Effects of human immunodeficiency virus and methamphetamine on cerebral metabolites measured with magnetic resonance spectroscopy

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.     

Cognitive deficits and degeneration of interneurons in HIV+ methamphetamine users

The cellular basis for cognitive deficits in HIV+ patients with and without a history of methamphetamine (METH) use is unclear. We found that HIV+ METH users had more severe loss of interneurons that was associated with cognitive impairment. Compared with other markers, loss of calbindin and parvalbumin interneurons in the frontal cortex was the most significant correlate to memory deficits, suggesting a role in neurobehavioral alterations of HIV+ METH users.     

Neuropsychological impairment among asymptomatic HIV-positive former intravenous drug users.

OBJECTIVE: To evaluate the influence of human immunodeficiency virus (HIV) infection and situation of drug consumption on neuropsychological impairment in asymptomatic HIV-positive (HIV+) former intravenous drug users (IVDUs) of Spanish nationality. BACKGROUND: Currently, we have no data about neuropsychological impairment in asymptomatic HIV+ IVDUs taking into account different situations of drug consumption. METHOD: A neuropsychological evaluation was made of four groups of IVDUs: 33 abstinent HIV+ IVDUs, 21 methadone-maintained HIV+ IVDUs, 27 abstinent HIV-negative (HIV-) IVDUs, and 21 methadone-maintained HIV- IVDUs. Their neuropsychological impairment rates were determined taking as a reference the performance of 23 HIV- subjects without history of drug abuse. RESULTS: The rate of neuropsychological impairment of methadone-maintained HIV+ patients (48%) and that of those in abstinence (24%) is greater than that of HIV- subjects in a similar condition (19% and 11%). The impairment rate of the methadone-maintained HIV+ group is significantly greater than that of the abstinent HIV+. Methadone-maintained HIV+ subjects with neuropsychological impairment have fewer education years than those not impaired; likewise, the percentages of subjects with significant immunodepression, detectable viral load, and without antiretroviral treatments are higher among methadone-maintained subjects with neuropsychological impairment. CONCLUSIONS: This study emphasizes the association of asymptomatic HIV infection with neuropsychological impairment in IVDUs and reveals the importance of the drug consumption situation in relation to this risk, being methadone-maintained IVDUs more likely to suffer from it. This fact seems to be related to the worsening of the infection and its treatment and to educational level.     

Dopamine receptor D3 genetic polymorphism (rs6280TC) is associated with rates of cognitive impairment in methamphetamine-dependent men with HIV: preliminary findings

Macrophages are one of HIV-1’s principal targets and chiefly responsible for translocating HIV into the central nervous system (CNS). Previous research suggested an increase in macrophages being infected by HIV in the presence of methamphetamine (METH) or increased extracellular dopamine (DA). Experimental studies indicate that this is mediated by DA receptors, including DA receptor D3 (DRD3), which is expressed in macrophages. A single nucleotide polymorphism (SNP) of the DRD3 gene (rs6280TC) modulates its dopamine binding affinity, resulting in the possibility that inheriting a variant of this SNP increases macrophage susceptibility to HIV infection in the presence of METH and DA, particularly in the CNS where METH is sequestered, leading to cognitive impairment (CI). Thus, we conducted a retrospective clinical investigation to evaluate whether rs6280TC is associated with CI among HIV-positive METH users. We stratified 310 males by HIV serostatus (HIV-positive, -negative) and METH dependence (METH-positive, -negative) and then by rs6280TC genotype (CC, CT, and TT). Genotypic groups within each of four HIV/METH groups were compared for rates of CI. We hypothesized that only HIV-positive/METH-positive carriers of the C allele, which increases the DRD3’s binding to DA, would be more likely to develop CI. Cochran–Armitage test for trends in proportions yielded significant (p < 0.05) association between three genotypes and impairment rates in the hypothesized order, but only among HIV-positive/METH-positive subjects. The results also confirmed that C allele carriers (CC and CT, 53.3%) in this group had higher impairment rates (p = 0.05) than TT carriers (33.3%). These findings support the theory that rs6280TC influences the frequency of CI in HIV-positive/METH-positive males.     

Neurobehavioral effects of human immunodeficiency virus infection among former plasma donors in rural China

The human immunodeficiency virus (HIV) epidemic in China has expanded rapidly in recent years, but little is known about the prevalence and features of HIV-associated neurocognitive disorders (HANDs) in this part of the world. We administered a comprehensive Western neuropsychological (NP) test battery to 203 HIV+ and 198 HIV- former plasma donors in the rural area of Anhui province. They found that 26% of the HIV- samples, and 46% of the HIV+ samples, were infected with hepatitis C virus (HCV), which can also have central nervous system (CNS) effects. To classify NP impairment, we developed demographically corrected test norms based upon individuals free of both infections (N=141). Using a global summary score, NP impairment was found in 34.2% of the HIV-monoinfected group and 39.7% of the coinfected group, as compared to 12.7% of the uninfected controls (P<.001). HIV+ participants with acquired immunodeficiency syndrome (AIDS) were more likely to be impaired (43%) than non-AIDS individuals (29%; P<.05). Lastly, when all infection groups were combined, participants with NP impairment reported more cognitive complaints (P<.01) and increased dependence in everyday functioning (P=.01). In sum, NP impairment in this large rural Chinese sample was associated with both HIV and HCV infections, and the impairment's prevalence, severity, and pattern were similar to those reported by Western studies. Clinical significance of NP impairment in this population is suggested by the participants' reports of reduced everyday functioning. These findings indicate that HAND is likely to be an important feature of HIV infection in developing countries, underscoring the need for international efforts to develop CNS-relevant treatments.     

Functional interactions of HIV-infection and methamphetamine dependence during motor programming

Methamphetamine (METH) dependence is frequently comorbid with HIV infection and both have been linked to alterations of brain structure and function. In a previous study, we showed that the brain volume loss characteristic of HIV infection contrasts with METH-related volume increases in striatum and parietal cortex, suggesting distinct neurobiological responses to HIV and METH (Jernigan et al., 2005). Functional magnetic resonance imaging (fMRI) has the potential to reveal functional interactions between the effects of HIV and METH. In the present study, 50 participants were studied in four groups: an HIV+ group, a recently METH-dependent group, a dually affected group, and a group of unaffected community comparison subjects. An fMRI paradigm consisting of motor sequencing tasks of varying levels of complexity was administered to examine blood oxygenation level dependent (BOLD) changes. Within all groups, activity increased significantly with increasing task complexity in large clusters within sensorimotor and parietal cortex, basal ganglia, cerebellum, and cingulate. The task complexity effect was regressed on HIV status, METH status, and the HIV×METH interaction term in a simultaneous multiple regression. HIV was associated with less complexity-related activation in striatum, whereas METH was associated with less complexity-related activation in parietal regions. Significant interaction effects were observed in both cortical and subcortical regions; and, contrary to expectations, the complexity-related activation was less aberrant in dually affected than in single risk participants, in spite of comparable levels of neurocognitive impairment among the clinical groups. Thus, HIV and METH dependence, perhaps through their effects on dopaminergic systems, may have opposing functional effects on neural circuits involved in motor programming.     

Early neuropsychological impairment in HIV-seropositive intravenous drug users: evidence from the Italian Multicentre Neuropsychological HIV Study

The aim of the Italian Multicentre Neuropsychological HIV Study is to assess the prevalence and natural history of cognitive deficit in intravenous drug users (IVDUS) during the asymptomatic phase of HIV infection. The study is currently being conducted in four centres (Napoli, Benevento, Verona and Pavia) whose catchment areas are characterized by different levels of prevalence of HIV infection. Cognitive evaluation is being performed by means of a standardized neuropsychological test battery. A total of 251 subjects (167 males and 84 females) have been recruited in the cross-sectional phase of the study, including 75 asymptomatic HIV-seropositive IVDUS (HIV+/IVDUS), 97 HIV-seronegative IVDUS (HIV-/IVDUS) and 79 non-IVDU seronegative controls matched to IVDUS with regard to sex, age and educational level. The prevalence of global cognitive impairment (performance at least 1.5 standard deviations worse than the average of the control group, on at least two out of five tests) was significantly higher in HIV+/IVDUS than in either HIV-/IVDUS (22.7% vs. 8.2%; P<0.01) or healthy controls (22.7% vs. 2.5%; P<0.001). The difference between HIV-/IVDUS and healthy controls was not statistically significant (8.2% vs. 2.5%; P=0.19). The results of this study lend further support to the ‘cerebral reserve’ model. The cerebral reserve could indeed be reduced in IVDUS as a consequence of chronic exposure to the substance of abuse, so that these subjects become more vulnerable to direct and indirect neurotoxic effects of HIV.     

Neuropsychological evaluation and follow up in jcv- and non-jcv-related leukoencephalopathies in HIV infection

The introduction of highly active antiretroviral therapy does not seem to have altered the incidence of progressive multifocal leukoencephalopathy (PML) in HIV infection. Moreover, the occurrence of a HIV-related leukoencephalopathy, called not determined leukoencephalopaties (NDLE), has been reported. As neuropsychological impairment remains highly prevalent in HIV infection, the aim of this study is to describe the neuropsychological profile of PML and NDLE patients, analyzing the time-related changes. Clinical and neuropsychological data from 32 patients (17 PML, 15 NDLE) were compared with two control groups: (1) asymptomatic HIV+ patients without magnetic resonance imaging evidence of leukoencephalopathy; (2) age-/gender-/education-matched healthy subjects. Patients with rapidly worsening PML were significantly impaired on all neuropsychological tests, while PML with more benign course and NDLE groups showed a dysexecutive pattern of impairment. Asymptomatic HIV+ subjects showed mild and isolated cognitive deficits, without functional impact. Cognitive impairment should therefore be considered a key feature from HIV infection diagnosis.     

Cerebrospinal fluid pleocytosis as a predictive factor for CSF and plasma HIV RNA discordance and escape

The aims of this study were to investigate the frequency of HIV-1 RNA level discordance between the cerebrospinal fluid (CSF) and plasma and of CSF viral escape (CVE) in patients with HIV-1 subtype C on antiretroviral therapy, and evaluate the CSF white blood cell (WBC) performance characteristics in predicting CSF discordance in HIV+ group and the frequency of cognitive impairment in individuals with CSF HIV discordance or escape. HIV-1 RNA levels were assessed in plasma and CSF samples from 68 HIV+ participants without opportunistic infection. CSF discordance was found in 7.4% and CVE in 10%, with comparable frequencies between HIV-1B and C. Twenty samples (29%) showed increased CSF WBC counts. This group had higher CSF and plasma HIV-1 RNA levels than the group with normal WBC counts (p?<?0.0001 and 0.006, respectively). The odds of CSF discordance were 18 times higher for a person with CSF WBC count of >?5 cells/mm³ than the group with normal CSF WBC count. CSF WBC counts (cut-off of 15 cells/mm³) showed high-performance characteristics as a predictive biomarker of CSF discordance (AUC the ROC curve 0.98). The frequency of cognitive impairment for CSF escape or discordance was 83% and 80%. The odds of cognitive impairment in these groups were 19 and 15 times higher than those for an HIV(?) person. Viral discordance or escape in the CNS occurs at a comparable frequency for HIV-1C and HIV-1B. The CSF WBC count was effective as a predictive biomarker of CSF and plasma discordance.

     

Neurocognitive impairment with hepatitis C and HIV co-infection in Southern Brazil

Although cognitive impairment has been well documented in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) mono-infections, research on neurocognitive effects is limited in the context of HIV/HCV co-infection. The aims of this study were to explore the interplay between HIV and HCV infections in the expression of neurocognitive impairment (NCI), and to examine the differences in test performance between HIV/HCV co-infected and HIV or HCV mono-infected patients. A total of 128 participants from Southern Brazil underwent a comprehensive neuropsychological (NP) battery comprising 18 tests. Participants were grouped according to their serological status: HCV mono-infected (n?=?20), HIV mono-infected (n?=?48), HIV/HCV co-infected (n?=?12), and HIV?/HCV-uninfected controls (n?=?48). The frequencies of HIV subtypes B and C between the HIV mono-infected and HIV/HCV co-infected groups were comparable. There was greater prevalence of neuropsychological impairment among all three infection groups compared with the uninfected control group, but no statistically significant differences among mono- and co-infected groups were found. HCV infection was associated with cognitive deficits, independently of liver dysfunction. HCV infection did not show an additive effect on neurocognitive function among HIV+. NCI was independent of HCV RNA on peripheral blood, CSF, and hepatic injury. While we did not find additive global effect, in the present study, there was some evidence of additive HIV/HCV co-infection effects in speed of information processing, executive function, and verbal fluency domains when comparing the co-infected group with the other three groups. NP impairment was not dependent on HCV subtypes.     

Heavy alcohol consumption in individuals with HIV infection: effects on neuropsychological performance.

Higher rates of alcohol use have been reported in HIV+ individuals compared to the general population. Both heavy alcohol use and HIV infection are associated with increased risk of neuropsychological (NP) impairment. We examined effects of heavy active alcohol use and HIV on NP functioning in a large sample of community-residing HIV+ individuals and HIV- controls. The four main study groups included 72 HIV- light/non-drinkers, 70 HIV- heavy drinkers (>100 drinks per month), 70 HIV+ light/non-drinkers, and 56 HIV+ heavy drinkers. The heavy drinking group was further subdivided to assess effects of the heaviest levels of active alcohol use (>6 drinks per day) on NP functioning. A comprehensive NP battery was administered. Multivariate analysis of covariance was employed to examine the effect of HIV and alcohol on NP functioning after adjusting for group differences in age and estimated premorbid verbal intellectual functioning. The analyses identified main effects of heavy drinking and HIV on NP function, with greatest effects involving the contrast of HIV+ heavy drinkers and the HIV- light drinkers. Synergistic effects of heaviest current drinking and HIV infection were identified in analyses of motor and visuomotor speed. Supplementary analyses also revealed better NP function in the HIV+ group with antiretroviral treatment (ART) and lower level of viral burden, a finding that was consistent across levels of alcohol consumption. Finally, heavy alcohol use and executive functioning difficulties were associated with lower levels of self-reported medication adherence in the HIV+ group. The findings suggest that active heavy alcohol use and HIV infection have additive adverse effects on NP function, that they may show synergistic effects in circumstances of very heavy active alcohol use, and that heavy drinking and executive functioning may mediate health-related behaviors in HIV disease.     

Interactions of HIV and methamphetamine: Cellular and molecular mechanisms of toxicity potentiation

Methamphetamine (METH) is a highly addictive psychostimulant drug, whose abuse has reached epidemic proportions worldwide. METH use is disproportionally represented among populations at high risks for developing HIV infection or who are already infected with the virus. Psychostimulant abuse has been reported to exacerbate the cognitive deficits and neurodegenerative abnormalities observed in HIV-positive patients. Thus, the purpose of the present paper is to review the clinical and basic observations that METH potentiates the adverse effects of HIV infection. An additional purpose is to provide a synthesis of the cellular and molecular mechanisms that might be responsible for the increased toxicity observed in co-morbid patients. The reviewed data indicate that METH and HIV proteins, including gp120, gp41, Tat, Vpr and Nef, converge on various caspase-dependent death pathways to cause neuronal apoptosis. The role of reactive microgliosis in METH- and in HIV-induced toxicity is also discussed.     

Perfusion MRI and computerized cognitive test abnormalities in abstinent methamphetamine users

This study aims to determine possible persistent abnormalities in regional cerebral blood flow (relative rCBF) and cognitive function in abstinent methamphetamine (METH) users. Twenty METH-dependent subjects (abstinent for 8+/-2 months) and 20 age- and gender-matched controls were evaluated with perfusion magnetic resonance imaging (pMRI) and neuropsychological tests. METH users showed decreased relative rCBF bilaterally in putamen/insular cortices (right: -12%; left: -10%) and the right lateral parietal brain region (-11%), but increased relative rCBF bilaterally in the left temporoparietal white matter (+13%), the left occipital brain region: (+10%) and the right posterior parietal region (+24%). Interaction effects were observed between METH and gender in the right occipital cortex and a midline brain region; female METH users showed increased relative rCBF (+15% both regions) whereas the male METH users had decreased relative rCBF (-10% and -18%, respectively). METH users performed within normal ranges on standard neuropsychological tests; however, they were slower on several tasks on the California Computerized Assessment Package (CalCAP), especially tasks that required working memory. These findings suggest that METH abuse is associated with persistent physiologic changes in the brain, and these changes are accompanied by slower reaction times on computerized measures of cognitive function.     

Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South India

Most studies of cognitive functioning in human immunodeficiency virus type 1 (HIV-1)-seropositive (HIV-1+) subjects have been done in the United States and Europe, where clade B infections predominate. However, in other parts of the world such as South India, where clade C HIV is most common, the prevalence of HIV-1 is increasing. Standardized neuropsychological tests were used to assess cognitive functioning in a sample of 119 adults infected with clade C HIV-1 who were not on antiretroviral medications. The subjects did not have neurological or psychiatric illness and were functioning adequately. Neuropsychological test performance was compared with gender-, age-, and education-matched normative data derived from a sample of 540 healthy volunteers and a matched cohort of 126 healthy, HIV-1-seronegative individuals. Among the seropositive subjects, 60.5% had mild to moderate cognitive deficits characterized by deficits in the domains of fluency, working memory, and learning and memory. None of the subjects had severe cognitive deficits. The HIV-1+ sample was classified into groups according to the level of immune suppression as defined by CD4 count (<200, 201–499, and >500 cells/mm³) and viral load (<5000, 5001–30,000, 30,001–99,999, 100,000–1,000,000, and >1,000,001 copies). Although the most immunosuppressed group (CD4 count <200 cells/mm³ or viral load >1,000,001 copies) was small, their rate of impairment in visual working memory was greater when compared to groups with better immune functioning. Mild to moderate cognitive deficits can be identified on standardized neuropsychological tests in clade C-infected HIV-1+ adults who do not have any clinically identifiable functional impairment. The prevalence of cognitive deficits is similar to that reported in antiretroviral treatment-naïve individuals infected with clade B virus in the western world.     

Effects of immunosuppression and disease severity upon neuropsychological function in HIV infection

Effects of immunosuppression and illness severity upon neuropsychological function were assessed in a group of homosexual men with AIDS across 6 months. Participants included 62 who were seronegative (HIV-), 74 asymptomatic seropositives (HIV+A), 31 symptomatic seropositives (HIV+S), 23 with AIDS defining illnesses (AIDS-DI), and 10 who were diagnosed with AIDS solely on the basis of CD4+ levels falling below 200 /mm3 (AIDS-CD4). Groups were equivalent in age, education, and IQ. None were drug users, and none experienced a change in disease status across the 6-month inter-test interval. There was little evidence of cognitive decline across time. Nonetheless, after collapsing across time intervals, the AIDS-DI group had worse new-learning than all other groups. Additionally, the AIDS-DI demonstrated a greater number of impaired performances than the other participant groups. The data suggest that cognitive impairment in AIDS is unlikely due to independent contributions of immunosuppression and illness. Rather neurobehavioral deficits are more likely attributable to a combination of the two.     

Erratum To: Neuropsychological deficits in human immunodeficiency virus type 1 clade C-seropositive adults from South India

Most studies of cognitive functioning in human immunodeficiency virus type 1 (HIV-1)-seropositive (HIV-1+) subjects have been done in the United States and Europe, where clade B infections predominate. However, in other parts of the world such as South India, where clade C HIV is most common, the prevalence of HIV-1 is increasing. Standardized neuropsychological tests were used to assess cognitive functioning in a sample of 119 adults infected with clade C HIV-1 who were not on antiretroviral medications. The subjects did not have neurological or psychiatric illness and were functioning adequately. Neuropsychological test performance was compared with gender-, age-, and education-matched normative data derived from a sample of 540 healthy volunteers and a matched cohort of 126 healthy, HIV-1-seronegative individuals. Among the seropositive subjects, 60.5% had mild to moderate cognitive deficits characterized by deficits in the domains of fluency, working memory, and learning and memory. None of the subjects had severe cognitive deficits. The HIV-1+ sample was classified into groups according to the level of immune suppression as defined by CD4 count (<200, 201–499, and >500 cells/mm³) and viral load (<5000, 5001–30,000, 30,001–99,999, 100,000–1,000,000, and >1,000,001 copies). Although the most immunosuppressed group (CD4 count <200 cells/mm³ or viral load >1,000,001 copies) was small, their rate of impairment in visual working memory was greater when compared to groups with better immune functioning. Mild to moderate cognitive deficits can be identified on standardized neuropsychological tests in clade C-infected HIV-1+ adults who do not have any clinically identifiable functional impairment. The prevalence of cognitive deficits is similar to that reported in antiretroviral treatment-naïve individuals infected with clade B virus in the western world.     

Risk for cognitive impairment among HIV-infected persons with bipolar disorder

Clinicians and clinical neuroscientists are aware that individuals with bipolar disorder are at greater risk for developing serious medical, psychiatric, and substance-use comorbidities as compared with the general population.^1,2 Less widely appreciated, however, is the observation that HIV infection appears to be more prevalent among persons with bipolar disorder and that both conditions pose significant risk for cognitive impairment.³ Higher rates of HIV infection among persons with bipolar disorder should not be surprising, given that infection and transmission of HIV involves risk factors that converge with bipolar disorder (eg, impulsivity, substance abuse). These factors likely also worsen adherence to treatment for both bipolar and HIV illness, and may adversely impact health-related quality of life and therapeutic outcomes. The public health consequence may be that nonadherence to antiretroviral therapy could lead to higher rates of transmission of treatment-resistant strains of HIV that can evolve with sporadic adherence. The intersection of bipolar disorder and HIV therefore merits discussion by clinicians, researchers, and policy makers.If mental health clinicians adopt the recent Centers for Disease Control recommendation that all persons in clinical care be tested for HIV, we might expect that more HIV-infected persons with bipolar disorder will be identified who had not previously been diagnosed or treated for existing HIV infection.⁴ When addressing the complex combination of HIV infection, substance abuse or dependence, and bipolar disorder, it is important to recognize that each of these factors may be associated with substantial cognitive deficits. These neurocognitive impairments may impact on the ability to function in social and occupational settings, to follow through with treatment recommendations, and to manage their demanding medical conditions.Below we review the evidence for neuropsychological (NP) impairment among persons with bipolar disorder, HIV infection, and substance dependence (ie, methamphetamine dependence) as independent disorders. Our hypothesis, and the basis for our ongoing research, is that the presence of significant medical comorbidities (eg, HIV infection) and substance use (eg, methamphetamine dependence) may further compound the risk for additive neurocognitive impairments among persons with bipolar disorder. We describe our new program of research in bipolar disorder and comorbid HIV, and present data showing elevated rates of methamphetamine dependence among persons with bipolar disorder. Finally, we discuss how cognitive impairment may be a significant predictor of everyday functioning difficulties (eg, medication nonadherence).     

Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK1/2 activation in the prefrontal cortex of mice.

BACKGROUND: Recent clinical studies have suggested that chronic use of methamphetamine (METH) induces long-term cognitive deficits. To clarify the mechanism of METH-induced cognitive impairment, we investigated the effect of METH on cognitive function in mice. METHODS: Mice were repeatedly administered METH for 7 days, and their cognitive function was assessed using a novel-object recognition task. Therapeutic effects of clozapine and haloperidol on METH-induced cognitive impairment were investigated. Western blotting and specific inhibitors were employed to determine the role of extracellular signal-regulated kinase 1/2 (ERK1/2). RESULTS: Repeated METH treatment induced an impairment of recognition of novel objects and behavioral sensitization. These effects persisted for at least 28 days after the drug withdrawal. Clozapine, but not haloperidol, reduced METH-induced cognitive impairment. Hyperphosphorylation of ERK1/2 was found in the prefrontal cortex of mice exposed to the novel objects, but was abolished in mice treated with METH. Inhibition of ERK1/2 by the microinjection of PD98059 into the prefrontal cortex resulted in cognitive impairment. CONCLUSIONS: These results suggest that repeated METH treatment induces cognitive impairment, which is associated with the dysfunction of the ERK1/2 pathway in the prefrontal cortex.     

Visual attention deficits are associated with driving accidents in cognitively-impaired HIV-infected individuals

Previous research has found HIV-associated neuropsychological (NP) dysfunction to be associated with impaired driving skills. To determine whether specific impairments in visual attention impart an increased accident risk, we assessed 21 HIV seronegative (HIV-) and 42 seropositive (HIV+) participants on NP tests and the Useful Field of View (UFOV), a computerized test of visual attention. HIV+ participants performed significantly worse than the HIV- participants on the UFOV, particularly on the Divided Attention subtest. Poor UFOV performance was associated with higher accident rates in the past year, with a trend for NP impairment to also predict more accidents. The highest number of accidents occurred in the group with a "high risk" UFOV designation and NP impairment; this category correctly classified 93% of HIV+ participants as to who did, and did not, have an accident. Clinicians should attend to visual attention as well as general cognitive status in estimating which patients are at risk for impaired driving.     

Peripheral biomarkers do not correlate with cognitive impairment in highly active antiretroviral therapy—treated subjects with human immunodeficiency virus type 1 infection

Neuropsychological (NP) impairments in human immunodeficiency virus (HIV)-infected individuals remain high despite the introduction of highly active antiretroviral therapy (HAART). We sought to determine whether or not a monocyte gene expression profile along with other peripheral factors would correlate with neuropsychological impairment among HIV-infected individuals. Forty-four HIV-1-seropositive subjects (HIV+) on HAART and 11 HIV-1-seronegative controls (HIV−) had NP testing and blood drawn for monocyte gene expression analysis. All HIV+ subjects were assessed for CD4 counts, apolipoprotein E (ApoE) genotype, viral load, and plasma lipopolysaccharide (LPS) and soluble CD14 (sCD14). NP scores were normalized to age, gender, and education. Twenty-five percent of HIV+ individuals showed abnormal NP testing results (>1.5 SD below normal in two domains). HIV+ individuals had deficits in attention/working memory, verbal learning, and information processing speed compared to HIV− controls. There was no correlation between overall NP impairment and plasma viral load, level of education, age, ethnic diversity, sCD14, plasma LPS, CD4 cell count, ApoE genotype, or years of infection. However, greater years of infection had worse visual learning performance. sCD14 and CD4 nadir positively correlated with information processing speed and fine motor skills, respectively. LPS correlated with viral load but not cognitive impairment. Monocyte gene expression confirmed a chronic inflammatory profile that correlated with viral load but not cognition. No blood index or profile was associated with overall NP impairment.