiency virus (HIV) enters the brain soon after seroconversion and can cause HIV-associated neurocognitive disorders (HAND). Although the more severe and progressive forms of HAND are less prevalent due to combination antiretroviral therapy (cART), ~40% of HIV-infected (HIV+) patients continue to have cognitive impairment. Some HIV+ individuals who have effective plasma HIV-1 RNA suppression with cART still develop HAND. It is often difficult to diagnose HAND in the outpatient setting as detailed neuropsychological performance testing is required. Additional biomarkers that are relatively easy to obtain and clinically relevant are needed for assessing HIV-associated neuropathologic changes. Recently developed noninvasive magnetic resonance imaging (MRI) techniques have great potential to serve as biomarkers. The authors review the application of some of these neuroimaging techniques, magnetic resonance spectroscopy (MRS), volumetric MRI, diffusion tensor imaging (DTI), functional MRI (fMRI), in HIV+ individuals. Each of the neuroimaging methods offers unique insight into mechanisms underlying neuro HIV, could monitor disease progression, and may assist in evaluating the efficacy of particular cART regimens. It is hoped that considerable progress will continue to occur such that some of these neuroimaging methods will be incorporated across multiple sites and included in future HAND guidelines. [ABSTRACT FROM AUTHOR]

Neurocognitive impairment remains prevalent in HIV-infected (HIV+) individuals despite highly active antiretroviral therapy (HAART). We assessed the impact of HIV, HAART, and aging using structural neuroimaging.Seventy-eight participants [HIV- (n = 26), HIV+ on stable HAART (HIV+/HAART+; n = 26), HIV+ naive to HAART (HIV+/HAART-; n = 26)] completed neuroimaging and neuropsychological testing. A subset of HIV+ subjects (n = 12) performed longitudinal assessments before and after initiating HAART. Neuropsychological tests evaluated memory, psychomotor speed, and executive function, and a composite neuropsychological score was calculated based on normalized performances (neuropsychological summary Z score, NPZ-4). Volumetrics were evaluated for the amygdala, caudate, thalamus, hippocampus, putamen, corpus callosum, and cerebral gray and white matter. A 3-group 1-way analysis of variance assessed differences in neuroimaging and neuropsychological indices. Correlations were examined between NPZ-4 and volumetrics. Exploratory testing using a broken-stick regression model evaluated self-reported duration of HIV infection on brain structure.HIV+ individuals had significant reductions in brain volumetrics within select subcortical regions (amygdala, caudate, and corpus callosum) compared with HIV- participants. However, HAART did not affect brain structure as regional volumes were similar for HIV+/HAART- and HIV+/HAART+. No association existed between NPZ-4 and volumetrics. HIV and aging were independently associated with volumetric reductions. Exploratory analyses suggest caudate atrophy due to HIV slowly occurs after self-reported seroconversion.HIV associated volumetric reductions within the amygdala, caudate, and corpus callosum occurs despite HAART. A gradual decline in caudate volume occurs after self-reported seroconversion. HIV and aging independently increase brain vulnerability. Additional longitudinal structural magnetic resonance imaging studies, especially within older HIV+ participants, are required. [ABSTRACT FROM AUTHOR]

Background: Integrase inhibitors (INSTIs) have been associated with poorer cognition in people with HIV (PWH). We examined the impact of switching to INSTIs on neuropsychological (NP) outcomes in PWH 40 years of age and older. Methods: From the AIDS Clinical Trials Group observational cohort study, HAILO, we identified PWH who switched to INSTIs, had $2 NP assessments before and at least 1 after switch, and maintained viral suppression while on INSTIs. NP performance was assessed with a composite score (NPZ4) including Hopkins Verbal Learning Test (HVLT-R), Digit Symbol test (DSY), Trail Making A, and Trail Making B, while adjusting for covariates and learning effects. Outcomes changes from preswitch and postswitch periods were estimated using piecewise linear mixed models. Results: Among 395 PWH (mean age 54 years, 81% male, 20% Hispanic, and 29% Black) NPZ4 increased preswitch and postswitch. There was no difference in slopes between periods for NPZ4 [preswitch 0.036/year (95% CI: 0.03 to 0.043); postswitch 0.022/year (95% CI: 0.006 to 0.005); P = 0.147]. All tests scores improved preswitch (P, 0.01). Postswitch, Trail Making A and DSY increased (all P, 0.01) without differences in rate of change (all P . 0.05). HVLT-R had a nonsignificant decrease postswitch (P = 0.22), resulting in a significant preswitch vs postswitch difference in slopes (P = 0.03). Conclusions: NP performance improved regardless of INSTI use. There was an attenuation of improvement in verbal memory in the Post-switch vs preswitch period. The clinical significance of these changes is unclear but, overall, INSTIs did not have a consistent detrimental effect on NP outcomes. [ABSTRACT FROM AUTHOR]

Background: Cardiometabolic and cerebrovascular disease are strong independent contributors to cognitive impairment in people living with HIV. Data suggest that cardiovascular risk may play a greater role in cognitive health in women than in men with HIV. Methods: We performed a cross-sectional study of 104 participants with virologically suppressed HIV from 2 clinics in urban China. Participants underwent neuropsychological testing from which we calculated T scores globally and in 5 cognitive domains. We assessed cerebral vasoreactivity of the middle cerebral arteries in response to breath holding. We constructed linear regression models to determine associations between cerebrovascular and cognitive function overall and stratified by sex. Results: Women were younger than men (48 versus 51 years, P = 0.053), had fewer years of education (9 years versus 12 years, P = 0.004), and fewer cardiometabolic risk factors (0 versus 1 factor, P = 0.008). In a model with all participants, cerebrovascular function was significantly associated with global cognition (2.74 higher T score per 1-point higher cerebral vasoreactivity [SE 1.30], P = 0.037). Cerebrovascular function remained significantly associated with global cognition among women (4.15 higher T score [SE 1.78], P = 0.028) but not men (1.70 higher T score [SE 1.74], P = 0.33). The relationships between cerebrovascular function and specific cognitive domains followed a similar pattern, with significant associations present among women but not men. Conclusions: Women with well-controlled HIV may be more vulnerable to the effect of cerebrovascular injury on cognitive health than men. Studies evaluating strategies to protect against cognitive impairment in people living with HIV should include adequate representation of women and stratification of analyses by sex. [ABSTRACT FROM AUTHOR]

Background: Despite improved survival rates, neurocognitive impairment persists in persons living with HIV (PLWH). An active lifestyle is linked to improved cognition among PLWH, yet the neural substrates remain unclear. Diffusion tensor imaging and diffusion basis spectrum imaging measure HIV-related changes in brain white matter integrity. We used these measures of structural brain integrity to assess white matter changes, physical fitness, and cognition in a cross-sectional study of PLWH. Methods: Forty-four virologically well-controlled PLWH were recruited (average age of 56 years, a median recent CD4+ count of 682 cells/mm3). Diffusion tensor imaging -derived fractional anisotropy (FA) and diffusion basis spectrum imaging-derived axonal density were calculated. Cardiorespiratory fitness [maximal volume of oxygen consumption (VO2 max)] was measured by performing indirect calorimetry during exercise to volitional exhaustion. Cardiovascular risk was assessed by the Framingham risk score. Neuropsychological performance (NP) testing evaluated learning, memory, psychomotor/processing speed, and executive function. Partial correlations assessed the relationships among cardiorespiratory fitness, neuroimaging, NP, and HIV clinical metrics (CD4+ count and time since diagnosis). Results: Higher VO2 max was associated with higher FA and higher axonal density in multiple white matter tracts, including the corticospinal tract and superior longitudinal fasciculus. Better NP in the motor/psychomotor domain was positively associated with FA and axonal density in diverse tracts including those associated with motor and visuospatial processing. However, higher VO2 max was not associated with NP or HIV clinical metrics. Conclusions: An active lifestyle promoting cardiorespiratory fitness may lead to better white matter integrity and decreased susceptibility to cognitive decline in virologically well-controlled PLWH. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is Available in the Text. Background: The relationship between HIV infection, the functional organization of the brain, cognitive impairment, and aging remains poorly understood. Understanding disease progression over the life span is vital for the care of people living with HIV (PLWH). Setting: Virologically suppressed PLWH (n = 297) on combination antiretroviral therapy and 1509 HIV-uninfected healthy controls were evaluated. PLWH were further classified as cognitively normal (CN) or cognitively impaired (CI) based on neuropsychological testing. Methods: Feature selection identified resting-state networks (RSNs) that predicted HIV status and cognitive status within specific age bins (younger than 35 years, 35–55 years, and older than 55 years). Deep learning models generated voxelwise maps of RSNs to identify regional differences. Results: Salience (SAL) and parietal memory networks (PMNs) differentiated individuals by HIV status. When comparing controls with PLWH CN, the PMN and SAL had the strongest predictive strength across all ages. When comparing controls with PLWH CI, the SAL, PMN, and frontal parietal network (FPN) were the best predictors. When comparing PLWH CN with PLWH CI, the SAL, FPN, basal ganglia, and ventral attention were the strongest predictors. Only minor variability in predictive strength was observed with aging. Anatomically, differences in RSN topology occurred primarily in the dorsal and rostral lateral prefrontal cortex, cingulate, and caudate. Conclusion: Machine learning identified RSNs that classified individuals by HIV status and cognitive status. The PMN and SAL were sensitive for discriminating HIV status, with involvement of FPN occurring with cognitive impairment. Minor differences in RSN predictive strength were observed by age. These results suggest that specific RSNs are affected by HIV, aging, and HIV-associated cognitive impairment. [ABSTRACT FROM AUTHOR]

Objective: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH. Design: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV2) controls completed TSPO-PET imaging using the radiotracer [11C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [11C] PBR28 binding. Methods: [11C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV2 controls. Pearson correlation evaluated the association between [11C]PBR28 binding and cognition and clinical measures of HIV. Results: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [11C]PBR28 binding in PLWH compared with HIV2 controls. In addition, [11C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [11C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [11C] PBR28 binding in PLWH. Conclusions: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV2 controls. [ABSTRACT FROM AUTHOR]

Background: Frailty is an important clinical concern for the aging population of people living with HIV (PLWH). The objective of this study was to identify the combination of risk features that distinguish frail from nonfrail individuals. Setting: Machine learning analysis of highly dimensional risk features was performed on a clinical cohort of PLWH. Methods: Participants included 105 older (average age = 55.6) PLWH, with at least a 3-month history of combination antiretroviral therapy (median CD4 = 546). Predictors included demographics, HIV clinical markers, comorbid health conditions, cognition, and neuroimaging (ie, volumetrics, resting-state functional connectivity, and cerebral blood flow). Gradient-boosted multivariate regressions were implemented to establish linear and interactive classification models. Model performance was determined by sensitivity/specificity (F1 score) with 5-fold cross validation. Results: The linear gradient-boosted multivariate regression classifier included lower current CD4 count, lower psychomotor performance, and multiple neuroimaging indices (volumes, network connectivity, and blood flow) in visual and motor brain systems (F1 score = 71%; precision = 84%; and sensitivity = 66%). The interactive model identified novel synergies between neuroimaging features, female sex, symptoms of depression, and current CD4 count. Conclusions: Data-driven algorithms built from highly dimensional clinical and brain imaging features implicate disruption to the visuomotor system in older PLWH designated as frail individuals. Interactions between lower CD4 count, female sex, depressive symptoms, and neuroimaging features suggest potentiation of risk mechanisms. Longitudinal data-driven studies are needed to guide clinical strategies capable of preventing the development of frailty as PLWH reach advanced age. [ABSTRACT FROM AUTHOR]

Background: Deep learning algorithms of cerebral blood flow were used to classify cognitive impairment and frailty in people living with HIV (PLWH). Feature extraction techniques identified brain regions that were the strongest predictors. Setting: Virologically suppressed (< 50 copies/mL) PLWH (n = 125) on combination antiretroviral therapy were enrolled. Participants averaged 51.4 (11.4) years of age and 13.7 (2.8) years of education. Participants were administered a neuropsychological battery, assessed for frailty, and completed structural neuroimaging. Methods: Deep neural network (DNN) models were trained to classify PLWH as cognitively unimpaired or impaired based on neuropsychological tests (Hopkins Verbal Learning Test-Revised and Brief Visuospatial Memory Test-Revised, Trail making, Letter-Number Sequencing, Verbal Fluency, and Color Word Interference), as well as frail, prefrail, or nonfrail based on the Fried phenotype criteria (at least 3 of the following 5: weight loss, physical inactivity, exhaustion, grip strength, walking time). Results: DNNs classified individuals with cognitive impairment in the learning, memory, and executive domains with 82%-86% accuracy (0.81-0.87 AUC). Our model classified nonfrail, prefrail, and frail PLWH with 75% accuracy. The strongest predictors of cognitive impairment were cortical (parietal, occipital, and temporal) and subcortical (amygdala, caudate, and hippocampus) regions, whereas the strongest predictors of frailty were subcortical (amygdala, caudate, hippocampus, thalamus, pallidum, and cerebellum). Conclusions: DNN models achieved high accuracy in classifying cognitive impairment and frailty status in PLWH. Feature selection algorithms identified predictive regions in each domain and identified overlapping regions between cognitive impairment and frailty. Our results suggest frailty in HIV is primarily subcortical, whereas cognitive impairment in HIV involves subcortical and cortical brain regions. [ABSTRACT FROM AUTHOR]

Objectives: Studies of HIV-associated brain atrophy often focus on a priori brain regions of interest, which can introduce bias. A datadriven, minimally biased approach was used to analyze changes in brain volumetrics associated with HIV and their relationship to aging, viral factors, combination antiretroviral therapy (cART), and gender, and smoking. Design: A cross-sectional study of 51 HIV-uninfected (HIV2) and 146 HIV-infected (HIV+) participants. Methods: Structural MRI of participants was analyzed using principal component analysis (PCA) to reduce dimensionality and determine topographies of volumetric changes. Neuropsychological (NP) assessment was examined using global and domain-specific scores. The effects of HIV disease factors (eg, viral load, CD4, etc.) on brain volumes and neuropsychological were investigated using penalized regression (LASSO). Results: Two components of interest were visualized using principal component analysis. An aging effect predominated for both components. The first component, a cortically weighted topography, accounted for a majority of variance across participants (43.5% of variance) and showed independent effects of HIV and smoking. A secondary, subcortically weighted topography (4.6%) showed HIV-status accentuated age-related volume loss. In HIV+ patients, the cortical topography correlated with global neuropsychological scores and nadir CD4, whereas subcortical volume loss was associated with recent viral load. Conclusions: Cortical regions showed the most prominent volumetric changes because of aging and HIV. Within HIV+ participants, cortical volumes were associated with immune history, whereas subcortical changes correlated with current immune function. Cognitive function was primarily associated with cortical volume changes. Observed volumetric changes in chronic HIV+ patients may reflect both past infection history and current viral status. [ABSTRACT FROM AUTHOR]

The symptom burden of HIV-associated neurocognitive disorder (HAND) is high among older individuals, and treatment options are limited. Mindfulness-based stress reduction (MBSR) has potential to improve neurocognitive performance, psychosocial wellbeing, and quality of life, but empirical studies in this growing vulnerable population are lacking. In this trial, participants (N = 180) age 55 and older who are living with HIV infection, are on combination antiretroviral therapy with suppressed viral loads, and yet continue to experience behavioral and cognitive symptoms of HAND, are randomized to MBSR or to a waitlist control arm that receives MBSR following a 16-week period of standard care. Primary outcomes (attention, executive function, stress, anxiety, depression, everyday functioning, quality of life) and potential mediators (affect, mindfulness) and moderators (social support, loneliness) are assessed at baseline and weeks 8, 16, and 48 in both groups, with an additional assessment at week 24 (post-MBSR) in the crossover control group. Assessments include self-report and objective measures (e.g., neuropsychological assessment, neurological exam, clinical labs). In addition, a subset of participants (n = 30 per group) are randomly selected to undergo fMRI to evaluate changes in functional connectivity networks and their relationship to changes in neuropsychological outcomes. Forthcoming findings from this randomized controlled trial have the potential to contribute to a growing public health need as the number of older adults with HAND is expected to rise [ABSTRACT FROM AUTHOR]