Chronic inflammation and immune activation potentially predispose PLWH to greater risk for premature and accentuated aging, making prevention and treatment of comorbidities an important component of HIV-related care . Specifically, the three most common comorbidities for PLWH are hypertension, hyperlipidemia, and endocrine disease , which are all components of metabolic syndrome . MetS is conceptualized as a constellation of interrelated metabolic risk factors associated with an increased risk of developing cardiovascular disease : Expert Panel on Detection and Treatment of High Blood Cholesterol in Adults 2002. MetS is defined differently by various organizations, but generally includes visceral obesity, hypertension, endothelial dysfunction, atherogenic dyslipidemia, and insulin resistance . MetS is common in the USA, with approximately 34–35% of adults aged 18 years or older in the general population falling within the clinical criteria, and greater prevalence of MetS is observed with increasing age . Furthermore, MetS has also been consistently linked to neurocognitive dysfunction and brain abnormalities . Among PLWH, MetS is highly prevalent and there is evidence that its impact on neurocognitive impairment might be even more notable among PLWH than in the general population , possibly because of the impact of MetS on blood–brain barrier integrity and systemic inflammation . Aside from MetS, neurocognitive impairment is prevalent in HIV, occurring in approximately 40% of PLWH . HIV infiltrates the central nervous system early in the course of disease, resulting in neurocognitive impairment, which is often mild to moderate in severity in the era of combination ART. Another manifestation of CNS dysfunction in HIV are neurobehavioral disturbances or changes in daily behavior indicative of problems with motivation, initiating and organizing behavioral responses,cannabis drainage system and regulating emotional and behavioral responses in appropriate contexts .
These neurobehavioral disturbances have been empirically linked to frontal-subcortical dysregulation and central nervous system disease and may be present in the absence of neurocognitive impairment . Previous research has shown a consistent link between HIV serostatus and increased neurobehavioral disturbances, particularly increased apathy , disinhibition , and executive dysfunction . However, no studies have investigated the role of MetS on neurobehavioral disturbances associated with HIV. The main purpose of the present study was to examine the association between MetS and neurobehavioral disturbances in the context of HIV disease. Given prior findings by Yu et al. , we hypothesized that there would be an interaction between HIV serostatus and MetS on neurobehavioral disturbances, such that the association between MetS and neurobehavioral disturbances would be stronger among PLWH than among a HIV-uninfected comparison group, even after controlling for significant demographic and psychiatric characteristics and neurocognitive impairment.Participants included 215 adults enrolled in the baseline visit of the MultiDimensional Successful Aging among HIV-Infected Adults study conducted at the University of California San Diego HIV Neurobehavioral Research Program and the UCSD Sam and Rose Stein Institute for Research on Aging from 2013 to 2015 . Inclusion criteria included being between the ages of 36–65 years old, being fluent in English, and having the ability to provide informed consent. Exclusion criteria included the presence of a neurologic condition other than HIV known to impact cognitive functioning , diagnosis of a psychotic condition that could impact neurocognitive test performance , and having a positive urine toxicology screen on day of testing for an illicit substance other than cannabis.In order to be included in present analyses, participants had to have data available on the main variables of interest, i.e., MetS and neurobehavioral disturbances.
The UCSD Institutional Review Board approved the study, and all participants provided written informed consent and were compensated for participating. Participants self-reported demographic characteristics and completed a comprehensive neuropsychiatric and neuromedical evaluation in individual sessions conducted by trained study staff.Neurobehavioral disturbances were assessed via the 46-item self-report version of the Frontal Systems Behavior Scale . Participants provide retrospective ratings of how often they experience specific neurobehavioral symptoms “before the illness or injury” and “at the present time” using a Likert-type scale ranging from 1 to 5 . The scale yields T-scores adjusted for demographics for the entire scale and three sub-scales measuring apathy, disinhibition, and executive dysfunction. T-scores have a mean of 50 and a standard deviation of 10, and higher T-scores indicate greater reports of neurobehavioral disturbances, with a Tscore of 65 and higher suggesting clinical neurobehavioral disturbance. Previous studies have reported good internal reliability and consistent factor structure of the FrSBe sub-scales . Consistent with previous research present time FrSBe T-scores were used as the outcome of interest for the current study.All statistical analyses were conducted using SPSS 24 and JMP 11.0.0 and considered statistically significant at p < .05. Descriptive statistics were computed for FrsBe scores, MetS, demographic and psychiatric characteristics, neurocognitive impairment, and HIV disease characteristics. Group comparisons by HIV serostatus on demographic and psychiatric characteristics and neurocognitive impairment were conducted . HIV serostatus and MetS group differences on FrsBe scores were also conducted via independent sample t tests. In order to examine the potential interactive effect of HIV and MetS on neurobehavioral disturbances, we conducted a series of linear regression models with terms for HIV serostatus, MetS, and their interaction on each FrSBe subscale. In cases where the interaction term was not significant,it was removed from the model. The independent and unique effect of HIV serostatus and MetS on each FrSBe subscale was then assessed by evaluating linear regression models that included terms for HIV serostatus, MetS,indoor cannabis grow system and relevant covariates. In order to adjust for relevant covariates while also obtaining a parsimonious model for each FrSBe subscale, we followed these steps: identified sociodemographic and psychiatric variables in Table 1 that were associated with each FrSBe subscale at p < .10 via a series of univariate regression models; entered variables identified in Step 1 of the linear regression models and applied a stepwise backwards selection method based on Akaike information criterion to obtain a parsimonious model for each FrSBe subscale.
Age, sex, and education were not considered as possible covariates as FrSBe T-scores are adjusted for those demographic factors.MetS disproportionally impacts neurocognitive impairment, a marker of central nervous system dysfunction, among PLHIV compared to HIV-uninfected persons . Present findings revealed that similar interactive effects of HIV serostatus and MetS were not observed in the present sample on other behavioral manifestations associated with central nervous system dysfunction, i.e., neurobehavioral disturbances . Instead, there was an additive effect such that being HIV seropositive and having a clinical identification of MetS were independently associated with greater apathy and executive dysfunction, and there was a significant effect of HIV serostatus only on disinhibition. The presence of greater difficulties with neurobehavioral disturbances in PLWH compared to the HIV-uninfected comparison group aligns with previous research . When looking at the frontal subcortical circuits that may be affected, neuroimaging research has documented links between damage to the anterior cingulate cortex, dorsolateral prefrontal cortex, and orbital frontal cortex with difficulties with apathy, executive dysfunction, and disinhibition, respectively . Further, HIV-associated structural changes in both gray and white matter corresponding to these same areas have been documented . These cross-sectional findings inform the hypothesis that neurobehavioral disturbances seen in PLWH are associated with disease-related volume reduction and over-activation in comparison to HIV-uninfected comparison participants. These findings are of great interest not only from understanding how HIV affects the brain but also everyday functioning. For example, previous studies have shown associations between apathy and IADL decline, disability, and quality of life ; disinhibition, impulsivity, and risk-taking behaviors ; and executive dysfunction and ART medication adherence and employment status in PLWH. Further research is needed to understand association directionality and how these associations progress with age over time. While MetS and the related risk factors have been shown to be an important and unique predictor of neurocognitive change and decline in the general population , little is known on how MetS is related to neurobehavioral disturbances. Previous research has shown that the presence of MetS is associated with increased odds of presenting with higher white matter hyperintensity volumes and characterized by an anterior-posterior pattern of deterioration, such that greater deterioration is observed in the frontal lobe structures . Although not fully understood, several possible hypotheses on the mechanisms underlying the association between MetS and central nervous system dysfunction have been proposed, such as neuroinflammation, oxidative stress, abnormal brain lipid metabolism, altered cerebral hemodynamics, regional hypoperfusion, impaired cerebrovascular reactivity, and small vessel disease . While the current findings are based on self-report, greater difficulties with apathy and executive dysfunction parallels the known associations between MetS and brain structure and function. Specifically, executive function, typically measured by neuropsychology test performance, appears to be particularly sensitive to the neurologic impact of MetS .
Examination of individual components of MetS indicates that insulin resistance , diabetes mellitus , obesity , and hypertension have been linked to impaired performance on executive function tasks. Interestingly, HIV serostatus and MetS were independently associated with increased neurobehavioral disturbances within the same model, but there was no evidence of a statistical interaction. This is somewhat inconsistent with findings from Yu et al. who found evidence of an interaction on neurocognitive performance, such that association between MetS and neurocognitive impairment was stronger among PLWH than an HIV-uninfected comparison group. Yu et al. included a similar sample to ours, indicating that differences in participants’ characteristics are unlikely to explain differential findings across studies. At least part of the reason for the apparent inconsistency might be that while neurocognitive impairment and neurobehavioral disturbances are both indicative of underlying central nervous system dysfunction, there is evidence that they can exist in isolation from one another . Neurobehavioral disturbances are usually associated with dysfunction to frontal-subcortical circuitry, while our index of global neurocognitive deficits includes various neurocognitive domains which are mediated by a variety of brain structures. Furthermore, prior findings indicate that the impact of MetS on neurocognition among PLWH is most notable in the domains of learning and motor functioning, with smaller effects on executive function . Additionally, differences in HIV and MetS findings with neurobehavioral disturbances could allude to differential impacts on frontal-subcortical circuitry as there are both shared and segregated components to their structure that can only be better investigated and understood using neuroimaging and longitudinal design.Given the high prevalence of MetS and related negative health outcomes, efforts to prevent, treat, and possibly reverse the effects of MetS in middle-aged and older adults is of the greatest public health interest .Additionally, increasing daily physical exercise and reducing physical inactivity in combination with a healthy diet has also shown to be effective in reducing metabolic risk and reversing MetS components . These lifestyle modifications may be particularly important for PLWH as previous research has shown varying levels of sedentary leisure time and physical inactivity . For example, Moore et al. showed using ecological momentary assessment in a sample of middle-aged PLWH that 32% of their time was spent engaging in passive leisure activity compared to only 5% of their time which was spent engaging in physical exercise. Given the links between neurocognition and physical activity in PLWH , more research is needed to see if interventions designed to increase physical activity for an example and improve diet may further reverse MetS components as well as the related-cognitive consequences.While we have discussed findings primarily in the direction of HIV and MetS impacting neurobehavioral disturbances, it is important to consider that the directionality of the findings cannot be ascertained in the context of the present cross-sectional analyses. It might be the case that pre-existing neurobehavioral disturbances resulted in persons being more likely to acquire HIV and/or MetS. Additionally, given the strong association between certain ART regimens and lipid and glucose metabolism in PLWH and the high prevalence of these drug class types in our sample, further longitudinal investigation of lifetime and current ART regimens may provide more detail on the associations between HIV, MetS, and neurobehavioral disturbances. Another limitation included that neurobehavioral disturbances were based on self-report rather than informant report, observation, or performance-based tasks. While self-report might provide insight into daily behavior that may not be adequately captured or assessed with laboratory or clinic testing, self-report may also be confounded with bias, lack of awareness, and stigma of disease.