NeuroAIDS Research Research Articles

Screening for HIV-associated neurocognitive impairment: Development and validation of an abbreviated neuropsychological test battery for use in South African clinical settings.

The HIV Neurobehavioral Research Center International Neurobehavioral Battery is a culturally valid battery sensitive to the neurocognitive (NC) effects of HIV-infection. However, its lengthy administration time makes the battery impractical in resource-limited settings, like South Africa, which are often faced with an overwhelming disease burden, a lack of neurological and neuropsychological (NP) expertise, and staff shortages. The present study therefore sought to develop an abbreviated version of the HNRC Battery and validate this battery in a sample of people with HIV (PWH) in South Africa. The present study therefore sought to develop an abbreviated version of the HNRC battery and validate this battery in a sample of people with HIV (PWH) in South Africa. Six measures were selected based on the NC test performances of 103 HIV-positive and 135 HIV-negative South African adults. For the validation, a subgroup of 103 PWH completed the full version of the battery, while the other subgroup of 52 PWH completed only the abbreviated version. Deficit scores of each participant were calculated. These scores were used as the gold standard against which the abbreviated battery was compared. There was a reduction of 81% in administration time when compared to the full version of the battery. The abbreviated battery demonstrated good sensitivity (75.0%) and excellent specificity (94.9%) when compared with the full version. The abbreviated battery showed good diagnostic accuracy in identifying NC impairment in an HIV-positive South African sample with a significant reduction in administration time, making it a more practical option in busy South African clinic settings. The results of this study may facilitate the growth of neuroAIDS research and aid initial identification of HIV-related NC impairment in resource-constrained settings. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Higher Comorbidity Burden Predicts Worsening Neurocognitive Trajectories in People with HIV

Background: Comorbidities linked to aging such as diabetes mellitus, pulmonary disease and renal insufficiency accumulate at a faster rate in people with HIV (PWH) than in the general population. We evaluated whether the Charlson Index, a multimorbidity scale comprising 17 variables that has been validated in previous studies, predicted neurocognitive trajectories in PWH. Methods: Neurocognition was measured by averaging scaled scores from all assessments in a comprehensive neuropsychological battery. Multilevel modeling was used to examine between- and within-person predictors of global neurocognition. At the between-person level, average Charlson Index (averaged within each person across all their visits) was examined as a predictor of neurocognitive change over time, covarying for the effect of HIV disease characteristics (proportion of visits virally suppressed, average CD4). At the within-person level, Charlson Index was used to predict fluctuations in global neurocognition at the same and next visit, covarying for visit-specific effects of viral load detectability and current CD4 count. Results: Participants were 1195 PWH (mean age at baseline = 43·0; SD 9·7) followed for an average of over 7·1 years (SD = 5·0; range = 0·5 to 20·5 years). Between persons, higher average Charlson index scores were associated with faster rates of global neurocognitive decline (standardized β = -0·050 [0·015], p = 0·001)· This global effect was driven by significant declines in the domains of executive functioning (p = 0·001) and working memory (p = 0·007). HIV disease characteristics did not predict trajectories of neurocognitive change (ps > 0·05). At the within-person level of the model, lower current CD4+ lymphocytes (β = 0·043 [0·009]; p < 0·001), detectable plasma HIV RNA (β = 0·018 [0·006]; p = 0·001), and higher Charlson Index score (β =-0·046 [0·015]; p = 0·003) independently predicted worse concurrent global neurocognitive performance. Time-lag analyses demonstrated that increasing comorbidities occurred concurrent with, not before, neurocognitive decline. Conclusion: The impact of comorbidities on trajectories of neurocognitive decline was greater than that of HIV disease factors and independent of chronological age. Although correlative, the temporal relationship between accumulating comorbidities and neurocognitive decline suggests that interventions to prevent or ameliorate a variety of comorbidities may improve neurocognitive prognosis for PWH. Funding Statement: This publication was made possible through funding by the NIMH and NINDS by the following grants: HIV Neurobehavioral Research Center (HNRC): P30 MH62512 Manhattan HIV Brain Bank (MHBB): U24MH100931 Texas NeuroAIDS Research Center (TNRC): U24MH100930 National Neurological AIDS Bank (NNAB): U24MH100929 California NeuroAIDS Tissue Network (CNTN): U24MH100928 Data Coordinating Center (DCC): U24MH100925 Translational Methamphetamine AIDS Research Center (TMARC): P50 DA026306 Declaration of Interests: None to declare. Ethics Approval Statement: UCSD's Human Research Protections Program (irb.ucsd.edu) approved all study procedures, and all participants provided written informed consent.

Circulating Levels of ATP Is a Biomarker of HIV Cognitive Impairment

Background: In developed countries, Human Immunodeficiency Virus type-1 (HIV-1) infection has become a chronic disease despite the positive effects of anti-retroviral therapies (ART) but still at least half of the HIV infected population shown signs of cognitive impairment. Therefore, biomarkers of HIV cognitive decline are urgently needed. Methods: We analyze the opening of one of the larger channels expressed by humans, pannexin-1 channels, in the uninfected and HIV infected population (n=175). Upon opening several intracellular second messengers are released into the extracellular space including PGE2 and ATP in serum/plasma. We correlated the cognitive status of the patients with circulating levels of both factors upon a visit to the clinic. Findings: Here, we demonstrate that pannexin channels on fresh PBMCs from uninfected individuals are closed. In contrast, all HIV-infected individuals analyzed, even the ones under effective ART, had a spontaneous opening of pannexin-1 channels and increased circulating levels of PGE2 and ATP. These results suggest that even low or undetectable levels of HIV result in chronic inflammation and opening of pannexin-1 channels. Furthermore, we found that circulating levels of ATP, but not PGE2, correlated with the cognitive status of people living with HIV. Interpretation: We propose that circulating levels of ATP could predict CNS compromise and lead to the breakthroughs necessary to detect and prevent brain compromise in the HIV-infected population. Funding Statement: This work was funded by The National Institute of Mental Health grant, MH096625, the National Institute of Neurological Disorders and Stroke, NS105584, and UTMB internal funding (to E.A.E). Research in the Geiger (J.D.G.) laboratory was supported by the National Institute of General Medical Sciences under award numbers P30GM100329 and U54GM115458, the National Institute of Mental Health under award numbers R01MH100972 and R01MH105329, the National Institute of Neurological Diseases and Stroke under award number R01NS065957, and the National Institute of Drug Abuse under award number 2R01DA032444. The NNTC is made possible through funding from the NIMH and NINDS by the following grants: Manhattan HIV Brain Bank (MHBB): U24MH100931; Texas NeuroAIDS Research Center (TNRC): U24MH100930; National Neurological AIDS Bank (NNAB): U24MH100929; California NeuroAIDS Tissue Network (CNTN): U24MH100928; and Data Coordinating Center (DCC): U24MH100925. The authors also acknowledge the New Jersey and New York Blood Center, the Alfred P. Sloan Foundation Minority fellowship (to S.V.) and Mount Sinai NeuroAIDS Disparities Summer Institute, R25 MH080663 (to S.V. trainee). Declaration of Interests: The authors stated: None. Ethics Approval Statement: Patients gave written, informed consent for the provision of blood for the purposes of HIV research before inclusion in the current CHARTER pilot study. The protocol for blood collection and analysis was approved by the Mount Sinai, Rutgers University and University of Texas Medical Branch Institutional Review Board (Protocol Numbers, Pro20140000794, Pro2012001303, 18-0136, 18-0135, 18-0134).

Transgenic mice expressing HIV-1 envelope protein gp120 in the brain as an animal model in neuroAIDS research.

HIV-1 infection causes injury to the central nervous system (CNS) and is often associated with neurocognitive disorders. One model for brain damage seen in AIDS patients is the transgenic (tg) mouse expressing a soluble envelope protein gp120 of HIV-1 LAV in the brain in astrocytes under the control of the promoter of glial fibrillary acidic protein. These GFAP-gp120tg mice manifest several key neuropathological features observed in AIDS brains, such as decreased synaptic and dendritic density, increased numbers of activated microglia, and pronounced astrocytosis. Several recent studies show that brains of GFAP-gp120tg mice and neurocognitively impaired HIV patients share also a significant number of differentially regulated genes, activation of innate immunity and other cellular signaling pathways, disturbed neurogenesis, and learning deficits. These findings support the continued relevance of the GFAP-gp120tg mouse as a useful model to investigate neurodegenerative mechanisms and develop therapeutic strategies to mitigate the consequences associated with HIV infection of the CNS, neuroAIDS, and HAND.

Assessing health-related resiliency in HIV+ Latin women: Preliminary psychometric findings.

BackgroundHIV-associated vulnerabilities—especially those linked to psychological issues—and limited mental health–treatment resources have the potential to adversely affect the health statuses of individuals. The concept of resilience has been introduced in the literature to shift the emphasis from vulnerability to protective factors. Resilience, however, is an evolving construct and is measured in various ways, though rarely among underserved, minority populations. Herein, we present the preliminary psychometric properties of a sample of HIV-seropositive Puerto Rican women, measured using a newly developed health-related resilience scale.Methods and designThe Resilience Scales for Children and Adolescents, an instrument with solid test construction properties, acted as a model in the development (in both English and Spanish) of the HRRS, providing the same dimensions and most of the same subscales. The present sample was nested within the Hispanic-Latino longitudinal cohort of women (HLLC), that is part of the NeuroAIDS Research Program at the University of Puerto Rico (UPR), Medical Sciences Campus (MSC). Forty-five consecutively recruited, HIV+ women from the HLLC completed a demographic survey, the HRRS, and the Beck Depression Inventory-I, Spanish version.ResultsThe results demonstrate excellent overall internal consistency for the total HRRS score (α = 0.95). Each of the dimensional scores also evidenced acceptable internal consistency (α ≥ 0.88). All the dimensional and subscale content validity indices were above the 0.42 cut-off. Analysis revealed a significant negative correlation between the HRRS total score and BDI-I-S (r(45) = -0.453, p < 0.003).ConclusionAlbeit preliminary in nature, the present study provides support for the HRRS as a measure to assess resilience among individuals living with chronic medical conditions. Minority populations, especially non-English speaking ones, are understudied across the field of medicine, and when efforts are made to include these patient groups, measurement is rarely tailored to their unique cultural and linguistic experiences. The HRRS is a measure that addresses these notable voids in the medical literature.

Does age influence the frequency of anxiety symptoms and disorders in HIV disease?

ABSTRACTThe current study examined the individual and combined effects of age and HIV serostatus on anxiety symptoms and diagnoses among a community sample. Participants included 163 Older (50+ years) HIV+ persons, 113 Younger (<40) HIV+ persons, 95 Older HIV- persons, and 75 Younger HIV- persons who completed the Profile of Mood States and the Composite International Diagnostic Interview as part of a baseline neuroAIDS research assessment. Results showed that HIV infection was associated with significantly higher rates of anxiety symptoms as well as 12-month and lifetime diagnoses of Generalized Anxiety Disorder (GAD) and Panic Disorder (PD). There was no significant effect of age and no significant interaction between HIV serostatus and age; however, Older HIV+ participants were significantly older at onset of anxiety diagnoses as compared to their Younger HIV+ counterparts. Among both Older and Younger HIV+ participants, there were high rates of comorbidity between anxiety disorders and Major Depressive and methamphetamine use disorders. Across the lifespan, HIV-associated neurocognitive disorders interacted with 12-month anxiety disorders to increase risk of poorer everyday functioning outcomes. Overall, these data suggest that HIV disease and its comorbidities are related to elevated anxiety symptoms and diagnoses in both younger and older adults.

Advancing research in NeuroAIDS using collaboration and public data sharing.

In this issue of BMC Medical Genomics Griffin et al. present a user-friendly and freely accessible HIV-associated neurocognitive disorder (HAND) genomic database that compiles viral (HIV-1) genetic sequences and other relevant clinical and treatment data. We discuss the benefits and caveats of public data sharing in NeuroAIDS research, while emphasizing the importance of such novel initiatives for advancing knowledge.

Reply

This paper represents the third paper generated from a protocol that included HIV seropositive and seronegative participants. As discussed in the methods section, more specific detail regarding the full protocol and methods has been published previously. This includes the protocol for measuring sleep based on well-established methods and validated tools including in lab polysomnography, 2 week ambulatory actigraphy monitoring, electronic sleep diaries and clinical sleep evaluations conducted by sleep medicine trained experts.1,2,3 The reviewer's suggestions regarding the merit of including a control group in this subgroup analysis paper raises an issue that the scientific community is now beginning to openly discuss. This issue has been raised in other disciplines, such as cognitive aging, particularly when exploring cross-ethnic groups in cognitive performance. For example, in the cognitive aging literature, researchers have often explored cognitive function in minority samples by conducting cross-group research, in which a control group of white participants is included in the study. However, some researchers have proposed that these studies do not appreciate the unique cognitive attributes of the minority group of interest.4,5 Furthermore, they do not account for factors that may explain the within-group variability in cognitive function often observed in minority groups.6 As a result, these researchers suggest that within-group research is a more reliable and valid approach than cross-group research for identifying the underlying sources of poor cognitive functioning within minority samples, and subsequently, explaining the racial group differences in cognitive performance often reported in previous literature. This same theoretical perspective could also be applied to clinical samples, such as our HIV sample. Cognitive deficits have been long recognized as a being prevalent in HIV seropositive individuals, even those who are aviremic. Indeed, the NeuroAIDS research community is actively searching for underlying pathophysiologic mechanisms, despite virological stability on cART. Furthermore, the cognitive functioning and/or deficits are likely to vary greatly within a diverse HIV cohort much less between seropositive HIV subjects and seronegative “controls.” The within-group approach will be useful in identifying the factors that explain the within-group variability in cognitive function observed in HIV samples, and, subsequently, will assist researchers in understanding the mechanisms for cognitive deficits within HIV individuals. The cross-group approach of making comparisons between a HIV sample and non-HIV control sample would ignore this within-group variability and would not adequately address the nature of variability in cognitive performance among the HIV individuals. As a result, a cross-group approach may limit the potential for identifying mechanisms for the cognitive deficits observed in HIV individuals and strategies of intervention for this population. In summary we appreciate the interest in our paper. As highlighted by the reviewer's comments, we believe that the overarching message is the need for further investigations into this relationship; as it certainly encompasses a complex inter-relationship both physiologically, environmentally, and socio-culturally.

Global NeuroAIDS Roundtable

In May 2012, the Division of AIDS Research at the National Institute of Mental Health (NIMH) organized the "Global NeuroAIDS Roundtable" in conjunction with the 11th International Symposium on Neurovirology and the 2012 Conference on HIV in the Nervous System. The meeting was held in New York, NY, USA and brought together NIMH-funded investigators who are currently working on projects related to the neurological complications of AIDS (NeuroAIDS) in Africa, Asia, Eastern Europe, and Latin America in order to provide an opportunity to share their recent findings and discuss the challenges encountered within each country. The major goals of the roundtable were to evaluate HIV-associated neurocognitive impairment and determine if it may be directly attributable to distinct HIV subtypes or clades and to discuss the future priorities for global NeuroAIDS research. At the "Global NeuroAIDS Roundtable", presentations of preliminary research indicated that HIV-associated neurocognitive impairment is prevalent in all countries examined regardless of which HIV clade is present in the region. The only clear-cut difference between HIV-1 clades was in relation to subtypes A and D in Uganda. However, a key point that emerged from the discussions was that there is an urgent need to standardize neurocognitive assessment methodologies across the globe before definitive conclusions can be drawn regarding the relationship between HIV clade diversity and neuropathogenesis. Future research directions were also discussed at the roundtable with particular emphasis on the potential of viral and host factor molecular interactions to impact the pathophysiology of HIV-associated neurocognitive disorders (HAND) from a global perspective.

NeuroAIDS in sub-Saharan Africa: A clinical review

NeuroAIDS affects half of the 22 million people currently living with HIV/AIDS in sub-Saharan Africa, where cryptococcal meningitis alone is responsible for 504,000 deaths annually. A good understanding of NeuroAIDS may help improve disease-free survival in patients at risk and optimize resource utilization by caregivers. In this review, we aimed to provide a summary of major NeuroAIDS syndromes of relevance in Africa. We searched Medline for English language literature to identify relevant publications, using the search terms "NeuroAIDS" and "HIV AND nervous system." The most common NeuroAIDS syndrome is HIV-associated neurocognitive disorders (HAND), which affects over 1.5 million Africans yearly. While incidence of HAND has decreased with the use of highly active antiretroviral therapy, prevalence has increased due to longer life expectancy. Other NeuroAIDS syndromes include tuberculous meningitis and intracerebral tuberculoma, cryptococcal meningitis, toxoplasma encephalitis, progressive multifocal leukoencephalopathy, primary central nervous system lymphoma, stroke, and distal sensory polyneuropathy. NeuroAIDS care and research in Africa are hindered by resource limitations. Inadequate neuroimaging and laboratory facilities result in diagnostic delays and confusion, while limited access to drugs leads to inappropriate treatment. However, the situation may be improving. Better funding of HIV care by African governments and donor agencies have resulted in decreasing HIV prevalence and prolonged survival. Yet, central nervous system opportunistic infections remain important causes of death and disability among African patients with HIV/AIDS. There is the need for additional funding to improve access to antibiotics and to facilitate further research into NeuroAIDS and its treatment.

Construct Validity of the Item-Specific Deficit Approach to the California Verbal Learning Test (2nd Ed) in HIV Infection

Impairment in list learning and recall is prevalent in HIV-infected individuals and is strongly predictive of everyday functioning outcomes. Consistent with its predominant frontostriatal pathology, the memory profile associated with HIV infection is best characterized as a mixed encoding/retrieval profile. The Item-Specific Deficit Approach (ISDA) was developed by Wright et al. (2009) to elicit indices of Encoding, Consolidation, and Retrieval from the well-validated California Verbal Learning Test (CVLT; Delis, Kramer, Kaplan, & Ober, 1987, 2000). The current study evaluated construct validity of the ISDA for the CVLT-II in 40 persons with HIV-associated neurocognitive disorders (HIV+/HAND+), 103 HIV-infected persons without HAND (HIV+/HAND−), and 43 seronegative comparison participants (HIV–). Results provided mixed support for the construct validity of ISDA indices. HIV+/HAND+ individuals performed significantly more poorly than persons in the HIV+/HAND− and HIV− groups on ISDA Encoding, Consolidation, and Retrieval deficit indices, which demonstrated adequate classification accuracy for diagnosing HIV+/HAND+ participants and evidence of both convergent (e.g., episodic memory) and divergent (e.g., motor skills) correlations in the HIV+/HAND+ participants. However, highly intercorrelated ISDA indices and traditional CVLT-II measures showed comparable between-groups effect sizes, classification accuracy, and correlations to other memory tests, thereby raising uncertainties about the incremental value of the ISDA approach in clinical neuroAIDS research.

Central Nervous System Infection by HIV-1: Special Emphasis to NeuroAIDS in India

Advent of combinatorial antiretroviral therapy has widely declined the number of HIV related deaths. It has however resulted in an increase in number of people living with HIV, and their morbidity in terms of their compromised brain functions, thereby worsening the overall scenario in the form of HIV associated neurocognitive impairment that are studied under the umbrella of neuroAIDS. Productively infected macrophages “hijack” brain parenchyma, resulting in slow neurodegeneration especially in the basal ganglia, hippocampus, prefrontal cortex and white matter. Although not directly infected, neurons undergo apoptosis via different pathways as discussed in the review. In addition, more devastating is the condition when HIV synergizes with drugs of abuse and brings in oxidative stress, elevation of inflammatory cytokines and increased calcium waves ultimately leading to augmented excitotoxicity. Mother to child transmission has been another important risk factor in the field of HIV rendering the neonates afflicted with severe neurodevelopmental delays and reduced immune response. Increase in several cytokines and other molecules have been promising in early diagnosis of the syndrome, but search for a biomarker is still on. In this review, we have outlined the recent developments in the field, practical challenges in neuroAIDS research and possible future directions that may help in better management of the disease.

NeuroAIDS in Africa

In July 2009, the Center for Mental Health Research on AIDS at the National Institute of Mental Health organized and supported the meeting "NeuroAIDS in Africa." This meeting was held in Cape Town, South Africa, and was affiliated with the 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Presentations began with an overview of the epidemiology of HIV in sub-Saharan Africa, the molecular epidemiology of HIV, HIV-associated neurocognitive disorders (HANDs), and HAND treatment. These introductory talks were followed by presentations on HAND research and clinical care in Botswana, Cameroon, Ethiopia, The Gambia, Kenya, Malawi, Nigeria, Senegal, South Africa, Uganda, and Zambia. Topics discussed included best practices for assessing neurocognitive disorders, patterns of central nervous system (CNS) involvement in the region, subtype-associated risk for HAND, pediatric HIV assessments and neurodevelopment, HIV-associated CNS opportunistic infections and immune reconstitution syndrome, the evolving changes in treatment implementation, and various opportunities and strategies for NeuroAIDS research and capacity building in the region.

Translational research in NeuroAIDS: a neuroimmune pharmacology-related course.

Neuroimmune pharmacology (NIP) can be considered a multidisciplinary science where areas of neuroscience, immunology, and pharmacology intersect in neurological disorders. The R25 training program titled "Translational Research in NeuroAIDS and Mental Health (TR-NAMH): An innovative mentoring program to promote diversity in NeuroAIDS Research (R25 MH080661)" at the Johns Hopkins University is a web-based interactive course with the goal to improve the capacity of high quality research by developing mentoring programs for (1) doctoral and postdoctoral candidates and junior faculty from racial and ethnic minorities and (2) non-minority individuals at the same levels, whose research focuses on NeuroAIDS disparity issues such as HIV-associated neurocognitive disorders (HAND). This web-based interactive course overcomes the limitations of traditional education such as access to expert faculty and financial burden of scientists from racial and ethnic minority groups in the field of NeuroAIDS research and NIP and identifies rich nurturing environments for investigators to support their careers. The TR-NAMH program identifies a cadre of talented students and investigators eager to commit to innovative educational and training sessions in NeuroAIDS and NIP. The interplay between NIP changes precipitated by HIV infection in the brain makes the study of HAND an outstanding way to integrate important concepts from these two fields. The course includes activities besides those related to didactic learning such as research training and long-term mentoring; hence, the newly learned topics in NIP are continually reinforced and implemented in real-time experiences. We describe how NIP is integrated in the TR-NAMH program in the context of HAND.

Cognitive Neuropsychology of HIV-Associated Neurocognitive Disorders

Advances in the treatment of the human immunodeficiency virus (HIV) have dramatically improved survival rates over the past 10 years, but HIV-associated neurocognitive disorders (HAND) remain highly prevalent and continue to represent a significant public health problem. This review provides an update on the nature, extent, and diagnosis of HAND. Particular emphasis is placed on critically evaluating research within the realm of cognitive neuropsychology that aims to elucidate the component processes of HAND across the domains of executive functions, motor skills, speeded information processing, episodic memory, attention/working memory, language, and visuoperception. In addition to clarifying the cognitive mechanisms of HAND (e.g., impaired cognitive control), the cognitive neuropsychology approach may enhance the ecological validity of neuroAIDS research and inform the development of much needed novel, targeted cognitive and behavioral therapies.

Planning Future Strategies for Domestic and International NeuroAIDS Research, July 24–25, 2008

The National Institute of Mental Health in cooperation with the National Institute on Drug Abuse and the National Institute of Neurological Disorders and Stroke organized a meeting on July 24–25, 2008 to develop novel research directions for neuroAIDS research. The deliberations of this meeting are outlined in this brief report. Several critical research areas in neuroAIDS were identified as areas of emphasis. Opportunities for collaborations between large NIH-funded projects were also discussed.

A sensitive and rapid liquid chromatography-tandem mass spectrometry method for the quantification of the novel neurokinin-1 receptor antagonist aprepitant in rhesus macaque plasma, and cerebral spinal fluid, and human plasma with application in translational NeuroAIDs research

A sensitive and rapid liquid chromatography-tandem mass spectrometry method has been developed for to assess therapeutic exposures of aprepitant in HIV-infected patients and rhesus macaques. The method utilized a simple sample-preparation procedure of protein precipitation with methanol. Chromatographic separation was performed on a reversed phase C8 column (Hypersil Gold, 50mm×2.1mm, 3μm) using a mobile phase composed of acetonitrile and water in 0.5% formic acid through gradient elution. Electro-spray ionization in positive mode was incorporated in the tandem mass spectrometric detection. The lower limit of quantitation of aprepitant in plasma of rhesus macaques and human and cerebral spinal fluid of rhesus macaques were 1, 1, and 0.1ng/mL, respectively. The method has been successfully employed to measure aprepitant in preclinical and clinical samples collected from three SIV-infected rhesus macaques and ten patients with HIV infection. In conclusion, this liquid chromatography-tandem mass spectrometry method is suitable for preclinical–clinical translational research exploring exposure–response relationships with aprepitant as well as therapeutic drug monitoring of aprepitant.

Neurobehavioral effects of HIV-1 infection in China and the United States: a pilot study.

The HIV epidemic in China has been increasing exponentially, yet there have been no studies of the neurobehavioral effects of HIV infection in that country. Most neuroAIDS research has been conducted in Western countries using Western neuropsychological (NP) methods, and it is unclear whether these testing methods are appropriate for use in China. Twenty-eight HIV seropositive (HIV+) and twenty-three HIV seronegative (HIV-) individuals with comparable gender, age, and education distributions were recruited in Beijing and the rural Anhui province in China. Thirty-nine HIV+ and thirty-one HIV- individuals were selected from a larger U.S. cohort recruited at the HIV Neurobehavioral Research Center, in San Diego, to be matched to the Chinese sample for age, disease status, and treatment variables. The NP test battery used with the U.S. and China cohorts included instruments widely used to study HIV infection in the United States. It consisted of 14 individual test measures, each assigned to one of seven ability areas thought to be especially vulnerable to effects of HIV on the brain (i.e., verbal fluency, abstraction/executive function, speed of information processing, working memory, learning, delayed recall, and motor function). To explore the cross-cultural equivalence and validity of the NP measures, we compared our Chinese and U.S. samples on the individual tests, as well as mean scaled scores for the total battery and seven ability domains. On each NP test measure, the mean of the Chinese HIV+ group was worse than that of the HIV- group. A series of 2x2 analyses of variance involving HIV+ and HIV- groups from both countries revealed highly significant HIV effects on the Global and all Domain mean scaled scores. Country effects appeared on two of the individual ability areas, at least partly due to education differences between the two countries. Importantly, the absence of HIV-by-Country interactions suggests that the NP effects of HIV are similar in the two countries. The NP test battery that was chosen and adapted for use in this study of HIV in China appears to have good cross-cultural equivalence, but appropriate Chinese norms will be needed to identify disease-related impairment in individual Chinese people. To inform the development of such norms, a much larger study of demographic effects will be needed, especially considering the wide range of education in that country.

Levels of human immunodeficiency virus type 1 (HIV-1) replication in macrophages determines the severity of murine HIV-1 encephalitis.

The presence of specific neuroinvasive strains and necessity for brain viral replication for disease progression remain controversial issues in neuro-AIDS research. To investigate these questions, the authors injected human monocyte-derived macrophages (MDMs) infected with diverse viral strains were injected into the caudate and putamen of severe combined immunodeficient (SCID) mice. Independent of viral strain, infected MDMs became immunologically activated and elicited profound inflammatory reactions in brain areas most affected in humans. The intensity of neuropathologic changes, including microglial reactions, paralleled levels of viral infection and numbers of infected MDMs. The data suggest that HIV-1-associated neurological disease is related to the level of productive viral infection in activated macrophages. Virus infection, per se, may affect the ability of macrophages to respond to immune stimuli by overproduction of proinflammatory factors and neurotoxins, leading to neuronal dysfunction.