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

Central adiposity and brain vulnerability in mid-life : evidence for early risk

This set of projects focused on visceral fat, measured using proximal and direct methods. Specifically, I was interested in the effects of visceral fat on brain structure and integrity in middle age. Study 1 looked at waist to hip ratio (WHR) as a proximal measure of visceral fat and used statistical mediation to directly examine a possible mechanism behind the relationship between visceral fat and cognitive decline. Reductions in executive function seen in middle-aged adults with high visceral fat were found to occur in the context of lowered serum brain derived neurotrophic factor (BDNF) a key neurotrophin involved in synaptic plasticity as well as neuronal regeneration. Study 2 utilized Dual Energy X Ray Absorptiometry (DXA) to directly estimate visceral fat mass and volume as well as thickness of the cortical mantle in middle age. High-resolution Magnetization Prepared Rapid Acquisition Gradient Echo (MPRAGE) images were used. High visceral fat was found to predict increased thickness in the posterior cingulate cortex independently of age and cardiovascular risk in a cognitively intact middle-aged sample. Study 3 examined changes in concentrations of crucial cerebral metabolites in the posterior cingulate cortex among individuals with high visceral fat. Results indicated that visceral fat predicted reduced concentrations of N Acetyl Asparate, a marker of neuronal viability and increased concentrations of myo-inositol, a glial marker that is implicated in a number of disease states including prodromal Alzheimer’s Disease and Multiple Sclerosis. Collectively, the 3 studies highlight important evidence for early brain vulnerability even in cognitively intact middle- aged adults with high levels of cognitive reserve. An important next step would be to examine modifiable mediators of these relationships, such as inflammation and BDNF so that targeted interventions may be developed.Psycholog

Comparison of Magnetic Resonance Spectroscopy (MRS) data in children with and without HIV at 11-12 years

Although HIV and antiretroviral drugs have been shown to cause damage in the brain, the long-term impacts of perinatal infection, early treatment and exposure in children at 11 years, remain unclear. The effects of HIV and antiretroviral therapy (ART), whilst indistinguishable, can be investigated at a chemical level through proton magnetic resonance spectroscopy (1H-MRS). Previous studies in children have largely focused on individual metabolite changes. However, several adult studies have now advanced beyond this to address patterns of metabolic activity that are altered with HIV infection. Using a 3T Skyra scanner, 136 children (76 HIV+, 30 HEU, 30 HU; 71 males) between the ages of 11.0- 12.5 years, and from a similar socioeconomic background, were scanned. In this study metabolite concentrations were quantified within the basal ganglia (BG), midfrontal gray matter (MFGM) and peritrigonal white matter (PWM). We utilised linear regression to investigate individual metabolite differences, comparing HIV-infected (HIV+) children from the Children with HIV Early Antiretroviral Therapy (CHER) trial, and HIV-exposed-uninfected (HEU) children, to HIV-unexposed (HU) children. Pearson's correlation analysis, factor analysis and logistic regression were then used to study alterations in metabolic patterns between HIV+ and HIV-uninfected (HIV-) children. Analysis of the data was carried out in R. We found elevated total choline in the BG (p = 0.03) and MFGM (p < 0.001) of HIV+ children, as well as reduced PWM total NAA (p = 0.03) and total creatine (p = 0.01). Altered metabolite concentrations were further observed in HEU children. Additionally, we identified a cross-regional coupling of choline which distinguishes HIV+ from HIV- children (p < 0.001). These findings indicate that multiregional inflammation and PWM axonal damage are occurring in HIV+ children at 11 years. Ultimately, the consequences of perinatal HIV acquisition, in spite of early treatment, continue to be seen at 11 years, as do the impacts of exposure

Disease-induced neuroinflammation and depression

Progression of major depression, a multifactorial disorder with a neuroinflammatory signature, seems to be associated with the disruption of body allostasis. High rates of comorbidity between depression and specific medical disorders, such as, stroke, chronic pain conditions, diabetes mellitus, and human immunodeficiency virus (HIV) infection, have been extensively reported. In this review, we discuss how these medical disorders may predispose an individual to develop depression by examining the impact of these disorders on some hallmarks of neuroinflammation known to be impaired in depressed patients: altered permeability of the blood brain barrier, immune cells infiltration, activated microglia, increased cytokines production, and the role of inflammasomes. In all four pathologies, blood brain barrier integrity was altered, allowing the infiltration of peripheral factors, known to activate resident microglia. Evidence indicated morphological changes in the glial population, increased levels of circulating pro-inflammatory cytokines or increased production of these mediators within the brain, all fundamental in neuroinflammation, for the four medical disorders considered. Moreover, activity of the kynurenine pathway appeared to be enhanced. With respect to the inflammasome NLRP3, a new target whose role in neuroinflammation is emerging as being important, accumulating data suggest its involvement in the pathogenesis of brain injury following stroke, chronic pain conditions, diabetes mellitus or in HIV associated immune impairment. Finally, data gathered over the last 10 years, indicate and confirm that depression, stroke, chronic pain, diabetes, and HIV infection share a combination of underlying molecular, cellular and network mechanisms leading to a general increase in the neuroinflammatory burden for the individual

Inhibitory Control Deficits Associated with Upregulation of CB1R in the HIV-1 Tat Transgenic Mouse Model of Hand

In the era of combined antiretroviral therapy, HIV-1 infected individuals are living longer lives; however, longevity is met with an increasing number of HIV-1 associated neurocognitive disorders (HAND) diagnoses. The transactivator of transcription (Tat) is known to mediate the neurotoxic effects in HAND by acting directly on neurons and also indirectly via its actions on glia. The Go/No-Go (GNG) task was used to examine HAND in the Tat transgenic mouse model. The GNG task involves subjects discriminating between two stimuli sets in order to determine whether or not to inhibit a previously trained response. Data reveal inhibitory control deficits in female Tat(+) mice (p = .048) and an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group (p < .05). A significant negative correlation was noted between inhibitory control and IL CB1R expression (r = -.543, p = .045), with CB1R expression predicting 30% of the variance of inhibitory control (R(2) = .295, p = .045). Furthermore, there was a significant increase in spontaneous excitatory postsynaptic current (sEPSC) frequencies in Tat(+) compared to Tat(-) mice (p = .008, across sexes). The increase in sEPSC frequency was significantly attenuated by bath application of PF3845, a fatty acid amide hydrolase (FAAH) enzyme inhibitor (p < .001). Overall, the GNG task is a viable measure to assess inhibitory control deficits in Tat transgenic mice and results suggest a potential therapeutic treatment for the observed deficits with drugs which modulate endocannabinoid enzyme activity. Graphical Abstract Results of the Go/No-Go operant conditioning task reveal inhibitory control deficits in female transgenic Tat(+) mice without significantly affecting males. The demonstrated inhibitory control deficits appear to be associated with an upregulation of cannabinoid type 1 receptors (CB1R) in the infralimbic (IL) cortex in the same female Tat(+) group

The relationship between neurocognitive disorders, prospective memory impairment and white matter damage in clade C HIV-positive subjects

Includes bibliographical references.AIMS: To examine the relationship between prospective memory, cognitive function and Diffusion tensor imaging (DTI)/ White matter integrity of human immunodeficiency virus (HIV) positive individuals in the Western Cape. We hypothesize that: 1. Individuals infected with HIV will exhibit significantly poorer microstructural integrity of the white matter than HIV negative individuals, as determined by in vivo diffusion tensor imaging. We expect that values of fractional anisotropy (FA) - a measure of directional water diffusion- in the frontal white matter will be significantly lower among HIV patients compared to controls 2. Lower FA measured in the frontal white matter will correlate significantly with impaired performance on tests of prospective memor

Glia in Health and Disease

The book will highlight the role played by glial cells in the central and peripheral nervous systems in both healthy and unhealthy individuals. Among all processes involved, we will discuss the importance of the enteric nervous system in the control of gut homeostasis, in the interaction with the immune system, and its participation in pathological conditions such as metabolic syndrome. We will also look at the relevance of astrocytes during synaptic transmission and the regulation of plasticity by releasing gliotransmitters. Ultimately, we will highlight the influence of astrocytes during the development of a number of neurodegenerative diseases, such as multiple sclerosis and Alzheimer’s disease, focusing on how the serum levels of the astrocytic protein S100B can be used as a biomarker for clinical decisions