Unravelling the triad of neuroinvasion, neurodissemination, and neuroinflammation of human immunodeficiency virus type 1 in the central nervous system.

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.

Awareness and Knowledge of HIV-Associated Neurocognitive Disorder Among Middle-Aged and Older People Living With HIV/AIDS in Southern Nevada: Implications for HIV/AIDS Community-Based Education Programs.

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.

Racial differences in scores on the HIV Dementia Scale: mediating effects of literacy and screening utility among Black and White persons with HIV disease.

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.

The cognitive remediation of attention in HIV-associated neurocognitive disorders (HAND): A meta-analysis and systematic review.

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).

HIV-Associated Dementia: Associated Factors and Characteristics of Cognitive Domain Abnormalities in Elderly People Living with HIV Treated with Highly Active Antiretroviral Therapy.

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.

Neurological manifestation with special reference to HIV-associated neurocognitive disorder (HAND) among people on anti-retroviral treatment in India.

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.

Contemporary trends in HIV-associated neurocognitive disorders in Ghana.

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.

Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.

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.

Proteomics and metabolomics of HIV-associated neurocognitive disorders: A systematic review.

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.

Is the use of the QPC cognitive complaints questionnaire relevant for the screening strategy of HIV-Associated neurocognitive disorders?

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/mm3 and 23.1% had a CDC stage C. Median CD4 cell count was 686/mm3. 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.

Psycho-behavioral factors associated with neurocognitive performance among people living with HIV on antiretroviral therapy in Accra, Ghana.

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.

HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History.

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.

Male HIV-1 transgenic rats show reduced cocaine-maintained lever-pressing compared to F344 wildtype rats despite similar baseline locomotion.

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.

Selective Estrogen Receptor ß Agonists: a Therapeutic Approach for HIV-1 Associated Neurocognitive Disorders.

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 ß 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.

Not a victim: How self-deception saved David.

This paper summarizes a course of psychotherapy in which the therapist integrated concepts and strategies from psychoanalytic and cognitive-behavioral orientations in treating a gay man with HIV-associated neurocognitive disorder and a history of sexual abuse. The article highlights the psychologically protective function that deception served in the treatment of this patient, and how the therapist navigated the fragility of these inner fictions. Further, it illustrates the way in which the therapist-patient dynamic was colored by a psychoanalytic process known as projective identification.

Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis.

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.

Longitudinal brain atrophy patterns and neuropsychological performance in older adults with HIV-associated neurocognitive disorder compared with early Alzheimer's disease.

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.

Inhibitory Control Deficits Associated with Upregulation of CB1R in the HIV-1 Tat Transgenic Mouse Model of Hand.

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 (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group (p < .05). A significant negative correlation was noted between inhibitory control and IL CB1R expression (r = -.543, p = .045), with CB1R expression predicting 30% of the variance of inhibitory control (R2 = .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 (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group.

Prevalence and Risk Factors of HIV-Associated Neurocognitive Disorders in Rural Southwestern Uganda.

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.