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.

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.

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.

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 (F(3,23) = 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.

Additive deleterious effects of methamphetamine dependence and immunosuppression on neuropsychological functioning in HIV infection.

Methamphetamine (MA) dependence and HIV infection are independently associated with cerebral dysfunction, especially within frontal-basal ganglia circuits. Recent evidence indicates that MA dependence has an additive effect on neuropsychological (NP) deficits associated with HIV infection. This study extends prior findings by examining the combined effects of MA dependence (MA+) and immunosuppression (i.e., CD4 lymphocyte count <200) on NP functioning in 284 HIV+ individuals. Prevalence of NP impairment was examined in four demographically comparable groups: (1) MA+/CD4 < 200; (2) MA+/CD4 > or = 200; (3) MA-/CD4 < 200; and (4) MA-/CD4 > or = 200. Results revealed that both MA dependence and immunosuppression were significant predictors of NP impairment. More importantly, additive effects were evident whereby the MA+/CD4 < 200 group exhibited the highest rate of NP impairment. Findings indicate that MA dependence conveys an additive deleterious impact on NP status in immunosuppressed persons with HIV infection, perhaps reflecting the combined effects of neuropathophysiological mechanisms in fronto-striatal circuits.

Statistical power of studies examining the cognitive effects of subthalamic nucleus deep brain stimulation in Parkinson's disease.

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 Parkinson's 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.

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.

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 corrected T-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 corrected T-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.

Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure.

Abuse of the stimulant drug methamphetamine is associated with neural injury and neuropsychological (NP) deficits, while the residual effects of marijuana use remain uncertain. We sought to determine if methamphetamine dependent persons who also met criteria for marijuana abuse or dependence evidenced different NP performance than those with dependence for methamphetamine alone. We examined three groups that did not differ significantly on important demographic factors: (1) subjects with a history of methamphetamine dependence and history of marijuana abuse/dependence (METH+/MJ+, n=27); (2) methamphetamine dependent subjects without history of marijuana abuse/dependence (METH+/MJ-, n=26); (3) a control group with minimal or no drug use (n=41). A comprehensive NP battery was administered and performance was quantified for five cognitive ability areas. The METH+/MJ- group generally demonstrated the greatest NP impairment, with statistically significant differences observed between the METH+/MJ- and control group in learning, retention/retrieval, and a summary score of global NP performance. The METH+/MJ+ group did not differ significantly from the control or METH+/MJ- group on any NP ability. However, there was a significant linear trend in the global NP score suggesting that the METH+/MJ+ performed intermediate to the control and METH+/MJ- groups. Based on these findings, we cannot conclude that there is a protective effect of marijuana use in methamphetamine users; however, marijuana use clearly did not appear to exacerbate methamphetamine neurotoxicity. Further investigations are needed to determine if the emerging literature, suggesting that certain cannabinoids might have neuroprotective actions, is generalizable to community-dwelling substance abusers.

Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV.

We examined the interrater (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.

Qualitative aspects of verbal fluency in HIV-associated dementia: a deficit in rule-guided lexical-semantic search processes?

HIV-associated dementia (HAD) is widely considered a "subcortical" dementia that involves a disruption of frontal-basal ganglia circuits. Deficits in verbal fluency are common in HAD; however, the cognitive underpinnings of these deficits are not well understood. To elucidate the cognitive mechanisms underlying the diminished verbal fluency output in HAD, we examined several qualitative aspects of letter fluency in 21 individuals with HAD, 51 nondemented persons with HIV infection (HIV+), and 30 healthy controls (HC) who were comparable for age, education, sex, ethnicity, and estimated premorbid verbal intelligence. The verbal fluency protocols were scored to obtain the total number of correct words, average phonemic cluster size, total number of switches between phonemic clusters, and the proportion of error responses (i.e., intrusions, perseverations, and variants). Consistent with prior research, HAD participants produced significantly fewer total correct words relative to the HC and nondemented HIV+ groups. The HAD group also demonstrated fewer switches and a higher proportion of response errors (especially intrusion errors), but no differences were observed in average cluster size. Findings are interpreted as reflecting a disruption of rule-guided lexical-semantic search strategies in HAD, perhaps mediated by prefrontal-striatal circuit dysfunction, rather than depleted lexical-semantic memory stores.

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.

Cognitive asymmetries associated with apolipoprotein E genotype in patients with Alzheimer's disease.

The relationship between apolipoprotein E (apoE) genotype and cognitive performance was examined in 200 patients with probable Alzheimer's disease (AD). Differences between composite measures of verbal and nonverbal functioning were used to define asymmetric patterns of cognition. Patients who were homozygous for apoE epsilon4 demonstrated relatively worse nonverbal as compared to verbal cognitive ability. In contrast, participants who were heterozygous for apoE epsilon4 or who possessed no epsilon4 allele demonstrated relatively equivalent verbal and nonverbal cognitive abilities. Although age and dementia severity also contributed to these patterns, apoE genotype appears to have a significant unique contribution to cognitive performance in these individuals. The epsilon4 allele may thus be associated with a specific neurocognitive phenotype among patients with AD, with the overall pattern of cognitive asymmetry dependent upon epsilon4 dose.

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> or =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.