This study proposes to determine if a novel MRI contrast agent (ferumoxytol) can identify monocyte/macrophage (M/MF) mediated inflammation on brain MRI in HIV-infected individuals. Our proposal is clinically relevant given the key role M/MF are believed to have in the persistence of neurocognitive impairment (NCI) associated with HIV-associated neurocognitive disorders (HAND) in the era of effective combination antiretroviral therapies (cART). Currently, there is no effective neuroimaging modality available to define the extent of M/MF-mediated inflammation in HAND either as a diagnostic tool or to assist in defining improvement in clinical trials addressing HAND. Ferumoxytol is an ultra-small iron oxide which is FDA approved for the treatment of iron deficiency anemia in patients with chronic kidney disease. In addition, ferumoxytol is avidly taken up by circulating M/MF. The paramagnetic and biologic properties of ferumoxytol make it appealing to use as a brain MRI contrast agent to study ongoing M/MF-mediated inflammation in HAND. In a pilot study of 4 HIV-infected (HIV+) individuals with NCI despite suppressed plasma viremia on a stable cART regimen, ferumoxytol-enhanced brain MRI demonstrated a diffuse tram track appearance in or adjacent to the arterial and venous intracranial vessel walls of the peripheral cortical and deep white matter vasculature suggesting perivascular ferumoxytol uptake in M/MF. These perivascular tram track hyperintensities may represent inflammation from the perivascular M/MF demonstrated in autopsy studies of HIV-infected patients with undetectable plasma HIV viral loads who died while on cART. It is hypothesized that these perivascular M/MF traffic across the blood brain barrier and trigger an inflammatory cascade, resulting in neuronal dysfunction and ultimately NCI. We propose to expand on our preliminary results to recruit 10 HIV+ subjects with suppressed plasma viremia on cART and NCI and compare ferumoxytol-enhancement on brain MRI to controls, which will include 10 HIV+ and 10 HIV-uninfected subjects without NCI (Specific Aim I). We expect perivascular tram track hyperintensities will be present more frequently on ferumoxytol-enhanced brain MRI in HIV+ subjects with NCI. We will also use a new quantitative MRI method that is sensitive to the paramagnetic properties of iron (quantitative susceptibility mapping, QSM) to quantitate ferumoxytol-enhancement on brain MRI (Specific Aim II). We expect ferumoxytol enhancement can be measured with QSM and will be increased in HIV-infected subjects with NCI compared to controls.
This grant will examine if a new MRI contrast dye that targets monocytes (ferumoxytol) can be used to detect inflammation due to monocyte on brain MRIs in HIV-infected individuals with cognitive impairment. A brain MRI analysis technique called quantitative susceptibility mapping will be used to quantitate monocyte-mediated inflammation on ferumoxtyol-enhanced brain MRIs.
| Chow, Dominic C; Kagihara, Jamie M; Zhang, Guangxiang et al. (2016) Non-classical monocytes predict progression of carotid artery bifurcation intima-media thickness in HIV-infected individuals on stable antiretroviral therapy. HIV Clin Trials 17:114-22 |
| Kallianpur, Kalpana J; Gerschenson, Mariana; Mitchell, Brooks I et al. (2016) Oxidative mitochondrial DNA damage in peripheral blood mononuclear cells is associated with reduced volumes of hippocampus and subcortical gray matter in chronically HIV-infected patients. Mitochondrion 28:8-15 |
