Positron Emission Tomography (PET) to Study Brain Signaling

Objective

The binding of neurotransmitters and certain drugs to neuroreceptors in the brain is considered to modify cognition and behavior by activating certain receptor-coupled effector enzymes and initiating signal transduction cascades. One of these effector enzymes is phospholipase A2 (PLA2), which when activated will release arachidonic acid (AA) from phospholipids and initiate the AA cascade (Fitzpatrick and Soberman, 2001). AA and its eicosanoid metabolites have multiple biological actions. We have developed an imaging method to quantify and localize brain signal transduction involving PLA2 and AA in unanesthetized rats and monkeys, using quantitative autoradiography or positron emission tomography (PET), and radiolabeled AA. The aim of this protocol is to extend this method to humans with PET, when brain imaging AA signaling in two experimental conditions (dark and visual flash stimulation at a frequency of 3 Hz or 8Hz) in the same subject in the same PET session. Radioactive [1-11C]AA will be injected intravenously in each condition, and PET will be used to measure its incorporation coefficient k* in individual brain regions. Animal studies and modeling have shown that the incorporation coefficient is proportion to PLA2 activation and the release of AA from brain phospholipids (Rapoport, 2003). In addition, [15O]H20 will be injected in each condition to measure regional cerebral blood flow (rCBF). Based on our prior studies in human subjects of rCBF during visual activation by flashing lights at different frequencies (Mentis et al., 1997; Mentis et al., 1998; Mentis et al., 1996), we hypothesize that statistically significant increments in rCBF and [11C]AA incorporation into brain will be increased during visual activation compared with the dark (unactivated) condition. These increments should be evident in primary visual cortex, association visual cortex, thalamus, and frontal cortex. If our hypothesis proves correct and our method to measure [11C]AA incorporation both during stimulation and in the dark proves feasible in the same subject in the PET session, we believe that the method could be applied generally in humans to examine brain PLA2-related signal transduction during physiological or pharmacological activation and in healthy aging (Giovacchini et al., In press) and disease, particularly Parkinson and Alzheimer disease (Hayakawa et al., 2001; Nariai et al., 1991).

Study population

We plan to study 30 normal volunteers, each of whom will be subjected two stimulation conditions in the same PET session, visual stimulation at a frequency of 3 or 8 Hz, or a dark condition (0 Hz).

Design

Each PET scan session will last approximately 3 hours. Each subject will receive a total of four [15O]H20 injections to measure regional cerebral blood flow (rCBF), and two [11C]AA infusions to measure incorporation k* for AA during a single PET scan session. He/she will have an arterial catheter and venous line inserted during the entire session, and one transmission scan at the beginning of the session. The order of the scans will be randomized. The order of 4 blood flow scans will be: Rest-Photic Activation-Photic Activation-Rest OR Photic Activation-Rest-Rest-Photic Activation. The order of two [C11]AA scans will be Rest-Photic Stimulation Or Photic Stimulation-Rest.

Stimulation will be conducted via LED goggles at a flash frequency of 3 Hz and 8 Hz, evenly divided among the 30 subjects, and at 0 Hz (dark condition). Statistical parametric mapping and other statistical procedures will be used to identify brain regions in which k* for AA and/or rCBF is elevated at 3 Hz compared with the dark condition; at 8 Hz compared with the dark condition; and at 8 Hz compared with 3 Hz condition.