CD4 nadir and neurocognitive trajectories in people living with HIV.

Human immunodeficiency virus-associated neurocognitive disorders persist in the combination antiretroviral therapy era. CD4 nadir is a well-established predictor of cognition cross-sectionally, but its impact on longitudinal neurocognitive (NC) trajectories is unclear. The few studies on this topic examined trajectories of global cognition, rather than specific NC domains. The current study examined CD4 nadir in relation to domain-specific NC decline. 132 HIV + adults from the Temple/Drexel Comprehensive NeuroHIV Center, Clinical and Translational Research Support Core Cohort were administered comprehensive NC assessments longitudinally, with last visit occurring an average of 12 years after CD4 nadir. Linear mixed models were used to examine CD4 nadir in relation to longitudinal NC trajectories in three empirically identified NC domains: speed/executive function (S/EF), visuospatial memory (VM), and verbal fluency (VF). CD4 nadir was associated with change in VF (p = 0.020), but not with S/EF or VM. Specifically, those with CD4 nadir < 200 demonstrated increasing VF over time (p = .002), whereas those with CD4 nadir > 200 demonstrated stable VF (p = .568), though these differing trajectories may partly reflect regression to the mean or differential practice effect. CD4 dynamics over time were analyzed as potential mechanisms for the identified associations, with mixed findings. While low CD4 nadir has been associated with weaker neurocognition among people living with HIV, the results of this study suggest that low CD4 nadir is not associated with ongoing decline a decade later. Nadir-related deficits in VF may be stable or even improve over time, possibly reflecting the beneficial cognitive effects of long-term treatment and immune reconstitution.

Examining virtual driving test performance and its relationship to individuals with HIV-associated neurocognitive disorders.

Significance: Existing screening tools for HIV-associated neurocognitive disorders (HAND) are often clinically impractical for detecting milder forms of impairment. The formal diagnosis of HAND requires an assessment of both cognition and impairment in activities of daily living (ADL). To address the critical need for identifying patients who may have disability associated with HAND, we implemented a low-cost screening tool, the Virtual Driving Test (VDT) platform, in a vulnerable cohort of people with HIV (PWH). The VDT presents an opportunity to cost-effectively screen for milder forms of impairment while providing practical guidance for a cognitively demanding ADL. Objectives: We aimed to: (1) evaluate whether VDT performance variables were associated with a HAND diagnosis and if so; (2) systematically identify a manageable subset of variables for use in a future screening model for HAND. As a secondary objective, we examined the relative associations of identified variables with impairment within the individual domains used to diagnose HAND. Methods: In a cross-sectional design, 62 PWH were recruited from an established HIV cohort and completed a comprehensive neuropsychological assessment (CNPA), followed by a self-directed VDT. Dichotomized diagnoses of HAND-specific impairment and impairment within each of the seven CNPA domains were ascertained. A systematic variable selection process was used to reduce the large amount of VDT data generated, to a smaller subset of VDT variables, estimated to be associated with HAND. In addition, we examined associations between the identified variables and impairment within each of the CNPA domains. Results: More than half of the participants (N = 35) had a confirmed presence of HAND. A subset of twenty VDT performance variables was isolated and then ranked by the strength of its estimated associations with HAND. In addition, several variables within the final subset had statistically significant associations with impairment in motor function, executive function, and attention and working memory, consistent with previous research. Conclusion: We identified a subset of VDT performance variables that are associated with HAND and assess relevant functional abilities among individuals with HAND. Additional research is required to develop and validate a predictive HAND screening model incorporating this subset.

Diagnosing Mild Cognitive Impairment Among Racially Diverse Older Adults: Comparison of Consensus, Actuarial, and Statistical Methods.

BACKGROUND: Actuarial and statistical methods have been proposed as alternatives to conventional methods of diagnosing mild cognitive impairment (MCI), with the aim of enhancing diagnostic and prognostic validity, but have not been compared in racially diverse samples. OBJECTIVE: We compared the agreement of consensus, actuarial, and statistical MCI diagnostic methods, and their relationship to race and prognostic indicators, among diverse older adults. METHODS: Participants (N = 354; M age = 71; 68% White, 29% Black) were diagnosed with MCI or normal cognition (NC) according to clinical consensus, actuarial neuropsychological criteria (Jak/Bondi), and latent class analysis (LCA). We examined associations with race/ethnicity, longitudinal cognitive and functional change, and incident dementia. RESULTS: MCI rates by consensus, actuarial criteria, and LCA were 44%, 53%, and 41%, respectively. LCA identified three MCI subtypes (memory; memory/language; memory/executive) and two NC classes (low normal; high normal). Diagnostic agreement was substantial, but agreement of the actuarial method with consensus and LCA was weaker than the agreement between consensus and LCA. Among cases classified as MCI by actuarial criteria only, Black participants were over-represented, and outcomes were generally similar to those of NC participants. Consensus diagnoses best predicted longitudinal outcomes overall, whereas actuarial diagnoses best predicted longitudinal functional change among Black participants. CONCLUSION: Consensus diagnoses optimize specificity in predicting dementia, but among Black older adults, actuarial diagnoses may be more sensitive to early signs of decline. Results highlight the need for cross-cultural validity in MCI diagnosis and should be explored in community- and population-based samples.

Improving prediction of sudden unexpected death in epilepsy: From SUDEP-7 to SUDEP-3.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a significant cause of mortality in epilepsy. The aim of this study is to evaluate the validity of the SUDEP-7 inventory and its components as tools for predicting SUDEP risk, and to develop and validate an improved inventory. METHODS: The study included 28 patients who underwent video-electroencephalography (EEG) monitoring and later died of SUDEP, and 56 age- and sex-matched control patients with epilepsy. The SUDEP-7 score, its individual components, and an alternative inventory were examined as predictors of SUDEP. RESULTS: SUDEP-7 scores were significantly higher among SUDEP patients compared with controls, both at time of admission (p = 0.024) and most recent follow-up (p = 0.016). SUDEP-7 scores declined only among controls, who demonstrated reduced seizure frequency. Seizure freedom after epilepsy surgery was also associated with survival. Several components of the SUDEP-7 inventory were independently associated with higher risk of SUDEP, including more than three generalized tonic-clonic (GTC) seizures (p = 0.002), one or more GTC seizures (p = 0.001), or one or more seizures of any type within the last year (p = 0.013), and intellectual disability (p = 0.031). In stepwise regression models, SUDEP-7 scores did not enhance the prediction of SUDEP over either GTC seizure frequency or seizure frequency alone. A novel SUDEP-3 inventory comprising GTC seizure frequency, seizure frequency, and intellectual disability (p < 0.001) outperformed the SUDEP-7 inventory (p = 0.010) in predicting SUDEP. SIGNIFICANCE: Our findings demonstrate the limitations of the SUDEP-7 inventory. We propose a new three-item SUDEP-3 inventory, which predicts SUDEP better than the SUDEP-7.

Age and Graphomotor Decision Making Assessed with the Digital Clock Drawing Test: The Framingham Heart Study.

BACKGROUND: Digital Clock Drawing Test (dCDT) technology enables the examination of detailed neurocognitive behavior as behavior unfolds in real time; a capability that cannot be obtained using a traditional pen and paper testing format. OBJECTIVE: Parameters obtained from the dCDT were used to investigate neurocognitive constructs related to higher-order neurocognitive decision making and information processing speed. The current research sought to determine the effect of age as related to combined motor and non-motor components of drawing, and higher-order decision making latencies. METHODS: A large group of stroke- and dementia- free Framingham Heart Study participants were administered the dCDT to command and copy with hands set for "10 after 11". Six age groups (age range 28-98) were constructed. RESULTS: Differences between age groups were found for total time to completion, total pen stroke count, and higher-order decision making latencies in both command and copy test conditions. CONCLUSION: Longer age-related decision making latencies may reflect a greater need for working memory and increased self-monitoring in older subjects. These latency measures have potential to serve as neurocognitive biomarkers of Alzheimer's disease and other insidious neurodegenerative disorders.

Heterogeneity of Neuropsychological Impairment in HIV Infection: Contributions from Mild Cognitive Impairment.

Despite longstanding acknowledgement of the heterogeneity of HIV-associated neurocognitive disorders (HAND), existing HAND diagnostic methods classify according to the degree of impairment, without regard to the pattern of neuropsychological strengths and weaknesses. Research in mild cognitive impairment (MCI) has demonstrated that classifying individuals into subtypes by both their level and pattern of impairment, using either conventional or statistical methods, has etiologic and prognostic utility. Methods for characterizing the heterogeneity of MCI provide a framework that can be applied to other disorders and may be useful in clarifying some of the current challenges in the study of HAND. A small number of studies have applied these methods to examine the heterogeneity of neurocognitive function among individuals with HIV. Most have supported the existence of multiple subtypes of neurocognitive impairment, with some evidence for distinct clinicodemographic features of these subtypes, but a number of gaps exist. Following a review of diagnostic methods and challenges in the study of HAND, we summarize the literature regarding conventional and empirical subtypes of MCI and HAND and identify directions for future research regarding neurocognitive heterogeneity in HIV infection.

Specific amino acids in HIV-1 Vpr are significantly associated with differences in patient neurocognitive status.

Even in the era of combination antiretroviral therapies used to combat human immunodeficiency virus type 1 (HIV-1) infection, up to 50 % of well-suppressed HIV-1-infected patients are still diagnosed with mild neurological deficits referred to as HIV-associated neurocognitive disorders (HAND). The multifactorial nature of HAND likely involves the HIV-1 accessory protein viral protein R (Vpr) as an agent of neuropathogenesis. To investigate the effect of naturally occurring variations in Vpr on HAND in well-suppressed HIV-1-infected patients, bioinformatic analyses were used to correlate peripheral blood-derived Vpr sequences with patient neurocognitive performance, as measured by comprehensive neuropsychological assessment and the resulting Global Deficit Score (GDS). Our studies revealed unique associations between GDS and the presence of specific amino acid changes in peripheral blood-derived Vpr sequences [neuropsychological impairment Vpr (niVpr) variants]. Amino acids N41 and A55 in the Vpr sequence were associated with more pronounced neurocognitive deficits (higher GDS). In contrast, amino acids I37 and S41 were connected to measurably lower GDS. All niVpr variants were also detected in DNA isolated from HIV-1-infected brain tissues. The implication of these results is that niVpr variants alter the genesis and/or progression of HAND through differences in Vpr-mediated effects in the peripheral blood and/or the brain.

Grit in adolescence is protective of late-life cognition: non-cognitive factors and cognitive reserve.

Various psychological assets have been shown to protect against late-life cognitive impairment by promoting cognitive reserve. While factors such as educational attainment and IQ are well-established contributors to cognitive reserve, noncognitive factors, such as grit, have not been studied in this regard. We examined the contribution of adolescent grit, indexed by high school class rank controlling for IQ, to late-life cognition and its decline among approximately 4000 participants in the Wisconsin Longitudinal Study, a random sample of high school graduates followed from 1957 to 2011. Adolescent grit significantly predicted both immediate and delayed memory at ages 64 and 71, over and above the contribution of IQ. While the relative contributions of IQ and grit to immediate memory were comparable, grit was a stronger predictor of delayed memory. Cognitive reserve has noncognitive, as well as cognitive, components.

Facial emotion recognition impairments are associated with brain volume abnormalities in individuals with HIV.

Impaired facial emotion recognition abilities in HIV+ patients are well documented, but little is known about the neural etiology of these difficulties. We examined the relation of facial emotion recognition abilities to regional brain volumes in 44 HIV-positive (HIV+) and 44 HIV-negative control (HC) adults. Volumes of structures implicated in HIV-associated neuropathology and emotion recognition were measured on MRI using an automated segmentation tool. Relative to HC, HIV+ patients demonstrated emotion recognition impairments for fearful expressions, reduced anterior cingulate cortex (ACC) volumes, and increased amygdala volumes. In the HIV+ group, fear recognition impairments correlated significantly with ACC, but not amygdala volumes. ACC reductions were also associated with lower nadir CD4 levels (i.e., greater HIV-disease severity). These findings extend our understanding of the neurobiological substrates underlying an essential social function, facial emotion recognition, in HIV+ individuals and implicate HIV-related ACC atrophy in the impairment of these abilities.

Plasma cytokine levels are related to brain volumes in HIV-infected individuals.

HIV-infected individuals frequently exhibit brain dysfunction despite antiretroviral treatment. The neuropathological mechanisms underlying these abnormalities remain unclear, pointing to the importance of identifying biomarkers sensitive to brain dysfunction. We examined 74 medically stable HIV-infected individuals using T1-weighted MRI. Volumes of the cortical grey matter (GM), white matter (WM), caudate, putamen, globus pallidus, thalamus, hippocampus, amygdala, and ventricles were derived using automated parcellation. A panel of plasma cytokines was measured using multiplexed bead array immunoassay. A model selection algorithm was used to select the combination of clinical and cytokine markers that best predicted each brain volumetric measure in a series of linear regression models. Higher CD4 nadir, shorter HIV infection duration, and antiretroviral treatment were significantly related to higher volumes of the putamen, thalamus, hippocampus, and WM. Older age was related to lower volumes in most brain regions and higher ventricular volume. Higher IFN-γ, MCP-1, and TNF-α were related to higher volumes of the putamen, pallidum, amygdala, GM, and WM. Higher IL-1ß, IL-6, IL-16, IL-18, IP-10, MIP-1ß, and SDF-1α were related to lower volumes of the putamen, pallidum, thalamus, hippocampus, amygdala, GM, and WM; and higher ventricular volume. The current findings provide evidence linking smaller brain volumes to HIV disease history, antiretroviral treatment, and advanced age. Cytokine markers, especially IL-6 and IL-16, showed robust association with brain volumes even after accounting for other clinical variables, demonstrating their utility in examining the mechanisms of HIV-associated brain abnormalities.

Commissions and omissions are dissociable aspects of everyday action impairment in schizophrenia.

Prior research using performance-based assessment of functional impairment has informed a novel neuropsychological model of everyday action impairment in dementia in which omission errors (i.e., failure to complete task steps) dissociate from commission errors (i.e., inaccurate performance of task steps) and have unique neuropsychological correlates. However, this model has not been tested in other populations. The present study examined whether this model extends to schizophrenia. Fifty-four individuals with schizophrenia or schizoaffective disorder were administered a neuropsychological protocol and the Naturalistic Action Test (NAT), a performance-based measure of everyday action. A principal component analysis (PCA) was performed to examine the construct(s) comprising everyday action impairment, and correlations between the resultant component(s) and neuropsychological tests were examined. Results showed that omissions and a subset of commissions were distinct components of everyday action. However, results did not support unique associations between these components and specific neuropsychological measures. These findings extend the omission-commission model to schizophrenia and may have important implications for efficient assessment and effective rehabilitation of functional impairment, such as the potential efficacy of targeted interventions for the rehabilitation of omission and commission deficits in everyday functioning. Larger studies with prospective designs are needed to replicate the present preliminary findings.

Verbal memory declines more rapidly with age in HIV infected versus uninfected adults.

OBJECTIVES: 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. METHOD: 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. RESULTS: 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. CONCLUSIONS: 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.

The effects of cigarette smoking on learning and memory performance among people living with HIV/AIDS.

The purpose of this study was to examine the effects of smoking (past and current) on multiple domains of cognitive functioning in a sample of people living with HIV/AIDS (PLWHA). We hypothesized that among PLWHA, current smokers would demonstrate poorer cognitive functioning when compared to non-smokers, specifically in the cognitive domains of auditory-verbal learning and memory, visuospatial memory, overall cognitive efficiency, executive skills, processing speed, and working memory. Results suggest that in patients being treated for HIV infection, current smoking is negatively associated with learning, memory, and global cognitive functioning. There was also some evidence that cognitive deficits in learning associated with smoking were more pronounced among men compared to women. However, the cause of these effects is not at all clear. In multivariate models, the differences associated with smoking were non-significant when adjusting for education and hepatitis C virus infection. Therefore, smoking may simply reflect a general tendency to more widespread deficits and comorbidities rather than directly impacting cognitive function. Future studies should attempt to examine a priori cognitive factors which contribute to smoking debut and other associated risk factors in order to understand why smoking may be a marker for other risk factors and may ultimately influence neurocognitive functioning critical to daily activities and adherence.

Effects of HIV and early life stress on amygdala morphometry and neurocognitive function.

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.

Neurocognitive effects of HIV, hepatitis C, and substance use history.

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.

Clinical contributors to cerebral white matter integrity in HIV-infected individuals.

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 years with chronic HIV infection. Fractional anisotropy and mean diffusivity 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 effects of HIV disease in the context of other comorbidities, in particular HCV coinfection and aging.

Plasma cytokine concentrations associated with HIV/hepatitis C coinfection are related to attention, executive and psychomotor functioning.

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 13 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 7 of the 13 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.

Facial emotion recognition impairments in individuals with HIV.

Characterized by frontostriatal dysfunction, human immunodeficiency virus (HIV) is associated with cognitive and psychiatric abnormalities. Several studies have noted impaired facial emotion recognition abilities in patient populations that demonstrate frontostriatal dysfunction; however, facial emotion recognition abilities have not been systematically examined in HIV patients. The current study investigated facial emotion recognition in 50 nondemented HIV-seropositive adults and 50 control participants relative to their performance on a nonemotional landscape categorization control task. We examined the relation of HIV-disease factors (nadir and current CD4 levels) to emotion recognition abilities and assessed the psychosocial impact of emotion recognition abnormalities. Compared to control participants, HIV patients performed normally on the control task but demonstrated significant impairments in facial emotion recognition, specifically for fear. HIV patients reported greater psychosocial impairments, which correlated with increased emotion recognition difficulties. Lower current CD4 counts were associated with poorer anger recognition. In summary, our results indicate that chronic HIV infection may contribute to emotion processing problems among HIV patients. We suggest that disruptions of frontostriatal structures and their connections with cortico-limbic networks may contribute to emotion recognition abnormalities in HIV. Our findings also highlight the significant psychosocial impact that emotion recognition abnormalities have on individuals with HIV.