Dr. Michael R. Kilbourn
Division of Nuclear Medicine
B1 G412 University Hospital Box 0028
Ann Arbor, MI 48109-0028
Phone: 734-763-9244
Fax: 734-764-0288
E-mail: mkilbour@umich.edu
Number of Human Subjects projects reported: 1
| UMH-87-DE-FG02-87ER60561 | "Advancing PET Science for New Measures of Brain Function" |
"Advancing PET Science for New Measures of Brain Function"
Principal Investigator: Dr. Michael R. Kilbourn, University of Michigan Hospitals
Project started in: 1987
Funding for Human Subjects Research:
This project involves the use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 5
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 12/19/02
IRB approval number: 2002-0891
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The general goal of the proposed work is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research proposed here will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.
The significance of this research centers on the concept that, rather than examining particular aspects of the working brain in isolation, we would like to provide a broader more global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter, and also is both labor intensive and time consuming since metabolite corrected concentration time courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project, we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
Subjects will have two 5 to 10 minute transmission scans performed for measurement of attenuation factors for the PET scan. Subjects involved in this project will be injected via venous catheter with one of the two following injection scenarios:
1) one injection of 12 mCi [11C]MP + two injections, 12 mCi each of [11C]RAC
OR
2) one injection of 12 mCi [11C]RAC + two injections, 12 mCi each of [11C]MP.
All injections will be administered via the intravenous catheter. Injections will be made as a discreet bolus and/or as a continuous infusion over the study duration.
INVOLVEMENT OF HUMAN SUBJECTS
A brief medical and neurologic screening will take less than one hour to complete. PET imaging will take approximately four hours to complete. A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. Subjects will be injected with [11C]RAC. PET imaging will begin simultaneously. Twenty or thirty minutes later subjects will be injected with [11C]MP. Imaging will continue for another 60 minutes. The order of tracer injection will be switched. The first tracer will be injected as a bolus plus a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion.
Visual stimulation challenge studies will be performed to test identifiability of transport parameters from binding parameters. During one tracer administration, the subject will be scanned with eyes closed. When the other tracer is administered, the subject will be scanned while watching an alternating annual checkerboard throughout the first 15 minutes after the tracer administration is begun. This procedure selectively increases cerebral blood flow to the visual cortex, and hence, the value of the transport rate constant in the visual cortex for one of the ligands should be increased, while not affecting the transport estimate for the other ligand, or either of the binding parameters.
RISKS
Risks consist of low-level radiation exposure, cannulation of a cutaneous vein, and idiosyncratic/allergic reaction to the study radiopharmaceutical.
PRIVACY/CONFIDENTIALITY/CONSENT
A research subject will not be personally identified during presentation or write-up of the data. PET research data have limited accessibility. Written informed consent will be obtained during a face-to-face visit.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 04/10/03
IRB approval number: 1999-0684
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 5
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The goal of this research is to develop and test methods to study multiple neuropharmacological parameters simultaneously using quantitative positron emission tomography (PET). Currently, we are completing the initial phase of this research proving the feasibility of doing dual tracer studies which allow studies that currently take four hours to be completed in two hours. Results appear promising and demonstrate that multiple neuropharmacological measures can be made in a single scanning session. Previously, we studied two different pairs of tracers under baseline conditions [11C]flumazenil ([11C]FMZ) and [11C]dihydrotetrabenazine ([11C]DTBZ) or [11C]FMZ and [11C]Methylpiperidinyl Propionate ([11C]PMP). The goal of this current project is to extend this work to perform validation studies following a pharmacological intervention demonstrating both sensitivity and specificity to particularly interventions. We have chosen two known interventions to validate dual-tracer studies using these same two tracer pairs. These interventions will validate sensitivity and specificity to pharmacological intervention using two challenges already studies in our facility, 1) administration of a partial blocking dose of unlabeled flumazenil (effecting only [11C]FMZ binding measures) or administration of physostigmine, an acetylcholinesterase inhibitor (effecting only ([11C]PMP hydrolysis measures).
Brain functions are modulated by connections between cerebral structures and interactions among different neurochemical systems. Disease processes often involve multiple cerebral structures and different neurochemical systems that interact with each other. Changes in a neurochemical system in one part of the brain consequently affect other neurochemical systems in different areas of the brain. The significance of this work centers on the concept that, rather than examining particular aspects of the working brain in isolation, we would like to validate methods that can provide a broader more global view of cerebral function. We wish to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just examine one component at a time without seeing how this system fits into the overall workings of the human brain. Our work to date has centered on demonstrating that dual scans are indeed feasible and on optimizing the data acquisition and analysis protocols for such studies. The significance of this particular aspect of the project relates to the overall goal of studying how two different neuroreceptor systems interact. One way to do this is to perturb the systems by giving a pharmacologic challenge. Here we are performing validation studies to demonstrate that when known pharmacologic challenges are given ("cold" flumazenil or physostigmine) we can appropriately separate these effects based on the measured PET data.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
A transmission scan will be performed for measurement of attenuation factors. The exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects involved in this research project will be injected according to one of the following injection scenarios:
1. [11C]FMZ + [11C]PMP (baseline)
[11C]FMZ + [11C]PMP (physostigmine intervention)
OR
2. [11C]FMZ + [11C]PMP (baseline)
[11C]FMZ + [11C]PMP (Romazicon intervention)
OR
3. [11C]FMZ + [11C]DTBZ (baseline)
[11C]FMZ + [11C]DTBZ (Romazicon intervention)
INVOLVEMENT OF HUMAN SUBJECTS
A brief medical and neurologic examination will be done. PET imaging will take approximately four hours. A radial artery and a vein will be catheterized to allow for blood sampling and radiopharmaceutical injection. Subjects will be positioned in the PET scanner and the transmission scan will be done. The subject will be injected with 12 mCi of [11C]FMZ. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Approximately fifteen minutes post-injection the subject will be injected with 12 mCi [11C]DTBZ OR 12 mCi [11C]PMP. Imaging and blood sampling will continue for sixty minutes. When this first set of studies is completed a pharmacologic intervention will be administered. If a subject was injected with [11C]DTBZ the pharmacologic intervention will be the administration of cold flumazenil. For half of the subjects injected with [11C]PMP the pharmacologic intervention will be physostigmine. For the other half, the intervention will be cold flumazenil. A second set of identical PET scans will be performed. At the completion of the PET imaging, the catheters will be removed the subject will be released. An arterial input function will be generated from the arterial blood samples and coupled with the dynamic PET to generate quantitative images.
RISKS
Risks include low-level radiation exposure, cannulation of the radial artery, cannulation of a cutaneous vein, and idiosyncratic/allergic reaction to the study radiopharmaceutical.
PRIVACY/CONFIDENTIALITY/CONSENT
Subjects will not be personally identified during presentation or report of the data. PET research data has limited accessibility. Written informed consent will be obtained from all subjects.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 12/19/02
IRB approval number: 2002-0892
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 0
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The general goal of the proposed work is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes, in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research proposed here will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.
The significance of this research centers on the concept that rather than examining particular aspects of the working brain in isolation, we would like to provide a broader more global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter, and also is both labor intensive and time consuming since metabolite corrected concentration time courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project, we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
Subjects will have two 5 to 10 minute transmission scans performed for measurement of attenuation factors for the PET scan. Subjects involved in this research project will be injected via venous catheter with [11C]RAC and [11C]CFN. The injection of these radiotracers allows for PET imaging of dopamine ([11C]RAC) and mu-opioid ([11C]CFN) binding density.
INVOLVEMENT OF HUMAN SUBJECTS
A brief medical and neurologic screening will take less than one hour to complete. PET imaging will take approximately four hours if completed on one day or 2.5 hours on each of two days.
Part One: A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. A pharmacologic intervention may be administered. This will be the intravenous administration of naloxone. It will be injected as a bolus followed by continuous infusion for the duration of the study. Subjects will be injected with [11C]RAC. Dynamic PET imaging will begin simultaneously. Twenty or thirty minutes post-injection subjects will be injected with [11C]CFN. Imaging will continue for sixty minutes. The order of tracer injection may be switched. The first tracer will be injected as a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion.
Part Two: An intravenous line is needed for the injection of [11C]RAC and/or [11C]CFN. This line may also be used for the administration of naloxone. A transmission scan will be performed. PET imaging will take 80 to 90 minutes to complete. Subjects' data will be referenced by hospital registration number. Subjects will not be identified personally in reports or presentations of data.
RISKS
Risks include low-level radiation exposure, cannulation of a cutaneous vein, reaction to cold mass component of [11C]carfentanil, idiosyncratic/allergic reaction to the study radiopharmaceutical, and idiosyncratic/allergic reaction to pharmacologic intervention.
PRIVACY/CONFIDENTIALITY/CONSENT
A research subject will not be personally identified during presentation or write-up of the data. PET research data has limited accessibility. Written informed consent will be obtained during a face-to-face visit after the study has been fully explained to the research subject and all questions have been fully answered.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 12/19/02
IRB approval number: 2002-0893
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 2
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The general goal of the proposed work is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes, in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research proposed here will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.
The significance of this research centers on the concept that rather than examining particular aspects of the working brain in isolation, we would like to provide a broader, global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter and also is both labor intensive and time consuming since metabolite corrected concentration time courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
Subjects will have two 5 to 10 minute transmission scan performed for measurement of attenuation factors for the PET scan. Subjects involved in this research project will be injected via venous catheter with [11C]FMZ and [11C]PMP or [11C]BMP. The injection of these radiotracers allows for PET imaging of benzodiazepine receptor binding ([11C]FMZ) and cholinesterase activity ([11C]PMP and BMP).
INVOLVEMENT OF SUBJECTS
A brief medical and neurologic screening will take less than one hour to complete. PET imaging will take approximately four hours if completed in one day or 2.5 hours on each of two days.
Part One: A radial artery may be catheterized to allow for blood sampling. A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. A pharmacologic intervention may be administered. This will be the intravenous administration of cold flumazenil. It will be injected as a bolus followed by continuous infusion for the duration of the study. Subjects will be injected with [11C]FMZ. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Twenty or thirty minutes post-injection subjects will be injected with [11C]PMP or [11C]BMP. Imaging and blood sampling will continue for sixty minutes. The order of tracer injection may be switched. The first tracer will be injected as a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion. An arterial input function will be generated and coupled with the PET images to generate quantitative images.
Part Two: An intravenous line is needed for the injection of [11C]FMZ and [11C]PMP. This line may also be used for the administration of cold flumazenil. A transmission scan will be performed. PET imaging will take 80 to 90 minutes to complete. No blood sampling will occur.
RISKS
Risks include low-level radiation exposure, cannulation of the radial artery, cannulation of a cutaneous vein, idiosyncratic/allergic reaction to the study radiopharmaceutical, and idiosyncratic/allergic reaction to pharmacologic intervention.
PRIVACY/CONFIDENTIALITY/CONSENT
A research subject will not be personally identified during presentation or report of the data. PET research data has limited accessibility. Written informed consent will be obtained during a face-to-face visit after the study has been fully explained to the research subject and all questions have been fully answered.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Approving Institution: University of Michigan Hospitals
Most recent approval: 12/19/02
IRB approval number: 2002-0894
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 22
Reporting period for number of human subjects:
Fiscal Year 2003
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The general goal of the proposed work is to estimate multiple neuropharmacological parameters within a single non-invasive positron emission tomography (PET) procedure. In this new work, we seek to develop a method that involves injection of two different PET radiotracers, separated by 20 to 30 minutes, in a single dynamic acquisition but does not require arterial blood sampling. Such studies will offer many advantages for human PET imaging where the invasive, complicated, and time-consuming effort of arterial plasma sampling and metabolite correction are not always feasible. The research proposed here will develop, test, and validate data acquisition and analysis methods designed specifically for the purpose of quantifying multiple pharmacological measures non-invasively from dual-radioligand dynamic PET studies. These methods will use modified reference region techniques instead of input functions obtained from arterial blood sampling. We will apply a combination of Logan plot, reference tissue model, and shape analysis approaches for the estimation of multiple neuropharmacological parameters.
The significance of this research centers on the concept that rather than examining particular aspects of the working brain in isolation, we would like to provide a broader more global view of cerebral function. We wish to be able to examine interactions between various neuropharmacological systems and to study effects that one neurotransmitter/receptor system has on another, not just to examine one component at a time without seeing how it fits into the overall workings of the human brain. Our previous work along the same line has shown it possible to measure multiple neuropharmacological parameters from a dual-radiotracer, single-acquisition PET study, but using a protocol that requires determination of the arterial plasma input functions for both radiotracers. This aspect of the experimental protocol is somewhat invasive requiring placement of an arterial catheter and also is both labor intensive and time consuming since metabolite corrected concentration times courses are needed for both tracers. Many protocols for single-injection PET studies have been developed that avoid the need for input function determination. In this project, we seek to develop a method that involves injection of two different PET radiotracers (separated by a short time) in a single dynamic acquisition that does not require arterial blood sampling.
IONIZING RADIATION AND RADIOACTIVE SUBSTANCES
Subjects will have two 5 to 10 minute transmission scan performed for measurement of attenuation factors for the PET scan. Subjects involved in this research project will be injected via venous catheter with [11C]FMZ and [11C]DTBZ. The injection of these radiotracers allows for PET imaging of benzodiazepine receptor binding ([11C]FMZ) and monoamine storage vesicles ([11C]DTBZ).
INVOLVEMENT OF SUBJECTS
Subjects will undergo a medical examination and physical history to rule out underlying abnormalities. Subjects will participate in a two-part PET imaging session of the brain. Subjects may be studied on one or two days, one day to one month apart.
Part One: A radial artery may be catheterized to allow for blood sampling. A vein will be catheterized for injections. Subjects will be positioned in the PET scanner. A transmission scan will be done to calculate attenuation correction factors. A pharmacologic intervention may be administered. This will be the intravenous administration of cold flumazenil. It will be injected as a bolus followed by continuous infusion for the duration of the study. Subjects will be injected with [11C]FMZ. Arterial blood sampling and dynamic PET imaging will begin simultaneously. Twenty or thirty minutes post-injection subjects will be injected with [11C]DTBZ. Imaging and blood sampling will continue for sixty minutes. The order of tracer injection may be switched. The first tracer will be injected as a continuous infusion. The second tracer will be injected as a bolus or fractionated into a bolus and continuous infusion. An arterial input function will be generated and coupled with the PET images to generate quantitative images.
Part Two: An intravenous line is needed for the injection of [11C]FMZ and/or [11C]DTBZ. This line may also be used for the administration of cold flumazenil. A transmission scan will be performed. PET imaging will take 80 to 90 minutes to complete. No blood sampling will occur.
RISKS
Risks consist of low-level radiation exposure, cannulation of the radial artery, cannulation of a cutaneous vein, idiosyncratic/allergic reaction to the study radiopharmaceutical, and idiosyncratic/allergic reaction to pharmacologic intervention.
PRIVACY/CONFIDENTIALITY/CONSENT
A research subject will not be personally identified during presentation or report of the data. PET research data has limited accessibility. Written informed consent will be obtained during a face-to-face visit after the study has been fully explained to the research subject and all questions have been fully answered.