HIV-associated Neurocognitive Disorders Research Articles

Cluster analysis dissecting cognitive deficits in older adults with major depressive disorder and the association with neurofilament light chain

BackgroundCognitive impairment is a growing problem with increasing burden in global aging. Older adults with major depressive disorder (MDD) have higher risk of dementia. Neurofilament light chain (NfL) has been proven as a potential biomarker in neurodegenerative disease, including dementia. We aimed to investigate the association between cognitive deficits and NfL levels in older adults with MDD.MethodsIn this cross-sectional study, we enrolled 39 MDD patients and 15 individuals with mild neurocognitive disorder or major neurocognitive disorder, Alzheimer’s type, as controls, from a tertiary psychiatric hospital. Both groups were over age 65 and with matched Mini-Mental State Examination (MMSE) score. Demographic data, clinical variables, and plasma NfL levels were obtained. We used cluster analysis according to their cognitive profile and estimated the correlation between plasma NfL levels and each cognitive domain.ResultsIn the MDD group, participants had higher rate of family psychiatry history and current alcohol use habit compared with controls. Control group of neurocognitive disorders showed significantly lower score in total MMSE and higher plasma NfL levels. Part of the MDD patients presented cognitive deficits clustered with that of neurocognitive disorders (cluster A). In cluster A, the total MMSE score (r=-0.58277, p=0.0287) and the comprehension domain (r=-0.71717, p=0.0039) were negatively correlated to NfL levels after adjusting for age, while the associations had not been observed in the other cluster.ConclusionsWe noted the negative correlation between NfL levels and cognition in MDD patients clustered with neurodegenerative disorder, Alzheimer’s type. NfL could be a promising candidate as a biomarker to predict subtype of patients in MDD to develop cognitive decline. Further longitudinal studies and within MDD cluster analysis are required to validate our findings for clinical implications.

Multimodal Approach to Neurocognitive Function in People Living with HIV in the cART Era: A Comprehensive Review.

Combination antiretroviral treatment (cART) has revolutionized the management of human immunodeficiency virus (HIV) and has markedly improved the disease burden and life expectancy of people living with HIV. HIV enters the central nervous system (CNS) early in the course of infection, establishes latency, and produces a pro-inflammatory milieu that may affect cognitive functions, even in the cART era. Whereas severe forms of neurocognitive impairment (NCI) such as HIV-associated dementia have declined over the last decades, milder forms have become more prevalent, are commonly multifactorial, and are associated with comorbidity burdens, mental health, cART neurotoxicity, and ageing. Since 2007, the Frascati criteria have been used to characterize and classify HIV-associated neurocognitive disorders (HAND) into three stages, namely asymptomatic neurocognitive impairment (ANI), mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). These criteria are based on a comprehensive neuropsychological assessment that presupposes the availability of validated, demographically adjusted, and normative population data. Novel neuroimaging modalities and biomarkers have been proposed in order to complement NCI assessments, elucidate neuropathogenic mechanisms, and support HIV-associated NCI diagnosis, monitoring, and prognosis. By integrating neuropsychological assessments with biomarkers and neuroimaging into a holistic care approach, clinicians can enhance diagnostic accuracy, prognosis, and patient outcomes. This review interrogates the value of these modes of assessment and proposes a unified approach to NCI diagnosis.

KYNA Ameliorates Glutamate Toxicity of HAND by Enhancing Glutamate Uptake in A2 Astrocytes.

Reactive astrocytes are key players in HIV-associated neurocognitive disorders (HAND), and different types of reactive astrocytes play opposing roles in the neuropathologic progression of HAND. A recent study by our group found that gp120 mediates A1 astrocytes (neurotoxicity), which secrete proinflammatory factors and promote HAND disease progression. Here, by comparing the expression of A2 astrocyte (neuroprotective) markers in the brains of gp120 tgm mice and gp120+/α7nAChR-/- mice, we found that inhibition of alpha 7 nicotinic acetylcholine receptor (α7nAChR) promotes A2 astrocyte generation. Notably, kynurenine acid (KYNA) is an antagonist of α7nAChR, and is able to promote the formation of A2 astrocytes, the secretion of neurotrophic factors, and the enhancement of glutamate uptake through blocking the activation of α7nAChR/NF-κB signaling. In addition, learning, memory and mood disorders were significantly improved in gp120 tgm mice by intraperitoneal injection of kynurenine (KYN) and probenecid (PROB). Meanwhile, the number of A2 astrocytes in the mouse brain was significantly increased and glutamate toxicity was reduced. Taken together, KYNA was able to promote A2 astrocyte production and neurotrophic factor secretion, reduce glutamate toxicity, and ameliorate gp120-induced neuropathological deficits. These findings contribute to our understanding of the role that reactive astrocytes play in the development of HAND pathology and provide new evidence for the treatment of HAND via the tryptophan pathway.

Molecular Role of HIV-1 Human Receptors (CCL5-CCR5 Axis) in neuroAIDS: A Systematic Review.

Chronic HIV-1 infection can cause neurological illness, also known as HIV-associated neurocognitive disorders (HAND). The elevated level of pro-inflammatory cytokines and chemokines, such as C-C Chemokine Ligand 5 (CCL5/RANTES), is one of the ways of causing HIV-1-mediated neuroinflammation. C-C Chemokine Receptor 5 (CCR5) is the main coreceptor for viral entry into host cells and for mediating induction of CCL5/RANTES. CCR5 and CCL5 are part of a correlated axis of immune pathways used for effective protection against the HIV-1 virus. The purpose of this paper was to review the literary knowledge about the immunopathological relationship between this immune complex and neuroAIDS. A systematic review of the literature was conducted based on the selection and search of articles, available in English, Spanish, or Portuguese in the time frame of 1990-2022, of primary and secondary types in the PUBMED, Science Direct, SciELO, and LILACS databases through descriptors (MeSH) together with "AND": "CCR5"; "CCL5"; "neurological manifestations"; or "HIV". The methodological quality of the articles was assessed using the JBI Checklists and the PRISMA 2020 writing guidelines were followed. A total of 36 articles were included in the final composition of the review. The main cells of the CNS affected by neuroAIDS are: neurons; microglia; astrocytes; and oligodendrocytes. Molecular devices and their associations with cellular injuries have been described from the entry of the virus into the host's CNS cell to the generation of mental disorders. Furthermore, divergent results were found about the levels of CCL5/RANTES secretion and the generation of immunopathogenesis, while all condensed research for CCR5 indicated that elevation of this receptor causes more neurodegenerative manifestations. Therefore, new therapeutic and interventional strategies can be conditioned on the immunological direction proposed in this review for the disease.

Modeling HIV-1 infection and NeuroHIV in hiPSCs-derived cerebral organoid cultures

The human immunodeficiency virus (HIV) epidemic is an ongoing global health problem affecting 38 million people worldwide with nearly 1.6 million new infections every year. Despite the advent of combined antiretroviral therapy (cART), a large percentage of people with HIV (PWH) still develop neurological deficits, grouped into the term of HIV-associated neurocognitive disorders (HAND). Investigating the neuropathology of HIV is important for understanding mechanisms associated with cognitive impairment seen in PWH. The major obstacle for studying neuroHIV is the lack of suitable in vitro human culture models that could shed light into the HIV-CNS interactions. Recent advances in induced pluripotent stem cell (iPSC) culture and 3D brain organoid systems have allowed the generation of 2D and 3D culture methods that possess a potential to serve as a model of neurotropic viral diseases, including HIV. In this study, we first generated and characterized several hiPSC lines from healthy human donor skin fibroblast cells. hiPSCs were then used for the generation of microglia-containing human cerebral organoids (hCOs). Once fully characterized, hCOs were infected with HIV-1 in the presence and absence of cART regimens and viral infection was studied by cellular, molecular/biochemical, and virological assays. Our results revealed that hCOs were productively infected with HIV-1 as evident by viral p24-ELISA in culture media, RT-qPCR and RNAscope analysis of viral RNA, as well as ddPCR analysis of proviral HIV-1 in genomic DNA samples. More interestingly, replication and gene expression of HIV-1 were also greatly suppressed by cART in hCOs as early as 7 days post-infections. Our results suggest that hCOs derived from hiPSCs support HIV-1 replication and gene expression and may serve as a unique platform to better understand neuropathology of HIV infection in the brain.

Diagnosis of HIV-associated Neurocognitive Disorder (HAND) in Latin America: A Scoping Review (P9-13.002)

Diagnosis of HIV-associated Neurocognitive Disorder (HAND) in Latin America: A Scoping Review (P9-13.002)

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.

Neuropathogenic role of astrocyte-derived extracellular vesicles in HIV-associated neurocognitive disorders.

Our previous findings demonstrated that astrocytic HIF-1α plays a major role in HIV-1 Tat-mediated amyloidosis which can lead to Alzheimer's-like pathology-a comorbidity of HIV-Associated Neurocognitive Disorders (HAND). These amyloids can be shuttled in extracellular vesicles, and we sought to assess whether HIV-1 Tat stimulated astrocyte-derived EVs (ADEVs) containing the toxic amyloids could result in neuronal injury in vitro and in vivo. We thus hypothesized that blocking HIF-1α could likely mitigate HIV-1 Tat-ADEV-mediated neuronal injury. Rat hippocampal neurons when exposed to HIV-1 Tat-ADEVs carrying the toxic amyloids exhibited amyloid accumulation and synaptodendritic injury, leading to functional loss as evidenced by alterations in miniature excitatory post synaptic currents. The silencing of astrocytic HIF-1α not only reduced the biogenesis of ADEVs, as well as amyloid cargos, but also ameliorated neuronal synaptodegeneration. Next, we determined the effect of HIV-1 Tat-ADEVs carrying amyloids in the hippocampus of naive mice brains. Naive mice receiving the HIV-1 Tat-ADEVs, exhibited behavioural changes, and Alzheimer's 's-like pathology accompanied by synaptodegeneration. This impairment(s) was not observed in mice injected with HIF-1α silenced ADEVs. This is the first report demonstrating the role of amyloid-carrying ADEVs in mediating synaptodegeneration leading to behavioural changes associated with HAND and highlights the protective role of HIF-1α.

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.

Maintaining Dignity and Autonomy in the Process of Aging

For decades, research has shown that ageism undermines older adults’ mental and physical health by implying they are less capable and worthy of care. The preservation of dignity and autonomy when confronted by a declining capacity for autonomous decision making due to physical or cognitive disability is difficult and can create personal and ethical dilemmas for providers and patients. It is projected that by 2050, 22.5% of the North American population will be over 65. In addition, statistics show that by 2060, 13.9 million Americans aged 65 and older are projected to be diagnosed with Alzheimer's disease and related dementias. The incidence for mild cognitive impairment (MCI) or mild neurocognitive disorder may be twice as high as dementia. The Universal Declaration of Human Rights adopted in 1948 states that all people are "free and equal in dignity and rights". However, this concept has not been implemented for all older adults especially those with cognitive impairment. Therefore, it is even more critical that mental health providers use their voice to educate people about the negative impact of ageism and advocate for older people in clinical settings.This workshop challenges conventional thinking about our aging population and moral concepts related to ageism, justice, and maintaining dignity and autonomy. This presentation will provide information on how to foster intergenerational solidarity that reduces ageism and benefits people of all ages. The presenters will discuss how autonomy plays a key role in this solidarity as it implies responsibilities as well as rights. In addition, a discussion of ethical theories which suggest that older adults are morally obligated to be productive with their talent and professions will be explained. Residents in long-term care are even more likely to be impacted by ageism as the prevailing belief in our culture is that life lived in independence is of more value than life lived in a facility. The workshop will discuss how providers who work in long term care can support residents and try to ensure their decisions and behaviors are as free from bias as possible. The presenters will use real life case scenarios to engage participants and facilitate learning about these issues.

Association between multimorbidity and cognitive decline in the elderly population of the Eastern Province, Saudi Arabia.

Cognitive decline affects the quality of life, and dementia affects independence in daily life activities. Multimorbidity in older adults is associated with a higher risk of cognitive impairment. This research aims to study the relationship between cognitive decline and multimorbidity in the elderly population in the Eastern Province, Saudi Arabia. This cross-sectional research was conducted from July to October 2022 among adults over 60 years. All patients with two or more comorbidities were contacted for a face-to-face interview and cognitive testing to estimate cognitive function by trained family physicians using St. Louis University Mental State Examination. ANOVA and Chi-square test were used to test for statistical significance. Binary logistic regression was used to show the odds of having cognitive impairment and multimorbidity. All tests were performed at 5% level of significance. The study involved 343 individuals; majority (74.1%) aged 60-75 years and were males (67.9%). Hypertension, diabetes, and chronic pain were reported by 56%, 48%, and 44% participants, respectively. Thirty percent participants had 3 or more comorbidities. About 36% had mild neurocognitive disorder and 31.2% had dementia. The results showed that age, gender (female), diabetes, stroke, chronic pain, and multimorbidity were significantly associated with cognitive impairment. In our study, hypertension, coronary artery diseases, depression, and anxiety were not significantly associated with risk of cognitive decline. Our study found that multimorbidity is significantly associated with cognitive decline. Controlling comorbidities and preventing risk factors in midlife could help in delaying the progression of the disease.

Psychiatric disorder in prolonged post-concussive syndrom : clinical assessment, physiopathology and management review of the literature

IntroductionAccording to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), post concussive syndrome (PCS) is given a diagnosis of either major or mild neurocognitive disorder (NCD) due to traumatic brain injury TBI. However Persistent post-concussion symptoms (PPCS) are more complex, and typically involve multidisciplinary assessment and management. The symptoms are varied, non-specific and the therapeutic process is defiant for psychiatrist.ObjectivesTo investigate the semiology of persistent post-concussion syndrome (PPCS) and the therapeutic challenges it poses.MethodsA literature review was made on Pubmed, Google Scholar and Cochrane library using keywords: “post-concussive syndrome”,”psychiatric disorder”, “depression”,”post-traumatic stress disorder”,”treatment”, “physiopathology”.ResultsThe physiopathology of persistent PCS is controversy.The Symptoms are due to the Concept of “Symptom Generators” which results from the alterations in neurophysiology and neuropathology secondary to the injury, and pre- or post-injury psychological factors physiological concussion. The Global cerebral metabolic disturbance, the autonomic nervous system dysfunction and the cerebral blood flow dysregulation induce biochemical cascade,excitotoxic reaction and immunotoxicity.Clinical diagnoses associated with PPCS are:Major depressive disorder,Post traumatic stress disorder,Anxiety disorder,Substance abuse disorder,Psychotic disorder and Antisocial personality disorder. For the non pharmacological management: A systematically early information and a graded physical exercise in addition to other treatment are essential.Antidepressant, benzodiazepine and mood-stabilizer are the most recommended treatments for psychiatric symptoms. Atypical neuroleptics are indicated in delirant disorder, behavior disorder and antisocial personality disorder.Some studies suggest the methylphenidate and biperiden to treat several cognitive impairment and severe behavior disorder.Conclusions(PPCS) is far from being a subjective complaint by patients. It is a complex clinical entity that groups symptoms that overlap with other psychiatric diagnoses, such as depression, post-traumatic stress disorder, and mood disorders. Early neuropsychiatric assessment and personalized pharmacological and psychotherapeutic treatment are essential factors in the prognosis of the disease.Disclosure of InterestNone Declared

Cognitive impairment and neurocognitive profiles among people living with HIV and HIV-negative individuals older over 50 years: a comparison of IHDS, MMSE and MoCA.

We aimed to examine the l differences in the assessment of neurocognitive impairment (NCI) using cognitive screening tools between PLWH and HIV-negative individuals and further compare the neurocognitive profiles between the two groups. This was baseline evaluation of Pudong HIV Aging Cohort, including 465 people living with HIV (PLWH) and 465 HIV-negative individuals aged over 50 years matched by age (± 3 years), sex and education. NCI was assessed using the Chinese version of Mini-mental State Examination (MMSE), the International HIV Dementia Scale (IHDS) and Beijing version of Montreal Cognitive Assessment (MoCA). In total, 258 (55.5%), 91 (19.6%), 273 (58.7%) of PLWH were classified as having NCI by the IHDS, MMSE and MoCA, compared to 90 (19.4%), 25 (5.4%), 135 (29.0%) of HIV-negative individuals, respectively (p < 0.05); such associations remained significant in multivariable analysis. PLWH showed a larger overlap of NCI detected by IHDS, MMSE, and MoCA. IHDS and MoCA detected almost all of the NCI detected by MMSE. IHDS-motor and psychomotor speeds and MoCA-executive function showed the greatest disparities between two groups. In multivariable analysis, older age and more depressive symptoms were positively associated with NCI regardless of the screening tools or HIV serostatus. PLWH over 50 years old display a higher prevalence of NCI and distinct neurocognitive profiles compared to HIV-negative individuals, despite viral suppression. Given the more considerable overlap in NCI classification in PLWH, it is advisable to choose one screening tool such as IHDS or MoCA to identify those potentially having NCI and then refer to more comprehensive neuropsychological assessment.

Implications of vascular depression for successful cognitive aging in HIV Disease.

Although older adults with HIV are at high risk for mild neurocognitive disorders, a subset experience successful cognitive aging (SCA). HIV is associated with an increased risk of vascular depression (VasDep), which can affect cognitive and daily functioning. The current study examined whether VasDep impedes SCA among older adults with HIV. 136 persons with HIV aged 50 years and older were classified as either SCA+ (n = 37) or SCA- (n = 99) based on a battery of demographically adjusted neurocognitive tests and self-reported cognitive symptoms. Participants were also stratified on the presence of vascular disease (e.g., hypertension) and current depression as determined by the Composite International Diagnostic Interview and the Depression/Dejection scale of the Profile of Mood States. A Cochran-Armitage test revealed a significant additive effect of vascular disease and depression on SCA in this sample of older adults with HIV (z = 4.13, p <.0001). Individuals with VasDep had the lowest frequency of SCA+ (0%), which differed significantly from the group with only vascular disease (30%, OR = 0.04, CI = 0.002,0.68)) and the group with neither vascular disease nor depression (47% OR = 0.02, CI = 0.33,0.001). Findings were not confounded by demographics, HIV disease severity, or other psychiatric and medical factors (ps > 0.05). These data suggest that presence of VasDep may be a barrier to SCA in older adults with HIV disease. Prospective, longitudinal studies with neuroimaging-based operationalizations of VasDep are needed to further clarify this risk factor's role in the maintenance of cognitive and brain health in persons with HIV disease.

Methamphetamine Enhancement of HIV-1 gp120-Mediated NLRP3 Inflammasome Activation and Resultant Proinflammatory Responses in Rat Microglial Cultures.

Human Immunodeficiency Virus type 1 (HIV-1)-associated neurocognitive disorders (HANDs) remain prevalent in HIV-1-infected individuals despite the evident success of combined antiretroviral therapy (cART). The mechanisms underlying HAND prevalence in the cART era remain perplexing. Ample evidence indicates that HIV-1 envelope glycoprotein protein 120 (gp120), a potent neurotoxin, plays a pivotal role in HAND pathogenesis. Methamphetamine (Meth) abuse exacerbates HANDs, but how this occurs is not fully understood. We hypothesize that Meth exacerbates HANDs by enhancing gp120-mediated neuroinflammation. To test this hypothesis, we studied the effect of Meth on gp120-induced microglial activation and the resultant production of proinflammatory cytokines in primary rat microglial cultures. Our results show that Meth enhanced gp120-induced microglial activation, as revealed by immunostaining and Iba-1 expression, and potentiated gp120-mediated NLRP3 expression and IL-1β processing and release, as assayed by immunoblotting and ELISA. Meth also augmented the co-localization of NLRP3 and caspase-1, increased the numbers of NLRP3 puncta and ROS production, increased the levels of iNOS expression and NO production, and increased the levels of cleaved gasderminD (GSDMD-N; an executor of pyroptosis) in gp120-primed microglia. The Meth-associated effects were attenuated or blocked by MCC950, an NLRP3 inhibitor, or Mito-TEMPO, a mitochondrial superoxide scavenger. These results suggest that Meth enhances gp120-associated microglial NLRP3 activation and the resultant proinflammatory responses via mitochondria-dependent signaling.

Acute Administration of HIV-1 Tat Protein Drives Glutamatergic Alterations in a Rodent Model of HIV-Associated Neurocognitive Disorders

HIV-1-associated neurocognitive disorders (HAND) are a major comorbidity of HIV-1 infection, marked by impairment of executive function varying in severity. HAND affects nearly half of people living with HIV (PLWH), with mild forms predominating since the use of anti-retroviral therapies (ART). The HIV-1 transactivator of transcription (Tat) protein is found in the cerebrospinal fluid of patients adherent to ART, and its administration or expression in animals causes cognitive symptoms. Studies of Tat interaction with the N-methyl-D-aspartate receptor (NMDAR) suggest that glutamate toxicity contributes to Tat-induced impairments. To identify changes in regional glutamatergic circuitry underlying cognitive impairment, we injected recombinant Tat86 or saline to medial prefrontal cortex (mPFC) of male Sprague–Dawley rats. Rats were assessed with behavioral tasks that involve intact functioning of mPFC including the novel object recognition (NOR), spatial object recognition (SOR), and temporal order (TO) tasks at 1 and 2 postoperative weeks. Following testing, mPFC tissue was collected and analyzed by RT-PCR. Results showed Tat86 in mPFC-induced impairment in SOR, and upregulation of Grin1 and Grin2a transcripts. To further understand the mechanism of Tat toxicity, we assessed the effects of full-length Tat101 on gene expression in mPFC by RNA sequencing. The results of RNAseq suggest that glutamatergic effects of Tat86 are maintained with Tat101, as Grin2a was upregulated in Tat101-injected tissue, among other differentially expressed genes. Spatial learning and memory impairment and Grin2a upregulation suggest that exposure to Tat protein drives adaptation in mPFC, altering the function of circuitry supporting spatial learning and memory.

Host single nucleotide polymorphisms and biomarkers of neuronal damage and inflammation in people living with HIV

ObjectivesBlood-brain barrier impairment is frequent in people living with human immunodeficiency virus (PLWHIV), affecting the penetration of target cells and antiretrovirals into the central nervous system, through transporters (e.g. ABCB1), leading to neuroinflammation. This study aimed to identify variants of genes encoding transporters able to predict neuroinflammation biomarker levels. MethodsCerebrospinal fluid (CSF) and plasma samples were obtained from PLWHIV. The CSF biomarkers were quantified by commercial assays. Genetic variants were evaluated through real-time polymerase chain reaction (PCR). ResultsA total of 107 PLWHIV (163 samples) were included in the study: 79% were male, median age was 48.5 years, CD4% was 25%, and HIV-associated neurocognitive disorder (HAND) was observed in 17.8%. The ABCB1 2677G>T genetic variant showed a different allelic distribution according to the clinical group (P = 0.026). In linear regression analyses, HIV-related central nervous system disorders, ABCG2 1194+928CC genotype, log viral load, CSF-to-serum albumin ratio, β-1,42 levels, and CSF proteins were retained in the final model as factors independently associated with CSF neopterin levels; CSF proteins and integrase inhibitor use were associated with CSF tau level in the multivariate model. Phospho-tau regression analysis reported the ABCB1 2677GT/TT genotype and CSF proteins as predictors in the final model; sex, protease inhibitors, neopterin, and ABCB1 2677 GT/ TT genotype were predictors in the multivariate regression for β-1,42. ConclusionsFor the first time, pharmacogenetic and clinical features were found to be predictors of neuro-inflammation biomarkers.

Mindfulness-Based Stress Reduction for Symptom Management in Older Individuals with HIV-Associated Neurocognitive Disorder.

The growing number of people aging with HIV represents a group vulnerable to the symptom burdens of HIV-associated neurocognitive disorder (HAND). Among younger groups, Mindfulness-Based Stress Reduction (MBSR) has been shown to help people living with HIV manage HIV-related and other life stress, and although there is some theoretical and empirical evidence that it may be effective among those with cognitive deficits, the approach has not been studied in older populations with HAND. Participants (n = 180) 55years or older with HIV and cognitive impairment were randomly assigned to either an 8-week MBSR arm or a waitlist control. We assessed the impact of MBSR compared to a waitlist control on psychological outcomes [stress, anxiety, depression, and quality of life (QOL)] and cognitive metrics (e.g., speed of information processing, working memory, attention, impulsivity) measured at baseline, immediately post intervention (8weeks) and one month later (16weeks). Intent to treat analyses showed significant improvement in the MBSR group compared to control on symptoms of depression from baseline to 8weeks, however, the difference was not sustained at 16weeks. The MBSR group also showed improvement in perceived QOL from baseline to 16weeks compared to the waitlist control group. Cognitive performance did not differ between the two treatment arms. MBSR shows promise as a tool to help alleviate the symptom burden of depression and low QOL in older individuals living with HAND and future work should address methods to better sustain the beneficial impact on depression and QOL.

Quantitative Proteomics Reveal That CB2R Agonist JWH-133 Downregulates NF-κB Activation, Oxidative Stress, and Lysosomal Exocytosis from HIV-Infected Macrophages.

HIV-associated neurocognitive disorders (HAND) affect 15-55% of HIV-positive patients and effective therapies are unavailable. HIV-infected monocyte-derived macrophages (MDM) invade the brain of these individuals, promoting neurotoxicity. We demonstrated an increased expression of cathepsin B (CATB), a lysosomal protease, in monocytes and post-mortem brain tissues of women with HAND. Increased CATB release from HIV-infected MDM leads to neurotoxicity, and their secretion is associated with NF-κB activation, oxidative stress, and lysosomal exocytosis. Cannabinoid receptor 2 (CB2R) agonist, JWH-133, decreases HIV-1 replication, CATB secretion, and neurotoxicity from HIV-infected MDM, but the mechanisms are not entirely understood. We hypothesized that HIV-1 infection upregulates the expression of proteins associated with oxidative stress and that a CB2R agonist could reverse these effects. MDM were isolated from healthy women donors (n = 3), infected with HIV-1ADA, and treated with JWH-133. After 13 days post-infection, cell lysates were labeled by Tandem Mass Tag (TMT) and analyzed by LC/MS/MS quantitative proteomics bioinformatics. While HIV-1 infection upregulated CATB, NF-κB signaling, Nrf2-mediated oxidative stress response, and lysosomal exocytosis, JWH-133 treatment downregulated the expression of the proteins involved in these pathways. Our results suggest that JWH-133 is a potential alternative therapy against HIV-induced neurotoxicity and warrant in vivo studies to test its potential against HAND.

Cognitive Impairment in People Living with HIV and the Impact of Mood: Results from a Cross-Sectional Study.

Background: Human Immunodeficiency Virus (HIV) infection represents a significant public health concern and, consequently, the incidence of HIV-Associated Neurocognitive Disorder (HAND) has grown over the years. The present study aims to assess HAND with the Montreal Cognitive Assessment (MoCA) in People Living With HIV/AIDS (PLWHA) to find significant associations with cognitive impairment. Methods: The study included 210 PLWHA, aged from 30 to 81 years, of whom, 137 (65.2%) were males. They were assessed at the Immunology Service of the University Hospital of Monserrato, Cagliari, Italy, between November 2022 and April 2023. Results: The sample showed an overall optimal response to antiretroviral therapy, as shown by the excellent levels of CD4+ lymphocytes and HIV RNA copies. A sum of 115 subjects (54.8%) were considered cognitively impaired and the multivariate analysis demonstrated that it was independently associated with duration of infection (OR: 0.96), age (OR: 1.12), alanine aminotransferase (ALT) (OR: 1.02), and depression (OR: 1.33). By dichotomizing the variables, the significance of the association was confirmed for age (65-year threshold) (χ2: 5.142, p = 0.0233) and depression (χ2: 7.834, p = 0.0051). Conclusions: Our study demonstrates that it is hard to find both statistically and clinically significantly associated variables with cognitive impairment in PLWHA, and that the strongest independent association is with depressed mood.