Imaging Inflammation in AIS Dementia: PET with [11C] Arachidonic Acid

Lay Summary

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.

Abstract

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.