Impairment In HIV-infected Individuals Research Articles

Altered metabolism in right basal ganglia associated with asymptomatic neurocognitive impairment in HIV-infected individuals

BackgroundOnly few studies have focused on the metabolite differences between asymptomatic neurocognitive impairment (ANI) and cognitively normal people living with HIV (PLWH). The current study aims to examine whether brain metabolisms in basal ganglia (BG) by magnetic resonance spectroscopy (MRS) were potential to discriminate ANI from cognitively normal PLWH. MethodsAccording to neuropsychological (NP) test, 80 PLWH (37.4 ± 10.2 years) were divided into ANI group (HIV-ANI, n = 31) and NP normal group (HIV-normal, n = 49). Brain metabolisms by MRS from right BG were compared between groups, including N-acetylaspartate and N-acetyl aspartylglutamate (tNAA), creatine and phosphocreatine (tCr), and choline-containing compounds (tCho). A total value of three metabolites were introduced. All brain metabolisms were evaluated as its percentage of total. Furthermore, correlations between MRS and NP and clinical measures were evaluated. A logistic regression model was applied, and the AUC values for the model and the continuous factors were compared using receiver operating curve (ROC) analysis. ResultsCompared to HIV-normal group, tNAA/total was lower and tCr/total was higher in the HIV-ANI group (P < 0.05). Both tNAA/total and tCr/total values were correlated with NP score (P < 0.05), especially in verbal fluency, speed of information processing, learning, and recall (P < 0.05). The logistic model included BG-tCr/total, current CD4 and infection years of PLWH. The AUC value for the BG-tCr/total was 0.696 and was not significantly lower than that for logistic model (P < 0.01). ConclusionThe altered brain metabolites in the right BG were found in the ANI group compared to PLWH with normal cognition, and further associated with NP deficits. The current findings indicated that brain metabolites assessed by MRS has the potential to discriminate ANI from cognitively normal PLWH.

A modern view on the prevention and treatment of HIV-associated neurocognitive disorders

Acquired Immune Deficiency Syndrome (AIDS) is now considered one of the most global pandemics in human history. Despite the use of highly active antiretroviral therapy (HAART), HIV-1 infection is often accompanied by the development of CNS disorders, including neurocognitive disorders. The use of etiologic therapy has successfully prevented many of the possible terminal complications of the disease, but as patient survival time increases, the prevalence of cognitive impairment among AIDS patients is increasing. Theclinical manifestations of these disorders can rapidly progress from subtle attention deficits and behavioral disorders to the development of dementia. Diagnosing neurocognitive impairment in HIV-infected patients is usually difficult and requires consistent diagnostic procedures from the clinician, including initial screening and, if necessary, neuropsychiatric testing and neuroimaging. Early diagnosis and correction of neurocognitive impairment in HIV-infected individuals with adequate antiretroviral therapy is essential for successful treatment. The review also considers the use of drugs for the prevention and treatment of neurocognitive impairment, taking into account the peculiarities of persistence of the pathogen in the nervous system and the capabilities of modern medicine. One of the most promising methods of supporting therapy for such disorders is the delivery of antiretroviral drugs using various nanosystems (polymeric nanoparticles, lipid nanoparticles, nanogels, magnetic particles).

Neurocognitive and Neuroarchitectural Changes in the Prefrontal Cortex of Wistar Rats Treated with Highly Active Antiretroviral Therapy

The use of highly active antiretroviral therapy has proven to be highly effective in the treatment of human immunodeficiency virus 1 (HIV-1) infection. However, its impact on cognition has not been fully explored. This study was designed to assess the impacts of antiretroviral therapy on cognitive function and histoarchitecture of the prefrontal cortex of Wistar rats. Forty adult male Wistar rats weighing 180-200 g were randomly assigned to 4 groups: control, tenofovir, lamivudine and efavirenz (n=10), which received 1 ml distilled water and 6 mg/kg, 6 mg/kg and 12 mg/kg, respectively. Spatial memory scores were assessed using the Y-maze test. Following behavioural studies, the animals were euthanized, and their whole brains harvested. The prefrontal cortex was sectioned and processed for oxidative stress, histological and immunohistochemical analyses. There was a significant decrease in percentage alternation evaluated from the right/wrong decisions scored from the tenofovir and lamivudine groups, compared to the control group (p&lt;0.05). malondialdehyde (MDA) and reduced glutathione (GSH) levels were elevated following lamivudine and tenofovir exposure in the rats’ prefrontal cortices, respectively, compared to control (p&lt;0.05). There were also significant alterations of cortical pyramidal cells in the tenofovir and lamivudine groups. Additionally, marked astrogliosis with increased glial fibrillary acidic protein expression was observed, consistent with the structural alterations, especially in the lamivudine group. Our findings suggest that, of the three highly active antiretroviral therapy (HAART) drugs studied, lamivudine may be a major culprit in the progressive neurological damage and cognitive impairment in HIV-infected individuals on HAART.

Detecting cognitive impairment in HIV-infected individuals using mutual connectivity analysis of resting state functional MRI

It is estimated that more than 50% of the individuals affected with Human Immunodeficiency Virus (HIV) present deficits in multiple cognitive domains, collectively known as HIV-associated neurocognitive disorder (HAND). Early stages of brain injury may be clinically silent but potentially measurable via neuroimaging. A total of 40 subjects (20 HIV positive and 20 age-matched controls) volunteered for the study. All subjects underwent a standard battery of neuropsychological tests used for the clinical diagnosis of HAND. Fourteen HIV+ and five healthy subjects showed signs of neurological impairment. Connectivity was computed using mutual connectivity analysis (MCA) with generalized radial basis function neural network, a framework for quantifying non-linear connectivity as well as conventional correlation from 160 regional time-series that were extracted based on the Dosenbach (DOS) atlas. We subsequently applied graph theoretic as well as network analysis approaches for characterizing the connectivity matrices obtained and localizing between-group differences. We focused on trying to detect cognitive impairment using the subset of 29 (14 subjects with HAND and 15 cognitively normal controls) subjects. For the global analysis, significant differences (p < 0.05) were seen in the variance in degree, modularity and Smallworldness. Regional analysis revealed changes occurring mainly in portions of the lateral occipital cortex and the cingulate cortex. Furthermore, using Network Based Statistics (NBS), we uncovered an affected sub-network of 19 nodes comprising predominantly of regions of the default mode network. Similar analysis using the conventional correlation method revealed no significant results at a global scale, while regional analysis shows some differences spread across resting state networks. These results suggest that there is a subtle reorganization occurring in the topology of brain networks in HAND, which can be captured using improved connectivity analysis.

Inflammatory Mechanisms and Cascades Contributing to Neurocognitive Impairment in HIV/AIDS.

Neurocognitive impairment caused by chronic human immunodeficiency virus (HIV) infection is a growing concern. In this chapter we discuss the inflammatory mechanisms underlying the pathology of asymptomatic and mild neurocognitive impairment in the context of antiretroviral therapy. We discuss the role of HIV, viral proteins, and virally infected cells on the development of neuroinflammation and the effect of viral proteins on the cells of the central nervous system.We examine how these collective factors result in an inflammatory context that triggers the development of neurocognitive impairment in HIV. We assess the contribution of antiretrovirals and drugs of abuse, including methamphetamine, cannabis, and opioids, to the neurotoxic and neuroinflammatory milieu that leads to the development of neurocognitive impairment in HIV-infected individuals. We also examined circulating biomarkers, NF-L, sCD163, and sCD14, pertinent to identifying changes in the CNS that could indicate real-time changes in patient physiology. Lastly, we discuss future studies, such as exosomes and the microbiome, which could play a role in the HIV-induced neuroinflammation that eventually manifests as cognitive impairment.

Incidence and predictors of tenofovir disoproxil fumarate-induced renal impairment in HIV infected Nigerian patients

The use of tenofovir disoproxil fumarate (TDF) in the treatment of HIV infection has been associated with renal dysfunction. In Nigeria, data on the incidence and risk factors of TDF nephrotoxicity is sparse. We determined the cumulative incidence of and risk factors for TDF-induced renal impairment in HIV-infected individuals accessing care at the antiretroviral therapy (ART) clinic of Jos University Teaching Hospital, Nigeria. This retrospective cohort analysis included patients aged ≥16 years that initiated ART between January 2008 and December 2011. Renal impairment, defined as glomerular filtration rate GFR <60 mL/min/1.73 sqm using the Modification of Diet in Renal Disease (MDRD) equation was assessed at baseline and at 48 weeks on ART. Logistic regression was performed to determine factors associated with incident renal impairment. The mean age was 39±9 years, and 67.1% were female. The cumulative incidence of renal impairment among the TDF-exposed and TDF-unexposed groups was 4.6% and 2.3% respectively (p<0.001). TDF exposure was significantly associated with renal impairment [OR=2.0, 95%CI=(1.48-2.89), p<0.001] in bivariate analysis. In multivariate analysis, older age (aOR=1.06, 95%CI=(1.05-1.08), p<0.001), TDF exposure [aOR=1.85, 95%CI=(1.31-2.60), p<0.001] and co-morbidities [aOR=2.71, 95%CI=(1.72-4.25), p<0.001] were significantly associated with renal impairment. TDF exposure, aging and comorbidities were predictors of renal toxicity among HIV positive patients. Regular monitoring of renal function in such high-risk individuals is recommended.

‘Plasma monocyte-derived extracellular vesicles are associated with neurocognitive impairment in HIV infected individuals.’

Abstract Monocytes contribute to the neuropathogenesis of HIV-related cognitive impairment (CI) as they enter the central nervous system and initiate a cascade of neuroinflammatory events. Extracellular vesicles (EVs) are potent vehicles of intercellular signaling and may reflect the state of cells in the brain under healthy and pathological conditions. We measured EVs in plasma from 79 HIV-infected adults enrolled in the Hawaii Aging with HIV Cohort, classified as having either normal cognition (n=16) or CI based on meeting criteria for HIV-Associated Dementia (n=25) or Mild Cognitive Motor Disorder (n=38). We tested whether EV phenotypes differed between those with and without CI. EVs expressing monocyte-associated markers (EVs/μl) were significantly higher in HIV+ donors with CI compared to those without CI: CD14 (819 vs. 118.5, p=0.017), CD4 (261 vs. 45, p=0.001), CD16 (898 vs. 215, p&amp;lt;0.0001), CD163 (1660 vs. 55, p=0.010), and CCR5 (202 vs. 43.5, p=0.009). In addition, increased levels of EVs expressing neural markers were found in HIV+ adults with CI compared to those without CI: MAP2 (531 vs. 103.5, p=0.013), GFAP (1810 vs. 775, p=0.036), and CD200 (1216 vs. 36.5, p=0.005). There was no significant difference between the two groups in age, CD4 count, viral load, and, EVs expressing CD3, CD41a, CD62p, CD63, CCR2 and CD11b. Levels of CD16-expressing EVs negatively correlated with the degree of CI using a composite of 8 neuropsychological (NP) tests to compute a summary NPZ-8 score (r=−0.224, p=0.046). Our findings reveal that EVs expressing monocyte activation and neural damage markers correlate with CI in HIV+ adults. These techniques reveal novel circulating biomarkers of CI, and neuronal pathogenesis markers utilizing peripheral blood.

Memory Impairment in HIV-Infected Individuals with Early and Late Initiation of Regular Marijuana Use.

Marijuana use is disproportionately prevalent among HIV-infected individuals. The strongest neurocognitive effect of marijuana use is impairment in the domain of memory. Memory impairment is also high among HIV-infected persons. The present study examined 69 HIV-infected individuals who were stratified by age of regular marijuana initiation to investigate how marijuana use impacts neurocognitive functioning. A comprehensive battery assessed substance use and neurocognitive functioning. Findings indicated early onset marijuana users (regular use prior to age 18), compared to non-marijuana users and late onset marijuana users (regular use at age 18 or later), were over 8 times more likely to have learning impairment and nearly 4 times more likely to have memory impairment. A similar pattern of early onset marijuana users performing worse in learning emerged when examining domain deficit scores. The potential for early onset of regular marijuana use to exacerbate already high levels of memory impairment among HIV-infected persons has important clinical implications, including increased potential for medication non-adherence and difficulty with independent living.

Neurosyphilis Increases Human Immunodeficiency Virus (HIV)-associated Central Nervous System Inflammation but Does Not Explain Cognitive Impairment in HIV-infected Individuals With Syphilis.

Individuals infected with human immunodeficiency virus (HIV) who have previously had syphilis may have cognitive impairment. We tested the hypothesis that neurosyphilis causes cognitive impairment in HIV by amplifying HIV-related central nervous system (CNS) inflammation. HIV-infected participants enrolled in a study of cerebrospinal fluid (CSF) abnormalities in syphilis underwent the mental alternation test (MAT), venipuncture, and lumbar puncture. CSF concentrations of chemokine (C-X-C motif) ligand 10 (CXCL10), chemokine (C-C motif) ligand 2 (CCL2), and neurofilament light (NFL) were determined by commercial assays. The proportion of peripheral blood mononuclear cells (PBMCs) and of CSF white blood cells (WBCs) that were activated monocytes (CD14+CD16+) was determined by flow cytometry. Neurosyphilis was defined as detection of Treponema pallidum 16S RNA in CSF or CSF white blood cells (WBCs) >20/uL or a reactive CSF-Venereal Disease Research Laboratory (VDRL) test; uncomplicated syphilis was defined as undetectable CSF T. pallidum, CSF WBCs ≤5/uL and nonreactive CSF-VDRL. MAT <18 was considered low. Median proportion of PBMCs that were activated monocytes (16.6 vs. 5.3), and median CSF CXCL10 (10658 vs. 2530 units), CCL2 (519 vs. 337 units) and HIV RNA (727 vs. 50 c/mL) were higher in neurosyphilis than in uncomplicated syphilis (P ≤ .001 for all comparisons). Neurosyphilis was not related to low MAT scores. Participants with low MAT scores had higher median CSF CXCL10 (10299 vs. 3650 units, P = .008) and CCL2 (519 vs. 365 units, P = .04) concentrations than those with high MAT scores. Neurosyphilis may augment HIV-associated CNS inflammation, but it does not explain cognitive impairment in HIV-infected individuals with syphilis.

Screening for Neurocognitive Impairment in HIV-Infected Individuals at First Contact after HIV Diagnosis: The Experience of a Large Clinical Center in Northern Italy.

Neurocognitive disorders are emerging, probably underestimated, complications in HIV-infected people. The aim of the study was to assess neurocognitive profiles of newly detected HIV-infected patients. We performed an observational retrospective single-cohort study. Illiterates and patients with neurologic symptoms or previous psychiatric diagnosis were excluded. Neuropsychological profiles were assessed using a validated battery of neuropsychological tests. We included 206 patients; with males representing the majority of them (85%). Risk factors for HIV acquisition were unprotected sexual intercourse (homo/bisexual in 39.8% and heterosexual in 60.2%). Thirty-nine patients (18.9%) were previous injection drug users, while 41 (19.9%) were alcohol abusers. Mean education was 11.1 years (SD—standard deviation—3.7). A high prevalence of HIV-associated neurocognitive disorders (HAND, 47.1%) was present in HIV-infected patients: particularly, asymptomatic neurocognitive impairment (ANI) was found in 30.6%, mild neurocognitive disorder (MND) in 15% and HIV-associated dementia (HAD) in 1.5%. Male gender, low degree of education, AIDS diagnosis and gepatitis B virus (HBV) co-infection were factors independently associated with HAND in a multivariable logistic regression model. Our data suggest that patient-specific factors and AIDS diagnosis have a certain kind of impact in HAND occurrence. A complete neuropsychological screening must be recommended in all patients at HIV-infection diagnosis.

HIV-associated neurocognitive disorders and central nervous system drug penetration: what next?

The current prevalence of cognitive impairment in HIV-infected individuals is surprisingly high, even in those with undetectable plasma HIV RNA. The aetiology is unknown but one possibility is inadequate control of persistent central nervous system (CNS) HIV infection. The CNS Penetration Effectiveness (CPE) rank has been proposed to predict how well an antiretroviral regimen treats CNS infection. Fabbiani et al. report that 'correcting' the CPE rank of each drug in an individual's regimen for the results of genotypic susceptibility (the CPE-GSS score) results in better ability to predict whether the regimen will improve cognition. The CPE-GSS score may help us better understand the aetiology of HIV-associated cognitive impairment. Whether it will be useful in the management of individual patients requires further study.

Neurocognitive impairment in HIV-infected individuals with previous syphilis

Cognitive impairment is common in HIV-infected individuals, as is syphilis. Treponema pallidum, the bacterium that causes syphilis, invades the central nervous system early in disease. We hypothesized that HIV-infected patients with a history of syphilis or neurosyphilis would have more cognitive impairment than HIV-infected individuals without these infections. Eighty-two of 1574 enrollees in CHARTER, a prospective, observational study, had reactive serum rapid plasma reagin (RPR) tests. They were matched to 84 controls with non-reactive RPR by age, gender, ethnicity and HIV risk factor. Participants underwent comprehensive neuropsychological (NP) evaluations. RPR results were confirmed and serum fluorescent treponemal antibody absorption (FTA-ABS) test reactivity determined at a central laboratory. Sera from 101 of 166 participants were FTA-ABS reactive, indicating past or current syphilis. Among the 136 individuals without confounding conditions, compared with patients who had never had syphilis, those with prior syphilis had a greater number of impaired NP test domains (1.90 SD [1.77] versus 1.25 [1.52], P = 0.03), a higher global deficit score (0.47 [0.46] versus 0.31 [0.33], P = 0.03), and more were impaired in the NP learning domain (36 [42.9%] of 84 versus 13 [25.0%] of 52, P = 0.04). These effects of prior syphilis remained after controlling for education and premorbid intelligence.

Effects of HIV and Early Life Stress on Amygdala Morphometry and Neurocognitive Function

Both HIV infection and high levels of early life stress (ELS) have been related to abnormalities in frontal-subcortical structures, yet the combined effects of HIV and ELS on brain structure and function have not been previously investigated. In this study we assessed 49 non-demented HIV-seropositive (HIV+) and 47 age-matched HIV-seronegative healthy control (HC) adults. Levels of ELS exposure were quantified and used to define four HIV-ELS groups: HC Low-ELS (N = 20); HC High-ELS (N = 27); HIV+ Low-ELS (N = 24); HIV+ High-ELS (N = 25). An automated segmentation tool measured volumes of brain structures known to show HIV-related or ELS-related effects; a brief neurocognitive battery was administered. A significant HIV-ELS interaction was observed for amygdala volumes, which was driven by enlargements in HIV+ High-ELS participants. The HIV+ High-ELS group also demonstrated significant reductions in psychomotor/processing speed compared with HC Low-ELS. Regression analyses in the HIV+ group revealed that amygdala enlargements were associated with higher ELS, lower nadir CD4 counts, and reduced psychomotor/processing speed. Our results suggest that HIV infection and high ELS interact to increase amygdala volume, which is associated with neurocognitive dysfunction in HIV+ patients. These findings highlight the lasting neuropathological influence of ELS and suggest that high ELS may be a significant risk factor for neurocognitive impairment in HIV-infected individuals.

Monocyte maturation, HIV susceptibility, and transmigration across the blood brain barrier are critical in HIV neuropathogenesis

HIV continues to be a global health crisis with more than 34 million people infected worldwide (UNAIDS: Report on the Global AIDS Epidemic 2010, Geneva, World Health Organization). HIV enters the CNS within 2 weeks of infection and establishes a spectrum of HAND in a large percentage of infected individuals. These neurologic deficits greatly impact the quality of life of those infected with HIV. The establishment of HAND is largely attributed to monocyte transmigration, particularly that of a mature CD14(+)CD16(+) monocyte population, which is more susceptible to HIV infection, across the BBB into the CNS parenchyma in response to chemotactic signals. To enter the CNS, junctional proteins on the monocytes must participate in homo- and heterotypic interactions with those present on BMVECs of the BBB as they transmigrate across the barrier. This transmigration is responsible for bringing virus into the brain and establishing chronic neuroinflammation. While there is baseline trafficking of monocytes into the CNS, the increased chemotactic signals present during HIV infection of the brain promote exuberant monocyte transmigration into the CNS. This review will discuss the mechanisms of monocyte differentiation/maturation, HIV infectivity, and transmigration into the CNS parenchyma that contribute to the establishment of cognitive impairment in HIV-infected individuals. It will focus on markers of monocyte subpopulations, how differentiation/maturation alters HIV infectivity, and the mechanisms that promote their increased transmigration across the BBB into the CNS.

Moderate intensity exercise training reverses functional aerobic impairment in HIV-infected individuals

HIV infection and HIV drug therapies result in physical and psychological challenges to those living with HIV. These conditions contribute to decreased functional aerobic capacity (FAC). The aim of this study was to determine the effects of a combined moderate-intensity aerobic and resistance exercise intervention on the FAC of HIV-infected individuals. Forty HIV-infected individuals were randomized to an exercise group (EX) who completed six weeks of moderate-intensity exercise training, or to a control group (CON) that did not receive the exercise intervention. Twice weekly, the EX group completed 30 minutes of moderate-intensity aerobic training followed by moderate-intensity resistance training. Prior to, and following, the intervention the FAC for each subject was determined by graded exercise treadmill stress test (GXT). At baseline testing, the mean FAC as determined by treadmill time-based estimation of maximal oxygen consumption was 25% below age-predicted values, a level of reduction indicating the presence of functional aerobic impairment (FAI). Following the intervention, the EX had a significant increase in time to fatigue and estimated VO2 max (p<.001). Further, FAI was eliminated (1% above age predicted values) during the exercise training. The EX group also experienced decreased heart rates during Stages 1 (p=.02), 2 (p=.01), 4 (p=.05) and 6 (p=.02) of the GXT. The CON had no significant changes during the intervention period. These data indicate that six weeks of combined moderate-intensity aerobic and resistance training can improve FAC and eliminate FAI in those with HIV. Results suggest that the functional limitations common in HIV-infected individuals are due in part to detraining that is reversible through moderate exercise adherence.

Prevalence of cognitive disorders differs as a function of age in HIV virus infection

Ten per cent of all new cases of AIDS in the United States are in persons older than 50 years. This is particularly problematical in the case of the neuropsychiatric consequences of HIV, because there are neuropsychiatric disorders which become common in older individuals in the absence of HIV. The purpose of this report is to describe the prevalence and incidence of cognitive impairment in HIV-infected individuals enrolled in a community-based study. The study consisted of community-based, sentinel survey physician referrals of HIV-infected patients, with volunteer recruitment of risk-appropriate seronegative controls. One-year longitudinal follow-up study. Detailed neuropsychiatric evaluations were performed at study entry and after one year. A brief, interim visit tracked incident change. Each subject's neuropsychological test performance was classified as normal, demented, or cognitive impairment (not demented). The prevalence of cognitive disorder among HIV-positive individuals over 50 years was significantly greater than in individuals younger than 50 years. Among older participants, dementia was the more common classification (23%), whereas among younger participants, a milder form of cognitive impairment was more prevalent (22%). Alcohol abuse/dependence was a significant risk factor for a disorder, whereas greater education was a protective factor. The one-year incidence of disorder in the sample overall was low (7.3%), and age was not a significant risk factor. However, HIV viral load at study entry was significantly higher among those participants who had developed cognitive impairment one year later. Age is a significant risk modifier for prevalent neuropsychological disorder.