Browsing by Subject "HIV-associated neurocognitive disorders"
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Item Blood-Based Inflammation Biomarkers of Neurocognitive Impairment in People Living with HIV(2020-05) Swanta, Naomi K.; Borgmann, Kathleen; Berg, Rance E.; Cunningham, Rebecca L.; Johnson, Leigh A.; Yan, Liang-JunRace and sex minorities are disproportionately affected by HIV in the United States. Approximately 50% of people living with HIV (PLWH) experience HIV-associated neurocognitive disorders (HAND). ART has decreased incidence of HAD but the less severe forms of HAND has increased. Diagnosis of HAND is challenging as the often-subtle forms of impairment are not as overt as dementia. HIV infection promotes neurocognitive dysfunction through persistent inflammation, which correlates with the severity of impairment. The objective of this study was to identify blood-based cytokines that associate with, and could predict, neurocognitive functioning in a demographically balanced cohort of PLWH. Inflammatory biomarkers of HIV-associated neurocognitive impairment could improve current diagnosis methods and may be specific for populations disproportionately affected by the HIV. Seven neurocognitive domains were evaluated in 121 seropositive African American, Non-Hispanic White and White Hispanic men and women using computerized assessments. A panel of 26 inflammation-associated cytokines were measured in plasma and blood mononuclear cells. Significant associations among neurocognitive functioning and HIV-related parameters, relevant sociodemographic variables and cytokine panel were determined using multivariate and univariate regression analyses. Following corrections for education, CD4 T cell counts, viral load and eliminating outliers. Our results demonstrate that chemokine C-C motif ligand (CCL) 8 significantly correlated with memory, complex attention, cognitive flexibility, psychomotor speed, executive functioning and processing speed. Tissue inhibitor of metalloproteinases-1 (TIMP-1) significantly correlated with the aforementioned domains except memory and processing speed. In addition, interleukin (IL) - 23 significantly associated with executive functioning and processing speed. The biomarkers demonstrated a negative correlation to neurocognitive functioning. Race disparities were identified in memory and CCL8, furthermore, sex disparities were identified in executive functioning and TIMP-1. The plasma biomarkers were evaluated as predictive classifiers of neurocognitive functioning. Decision tree models for NCI and executive functioning predicted visit two at 67.2% accuracy. Collectively, these data identified blood-based inflammatory biomarkers of neurocognitive function with the potential to assist in the diagnosis of HIV-associated neurocognitive impairments in PLWH.Item TAARgeting Astrogliosis and Mitochondrial Dysfunction during METH Exposure and HIV-relevant Neuroinflammation(2017-12-01) Borgmann, Kathleen; Ghorpade, Anuja; Wordinger, Robert J.; Berg, Rance E.As a popular psychostimulant, methamphetamine (METH) use leads to long-lasting, strong euphoric effects. METH exacerbates the severity and onset of HIV-associated neurocognitive disorders (HAND), which affect 30-70% of the 37.6 million people globally infected with HIV. Most neurodegenerative diseases share neuroinflammation as a common pathogenic mechanism. Neuroinflammation, HIV and METH dysregulate a wide range of brain functions including neuronal signaling, glial activation, viral infection, oxidative stress and excitotoxicity. Since neuroglia determine the outcome of neurological disease, we investigate the mechanisms regulating astrocyte-mediated neurotoxicity in the context of METH and HIV comorbidity. To these ends, we examined the expression, localization and function of the novel METH astrocyte receptor, trace amine associated receptor 1 (TAAR1) in an extended METH in vitro model, which mimics chronic residual METH concentrations between binges, and HIV-associated activation. In our model, TAAR1 levels and localization to the endoplasmic reticulum and plasma membranes increased with METH and HIV-induced astrogliosis. Extended physiological METH exposure led to augmented calcium flux, a mechanism known to mediate ER and mitochondrial, and oxidative stress. METH induced dysregulation of astrocyte mitochondrial morphology by elevating mitofusin expression and inhibitory phosphorylation of dynamin-related protein-1. While METH decreased oxygen consumption and ATP levels during acute exposure, chronic treatment significantly enhanced both. Together, these changes increased expression of antioxidant proteins, augmenting the astrocyte’s oxidative capacity, but also oxidative damage. METH and HIV activation impaired excitatory amino acid transporter 2 (EAAT2) expression and activity, which were recovered by inhibition of TAAR1 with EPPTB, a TAAR1 selective antagonist. Together, these data highlight several mechanisms regulating METH/HIV-induced, astroglia-mediated neurotoxicity and the potential for astrocyte targeted intervention via TAAR1 during chronic disease. We propose that equilibrium between agonism of neuronal TAAR1 and antagonism of astrocyte TAAR1 will need to be further investigated to balance the neuroprotective benefits of TAAR1 targeting drugs in the CNS during HIV and METH comorbidity.