In particular, examination of biomarkers of stress and trauma in PLWH may help to understand mechanisms underlying the associations between TES and neurocognitive and everyday function observed in this study. Efforts to reduce trauma, poverty, and other stressful contexts and developing resources to help people manage and cope with past and current adverse circumstances could be relevant to decreasing neurocognitive impairment, particularly the high rates of mild neurocognitive disorder, in PLWH. Historical descriptions of the stimulatory effects of Cannabis sativa on feeding are now explained by the ability of its psycho active constituent 9 -tetrahydrocannabinol to interact with CB1 cannabinoid receptors.Moreover, THC increases fat intake in laboratory animals and stimulates appetite in humans. The selective CB1 receptor antagonist SR141716A counteracts these effects and, when administered alone, decreases standard chow intake and caloric consumption , presumably by antagonizing the actions of endogenously released endocan nabinoids such as anandamide and 2-arachidonoylglycerol. These results suggest that endocannabinoid substances may play a role in the promotion of food intake, possibly by delaying satiety. It is generally thought that the hyperphagic actions of canna binoids are mediated by CB1 receptors located in brain circuits involved in the regulation of motivated behaviors. Thus, infusions of anandamide in the ventromedial hypothalamus were shown to promote hyperphagia , whereas the anorectic effects of leptin were found to be associated with a decrease in hypothalamic anandamide levels. Nevertheless,cannabis grow equipment evidence suggests that cannabinoids also may promote feeding by acting at periph eral sites. Indeed, CB1 receptors are found on nerve terminals innervating the gastrointestinal tract , which are known to be involved in mediating satiety signals that originated in the gut.
To test this hypothesis, in the present study we have examined the impact of feeding on intestinal anandamide accumulation, the effects of central versus peripheral systemic administration of cannabinoid receptor agonists on feeding behavior, and the effects of sensory deafferentation on cannabinoid-induced hyperphagia.The present results suggest, first, that systemically administered cannabinoid agents affect food intake predominantly by engaging peripheral CB1 receptors lo calized to capsaicin-sensitive sensory terminals and, second, that intestinal anandamide is a relevant signal for the regulation of feeding. Two observations support the idea that cannabinoid agents modulate feeding through a peripheral mechanism. First, the lack of effect of central administration of cannabinoid antagonists such as SR14116A and 6-iodo-2-methyl-1-[2-ethyl]-[1H]-indol-3-yl methanone on food intake in food-deprived animals and, second, the ability of capsaicin-induced deafferentation to prevent changes in feeding elicited by the peripheral administra tion of cannabinoid drugs. Moreover, the similar pattern of ex pression of the early gene c-fos on hypothalamic and brainstem areas regulating food intake after both the peripheral adminis tration of either CB1 agonists and antagonists and the acute administration of peripherally acting satiety modulators such as gastrointestinal hormones or feeding inhibitors such as OEA further support the peripheral actions of cannabinoids on food intake. Finally, the fact that the CB1 receptor antagonist SR141716A was active only after intraperitoneal or oral administration but not after subcutaneous injection further supports this hypothesis. These results do exclude the possibility that peripheral anandamide also modulates feeding by acting on specific hypothalamic areas involved in caloric homeostasis. However, they do suggest that the predominant effects of systemically administered SR141716A are mediated by peripheral CB1 receptors, which may thus represent a potential target for anorexic agents. The concentration of anandamide in intestinal tissue increases during food deprivation, reaching levels that are threefold greater than those needed to half maximally activate CB1 receptors. This surge in anandamide levels, the mechanism of which is unknown, may serve as a short-range hunger signal to promote feeding.
This idea is supported by the ability of SR141716A to reduce food intake after systemic but not central administration. Locally produced anandamide also may be involved in the regulation of gastric emptying and intestinal peri stalsis, two processes that are inhibited by this endocannabinoid. Thus, intestinal anandamide appears to serve as an integrative signal that concomitantly regulates food intake and gastrointestinal motility. The predominant peripheral component of feeding suppression induced by SR141716A led us to analyze whether the modulation of food intake derived from CB1 receptor stimulation/blockade may interact with that produced by the noncannabinoid anand amide analog OEA. Our results indicate that the hyperphagic effects elicited by CB1 receptor stimulation were counteracted by the administration of OEA, whereas CB1 receptor blockade potentiates the suppression of feeding evoked by OEA. Because the intestinal levels of anandamide and OEA are inversely correlated , it is tempting to speculate that both compounds act in a coordinated manner to control feeding responses through their opposing actions on sensory nerve terminals within the gut.The Human Immunoeficiency Virus enters the central nervous system within days of initial infection , in many cases leading to neurological, cognitive, and behavioral complications. Cognitive deficits are a common feature of HIV/AIDS. While the incidence of HIV-associated dementia has considerably decreased in the era of modern ART suppressing viral replication, mild cognitive deficits with no change in everyday function persist in 24% [95% confidence interval = 20.3–26.8] of people with HIV and mild cognitive deficits with mildly decreased everyday function persist in about 13.3% of PWH. Although executive function and memory deficits are most common in PWH in the post-ART era, the characterization of cognitive impairment in HIV is highly variable with deficits observed in a range of cognitive domains. Previous studies using statistical clustering techniques have identified differing profiles of cognitive function among PWH with some profiles resembling global impairment across domains while other profiles resemble more domain-specific impairment,mobile vertical rack particularly in the domains of episodic memory and executive function. Similarly, there is also substantial variability in the risk factors associated with cognitive deficits among PWH that range from biological , demographic to psychosocial factors.
The persistence of cognitive impairment in the era of modern ART among PWH and the variability in the profiles and risk factors associated with cognitive impairment suggests that non-HIV factors associated with aging, comorbid conditions and psychosocial risk factors likely contribute to cognitive impairment given the high prevalence of these factors among PWH. With this in mind, we propose looking beyond the construct of HIV-associated neurocognitive disorders to identify the underlying pathophysiology linked to cognitive impairment as HAND requires other comorbidities to be ruled out as primary contributing factors. Biological sex is an important determinant of cognitive impairment among PWH. In a recent literature review of sex differences in cognitive impairment among PWH , seven cross-sectional and one longitudinal analysis identified sex differences on global measures of cognitive impairment among PWH. Additionally, six cross-sectional and one longitudinal analysis also reported sex differences in domain-specific cognitive performance. The strongest available evidence of adequately-powered studies indicates that WWH show greater deficits than MWH in the domains of learning and memory followed by speed of information processing and motor functioning, with inconsistent findings in executive functioning. The greater vulnerability of WWH to cognitive impairment may reflect sociodemographic differences between men and women with HIV. WWH tend to have a higher prevalence of psychosocial risk factors including poverty, low literacy levels, low educational attainment, substance abuse, poor mental health, and barriers to health care services as compared to MWH. These psychosocial risk factors may have biological effects on the brain that lead to reduced cognitive reserve among WWH as evidenced by findings of greater susceptibility of cognitive function to the effects of mental health factors among WWH vs. MWH. Additionally, biological factors such as sex steroid hormones and female-specific hormonal milieus may contribute to sex differences in cognitive test performance in PWH. However, it remains unclear how MWH and WWH may differ in the patterns of cognitive impairment and risk factors associated with these patterns of cognitive impairment. Previous reports of impairment profiles among PWH have identified them in combined samples of men and women , masking possible sex-specific patterns of cognitive impairment among PWH. Furthermore, although a number of studies reported sex differences in the presence and pattern of cognitive impairment and greater cognitive decline compared to MWH , only one study was adequately powered to address meaningful sex difference in global cognitive function. A well-powered examination of the patterns and determinants of cognitive impairment by sex, that also controls for other demographic differences between WWH and MWH , can help to clarify the contribution of sex to heterogeneity in cognitive impairment among PWH. Such an examination could also clarify the related psychosocial vs. biological factors and, thereby, optimize risk assessments and intervention strategies in both sexes.
Leveraging comprehensive neuropsychological data from the large-scale cohort of the HIV Neurobehavioral Research Program at the University of California-San Diego, we used novel machine learning methods to identify differing profiles of cognitive function in PWH and to evaluate how these profiles differ between women and men in sex-stratifified analyses. Rather, than using traditional cognitive domain scores, we used each of the NP test outcomes given that prior studies indicate that the correlation of NP test scores does not map to traditional domain scores in PWH. Furthermore, we determined how sociodemographic , clinical and biological factors related to cognitive profiles within women and men. Based on previous studies among PWH , we hypothesized that the machine learning approach would identify distinct subgroups of individuals with normal cognitive function, global cognitive impairment, and domain specific cognitive impairment. We further hypothesized that groups with domain-specific cognitive impairment would differ by sex, with WWH showing more consistent memory and processing speed impairment than MWH. Finally, we expected that similar sociodemographic/clinical/biological determinants would distinguish cognitive profiles among WWH and MWH; however, in line with previous research , we expected that depressive symptoms would be more strongly associated with cognitive impairment profiles among WWH than MWH. Study assessment details have been published elsewhere. The UCSD Institutional Review Board approved the studies. Participants provided written informed consent and were compensated for their participation. Exclusion criteria for the parent studies included history of non-HIV-related neurological, medical, or psychiatric disorders that affect brain functioning , learning disabilities, and a first language that was not English. Inclusion in the current study required completion of neuropsychological and neuromedical evaluations at the baseline study visit. Exclusion criteria for the current study included a positive urine toxicology test for illicit drugs or Breathalyzer test for alcohol on the day of clinic visit on the day of study visit. NP test performance was assessed through a comprehensive, standardized, battery of tests that measure seven domains of cognition, including complex motor skills, executive function, attention/working memory, episodic learning, episodic memory , verbal fluency, and information processing speed. Motor skills were assessed by the Grooved Pegboard Dominant and Non-dominant Hand tests. Executive functioning was assessed by the Trail Making Test -Part B and the Stroop Color and Word Test interference score. Attention/working memory was assessed by the Paced Auditory Serial Addition Task. Episodic learning was assessed by the Total Learning scores of the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised. Episodic memory was assessed by the Delayed Recall and Recognition scores of the HVLT-R and BVMT-R. Verbal Fluency was assessed by the “FAS” Letter Fluency test. Information processing speed was assessed by the WAIS-III Digit Symbol Test , the TMT-Part A, and the Stroop Color and Word Test color naming score. Raw test scores were transformed into age-, education-, sex-, and race/ethnicity-adjusted T-scores based on normative samples of HIV-uninfected persons. The use of demographically-adjusted T-scores are intended to control for these demographic effects as they occur in the general population. We examined sociodemographic, clinical, and biological factors associated with cognitive impairment in the literature and available with enough participants to be adequately powered in analyses. Sociodemographic factors included age, years of education, and race/ethnicity. Although these factors were used to create the T-scores, there can still be remaining demographic associations with cognition within clinical populations such as PWH. For example, there is considerable interest in the possibility of abnormal cognitive aging PWH; also, in general, older PWH tend to have had their infections longer, may have had longer periods without benefit of suppressive ART, and more history of worse immunosuppression.