This is a cross-sectional, observational study to determine the frequency and associated features of HIV-associated neurocognitive disorders (HAND) in a large, diverse sample of infected individuals ...in the era of combination antiretroviral therapy (CART).
A total of 1,555 HIV-infected adults were recruited from 6 university clinics across the United States, with minimal exclusions. We used standardized neuromedical, psychiatric, and neuropsychological (NP) examinations, and recently published criteria for diagnosing HAND and classifying 3 levels of comorbidity (minimal to severe non-HIV risks for NP impairment).
Fifty-two percent of the total sample had NP impairment, with higher rates in groups with greater comorbidity burden (40%, 59%, and 83%). Prevalence estimates for specific HAND diagnoses (excluding severely confounded cases) were 33% for asymptomatic neurocognitive impairment, 12% for mild neurocognitive disorder, and only 2% for HIV-associated dementia (HAD). Among participants with minimal comorbidities (n = 843), history of low nadir CD4 was a strong predictor of impairment, and the lowest impairment rate on CART occurred in the subset with suppressed plasma viral loads and nadir CD4 ≥200 cells/mm(3) (30% vs 47% in remaining subgroups).
The most severe HAND diagnosis (HAD) was rare, but milder forms of impairment remained common, even among those receiving CART who had minimal comorbidities. Future studies should clarify whether early disease events (e.g., profound CD4 decline) may trigger chronic CNS changes, and whether early CART prevents or reverses these changes.
Abstract We evaluated the impact of latent toxoplasmosis (LT) on neurocognitive (NC) and neurobehavioural functioning in young adults with and without chronic HIV infection, using a standardised NC ...test battery, self-reported Beck Depression Inventory, Frontal System
Behavior
Scale, MINI-International Neuropsychiatric Interview and risk-assessment battery. 194 young adults (median age 24 years, 48.2% males) with chronic HIV infection (HIV +) since childhood and 51 HIV seronegative (HIV −) participants were included. HIV + individuals had good current immunological status (median CD4: 479 cells/μL) despite a low CD4 nadir (median: 93 cells/μL). LT (positive anti-Toxoplasma IgG antibodies) was present in one third of participants. The impairment rates in the HIV −
with and without Toxo were not significantly different ( p = 0.17). However, we observed an increasing trend ( p < 0.001) in impairment rates with HIV and LT status: HIV −
/LT −
(6.1%); HIV −
/LT + (22%), HIV +/LT −
(31%), HIV +/LT + (49%). In a multivariable analysis using the entire study group there were main effects on cognition for HIV and also for LT. Within the HIV + group LT was associated with worse performance globally ( p = 0.006), in memory ( p = 0.009), speed of information processing ( p = 0.01), verbal ( p = 0.02) and learning ( p = 0.02) domains. LT was not associated with depressive symptoms, frontal systems dysfunction or risk behaviors in any of the groups. HIV participants with lower Toxoplasma antibody concentration had worse NC performance, with higher GDS values ( p = 0.03) and worse learning ( p = 0.002), memory ( p = 0.006), speed of information processing ( p = 0.01) T scores. Latent Toxoplasmosis may contribute to NC impairment in young adults, including those with and without chronic HIV infection.
HIV-associated neurocognitive disorder (HAND) is characterized by chronic immune activation. We aimed to identify biomarkers associated with HAND and to investigate their association with cognitive ...function and sex, in a homogenous cohort of HIV-infected (HIV+) young adults, parenterally infected during early childhood. One hundred forty-four HIV+ Romanian participants (51% women) without major confounders underwent standardized neurocognitive and medical evaluation in a cross-sectional study. IFN-γ, IL-1β, IL-6, CCL2, CXCL8, CXCL10, and TNF-α were measured in plasma in all participants and in cerebrospinal fluid (CSF) in a subgroup of 56 study participants. Biomarkers were compared with neurocognitive outcomes, and the influence of sex and HIV disease biomarkers was assessed. In this cohort of young adults (median age of 24 years), the rate of neurocognitive impairment (NCI) was 36.1%. Median current CD4+ count was 479 cells/mm
3
and 36.8% had detectable plasma viral load. Women had better HIV-associated overall status. In plasma, controlling for sex, higher levels of IL-6 and TNF-α were associated with NCI (
p
< 0.05). Plasma CXCL10 showed a significant interaction with sex (
p
= 0.02); higher values were associated with NCI in women only (
p
= 0.02). Individuals with undetectable viral load had significantly lower plasma CXCL10 (
p
< 0.001) and CCL2 (
p
= 0.02) levels, and CSF CXCL10 (
p
= 0.01), IL-6 (
p
= 0.04), and TNF-α (
p
= 0.04) levels. NCI in young men and women living with HIV was associated with higher IL-6 and TNF-α in plasma, but not in the CSF. CXCL10 was identified as a biomarker of NCI specifically in women with chronic HIV infection.
Apathy is a relatively common clinical feature of HIV-Associated Neurocognitive Disorders, but little is known about its implications for everyday functioning outcomes. In the present study, we ...examined the associations between apathy and self-reported instrumental activities of daily living (IADL) and neurocognitive complaints in 75 participants with HIV infection and 52 demographically comparable seronegative comparison subjects. All volunteers completed the apathy subscale of the Frontal Systems Behavioral Scale as part of a comprehensive neuromedical, psychiatric, and neurocognitive research evaluation. When compared with the seronegative comparison participants, the HIV+ group reported significantly higher current levels of apathy, but did not differ in self-report of prior (i.e., pre-seroconversion) apathy. Higher current apathy self-ratings were associated with greater severity of IADL declines and more numerous cognitive complaints in the HIV+ sample, even after adjusting for potential psychiatric (e.g., depression), medical (e.g., hepatitis C co-infection), and neurocognitive predictors. Cognitive complaints, but not IADLs, were also uniquely associated with ratings of executive dysfunction and disinhibition. All told, these findings suggest that apathy may make a unique contribution to important everyday functioning outcomes among persons living with HIV infection. The clinical detection of apathy may help identify HIV-infected individuals at particular risk for functional impairments who may require additional support to maintain independence.
Abstract
Proving driving under the influence of cannabis (DUIC) is difficult. Establishing a biomarker of recent use to supplement behavioral observations may be a useful alternative strategy. We ...determined whether cannabinoid concentrations in blood, oral fluid (OF) or breath could identify use within the past 3 h—likely the period of the greatest impairment. In a randomized trial, 191 frequent (≥4/week) and occasional (<4/week) cannabis users smoked one cannabis (placebo 0.02%, or 5.9% or 13.4% Δ9-tetrahydrocannabinol THC) cigarette ad libitum. Blood, OF and breath samples were collected prior to and up to 6 h after smoking. Samples were analyzed for 10 cannabinoids in OF, 8 in blood and THC in breath. Frequent users had more residual THC in blood and were more likely to be categorized as ‘recently used’ prior to smoking; this did not occur in OF. Per se limits ranging from undetectable to 5 ng/mL THC in blood offered limited usefulness as biomarkers of recent use. Cannabinol (CBN, cutoff = 1 ng/mL) in blood offered 100% specificity but only 31.4% sensitivity, resulting in 100% positive predictive value (PPV) and 94.0% negative predictive value (NPV) at 4.3% prevalence; however, CBN may vary by cannabis chemovar. A 10 ng/mL THC cutoff in OF exhibited the overall highest performance to detect its use within 3 h (99.7% specificity, 82.4% sensitivity, 92.5% PPV and 99.2% NPV) but was still detectable in 23.2% of participants ∼4.4 h post-smoking, limiting specificity at later time points. OF THC may be a helpful indicator of recent cannabis intake, but this does not equate to impairment. Behavioral assessment of impairment is still required to determine DUIC. This study only involved cannabis inhalation, and additional research evaluating alternative routes of ingestion (i.e., oral) is needed.
To investigate the value of antemortem cognitive functioning in predicting postmortem evidence of HIV encephalitis (HIVE).
Thirty-nine subjects were assessed during life with a comprehensive ...neuropsychological battery and went on to autopsy within 18 months of testing. Cognitive impairment was determined by blind clinical ratings, based on demographically corrected test scores. Presence of HIVE was based on postmortem immunocytochemical detection of the viral protein gp41 or by measurement of HIV RNA by PCR in multiple brain areas as well as by histopathologic evidence such as microgliosis, presence of multinucleated giant cells, and myelin pallor in several brain regions.
The sensitivity and specificity of neurocognitive impairment in detecting the occurrence of HIVE were 67 and 92%. Eighteen of 19 subjects with antemortem neurocognitive impairment had evidence of HIV-related brain disease (positive predictive value = 95%).
Neuropsychological assessment can help select HIV-positive patients for treatment of CNS disease.
Although milder forms of HIV-associated neurocognitive disorder (HAND) remain prevalent, a correlation to neuronal injury has not been established in patients on antiretroviral therapy (ART). We ...examined the relationship between mild HAND and CSF neurofilament light protein (NFL), a biomarker of neuronal injury; and CSF neopterin, a biomarker of CNS immunoactivation, in virally suppressed patients on antiretroviral therapy (ART).
We selected 99 subjects on suppressive ART followed longitudinally from the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) study. Based on standardized comprehensive neurocognitive performance (NP) testing, subjects were classified as neurocognitively normal (NCN; n = 29) or impaired (NCI; n = 70). The NCI group included subjects with asymptomatic (ANI; n = 37) or mild (MND; n = 33) HAND. CSF biomarkers were analyzed on two occasions.
Geometric mean CSF neopterin was 25% higher in the NCI group (p = 0.04) and NFL and neopterin were significantly correlated within the NCI group (r = 0.30; p<0.001) but not in the NCN group (r = -0.13; p = 0.3). Additionally, a trend towards higher NFL was seen in the NCI group (p = 0.06).
Mild HAND was associated with increased intrathecal immune activation, and the correlation between neopterin and NFL found in NCI subjects indicates an association between neurocognitive impairment, CNS inflammation and neuronal damage. Together these findings suggest that NCI despite ART may represent an active pathological process within the CNS that needs further characterization in prospective studies.
Based upon prior findings with group means, a "prototypical pattern" of neuropsychological results with HIV infection has emerged: impaired executive functioning, motor skills, speed of information ...processing, and learning, with intact memory retention, most language skills, and visuospatial functioning. We examined neuropsychological results from 553 HIV+ adults to determine the number of patterns seen among individuals with HIV infection. Factor analysis of a relatively comprehensive neuropsychological battery identified 6 component factors: verbal memory (VeM), visual memory (ViM), processing speed (PS), attention/working memory (A/WM), executive function (EF), and motor (M). These factor scores were submitted to hierarchical cluster analysis, to determine the appropriate number of clusters or patterns in the cohort. Final cluster membership was then determined by K-means analysis, based on the
Lange, Iverson, Senior, and Chelune (2002)
method. A 6-cluster solution was found to be most appropriate. The definitions of the clusters were based upon ipsative scoring of factor scores to indicate relative strengths and weaknesses (independent of overall level of performance): Cluster 1: strong EF; Cluster 2: strong M, weak VeM and EF; Cluster 3: strong PS, weak ViM and EF; Cluster 4: strong VeM, weak M; Cluster 5: strong A/WM; Cluster 6: strong VeM, weak EF. Neuropsychological-impairment rates differed across clusters, but all 6 clusters contained substantial numbers of impaired and unimpaired individuals. Cluster membership was not explained by demographic variables or psychiatric or neuromedical confounds. Thus, there does not appear to be a single, prototypical pattern of neuropsychological impairment associated with HIV infection for this battery of representative neuropsychological tests.
Driving ability can be diminished amongst people with HIV with associated neurocognitive impairment (NCI). We explore the relationship between HIV status, NCI and driving ability in professional ...truck drivers. Forty male professional drivers (20 HIV-positive; mean age = 39.20 ± 7.05) completed a neuropsychological test battery, two driving simulator tasks that assessed driving ability, and a driving history and habits questionnaire. A higher proportion of HIV-positive drivers exhibited impaired overall cognitive performance (
p
≤ 0.001). Overall, drivers with NCI (defined as z ≤ 1.00) were more likely than those without NCI to crash (
p
= 0.002). There were no significant between-group (HIV-positive versus HIV-negative) differences with regard to self-reported on-road driving events. Professional drivers with NCI, as measured on a driving simulator, are at increased risk of making driving errors under high-risk conditions compared to their neurocognitively normal counterparts. These data should inform driver health management with regard to annual medical screening and surveillance.
To examine if HIV-seropositive (HIV+) individuals are at risk for impaired driving.
Sixty licensed drivers (40 HIV+, 20 HIV-) completed a neuropsychological (NP) test battery and driving assessments. ...Eleven HIV+ subjects were NP-impaired. Driving-related skills were assessed using 1) two driving simulations (examining accident avoidance and navigational abilities), 2) the Useful Field of View (UFOV) test, and 3) an on-road evaluation.
HIV+ NP-impaired subjects had greater difficulty than cognitively intact subjects on all driving measures, whereas the HIV- and HIV+ NP-normal groups performed similarly. On the UFOV, the HIV+ NP-impaired group had worse performance on Visual Processing and Divided Attention tasks but not in overall risk classification. They also had a higher number of simulator accidents (1.3 vs 2.0; p = 0.03), were less efficient at completing the navigation task (3.2 vs 9.2 blocks; p = 0.001), and were more likely to fail the on-road evaluation (6 vs 36%; p = 0.02). Impairment in Executive Functioning was the strongest NP predictor of failing the on-road drive test. NP performance and both simulations independently contributed to a model predicting 48% of the variance in on-road performance.
HIV+ NP-impaired individuals are at increased risk for on-road driving impairments, whereas HIV+ individuals with normal cognition are not at a significantly higher risk than HIV- subjects. Executive Functioning is most strongly associated with impaired on-road performance. Cognitive and simulator testing may each provide data in identifying driving-impaired individuals.
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