Nearly half of all HIV-positive individuals present with some form of HIV-associated neurocognitive disorder (HAND). The experiments described in this thesis examined the structural changes that occur in the brain as a result of HIV infection. While previous work has established that HIV targets the basal ganglia and fronto-striatal systems and impacts cortical and white matter pathways, it was unknown whether these changes occur in the absence of HAND. The studies described here focused on cognitively asymptomatic HIV+ individuals (CAHIV+) without HAND as determined by widely accepted neuropsychological performance guidelines. Experiment 1 utilized diffusion tensor imaging (DTI) to examine HIV-associated alterations in white matter (WM) fractional anisotropy (FA) in the absence of HAND in 23 HIV+ individuals and 17 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would show lower FA values than HIV- in the corpus callosum, frontotemporal, and parietal regions of interest (ROIs). CAHIV+ individuals demonstrated higher FA in the frontotemporal region and posterior corpus callosum, but lower FA in parietal WM relative to HIV- individuals. Experiment 2 utilized structural MRI to compare cortical thickness in 22 CAHIV+ individuals and 19 control participants (HIV-) matched for age, education, and verbal IQ. The hypothesis was that CAHIV+ participants would have thinner frontal, temporal, and parietal regions than HIV- participants. Reduced cortical thickness measures were identified in the cingulate and superior temporal gyri, with increased cortical thickness measures in the inferior occipital gyrus, for HIV+ participants compared to HIV-. Experiment 3 examined the relationship between the structural alterations identified in Experiments 1 and 2, neuropsychological performance on tests sensitive to HAND identification, and immunological characteristics in 30 HIV+ participants and 28 HIV- control participants. As hypothesized, regional FA values, cortical thickness, and viral load were related to neuropsychological composite scores for CAHIV+, but not HIV-. Together, results from these three studies suggest that regional FA and cortical alterations identified in CAHIV+ patients may contribute to the cognitive deficits often seen in later stages of HIV disease.

INTRODUCTION: HIV- associated neurocognitive disorder (HAND) and pathology are common manifestations of HIV-infection, and often persist in spite of controlled peripheral viremia. Severity of HAND can range from loss of concentration and psychological changes to frank dementia. Inflammatory host-immune responses and chemotaxis of immune cells into the CNS are thought to be integral to development of NeuroAIDS and HAND. OBJECTIVES: This studies' primary aim was to determine if significant differences existed between Substance P and NK1R expression in brain tissue samples of HIV-infected individuals with neurocognitive disorder or pathology. The secondary aim was to determine whether expression of HIV viral entry receptors CCR5 and CXCR4 correlate with expression of Substance P or NK1R. The tertiary aim of this study was to determine if age at death, CNS penetration-effectiveness of antiretroviral therapy, diagnosis before HAART, average plasma CD4, or abnormal alcohol or drug use increased prevalence of neurocognitive disease. STUDY DESIGN: Cross-sectional study of HIV-infected individuals (n=60) from the larger National NeuroAIDS Tissue Consortium Cohort. Pre-death demographic data, neurocognitive assessment, alcohol and drug use, ART regimens, date of diagnosis and death, and plasma CD4 levels, as well as pathology findings at autopsy and brain tissue samples were provided by the NNTC; expression levels of Substance P, NK1R, CCR5, and CXCR4 from brain samples were provided by Dr. Steven Douglas of The Children's Hospital of Philadelphia. RESULTS: In this sample of HIV-infected individuals, Substance P expression was significantly less in the cingulate cortex of individuals with (p=0.003). Within-subject expression patterns of CCR5 and truncated-NK1R in the cingulate cortex and cerebellum were both significantly altered by neuropathology and cannabis use; CCR5 expression was also significantly affected by opiate use. CCR5 and CXCR4 expression correlated strongly with truncated-NK1R expression. No between-subject factors significantly altered prevalence of neurocognitive impairment in this HIV-infected population. CONCLUSIONS: The study found significant changes in Substance P, NK1R, and CCR5 expression associated with neuropathology. Furthermore, in heterogeneous populations, expression patterns may be more important than overall level of expression in identifying risk factors for NeuroAIDS and other chronic diseases. / Epidemiology

This chapter will address the issue of risk for HIV-associated neurocognitive disorder (HAND), focusing on HIV-associated dementia (HAD), among persons living with HIV in relationship to the risk for other dementias. Advances in effective antiretroviral therapy (ART) have led to an increase in the prevalence of older persons surviving with HIV – in addition to older persons who become infected by HIV later in life. Hence, HIV is no longer a disease of younger persons, and additional attention has been brought to bear against the plight of older persons living with HIV – not only as it pertains to treatment but also to prevention. The additional risk caused by aging among older persons living with HIV is complex to asses, and HIV infection is a research area that requires a robust approach to multiple other factors causing neurocognitive impairment with older age. The long-term and potentially neurotoxic exposure to ART and the deleterious consequences of chronic infection with HIV and its associated neuro-inflammation have been described for health. This aids in the understanding of dementia risk factors in this patient population, but the comorbidities (HIV- and non-HIV-associated) occurring among older persons living with HIV must also be addressed to properly assess the overall impact on dementia risk in this group. This need also warrants our examination of the risk factors for other dementias (and comorbid dementias) in persons living with HIV versus the general population through the assessment and quantification of modifiable and non-modifiable risk factors identified as major contributors toward dementia.