Recent alcohol use was assessed via the HNRP Substance Use History form. This form is a modified timeline follow-back measure that assesses alcohol use metrics including the quantity and frequency of alcohol use in the last 30 days . The variable capturing the total number of drinks consumed in the last 30 days was calculated by multiplying the daily rate of alcohol consumption by the number of consumption days in the last 30 days . Total number of drinks consumed in the last 30 days will be hereafter referred to as total drinks. Participants who reported no recent alcohol consumption were included in analyses as alcohol abstainers, with total drinks coded as 0. Participants were administered a well-validated, comprehensive battery of neuropsychological tests designed in accordance with the international consensus conference recommendations for HIV-associated Neurocognitive Disorders . The battery assesses seven neurocognitive domains: verbal fluency, executive function, processing speed, learning, delayed recall, working memory, and motor skills. Individual test raw scores were converted into demographically-adjusted Tscores , which were then averaged across the entire battery and within each domain to derive mean global and domain-specific T-scores, respectively . HIV group differences on demographic, psychiatric, neurocognitive, and alcohol use characteristics were compared using independent t-tests, Wilcoxon tests,flood and drain tray and Chi-square statistics as appropriate. Separate multiple linear regressions examined the interaction between the quadratic effects of total drinks and HIV status on global and domain-specific T-scores.
Demographic variables that significantly differed by HIV status at a p < .05 threshold were included as covariates. Considering the high prevalence of lifetime AUD in both persons with and without HIV, lifetime AUD was included as a covariate. Additionally, diagnosis of a lifetime non-alcohol substance use disorder was included as a covariate to account for potential confounding effects of non-alcohol substance use on neurocognitive outcomes. A follow-up analysis was conducted for any model that did not reveal a significant or trend-level interaction term between the quadratic effect of total drinks and HIV status. The follow-up analysis examined the interaction between the linear effect of total drinks and HIV status on domain-specific T-scores, covarying for demographic variables included in primary regression analyses. As a secondary followup analysis, the independent effects of total drinks and HIV status were examined for any model that did not show a significant interaction term , covarying for the same demographic variables inprimary regression analyses. Regression analyses were performed using JMP Pro version 14.0.0 . Exploratory analyses, stratified by HIV status, employed the Johnson-Neyman technique to identify specific regions along the quadratic curve of total drinks at which total drinks had a statistically significant effect on neurocognition . Compared to simple slope analyses that describe quadratic effects based on how the effect of a predictor changes at different levels of that predictor, the J-N technique computes the full range of values for which the predictor slope is statistically significant. These boundaries are referred to as regions of significance.
Considering long-term heavy alcohol use may have ongoing neurocognitive effects, an additional exploratory analysis examined the association between lifetime history of AUD and alcohol abstinence using a Chi-squared statistic. Finally, we explored the associations between HIV disease characteristics and global neurocognitive function using independent t-tests. We have included any significant variables as covariates in the linear regression analysis by HIV-serostatus. These analyses were performed using JMP Pro version 14.0.0 .Results of linear regressions examining the interaction between the quadratic effect of total drinks and HIV status on neurocognitive outcomes are presented in Table 2. In these adjusted models, the interaction between the quadratic effect of total drinks and HIV status was significant for global function , executive function , learning , delayed recall , and motor skills . With respect to covariates, older age, a lifetime history of MDD, and a lifetime history of a non-alcohol substance use disorder were associated with worse neurocognitive performance across multiple domains. Follow-up analyses were conducted to examine the interaction between the linear effect of total drinks and HIV status on neurocognitive outcomes that showed no significant or trend-level interaction term . Similar adjusted linear regression models revealed no significant interaction effects between total drinks and HIV status on domain specific neurocognition . To further examine the independent effects of total drinks and HIV status on neurocognition, linear regression models examined the effects of HIV status, total drinks, and covariates from previous models on neurocognitive outcomes . In these adjusted models, HIV status was significantly associated with verbal fluency , processing speed , and working memory , such that PWH performed significantly worse than their HIV- counterparts. There were no detected effects of total drinks on domain specific neurocognitive outcomes. Additional follow-up analyses on domains that revealed significant quadratic associations were stratified by HIV serostatus . Results exploring the associations between HIV disease characteristic and global neurocognitive function suggest a significant negative association between estimated duration of HIV disease and global neurocognitive function .
Therefore, estimated duration of disease was included as a covariate in the linear regression model for PWH. The number of total drinks was not associated with neurocognition in PWH. Our study is among the first to examine the curvilinear association between recent “low-risk” alcohol consumption and neurocognition among persons with and without HIV. Among HIV individuals, the association between low-risk drinking and neurocognition expectedly followed an inverted-J shaped pattern, with better neurocognition occurring at intermediate levels of “low-risk” drinking compared to alcohol abstinence and heavier consumption. Specifically, region of significance analyses indicated a positive slope of alcohol consumption on global neurocognitive function when the range of total drinks was zero to 18 drinks, whereas a negative slope emerged when the range of total drinks was 52 to 60 drinks; suggesting a potentially innocuous range between 18 to 52 drinks per month for HIV- individuals. This global effect was driven by abilities supported by frontal brain regions where alcohol metabolism is thought to be particularly active . Additionally, consistent with our hypotheses, there was no quadratic association between level of low-risk alcohol consumption and neurocognition among PWH. This suggests the presence of other factors that may supersede the potentially beneficial neurocognitive effects of low-risk alcohol consumption in the context of HIV. For example, age was significantly associated with global function, executive function, learning, and delayed recall in PWH, despite using age-adjusted T-scores in analyses. Extant literature suggests that the inverted-J shaped association is not unique to neurocognition, which may point towards possible mechanisms underlying the neuroprotective effect of low-risk alcohol consumption. For example, evidence supports a cardioprotective effect of low-risk alcohol consumption including a reduced risk of coronary heart disease, myocardial infarction, ischemic stroke, peripheral arterial disease, and all-cause mortality . There is a higher risk among alcohol abstainers and when alcohol consumption is high,hydroponic tables canada and lower risk when alcohol consumption is low . Although our data does not directly measure pathways underlying a potential neuroprotective effect of low-risk alcohol consumption, including its specificity to HIV- adults, several plausible bio-psychosocial mechanisms can be drawn from the extant literature. From a biological perspective, low-risk alcohol use has been linked to increased high-density lipoprotein levels and may carry antithrombotic, antioxidative, and anti-inflammatory effects that benefit the neurovascular unit . Additionally, alcohol may directly enhance learning and executive function via stimulation of acetylcholine in the prefrontal cortex and hippocampus . Considering that alcohol consumption increases HDL cholesterol levels, it has been proposed that the association between HDL cholesterol and lowered risk of coronary heart disease is mediated in part by alcohol-induced increases in HDL cholesterol . Other possible mechanisms underlying the observed beneficial effect of low-risk drinking on neurocognition among HIV- individuals in our sample may involve lifestyle factors and/or indicators of socioeconomic status not measured in the current study. For example, previous research exploring beneficial effects of drinking have suggested that low-risk alcohol consumption may be an indicator of higher socioeconomic status and engagement in a healthier lifestyle that includes better nutrition and physical activity . Moreover, persons of lower socioeconomic status may not have the means to afford alcohol and be more medically compromised which could lead to voluntary or medically recommended abstinence . In addition, it is also well known that individuals of higher socioeconomic status are less likely to experience negative consequences from alcohol use compared to those of lower socioeconomic status who drink the same amount .
It is possible that our sample of HIV- participants were of relatively high socioeconomic status, especially compared to our sample of PWH, as HIV disproportionately affects individuals from lower income areas with fewer resources . Although we examined associations between certain HIV disease characteristics, alcohol use, and neurocognition, PWH face additional bio-psychosocial disadvantages that may explain the lack of beneficial effects of low-risk drinking among this group. Even in the context of low-risk use, the immuno suppressant properties of alcohol may counteract the cardio protective effects on downstream neurocognitive health among PWH, as immunosuppression leads to greater viral infectivity, replication, and subsequently poorer neuronal integrity . Furthermore, our HIV groups had different proportions of individuals with current and lifetime depression, with significantly higher rates among PWH. Depression is known to have adverse effects on neurocognitive performance in HIV , possibly limiting the expression of potentially beneficial effects of low-risk drinking among our PWH sample. The current study has several limitations. Although we detected effects that remained statistically significant after adjusting for relevant covariates, there could be potential unmeasured health and lifestyle confounders such as disability, social status, and reason for drinking, that may mediate the association between alcohol consumption and neurocognition. Next, our sample of low risk drinkers, especially among the HIV- group, had fewer drinkers on the high end of the low-risk drinking range, more alcohol abstainers, and more drinkers on the lower end of the low-risk drinking range. Furthermore, we did not have any method to verify self-reported alcohol abstinence. Despite our skewed sample in terms of levels of alcohol consumption, we still detected robust effects even after adjusting for relevant covariates. Objectively measured recent alcohol consumption would have reduced the possibility of misreporting alcohol abstinence, drinking quantities, and frequency; however, we believe structured interviews are still clinically relevant given that our timeline follow back was only 30 days prior. Future alcohol consumption research should employ methodologies to capture real time and ecologically valid data, rather than relying on retrospective recall. While the full range of “low-risk” drinking does not have discretely defined cut-points for minimal, light, and moderate alcohol use, our inclusion of the J-N technique allowed us to identify specific boundaries of recent alcohol consumption in which alcohol confers neurocognitive benefits or risks among HIV individuals. Although these analyses may help clinical efforts at identifying intervals of safe drinking for certain populations, interpretations must caution against the differences in low-risk drinking criteria for men and women. According to the NIAAA criteria for low-risk drinking, we included women who self-report 0-30 drinks in the last 30 days, and men who self-report 0-60 drinks. Therefore, the results of the J-N technique for lower regions of significance are applicable to both men and women, whereas the results in the upper regions of significance are applicable only to men. Future work with equal sample sizes by sex should investigate the associations between recent drinking and neurocognitive function to further adjust for sex differences. In conclusion, our results are consistent with the hypothesis of a curvilinear association between recent alcohol consumption and neurocognition within the range of low-risk drinking and only among HIV- older adults, such that intermediate levels of recent alcohol use were associated with better neurocognition compared to alcohol abstinence as well as lower and higher ranges of low-risk consumption. Among PWH, there were no detected beneficial or deleterious effects of low-risk alcohol consumption on neurocognition, suggesting that other factors that may supersede the neurocognitive effects of low-risk alcohol consumption in the context of HIV. There are two principal lines of evidence supporting the existence of an endogenous cannabinoid system. First, it is clear that cannabimimetic drugs exert their effects by binding with high affinity to selective membrane receptors . Second, substances with cannabimimetic properties, but with chemical structures that greatly differ from those found in plants, have been discovered in animal tissues .