MR Imaging Biomarkers in HIV associated Neurocognitive Impairment in the Era of cART

HIV associated neurocognitive disorder (HAND) continues to occur despite virally suppressive combination of antiretroviral therapy. The viral toxins, neuroinflammation secondary to host factor (ARV toxicity, immune reconstitution are additional factors) and the comorbidities in combination or individually appear to drive the ongoing HAND. Although in the pre-cART era the biomarkers of HIV dementia were clearly laid out in terms of clinical, biochemical and imaging criteria, in the cART era this has become more blurred. Some of the observations drawn from the imaging studies to identify the pathological underpinnings have shown conflicting results by different authors. The cause of these contradictory imaging observations are multifocal but principally linked to the observation that “HIV neural injury is not a one-time event”. Therefore, the paradigm of imaging should be tailored to the diversity of the disease spectrum. I have used the advanced imaging techniques to identify if there are any imaging techniques which can demonstrate the ongoing neural injury as well as monitor the response to the therapy in this research using both cross sectional and longitudinal experiments. I have also explored if there is any imaging equivalent to identify the neuroinflammation

Comparison of resting state functional networks in HIV infected and uninfected children at age 9 years

Over 2.5 million children are infected with HIV, the majority of whom reside in Sub-Saharan Africa. Treatment coverage is steadily gaining momentum, reducing mortality and morbidity. Yet little is known about brain development in HIV-infected (HIV+) children who are on highly-active antiretroviral therapy (ART), with viral load suppression from a young age. Here, we use resting state fMRI (rs-fMRI) to examine the impact of HIV and ART on the development of functional networks in 9-year-old vertically HIV-infected children compared to age-matched controls of similar socioeconomic status. We present analyses for a sample of 40 HIV+ (9.2 ± 0.20 years; 16 males) children from the Children with HIV Early Antiretroviral (CHER) clinical trial (Cotton et al. 2013; Violari et al. 2008) and 24 uninfected (12 exposed; 12 males; 9.6 ± 0.52 years) controls from an interlinking vaccine trial (Madhi et al. 2010). Scans were performed at the Cape Universities Body Imaging Centre (CUBIC) in Cape Town, South Africa. We investigated HIV-related differences in within- and between-network functional connectivity (FC) using independent component analysis(ICA) and seed-based correlation analysis (SCA). For SCA, seeds were placed in the structural core, in regions implicated in HIV-related between-group differences at age 7 years, and in regions associated with neuropsychological domains impaired in our cohort. In addition, we evaluated associations of past and present immune health measures with within-network connectivity using ICA. We found no HIV-related intra-network FC differences within any ICA-generated RSNs at age 9 years, perhaps as a result of within-network connectivity not being sufficiently robust at this age. We found a positive association of CD4%, both current and in infancy, with functional integration of left lobule 7 into the cerebellum network at age 9 years. Long-term impact of early immune health supports recently-revised policies of commencing ART immediately in HIV+ neonates. ii Compared to uninfected children, HIV+ children had increased FC to several seeds. Firstly, to seeds associated with the planning and visual perception neuropsychological domains. Secondly, to structural core seeds in the extrastriate visual cortex (of the medial visual network) and the right angular gyrus (of the temporoparietal network). Finally, to left paracentral (somatosensory network) and right precuneus (posterior DMN) seeds previously revealing between-group differences at age 7 years. The connections with greater FC in HIV+ children may variously indicate functional recruitment of additional brain capacity, immature excess of short-range connections, and/or immature excess of between-network connections. In conclusion, despite early ART and early virologic suppression, HIV+ children demonstrate instances of abnormal FC at age 9 years. Disruption to visual cortex is marked, consistent with indications from neuropsychological testing that visual perception is disrupted. The profile of HIV- and/or ART-related effects on FC differs considerably between the two ages of 7 and 9 years, but both show characteristics of immature functional organisation compared with age-matched controls

Biomarker discovery and statistical modeling with applications in childhood epilepsy and Angelman syndrome

Biomarker discovery and statistical modeling reveals the brain activity that supports brain function and dysfunction. Detecting abnormal brain activity is critical for developing biomarkers of disease, elucidating disease mechanisms and evolution, and ultimately improving disease course. In my thesis, we develop statistical methodology to characterize neural activity in disease from noisy electrophysiological recordings. First, we develop a modification of a classic statistical modeling approach - multivariate Granger causality - to infer coordinated activity between brain regions. Assuming the signaling dependencies vary smoothly, we propose to write the history terms in autoregressive models of the signals using a lower dimensional spline basis. This procedure requires fewer parameters than the standard approach, thus increasing the statistical power. we show that this procedure accurately estimates brain dynamics in simulations and examples of physiological recordings from a patient with pharmacoresistant epilepsy. This work provides a statistical framework to understand alternations in coordinated brain activity in disease. Second, we demonstrate that sleep spindles, thalamically-driven neural rhythms (9-15 Hz) associated with sleep-dependent learning, are a reliable biomarker for Rolandic epilepsy. Rolandic epilepsy is the most common form of childhood epilepsy and characterized by nocturnal focal epileptic discharges as well as neurocognitive deficits. We show that sleep spindle rate is reduced regionally across cortex and correlated with poor cognitive performance in epilepsy. These results provide evidence for a regional disruption to the thalamocortical circuit in Rolandic epilepsy, and a potential mechanistic explanation for the cognitive deficits observed. Finally, we develop a procedure to utilize delta rhythms (2-4 Hz), a sensitive biomarker for Angelman syndrome, as a non-invasive measure of treatment efficacy in clinical trials. Angelman syndrome is a rare neurodevelopmental disorder caused by reduced expression of the UBE3A protein. Many disease-modifying treatments are being developed to reinstate UBE3A expression. To aid in clinical trials, we propose a procedure that detects therapeutic improvements in delta power outside of the natural variability over age by developing a longitudinal natural history model of delta power. These results demonstrate the utility of biomarker discovery and statistical modeling for elucidating disease course and mechanisms with the long-term goal of improving patient outcomes

Fluctuations of attention network activation during the resting state reflect fluctuations in subjective attentional state.

peer reviewe

Multi-level characterization and information extraction in directed and node-labeled functional brain networks

Current research in computational neuroscience puts great emphasis on the computation and analysis of the functional connectivity of the brain. The methodological developments presented in this work are concerned with a group-specific comprehensive analysis of networks that represent functional interaction patterns. Four application studies are presented, in which functional brain network samples of different clinical background were analyzed in different ways, using combinations of established approaches and own methodological developments. Study I is concerned with a sample-specific decomposition of the functional brain networks of depressed subjects and healthy controls into small functionally important and recurring subnetworks (motifs) using own developments. Study II investigates whether lithium treatment effects are reflected in the functional brain networks of HIV-positive subjects with diagnosed cognitive impairment. For it, microscopic and macroscopic structural properties were analyzed. Study III explores spatially highly resolved functional brain networks with regard to a functional segmentation given by identified module (community) structure. Also, ground truth networks with known module structure were generated using own methodological developments. They formed the basis of a comprehensive simulation study that quantified module structure quality and preservation in order to evaluate the effects of a novel approach for the identification of connectivity (lsGCI). Study IV tracks the time-evolution of module structure and introduces a newly developed own approach for the determination of edge weight thresholds based on multicriteria optimization. The methodological challenges that underly these different topological analyses, but also the various opportunities to gain an improved understanding of neural information processing among brain areas were highlighted by this work and the presented results

An exploration of sociodemographic and psychosocial determinants of cognitive performance in a peri-urban clinic population of people with HIV in Cape Town, South Africa

Introduction. Numerous studies, conducted in many different countries, report that cognitive impairment is highly prevalent in people with HIV (PWH). Such impairment can affect adherence to antiretroviral therapy (ART), and adherence is, in turn, essential for PWH to achieve viral suppression. The gold standard to confirm cognitive impairment is a neuropsychological assessment. However, accurate interpretation of neuropsychological test performance requires consideration of, for instance, how impairment is determined and how accurately the contribution of non-HIV factors to poor cognitive test performance is described. These non-HIV factors include sociodemographic variables (e.g., age, sex, educational attainment), psychosocial variables (e.g., socioeconomic status, food security, quality of life), psychiatric variables (e.g., depression, problematic alcohol use), and other medical co-morbidities. Because many existing studies of PWH do not account for (a) the fact that current quantitative methods for defining cognitive impairment may not accurately reflect HIV-associated brain injury, and (b) possible contributions of non-HIV factors to cognitive test performance, it is possible that the reported prevalence rates of cognitive impairment in PWH are inaccurate (or, at least, do not solely reflect the contributions of HIV disease to the impairment). Another uncertainty in the HIV neuropsychology literature concerns sex differences in the cognitive performance of PWH. Some recent studies suggest that women with HIV (WWH) may present with greater cognitive impairment than men with HIV (MWH). Such a sex difference is of potentially significant concern for South African clinicians because two-thirds of the population of PWH in this country are women. However, there is no definitive empirical evidence regarding whether this sex difference exists to a clinically significant degree (in South Africa, specifically, as well as globally) and what its underlying mechanisms might be. To address the knowledge gaps outlined above, this thesis set out to explore the following aims: (1) investigate sex differences in the cognitive performance of PWH by reviewing the current published literature; (2) determine if sex differences exist in a clinic sample of South African PWH; (3) determine how much variation in reported prevalence rates of HIV-associated cognitive impairment are due to the method used to define impairment, and which method correlates best with MRI biomarkers of HIVrelated brain injury in a South African sample of PWH; (4) investigate the contribution of sociodemographic and psychosocial variables, as well as HIV-disease factors and other medical and psychiatric comorbidities, to cognitive performance in a South African sample of PWH; and (5) investigate associations between cognitive performance and ART adherence in 10 a South African sample of PWH. Each of these aims was explored in a separate study. Hence, this thesis reports on findings from five separate journal manuscripts. Method. Study 1 was a systematic review and meta-analysis summarizing the findings of published studies investigating differences in cognitive performance between WWH and MWH. An extensive systematic search of the literature across several databases found 4062 unique articles of potential interest. After thorough screening of that pool of articles, 11 studies (total N = 3333) were included in the narrative systematic review and 6 studies (total N = 2852) were included in the meta-analysis. Effect sizes were calculated to estimate between-sex differences in cognitive performance, both globally and within discrete cognitive domains. Study 2 investigated sex differences in cognitive performance in a sample of PWH with comorbid MDD (N = 105). All participants were attending community clinics in Khayelitsha, a peri-urban community in Cape Town, South Africa, and were part of a larger research program for a randomised controlled trial of a cognitive-behavioral treatment for ART adherence and depression (CBT-AD). As part of this program, they completed baseline neuropsychological, psychiatric, and sociodemographic assessments. T-tests and multivariable regressions controlling for covariates compared baseline cognitive performance of WWH and MWH, both globally and within discrete cognitive domains. Study 3 applied 20 different quantitative methods of determining cognitive impairment to existing data from a different sample of PWH (N = 148). These individuals had also been recruited from community clinics in Khayelitsha, and had completed a comprehensive neuropsychological assessment and a 3T structural MRI and diffusion tensor imaging (DTI) session. Logistic regression models investigated the association between each method and HIV-related neuroimaging abnormalities. Study 4 again used data from the sample of PWH with comorbid MDD who participated in the larger CBT-AD research program. This study investigated which sociodemographic, psychosocial, psychiatric, and medical variables (as measured at baseline) were associated with baseline cognitive performance. Post-baseline, 33 participants were assigned to CBT-AD and 72 to standard-of-care treatment; 81 participants (nCBT-AD = 29) had a follow-up assessment 8 months post-baseline. This study also investigated whether, from baseline to follow-up, depression and cognitive performance improved significantly more in the participants who had received CBT-AD, and examined associations between post-intervention improvements in depression and cognitive performance. Study 5 assessed ART adherence in the same sample of PWH with comorbid MDD. Mixed-effects regression models estimated the relationship between ART adherence (as measured by both self-report and objective measures, and by degree of HIV viral suppression) with cognitive performance 11 and with other sociodemographic, psychosocial, and psychiatric variables at both baseline and follow-up. Results. Study 1: Analyses suggested that, in terms of overall cognitive functioning, there were no significant differences in cognitive performance between WWH and MWH. However, WWH did perform significantly more poorly than MWH in the domains of psychomotor coordination and visuospatial learning and memory. Additionally, the review suggested that cognitive differences between WWH and MWH might be accounted for by sex-based variation in educational and psychiatric characteristics among study samples. Study 2: Analyses suggested that, in our sample of PWH with comorbid MDD, there were no significant differences in cognitive performance between WWH and MWH. Study 3: Findings suggested that there was marked variation in rates of cognitive impairment (20– 97%) depending on which method was used to define impairment, and that none of these methods accurately reflected HIV-associated brain injury. Study 4: Analyses suggested that less education and greater food insecurity were the strongest predictors of global cognitive performance. Improvement in depression severity was not significantly associated with improved cognitive performance, except in the domain of Attention/Working Memory. Overall, factors associated with cognitive performance were unrelated to HIV disease and other medical factors. Study 5: Analyses identified poor global cognitive performance as a potential barrier to achieving HIV suppression. Conclusion. Taken together, the findings from the five studies contained within this thesis suggest that one oft-mooted sociodemographic influence on cognitive performance in PWH, sex, was not a consistent influence on such performance. However, non-biological (mainly psychosocial and socioeconomic) factors were stronger predictors of cognitive performance in PWH than medical factors (including HIV-disease variables). Current quantitative criteria for defining cognitive impairment in PWH also do not accurately reflect the biological effects of HIV in the brain. The implication of these findings is that research studies may be misclassifying PWH as cognitively impaired and consequently overestimating the prevalence of cognitive impairment in this population. When conducting clinical assessments of PWH, future research studies should measure and consider the strong influence of psychosocial and socioeconomic factors on cognitive test performance. Ideally, a diagnosis of impairment should only be made after a comprehensive clinical assessment that includes a detailed history taking. Overall, we need new criteria for defining cognitive impairment in diverse global populations of PWH. Ideally these criteria should be applicable to both research and clinical settings. Assessing for cognitive impairment among PWH and then providing 12 appropriate support could help achieve viral suppression in patients with non-optimal adherence to ART. At public policy levels, addressing larger psychosocial issues (e.g., food insecurity and low educational attainment) may also help improve cognitive performance in PWH

A Novel Role for and Potential Therapeutic Targeting of Heme Oxygenase-1 in HIV Neuropathogenesis

HIV-associated neurocognitive disorders (HAND) affect up to 50% of HIV-infected adults despite potent viral suppression with antiretroviral therapy (ART) and are associated with persistent neuronal damage, monocyte/macrophage activation, chronic inflammation, and oxidative stress. Heme oxygenase-1 (HO-1) is a highly inducible, detoxifying enzyme critical for limiting oxidative stress, inflammation, and cellular injury within the central nervous system (CNS) and other tissues. Our analysis of HO-1 expression in the brain prefrontal cortex from HIV-infected individuals demonstrated a significant HO-1 protein deficiency, even in HIV-infected subjects treated with ART. This HO-1 deficiency associated with a diagnosis of HAND and HIV-encephalitis (HIVE) as well as with elevated CNS HIV replication, type I interferon responses, and macrophage activation. Within this cohort longer variants of a HO-1 promoter region (GT)n microsatellite polymorphism, which cause reduced HO-1 gene expression, associated with increased risk of HIVE and elevated CNS macrophage activation. HIV replication in macrophages, a primary CNS HIV reservoir, selectively reduced HO-1 protein and RNA expression and induced production of neurotoxic levels of glutamate. This HO-1 deficiency and associated neurotoxin production was a conserved feature of infection with macrophage-tropic HIV-1 and HIV-2 strains that correlated closely with the extent of replication. ART regimens applied to macrophages after HIV infection was established failed to prevent this HO-1 loss and associated neurotoxin production. HO-1 siRNA knockdown and enzymatic inhibition in HIV-infected macrophages increased supernatant glutamate and neurotoxicity. In contrast, increasing HO-1 expression through siRNA derepression or with pharmacologic inducers, including the CNS-penetrating drug dimethyl fumarate (DMF), decreased supernatant glutamate and neurotoxicity. These findings identify HO-1 as a host factor that is deficient in the brains of HIV-infected individuals and suggest that loss of HO-1 and its protective functions may contribute to HIV neuropathogenesis. Moreover, this work defines a predictable and conserved relationship between HIV replication, HO-1 loss, and neurotoxin production in macrophages that likely reflects processes in place in the HIV-infected brain of individuals receiving ART. Correcting this HO-1 deficiency could provide a novel approach for neuroprotection in individuals with or at risk for developing HAND above that provided by current ART