Dr. David
E. Kuhl
Division of Nuclear Medicine
B1 G505 UH
Ann Arbor, MI 48109-0028
Phone: 734-936-5388
Fax: 734-936-8182
E-mail: dkuhl@umich.edu
Number of Human Subjects projects reported: 1
Project Identifier:
UMH-87-DE-FG02-87ER60561
Project Title:
"Advancing PET Science for New Measures of Brain Function"
Principal Investigator: Dr. David E. Kuhl, 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: 2
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Most recent IRB approval: 07/08/99
IRB approval number: 98-299
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 4
Reporting period for number of human subjects:
Fiscal Year 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
OBJECTIVES AND METHODOLOGY
The goal of this project is two-fold: first, to improve the quantitative accuracy of the measurement of presynaptic dopamine terminal density in the striatum, and second, to determine feasibility of quantitative imaging of presynaptic aminergic terminal density in brain regions other than the striatum. Both aims will be accomplished by using two separate isomers of dihydrotetrabenazine (DTBZ): both (+)-a-[11C]DTBZ and (-)-a-[11C]DTBZ. The (+) isomer has been shown to be active, while the (-) isomer is inactive at aminergic binding sites. Dopaminergic, noradrenergic, and serotonergic neurons contain presynaptic vesicles which concentrate and subsequently release transmitter upon stimulation. Drugs which bind to active sites on these vesicles are known, and are useful in the clinical management of hyperkinetic movement disorders. Among these drugs, the best known is reserpine, which potently and noncompetitively inhibits uptake of transmitter into vesicles. An alternative drug used in Europe, tetrabenazine, is not yet approved for use in the US, but has considerably fewer side-effects, and results in a shorter duration of effect. We already have investigated the use of (+/-)-a-[11C]dihydrotetrabenazine for localization of aminergic nerve terminals with PET, which like tetrabenazine, binds to presynaptic terminal sites, but does not produce metabolites which enter the brain. The (+/-) tracer contains equal portions of active and inactive isomers, and thus half the injected radioactive dose has no specificity for the binding site of interest. Since the time of the original study, separation of the two isomers has been achieved, yielding both pure (+) and pure (-) isomers. Further PET studies in humans have been performed with the active isomer, (+)-a-[11C]DTBZ, improving the signal-to-noise of the PET scans. One problem in the analysis of any tracer is that both specific and non-specific binding occurs in vivo, and it is often difficult to determine precisely the specifically bound component (which is what we are interested in) of the total uptake. Binding site density is high in the basal ganglia, and thus in normal subjects the non-specific component is not particularly problematic. However, in diseases such as Parkinson's disease where the binding density is severely reduced, an accurate assessment of the non-specifically bound component becomes more important. The goal 1 of this project addresses this issue. The binding site density in the cortex, thalamus, cerebellum, and brainstem structures is considerably lower, and the majority of uptake is non-specific. If binding in these regions is to be quantified, which is goal 2 of the project, accurate assessment of non-specific binding is essential. This has proven to be difficult using only the active isomer. Both goals can be achieved by using separate injections of the two isomers, (+) having both specific and non-specific uptake and (-) having only non-specific uptake. We will test the feasibility of using (-)-a-[11C]DTBZ in addition to (+)-a-[11C]DTBZ, in paired PET studies, to better quantify presynaptic aminergic terminal density in both striatum and cortex.
RADIOACTIVE SUBSTANCES AND EXPOSURES
Subjects are exposed internally to ionizing radiation in the form of gamma rays. Subjects involved in this research project will be injected via venous catheter with two separate bolus injections of [11C]dihydrotetrabenazine, [11C]DTBZ. The injection of this radiotracer allows for PET imaging of monoamine storage vesicles. For each of the injections of [11C]DTBZ the biological effect of radiation is approximately 0.327 rem, 0.657 cumulatively. The effective dose and risk of this level of exposure is less than that of a single CT exam of the chest. Subjects are exposed externally to ionizing radiation from a 10 - 15 minute transmission scan performed for measurement of attenuation factors for the PET scan. The exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
INVOLVEMENT OF HUMAN SUBJECTS
Subject Selection
Criteria for Inclusion of Subjects:
Normal subjects will be recruited by advertisement as approved by the IRB. Subjects will be free of significant neurologic, psychiatric, or medical illness. Informed consent will be required from subjects prior to all procedures.
Criteria for Exclusion of Subjects:
Individuals under 18 years of age. Pregnant or breast-feeding females. Subjects with undiagnosed neurologic or psychiatric conditions, with concurrent medical illness, or with history of prior significant illness (with lasting influence on brain or other organ function). Subjects concurrently taking prescription or over-the-counter medications. Subjects with recent history of recreational drug use (particularly cocaine use), recent smokers, excessive daily intake of caffeine (>500 mg/day), or with alcohol-dependence.
Experimental Procedures
1). Telephone screening will exclude recruitment of subjects with significant or prior illness or other exclusionary factors.
2). A medical history and a neurologic examination will be performed on all subjects prior to the PET scan to verify this information, and to detect occult abnormalities.
3). Intravenous and radial artery catheters will be inserted to permit injection of the radiopharmaceuticals and withdrawal of plasma samples, respectively.
4). A dose of 16 mCi of one isomer of [11C]dihydrotetrabenazine will be injected intravenously.
5). A series of dynamic PET scans will be initiated with duration increasing from 30 sec to 10 min over a 60 min imaging period.
6). Timed samples of arterial plasma will be collected to determine the concentration curve of tracer.
7). Two hours after the first injection has been administered steps 4 - 6 will be repeated. The other isomer of [11C]dihydrotetrabenazine will be injected for the second PET scan.
8). The PET data will be analyzed using kinetic compartmental modeling to determine the sensitivity of tracer distribution to tissue delivery versus vesicular binding.
RISKS
Low-level radiation exposure
The biologic effects of this level of exposure are judged to be minimal. The effective dose and risk of the level of exposure is less than that from 2 CT exams of the chest. There is no documented biologic effect of radiation exposure at these levels, although statistically undetectable increases in the incidence of certain malignancies cannot be entirely excluded. There are no alternatives to the use of PET for non-invasive delineations of aminergic neurons. The risks are minimized by administering the smallest radiotracer doses acceptable for acquiring the necessary PET data, and by strict adherence to accepted protocols for dispensing and administration of radiopharmaceuticals. There should be no significant effect on fertility potential arising from these studies. Pregnant or breast-feeding females will be excluded from the study.
Cannulation of the radial artery
The likelihood of a complication (ischemic, hemorrhagic, infectious) from short-term percutaneous cannulation of the radial artery is small (substantially less than 1 in 1000). Local anesthesia and sterile technique are utilized to minimize discomfort and the risk of infection. Arterial cannulation is performed by an individual trained and experienced in the technique. The patency of the radial artery and adequacy of local hemostasis are verified by the PET technologists at the conclusion of the imaging session. A physician is immediately available throughout the imaging session for evaluation of potential complications. In the unlikely event of an ischemic complication, medical treatment with the use of either thrombolytic drugs and/or vascular surgery would be initiated. Infectious complications will be managed with the parenteral administration of antibiotics. The medical and surgical management of potential radial artery occlusion are expected to be successful in mitigating major ischemic injury to the hand. There are no alternative procedures to obtain the arterial tracer input functions necessary for quantification of the PET data. We have utilized this procedure for PET imaging protocols for over 10 years without serious complication. Any significant complications arising from the radial cannulation will be noted and reported to the IRB.
Cannulation of a cutaneous vein
The likelihood and severity of a complication (infectious, hemorrhagic) are minimal. Cannulation is performed by experienced personnel with aseptic technique. Infectious complications will be managed by parenteral administration of antibiotics. The subjects are instructed to contact one of the investigators (phone numbers provided on consent form), their personal physician, or the emergency room for evaluation of any potential adverse effect. There is no alternative to intravenous access for the administration of radiotracers for PET imaging.
Idiosyncratic/allergic reaction to the study radiopharmaceutical
The likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered. Subjects are continuously monitored and observed during the PET imaging session by a certified nuclear medicine technologist. A physician is immediately available during all PET imaging sessions and a crash cart is available in the PET imaging suite for emergency use. Allergic reactions will be treated with steroids, antihistamines and epinephrine, all of which are immediately available in the PET imaging suite. In the unlikely event of a severe allergic response, the subject will be hospitalized for observation following initial emergency treatment. There are no alternatives to the use of these radiopharmaceuticals for the PET measurements to be made. These measures are expected to control any allergic reaction encountered. All adverse reactions will be reported to the IRB.
Institutional Review Board (IRB) Review:
Type of Review: Full Board
Most recent IRB approval: 02/18/99
IRB approval number: 99-068
Number of human subjects who participated in this project/protocol/subproject in the last reporting period: 19
Reporting period for number of human subjects:
Fiscal Year 1999 (10/1/98-9/30/99)
Type(s) of Human Subjects Involvement:
OBJECTIVES & METHODOLOGY
The general goal of this research is to develop and test methods to study multiple neuropharmacological parameters simultaneously using quantitative positron emission tomography (PET). Currently, if one is interested in examining two distinct neuropharmacologic measures with PET, one has to perform two separate PET studies typically spaced in time by about 2 hours. An overall duration for such a study requires approximately 4 hours. The specific goal of this research is to evaluate the feasibility of performing dual-tracer PET studies, where two different PET radiotracers, each designed to provide information about a specific neuropharmacological system or parameter, are injected only 10-30 minutes apart. In this approach, only a single "overlapping" PET study is acquired and the duration of the entire study is shortened by 2 hours. Kinetic modeling and data analysis procedures have been developed and implemented, and computer simulations have been performed proving theoretical feasibility of extracting specific information about each radioligand from the single-acquisition dual-tracer PET scan. The preliminary phases of this research project has been completed and now we are at the point of requiring studies in normal human subjects to prove practical feasibility of the method.
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 which 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 working brain in isolation, we would like to validate methods which can 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 examine one component at a time without seeing how this system fits into the overall workings of the human brain. If one has to perform two PET studies to examine two distinct neuropharmacologic measures, several obvious limitations arise: 1) the long study times make it extremely difficult to study certain patient populations; 2) when obtaining neuropharmacologic measures at two distinct points in time separated by ~2 hours, the physiologic/pharmacologic state of the subject may have changed complicating interpretation of the results; 3) if one is interested in how two receptor systems interact, a study involving a pharmacologic challenge would require four PET scans, two separate baseline scans (one for each radioligand) and two challenge scans. Such a protocol currently would require multiple days to perform. With the proposed dual-tracer scanning capability, even this complicated study could be performed in a single half-day session. Until recently, the statistical quality of PET data did not justify these types of studies to be performed, and thus such challenging research protocols were typically not even considered. Approximately five years ago, methodology was first developed to perform 3-dimensional PET scanning which offers a great increase in scan sensitivity. Over the past few years, research in 3-D PET coupled with advances in computer processing power and data storage and handling capabilities have made 3-D PET a reality. 3-D PET scanning is routinely available at our facility, thus making multiple PET scan protocols fully plausible.
IONIZING RADIATION & RADIOACTIVE SUBSTANCES
Subjects will have a 10 - 15 minute transmission scan performed for measurement of attenuation factors for the PET scan. The additional 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 via venous catheter with one bolus injection of [11C]FMZ, and one bolus injection of[11C]DTBZ OR [11C]PMP . The injection of these radiotracers allows for PET imaging of benzodiazepine receptor binding, monoamine storage vesicles and acetylcholinesterase, respectively.
Subjects are exposed to ionizing radiation in the form of gamma rays. The biological effect of the radiation from the injection of [11C]FMZ is approximately 0.345 rem, from [11C]DTBZ approximately 0.548 rem, and 0.470 rem from the [11C]PMP. The cumulative effective dose and risk of this level of exposure is less than that of two CT exams of the chest.
INVOLVEMENT OF HUMAN SUBJECTS
General Procedures
Thirty normal subjects over the age of 18 will be studied. Subjects will be studied at random without regard to gender, ethnicity or race. Women of child bearing potential will be recruited for this study, but pregnant or breast-feeding females will be excluded. Subjects will undergo a brief medical examination and physical history to rule out any underlying abnormalities. Subjects will provide written informed consent prior to enrollment in this project. Subjects will participate for approximately three hours in a PET imaging session of the brain. A radial artery and an antecubital vein will be catheterized to allow for blood sampling and radiopharmaceutical injection, respectively. Subjects will be positioned in the PET scanner where they will undergo a brief transmission scan to calculate attenuation correction factors. The subject will be injected via the intravenous catheter with 15 mCi of [11C]flumazenil ([11C]FMZ). Arterial blood sampling and dynamic PET imaging will begin simultaneously. Fifteen to thirty minutes post-injection the subject will be injected with 15 mCi [11C]dihydrotetrabenazine ([11C]DTBZ) OR 15 mCi [11C]Methylpiperidinyl Propionate ([11C]PMP). Fifteen subjects will be studied with [11C]FMZ and [11C]DTBZ and fifteen subjects will be studied with [11C]FMZ and [11C]PMP. For each group the order of injections will be counter-balanced. Imaging and blood sampling will continue for another sixty minutes. At the completion of the PET imaging, the catheters will be removed and the subject will be asked to void and will be instructed to increase fluid intake and to urinate frequently for the remainder of the afternoon. An arterial input function will be generated from the arterial blood samples and coupled with the dynamic PET images through compartmental modelling to generate quantitative images. The subjects' data will be referenced by hospital registration number. The subject will not be identified personally in any write-ups or presentations of the data.
Risks
Low-level radiation exposure
The biologic effects of this level of exposure are judged to be minimal. The effective dose and risk of the level of exposure is less than that from 2 CT exams of the chest. There is no documented biologic effect of radiation exposure at these levels, although statistically undetectable increases in the incidence of certain malignancies cannot be entirely excluded. There are no alternatives to the use of PET for non-invasive delineations of benzodiazepine receptor binding, monoaminergic neurons or acetylcholinesterase. The risks are minimized by administering the smallest radiotracer doses acceptable for acquiring the necessary PET data, and by strict adherence to accepted protocols for dispensing and administration of radiopharmaceuticals. There should be no significant effect on fertility potential arising from these studies. Pregnant or breast-feeding females will be excluded from the study.
Cannulation of the radial artery
The likelihood of a complication (ischemic, hemorrhagic, infectious) from short-term percutaneous cannulation of the radial artery is small (substantially less than 1 in 1000). Local anesthesia and sterile technique are utilized to minimize discomfort and the risk of infection. Arterial cannulation is performed by an individual trained and experienced in the technique. The patency of the radial artery and adequacy of local hemostasis are verified by the PET technologists at the conclusion of the imaging session. A physician is immediately available throughout the imaging session for evaluation of potential complications. In the unlikely event of an ischemic complication, medical treatment with the use of either thrombolytic drugs and/or vascular surgery would be initiated. Infectious complications will be managed with the parenteral administration of antibiotics. The medical and surgical management of potential radial artery occlusion are expected to be successful in mitigating major ischemic injury to the hand. There are no alternative procedures to obtain the arterial tracer input functions necessary for quantification of the PET data. We have utilized this procedure for PET imaging protocols for over 10 years without serious complication. Any significant complications arising from the radial cannulation will be noted and reported to the IRB.
Cannulation of a cutaneous vein
The likelihood and severity of a complication (infectious, hemorrhagic) are minimal. Cannulation is performed by experienced personnel with aseptic technique. Infectious complications will be managed by parenteral administration of antibiotics. The subjects are instructed to contact one of the investigators (phone numbers provided on consent form), their personal physician, or the emergency room for evaluation of any potential adverse effect. There is no alternative to intravenous access for the administration of radiotracers for PET imaging.
Idiosyncratic/allergic reaction to the study radiopharmaceutical
The likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered. Subjects are continuously monitored and observed during the PET imaging session by a certified nuclear medicine technologist. A physician is immediately available during all PET imaging sessions and a "crash cart" is available in the PET imaging suite for emergency use. Allergic reactions will be treated with steroids, antihistamines and epinephrine, all of which are immediately available in the PET imaging suite. In the unlikely event of a severe allergic response, the subject will be hospitalized for observation following initial emergency treatment. There are no alternatives to the use of these radiopharmaceuticals for the PET measurements to be made. These measures are expected to control any allergic reaction encountered. All adverse reactions will be reported to the IRB.
Privacy/Confidentiality/Consent
A research subject will not be personally identified during presentation or write-up of the data. PET research data has limited accessability.
Written informed consent will be obtained after the procedure has been described to the subject in the Division of Nuclear Medicine by a researcher or technologist associated with the project.