Catherine L. Carey

Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons

Both HIV infection and methamphetamine dependence can be associated with brain dysfunction. Little is known, however, about the cognitive effects of concurrent HIV infection and methamphetamine dependence. The present study included 200 participants in 4 groups: HIV infected/methamphetamine dependent (HIV+/METH+), HIV negative/methamphetamine dependent (HIV-/METH+), HIV infected/methamphetamine nondependent (HIV+/METH-), and HIV negative/methamphetamine nondependent (HIV-/METH-). Study groups were comparable for age, education, and ethnicity, although the HIV-/METH- group had significantly more females. A comprehensive, demographically corrected neuropsychological battery was administered yielding a global performance score and scores for seven neurobehavioral domains. Rates of neuropsychological impairment were determined by cutoff scores derived from performances of a separate control group and validated with larger samples of HIV+ and HIV- participants from an independent cohort. Rates of global neuropsychological impairment were higher in the HIV+/METH+ (58%), HIV-/METH+ (40%) and HIV+/METH- (38%) groups compared to the HIV-/METH- (18%) group. Nonparametric analyses revealed a significant monotonic trend for global cognitive status across groups, with least impairment in the control group and highest prevalence of impairment in the group with concurrent HIV infection and methamphetamine dependence. The results indicate that HIV infection and methamphetamine dependence are each associated with neuropsychological deficits, and suggest that these factors in combination are associated with additive deleterious cognitive effects. This additivity may reflect common pathways to neural injury involving both cytotoxic and apoptotic mechanisms.

Non-acute (residual) neurocognitive effects of cannabis use: A meta-analytic study

The possible medicinal use of cannabinoids for chronic diseases emphasizes the need to understand the long-term effects of these compounds on the central nervous system. We provide a quantitative synthesis of empirical research pertaining to the non-acute (residual) effects of cannabis on the neurocognitive performance of adult human subjects. Out of 1,014 studies retrieved using a thorough search strategy, only 11 studies met essential a priori inclusion criteria, providing data for a total of 623 cannabis users and 409 non- or minimal users. Neuropsychological results were grouped into 8 ability domains, and effect sizes were calculated by domain for each study individually, and combined for the full set of studies. Using slightly liberalized criteria, an additional four studies were included in a second analysis, bringing the total number of subjects to 1,188 (i.e., 704 cannabis users and 484 non-users). With the exception of both the learning and forgetting domains, effect size confidence intervals for the remaining 6 domains included zero, suggesting a lack of effect. Few studies on the non-acute neurocognitive effects of cannabis meet current research standards; nevertheless, our results indicate that there might be decrements in the ability to learn and remember new information in chronic users, whereas other cognitive abilities are unaffected. However, from a neurocognitive standpoint, the small magnitude of these effect sizes suggests that if cannabis compounds are found to have therapeutic value, they may have an acceptable margin of safety under the more limited conditions of exposure that would likely obtain in a medical setting.

Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment.

Objective:To determine the association of markers of regional neurodegeneration (ND) at autopsy to degree of neurocognitive impairment in persons with HIV. Design:In a prospectively followed cohort of HIV-infected individuals we examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data. Methods:Twenty-seven HIV-infected individuals with both neuropsychological and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on: (1) microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and (2) synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain region: midfrontal cortex, hippocampus, and putamen. Results:The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. In a regression, hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment (F3,23 = 6.17; P < 0.01; R2 = 0.45). The correlations among regional ND measures demonstrated that ND is unevenly distributed across multiple brain regions. Conclusions:As the anatomic distribution and temporal progression of neuropathologic changes appears to differ across individuals, it is important to consider both cortical and subcortical brain regions in studies of neuropathogenesis and treatment of HIV-related brain disease. Furthermore, combining information from several markers of neural injury provided the strongest association with degree of neurocognitive impairment during life.

Initial Validation of a Screening Battery for the Detection of HIV-Associated Cognitive Impairment

This study sought to develop and validate a screening battery for detecting HIV-related neuropsychological(NP)impairment. Six NP measures representing the ability areas most likely affected by HIV infection were paired in 14 combinations and their diagnostic accuracy rates compared. The measures were selected from a larger NP battery administered to 190 HIV-seropositive(HIV + )participants. Screening battery performance was classified as NP impaired if demographically correctedT-scores fell below 40 on both tests, or below 35 on one test. Using blind clinical ratings of NP test results from the larger battery as the“gold standard”for global NP status(impaired or unimpaired), we found that several test combinations demonstrated adequate diagnostic accuracy in detecting NP impairment. The most sensitive test combinations were the Hopkins Verbal Learning Test–Revised(HVLT–R; Total Recall)and the Grooved Pegboard Test nondominant hand(PND)pair and the HVLT–R and WAIS-III Digit Symbol(DS)subtest pair(sensitivity = 78%and 75%, respectively). Both test combinations(HVLT–R/PND, HVLT–R/DS)were more accurate than the HIV Dementia Scale(HDS)in classifying HIV + participants as NP impaired or unimpaired. Results suggest that demographically correctedT-scores from pairs of common NP measures may serve as valid screening instruments to identify subjects with HIV-related neurocognitive impairment who could benefit from more extensive NP examination.

HIV-associated prospective memory impairment increases risk of dependence in everyday functioning.

HIV infection is associated with impairments in prospective memory (ProM), an aspect of episodic memory that refers to the ability to execute a future intention, such as remembering to take a medication at a specific time. The current study sought to examine the relationship between HIV-associated ProM impairment and the successful management of instrumental activities of daily living (IADLs). In a cohort of 66 HIV-infected individuals, ProM accounted for a significant proportion of variance in self-reported IADL dependence, over and above that which was explained by retrospective memory and by current affective distress. Analysis of component cognitive processes revealed that the relationship between HIV-associated ProM deficits and IADL dependence was driven by impaired cue detection and by deficits in self-initiated intention retrieval. Results were not better explained by demographic factors, HIV disease severity, psychiatric comorbidity, or substance use. Collectively, these data support the potential incremental ecological validity of ProM as a predictor of dependence in IADLs among persons living with HIV infection.

Prospective Memory in HIV-1 Infection

The cognitive deficits associated with HIV-1 infection are thought to primarily reflect neuropathophysiology within the fronto-striato-thalamo-cortical circuits. Prospective memory (ProM) is a cognitive function that is largely dependent on prefronto-striatal circuits, but has not previously been examined in an HIV-1 sample. A form of episodic memory, ProM involves the complex processes of forming, monitoring, and executing future intentions vis-à-vis ongoing distractions. The current study examined ProM in 42 participants with HIV-1 infection and 29 demographically similar seronegative healthy comparison (HC) subjects. The HIV-1 sample demonstrated deficits in time- and event-based ProM, as well as more frequent 24-hour delay ProM failures and task substitution errors relative to the HC group. In contrast, there were no significant differences in recognition performance, indicating that the HIV-1 group was able to accurately retain and recognize the ProM intention when retrieval demands were minimized. Secondary analyses revealed that ProM performance correlated with validated clinical measures of executive functions, episodic memory (free recall), and verbal working memory, but not with tests of semantic memory, retention, or recognition discrimination. Taken together, these findings indicate that HIV-1 infection is associated with ProM impairment that is primarily driven by a breakdown in the strategic (i.e., executive) aspects of retrieving future intentions, which is consistent with a prefronto-striatal circuit neuropathogenesis. The HNRC group is affiliated with the University of California, San Diego, the Naval Hospital, San Diego, and the San Diego Veterans Affairs Healthcare System, and includes: Director: Igor Grant, M.D.; Co-Directors: J. Hampton Atkinson, M.D., J. Allen McCutchan, M.D.; Center Manager: Thomas D. Marcotte, Ph.D.; Naval Hospital San Diego: Mark R. Wallace, M.D. (P.I.); Neuromedical Component: J. Allen McCutchan, M.D. (P.I.), Ronald J. Ellis, M.D., Ph.D., Scott Letendre, M.D., Rachel Schrier, Ph.D.; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), Mariana Cherner, Ph.D., Julie Rippeth, Ph.D., Joseph Sadek, Ph.D., Steven Paul Woods, Psy.D., Corinna Young, Ph.D.; Imaging Component: Terry Jernigan, Ph.D. (P.I.), John Hesselink, M.D., Michael J. Taylor, Ph.D.; Neuropathology Component: Eliezer Masliah, M.D. (P.I.), Dianne Langford, Ph.D.; Clinical Trials Component: J. Allen McCutchan, M.D., J. Hampton Atkinson, M.D., Ronald J. Ellis, M.D., Ph.D., Scott Letendre, M.D.; Data Management Unit: Daniel R. Masys, M.D. (P.I.), Michelle Frybarger, B.A. (Data Systems Manager); Statistics Unit: Ian Abramson, Ph.D. (P.I.), and Deborah Lazzaretto, M.S. Catherine L. Carey is now in the Department of Psychiatry at the University of California, San Francisco. Julie Rippeth is now in the Department of Psychology at Walter Reed Army Medical Center. The research described was also supported by DA12065, MH59745, MH62512, and MH073419 from the National Institutes of Health. The views expressed in this article are those of the authors and do not reflect the official policy or position of the Department of the Navy, Department of Defense, nor the United States Government. The authors extend their gratitude to Sarah Raskin, Ph.D. for her generosity in supplying a complementary version of the MIST for use in this study. We also thank Jennifer Marquie, Emily Conover, Emily Jo Rajotte, J. Cobb Scott, and Richard Seghers for their assistance with data collection and coding. Aspects of these data were presented as part of a symposium at the 33rd Annual Meeting of the International Neuropsychological Society in St. Louis, MO.

Subcortical Lacunes Are Associated With Executive Dysfunction in Cognitively Normal Elderly

Background and Purpose— The relationship between subcortical ischemic vascular disease (SIVD) and cognition in normal elderly is unclear, in part because of methodological inconsistencies across studies. To clarify this relationship, the current study investigated a well characterized cognitively normal elderly sample (≥55 years) with quantitative MRI and psychometrically robust neuropsychological measures within a multivariate model. Converging evidence suggests that SIVD selectively impairs frontal-executive tasks by disrupting frontal-subcortical circuits. We therefore hypothesized that MRI markers of SIVD would be selectively associated with worse executive functioning. Methods— We studied 94 participants who were cognitively and functionally normal. Volumetric measures of white matter signal hyperintensity (WMH), subcortical lacunes, hippocampal volume, and cortical gray matter were obtained to predict performance on composite measures of executive functioning and episodic memory. Results— Hierarchical regression demonstrated that after controlling for demographic variables, MMSE, and total intracranial volume, the total number of subcortical lacunes was the only significant predictor, with a greater number of lacunes associated with poorer executive performance. Hippocampal volume best predicted episodic memory performance. Conclusions— Results suggest that SIVD in the form of silent lacunes corresponds to poorer executive functioning even in otherwise normal elderly, which is consistent with the hypothesis that SIVD preferentially disrupts frontal-subcortical circuits. The clinical importance of these findings is highlighted by the fact that 33% of the normal elderly participants in this study had lacunar infarcts.

Deficient strategic control of verbal encoding and retrieval in individuals with methamphetamine dependence

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.

Psychometric characteristics of the memory for intentions screening test.

The construct of prospective memory (ProM), or “remembering to remember,” is hypothesized to play a critical role in normal activities of daily living and has increasingly been the focus of clinical research over the past 10 years. However, the assessment of ProM as part of routine clinical care is presently hampered by the paucity of psychometrically sound, validated ProM tests available in the neuropsychological literature. The Memory for Intentions Screening Test (MIST; Raskin, 2004) is a user-friendly, comprehensive measure of ProM that demonstrates preliminary evidence of construct validity. Extending this research, this study evaluated the psychometric characteristics of the MIST in a sample of 67 healthy adults. Despite a mildly restricted range of scores, results revealed excellent inter-rater reliability, adequate split-half reliability, and satisfactory inter-relationships between the MIST summary score, subscales, and error types. Analysis of demographic correlates showed that the MIST was independently associated with both age and education, but not with sex or ethnicity. These findings broadly support the psychometric properties of the MIST, specifically its reliability and expected relationships with demographic characteristics. Recommendations are provided regarding future research to enhance the clinical usefulness of the MIST.

Nonacute (residual) neuropsychological effects of cannabis use: a qualitative analysis and systematic review.

Because there is a possibility that cannabis or cannabis‐like molecules might be used as treatments for certain conditions in the future, it becomes important to consider the possible adverse effects of these compounds. In this paper, the authors review the evidence for persisting effects of nonacute cannabis use on the central nervous system, as reflected by alteration in neuropsychological performance. From the 40 articles that met criteria for inclusion in this review, the authors could not detect consistent evidence for persisting neuropsychological deficits in cannabis users; however, 22 of the 40 studies reported at least some subtle impairments. The inability to reach a firm conclusion results largely from methodological limitations inherent in most studies. These are considered in detail to inform future studies on (nonacute) consequences of cannabis consumption on cognitive abilities.