Elevated Biomarkers of Inflammation and Vascular Dysfunction Are Associated with Distal Sensory Polyneuropathy in People with HIV

Distal sensory polyneuropathy (DSP) is a disabling, chronic condition in people with HIV (PWH), even those with viral suppression of antiretroviral therapy (ART), and with a wide range of complications, such as reduced quality of life. Previous studies demonstrated that DSP is associated with inflammatory cytokines in PWH. Adhesion molecules, essential for normal vascular function, are perturbed in HIV and other conditions linked to DSP, but the link between adhesion molecules and DSP in PWH is unknown. This study aimed to determine whether DSP signs and symptoms were associated with a panel of plasma biomarkers of inflammation (d-dimer, sTNFRII, MCP-1, IL-6, IL-8, IP-10, sCD14) and vascular I integrity (ICAM-1, VCAM-1, uPAR, MMP-2, VEGF, uPAR, TIMP-1, TIMP-2) and differed between PWH and people without HIV (PWoH). A cross-sectional study was conducted among 143 participants (69 PWH and 74 PWoH) assessed by studies at the UC San Diego HIV Neurobehavioral Research Program. DSP signs and symptoms were clinically assessed for all participants. DSP was defined as two or more DSP signs: bilateral symmetrically reduced distal vibration, sharp sensation, and ankle reflexes. Participant-reported symptoms were neuropathic pain, paresthesias, and loss of sensation. Factor analyses reduced the dimensionality of the 15 biomarkers among all participants, yielding six factors. Logistic regression was used to assess the associations between biomarkers and DSP signs and symptoms, controlling for relevant demographic and clinical covariates. The 143 participants were 48.3% PWH, 47 (32.9%) women, and 47 (33.6%) Hispanics, with a mean age of 44.3 ± 12.9 years. Among PWH, the median (IQR) nadir and current CD4+ T-cells were 300 (178–448) and 643 (502–839), respectively. Participants with DSP were older but had similar distributions of gender and ethnicity to those without DSP. Multiple logistic regression showed that Factor 2 (sTNFRII and VCAM-1) and Factor 4 (MMP-2) were independently associated with DSP signs in both PWH and PWoH (OR [95% CI]: 5.45 [1.42–21.00], and 15.16 [1.07–215.22]), respectively. These findings suggest that inflammation and vascular integrity alterations may contribute to DSP pathogenesis in PWH, but not PWoH, possibly through endothelial dysfunction and axonal degeneration

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

Frailty and HIV disease severity synergistically increase risk of HIV-associated Neurocognitive Disorders.

BACKGROUND:Frailty disproportionally affects people with HIV (PWH) and increased frailty in this already vulnerable population is associated with worse neurocognitive functioning. Whether frailty interacts with current and modifiable markers of HIV disease severity to synergistically increase risk for HIV-Associated Neurocognitive Disorders (HAND), however, is unknown and important for informing the clinical care of aging PWH. SETTING:UC San Diego's HIV Neurobehavioral Research Program METHODS:: Participants were 178 people with HIV (PWH) evaluated between 2014 and 2019. HIV disease severity was measured by current CD4 count and plasma HIV RNA. HAND diagnoses were made according to the Frascati criteria using a seven-domain neuropsychological battery and the Fried Phenotype criteria was used to assess frailty syndrome (0 to 5 symptoms). The independent and interactive effects of frailty and current HIV disease severity (i.e., CD4 count and plasma HIV RNA) on HAND were examined using multiple logistic regression. RESULTS:There was an interaction between CD4 count and frailty on HAND. Simple slopes showed that CD4 count and the likelihood of HAND were negatively associated at >1.25 symptoms of frailty, and conversely, that frailty and HAND were negatively associated at 642 or less cells/mm. There was no significant independent or interactive effects of plasma HIV RNA and frailty on the likelihood of HAND. CONCLUSIONS:In addition to monitoring CD4 count, assessing for frailty may be critical in older adults with HIV to potentially mitigate poor neurobehavioral outcomes. Longitudinal follow-up studies are needed to determine the directionality of these findings

Frailty and HIV disease severity synergistically increase risk of HIV-associated Neurocognitive Disorders.

BACKGROUND:Frailty disproportionally affects people with HIV (PWH) and increased frailty in this already vulnerable population is associated with worse neurocognitive functioning. Whether frailty interacts with current and modifiable markers of HIV disease severity to synergistically increase risk for HIV-Associated Neurocognitive Disorders (HAND), however, is unknown and important for informing the clinical care of aging PWH. SETTING:UC San Diego's HIV Neurobehavioral Research Program METHODS:: Participants were 178 people with HIV (PWH) evaluated between 2014 and 2019. HIV disease severity was measured by current CD4 count and plasma HIV RNA. HAND diagnoses were made according to the Frascati criteria using a seven-domain neuropsychological battery and the Fried Phenotype criteria was used to assess frailty syndrome (0 to 5 symptoms). The independent and interactive effects of frailty and current HIV disease severity (i.e., CD4 count and plasma HIV RNA) on HAND were examined using multiple logistic regression. RESULTS:There was an interaction between CD4 count and frailty on HAND. Simple slopes showed that CD4 count and the likelihood of HAND were negatively associated at >1.25 symptoms of frailty, and conversely, that frailty and HAND were negatively associated at 642 or less cells/mm. There was no significant independent or interactive effects of plasma HIV RNA and frailty on the likelihood of HAND. CONCLUSIONS:In addition to monitoring CD4 count, assessing for frailty may be critical in older adults with HIV to potentially mitigate poor neurobehavioral outcomes. Longitudinal follow-up studies are needed to determine the directionality of these findings

COMT val158met genotype alters the effects of methamphetamine dependence on dopamine and dopamine-related executive function: preliminary findings

The Met-allele of the COMT Val158Met polymorphism slows metabolism and increases bioavailability of dopamine (DA) in the prefrontal cortex compared to the Val-allele. Healthy Met-carriers outperform Val-carriers on executive function (EF) tests, yet this 'advantage' disappears in methamphetamine (METH) dependence. Met-carriers may be disproportionately vulnerable to METH-related perturbations of DA, yet it is unknown whether COMT modulates METH effects on CSF DA biomarkers. Participants were 75 METH+ and 47 METH- men who underwent neurocognitive testing, COMT genotyping, and lumbar puncture. CSF was assayed for DA and its metabolite, homovanillic acid (HVA). Separate linear models regressed DA, HVA, and HVA/DA ratios on COMT, METH and their interaction. Pearson correlations examined associations between DA and EF. Significant interactions indicated that METH+ had lower DA and higher HVA/DA ratios among Met/Met, but not Val/Met-or Val/Val. Met/Met-exhibited the highest DA levels among METH-, whereas DA levels were comparable between Met/Met-and Val-carriers among METH+. Higher DA correlated with better EF in METH- Met/Met, but did not predict EF in the entire sample. DA was expectedly higher in METH- Met/Met, yet a discordant genotype-phenotype profile emerged in METH+ Met/Met, consistent with the notion that slow DA clearance exacerbates METH-associated DA dysregulation

Relationship of the balloon analog risk task to neurocognitive impairment differs by HIV serostatus and history of major depressive disorder.

HIV and major depressive disorder (MDD) commonly co-occur and are both linked to greater risk-taking behavior, possibly due to neurocognitive impairment (NCI). The present study examined the concordance of the Balloon Analog Risk Task (BART), a gold standard measure of risk-taking propensity, with NCI and real-world sexual risk behaviors in PWH with comorbid MDD. Participants included 259 adults, stratified by HIV serostatus (HIV + /HIV -) and lifetime MDD (MDD + /MDD -), who completed neuropsychological testing, the BART, and sexual risk behavior questionnaires. Logistic regression, stratified by HIV serostatus, examined joint effects of MDD and BART (linear and quadratic) on NCI. Follow-up linear regressions examined sexual risk behavior and neurocognitive domain T-scores as correlates of the BART. NCI prevalence was lowest in HIV - /MDD - , but BART scores did not differ by HIV/MDD status. In the HIV + group, BART performance predicted NCI such that high and low BART scores related to greater odds of NCI, but only in dual-risk HIV + /MDD + individuals. HIV + /MDD + individuals with both low and high BART scores exhibited poorer learning and recall, whereas processing speed and executive function were only poor in low BART risk-taking HIV + /MDD + . Higher BART scores linearly related to higher sexual risk behaviors only in MDD + individuals, independent of HIV serostatus. Low and high risk-taking on the BART may reflect discrete neurocognitive profiles in HIV + /MDD + individuals, with differential implications for real-world sexual risk behavior. HIV and comorbid MDD may disturb corticostriatal circuits responsible for integrating affective and neurocognitive components of decision-making, thereby contributing to risk-averse and risk-taking phenotypes