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Nearly 40% of people with HIV (PWH) experience HIV-associated Neurocognitive Disorder (HAND). In this 3-group efficacy study, 216 PWH 40 + years with HAND or borderline HAND were randomized to either: (1) 10 h of SOP training (n = 70); (2) 20 h of SOP training (n = 73), or (3) 10 h of Internet navigation training (n = 73; contact control group). Participants were administered a measure of SOP [i.e., the Useful Field of View Test (UFOV®)] at baseline, at posttest immediately after training, and at year 1 and year 2 follow up. Intent-to-treat linear mixed-effect models with subject-specific intercept and slope were fitted to estimate between-group mean differences at the follow-up time-points. At the post-intervention time-point, small beneficial SOP training effects were observed for the 10-h group in UFOV® total (d = 0.28, p = 0.002). Effects were of larger magnitude for the 20-h group in these same outcomes [UFOV® total (d = 0.43, p < 0.001)]. These results indicated better benefit with more training. No intervention effect was observed at year 1. At year 2, beneficial effects of small magnitude were observed again in the 10-h group [UFOV® total (d = 0.22, p = 0.253)] with larger small-to-moderate magnitude in the 20-h group [UFOV® total (d = 0.32, p = 0.104)]. This study suggests that SOP training can improve a key indicator of this cognitive performance and that treatment gains are small-to-moderate over a two-year period. Prior literature suggests slower SOP is predictive of impairment in everyday functioning in older PWH; such an approach could potentially improve everyday functioning in PWH., (© 2024. The Author(s).)

Human immunodeficiency virus-associated neurocognitive disorders persist in the combination antiretroviral therapy era. CD4 nadir is a well-established predictor of cognition cross-sectionally, but its impact on longitudinal neurocognitive (NC) trajectories is unclear. The few studies on this topic examined trajectories of global cognition, rather than specific NC domains. The current study examined CD4 nadir in relation to domain-specific NC decline. 132 HIV + adults from the Temple/Drexel Comprehensive NeuroHIV Center, Clinical and Translational Research Support Core Cohort were administered comprehensive NC assessments longitudinally, with last visit occurring an average of 12 years after CD4 nadir. Linear mixed models were used to examine CD4 nadir in relation to longitudinal NC trajectories in three empirically identified NC domains: speed/executive function (S/EF), visuospatial memory (VM), and verbal fluency (VF). CD4 nadir was associated with change in VF (p = 0.020), but not with S/EF or VM. Specifically, those with CD4 nadir < 200 demonstrated increasing VF over time (p = .002), whereas those with CD4 nadir > 200 demonstrated stable VF (p = .568), though these differing trajectories may partly reflect regression to the mean or differential practice effect. CD4 dynamics over time were analyzed as potential mechanisms for the identified associations, with mixed findings. While low CD4 nadir has been associated with weaker neurocognition among people living with HIV, the results of this study suggest that low CD4 nadir is not associated with ongoing decline a decade later. Nadir-related deficits in VF may be stable or even improve over time, possibly reflecting the beneficial cognitive effects of long-term treatment and immune reconstitution., (© 2024. The Author(s).)

Since the identification of human immunodeficiency virus type 1 (HIV-1) in 1983, many improvements have been made to control viral replication in the peripheral blood and to treat opportunistic infections. This has increased life expectancy but also the incidence of age-related central nervous system (CNS) disorders and HIV-associated neurodegeneration/neurocognitive impairment and depression collectively referred to as HIV-associated neurocognitive disorders (HAND). HAND encompasses a spectrum of different clinical presentations ranging from milder forms such as asymptomatic neurocognitive impairment or mild neurocognitive disorder to a severe HIV-associated dementia (HAD). Although control of viral replication and suppression of plasma viral load with combination antiretroviral therapy has reduced the incidence of HAD, it has not reversed milder forms of HAND. The objective of this review, is to describe the mechanisms by which HIV-1 invades and disseminates in the CNS, a crucial event leading to HAND. The review will present the evidence that underlies the relationship between HIV infection and HAND. Additionally, recent findings explaining the role of neuroinflammation in the pathogenesis of HAND will be discussed, along with prospects for treatment and control., (© 2024 The Authors. Reviews in Medical Virology published by John Wiley & Sons Ltd.)

Although a significant amount of biomedical research has been conducted to study HIV-associated neurocognitive disorder (HAND), there has been scant research done to assess the awareness and knowledge of this public health concern among middle-aged and older people living with HIV/AIDS (PLWH). Our qualitative community-based participatory research study sought to address this research gap by examining the awareness and knowledge of HAND among relevant stakeholders in southern Nevada, USA. We conducted 15 semistructured interviews with middle-aged and older PLWH to examine their awareness and knowledge of HAND and access to pertinent resources. After our thematic analysis of our interviews, we identified two overarching themes: (1) limited awareness and knowledge of HAND among PLWH, and (2) southern Nevada social determinants of health. Our findings underscore the importance of raising awareness and knowledge of HAND among PLWH through community-based education programs, and improving access to resources related to social determinants of health.

Abstract: Speed of processing (SOP) cognitive training may improve indicators of the quality of life (QoL) in people living with HIV. In this 2-year, longitudinal, randomized, controlled trial, 216 participants ages 40 years and older with HIV-associated neurocognitive disorder or borderline HIV-associated neurocognitive disorder were assigned to one of three groups: (a) 10 hr of SOP training (n = 70); (b) 20 hr of SOP training (n = 73), or (c) 10 hr of internet navigation control training (a contact control group; n = 73). Participants completed several QoL measures at baseline, posttest, and Year 1 and Year 2 follow-ups. Using linear mixed-effect models, no strong pattern of training effects across QoL outcomes was apparent, with small-magnitude, nonsignificant, between-group differences in depression, locus of control, and Medical Outcomes Study-HIV scales. In conclusion, despite prior work showing some transfer of SOP cognitive training improving QoL, that was not observed. Implications for research and practice are posited., (Copyright © 2024 Association of Nurses in AIDS Care.)

There are many obstacles to screening for HIV-associated neurocognitive disorders (HAND), including the influence of various sociodemographic effects on screening measures. This study examined possible racial bias on the HIV Dementia Scale (HDS) in screening for HAND among 39 Black and 84 White persons living with HIV (PLWH). Black PLWH had significantly lower raw HDS scores than White PLWH, which was mediated by lower oral word reading scores. Nevertheless, HDS scores were comparably predictive of clinical HAND diagnoses for Black and White PLWH as determined by a comprehensive battery; overall, individuals who failed the HDS were three times as likely to have HAND as compared to those who performed within normal limits (sensitivity = .26, specificity = .94). Consistent with prior literature exploring race-group differences, findings suggest that lower scores among Black PLWH compared to White PLWH on a commonly-used screening measure for HAND are partly explained by reading scores, perhaps reflecting differences in educational quality and opportunities. However, race-group differences did not affect the classification accuracy of the HDS in detecting HAND, although overall diagnostic accuracy was modest in both groups. Future work should determine the optimal neurocognitive screening methods for Black PLWH and other under-represented ethnoracial groups.

Background: Despite medical advances in Highly Active Antiretroviral Therapy (HAART), patients living with HIV continue to be at risk for developing HIV-associated neurocognitive disorders (HAND). The optimization of non-HAART interventions, including cognitive rehabilitation therapy (CRT), shows promise in reversing the impact of HAND. No data exist indicating the efficacy of CRT in remediating attention skills following neuroHIV. This paper presents a meta-analysis of randomised and non-randomised controlled trials (RCTs) to remediate attention skills following HIV CRT. Methods: The database search included literature from Google Scholar, ERIC, Cochrane Library, ISI Web of Knowledge, PubMed, PsycINFO, and grey literature published between 2013 and 2022. Inclusion criteria included studies with participants living with HIV who had undergone CRT intervention to remediate attention skills following neuroHIV. Exclusion criteria included case studies, non-human studies, and literature reviews. To assess study quality, including, randomisation, allocation concealment, participant and personnel blinding, the Cochrane Collaboration ratings system was applied. Results: A total of 14 studies met the inclusion criteria (n = 532). There were significant pre- to post-intervention between-group benefits due to CRT in the experimental group relative to control conditions for the remediation of attention skills following HIV acquisition (Hedges g = 0.251, 95% CI = 0.005 to 0.497; p < 0.05). No significant effects (p > 0.05) were demonstrated for subgroup analysis. Conclusions: To the author's knowledge, this is the first meta-analysis that exclusively analyses the remediation of attention skills in the era of HAART and neuroHIV, where all studies included participants diagnosed with HIV. The overall meta-analysis effect indicates the efficacy of CRT in remediating attention skills in HIV and HAND. It is recommended that future cognitive rehabilitation protocols to remediate attention skills should be context and population-specific and that they be supplemented by objective biomarkers indicating the efficacy of the CRT. Registration: Protocols.io (01/03/2023)., Competing Interests: No competing interests were disclosed., (Copyright: © 2023 Zondo S.)

This study aimed to evaluate the prevalence and associated factors of HIV-associated dementia (HAD) in people living with HIV (PLWH) aged ≥ 60 years who are currently treated with highly active antiretroviral therapy. A cross-sectional study was conducted on adult (age ≥ 60 years) PLWH at the infectious clinic, Vajira Hospital, Navamindradhiraj University, Thailand, between August 2019 and March 2021. We collected the patients' characteristics and performed Montreal Cognitive Assessment and Instrumental Activities of Daily Living test to determine whether they have HIV-associated neurocognitive disorders (HAND), which we further classified into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HAD. Finally, we evaluated the prevalence, associated factors, and characteristics of cognitive domain abnormalities in these patients. We enrolled 84 elderly PLWH patients consisting of 43 (51.2%) males. The mean patient age was 63 years (SD ± 3.9), and the median duration of HIV infection was 13 (SD ± 5.7) years. All the patients had undetectable HIV viral load. Among them, seven (8.3%) had no neurocognitive impairment, 61 (72.6%) had ANI, three (3.6%) had MND, and 13 (15.5%) had HAD. After confounder adjustment, the patient age of ≥ 65 years was found to be significantly associated with dementia (odds ratio = 5.97, 95% CI: 1.51-23.57). Significant difference in the mean score of all cognitive domains was observed between the patients with HAD and those with normal cognitive status. HAND is common in PLWH. Age older than ≥ 65 years is a risk factor of HAD.

Objective: The neurological manifestations and their severity in patients on antiretroviral treatment (ART) are currently unexplained. ‎We aimed at studying the prevalence of HIV Associated Neurological Disorders (HAND) among people on antiretroviral treatment, using the International HIV Dementia Scale (IHDS)., Patients and Methods: A predesigned and pretested proforma including the International HIV Dementia Scale (IHDS) was administered to 100 HIV patients attending to ART center of KIMS teaching Hospital (Koppal, Karnataka) from January 2020 to March 2020. The data was analyzed SPSS version 15 software. Descriptive statistics were used for demographic characteristics. The Student's t-test and chi-square test methods were applied to determine the relationship between qualitative characteristics., Results: The prevalence was found to be 59%. Out of 100, 57 HIV patients scored less than 10 whereas 43 HIV patients scored ≥10 on the IHDS scale. The mean age of the study population was 39.14 ±13.01 years; the total IHDS score was 9.96±1.53 and the CD4 count was 427.91±226.0. This study demonstrated that the patients with CD4 count more than 350 (i.e., 63.60%) had a better IHDS score., Conclusions: Neurocognitive disorder was found to be more common than anticipated. All ICTC Centers need to consider assessing HIV-associated neurocognitive disability (HAND), and the International HIV Dementia Scale (IHDS) as one instrument for such assessment.

Background: Widespread introduction of early combination antiretroviral therapy (cART) for People Living with HIV (PLWH) will influence the burden, profile, and trajectory of HIV-associated neurocognitive disorders (HAND) in the 21st century., Objectives: To assess the prevalence and trajectory of HAND among PLWH in a Ghanaian tertiary medical center., Methods: We analyzed the dataset of a study involving PLWH established on cART (n = 256) and PLWH not initially on cART (n = 244). HIV-negative individuals (n = 246) served as normative controls for neurocognitive assessments. HAND was defined according to the Frascati criteria into asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia (HAD) at enrollment and at month 12. Multivariate logistic regression models were fitted to identify factors associated with HAND., Results: Among PLWH on cART, 21.5%, 3.5% and 0.0% had ANI, MND and HAD respectively compared with 20.1%, 9.8% and 2.0% among PLWH cART naïve, p < 0.0001. Overall, 71.6%, 20.8%, 6.6% and 1.0% had no cognitive impairment, ANI, MND and HAD at baseline. Among participants who completed month 12 follow-up, 55.2% had no cognitive impairment, 43.5%, 1.2%, 0.0% had ANI, MND and HAD respectively, p < 0.0001. Adjusted odds ratio (95% CI) of six independent predictors of HAND at month 12 were no education (3.29;1.81-6.00), stage 4 disease (4.64;1.37-15.69), hypertension (2.28;1.10-4.73), nevirapine use (2.05;1.04-4.05), baseline viral load (0.66;0.56-0.77), and cigarette use (0.10; 0.03-0.42)., Conclusion: Most Ghanaian patients in the post-cART era with HAND had mild neurocognitive impairments. The impact of hypertension on progression of HAND warrants further evaluation in our settings., (Copyright © 2021 Elsevier B.V. All rights reserved.)

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

HIV-associated neurocognitive disorders (HAND) are common features of the effect of human immunodeficiency virus (HIV)-1 within the central nervous system (CNS). The underlying neuropathophysiology of HAND is incompletely known. Furthermore, there are no markers to effectively predict or stratify the risk of HAND. Recent advancements in the fields of proteomics and metabolomics have shown promise in addressing these concerns, however, it is not clear if these approaches may provide new insight into pathways and markers related to HAND. We therefore conducted a systematic review of studies using proteomic and/or metabolomic approaches in the aim of identifying pathways or markers associated with neurocognitive impairment in people living with HIV (PLWH). Thirteen studies were eligible, including 11 proteomic and 2 metabolomic investigations of HIV-positive clinical samples (cerebrospinal fluid (CSF), brain tissue, and serum). Across varying profiling techniques and sample types, the majority of studies found an association of markers with neurocognitive function in PLWH. These included metabolic marker myo-inositol and proteomic markers superoxide dismutase, gelsolin, afamin, sphingomyelin, and ceramide. Certain markers were found to be dysregulated across various sample types. Afamin and gelsolin overlapped in studies of blood and CSF and sphingomyelin and ceramide overlapped in studies of CSF and brain tissue. The association of these markers with neurocognitive functioning may indicate the activity of certain pathways, potentially those related to the underlying neuropathophysiology of HAND., (© 2021 International Society for Neurochemistry.)

Background: The screening strategy for HIV-Associated Neurocognitive Disorders (HAND) is challenging. The French Expert Report recommend the use of the Cognitive Complaints Questionnaire (QPC) and the Montreal Cognitive assessment. However, the QPC has never been studied in People Living with HIV (PLWH). This study aims to determine the degree of agreement between QPC and the presence of HAND according to Frascati criteria, established by a battery of neuropsychological tests., Methods: Data from patients who performed both a QPC and a battery of neuropsychological tests over a six-month follow-up period were evaluated retrospectively., Results: A total of 121 patients were selected, with a median age of 53.1 years old. Among participants, 92.6% had an undetectable plasma viral load, 49.6% had a nadir CD4 less than 200/mm 3 and 23.1% had a CDC stage C. Median CD4 cell count was 686/mm 3 . Prevalence of HAND was 57%, including 28.9% of Asymptomatic Neurocognitive Impairment, 24.8% of Mild Neurocognitive Disorder and 3.3% of HIV-associated Dementia. This analyze shows no agreement between QPC and HIV-associated neurocognitive disorders (kappa = -0.007)., Conclusions: The QPC is not relevant in the screening for HAND. Thus, it urges to develop a specific tool to assess cognitive complaints among PLWH.

The fronto-striatal circuitry, involving the nucleus accumbens, ventral tegmental area, and prefrontal cortex, mediates goal-directed behavior and is targeted by both drugs of abuse and HIV-1 infection. Acutely, both drugs and HIV-1 provoke increased dopamine activity within the circuit. However, chronic exposure to drugs or HIV-1 leads to dysregulation of the dopamine system as a result of fronto-striatal adaptations to oppose the effects of repeated instances of transiently increased dopamine. Specifically, chronic drug use leads to reduced dopaminergic tone, upregulation of dopamine transporters, and altered circuit connectivity, sending users into an allosteric state in which goal-directed behaviors are dysregulated (i.e., addiction). Similarly, chronic exposure to HIV-1, even with combination antiretroviral therapy (cART), dysregulates dopamine and dopamine transporter function and alters connectivity of the fronto-striatal circuit, contributing to apathy and clinical symptoms of HIV-1 associated neurocognitive disorders (HAND). Thus, in a drug user also exposed to HIV-1, dysregulation of the fronto-striatal dopamine circuit advances at an exacerbated rate and appears to be driven by mechanisms unique from those seen with chronic drug use or HIV-1 exposure alone. We posit that the effects of drug use and HIV-1 infection on microglia interact to drive the progression of motivational dysfunction at an accelerated rate. The current review will therefore explore how the fronto-striatal circuit adapts to drug use (using cocaine as an example), HIV-1 infection, and both together; emphasizing proper methods and providing future directions to develop treatments for pathologies disrupting goal-directed behaviors and improve clinical outcomes for affected patients. Graphical Abstract Drug use and HIV-1 in the fronto-striatal circuit. Drugs of abuse and HIV-1 infection both target the fronto-striatal circuit which mediates goal-directed behavior. Acutely, drugs and HIV-1 increase dopamine activity; in contrast chronic exposure produces circuit adaptions leading to dysregulation, addiction and/or apathy. Comorbid drug use and HIV-1 infection may interact with microglia to exacerbate motivational dysregulation.

The persistence of HIV-1 associated neurocognitive disorders (HAND) in the post-cART era, afflicting between 40 and 70% of HIV-1 seropositive individuals, supports a critical need for the development of adjunctive therapeutic treatments. Selective estrogen receptor β agonists, including S-Equol (SE), have been implicated as potential therapeutic targets for the treatment of neurocognitive disorders. In the present study, the therapeutic efficacy of 0.2 mg SE for the treatment of HAND was assessed to address two key questions in the HIV-1 transgenic (Tg) rat. First, does SE exhibit robust therapeutic efficacy when treatment is initiated relatively early (i.e., between 2 and 3 months of age) in the course of viral protein exposure? Second, does the therapeutic utility of SE generalize across multiple neurocognitive domains? Treatment with SE enhanced preattentive processes and stimulus-response learning to the level of controls in all (i.e., 100%) HIV-1 Tg animals. For sustained and selective attention, statistically significant effects were not observed in the overall analyses (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). However, given our a priori hypothesis, subsequent analyses were conducted, revealing enhanced sustained and selective attention, approximating controls, in a subset (i.e., 50%, n = 5 and 80%, n = 8, respectively) of HIV-1 Tg animals treated with SE. Thus, the therapeutic efficacy of SE is greater when treatment is initiated relatively early in the course of viral protein exposure and generalizes across neurocognitive domains, supporting an adjunctive therapeutic for HAND in the post-cART era. Graphical Abstract HIV-1 transgenic (Tg) and control animals were treated with either 0.2 mg S-Equol (SE) or placebo between 2 and 3 months of age (Control: Placebo, n = 10, SE, n = 10; HIV-1 Tg: Placebo, n = 10, SE, n = 10). Neurocognitive assessments, tapping preattentive processes, stimulus response learning, sustained attention and selective attention, were conducted to evaluate the utility of SE as a therapeutic for HIV-1 associated neurocognitive disorders (HAND). Planned comparisons between HIV-1 Tg and control animals treated with placebo were utilized to establish a genotype effect, revealing prominent neurocognitive impairments (NCI) in the HIV-1 Tg rat across all domains. Furthermore, to establish the utility of SE, HIV-1 Tg animals treated with SE were compared to control animals treated with placebo. Treatment with 0.2 mg SE ameliorated NCI, to levels that were indistinguishable from controls, in at least a subset (i.e., 50-100%) of HIV-1 Tg animals. Thus, SE supports an efficacious, adjunctive therapeutic for HAND.

Background: It is estimated that almost half of all people living with HIV have some form of neurocognitive impairment, but few studies have looked at the risk of neurocognitive impairment and its associated factors in Ghana, due in part to limited resources for such testing., Objectives: To examine neurocognitive performance in a group of Ghanaians living with HIV and possible factors that contribute to their performance., Methods: One hundred and four patients were assessed using a selection of brief non-invasive neuropsychological assessments as well as the International HIV Dementia Scale. Psycho-behavioural factors (alcohol use, depression, and medication adherence) as well as demographic characteristics and functional daily activities were assessed to determine their association with neurocognitive performance, using linear regression and receiver operating characteristic analyses., Result: About 48% of the participants met the criteria for risk of neurocognitive impairment. Age, education, and symptoms of depression were found to be significantly associated with the risk of impairment., Conclusion: Some people living with HIV showed risk of neurocognitive impairment, which was significantly associated with education, age and depressive symptoms. It is therefore important to consider routine neurocognitive screening in HIV management to recognize any risks for early interventions., (© 2020 Asiedu N et al.)

The HIV-1 transgenic (Tg) rat model is valuable for understanding HIV-associated neurocognitive disorders (HAND) and accompanying substance use and misuse. Tg and F344/NHsd wildtype (WT) rats were allowed to self-administer intrajugular cocaine. For the first 7 sessions, neither genotype self-administered cocaine (0.1 mg/kg/infusion) on a fixed ratio 1 schedule. We thus implemented a lever-cocaine "autoshaping" session followed by a series of manipulations changing dose and reinforcement schedule. Tg rats self-administered much less cocaine than WT rats throughout the study. Of 8 Tg rats, 5 modestly increased self-administration from sessions 36-50. Of those, only 3 showed a lever discrimination. Of 10 WT rats, 8 acquired robust self-administration by session 19; all WT rats self-administered cocaine by the end of the study. WT and Tg rats had similar baseline locomotor activity in the self-administration chamber suggesting that the low levels of cocaine intake in the Tg rats did not reflect a nonspecific motor impairment in this rat strain. Concomitant measurement of activity with self-administration revealed activity increases that followed increased cocaine intake. That relation held in Tg rats. Therefore, the present study provides evidence that HIV-1 Tg rats are less sensitive to the reinforcing effects of cocaine than their F344 WT counterparts., (© 2020 Society for the Experimental Analysis of Behavior.)

In the era of combined antiretroviral therapy, HIV-1 infected individuals are living longer lives; however, longevity is met with an increasing number of HIV-1 associated neurocognitive disorders (HAND) diagnoses. The transactivator of transcription (Tat) is known to mediate the neurotoxic effects in HAND by acting directly on neurons and also indirectly via its actions on glia. The Go/No-Go (GNG) task was used to examine HAND in the Tat transgenic mouse model. The GNG task involves subjects discriminating between two stimuli sets in order to determine whether or not to inhibit a previously trained response. Data reveal inhibitory control deficits in female Tat(+) mice (p = .048) and an upregulation of cannabinoid type 1 receptors (CB 1 R) in the infralimbic (IL) cortex in the same female Tat(+) group (p < .05). A significant negative correlation was noted between inhibitory control and IL CB 1 R expression (r = -.543, p = .045), with CB 1 R expression predicting 30% of the variance of inhibitory control (R 2  = .295, p = .045). Furthermore, there was a significant increase in spontaneous excitatory postsynaptic current (sEPSC) frequencies in Tat(+) compared to Tat(-) mice (p = .008, across sexes). The increase in sEPSC frequency was significantly attenuated by bath application of PF3845, a fatty acid amide hydrolase (FAAH) enzyme inhibitor (p < .001). Overall, the GNG task is a viable measure to assess inhibitory control deficits in Tat transgenic mice and results suggest a potential therapeutic treatment for the observed deficits with drugs which modulate endocannabinoid enzyme activity. Graphical Abstract Results of the Go/No-Go operant conditioning task reveal inhibitory control deficits in female transgenic Tat(+) mice without significantly affecting males. The demonstrated inhibitory control deficits appear to be associated with an upregulation of cannabinoid type 1 receptors (CB 1 R) in the infralimbic (IL) cortex in the same female Tat(+) group.

This study examined whether global HIV-associated neurocognitive impairment (NCI), assessed with the HIV-Dementia Scale (HDS), predicted mortality in an ethnically diverse sample of 209 HIV-positive adults. Participants were predominantly in the mid-range of illness at baseline, and followed over 13-years. At baseline, 31 (15%) participants scored in the NCI range (HDS ≤ 10); 58 (28%) died during follow-up. Baseline NCI was significantly associated with earlier mortality (HR = 2.10, 95% CI [1.10-4.00]) independent of sociodemographic and HIV disease-related covariates. Less errors on the antisaccade task, an index of executive/attention control, was the only HDS subtest predicting earlier mortality (HR = 0.72, 95% CI [0.58-0.90]). In the absence of an AIDS-defining condition, NCI, particularly in the executive/attention domain, is an independent prognostic marker of mortality in a diverse HIV-positive cohort. These findings highlight the clinical utility of brief cognitive screening measures in this population.

Although the CNS is immune privileged, continuous search for pathogens and tumours by immune cells within the CNS is indispensable. Thus, distinct immune-cell populations also cross the blood-brain barrier independently of inflammation/under homeostatic conditions. It was previously shown that effector memory T cells populate healthy CNS parenchyma in humans and, independently, that CCR5-expressing lymphocytes as well as CCR5 ligands are enriched in the CNS of patients with multiple sclerosis. Apart from the recently described CD8+ CNS tissue-resident memory T cells, we identified a population of CD4+CCR5high effector memory cells as brain parenchyma-surveilling cells. These cells used their high levels of VLA-4 to arrest on scattered VCAM1, their open-conformation LFA-1 to crawl preferentially against the flow in search for sites permissive for extravasation, and their stored granzyme K (GZMK) to induce local ICAM1 aggregation and perform trans-, rather than paracellular diapedesis through unstimulated primary brain microvascular endothelial cells. This study included peripheral blood mononuclear cell samples from 175 healthy donors, 29 patients infected with HIV, with neurological symptoms in terms of cognitive impairment, 73 patients with relapsing-remitting multiple sclerosis in remission, either 1-4 weeks before (n = 29), or 18-60 months after the initiation of natalizumab therapy (n = 44), as well as white matter brain tissue of three patients suffering from epilepsy. We here provide ex vivo evidence that CCR5highGZMK+CD4+ effector memory T cells are involved in CNS immune surveillance during homeostasis, but could also play a role in CNS pathology. Among CD4+ T cells, this subset was found to dominate the CNS of patients without neurological inflammation ex vivo. The reduction in peripheral blood of HIV-positive patients with neurological symptoms correlated to their CD4 count as a measure of disease progression. Their peripheral enrichment in multiple sclerosis patients and specific peripheral entrapment through the CNS infiltration inhibiting drug natalizumab additionally suggests a contribution to CNS autoimmune pathology. Our transcriptome analysis revealed a migratory phenotype sharing many features with tissue-resident memory and Th17.1 cells, most notably the transcription factor eomesodermin. Knowledge on this cell subset should enable future studies to find ways to strengthen the host defence against CNS-resident pathogens and brain tumours or to prevent CNS autoimmunity., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Fluid biomarkers for cognitive impairment have the advantage of being relatively noninvasive and capable of monitoring neuronal and other brain cell health in real time. Biomarkers can predict the onset of dementing illness, but also correlate with cognition in a dynamic way allowing us to follow treatment responses and determine brain recovery. Chronic HIV infection causes cognitive impairment in a subset of individuals suggesting "premature aging." Exosomes are small extracellular vesicles that are shed from all cells. They are important in normal cell-to-cell communication as they contain cellular proteins, mRNA transcripts, and miRNAs. Exosome cargo varies depending on the health of the cell and pathological state; specific proteins/mRNAs and/or miRNAs are present and may serve as biomarkers. Exosomes of variable cellular origin can be isolated from peripheral blood by various methods. Neuron-derived exosomes (NDEs) can be isolated using a precipitation/immunoaffinity approach using antibodies against neuronal cell adhesion molecule L1CAM and the contents queried for central nervous system (CNS) disorders including HIV-associated neurological disorders (HAND) and Alzheimer's disease (AD). As these studies are recent, numerous questions arise including which neuronal proteins are in NDEs and whether their contents differ in different CNS pathologies or with age. In addition, can the NDE cargo predict as well as diagnose cognitive impairment and could exosomal contents be used as therapeutic biomarkers, or theramarkers, of neuronal recovery from effective treatment? This mini-review will show some new data and review recent studies on NDE from individuals with HIV infection and AD. HIV-associated neurocognitive disorders (HAND) are pathologies seen in a subset of individuals with chronic HIV infection. They belong to the spectrum of neurodegenerative diseases that result in death or dysfunction of neurons with similarities to Alzheimer disease (AD) but also distinctive differences (reviewed (Canet et al., Front Cell Neurosci 12: 307, 2018)). Both disorders are difficult to diagnose without neuropsychological testing and both need new biomarkers to judge progression as well as recovery with treatment. Both disorders involve neuroinflammation and several common targets. AD is associated with aging and HIV is thought to initiate premature aging. In HIV infection, amyloid beta (Aβ), which is deposited in "plaques" in AD, is soluble and its relevance to HIV-associated cognitive impairment is controversial (Achim et al., J Neuroimmune Pharmacol 4: 190-199, 2009; Rempel and Pulliam, AIDS 19: 127-135, 2005). Aβ deposition is required for AD pathological diagnosis, but is not necessarily causative (Barage and Sonawane, Neuropeptides 52: 1-18, 2015; Hardy and Selkoe, Science 297: 353-356, 2002; Morris et al., Acta Neuropathol Commun 2: 135, 2014). Neurofilament light (NF-L) is a surrogate marker in plasma and cerebrospinal fluid (CSF) for neurodegeneration (Abu-Rumeileh et al., Alzheimers Res Ther 10: 3, 2018; Mattsson et al., JAMA Neurol 74: 557-566, 2017) but continues to be a controversial biomarker for both HAND and AD (Gisslen et al., EBioMedicine 3: 135-140, 2016; Kovacs et al., Eur J Neurol 24:1326-e77, 2017; Norgren et al., Brain Res 987: 25-31, 2003; Rolstad et al., J Alzheimers Dis 45: 873-881, 2015; Yilmaz et al., Expert Rev Mol Diagn 17: 761-770, 2017). Blood biomarkers are needed to advance both HAND and AD fields, as blood draws are less costly than neuroimaging and are minimally invasive compared to lumbar punctures required for CSF acquisition. Extracellular vesicles (EVs) are nanoscale membranous vesicles shed from all cells including those of the central nervous system (CNS) and found in all biofluids; they are divided into exosomes (30-150 nm) originating from late endosomes/multivesicular bodies and microvesicles (150-1000 nm) produced through budding of the plasma membrane. Both types of vesicles are implicated in the pathogenesis of neurodegenerative diseases and may provide biomarkers (Bellingham et al., Front Physiol 3: 124, 2012). In this report, we call the vesicles exosomes, since they are the predominant vesicles in our preparations. They are involved in cell-to-cell communication in normal homeostasis and can be carriers of toxic proteins (Aβ, tau) (Sardar Sinha et al., Acta Neuropathol 136: 41-56, 2018) shed by cells as waste or actively secreted in a degenerative process (review Gupta and Pulliam, J Neuroinflammation 11: 68, 2014). The idea that exosomes originating from a specific cell can be recovered in the plasma using cellular surface markers of interest is intriguing. Neuron derived exosomes (NDEs) were first described in 2015 and isolated using antibodies against neural cell adhesion molecules NCAM or L1CAM, after total plasma exosome isolation (Fiandaca et al., Alzheimers Dement 11: 600-607 e1, 2015). Characterization of NDEs follows guidelines endorsed by the International Society for Extracellular Vesicles and includes Nanoparticle Tracking Analysis (NTA) to determine EV concentration and average diameter; Western Blots for EV markers; ELISAs for neuronal proteins and transmission EM for visualization (Sun et al., AIDS 31: F9-F17, 2017; Tang et al., FASEB J 30: 3097-106, 2016). This innovative isolation of an exosome sub-population has generated interest in using NDE as biomarkers for neurodegenerative diseases like AD, HAND, traumatic brain injury, posttraumatic stress disorder and more (reviews Agoston et al., Brain Inj 31: 1195-1203, 2017; Gupta and Pulliam, J Neuroinflammation 11: 68, 2014; Hu et al., Cell Death Dis 7: e2481, 2016; Karnati et al., J Neurotrauma, 2018; Osier et al., Mol Neurobiol, 2018). Several biomarkers from plasma NDEs were recently reported by the Pulliam lab to be elevated in general cognitive impairment (Sun et al., AIDS 31: F9-F17, 2017). We review our collective data here on HAND and AD and add to the characterization of plasma NDEs as exciting biomarkers of neurodegeneration.

Older HIV-infected patients are at risk for both HIV-associated neurocognitive disorder (HAND) and Alzheimer's disease. We investigated neuroimaging and neuropsychological performance of 61 virally suppressed older adults with HAND (mean (SD) age 64.3 (3.9) years), 53 demographically matched individuals with mild cognitive impairment of the Alzheimer's type (MCI-AD; 65.0 [4.8]), and 89 healthy controls (65.0 [4.3]) cross-sectionally and over 20 months. At the baseline, both disease groups exhibited lower volumes in multiple cortical and subcortical regions compared with controls. Hippocampal volume differentiated MCI-AD from HAND. Cognitively, MCI-AD performed worse on memory and language compared with HAND. Adjusted longitudinal models revealed greater diffuse brain atrophy in MCI-AD compared with controls, whereas HAND showed greater atrophy in frontal gray matter and cerebellum compared with controls. Comparing HAND with MCI-AD showed similar atrophy rates in all brain regions explored, with no significant findings. MCI-AD exhibited more pronounced language decline compared with HAND. These findings reveal the need for further work on unique cognitive phenotypes and neuroimaging signatures of HAND compared with early AD, providing preliminary clinical insight for differential diagnosis of age-related brain dysfunction in geriatric neuroHIV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Advances in treatment of HIV have dramatically improved survival rates; HIV-associated neurocognitive disorders (HAND), however, remain highly prevalent and continue to represent a significant public health problem, especially in resource-limited settings. We completed a cross-sectional study to describe the prevalence and risk factors for HAND in rural Southwestern Uganda AIDS Support Organization Centers. After securing ethical clearance from relevant bodies, 393 participants were screened for HAND using the International HIV Dementia Scale. A cutoff score of ≤10 and a significance level of p ≤ .05 were set. More than half of the 393 participants (n = 229, 58.23%) screened positive for HAND. The associated risk factors were gender (odds ratio [OR] 0.54, p = .017), peasant farming (OR 1.70, p = .04), and older age (OR 1.03, p = .019). HIV-associated neurocognitive disorder remains one of the major complications of HIV despite improvement in antiretroviral therapy and life expectancies.

Neurocognitive impairment (NCI) is common in people aging with HIV and can adversely affect health-related quality of life. However, early NCI may be largely asymptomatic and neurocognitive function is rarely assessed in the context of routine clinical care. In this study, we considered the utility of two assessment tools as screens for NCI in patients attending a community-based clinic (N = 58; mean age = 57 years): the Montreal Cognitive Assessment (MoCA) and a 3-item cognitive concerns questionnaire derived from the HIV Dementia Scale. Health-related quality of life and depression/anxiety were also measured. Indication of NCI using the MoCA was more prevalent compared to the 3-item questionnaire and was associated with the patients' initial antiretroviral therapy commencing between the years of 1997 and 2001, independently of age. Findings of the MoCA were not confounded by existing mood disorders, unlike the 3-item questionnaire. Therefore, we suggest implementing the MoCA as an initial screen for NCI.

Plasma HIV RNA level has been shown to correlate with HIV disease progression, morbidity, and mortality. We examined the association between levels of plasma HIV RNA and cognitive function among patients in Nigeria. A total of 179 HIV-1-infected participants with available plasma HIV RNA results and followed longitudinally for up to 2 years were included in this study. Blood samples from participants were used for the measurement of plasma HIV RNA and CD4+ T cell count. Utilizing demographic and practice effect-adjusted T scores obtained from a seven-domain neuropsychological test battery, cognitive status was determined by the global deficit score (GDS) approach, with a GDS ≥ 0.5 indicating cognitive impairment. In a longitudinal multivariable linear regression analysis, adjusting for CD4 cell count, Beck's Depression Score, age, gender, years of education, and antiretroviral treatment status, global T scores decreased by 0.35 per log 10 increase in plasma HIV RNA [p = 0.033]. Adjusting for the same variables in a multivariable logistic regression, the odds of neurocognitive impairment were 28% higher per log 10 increase in plasma HIV RNA (OR 1.28 [95% CI 1.08, 1.51]; p = 0.005). There were statistically significant associations for the speed of information processing, executive, and verbal fluency domains in both linear and logistic regression analyses. We found a significant association between plasma HIV RNA levels and cognitive function in both baseline (cross-sectional) and longitudinal analyses. However, the latter was significantly attenuated due to weak association among antiretroviral-treated individuals.

Introduction: HIV-associated neurocognitive disorders (HAND) are estimated to affect approximately 50% of infected individuals at any one time. Dispersion, a type of intraindividual variability in neurocognitive test performance, has been identified as a potential behavioral marker of HAND; however, the specificity of dispersion to HAND and how it is influenced by participant effort when taking neurocognitive tests remain unclear., Method: Data were analyzed from 996 (474 HIV-, 522 HIV+) men enrolled in the Multicenter AIDS Cohort Study (MACS). Dispersion was calculated based on the standard deviation of an individual's test scores within a single assessment. Effort was determined using the Visual Analogue Effort Scale. Predictors of dispersion were determined using stepwise linear regression. Dispersion was compared between the HIV serostatus groups using analysis of covariance (ANCOVA), considering demographic and psychosocial variables that differed between the groups., Results: Contrary to our hypothesis, dispersion was not influenced by effort. Instead, poorer neurocognitive ability and race were the sole predictors of dispersion. Dispersion did not differ between the serostatus groups., Conclusions: Our results indicate that dispersion is a valid indicator of neurocognitive dysfunction that is not due to suboptimal effort; however, it is not specific to HIV and is therefore of limited utility as a behavioral marker of HIV-related neurocognitive impairment.

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)-β, 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, Aβ 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 Aβ 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 Aβ 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 Aβ 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/., (© 2018 International Society for Neurochemistry.)

Objective: HIV-associated neurocognitive disorder (HAND) occurs in a significant percentage of HIV-infected (HIV+) adults. Increased intraindividual variability (IIV) in cognitive function may be an early marker of emerging neurocognitive disorder, which suggests that IIV may be a sensitive measure of neurologic compromise in HIV. In the current study, we hypothesize that increased IIV may predict impending morbidity, including future cognitive decline and death., Method: In 708 HIV+ participants followed longitudinally for up to 14 years, we assessed the role of dispersion in forecasting death and cognitive decline. Incident neurocognitive impairment was predicted in a mixed-effects ordinal logistic regression model using age, gender, baseline mean cognitive functioning, CD4+, time followed, years of education, and dispersion at the previous visit. Death before the next visit was predicted in a binomial mixed-effects regression model using age, gender, baseline mean cognitive functioning, CD4+, time followed, years of education, and dispersion., Results: Point-in-time dispersion and change in dispersion between visits predict future cognitive decline and death in HIV+ individuals. Individuals with greater dispersion at a visit or who had larger changes in dispersion between visits were more likely to demonstrate greater neurocognitive impairment at the subsequent visit. Greater IIV was also associated with an increased risk of death prior to the subsequent visit, even after controlling for HAND severity and global cognitive functioning., Conclusions: We conclude that the IIV in cognitive functioning may be more predictive of future disease consequence than mean level of cognitive functioning. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Depression and chronic inflammation are common in persons infected with the human immunodeficiency virus (HIV+). Although depression and response to inflammatory challenge are shown to reflect activity in common neural networks, little is known regarding sub-clinical presentation in persons chronically infected with HIV. The relationship of resting-state functional connectivity (rsFC) between the subgenual anterior cingulate cortex (sgACC) and bilateral amygdala to Beck Depression Inventory-1 (BDI) scores were compared within a group of 23 HIV+ and 23 HIV-negative comparison adults. An interaction was found wherein lower rsFC between the sgACC and both right and left amygdala was associated with higher BDI scores in HIV+ individuals. Total BDI scores and plasma levels of IL-6, IL-8, TNF-α, and IL-10 made available from 10 of the HIV+ patients were regressed upon an index of spontaneous whole-brain activity at rest; i.e., the amplitude of low-frequency fluctuations (ALFFs). Elevated levels of depression and IL-6 were associated with increased ALFF in a cluster of voxels on the medial portion of the ventral surface of the frontal lobe (Brodmann Area 11). Within this sample of HIV+ individuals lower rsFC of the sgACC with subcortical limbic regions predicts greater burden of depressive symptomology whereas elevated activity in the adjacent BA 11 may reflect sickness, indexed by elevated IL-6, and associated depressive behaviors.

Background: Cognitive disorders are a common issue impacting those living with human immunodeficiency virus (HIV). Effective antiretroviral treatment has lessened the severity but not the frequency of these impairments. Such deficits reduce quality of life and present a significant challenge to clinicians in the context of an ageing HIV population with a growing number of comorbidities., Sources of Data: This review is based on recent published literature in the field of HIV-associated cognitive impairment (HAND)., Areas of Agreement: The pathogenesis of HAND is multifactorial and can be categorized into HIV viral factors, antiretroviral factors and individual factors. The risk factors associated with HAND are well documented., Areas of Controversy: The prevalence of HAND in HIV populations varies and is dependent on populations studied and assessment batteries used. Disease progression is poorly understood and has important implication for screening programmes. The relative contribution of pathogenic mechanisms causing HAND is unclear, but recent papers point to inflammation as a significant contributor., Growing Areas: The role of psychiatric diseases, such as depression, in the development and maintenance of HAND has recently been examined and requires clinical consideration. Furthermore, as the HIV population ages, its clinical management faces new challenges., Areas Timely for Developing Research: Identifying biomarkers for HAND which are practical in a clinical setting and utilizing new imaging technologies to better monitor diagnosis and disease progression. Furthermore, the development of therapeutics targeting inflammation appears of increasing importance.

HIV-associated neurocognitive disorders (HAND) include asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND) and HIV-associated dementia. Early recognition of HAND is crucial, and usually requires thorough neuropsychological testing. Neurological soft signs (NSS), i.e. minor motor and sensory changes, a common feature in severe psychiatric disorders, may facilitate early diagnosis. NSS were examined using the Heidelberg NSS Scale in 18 patients with ANI, 21 with MND, 28 HIV positive patients without HAND, and 39 healthy controls matched for age, gender, and education. The highest NSS scores were obtained in the MND patients (13.3 ± 10.0, p < 0.0001) followed by those with ANI (11.7 ± 10.6), the HIV positive subjects without neurocognitive deficits (8.0 ± 4.1) and the healthy controls (3.8 ± 3.2). This result was confirmed when age and years of school education were entered as covariates. No significant correlations between NSS and CD4 counts or any other clinical variables were found among the HIV positive groups. Our results demonstrate that NSS are frequently found in both ANI and MND but not HIV positive patients without neurocognitive deficits. NSS may facilitate the screening of HIV positive patients for ANI and MND as an easier and less expensive clinical tool., (Copyright © 2018. Published by Elsevier B.V.)

Background: HIV-associated neurocognitive disorders (HAND) are frequently occurring comorbidities in HIV-positive patients, diagnosed by means of a neuropsychological assessment (NPA). Due to the magnitude of the HIV-positive population in Sub-Saharan Africa, easy-to-use cognitive screening tools are essential., Methods: This was a cross-sectional clinical trial involving 44 HIV-positive patients (on stable cART) and 73 HIV-negative controls completing an NPA, the International HIV Dementia Scale (IHDS), and a culturally appropriate cognitive screening tool, the Montreal Cognitive Assessment-Basic (MoCA-B). HAND were diagnosed by calculating Z-scores using internationally published normative data on NPA, as well as by using data from the HIV-negative group to validate the MoCA-B., Results: One hundred and seventeen patients were included (25% male, median age 35 years, median 11 years of education). A moderate correlation was found between the MoCA-B and NPA total Z-score (Pearson's r=0.36, p=0.02). Area under the curve (AUC) values for MoCA-B and IHDS were 0.59 and 0.70, respectively. The prevalence of HAND in HIV-positive patients was 66% when calculating Z-scores using published normative data versus 48% when using the data from the present HIV-negative cohort., Conclusion: The MoCA-B appeared not to be a valid screening tool for HAND in this setting. The prevalence of HAND in this setting is high, but appeared overestimated when using published norms., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Paroxetine and fluconazole have neuroprotective effects in an in vitro model of HIV protein-mediated neuronal injury. This study evaluated the safety, tolerability, and efficacy of both paroxetine and fluconazole for the treatment of HIV-associated neurocognitive disorder (HAND). A 24-week randomized double-blind, placebo-controlled 2 × 2 factorial design study was used. HIV+ individuals with cognitive impairment were enrolled in the 24-week trial. Participants were randomly assigned to one of four groups: (1) paroxetine 20 mg/day, (2) fluconazole 100 mg every 12 h, (3) paroxetine and fluconazole, or (4) placebo. Safety, tolerability, and efficacy were evaluated. Forty-five HIV+ individuals were enrolled. Medications were well tolerated. Compared to no paroxetine arms, HIV+ individuals receiving paroxetine showed improved NPZ8 summary scores, (mean change = 0.25 vs - 0.19, p = 0.049), CalCAP sequential test reaction time (mean change = 0.34 vs -0.23, p = 0.014), Trail Making Part B test performance (mean change = 0.49 vs - 0.33, p = 0.041), and FAS verbal fluency (mean change = 0.25 vs 0.02, p = 0.020) but a decline in the Letter number sequencing test (mean change = - 0.40 vs 0.26, p = 0.023). Biomarkers of cellular stress, inflammation, and neuronal damage were not affected by paroxetine. HIV+ individuals receiving fluconazole did not show a benefit in cognition and showed an increase in multiple markers of cellular stress compared to the no fluconazole arms. In conclusion, paroxetine was associated with improvement in a summary neuropsychological test measure and in several neuropsychological tests but worse performance in one neuropsychological test. Further studies of paroxetine for the treatment of HAND and to define its precise neuroprotective properties are warranted.

HIV-associated neurocognitive disorders (HAND) remain frequent even among individuals receiving combined antiretroviral therapy (cART). In addition, HAND may adversely affect the quality of life and adherence to cART. There is scarce epidemiological information about HAND in Latin America. This cross-sectional study recruited HIV-infected patients from a tertiary teaching institution in São Paulo, Brazil, between May 2013 and February 2015. The patients were adults with at least 4 years of education and patients with current neurological or psychiatric diseases were excluded. HAND remain frequent even among individuals receiving cART, use of psychoactive substance, or inability to understand the content for neuropsychological evaluation. We used standardized tools to evaluate depression, use of psychoactive substances, and daily life activities, and we performed a comprehensive neuropsychological examination. HAND was classified using the Frascati criteria. Prevalence of HAND was estimated, and an associated variable of symptomatic HAND was identified by logistic regression. Four-hundred twelve HIV-infected patients were included [male: 281 (68%), mean age of 45.3 years]. Most of them [n = 340 (83.7%)] had an undetectable viral load. The prevalence of HAND was 73.6% (n = 303): 210 (50.9%) had asymptomatic neurocognitive involvement (ANI), 67 (16.2%) had mild neurocognitive disorder (MND), and 26 (6.3%) had HIV-associated dementia (HAD). The univariate logistic regression analysis showed that female gender, age older than 50 years, <11 years of schooling, CD4 count below 200 cells/mm 3 , presence of previous illnesses (e.g., diabetes, hypertension), opportunistic disease history, and a Beck Depression Inventory (BDI) score between 13 and 19 points were factors associated with symptomatic HAND (MND and HAD). However, a BDI score between 13 and 19 points was the single independent variable associated with symptomatic HAND. HAND was highly prevalent in São Paulo, Brazil, and ANI was the more frequent category of HAND. However, 22.5% of participants had symptomatic HAND. This finding constitutes a challenge in clinical practice. A BDI score between 13 and 19 points was the single independent variable associated with symptomatic HAND.

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

HIV-associated neurocognitive disorders (HAND) are increasingly prevalent despite the use of antiretroviral therapies. Previous research suggests that individual host factors play an important role in determining susceptibility to HAND. In this review, we propose that childhood trauma (CT) and HAND share several common aetiological mechanisms, namely hypothalamic-pituitary-adrenal axis dysregulation, neuroinflammation and oxidative stress. These convergent and consequent mechanisms may translate into an increased risk of developing HAND in individuals who have experienced early life stress. We provide an overview of basic and clinical research relating to these pathophysiological mechanisms and suggest that further research examine brain-derived neurotrophic factor and telomere length as common mediating factors and potential therapeutic targets for HAND and CT. Graphical abstract Both childhood trauma and HIV-associated neurocognitive disorders are associated with HPA axis dysregulation, inflammation and oxidative stress.

Introduction: The current study sought to determine the optimal impairment rating definition for a new HIV-associated neurocognitive disorder (HAND) screening procedure as compared to standard neuropsychological testing., Method: A total of 55 HIV-infected (HIV+; 19% AIDS; 87% on combination antiretroviral therapy, cART; 80% plasma undetectable) and 22 demographically comparable HIV-uninfected (HIV-) control adults (all male) enrolled in an urban Australian primary care cohort study completed the CogState computerized cognitive screen, a standard independence in activities of daily living (ADL) questionnaire, and a standard neuropsychological test battery. Local or American demographically adjusted norms were applied to the neuropsychological data, taking into account premorbid reading level. CogState norms that corrected for age and sex were applied to raw CogState data. The HAND Frascati classification criteria were implemented to determine "impairment" on both the standard neuropsychological test and the CogState-based screen using two established methods: a battery-wide summary score (global deficit score; GDS), and cognitive domain rating, both combined with ADL independence data. Criterion validity was operationalized by comparing rate of impairment derived from the CogState-based screen to that obtained from the standard neuropsychological test battery first in the combined HIV- and HIV+ sample, and then in the HIV+ sample only., Results: In the combined sample, CogState-based screen criterion validity was higher using the GDS (79% correct classification, 73% sensitivity, 82% specificity) over the cognitive domain rating (correct classification, sensitivity, specificity all 69%) method. A similar pattern was found for the HIV+ group separately [GDS (74% correct classification, 76% sensitivity, 71% specificity) versus cognitive domain rating (64% correct classification, 72% sensitivity, 57% specificity)]. The cases that resulted in disagreement across the two methods were those with borderline impaired/unimpaired cognitive performance., Conclusions: The GDS is a relatively easy statistical method for computing impairment rate when using the CogState-based screen that yields adequate criterion validity compared to standard neuropsychological testing. Feasibility of standardized test administration and appropriate interpretation of results for this CogState-based screen in primary care was enhanced by the training and consultation provided by study neuropsychologists.

Objective: Decision-making involves fronto-striatal brain areas that are particularly vulnerable to the effects of HIV infection. Some studies report impaired decision-making in people with HIV/AIDS with past or present addictions and/or accompanying HIV-associated neurocognitive disorders (HAND). The authors investigated risk-based decision-making in HIV/AIDS, separating individuals with or without accompanying HAND., Method: A total of 288 HIV-infected persons underwent standardized neuropsychological testing. Participants were profiled based on neuropsychological and clinical assessments into 2 groups, neurocognitively normal (NN, n = 205) and HAND (n = 83). Risk-based decision-making was assessed via the Game of Dice Task (GDT). Sample characteristics were summarized by principal component analysis (PCA) prior to regression analyses predicting GDT performance., Results: The NN group performed within the normative range of the GDT, but the HAND group was impaired in all GDT measures. Across all participants, GDT performance was predicted by a combination of psychiatric comorbidities, alcohol abuse, education/premorbid IQ, and neuropsychological performance. Further analyses revealed marijuana use as an important additional predictor of impaired GDT performance. Within the GDT-impaired HAND group only, past or present immunosuppression emerged as the most robust predictor of GDT performance. Metabolic disorders and antiretroviral toxicity were also predictors of GDT performance in the HAND group., Conclusion: The majority of HIV-infected individuals were unimpaired in the GDT. Some influence of psychiatric and substance use comorbidities on GDT performance emerged in the entire cohort. However, GDT deficits were restricted to individuals with HAND, related to immunosuppression, metabolic disorders and antiretroviral toxicity in this group only. (PsycINFO Database Record, ((c) 2017 APA, all rights reserved).)

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.

Background and Purpose: HIV-associated neurocognitive disorder still occurs despite virally suppressive combination antiretroviral therapy. In the pre-combination antiretroviral era and in patients without HIV suppression, HIV-associated neurocognitive disorder was caused by synaptodendritic injury resulting in impairment of neural networks, characterized by decreased attention, psychomotor slowing, and working memory deficits. Whether similar pathogenesis is true for HIV-associated neurocognitive disorder in the context of viral suppression is not clear. Resting-state fMRI has been shown to be efficient in detecting impaired neural networks in various neurologic illnesses. This pilot study aimed to assess resting-state functional connectivity of the brain in patients with active HIV-associated neurocognitive disorder in the context of HIV viral suppression in both blood and CSF., Materials and Methods: Eighteen patients with active HIV-associated neurocognitive disorder (recent diagnosis with progressing symptoms) on combination antiretroviral therapy with viral suppression in both blood and CSF and 9 demographically matched control subjects underwent resting-state functional MR imaging. The connectivity in the 6 known neural networks was assessed. To localize significant ROIs within the HIV and control group, we performed a seed-based correlation for each known resting-state network., Results: There were significant group differences between the control and HIV-associated neurocognitive disorder groups in the salience (0.26 versus 0.14, t = 2.6978, df = 25, P = .0123) and executive networks (0.52 versus 0.32, t = 2.2372, df = 25, P = .034). The covariate analysis with neuropsychological scores yielded statistically significant correlations in all 6 studied functional networks, with the most conspicuous correlation in salience networks., Conclusions: Active HIV-associated neurocognitive disorder in virally suppressed patients is associated with significantly decreased connectivity in the salience and executive networks, thereby making it potentially useful as a biomarker., (© 2017 by American Journal of Neuroradiology.)

We assessed the value of screening for cognitive abnormalities in a chronically infected HIV population (N = 388) and investigated the association with clinical correlates. The mean age was 48 years (±11), the majority of the patients were male (89%), the median duration of infection was 6 years [interquartile range (IQR) = 2-12], the median CD count was 600 (IQR = 450-780), and 326 (84%) had a viral load below 200 copies/mL. Screening for cognitive complaints was applied using the three Simioni questions and the international HIV dementia scale (iHDS). Neuropsychological assessment (NPA) included 13 well-validated tests assessing motor speed, concentration, and memory. A total of 69 patients completed the NPA. CD4 (nadir), viral load, combination antiretroviral therapy (cART) duration, and the presence of comorbidities were evaluated for associations with NPA result. A total of 127 (33%) reported cognitive complaints during screening. The sensitivity and specificity of the Simioni questions were 82% and 24%, respectively. Adding the iHDS resulted in a sensitivity of 50% and a specificity of 73%. A CD4 nadir count <50 cells/m 3 was associated with an abnormal NPA (p = 0.01). Comorbidities were more prevalent in patients with an abnormal NPA, although not statistically significant (p = 0.276). Age, current CD4, viral load, and cART duration were not associated with abnormal NPA. The authors conclude that current screening strategies are insufficient in detecting HIV-associated neurocognitive disorder. A low CD4 nadir is associated with poor neurocognitive outcome in HIV.

Background: Despite treatment with virologically suppressive antiretroviral therapy (ART), neurocognitive impairment may persist or develop de novo in aging HIV-infected individuals. We evaluated advancing age as a predictor of neurocognitive impairment in a large cohort of previously ART-naive individuals on long-term ART., Design: The AIDS Clinical Trials Group Longitudinal Linked Randomized Trials was a prospective cohort study of HIV-infected individuals originally enrolled in randomized ART trials. This analysis examined neurocognitive outcomes at least 2 years after ART initiation., Methods: All participants underwent annual neurocognitive testing consisting of Trail making A and B, the wechsler adult intelligence scale-revised Digit Symbol and Hopkins Verbal Learning Tests. Uni and multivariable repeated measures regression models evaluated factors associated with neurocognitive performance. Predictors at parent study entry (ART naive) included entry demographics, smoking, injection drug use, hepatitis B surface antigen, hepatitis C virus serostatus, history of stroke, ART regimen type, pre-ART nadir CD4 cell count, and plasma viral load and as well as time-updated plasma viral load and CD4 cell count., Results: The cohort comprised 3313 individuals with median pre-ART age of 38 years, 20% women; 36% Black, non-Hispanic; 22% Hispanic. Virologic suppression was maintained at 91% of follow-up visits. Neurocognitive performance improved with years of ART. After adjusting for the expected effects of age using norms from HIV-negative individuals, the odds of neurocognitive impairment at follow-up visits among the HIV infected increased by nearly 20% for each decade of advancing age., Conclusion: Despite continued virologic suppression and neurocognitive improvement in the cohort as a whole, older individuals were more likely to have neurocognitive impairment than younger individuals.

Background: Prevalence estimates of HIV-associated neurocognitive disorders (HAND) may be inflated. Estimates are determined via cohort studies in which participants may apply suboptimal effort on neurocognitive testing, thereby inflating estimates. Additionally, fluctuating HAND severity over time may be related to inconsistent effort. To address these hypotheses, we characterized effort in the Multicenter AIDS Cohort Study., Methods: After neurocognitive testing, 935 participants (525 HIV- and 410 HIV+) completed the visual analog effort scale (VAES), rating their effort from 0% to 100%. Those with <100% then indicated the reason(s) for suboptimal effort. K-means cluster analysis established 3 groups: high (mean = 97%), moderate (79%), and low effort (51%). Rates of HAND and other characteristics were compared between the groups. Linear regression examined the predictors of VAES score. Data from 57 participants who completed the VAES at 2 visits were analyzed to characterize the longitudinal relationship between effort and HAND severity., Results: Fifty-two percent of participants reported suboptimal effort (<100%), with no difference between serostatus groups. Common reasons included "tired" (43%) and "distracted" (36%). The lowest effort group had greater asymptomatic neurocognitive impairment and minor neurocognitive disorder diagnosis (25% and 33%) as compared with the moderate (23% and 15%) and the high (12% and 9%) effort groups. Predictors of suboptimal effort were self-reported memory impairment, African American race, and cocaine use. Change in effort between baseline and follow-up correlated with change in HAND severity., Conclusions: Suboptimal effort seems to inflate estimated HAND prevalence and explain fluctuation of severity over time. A simple modification of study protocols to optimize effort is indicated by the results.

HIV-associated neurocognitive disorders (HAND) occur in approximately 50% of HIV-infected individuals, yet available diagnostic criteria yield varying prevalence rates. This study examined the frequency, reliability, and sensitivity to everyday functioning problems of three HAND diagnostic criteria (DSM-5, Frascati, Gisslén). Participants included 361 adults with HIV disease and 199 seronegative adults. Neurocognitive status as defined by each of the three diagnostic systems was determined via a comprehensive neuropsychological battery. Everyday functioning was evaluated through self-report and clinician ratings. Results of logistic regressions revealed an association of HIV serostatus with Frascati-defined neurocognitive impairment (p = .027, OR = 1.7[1.1, 2.7]), but not DSM-5 or Gisslén-defined criteria (ps > .05). Frascati and DSM-5 criteria demonstrated agreement on 71% of observations, Frascati and Gisslén showed agreement on 80%, and DSM-5 and Gisslén criteria showed agreement on 46%, though reliability across the three criteria was poor. Only Frascati-defined neurocognitive impairment significantly predicted everyday functioning problems (p = .002, OR = 2.3[1.4, 3.8]). However, when both neurocognitive and complaint criteria were considered, the DSM-5 guidelines demonstrated significant relationships to everyday functioning, serostatus, and also increased reliability overtime compared to neurocognitive criteria alone (all ps < .05). A subset (n = 118) of the HIV+ group was assessed again after 14.0 (2.2) months. DSM-5 criteria evidenced significantly higher rates of incident neurocognitive disorder compared to both Frascati (p = .003) and Gisslén (p = .021) guidelines, while there were fewer remitting neurocognitive disorder diagnoses when Gisslén criteria were applied to the study sample compared to Frascati (p = .04). Future studies should aim to identify gold standard biological markers (e.g., neuropathology) and clinical outcomes associated with specific diagnostic criteria.

Over 50% of adults with HIV exhibit some form of HIV-associated neurocognitive disorder, ranging from mild asymptomatic neurocognitive impairment to HIV-associated dementia. As adults age with HIV and become susceptible to cardiovascular and metabolic comorbidities, the prevalence and severity of such neurocognitive disorders are likely to increase. With compromised renal and hepatic functioning often accompanying HIV, pharmaceutical interventions to address such neurocognitive disorders may not be the best strategy and are not without risks. Fortunately, as noted in the geriatric literature, cognitive training strategies have been shown to improve targeted neurocognitive domains and everyday functioning. A review of some of these cognitive training strategies, especially as they relate to aging with HIV, are highlighted and explained in the context of neuroAIDS, aging, and neurocognitive reserve. Implications for practice and research are provided., (© 2017 S. Karger AG, Basel.)

Background: HIV-associated neurocognitive disorder (HAND) is a great source of morbidity in sub-Saharan African region. However, the magnitude of this problem remains largely uninvestigated despite having the largest number of population with HIV/AIDS. The aim of this study is to determine the prevalence of HAND among patients attending a tertiary health facility in Nigeria., Method: We conducted a cross-sectional study among HIV-positive patients on antiretroviral therapy (ART) for at least 1 year. They were assessed using the International HIV Dementia Scale, Word Recall Test, Stick Design Test, Subjective Cognitive Complaint Questionnaire, Alcohol Use Disorder Identification Test, Drug Abuse Screening Test, Center for Epidemiological Study-Depression Scale, Instrumental Activity of Daily Living, and neurological examination. The CD4 count and viral load were determined for all the participants. A consensus diagnosis was made on each case based on the Frascati criteria. Data obtained were analyzed using "SPSS" for Windows version 15., Results: A total of 418 HIV-positive patients participated in the study, of which 325 (77.8%) are females. The mean age (standard deviation) of the participants was 37.2 (9.3) years. The prevalence of HAND was 21.5% (95% confidence interval [CI] = 17.6%-25.4%), of which 9.6% were asymptomatic. The significant predictors of HAND in this study are duration of illness (odds ratio [OR] = 1.33 P < .001), detectable viral load (OR = 0.19, P < .001), CD4 count (OR = 0.99, P < .001), education (OR = 0.94, P = .011), stopping medication (OR = 3.55 P = .01), and severity of illness (OR = 1.24, P = .005)., Conclusion: One-fifth of the HIV-positive patients in this study had HAND. Various sociodemographic and clinical features were related to the prevalence of HAND., Competing Interests: Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.