RESUMEN
Whilst the average lifespan of persons with HIV now approximates that of the general population, these individuals are at a much higher risk of developing cognitive impairment with â¼35-70% experiencing at least subtle cognitive deficits. Previous works suggest that HIV impacts both low-level primary sensory regions and higher-level association cortices. Notably, multiple neuroHIV studies have reported elevated levels of spontaneous cortical activity during the pre-stimulus baseline period of task-based experiments, but only a few have examined such activity during resting-state conditions. In the current study, we examined such spontaneous cortical activity using magnetoencephalography in 79 persons with HIV and 83 demographically matched seronegative controls and related this neural activity to performance on neuropsychological assessments of cognitive function. Consistent with previous works, persons with HIV exhibited stronger spontaneous gamma activity, particularly in inferior parietal, prefrontal and superior temporal cortices. In addition, serostatus moderated the relationship between spontaneous beta activity and attention, motor and processing speed scores, with controls but not persons with HIV showing stronger beta activity with better performance. The current results suggest that HIV predominantly impacts spontaneous activity in association cortices, consistent with alterations in higher-order brain function, and may be attributable to deficient GABAergic signalling, given its known role in the generation of gamma and beta oscillations. Overall, these effects align with previous studies showing aberrant spontaneous activity in persons with HIV and provide a critical new linkage to domain-specific cognitive dysfunction.
RESUMEN
Even in the modern era of combination antiretroviral therapy, aberrations in motor control remain a predominant symptom contributing to age-related functional dependencies (e.g., neurocognitive impairment) in people with HIV (PWH). While recent evidence implicates aberrant mitochondrial redox environments in the modulation of neural oscillatory activity serving motor control in PWH, the contribution of important clinical and demographic factors on this bioenergetic-neural-behavioral pathway is unknown. Herein, we evaluate the predictive capacity of clinical metrics pertinent to HIV (e.g., CD4 nadir, time with viremia) and age on mitochondrial redox-regulated sensorimotor brain-behavior dynamics in 69 virally-suppressed PWH. We used state-of-the-art systems biology and neuroscience approaches, including Seahorse analyzer of mitochondrial energetics, EPR spectroscopy of intracellular oxidant levels, antioxidant activity assays pertinent to superoxide and hydrogen peroxide (H2O2) redox environments, and magnetoencephalographic (MEG) imaging to quantify sensorimotor oscillatory dynamics. Our results demonstrate differential effects of redox systems on the neural dynamics serving motor function in PWH. In addition, measures of immune stability and duration of compromise due to HIV had dissociable effects on this pathway, above and beyond the effects of age alone. Moreover, peripheral measures of antioxidant activity (i.e., superoxide dismutase) fully mediated the relationship between immune stability and current behavioral performance, indicative of persistent oxidative environments serving motor control in the presence of virologic suppression. Taken together, our data suggest that disease-related factors, in particular, are stronger predictors of current redox, neural and behavioral profiles serving motor function, which may serve as effective targets for alleviating HIV-specific alterations in cognitive-motor function in the future.
Asunto(s)
Antioxidantes , Infecciones por VIH , Humanos , Peróxido de Hidrógeno , Infecciones por VIH/tratamiento farmacológico , Oxidación-Reducción , BiomarcadoresRESUMEN
Despite virologic suppression, people living with HIV (PLWH) remain at risk for developing cognitive impairment, with aberrations in motor control being a predominant symptom leading to functional dependencies in later life. While the neuroanatomical bases of motor dysfunction have recently been illuminated, the underlying molecular processes remain poorly understood. Herein, we evaluate the predictive capacity of the mitochondrial redox environment on sensorimotor brain-behavior dynamics in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art approaches, including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance spectroscopy to measure superoxide levels, antioxidant activity assays and dynamic magnetoencephalographic imaging to quantify sensorimotor oscillatory dynamics. We observed differential modulation of sensorimotor brain-behavior relationships by superoxide and hydrogen peroxide-sensitive features of the redox environment in PLWH, while only superoxide-sensitive features were related to optimal oscillatory response profiles and better motor performance in controls. Moreover, these divergent pathways may be attributable to immediate, separable mechanisms of action within the redox environment seen in PLWH, as evidenced by mediation analyses. These findings suggest that mitochondrial redox parameters are important modulators of healthy and pathological oscillations in motor systems and behavior, serving as potential targets for remedying HIV-related cognitive-motor dysfunction in the future.
Asunto(s)
Infecciones por VIH , Estado de Salud , Humanos , Encéfalo , MitocondriasRESUMEN
BACKGROUND: Despite effective combination antiretroviral therapy (cART), people living with HIV (PLWH) remain at risk for developing neurocognitive impairment primarily due to systemic inflammation that persists despite virologic suppression, albeit the mechanisms underlying such inflammation are poorly understood. METHODS: Herein, we evaluate the predictive capacity of the mitochondrial redox environment on circulating neuro- and T-lymphocyte-related inflammation and concomitant cognitive function in 40 virally-suppressed PLWH and 40 demographically-matched controls using structural equation modeling. We used state-of-the-art systems biology approaches including Seahorse Analyzer of mitochondrial function, electron paramagnetic resonance (EPR) spectroscopy to measure superoxide levels, antioxidant activity assays, and Meso Scale multiplex technology to quantify inflammatory proteins in the periphery. FINDINGS: We observed disturbances in mitochondrial function and the redox environment in PLWH compared to controls, which included reduced mitochondrial capacity (t(76) = -1.85, p = 0.034, 95% CI: -∞,-0.13), elevated levels of superoxide (t(75) = 1.70, p = 0.047, 95% CI: 8.01 E 3, ∞) and alterations in antioxidant defense mechanisms (t(74) = 1.76, p = 0.041, 95% CI: -710.92, ∞). Interestingly, alterations in both superoxide- and hydrogen peroxide-sensitive redox environments were differentially predictive of neuro-, but not T-lymphocyte-related inflammatory profiles in PLWH and controls, respectively (ps < 0.026). Finally, when accounting for superoxide-sensitive redox pathways, neuroinflammatory profiles significantly predicted domain-specific cognitive function across our sample (ß = -0.24, p = 0.034, 95% CI: -0.09, -0.004 for attention; ß = -0.26, p = 0.018, 95% CI: -0.10, -0.01 for premorbid function). INTERPRETATION: Our results suggest that precursors to neuroinflammation apparent in PLWH (i.e., mitochondrial function and redox environments) predict overall functionality and cognitive dysfunction and importantly, may serve as a proxy for characterizing inflammation-related functional decline in the future. FUNDING: National Institute of Mental Health, National Institute for Neurological Disorders and Stroke, National Institute on Drug Abuse, National Science Foundation.
Asunto(s)
Complejo SIDA Demencia/sangre , Estrés Oxidativo , Complejo SIDA Demencia/diagnóstico , Adulto , Anciano , Biomarcadores/sangre , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mitocondrias/metabolismo , Superóxidos/metabolismo , Linfocitos T/metabolismoRESUMEN
BACKGROUND: Measles outbreaks have become increasingly common due to deteriorating vaccination rates, fluctuating herd immunity, and varying antibody decline. Limited knowledge exists regarding prevalence and risk factors associated with measles seronegativity among persons with HIV (PWH). METHODS: This was a cross-sectional study conducted at an academic HIV clinic in Omaha, Nebraska. Participants were screened for the presence of measles IgG antibody. Demographic and clinical information was obtained through electronic medical record review. Simple and multivariable logistic regressions were performed to identify risk factors for measles seronegativity. RESULTS: Three hundred fifty-one participants were enrolled, with a measles seroprevalence rate of 70.3%. The mean age (range) was 48 (20-74) years, 77% were male, and 53% were Caucasian. The mean CD4 nadir (range) was 334 (1-1675) cells/mm3. At the time of testing, 86% and 87% of the seronegative and seropositive participants had an HIV RNAâ <50 copies/mL, respectively. Younger age was significantly associated with measles seronegativity (Pâ =â .003), as was birth year after 1957 (Pâ =â .021). Prior history of measles infection was associated with seropositivity (Pâ =â .011). All other risk factors evaluated, including written documentation of adequate vaccination, were not associated with seronegativity. CONCLUSIONS: Our study demonstrates a measles seroprevalence rate that is remarkably lower than previously reported in PWH (92%), and, more importantly, is considerably lower than the rate needed to maintain herd immunity (95%). With higher than expected seronegativity and absence of notable risk factors aside from age, our findings support expanded measles immunity screening for PWH who are at risk of measles exposure.