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Objectives: The objective of this study was to assess the usability of event-related-potentials (ERPs) during sustained, focused, and divided attention tasks as biomarkers for cognitive decline in HIV patients., Methods: EEG was acquired using a mobile/wireless 9-channel system in 39 persons with HIV, with well-controlled immune function and 63 healthy control participants (HCs) during three ERP tasks: sustained attention, focused attention, and divided attention., Results: The HIV-group evidenced smaller late positive potential (LPP) and larger P200 amplitudes across the tasks compared to the HC group. P200 amplitude was correlated (r = 0.56) with the estimated duration of infection. Both groups showed higher P200 and LPP amplitudes in response to infrequent stimuli; this effect was not significantly different between groups. In the sustained attention task, the HIV-group showed significantly slower reaction time than controls while maintaining the same level of accuracy. In the divided attention task, the HIV-group showed a trend towards faster/less accurate responses., Conclusions: HIV seropositive participants receiving anti-retroviral treatment (ART) demonstrated significantly larger P200 amplitude during three different attention tasks. This may reflect attentional deficits characterized by over-attending to non-target/distracting stimuli., Significance: These findings demonstrate the potential benefits of EEG-ERP metrics derived from attention tasks as neurocognitive biomarkers for HIV. This approach may reveal underlying causes of attentional deficits in HIV patients., Competing Interests: Declaration of Competing Interest Amir H. Meghdadi, Chris Berka, Greg Rupp, Stephanie Smith, Marija Stevanović Karić, and Christian Richard are all employees of Advanced Brain Monitoring, Inc., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To examine whether persons with asymptomatic neurocognitive impairment (ANI) were more likely to show progression to mild neurocognitive disorder or HIV-associated dementia than those who were neuropsychologically normal (NP-N)., Design: Longitudinal observational cohort study., Methods: Study sample included 720 HIV-1 seropositive persons (317 with ANI and 403 NP-N) receiving care in Toronto, Canada [83% were on antiretroviral treatment; 71% had undetectable (<50 copies/ml) plasma HIVRNA]. Neuropsychological assessments were conducted at 12 months intervals for a median follow-up time of 34 months. Neuropsychological data were corrected for age, education, sex, and race/ethnicity, and corrected for practice effect at follow-ups. Progression to mild neurocognitive disorder and HIV-associated dementia at each time point was determined using the Global Deficit Score and presence of cognitive symptoms., Results: Over the follow-up period, 170 individuals (24%) progressed to symptomatic HIV-associated neurocognitive disorders (HAND). Persons with ANI were more likely to progress to symptomatic HAND than persons with NP-N after adjusting for baseline and time-varying confounders (adjusted hazards ratio: 1.88; 95% confidence interval: 1.37-2.60; P < 0.001). Female sex, depression, and cigarette smoking were associated with higher risk of progression to symptomatic HAND, but traditional HIV markers and antiretroviral treatment were not., Conclusion: ANI is associated with a two-fold increased risk of progression to symptomatic HAND in a cohort with universal healthcare access. This represents the largest replication of comparable US results. Reproducibility of these findings indicate that routine monitoring of persons with ANI and exploration of clinical interventions to prevent or delay progression to symptomatic HAND are imperative., Search Terms: HIV, HAND, HIV-associated dementia, cohort study, replicability, reproducibility.

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.

HIV-associated neurocognitive disorders (HANDs) persist even with virologic suppression on combination antiretroviral therapy (cART), and the underlying pathophysiological mechanisms are not well understood. We performed structural magnetic resonance imaging and MR spectroscopy (MRS) in HIV+ individuals without major neurocognitive comorbidities. Study participants were classified as neurocognitively unimpaired (NU), asymptomatic (ANI), mild neurocognitive disorder (MND), or HIV-associated dementia (HAD). Using structural MRI, we measured volumes of cortical and subcortical gray matter and total and abnormal white matter (aWM). Using single-voxel MRS, we estimated metabolites in frontal gray matter (FGM) and frontal white matter (FWM) and basal ganglia (BG) regions. Adjusted odds ratios were used to compare HAND to NU. Among 253 participants, 40% met HAND criteria (21% ANI, 15% MND, and 4% HAD). Higher risk of HAND was associated with more aWM. Both HAD and MND also had smaller gray and white matter volumes than NU. Among individuals with undetectable plasma HIV RNA, structural volumetric findings were similar to the overall sample. MND had lower FWM creatine and higher FGM choline relative to NU, whereas HAD and ANI had lower BG N-acetyl aspartate relative to NU. In the virologically suppressed subgroup, however, ANI and MND had higher FGM choline compared to NU. Overall, HAND showed specific alterations (more aWM and inflammation; less gray matter volume and lower NAA). Some MR measures differentiated less severe subtypes of HAND from HAD. These MR alterations may represent legacy effects or accumulating changes, possibly related to medical comorbidities, antiretroviral therapy, or chronic effects of HIV brain infection.

Background: The prevalence of HIV-associated neurocognitive disorders (HAND) has not changed considerably in the last two decades. Potent antiretroviral therapy has shifted the severity of HAND to milder phenotypes, but excess morbidity and mortality continue to be associated with HAND. Changes in numerous markers of immune function, inflammation, and cellular stress have been repeatedly associated with HAND, but the underlying systems that drive these changes have not been identified., Method: In this study, we used systems informatics to interrogate the cerebrospinal fluid proteomic content of longitudinal samples obtained from HIV-infected adults with stably unimpaired, stably impaired, worsening, or improving neurocognitive performance., Results and Conclusion: The patterns of change in cerebrospinal fluid protein content implicated the induction of acute phase and complement systems as important regulators of neurocognitive status. Worsening neurocognitive performance was preceded by induction of acute phase and complement systems, whereas improving neurocognitive performance was preceded by a downregulation of these systems.

Objectives: To identify prognostic surrogate markers for change in cognitive states of HIV-infected patients., Design: Longitudinal cerebrospinal fluid (CSF) samples were collected from 98 HIV-infected patients identified by temporal change in cognitive states classified as normal, stably impaired, improving and worsening., Methods: The metabolic composition of CSF was analysed using H nuclear magnetic resonance (H NMR) spectroscopy that focused on energy metabolites. Metabolic biomarkers for cognitive states were identified using multivariate partial least squares regression modelling of the acquired spectra, combined with nonparametric analyses of metabolites with clinical features., Results: Multivariate modelling and cross-validated recursive partitioning identified several energy metabolites that, when combined with clinical variables, classified patients based on change in neurocognitive states. Prognostic identification for worsening was achieved with four features that included no change in a detectable plasma viral load, elevated citrate and acetate; decreased creatine, to produce a model with a predictive accuracy of 92%, sensitivity of 88% and 96% specificity. Prognosis for improvement contained seven features that included first visit age less than 47 years, new or continued use of antiretrovirals, elevated glutamine and glucose; decreased myo-inositol, β-glucose and creatinine to generate a model with a predictive accuracy of 92%, sensitivity of 100% and specificity of 84%., Conclusion: These CSF metabolic results suggest that worsening cognitive status in HIV-infected patients is associated with increased aerobic glycolysis, and improvements in cognitive status are associated with a shift to anaerobic glycolysis. Dietary, lifestyle and pharmacologic interventions that promote anaerobic glycolysis could protect the brain in setting of HIV infection with combined antiretroviral therapy.

Background: This study applies the updated HIV-Associated Neurocognitive Disorders (HAND) diagnostic algorithm., Methods: Participants were 210 HIV-infected-adults, classified using proposed HAND criteria: HIV-Associated Dementia (HAD), Mild Neurocognitive Disorder (MND), Asymptomatic Neurocognitive Impairment (ANI)., Results: The algorithm yielded: normal = 32.8%, ANI = 21.4%, MND = 34.3%, and HAD = 11.4%. Normal participants performed superior to HAND-defined participants on cognition, and HAD participants performed more poorly on global cognition and executive functioning. Two distinct subgroups of interest emerged: (1) functional decline without cognitive impairment; (2) severe cognitive impairment and minimal functional compromise., Conclusions: The algorithm discriminates between HIV-infected cognitively impaired individuals. Diagnosis yields two unique profiles requiring further investigation. Findings largely support the algorithm's utility for diagnosing HIV-cognitive-impairment, but suggest distinct subsets of individuals with discrepant cognitive/functional performances that may not be readily apparent by conventional application of HAND diagnosis.

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.

Objective: To examine if HIV-seropositive (HIV+) individuals are at risk for impaired driving., Methods: 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., Results: 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., Conclusion: 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.

In recent years, interest in the use of computerized neuropsychological (NP) assessment measures has increased. However, there are limited data regarding how performance on these measures relates to performance on more traditional, clinical instruments. In the present study, 82 HIV+ men, who were all believed on clinical grounds to have neurobehavioral impairment, completed a traditional NP battery (TNB) and the California Computerized Assessment Package (CalCAP, a collection of computerized reaction time tests). Summary scores based on a TNB, as well as those based on the CalCAP, demonstrated significant associations with both degree of immunosuppression (CD4 count) and detectable viral load in cerebrospinal fluid, but not with detectable viral load in plasma. Established norms on the TNB and CalCAP batteries resulted in classifying 57% and 49% of the HIV+ sample as impaired, respectively. When using the TNB as the "gold standard," impairment classifications based on CalCAP summary scores exhibited a sensitivity of 68% and a specificity of 77%. Overall agreement on impairment classifications between batteries was low (kappa = .44). Data from this study suggest that traditional NP batteries and computerized reaction time tests do not measure the same thing, and are not interchangeable in examining HIV-related NP impairments.

Objective: To investigate the value of antemortem cognitive functioning in predicting postmortem evidence of HIV encephalitis (HIVE)., Methods: 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., Results: 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%)., Conclusion: Neuropsychological assessment can help select HIV-positive patients for treatment of CNS disease.

HIV infection often results in neuropsychological (NP) impairment. In order to assess the impact that HIV-related NP deficits may have on automobile driving, we evaluated 68 HIV-seropositive drivers using an NP battery and two PC-based driving simulations. Thirty-two participants were classified as NP impaired; most (72%) evidenced only mild impairment, and none met criteria for HIV-associated dementia. After controlling for degree of immunosuppression and disease stage, NP-impaired participants failed a previously validated driving simulation at a much higher rate than cognitively intact participants [OR = 5.3, 95% CI (1.7, 17.0), p = .006]. Similarly, on a simulation of city driving, NP impaired participants were more likely to fail based upon the number of accidents [OR = 6.1, 95% CI (1.5, 24.6), p = .01]. Simulator performance was predicted by functioning in a number of NP domains, with NP tests accounting for 13-30% of the variance on the simulations. Although it would be premature to extrapolate these findings to impairment in on-the-road driving, they do argue for greater attention to the impact that even mild HIV-related NP deficits may have on driving skills.

Dendritic and synaptic damage (without frank neuronal loss) may be seen in milder human immunodeficiency virus (HIV)-related cognitive disorders. Synapse volume estimates, performed by stereological methods, could enhance the ability to detect subtle neuronal changes that may accompany cognitive impairment in HIV infection. For the present study, synaptic density and neuronal number were assessed by combined stereology/confocal microscopy and these measures were then correlated with ante-mortem levels of cognitive performance in AIDS patients. Three-dimensional stereological measures showed a significant correlation between reduced synaptic density and poor neuropsychological performance. To evaluate the specificity of any observed associations, additional variables including viral burden, astrogliosis and number of calbindin-immunoreactive neurons were measured. Factor analysis of a set of neuropathological variables revealed two factors; one defined by synaptic density and volume fraction, calbindin pyramidal neuronal densities and viral burden; the second by astrocytosis and calbindin interneuron density. Only the first factor correlated significantly with neuropsychological functioning during life. It is concluded that a combination of factors including synaptic damage, specific neuronal loss and increasing viral load underlies HIV-associated cognitive impairment. As synaptic damage is potentially reversible, early diagnosis and treatment of mild cogntive disorders may improve functioning and prevent the progression of brain disease.

The authors examined change in cerebral metabolic function over time by using PET in HIV-infected individuals diagnosed with AIDS. Ten subjects with AIDS received [18F]2-fluoro-2-deoxy-D-glucose PET scans and completed a comprehensive neuropsychological battery. The scan and test battery were repeated after 6 months. Over time, the subjects showed increased relative basal ganglia metabolism as well as increased parietal lobe metabolism. There were no statistically significant changes in neuropsychological performance. These results suggest that PET may be more sensitive than traditional neuropsychological evaluation to subtle central nervous system changes in AIDS.