This study examined neurologic abnormalities (as measured by proton magnetic resonance spectroscopy imaging and diffusion tensor imaging), neurocognitive performance, and fatigue among a sample of adults with hepatitis C virus (HCV). We hypothesized that HCV+ individuals would demonstrate structural brain abnormalities and neurocognitive compromise consistent with frontostriatal dysfunction as well as increased fatigue compared to controls.
Participants were 76 individuals diagnosed with HCV and 20 controls who underwent a comprehensive neurocognitive evaluation and clinical assessments. A subset of the HCV+ participants (n = 29) and all controls underwent MRI.
Individuals diagnosed with chronic HCV infection demonstrated greater fractional anisotropy in the striatum as well as greater mean diffusivity in the fronto-occiptal fasciculus and external capsule compared to HCV− controls. HCV+ participants also demonstrated lower levels of N-acetylaspartate in bilateral parietal white matter and elevations in myo-inosital (mI) in bilateral frontal white matter compared to HCV− controls (all p values < 0.05). HCV+ participants also demonstrated significantly poorer neuropsychological performance, particularly in processing speed and verbal fluency. HCV+ patients reported higher levels of fatigue than controls, and fatigue was significantly correlated with diffusivity in the superior fronto-occipital fasciculus, elevations in mI in frontal white matter, and overall cognitive performance.
Our results suggest that HCV-associated neurologic complications disrupt frontostriatal structures, which may result in increased fatigue and poorer cognitive performance, particularly in those cognitive domains regulated by frontostriatal regions.
Cognitive complaints are reported frequently after breast cancer treatments. Their association with neuropsychological (NP) test performance is not well-established.
Early-stage, posttreatment breast cancer patients were enrolled in a prospective, longitudinal, cohort study prior to starting endocrine therapy. Evaluation included an NP test battery and self-report questionnaires assessing symptoms, including cognitive complaints. Multivariable regression models assessed associations among cognitive complaints, mood, treatment exposures, and NP test performance.
One hundred eighty-nine breast cancer patients, aged 21–65 years, completed the evaluation; 23.3% endorsed higher memory complaints and 19.0% reported higher executive function complaints (>1 SD above the mean for healthy control sample). Regression modeling demonstrated a statistically significant association of higher memory complaints with combined chemotherapy and radiation treatments (P = .01), poorer NP verbal memory performance (P = .02), and higher depressive symptoms (P < .001), controlling for age and IQ. For executive functioning complaints, multivariable modeling controlling for age, IQ, and other confounds demonstrated statistically significant associations with better NP visual memory performance (P = .03) and higher depressive symptoms (P < .001), whereas combined chemotherapy and radiation treatment (P = .05) approached statistical significance.
About one in five post–adjuvant treatment breast cancer patients had elevated memory and/or executive function complaints that were statistically significantly associated with domain-specific NP test performances and depressive symptoms; combined chemotherapy and radiation treatment was also statistically significantly associated with memory complaints. These results and other emerging studies suggest that subjective cognitive complaints in part reflect objective NP performance, although their etiology and biology appear to be multifactorial, motivating further transdisciplinary research.
Fatigue is a common adverse effect of cancer treatment and may persist for years after treatment completion. However, risk factors for post-treatment fatigue have not been determined. On the basis of studies suggesting an inflammatory basis for fatigue, this study tested the hypothesis that expression-regulating polymorphisms in proinflammatory cytokine genes would predict post-treatment fatigue in breast cancer survivors.
Patients and Methods
Women diagnosed with early-stage breast cancer (n = 171) completed questionnaires to assess fatigue and other behavioral symptoms (ie, depressive symptoms, memory complaints, sleep disturbance) and provided blood for genotyping within 3 months after primary treatment. Genomic DNA was extracted from peripheral-blood leukocytes and assayed for single nucleotide polymorphisms (SNPs) in the promoter regions of three cytokine genes: ILB −511 C>T (rs16944), IL6 −174 G>C (rs1800795), and TNF −308 G>A (rs1800629). An additive genetic risk score was computed by summing the number of high-expression alleles (zero, one, or two) across all three polymorphisms.
The genetic risk index was significantly associated with fatigue; as the number of high-expression alleles increased, so did self-reported fatigue severity (P = .002). Analyses of individual SNPs showed that TNF −308 and IL6 −174 were independently associated with fatigue (P = .032). The genetic risk index was also associated with depressive symptoms (P = .007) and memory complaints (P = .016).
These findings further implicate inflammatory processes as contributors to cancer-related fatigue and suggest a new strategy for identifying and treating patients at risk for this symptom based on genetic variants in proinflammatory cytokine genes.
This study developed and then cross-validated a novel weighting algorithm based on multiple comorbid risk factors (stimulant use, vascular disease, hepatitis C, HIV disease severity, cognitive reserve) to predict cognitive functioning among 366 HIV+ adults. The resultant “risk severity score” was used to differentially weight, as a function of age, the impact and magnitude of multiple risk factors on cognition. Among older adults (> 50 years) the risk severity index was differentially predictive of learning/memory and verbal fluency, whereas among younger adults it was linked to working memory and executive function. Cognitive reserve was found to be the most robust predictor of neurocognition.
This study examined the effects of aging and cognitive impairment on medication and finance management in an HIV sample. We observed main effects of age (older < younger) and neuropsychological impairment on functional task performance. Interactions between age and cognition demonstrated that older impaired individuals performed significantly more poorly than all other comparison groups. There were no relationships between laboratory performance and self-reported medication and finance management. The interaction of advancing age and cognitive impairment may confer significant functional limitations for HIV individuals that may be better detected by performance-based measures of functional abilities rather than patient self-report.
Neuropsychology; HIV; Aging; Functional abilities; Medication management; Finance management
Neuropsychological (NP) dysfunction has been linked to poor medication adherence among HIV-infected adults. However, there is a dearth of research examining longitudinal changes in the relationship between NP status and adherence rates. We hypothesized that declines in NP functioning would be associated with a corresponding decline in medication adherence while stable NP functioning would be associated with stable or improving adherence rates. Participants included 215 HIV-infected adults who underwent cognitive testing at study entry and six months later. Compared to the NP stable group, the NP decline group showed a greater drop in adherence rates. Further analysis revealed that, beyond global NP, learning and memory was significantly associated with changes in adherence rates. These findings further support the link between cognitive functioning and medication adherence and illustrates the importance of documenting changes in cognitive abilities for identifying individuals at risk for poor adherence.
HIV; Medication adherence; HAART; Cognitive decline; Memory
Depression frequently co-occurs with HIV infection and can result in self-reported overestimates of cognitive deficits. Conversely, genuine cognitive dysfunction can lead to an under-appreciation of cognitive deficits. The degree to which depression and cognition influence self-report of capacity for instrumental activities of daily living (IADLs) requires further investigation. This study examined the effects of depression and cognitive deficits on self-appraisal of functional competence among 107 HIV-infected adults. As hypothesized, higher levels of depression were found among those who over-reported problems in medication management, driving, and cognition when compared to those who under-reported or provided accurate self-assessments. In contrast, genuine cognitive dysfunction was predictive of under-reporting of functional deficits. Together, these results suggest that over-reliance on self-reported functional status poses risk for error when diagnoses require documentation of both cognitive impairment and associated functional disability in everyday life.
Depression; Self-report; Functional ability; Cognition; HIV
The authors examined the impact of HIV, cognitive dysfunction, and depression on decision-making. HIV+ (N=100) and HIV− (N=26) participants were administered a comprehensive neuropsychological battery, a modified version of the Iowa Gambling Task, and a measure of depressive symptoms. HIV+ participants demonstrated more difficulties in learning the gambling task than did HIV− participants. Executive functioning and depression emerged as strong predictors of gambling task performance. Depression partially mediated the relationship between executive functioning and gambling performance. Our findings suggest that HIV infection, executive dysfunction, and depression place individuals at risk for poor decision-making.
Progression of HIV/AIDS is frequently associated with frontal/subcortical dysfunction and mean reaction time (RT) slowing. Beyond group means, within-subject variability of RT has been found to be particularly sensitive to frontal/subcortical dysfunction in other populations. However, the possible relevance of RT variability to HIV/AIDS patients remains unknown. This study evaluated the relationships between RT variability and indicators such as neurocognitive, behavioral, and immunological status. A total of 46 HIV-positive adults on antiretroviral medication regimens were included in this study. Overall performance of this sample was poorer than normative means on measures of RT latency, RT variability, and traditional neurocognitive domains. Results demonstrated that the measures of RT variability were associated with global cognition, medication adherence rates, and peak immunological dysfunction, above and beyond the effects of RT latency. These preliminary findings suggest that measures of RT variability may provide enhanced sensitivity to neurocognitive disease burden in HIV/AIDS relative to more traditional measures of mean RT or cognitive function.
AIDS; Cognitive ability; Medication adherence; Immunological status; Continuous Performance Test; CPT-II
Antiretroviral medications have been shown to benefit neurocognition in HIV/AIDS, and neurocognitive deficits are a risk factor for poor adherence to these medications. However, little is known about the predictive pathways linking medication adherence with cognitive ability.
In the current 6-month cohort study, antiretroviral medication adherence was tracked prospectively among 91 HIV-positive adults using electronic monitoring. Comprehensive neuropsychological evaluations were performed at baseline and 6 months.
Multivariate path analyses provided evidence that antiretroviral adherence and cognitive ability are reciprocally related, although the neurocognitive pathways of this relationship appear to vary by predictive direction. Executive function and learning/memory were most strongly predictive of levels of medication adherence achieved, whereas higher levels of adherence were predictive of relative improvements in a wide range of frontostriatal brain functions including processing speed, attention, executive functions, and motor functioning.
These data provide evidence that cognition and adherence are reciprocally related in HIV/AIDS. In particular, executive dysfunction may play a key role in this relationship. Interventions aimed at improving or preserving executive functions could hold promise for interrupting progressive declines in adherence and neurocognitive ability in HIV/AIDS.
= Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
= highly active antiretroviral therapy;
= Medication Event Monitoring System;
= protease inhibitor.
To examine the predictors of antiretroviral adherence among HIV-infected adults, with a particular focus on advancing age, neuropsychological dysfunction, and substance abuse.
Prospective observational design.
Participants were 148 HIV-infected adults between the ages of 25 and 69 years, all on a self-administered antiretroviral regimen. Medication adherence was tracked over a one-month period using an electronic monitoring device (medication event monitoring system caps). All participants completed a comprehensive battery of neuropsychological tests as well as a structured psychiatric interview.
The mean adherence rate for the entire cohort was 80.7%, with older patients (⩾ 50 years) demonstrating significantly better medication adherence than younger patients (87.5 versus 78.3%). Logistic regression analyses found that older patients were three times more likely to be classified as good adherers (defined as ⩾ 95% adherent). Neurocognitive impairment conferred a 2.5 times greater risk of poor adherence. Among the older patients, those who were classified as poor adherers performed significantly worse on neuropsychological testing, particularly on measures of executive function and psychomotor speed. Current drug abuse/dependence, but not current alcohol abuse/dependence, was also associated with sub-optimal medication adherence.
Although older age is associated with higher rates of antiretroviral adherence, older participants who were cognitively impaired showed disproportionate difficulty in adequately adhering to their medication regimen. As such, efforts to detect neuropsychological dysfunction, particularly among older patients, and a thorough assessment of substance abuse, appear to be essential for the effective treatment of HIV-infected adults.
aging; alcohol abuse; drug abuse; electronic monitoring; medication adherence; neuropsychology
Due to similar routes of viral transmission, many individuals infected with the human immunodeficiency virus (HIV) are also infected with the hepatitis C virus (HCV). Each virus can cause cognitive compromise among mono-infected individuals; evidence is accumulating that HIV/HCV co-infection may have a particularly deleterious impact on cognition. We present neuropsychological data obtained from 118 HIV+ adults with advanced HIV disease, 35 of whom were co-infected with HCV, who completed a comprehensive neurocognitive evaluation. Rates of global cognitive impairment were higher among co-infected patients than among those with HIV alone (63% vs. 43%). Within the specific domains of learning and memory, co-infected individuals were significantly more likely to be impaired than were the HIV mono-infected participants. Finally, we discuss implications of these findings and potential future directions for research in this area.
HIV infection; HCV infection; HIV/HCV co-infection; neurocognition
Human immunodeficiency virus (HIV)-infected adults frequently evidence both neurocognitive and psychiatric dysfunction. It was hypothesized that apathy and irritability, but not anxiety and depression, are related to HIV effects on frontal–subcortical systems. This hypothesis was evaluated by determining the degree to which these psychiatric features are associated with neurocognitive functioning that is dependent upon frontal–subcortical circuitry and, therefore, thought to be sensitive to the central nervous system effects of HIV. Rating scales assessing irritability, apathy, depression, and anxiety and a dual-task paradigm were administered to 189 HIV-seropositive (HIV+) and 53 HIV-seronegative participants. Deficits in dual-task performance and greater anxiety, depression, apathy, and irritability were observed in HIV+ participants. Simultaneous multivariate regression and communality analyses revealed that only apathy and irritability were associated with dual-task performance in HIV+ participants. Thus, these findings suggest that apathy and irritability, but not depression and anxiety, are likely associated with the effects of HIV on frontal–subcortical circuitry.
Human immunodeficiency virus; Apathy; Irritability; Depression; Anxiety; Cognition
Infection with hepatitis C virus (HCV) is commonly seen in persons with human immunodeficiency virus (HIV) infection, because the viruses share risk factors for transmission; coinfection is a leading cause of morbidity and mortality among HIV-infected persons. Neuropsychological consequences of HIV infection are well established, and studies of HCV-infected persons have revealed neuropsychiatric dysfunction in this population as well. Investigators now are focusing on neuropsychological sequelae of coinfection with HIV and HCV, and preliminary results suggest that coinfection has a possible deleterious effect on global cognitive functioning consistent with frontal-subcortical dysfunction. Data on neuropsychiatric symptoms in coinfected persons are inconclusive at this time and are complicated by important differences in study populations (e.g., injection drug use and disease severity). This review summarizes what is known about neuropsychological aspects of monoinfection with HIV and HCV, as well as coinfection, discusses implications of these findings, and suggests future directions for this research area.
This longitudinal study examined the impact of drug use and abuse on medication adherence among 150 HIV-infected individuals, 102 who tested urinalysis positive for recent illicit drug use. Medication adherence was tracked over a 6-month period using an electronic monitoring device (MEMS caps). Over the 6-month study drug-positive participants demonstrated significantly worse medication adherence than did drug-negative participants (63 vs. 79%, respectively). Logistic regression revealed that drug use was associated with over a fourfold greater risk of adherence failure. Stimulant users were at greatest risk for poor adherence. Based upon within-participants analyses comparing 3-day adherence rates when actively using versus not using drugs, this appears to be more a function of state rather than trait. These data suggest that it is the acute effects of intoxication, rather than stable features that may be characteristic of the drug-using populace, which leads to difficulties with medication adherence.
HIV infection; AIDS; Medication adherence; Drug use; Methamphetamine; Cocaine
This study examined the interactive effects of cerebrovascular risks, advancing age, and HIV infection on neurocognition, and explored whether pharmacological treatment of cerebrovascular risk factors attenuated neurocognitive dysfunction. Participants included 98 HIV-seropositive adults (cerebrovascular risk: 23.5%; age >50: 27.6%). Cerebrovascular risk was associated with slower processing speed even after controlling for age effects (b = −2.071; p = .04), and the interaction of age and cerebrovascular risk was associated with poorer verbal fluency (b = 1.276, p = .002). Participants with pharmacologically untreated cerebrovascular risk demonstrated reduced processing speed, learning/memory, and executive functioning relative to those on medication. Poor cerebrovascular health confers significant risk for HIV+ individuals, and this effect may be of greater consequence than advancing age. The cognitive impact of risk appears to be more pronounced in the absence of adequate pharmacological treatment.
Cerebrovascular; HIV/AIDS; Neurocognitive; Aging
Although most agree that poor adherence to antiretrovirals is a common problem, relatively few factors have been shown to consistently predict treatment failure. In this study, a theoretical framework encompassing demographic characteristics, health beliefs/attitudes, treatment self-efficacy, and neurocognitive status was examined in relationship to highly active antiretroviral therapy adherence.
Prospective, cross-sectional observational design.
Main Outcome Measures
Neuropsychological test performance, health beliefs and attitudes, and medication adherence tracked over a 1-month period using electronic monitoring technology (Medication Event Monitoring System caps).
The rate of poor adherence was twice as high among younger participants than with older participants (68% and 33%, respectively). Results of binary logistic regression revealed that low self-efficacy and lack of perceived treatment utility predicted poor adherence among younger individuals, whereas decreased levels of neurocognitive functioning remained the sole predictor of poor adherence among older participants.
These data support components of the health beliefs model in predicting medication adherence among younger HIV-positive individuals. However, risk of adherence failure in those ages 50 years and older appears most related to neurocognitive status.
HIV; HAART; adherence; health beliefs; cognitive function
The association between sensation seeking and visual selective attention was examined in 31 adults with the Human Immunodeficiency Virus (HIV). Sensation seeking was measured with Zuckerman’s Sensation Seeking Scale Form V (SSS-V). Selective attention was assessed with a perceptual span task, where a target letter-character must be identified in a quickly presented array of nontarget letter-characters. As predicted, sensation seeking was strongly associated (R2 = .229) with perceptual span performance in the array size 12 condition, where selective attention demands were greatest, but not in the easier conditions. The Disinhibition, Boredom Susceptibility, and Experience Seeking subscales of the SSS-V were associated with span performance. It is argued that personality factors such as sensation seeking may play a significant role in selective attention and related cognitive abilities in HIV positive adults. Furthermore, sensation seeking differences might explain certain inconsistencies in the HIV neuropsychology literature.
HIV; AIDS; Cognition; Personality; Performance; Individual differences
Both depression and neurocognitive compromise are commonly observed among persons infected with the Human Immunodeficiency Virus (HIV). To date, the majority of studies have failed to find a consistent relationship between mood and cognition among HIV-seropositive (HIV+) individuals, suggesting that these constructs are independent of one another. However, depression is a multi-dimensional syndrome and its measurement often utilizes multi-factorial instruments containing cognitive, affective, somatic, and motivational components. The degree to which various symptoms or dimensions of depression might be related to neuropsychological performance in HIV-1 infection is not typically explored and was a main objective of the current study. A sample of 247 HIV+ persons completed both a comprehensive neurocognitive battery and the Beck Depression Inventory (BDI) as part of a standard clinical evaluation at a major community hospital. To examine the dimensionality of the BDI, a principal components analysis was conducted which suggested a three-factor solution comprised of factors representing Self-Reproach (SR), Mood-Motivation Disturbance (MM), and Somatic Disturbance (SOM). The relationship between each of these three factors and neurocognitive performance was examined using both regression and analysis of variance techniques. These analyses showed the MM factor, more so than either the SR or SOM factors, to be associated with several aspects of neurocognitive performance, including verbal memory, executive functioning, and motor speed. These findings suggest that certain items on depression rating scales may be more indicative of central nervous system (CNS) involvement than others. The association between disturbance in mood and motivation and neurocognitive compromise may suggest that each are sequelae of disease specific mechanisms.
Decision making was assessed using a laboratory gambling task in 67 adults with the Human Immunodeficiency Virus (HIV+) and in 19 HIV-seronegative (HIV−) control participants. Neurocognitive test performance across several domains was also analyzed to examine potential cognitive mechanisms of gambling task performance. As predicted, the HIV+ group performed worse on the gambling task, indicating greater risky decision making. Specifically, the HIV+ group selected more cards from the “risky” or disadvantageous deck that included relatively large payoffs but infrequent large penalties. The control group also selected such risky cards but quickly learned to avoid them. Exploratory analyses also indicated that in the HIV+ group, but not in the control group, gambling task performance was correlated with Stroop Interference performance and long delay free recall on the California Verbal Learning Test, suggesting the role of inhibitory processes and verbal memory in the poorer gambling task performance in HIV. These findings indicate the usefulness of the gambling task as a laboratory tool to examine risky decision making and cognition in the HIV population.
HIV; decision making; gambling task; cognition
To evaluate the hypothesis that poor adherence to highly active antiretroviral treatment (HAART) would be more strongly related to cognitive impairment among older than among younger HIV-seropositive adults.
Setting and Participants
A volunteer sample of 431 HIV-infected adult patients prescribed self-administered HAART was recruited from community agencies and university-affiliated infectious disease clinics in the Los Angeles area.
Neurocognitive measures included tests of attention, information processing speed, learning/memory, verbal fluency, motor functioning, and executive functioning. Medication adherence was measured using microchip-embedded pill bottle caps (Medication Event Monitoring System) and self-report. Latent/structural analysis techniques were used to evaluate factor models of cognition and adherence.
Mean adherence rates were higher among older (≥50 years) than younger (<50 years) HIV-positive adults. However, latent/structural modeling demonstrated that neurocognitive impairment was associated with poorer medication adherence among older participants only. When cognitive subdomains were examined individually, executive functioning, motor functioning, and processing speed were most strongly related to adherence in this age group. CD4 count and drug problems were also more strongly associated with adherence among older than younger adults.
Older HIV-positive individuals with neurocognitive impairment or drug problems are at increased risk of suboptimal adherence to medication. Likewise, older adults may be especially vulnerable to immunological and neurocognitive dysfunction under conditions of suboptimal HAART adherence. These findings highlight the importance of optimizing medication adherence rates and evaluating neurocognition in the growing population of older HIV-infected patients.
HIV; AIDS; aging; cognition; medication adherence; executive functions