Lower UPSA-2 scores were related to lower education and WRAT-4 scores both in this study and the Blackstone et al. report, but in contrast to that study, our HIV+/ METH+ participants did not have lower education and WRAT-4 scores than the METH− groups, reflecting relatively intact premorbid intellectual functioning, or “cognitive reserve”, in the dually-affected participants. These cohort differences, and the observed relationship between cognitive reserve and everyday functioning, may help explain why prominent additive deficits of HIV and METH were seen in the Blackstone study but not the current one. Relatedly, the fact that the HIV−/METH+ participants in this study had higher, albeit non-significant, self-reported METH use than the HIV+/METH+ participants may also explain why dually-affected participants did not show more functional impairment than either singly-affected risk group. Self-report of more frequent and higher quantity of METH used was indeed related to lower UPSA-2 scores. We have previously observed a correlation between higher frequency of METH use and lower functioning scores in a smaller sample of HIV−/METH+ participants , a not-unexpected result given methamphetamine’s well-known neurotoxic effects especially in chronic users . With respect to the association between UPSA-2 Medication Management score and nadir CD4 count, a similar relationship has been reported previously , supporting the premise that disease indicators such as immunosuppression may have implications for everyday functional ability. Nadir CD4 is a historical marker of past disease severity and represents a legacy of brain injury that is believed to manifest later as increased risk for neurobehavioral deficits.
More puzzling, however,cannabis grow trays were the findings that worse scores on the Medication Management sub-scale were related to lower viral load; relatedly participants with undetectable viral load had lower scores on this scale than those with a detectable viral load. These observations are in contrast to a previous report associating detectable viral load to poorer neurocognitive functioning in HIV-positive women . Our findings are challenging to explain but perhaps other factors besides the ability to organize and recall a medication regimen may be driving ART non-adherence and subsequent detectable viral load, e.g., depression, apathy, limited access to medications, etc. Limitations of this study include lack of direct measures of ART adherence, which may have clouded our ability to understand the relationship between use of ART and everyday functioning in HIV-positive individuals. Additionally, there was a large variance in the METH use characteristics of the participants; for example in length of abstinence from the drug. These aspects of our study design likely precluded a refined analysis of the relationship between disease characteristics and functional ability. Furthermore, it can be argued that worse neurocognition and more severe depressive symptomatology in the risk groups may have driven the observed functional impairment. It is challenging to assess the causal relationships among these highly interrelated deficits, but independent of the causal pathway it is clear that METH and HIV are each associated with everyday functioning problems that have implications for how these individuals navigate through the challenges of daily life. Though not known as a primarily neurodegenerative disease, human immunod efficiency virus infection has been linked to cognitive impairment as well as cerebral metabolic changes.Currently, a set of research diagnostic criteria have been proposed to categorize HAND into three conditions: asymptomatic neurocognitive impairment, HIV-associated mild neurocognitive disorder, and HIV-associated dementia . Neuropsychological deficits in attention and learning have the highest prevalence in HIV+ patients ; as HIV disease progresses from early to later stages, executive functioning, information-processing speed, and motor functioning are associated with the greatest decline .
The precise neuroanatomical basis of the cognitive effects of HIV is still uncertain. Structural and functional brain imaging has revealed loss of gray and white matter volumes, increased white matter abnormality, and changes in perfusion and glucose metabolism associated with HIV . One indication of neuronal injury is reduced N-acetylaspartate , a putative marker of neuronal health and integrity, on magnetic resonance spectroscopy imaging . Increased HIV viral load and decreased CD4+ T-cell counts have been associated with decreased levels of NAA in the frontal white matter, frontal gray matter, and basal ganglia regions, suggesting that HIV infection may result in loss of neuronal integrity . Even when asymptomatic, persons with HIV infection may have decreased NAA levels in the basal ganglia region . With advanced ARV regimens, HIV infected individuals are living longer and in better health now than before. Paradoxically, HAND remains prevalent. For example, a recent study by the CHARTER group reported that 40–50% of people in HIV care, with the majority receiving HAART , have neurocognitive impairments . While the reasons for HAND persistence are unclear, one possibility is that certain coexisting factors might increase the brain’s vulnerability to HIV injury. Among such comorbidities, traumatic brain injury is commonplace. Since TBI still remains as a largely unexplored condition within the HIV population, we were interested in its potential effects in HIV-infected people. TBIs involve disruption of normal brain function that can be caused by a physical insult to the head, subjecting it to sudden acceleration and deceleration forces . The incidence of new TBIs each year in the United States is 2 million, which is approximately 35 times greater than the incidence of new HIV infection per year . The high prevalence of TBI in the general population suggests that TBI may be a common comorbidity in HIV+ persons that requires further investigation. The prevalence of HIV+ patients who have suffered from at least one TBI has not been reported systematically. However, in the 1,599 cases studied in the CHARTER program at the University of California, San Diego, approximately 21% reported head injury. Following a traumatic brain injury, people can experience a wide range of impairments in the cognitive, emotional, physical, and psychosocial domains and interactions amongst them .
People with moderate to severe TBI history can experience a range of cognitive deficits, with one of the most prevalent being difficulty in applying optimal strategies for learning and memory . MRS studies have confirmed that TBI patients also evidence lower NAA levels . Mild traumatic brain injury patients have also been shown to exhibit a 12% deficit in WBNAA , suggesting a loss in neuronal health following a head injury . To explore the possibility that TBI might enhance the effects of HIV on the brain, we performed comprehensive neuropsychological assessments with HIV-infected persons who did and did not have histories of TBI. We hypothesized that neurocognitive function in those with TBI would be worse than in those without, particularly in areas of cognition that have been implicated in each etiology—that is, working memory, attention, and executive function. We also performed a nested study on a subset of cases to examine changes in brain metabolites via MRS. Since HIV and TBI are each associated with decreases in NAA levels, we hypothesized that people with both HIV and TBI would evidence greater NAA reductions,vertical grow systems for sale suggestive of more neuronal injury.The results of this study indicate that HIV-infected participants who report substantial TBI, defined as a history of loss of consciousness greater than 30 minutes or complicated by neurological symptoms persisting more than 2 weeks after the injury, were significantly more impaired in working memory and executive functioning than the HIV+ TBI– group. Consistent with our neuropsychological test results, the HIV+TBI+ group also reported more neurocognitive problems, including memory and sensory complaints. From our MRS subset, we found that HIV and TBI together were associated with decreased NAA in the frontal gray matter and basal ganglia brain regions when compared to HIV participants without TBI. Our results are consistent with studies that have showed decreased levels of NAA associated with HIV alone and TBI alone; they also suggest greater reduction in neuronal integrity in those regions among the HIV+TBI+ group . Our groups were well equated on many factors that could have independently contributed to worse NP performance or metabolite changes. These matching factors included age, education, race/ethnicity, reading proficiency, and several HIV disease and treatment characteristics, including nadir CD4 count. Though individuals within the HIV+TBI+ group were somewhat more likely to be male , our use of gender-adjusted norms available for most of the neuropsychological tests make it unlikely that gender influenced the results. Furthermore, a study on neuropsychological performance in mild TBI patients revealed no statistically significant differences between male and female patients . The groups also had equivalent levels of depressive symptoms as well as current and past diagnoses of MDD, dysthymia, or both. Substance disorders were also comparable, with the exception of alcohol disorders, which were about 10% higher in the HIV+TBI+ group. However, analyses taking alcohol disorder diagnosis into account did not reveal any systematic effect for alcohol on CNS outcomes. From these data, we believe it is accurate to say that a history of more than minimal TBI in the setting of HIV is associated with mild enhancement of neurocognitive symptoms and signs, as well as more evidence of metabolite change in the brain. At the same time, the effect sizes for neuropsychological performance are surprisingly small , given that these were more than minimal injuries by history.
The effect sizes on reported cognition were somewhat higher and were not explained by differences in mood. This, coupled with the more robust effect on the metabolite NAA in the MRS sub-study, opens the possibility that TBI may be associated with more lingering brain effects than are being captured by neuropsychological testing. Our data are also consistent with another study that demonstrated that people who are HIV+TBI+ have significantly greater number of symptoms associated with mild TBI than do an HIV+TBI– group. The authors used the TIRR symptom checklist, which included the cluster of 25 symptoms specific to mild TBI that were higher in those with previous head injuries . Though the authors were the first to state the importance of recognizing the functional impact of TBI within the HIV population, our report has further explored what the impact is through analysis of neuropsychological tests, spectroscopy information, depressive symptoms, alcohol and drug abuse, and biological markers of HIV infection and AIDS disease. Although the effects of TBI on HIV neurocognitive outcomes have not received wide attention, there are indications that history of TBI can amplify the effects of other neurological diseases. For example, traumatic brain injury appears to increase the risk of neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease . Persisting difficulties with abstraction associated with alcoholism may also be amplified by head injury history . The mechanisms of the reinforcing effects of HIV and TBI on brain function are unknown. Reduction in NAA is consistent with neuronal injury associated with TBI leading to a disruption of neuronal mitochondrial activity, which subsequently leads to cognitive compromise. The lower NAA levels may also be compatible with the common neural injury mechanism of increased excitotoxicity: TBI alone could potentiate large fluxes of calcium that induce apoptosis in neurons associated with cognition . TBI has also been associated with inflammation . However, given that in the MRS sub-study there were no significant differences between HIV+TBI+ and HIV+TBI– in levels of myoinositol and choline, metabolites indicative of inflammation, it appears that an inflammatory process may not be linked to the TBI-associated cognitive worsening that follows. Instead, the patterns in our data suggest that persistent neuronal injury may be a factor. Since TBI has been linked to increased blood brain barrier permeability, it is possible that mechanisms associated with increased BBB permeability can enhance HIV’s penetration and virulence in HIV+TBI+ individuals . Viral proteins and inflammatory mediators could disrupt BBB regulation, allowing increased leukocyte migration and inducing subsequent neuronal damage and death . Our analyses were based on a study limited to HIV infected people. Therefore, though our results are compatible with a model of additivity, without examining HIV-uninfected groups that have TBI we cannot be certain whether these are additive or interactive effects. Because this was an exploratory study, we did not rigorously control for multiple comparisons, and thus the data must be regarded as preliminary. Furthermore, since our study was retrospective, some details about the TBIs were unavailable.