Persistent immune activation remains a key concern in the cART era and it is likely to synergize with the effects of aging. The results of this interaction are likely contributing to the high prevalence of vascular disease, including cerebral small vessel disease (CSVD), observed in older HIV infected individuals. The qualitative assessment of CVSD via standard clinical MR pulse sequences, provides a superficial assessment of the brain microstructure damage. More importantly, it does not offer a full understanding of pathomechanisms of CNS injury. In this regard, we propose to combine the information provided by two MR modalities that assess the integrity of tissue microstructure, MR elastography (MRE) and neurite-orientation- dispersion density imaging (NODDI). We hypothesize that the combination of these modalities can help us understand how immune activation affects the intracellular and extracellular neuronal compartments (NODDI) and associated changes in tissue viscoelastic properties (MRE). We will also be able to assess quantitatively the relationship among these imaging metrics and peripheral blood markers of immune activation and neuronal and glia dysfunction. Furthermore, we will be able to assess how changes in intracellular and extracellular neuronal compartments and changes in brain viscoelastic properties affect cognitive performance. MRE metrics have been shown to be altered in several neurodegenerative disorders and neuroinflammatory disorders such as multiple sclerosis. However, there is no data on its usefulness in the context of HIV infection. Neither are there data that incorporate MRE, NODDI, makers of immune activation, neuronal and glia dysfunction and cognitive performance, providing a comprehensive picture of how neuroinflammation is linked to CNS injury and decreased cognitive performance. The lack of knowledge has prompted us to submit this proposal. To our knowledge, this study represents the first application of brain MRE to assess the overall hypothesis that HIV-associated immune activation affects the brain viscoelastic properties, leading to cognitive dysfunction. To minimize cost and increase efficiency, we propose to address the specific aims listed below in a cross-sectional study that will co-enroll 60 participants (30 HIV+ and 30 HIV-) in our ongoing longitudinal study of HIV-associated CSVD (RO1 AG054328). The CSVD cohort has enrolled 140 of the expected 220 participants (110 HIV+, 110 HIV-). The study is on target to complete the enrolment by the summer of 2019.
In Aim 1, we will assess whether HIV infection influences brain viscoelastic properties and whether these changes are associated with systemic markers of immune activation (soluble CD14 and CD163, D-dimer, soluble tissue factor and TF+ monocytes).
In Aim 2, we will investigate the relationship between brain viscoelastic properties, neurites (axons and dendrites) morphology and the correlation of these imaging metrics to plasma levels of markers of neuronal and astrocyte dysfunction.
In Aim 3, we will determine if MRE and diffusion MR metrics are associated with cognitive performance.
Over a million people are thought to be HIV infected in the US and more than half of all HIV+ individuals are over the age of 50. Persistent immune activation remains a key concern in the combination antiretroviral therapy (cART) era and it is likely to synergize with the effects of aging. The interaction HIV-aging contributes to the high prevalence of vascular disease, including cerebral small vessel disease (CSVD), observed in older HIV infected individuals. In this proposal, we focus on two magnetic resonance imaging modalities that assess the integrity of brain tissue microstructure, MR elastography (MRE) and neurite-orientation-dispersion density imaging (NODDI). We will also measure peripheral blood markers of immune activation as well as markers of neuronal and glia dysfunction. The combination of these imaging modalities and peripheral blood biomarkers can help us understand how immune activation affects neurites morphology (NODDI) and associated changes in tissue viscoelastic properties (MRE). The ultimate goal is to refine our understanding of the mechanisms that lead to HIV-associated brain injury and its clinical correlate, cognitive impairment.
