Imaging Inflammation in AIS Dementia: PET with [11C] Arachidonic Acid
Dima Hammoud, M.D.
Johns Hopkins University, School of Medicine, Baltimore, MD
David Mahoney Neuroimaging Program
December 2005, for 3 years
Can PET Reveal How Some People with AIDS Develop AIDS-Associated Dementia?
The investigators will use PET imaging to determine the underlying molecular changes that occur in the brains of people with AIDS who have developed AIDS-associated dementia. The results could lead to a better understanding of how dementia occurs and, potentially, to a metabolic marker for predicting which people with AIDS are likely to develop dementia.
HIV, the virus that produces AIDS, is transported to the brain by blood cells that contain immune system white cells and macrophages. These blood cells cross the blood-brain-barrier. Once inside the brain, these blood cells interact with immune microglial cells that reside in the brain. This interaction causes the immune microglial cells to release multiple toxins that fight invaders but are also harmful to brain cells. One of these toxins is called “arachidonid acid” (AA); it is implicated in the development of AIDS-associated dementia.
Johns Hopkins researchers will label a radioactive form of AA and administer it intravenously while study participants are in the PET scanner. They will determine whether patients with AIDS-associated dementia take up the labeled AA in greater amounts than AIDS patients who do not have dementia, or healthy controls. They anticipate that AA is greater in people with AIDS-associated dementia.
Significance: This imaging study could help determine the molecular changes that underlie AIDS-associated dementia, and become a method for predicting which patients with AIDS are likely to develop dementia.
Imaging Inflammation in AIDS Dementia: PET with [11C] Arachidonic Acid
Neuroinflammatory changes associated with HIV infection of the central nervous system (CNS) are mediated by a multitude of cytokines and pro-apoptotic molecules induced by activated microglia. HIV-related inflammation leads to neuronal death and secondary neurological dysfunction, including HIV-associated dementia (HAD). Arachidonic acid (AA) and its metabolites produced during interaction between HIV-infected microglia and astrocytes are among the most commonly implicated agents in the pathophysiology of HAD.
In addition to the neurotoxic effects of AA, several groups have recently shown that HIV budding from the host cell occurs at specific cholesterol and sphingolipid-rich membrane microdomains called lipid rafts that are highly enriched in cholesterol and sphingomyelin, as well as in plasmenylethanolamines, particularly those containing AA. That process results in a viral membrane that is richer in AA than are the surrounding host cell membranes. Once released from the cell membrane, free AA is rapidly and stoichiometrically replaced by unesterified AA derived from plasma. That replacement can be imaged in vivo by cerebral [11C]AA positron emission tomography (PET) of HIV-infected individuals. In light of the role of AA in mediating neuronal injury in HAD and the AA-rich viral membranes in HIV, probing AA metabolism with PET will provide a sensitive method to detect abnormal AA metabolism, which will likely co-localize with the regions of greatest neuronal damage.
We will study three groups of subjects with [11C]AA-PET: HIV+ individuals who are demented, HIV+ individuals with normal cognition, and age-matched, healthy controls. The underlying hypothesis of this proposal is that we will demonstrate elevated [11C]AA in the brains of HIV+ non-demented individuals relative to normal controls, while patients with HAD will demonstrate an even greater elevation of [11C]AA in discrete brain regions, based on accelerated AA metabolism in the brains of infected individuals. We anticipate those changes to be most prominent in deep, predominantly gray matter structures, i.e., thalamus and brain stem, in keeping with other brain neuroimaging and pathological studies in patients with HAD. Imaging AA metabolism in vivo will advance our understanding of the cellular and molecular mechanisms underlying HAD, thereby providing a noninvasive biomarker of the disease, enabling the assessment of prognosis and establishment of concrete targets upon which to base anti-HAD therapy.
Dima Hammoud, M.D.
Assistant Professor of Radiology, Johns Hopkins
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.
Hammoud D.A., Endres C.J.,Chander A.R., Guilarte T.R., Wong D.F., Sacktor N.C., McArthur J.C., and Pomper M.G. Imaging glial cell activation with [ 11C]-R-PK11195 in patients with AIDS. J Neurovirol. 2005 Aug;11(4):346-55 .