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BackgroundAlcohol use is a risk factor for nonadherence to antiretroviral therapy (ART) among people living with HIV/AIDS (PLWHA); however, differences in ART adherence across levels of alcohol use are unclear. This study examined whether "at-risk" alcohol use, defined by National Institute of Alcohol Abuse and Alcoholism guidelines, was associated with ART nonadherence among PLWHA.MethodsParticipants were 535 HIV-infected adults enrolled in studies at the HIV Neurobehavioral Research Program. ART nonadherence was identified by either self-reported missed dose or plasma viral load detectability (≥50copies/ml). Potential covariates for multivariable logistic regression included demographics, depression, and substance use disorders.ResultsUsing a stepwise model selection procedure, we found that at-risk alcohol use (OR=0.64; p=0.032) and low education (OR=1.09 per 1year increase in education; p=0.009) significantly predict lower ART adherence.ConclusionsA greater focus on the treatment of at-risk alcohol use may improve ART adherence among HIV-infected persons.

To determine the relationships among body mass index (BMI), and HIV-associated neurocognitive impairment and the potential mediating effects of inflammatory cytokines. Among the HIV-infected individuals (N=90) included in this study, obesity was associated with slower processing speed (β = −.229, standard error (SE) = 2.15, p = .033), compared to participants with a normal BMI, after controlling for psychosocial and HIV clinical factors. Serum concentrations of the interleukin-16 (IL-16) cytokine were significantly associated with slowed processing speed (β = −.235, standard error (SE) = 1.62, p = .033) but did not mediate the relationship between obesity and processing speed These findings suggest that obesity may contribute to cognitive processing speed deficits in HIV-infected adults. Elevated concentrations of IL-16 are also associated with slowing, though the results suggest that obesity and IL-16 may exert independent effects.

Excessive alcohol use is common among people living with HIV. Given the growing prevalence of older HIV+ adults and observations indicating higher risk for neurocognitive impairment in older adults with either HIV infection or alcoholism, an increased understanding of their combined impact in the context of this increasingly aged population is crucial. We conducted comprehensive neurocognitive assessment in 112 older HIV+ individuals aged 50 to 69 years. Regression analyses were conducted to examine the interaction between age and the presence of lifetime alcohol dependence on neurocognitive measures, controlling for years of education, hepatitis C serostatus, and lifetime non-alcohol substance use disorder. Significant interactions of age and alcohol dependence history were found for global neurocognitive function, which was driven by the domains of executive function, processing speed, and semantic memory. Follow-up analyses indicated adverse effects of alcohol use history on neurocognitive measures that were evident only in HIV+ individuals 60 years and older. While mounting evidence in younger cohorts indicates adverse synergistic HIV/alcohol effects on neurocognitive function, our novel preliminary findings in this elderly HIV+ cohort demonstrated the importance of even a relatively distant alcohol use history on the expression of HIV-associated neurocognitive disorders that may not become apparent until much later in life.

Cognitive and functional neural correlates of human immunodeficiency virus (HIV) are only partially understood at present. Variability in neural response, which has been noted in the literature, may relate to clinical factors associated with HIV, including time since HIV diagnosis, CD4 count and nadir, HIV viral load, and comorbid infectious processes, especially hepatitis C. The present investigation evaluated working memory-related functional neural activation in 26 HIV+ participants, 28 demographically matched HIV-seronegative individuals, and 8 HIV+ individuals with hepatitis C coinfection. Analyses examined impact of HIV infection duration, CD4 count and nadir, HIV viral load, and hepatitis C serostatus. Results showed that HIV-seronegative participants had fastest reaction times, and during the working memory task, HIV+ participants with hepatitis C coinfection showed strongest bias toward commission errors; however, signal detection (i.e., overall task performance) was equivalent across groups. Functional magnetic resonance imaging (fMRI) results showed HIV-related greater activation to an easier vigilance task and HIV-related lower activation to a more difficult working memory task, consistent with reduced cognitive reserve. Hepatitis C coinfection related to diffuse neural dysregulation. Correlational analyses suggested relationships of increasingly severe disease with poorer functioning in brain regions linked to error monitoring and attention regulation.

The reasons for persistent brain dysfunction in chronically HIV-infected persons on stable combined antiretroviral therapies (CART) remain unclear. Host and viral factors along with their interactions were examined in 260 HIV-infected subjects who underwent magnetic resonance spectroscopy (MRS). Metabolite concentrations (NAA/Cr, Cho/Cr, MI/Cr, and Glx/Cr) were measured in the basal ganglia, the frontal white matter, and gray matter, and the best predictive models were selected using a bootstrap-enhanced Akaike information criterion (AIC). Depending on the metabolite and brain region, age, race, HIV RNA concentration, ADC stage, duration of HIV infection, nadir CD4, and/or their interactions were predictive of metabolite concentrations, particularly the basal ganglia NAA/Cr and the mid-frontal NAA/Cr and Glx/Cr, whereas current CD4 and the CPE index rarely or did not predict these changes. These results show for the first time that host and viral factors related to both current and past HIV status contribute to persisting cerebral metabolite abnormalities and provide a framework for further understanding neurological injury in the setting of chronic and stable disease.

In the current era of effective antiretroviral treatment, the number of older adults living with HIV is rapidly increasing. This study investigated the combined influence of age and HIV infection on longitudinal changes in verbal and visuospatial learning and memory.In this longitudinal, case-control design, 54 HIV seropositive and 30 seronegative individuals aged 40-74 years received neurocognitive assessments at baseline visits and again one year later. Assessment included tests of verbal and visuospatial learning and memory. Linear regression was used to predict baseline performance and longitudinal change on each test using HIV serostatus, age, and their interaction as predictors. Multivariate analysis of variance (MANOVA) was used to assess the effects of these predictors on overall baseline performance and overall longitudinal change.The interaction of HIV and age significantly predicted longitudinal change in verbal memory performance, as did HIV status, indicating that although the seropositive group declined more than the seronegative group overall, the rate of decline depended on age such that greater age was associated with a greater decline in this group. The regression models for visuospatial learning and memory were significant at baseline, but did not predict change over time. HIV status significantly predicted overall baseline performance and overall longitudinal change.This is the first longitudinal study focused on the effects of age and HIV on memory. Findings suggest that age and HIV interact to produce larger declines in verbal memory over time. Further research is needed to gain a greater understanding of the effects of HIV on the aging brain.

Prior studies examining the combined adverse effects of HIV and methamphetamine (MA) on the central nervous system (CNS) have focused on younger to middle-aged adults with recent MA use diagnoses. Aging, HIV, and MA all converge on prefrontal and temporolimbic neural systems and confer independent risk for neurocognitive and functional decline. Thus, this study sought to determine the residual impact of a remote history of MA dependence on neurocognitive and real-world outcomes in older people living with HIV (PLWH). Participants included 116 older (≥50 years) and 94 younger (

Chronic systemic immune activation and inflammatory processes have been linked to brain dysfunction in medically stable HIV-infected people. We investigated the association between verbal memory performance and plasma concentrations of 13 cytokines measured using multiplexed bead array immunoassay in 74 HIV-seropositive individuals and 50 HIV-seronegative controls. Memory performance was positively related to levels of IL-8 and IFN-γ, and negatively related to IL-10 and IL-18 and to hepatitis C infection. Memory performance was not significantly related to HIV disease markers. The results indicate the importance of systemic immune and inflammatory markers to neurocognitive function in chronic and stable HIV disease.

Objectives To examine whether depression and apathy are independently associated with longitudinal trajectories of cortical atrophy in the entorhinal cortex compared with frontal subregions previously implicated in late-life mood disturbance. Methods Data from 334 participants classified as having mild cognitive impairment in the Alzheimer's Disease Neuroimaging Initiative (ADNI) were analyzed by using multilevel models for change adjusted for age, global cognitive status, and total intracranial volume at enrollment. Participants in ADNI were recruited from >50 clinical research sites in the United States and Canada. Depression and apathy were identified by informants using the Neuropsychiatric Inventory Questionnaire. Serial magnetic resonance imaging was performed on 1.5-Tesla scanners according to the standardized ADNI-1 protocol on an average of 5 occasions over an average of 30.5 months. Regional cortical thickness values were derived from longitudinal data processing in FreeSurfer version 4.4. Results Depression was associated with reduced cortical thickness in the entorhinal cortex at baseline and accelerated atrophy in the anterior cingulate cortex. Similar relationships between depression and the orbitofrontal cortex and between apathy and the anterior cingulate cortex were not significant. Conclusions In mild cognitive impairment, depression signs are a better marker of longitudinal cortical atrophy than apathy. Results are consistent with hypotheses that depression is an early sign of a more aggressive neurodegenerative process or that depression lowers brain reserve capacity, allowing for more rapid progression of Alzheimer disease neuropathology.

Alcohol use is typically initiated during adolescence, a period known to be critical in neurodevelopment. The adolescent brain may be particularly susceptible to the harmful effects of alcohol. While the cognitive deficits associated with alcohol use during adolescence have been well-documented, the neural substrates underlying these effects remain inadequately understood. Cerebral white matter has been suggested as a primary site of alcohol-related damage and diffusion tensor imaging (DTI) allows for the quantification of white matter integrity in vivo. This review summarizes results from both cross-sectional and longitudinal studies employing DTI that indicate that white matter tracts, particularly those thought to be involved in executive functioning, continue to develop throughout adolescence and into adulthood. Numerous DTI studies reveal a positive correlation between white matter integrity and neurocognitive performance and, in adults, the detrimental effects of prolonged alcohol-dependence on white matter integrity. We provide a comprehensive review of the DTI studies exploring the relationship between alcohol use and white matter integrity in adolescents. Results from most of these studies suggest that alcohol use is associated with reduced white matter integrity, particularly in the superior longitudinal fasciculus (SLF), and some evidence suggests that this relationship may be influenced by sex. We conclude by highlighting confounds and limitations of the available research and suggesting directions for future research.

Emerging evidence suggests that CNS injury and neurocognitive impairment persist in the setting of chronic HIV infection and combination antiretroviral therapy (CART). Yet, whether neurological injury can progress in this setting remains uncertain. Magnetic resonance spectroscopy and neurocognitive and clinical assessments were performed over 2 years in 226 HIV-infected individuals on stable CART, including 138 individuals who were neurocognitively asymptomatic (NA). Concentrations of N-acetylaspartate (NAA), creatine (Cr), choline (Cho), myoinositol, and glutamate/glutamine (Glx) were measured in the midfrontal cortex (MFC), frontal white matter (FWM), and basal ganglia (BG). Longitudinal changes in metabolite levels were determined using linear mixed effect models, as were metabolite changes in relation to global neurocognitive function. HIV-infected subjects showed significant annual decreases in brain metabolite levels in all regions examined, including NAA (2.95 %) and Cho (2.61 %) in the FWM; NAA (1.89 %), Cr (1.84 %), Cho (2.19 %), and Glx (6.05 %) in the MFC; and Glx (2.80 %) in the BG. Similar metabolite decreases were observed in the NA and subclinically impaired subgroups, including subjects with virologic suppression in plasma and CSF. Neurocognitive decline was associated with longitudinal decreases in Glx in the FWM and the BG, and in NAA in the BG. Widespread progressive changes in the brain, including neuronal injury, occur in chronically HIV-infected persons despite stable antiretroviral treatment and virologic suppression and can lead to neurocognitive declines. The basis for these findings is poorly understood and warrants further study.

Background The acute consumption of excessive quantities of alcohol causes well-recognized neurophysiological and cognitive alterations. As people reach advanced age, they are more prone to cognitive decline. To date, the interaction of current heavy alcohol (ethanol [EtOH]) consumption and aging remains unclear. This study tested the hypothesis that negative consequences of current heavy alcohol consumption on neurocognitive function are worse with advanced age. Further, we evaluated the relations between lifetime history of alcohol dependence and neurocognitive function Methods Sixty-six participants underwent a comprehensive neurocognitive battery. Current heavy EtOH drinkers were classified using National Institute on Alcohol Abuse and Alcoholism criteria (EtOH heavy, n = 21) based on the Timeline follow-back and a structured clinical interview and compared to nondrinkers, and moderate drinkers (EtOH low, n = 45). Of the total population, 53.3% had a lifetime history of alcohol dependence. Neurocognitive data were grouped and analyzed relative to global and domain scores assessing: global cognitive function, attention/executive function, learning, memory, motor function, verbal function, and speed of processing. Results Heavy current EtOH consumption in older adults was associated with poorer global cognitive function, learning, memory, and motor function (ps

HIV-infected people frequently exhibit brain dysfunction characterized by preferential damage to the cerebral white matter. Despite suppressed viral load and reconstituted immune function afforded by combination antiretroviral therapy (CART), brain dysfunction continues to be observed even in medically stable individuals. To provide insight into the etiology of HIV-associated brain dysfunction in the CART era, we examined the effects of HIV disease markers, antiretroviral treatment, hepatitis C (HCV) coinfection, and age on DTI measures of white matter integrity in a cohort of 85 individuals aged 23 to 65 with chronic HIV infection. Fractional anisotropy (FA) and mean diffusivity (MD) were derived from 29 cerebral white matter regions, which were segmented on each individual brain using a high-resolution T1-weighted image and registered to diffusion images. Significant effects of clinical variables were found on white matter abnormalities in nearly all brain regions examined. Most notably, HCV coinfection and older age were associated with decreased anisotropy or increased diffusivity in the majority of brain regions. Individuals with higher current CD4 levels exhibited higher anisotropy in parietal lobe regions, while those undergoing antiretroviral treatment exhibited higher anisotropy in temporal lobe regions. The observed diffuse pattern of white matter injury suggests that future neuroimaging studies should employ methodologies that are not limited to circumscribed regions of interest. The current findings underline the multifactorial nature of HIV-associated brain dysfunction in the CART era, and the importance of examining the effect of HIV disease in the context of other comorbidities, in particular HCV coinfection and aging.

The goals of this paper are to review the most popular methods of predictor selection in regression models, to explain why some fail when the number P of explanatory variables exceeds the number N of participants, and to discuss alternative statistical methods that can be employed in this case. We focus on penalized least squares methods in regression models, and discuss in detail two such methods that are well established in the statistical literature, the LASSO and Elastic Net. We introduce bootstrap enhancements of these methods, the BE-LASSO and BE-Enet, that allow the user to attach a measure of uncertainty to each variable selected. Our work is motivated by a multimodal neuroimaging dataset that consists of morphometric measures (volumes at several anatomical regions of interest), white matter integrity measures from diffusion weighted data (fractional anisotropy, mean diffusivity, axial diffusivity and radial diffusivity) and clinical and demographic variables (age, education, alcohol and drug history). In this dataset, the number P of explanatory variables exceeds the number N of participants. We use the BE-LASSO and BE-Enet to provide the first statistical analysis that allows the assessment of neurocognitive performance from high dimensional neuroimaging and clinical predictors, including their interactions. The major novelty of this analysis is that biomarker selection and dimension reduction are accomplished with a view towards obtaining good predictions for the outcome of interest (i.e., the neurocognitive indices), unlike principal component analysis that are performed only on the predictors' space independently of the outcome of interest.

Cytokine disturbances have been linked to brain dysfunction among HIV-infected people. Past studies have not simultaneously examined a large set of cytokine measures and their relationships to HIV-associated neurocognitive deficits. We hypothesized that performance on measures of attention, and executive and psychomotor functions would be associated with plasma cytokine concentrations in HIV-infected individuals. Plasma samples drawn from 30 HIV-infected and 37 HIV seronegative individuals were analyzed via xMAP multiplexed bead array immunoassay to determine concentrations of thirteen cytokines. Performance on Trail Making A/B, Stroop Test, Letter Number Sequencing, Digit Symbol Coding, Symbol Search, and Grooved Pegboard tests was assessed. Statistical analyses were performed to examine group differences in cytokine concentrations, and associations between cytokine and HIV clinical variables and neurocognitive performance. Significant HIV effects were found on seven of the thirteen cytokines, primarily with respect to interleukins. HIV clinical factors (CD4 and HIV RNA levels, duration of illness, antiretroviral treatment) and hepatitis C status were associated with specific plasma cytokine concentrations. Neurocognitive measures were associated with cytokine concentrations, most consistently among the interleukins and IP-10. Generally, cytokine concentrations were among the strongest predictors of neurocognitive function relative to other clinical factors, which reinforces their potential importance in examining the neuropathological processes of HIV. The findings also point to the potential value of simultaneously examining a panel of biomarkers. The current results suggest that a complex relationship likely exists among cytokines [how?], and that these relationships are mediated not only by HIV infection, but also by antiretroviral treatment and other comorbid conditions.

Cerebral metabolite disturbances occur among human immunodeficiency virus (HIV)-infected people, and are thought to reflect neuropathology, including proinflammatory processes, and neuronal loss. HIV-associated cortical atrophy continues to occur, though its basis is not well understood, and the relationship of cerebral metabolic disturbance to structural brain abnormalities in HIV has not been well delineated. We hypothesized that metabolite disturbances would be associated with reduced cortical and subcortical volumes. Cerebral volumes were measured in 67 HIV-infected people, including 10 people with mild dementia (acquired immunodeficiency syndrome [AIDS] dimentia complex [ADC] stage >1) via automated magnetic resonance imaging (MRI) segmentation. Magnetic resonance spectroscopy (MRS) was used to measure levels of cerebral metabolites N-acetylaspartate (NAA), myo-inositol (MI), choline-containing compounds (Cho), glutamate/glutamine (Glx), and creatine (Cr) from three brain regions (frontal gray matter, frontal white matter, basal ganglia). Analyses were conducted to examine the associations between MRS and cerebral volumetric measures using both absolute and relative metabolite concentrations. NAA in the mid-frontal gray matter was most consistently associated with cortical (global, frontal, and parietal), ventricular, and caudate volumes based on analysis of absolute metabolite levels, whereas temporal lobe volume was associated with basal ganglia NAA and Glx, and Cho concentrations in the frontal cortex and basal ganglia. Hippocampal volume was associated with frontal white matter NAA, whereas thalamic volume was associated with both frontal white matter NAA and basal ganglia Glx. Analyses of relative metabolite concentrations (referenced to Cr) yielded weaker effects, although more metabolites were retained as significant predictors in the models than the analysis of absolute concentrations. These findings demonstrate that reduced cortical and subcortical volumes, which have been previously found to be linked to HIV status and history, are also strongly associated with the degree of cerebral metabolite disturbance observed via MRS. Reduced cortical and hippocampal volumes were most strongly associated with decreased NAA, though reduced Glx also tended to be associated with reduced cortical and subcortical volumes (caudate and thalamus) as well, suggesting both neuronal and glial disturbances. Interestingly, metabolite-volumetric relationships were not limited to the cortical region from which MRS was measured, possibly reflecting shared pathophysiological processes. The relationships between Cho and volumetric measures suggest a complicated relationship possibly related to the effects of inflammatory processes on brain volume. The findings demonstrate the relationship between MRI-derived measures of cerebral metabolite disturbances and structural brain integrity, which has implication in understanding HIV-associated neuropathological mechanisms.

The frequent co-occurrence of Alzheimer's disease (AD) pathology in patients with normal pressure hydrocephalus suggests a possible link between ventricular dilation and AD. If enlarging ventricles serve as a marker of faulty cerebrospinal fluid (CSF) clearance mechanisms, then a relationship may be demonstrable between increasing ventricular volume and decreasing levels of amyloid-beta peptide (Abeta) in CSF in preclinical and early AD. CSF biomarker data (Abeta, tau, and phosphorylated tau) as well as direct measurements of whole brain and ventricular volumes were obtained from the Alzheimer's Disease Neuroimaging Initiative dataset. The ratio of ventricular volume to whole brain volume was derived as a secondary independent measure. Baseline data were used for the group analyses of 288 subjects classified as being either normal (n=87), having the syndrome of mild cognitive impairment (n=136), or mild AD (n=65). Linear regression models were derived for each biomarker as the dependent variable, using the MRI volume measures and age as independent variables. For controls, ventricular volume was negatively associated with CSF Abeta in APOE epsilon4 positive subjects. A different pattern was seen in AD subjects, in whom ventricular volume was negatively associated with tau, but not Abeta in epsilon4 positive subjects. Increased ventricular volume may be associated with decreased levels of CSF Abeta in preclinical AD. The basis for the apparent effect of APOE epsilon4 genotype on the relationship of ventricular volume to Abeta and tau levels is unknown, but could involve altered CSF-blood-brain barrier function during the course of disease.

Approximately half of those infected with the human immunodeficiency virus (HIV) exhibit cognitive impairment, which has been related to cerebral white matter damage. Despite the effectiveness of antiretroviral treatment, cognitive impairment remains common even in individuals with undetectable viral loads. One explanation for this may be subtherapeutic concentrations of some antiretrovirals in the central nervous system (CNS). We utilized diffusion tensor imaging and a comprehensive neuropsychological evaluation to investigate the relationship of white matter integrity to cognitive impairment and antiretroviral treatment variables. Participants included 39 HIV-infected individuals (49% with acquired immunodeficiency syndrome [AIDS]; mean CD4 = 529) and 25 seronegative subjects. Diffusion tensor imaging indices were mapped onto a common whole-brain white matter tract skeleton, allowing between-subject voxelwise comparisons. The total HIV-infected group exhibited abnormal white matter in the internal capsule, inferior longitudinal fasciculus, and optic radiation; whereas those with AIDS exhibited more widespread damage, including in the internal capsule and the corpus callosum. Cognitive impairment in the HIV-infected group was related to white matter injury in the internal capsule, corpus callosum, and superior longitudinal fasciculus. White matter injury was not found to be associated with HIV viral load or estimated CNS penetration of antiretrovirals. Diffusion tensor imaging was useful in identifying changes in white matter tracts associated with more advanced HIV infection. Relationships between diffusion alterations in specific white matter tracts and cognitive impairment support the potential utility of diffusion tensor imaging in examining the anatomical underpinnings of HIV-related cognitive impairment. The study also confirms that CNS injury is evident in persons infected with HIV despite effective antiretroviral treatment.

Both HIV disease and advanced age have been associated with alterations to cerebral white matter, as measured with white matter hyperintensities (WMH) on fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI), and more recently with diffusion tensor imaging (DTI). This study investigates the combined effects of age and HIV serostatus on WMH and DTI measures, as well as the relationships between these white matter measures, in 88 HIV seropositive (HIV+) and 49 seronegative (HIV-) individuals aged 23-79 years. A whole-brain volumetric measure of WMH was quantified from FLAIR images using a semi-automated process, while fractional anisotropy (FA) was calculated for 15 regions of a whole-brain white matter skeleton generated using tract-based spatial statistics (TBSS). An age by HIV interaction was found indicating a significant association between WMH and older age in HIV+ participants only. Similarly, significant age by HIV interactions were found indicating stronger associations between older age and decreased FA in the posterior limbs of the internal capsules, cerebral peduncles, and anterior corona radiata in HIV+ vs. HIV- participants. The interactive effects of HIV and age were stronger with respect to whole-brain WMH than for any of the FA measures. Among HIV+ participants, greater WMH and lower anterior corona radiata FA were associated with active hepatitis C virus infection, a history of AIDS, and higher current CD4 cell count. Results indicate that age exacerbates HIV-associated abnormalities of whole-brain WMH and fronto-subcortical white matter integrity.

Both HIV infection and high levels of early life stress (ELS) have been related to abnormalities in frontal-subcortical structures, yet the combined effects of HIV and ELS on brain structure and function have not been previously investigated. In this study we assessed 49 non-demented HIV-seropositive (HIV+) and 47 age-matched HIV-seronegative healthy control (HC) adults. Levels of ELS exposure were quantified and used to define four HIV-ELS groups: HC Low-ELS (N= 20); HC High-ELS (N= 27); HIV+ Low-ELS (N= 24); HIV+ High-ELS (N= 25). An automated segmentation tool measured volumes of brain structures known to show HIV-related or ELS-related effects; a brief neurocognitive battery was administered. A significant HIV-ELS interaction was observed for amygdala volumes, which was driven by enlargements in HIV+ High-ELS participants. The HIV+ High-ELS group also demonstrated significant reductions in psychomotor/processing speed compared with HC Low-ELS. Regression analyses in the HIV+ group revealed that amygdala enlargements were associated with higher ELS, lower nadir CD4 counts, and reduced psychomotor/processing speed. Our results suggest that HIV infection and high ELS interact to increase amygdala volume, which is associated with neurocognitive dysfunction in HIV+ patients. These findings highlight the lasting neuropathological influence of ELS and suggest that high ELS may be a significant risk factor for neurocognitive impairment in HIV-infected individuals. (JINS, 2012,19, 1–12)

HIV-associated neurocognitive dysfunction persists in the highly active antiretroviral therapy (HAART) era and may be exacerbated by comorbidities, including substance use and hepatitis C virus (HCV) infection. However, the neurocognitive impact of HIV, HCV, and substance use in the HAART era is still not well understood. In the current study, 115 HIV-infected and 72 HIV-seronegative individuals with significant rates of lifetime substance dependence and HCV infection received comprehensive neuropsychological assessment. We examined the effects of HIV serostatus, HCV infection, and substance use history on neurocognitive functioning. We also examined relationships between HIV disease measures (current and nadir CD4, HIV RNA, duration of infection) and cognitive functioning. Approximately half of HIV-infected participants exhibited neurocognitive impairment. Detectable HIV RNA but not HIV serostatus was significantly associated with cognitive functioning. HCV was among the factors most consistently associated with poorer neurocognitive performance across domains, while substance use was less strongly associated with cognitive performance. The results suggest that neurocognitive impairment continues to occur in HIV-infected individuals in association with poor virologic control and comorbid conditions, particularly HCV coinfection. (JINS, 2012,18, 68–78)

White matter damage from chronic alcohol abuse is a consistent finding in neuropathological and structural magnetic resonance imaging (MRI) studies (Estruch et al., 1997; Harper, 1998; Harper and Kril, 1991; Harper et al., 1985; Hommer et al., 1996; Pfefferbaum et al., 1996). According to postmortem analyses, white matter anomalies associated with alcohol abuse include overall volume reduction, demyelination, microtubule disturbance, and axonal subtraction (Alling and Bostrom, 1980; Harper and Kril, 1989; Harper et al., 1987; Kril et al., 1997; Paula-Barbosa and Tavares, 1985). Pathological evidence also indicates that these white matter anomalies are especially prominent in the frontal lobes (Harper and Kril, 1989; Kril et al., 1997; Torvik, 1987). Consistent with neuropathological research, structural MRI studies report loss in white matter integrity that is associated with shrinkage to the frontal lobes (Dirksen et al., 2006; Oscar-Berman and Marinkovic, 2007; Rosenbloom et al., 2003; Schlaepfer et al., 2006). For example, referring to statistically significant regional brain volume differences measured with MRI, Pfefferbaum and colleagues (1997) described greater white matter deficits in the prefrontal and other frontal regions compared to anterior temporal, anterior parietal, and posterior parietal lobes in chronic alcoholics. Diffusion tensor imaging (DTI) studies have identified decreases in fractional anisotropy values in frontal white matter and limbic pathways (Yeh et al., 2009) as well as in the 5 main subregions of the corpus callosum–the rostrum, genu, body, isthmus, and splenium–with the greatest loss to the genu subregion and less shrinkage to the body and splenium (Pfefferbaum et al., 2000, 2006a). Neuropsychological changes from alcohol exposure parallel modifications in brain structure specified in the neuropathology and neuroimaging studies, especially cognitive deficits associated with frontal lobe dysfunction (Dirksen et al., 2006). Broadly speaking, functional deficiencies in alcohol dependence include deficits in abstract thinking, problem-solving, spatial and verbal learning, working memory, attention, and perceptual motor skills (Grant, 1987; Grant et al., 1979, 1984; Harper and Matsumoto, 2005; Pfefferbaum et al., 2000, 2006a; Rourke and Grant, 2009). More specifically, general disruptions to the integrity of the corpus callosum correlate with impairments in interhemispheric processing speed (Davies et al., 2005; Schulte et al., 2005). Callosal micro-structure integrity also predicts, at least in part, visuospatial global–local integration ability in alcohol-dependent subjects, a function also requiring the integration of information from both hemispheres (Muller-Oehring et al., 2009). DTI studies using fiber tractography as well as postmortem analyses indicate that the genu, the anterior section of the corpus callosum, connects left and right hemispheres of the pre-frontal cortex while the posterior segment, the splenium, connects temporal, parietal, and occipital cortices (Abe et al., 2004; Hofer and Frahm, 2006; Huang et al., 2005; Pandya and Seltzer, 1986; Sullivan et al., 2006). Previous research has found that changes in the genu are associated with alcohol-related neuropsychological impairments on frontal lobe-mediated tasks such as Trail Making and Digit Symbol Tests (Jokinen et al., 2007). Furthermore, deficiencies in the genu, specifically, contribute to deficits in attention and working memory (Jokinen et al., 2007; Pfefferbaum et al., 2000, 2006a). Neuroimaging studies of detoxified alcoholics also report evidence of reversal of alcohol-related structural changes to the brain after the periods of abstinence (Sullivan and Pfefferbaum, 2005). As with the greater original harmful effects in white matter (Harper and Kril, 1991; Harper et al., 1985), recovery is also often observed in the white matter. In their MRI study, Shear and colleagues (1994) discovered that recently detoxified subjects examined 1 month after their last drink and after 3 months of abstinence exhibited white matter volume increases, while those who resumed drinking did not. Another study that used deformation-based morphometry (Cardenas et al., 2007) found that the frontal and temporal lobes are vulnerable to the effects of heavy alcohol consumption and that recovery is observed in these abstinent heavy drinkers compared to relapsers. Finally, a multimodal MRI and DTI study demonstrated that alcohol-dependent subjects showed white matter recovery–both in microstructural integrity and volume–depending on smoking status (Gazdzinski et al., 2010). Additional studies confirm white matter recovery during periods of abstinence through changes in magnetic resonance spectroscopy (MRS) metabolites that have been observed to be correlated with white matter improvements. Ende and colleagues (2005) found a statistically significant increase in choline-containing compounds in their follow-up measurement in abstinent alcohol-dependent patients indicating an improved cerebral metabolism of lipids in membranes and myelin. Bartsch and colleagues (2007) also found that 1H-MRS levels of cerebellar choline and frontomesial N-acetylaspartate were significantly augmented after short-term sobriety, and that these increases were associated with global brain volume recovery. The current study hypothesized that the significant declines in microstructural integrity as measured with DTI in the corpus callosumof recentlydetoxifiedalcohol-dependentpatients (RDA) will be partially ameliorated after a year of abstinence fromalcohol. As previously reported, the frontal lobesmay be especially susceptible tomicrostructural whitematter changes in alcoholic patients. The majority of fibers that connect the 2 sides of the frontal lobes course through the genu and body of the corpus callosum; while the splenium connects temporal and occipital regions. Therefore, the current study hypothesized that, paralleling previous findings of preferential frontal damage, the genu of the corpus callosum would exhibit the greatest white matter disruption in RDA, followed by the body and the splenium. Finally, the current study hypothesized that frontal/executive functions similar to those previously found to be susceptible to the effects of alcohol dependence (Jokinen et al., 2007; Pfefferbaum et al., 2000, 2006a) will show the significant improvements after a year of abstinent that parallels improvements inDTImeasures. 2 sides of the frontal lobes course through the genu and body of the corpus callosum; while the splenium connects temporal and occipital regions. Therefore, the current study hypothesized that, paralleling previous findings of preferential frontal damage, the genu of the corpus callosum would exhibit the greatest white matter disruption in RDA, followed by the body and the splenium. Finally, the current study hypothesized that frontal/executive functions similar to those previously found to be susceptible to the effects of alcohol dependence (Jokinen et al., 2007; Pfefferbaum et al., 2000, 2006a) will show the significant improvements after a year of abstinent that parallels improvements in DTI measures.

Background Previous research has associated abnormalities in frontal lobe functioning with alcohol relapse. In this study, we used diffusion tensor imaging to investigate whether frontal white matter integrity measured at the start of treatment differs between persons with alcohol use disorders (AUD) who sustain treatment gains and those who return to heavy use after treatment. Methods Forty-five treatment-seeking AUD inpatients and 30 healthy control subjects were included in the study. Six months after completing treatment, 16 of the AUD participants had resumed heavy use (RHU) and 29 others remained abstinent or drank minimally (treatment sustainers [TS]). Voxel-wise group comparisons (TS vs. RHU) were performed on fractional anisotropy (FA), radial diffusivity (RD), and axial diffusivity maps generated from each subject's diffusion tensor imaging scan at the start of treatment. Results We found significantly lower FA and significantly higher RD in the frontal lobes of the RHU group, relative to the TS group. The RHU group data are consistent with previous reports of abnormal frontal white matter tract abnormalities in persons with AUD. Conclusions It is possible that the lower FA and higher RD in the RHU group reflect microstructural injury to frontal circuitries, and these may underlie the reduced cognitive control amid heightened reward sensitivity associated with resumption of heavy drinking.

Objective To study white matter integrity with diffusion tensor imaging in adolescents with prenatal cocaine exposure, tobacco exposure, or both. Study design Subjects included 20 adolescents with prenatal cocaine exposure (15 with tobacco exposure) and 20 non-cocaine-exposed subjects (8 with tobacco exposure). Diffusion tensor imaging measures were assessed in 5 subregions of the corpus callosum. The Sensation Seeking Scale for Children was administered to evaluate behavioral inhibition. Results No significant differences were found between the cocaine-exposed and non-cocaine-exposed groups in each subregion of the corpus callosum on measures of fractional anisotropy (FA) and mean diffusivity, although the cocaine-exposed group showed a trend (P = .06) toward higher FA in projections to the supplementary motor area and premotor cortex. Prenatal tobacco exposure was associated with decreased FA in the supplementary motor area and premotor cortex projections after adjustment for relevant co-variates (P = .03). Decreased FA was related to more sensation seeking in the adolescents who were prenatally exposed to tobacco. Conclusion Prenatal tobacco exposure could affect white matter integrity, which is related to sensation seeking in adolescents. Developmental neurotoxins might have differential influences on white matter maturation in adolescence.

Cerebral atrophy is a well-described, but poorly understood complication of human immunodeficiency virus (HIV) infection. Despite reduced prevalence of HIV-associated dementia in the highly active antiretroviral therapy (HAART) era, HIV continues to affect the brains of patients with chronic infection. In this study we examine patterns of brain volume loss in HIV-infected patients on HAART, and demographic and clinical factors contributing to brain volume loss. We hypothesized that nadir CD4+ lymphocyte count, duration of HIV infection, and age would be associated with reduced cortical volumes. Volumes of cortical and subcortical regions in 69 HIV-infected neuroasymptomatic (NA) individuals and 13 with at least mild acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) were measured using voxel-based morphometry. Demographic and clinical factors (age, plasma HIV RNA level, current and nadir CD4 counts, duration of infection, central nervous system [CNS] penetration of antiretroviral regimen) along with their interactions were entered into a regression model selection algorithm to determine the final models that best described regional brain volumes. Relative to NA, individuals with ADC exhibited decreased total gray matter and parietal cortex volumes and increased total ventricular volumes. Final regression models showed overall cerebral volume, including gray and white matter volume and volumes of the parietal, temporal, and frontal lobes and the hippocampus, were most strongly associated with disease history factors (nadir CD4 and duration of infection). In contrast, basal ganglia volumes were related most strongly to current disease factors, most notably plasma HIV RNA. These findings indicate that individuals with a history of chronic HIV infection with previous episodes of severely impaired immune function, as reflected by reduced nadir CD4+ lymphocyte count, may be at greatest risk for cerebral atrophy. The pattern of HIV-associated brain loss may be changing from a subcortical to a cortical disease among patients who are largely asymptomatic on HAART.

Human immunodeficiency virus (HIV) and methamphetamine (METH) use disorders are associated with cerebral dysfunction. To determine whether these effects were evident on in vivo neuroimaging, quantitative, single voxel magnetic resonance (MR) spectroscopy was used to assess frontal white matter, frontal gray matter, and basal ganglia in 40 HIV+/METH+, 66 HIV+/METH-, 48 HIV-/METH+, and 51 HIV-/METH- participants. HIV was associated with lower N-acetylaspartate (NAA) in frontal white and frontal gray matter but METH was not associated with cerebral metabolite differences in any region. Among HIV+ individuals, lower CD4 counts and higher plasma HIV viral loads were associated with lower NAA in frontal gray matter and basal ganglia. The relationship between detectable plasma HIV viral load and NAA in frontal white matter was significantly stronger in the HIV+/METH+ group, compared to HIV+/METH-. Higher detectable plasma HIV viral load was significantly associated with higher myo-inositol (MI) in frontal white and gray matter for HIV+/METH+, but not HIV+/METH-. For the HIV-/METH+ group, lifetime duration of METH use was associated with higher choline levels in frontal gray matter and higher MI levels in basal ganglia. Our findings are consistent with significant disruption of neuronal integrity in the frontal lobes of HIV-infected individuals. Although METH was not associated with cerebral metabolite levels, other findings suggested that METH use did affect the brain. For example, the relationship between detectable plasma HIV viral load and NAA levels was limited to HIV+/METH+ individuals. This evidence indicates when HIV is poorly suppressed, METH may modify the effects of the virus on neuronal integrity.

Although HIV is detectable throughout the CNS, its preferential disruption of fronto-basal ganglia systems is thought to underlie the neurobehavioral syndrome of HIV-associated dementia. Semantic clustering, a measure of organizational strategy during learning and retrieval, is commonly impaired in patients with frontal systems dysfunction, but has not previously been evaluated in HIV-associated dementia. The current study examined semantic and serial clustering strategies on a list-learning task in 15 individuals with HIV-associated dementia, 44 HIV-infected individuals without dementia, and 24 healthy comparison subjects. Results indicated a stepwise decline in the use of semantic, but not serial, clustering with increasing severity of HIV-associated cognitive disorder. Findings suggest that HIV-associated dementia is associated with inefficient use of higher-level encoding and retrieval strategies, perhaps mediated by a disruption of fronto-basal ganglia systems.

Methamphetamine (MA) dependence is associated with deficits in episodic verbal memory, but the cognitive mechanisms underlying such impairments are not known. The authors evaluated a component process model of episodic verbal memory in 87 persons with MA dependence (MA+) and 71 demographically similar non-MA-using controls (MA-). Compared with MA- controls, MA+ participants demonstrated deficient overall learning, free recall, and utilization of semantic clustering, as well as higher rates of repetitions and intrusions. No between-groups differences were evident on measures of serial clustering, retention, or recognition discrimination. Taken together, these findings indicate that MA dependence is associated with deficient strategic (i.e., executive) control of verbal encoding and retrieval, which is consistent with the sequelae of MA-related prefronto-striatal circuit neurotoxicity.

Memory tests that are in a recall format have almost universally measured accuracy in terms of the number of target items reported by the examinee. However, this traditional scoring method can, in certain cases, result in artificially inflated memory accuracy scores. That is, just as a "yes" response bias and high false-positive rate on recognition testing can artificially inflate a patient's hit rate, so, too, a liberal response bias and high intrusion rate on recall testing can artificially inflate a patient's level of target recall. Recognition tests correct for this problem by using a discriminability measure that provides a single score of hit rate relative to false-positive rate; however, recall tests rarely provide a single score of recall accuracy that corrects for intrusion rate. In the present study, we examined the utility of a new recall discriminability measure that analyzes target recall relative to intrusion rate. Patients with Alzheimer's disease (AD) or Huntington's disease (HD) were administered the CVLT-II, which provides both the traditional measure of target recall and a new measure of recall discriminability. The results indicate that the new recall discriminability measure was superior to the traditional level of target recall measure in distinguishing the recall performance of AD and HD patients. Implications of these results for clinical practice and theories of memory disorder in dementia are discussed.