Neuroinflammatory changes associated with HIV infection of the central nervous system (CNS) are thought to be mediated by a multitude of cytokines and pro-apoptotic molecules, induced by microglial activation, leading eventually to neuronal death and secondary HIV-associated dementia (HAD). Arachidonic acid (AA) and its metabolites are some of the most commonly implicated agents in the pathophysiology of HAD. The hypothesis of this proposal is that [11C]AA in conjunction with positron emission tomography (PET) can be used to localize and quantify AA metabolism reflective of microglial activation and secondary neurological damage in patients with HAD.
1. To use [11C]AA- PET to image neuroinflammation in patients with HAD. We expect that we will see elevated [11C]AA uptake in the brains of patients with AIDS relative to age-matched controls and that patients with HAD will show an even greater elevation than that demonstrated in non-demented HIV+ individuals. We anticipate those changes to be most prominent in deep, predominantly gray matter, structures, i.e., thalamus and brain stem.
2. To correlate the degree of regional [11C]AA uptake not only with the presence of dementia, but also with serum markers of immune status, such as CD4 count.
We will study three groups of patients: 6 healthy controls, 6 HIV+ non-demented and 6 HIV+ demented patients based on the MSKCC dementia rating scale. Each subject will be scanned with our head-only, High Resolution Research Tomography (HRRT) PET scanner and will get an MRI scan of the brain for co-registration. Regional cerebral blood flow (rCBF) will be measured by injecting approximately 10 mCi of [15O] water as an intravenous bolus. Approximately 15 min later, 20 mCi of [11C]AA will be infused as a slow intravenous bolus. Serial dynamic 3D scans (30s to 5 min) will be acquired over a 1h period from the start of infusion. To determine a blood input function, arterial blood will be sampled throughout the PET study. In addition, blood samples will be acquired to characterize plasma radiolabeled metabolites in order to apply a metabolite correction to the blood curve. Plasma concentrations of [11C]CO2 and [11C]AA will be determined. Metabolite samples will be processed using a column-switch HPLC method developed in-house. In addition, a single blood sample taken before radiotracer injection will be used to assay for plasma protein binding.
Tissue uptake of [11C]AA will be quantified using a one-tissue (1T) irreversible model, which has a single parameter (K*) that represents the net rate of incorporation of [11C]AA. A blood volume term (Vb) will be included, and the 1T model will be fitted to generate parametric images of both K* and Vb. Regions of interest (ROIs) will be drawn on the parametric images in several gray matter regions and white matter. Mean values of K* and Vb will be determined in HIV and control subjects, and results will be compared using an unpaired t-test with statistical significance set at p < 0.05.