Julie D. Rippeth

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.

Interrater Reliability of Clinical Ratings and Neurocognitive Diagnoses in HIV

We examined the interrater reliability (IRR) of clinical ratings of neuropsychological (NP) impairment and neurocognitive diagnoses in HIV. Thirty participants with advanced HIV-infection who were enrolled in a multicenter HIV brain banking research project underwent comprehensive NP and neuromedical evaluations. Using a standardized system of guidelines, neuropsychologists from six participating sites independently assigned clinical ratings of NP impairment, as well as multilevel diagnoses reflecting the inferred etiology of the impairments and their effects on everyday functioning. Findings indicated excellent IRR in rating the presence and severity of NP impairment, but overall modest IRR for neurocognitive diagnoses. Not surprisingly, most diagnostic disagreements concerned the etiology of impairments in persons with medical and neuropsychiatric risk factors in addition to HIV.

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.

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.

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.

Statistical Power of Studies Examining the Cognitive Effects of Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease

ABSTRACT It has been argued that neuropsychological studies generally possess adequate statistical power to detect large effect sizes. However, low statistical power is problematic in neuropsychological research involving clinical populations and novel interventions for which available sample sizes are often limited. One notable example of this problem is evident in the literature regarding the cognitive sequelae of deep brain stimulation (DBS) of the subthalamic nucleus (STN) in persons with Parkinsons disease (PD). In the current review, a post hoc estimate of the statistical power of 30 studies examining cognitive effects of STN DBS in PD revealed adequate power to detect substantial cognitive declines (i.e., very large effect sizes), but surprisingly low estimated power to detect cognitive changes associated with conventionally small, medium, and large effect sizes. Such wide spread Type II error risk in the STN DBS cognitive outcomes literature may affect the clinical decision-making process as concerns the possible risk of postsurgical cognitive morbidity, as well as conceptual inferences to be drawn regarding the role of the STN in higher-level cognitive functions. Statistical and methodological recommendations (e.g., meta-analysis) are offered to enhance the power of current and future studies examining the neuropsychological sequelae of STN DBS in PD.

Demographically Adjusted Normative Standards for New Indices of Performance on the Paced Auditory Serial Addition Task (PASAT)

The Paced Auditory Serial Addition Task (PASAT) is a complex cognitive test sensitive to neuropsychological disorders. Its traditional Total Correct score seemingly reflects multiple cognitive abilities, including attention, working memory, and processing speed. Snyder, Aniskiewicz, and Snyder (1993) modified scoring guidelines for the PASAT to give credit only for “dyads.” This method emphasizes working memory operations and has been found superior to Total Correct scores at detecting cognitive impairments in several investigations. To date, normative standards are not available for the “dyad” scoring method, thus limiting its utility in clinical and research settings. The current investigation provides demographically adjusted normative data based on a sample of 500 healthy adults of varied age, education, sex, and race (African American and Caucasian) for various indices of performance on the PASAT, including “Total Dyads” obtained across the four PASAT trials. In addition, we describe and present normative data on four other indices designed to quantify various aspects of performance on the PASAT: invalid responding, effects of varied information processing speed demands, and tendency to omit responses and to make arithmetic errors.

Base Rate of Hiscock Digit Memory Test Failure in HIV-Associated Neurocognitive Disorders

There is an emergent need for base rate data on symptom validity tests (SVTs) in clinical populations that are likely to seek disability benefits. The inclusion of HIV under the Americans with Disabilities Act has prompted many persons with HIV-1 infection to apply for disability, which raises the concern that a subset of these individuals might feign cognitive deficits to obtain benefits. This brief report provides base rate data on one SVT, the Hiscock Digit Memory Test (HDMT), in a sample of 82 non-compensation-seeking, neuropsychologically impaired participants who met diagnostic criteria for an HIV-associated neurocognitive disorder. Approximately 98% of individuals with HIV-associated neurocognitive disorders performed above an established HDMT cutoff for suboptimal effort (i.e., HDMT = 90% accuracy), whilst 95% of the sample obtained perfect scores. Clinicians can therefore be confident that, in the absence of severe dementia or amnesia, HDMT scores below standard cutoffs are unlikely to be solely attributable to HIV-associated cognitive impairment.

Association between dyads and correct responses on the Paced Auditory Serial Addition Task (PASAT).

The sensitivity of the Paced Auditory Serial Addition Task (PASAT) to working memory deficits may be enhanced by examining “dyads” (i.e., correct responses immediately preceded by a correct response) as a complement to the traditional total correct summary score. In a sample of 397 mostly African American (79%) healthy adults, total dyad and total correct scores were highly correlated (r = .96, p < .001); however, the magnitude of this association diminished in faster stimulus presentation trials, particularly among participants with impaired working memory abilities.