Dr. David E. Kuhl
Division of Nuclear Medicine
B1 G505 UH
Ann Arbor, MI 48109-0028
Phone: 313-936-5388
Fax: 313-936-8182
Email: dkuhl@umich.edu
Projects are approved by an IRB located at: University of Michigan Hospitals.
The approving IRB operates under a Multiple Project Assurance (MPA) recognized by DOE or by the Department of Health and Human Services (HHS).
MPA number of the IRB: M-1184
Number of Human Subjects Projects reported: 3
Project Identifier: UMH-79-NS15655
Project Title:
Positron Emission Tomography (PET) Study of the Biochemistry and Metabolism of the Central Nervous System (CNS)
Principle Investigator:
Dr. David E. Kuhl
Project started in: 1979
Project Funding Information:
Project received funding in Fiscal Year 1995.
Project used human subjects in Fiscal Year 1995.
Funding Sources:
We studied 50 subjects in the fiscal year under this grant and we estimate a cost of $2500 per subject studied.
Total Funding: $320,000
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 6
Protocol/Subproject # 1
Protocol/Subproject Identifier: 90-434
IRB Review:
Type of Review: Full Board
Most Recent Approval: January 13, 1994
IRB Approval Number: 90-434
Number of Human Subjects in the Last Reporting Period for this Project: 3
(Reporting periods vary.)
Type of Human Subjects Involvement:
OBJECTIVES
FMZ (flumazenil) is an antagonist of the benzodiazepine binding site of the CNS GABA (gamma amino butyric acid) receptor -chlorine (CL) channel membrane complex. The drug has no effect on undrugged normal subjects but selectively reverses the depressant effects of benzodiazepines. The agent is specific for benzodiazepines and does not reverse barbiturate-mediated sedations. It has been reported that FMZ also reverses the coma seen in chronic hepatic encephalopathy and this observation has led to the suggestion that in hepatic encephalopathy, an endogenous benzodiazepine like substance is present in the brain. This is supported by binding competition studies using body fluids from human subjects with hepatic encephalopathy, and binding studies and mass spectographic evidence from brains of experimental animals with hepatic failure. Most recently, elevated concentrations of benzodiazepines have been found in the brains of patients with fulminant hepatic failure. The origins of these benzodiazepines is unknown. The most likely sources are dietary and/or gut flora.
A previous PET study of hepatic encephalopathy with 11C-FMZ showed significantly increased uptake in the brain. This was interpreted as indication that FMZ binding sites are increased in the brains of patients with hepatic encephalopathy. However, an alternate explanation is that plasma clearance of FMZ is prolonged in hepatic encephalopathy, and thus the increased brain accumulation of FMZ in this case is due to prolonged tissue exposure to the tracer.
We anticipate decreased 11C-FMZ binding in the brains of patients with hepatic encephalopathy due to competition of the tracer with the endogenous benzodiazepines for binding sites. If abnormalities in FMZ binding are found, then those patients who later undergo liver transplantation will be restudied at a time post transplantation when their clinical status is stable (approximately 6 months). This is to determine the reversibility of the changes in FMZ binding when normal hepatic function is restored. Plasma benzodiazepine ligand levels will be measured in collaboration with Dr. Basile of the National Institutes of Health.
METHODOLOGY
1. Subjects will be studied lying supine, immobile, in a basal state with eyes
and ears open.
2. A catheter will be placed in a radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
3. An intravenous catheter will be inserted into an arm for the administration
of radiopharmaceuticals.
4. A bolus of [11C]flumazenil, containing up to 50 mCi and 27 µg, will be
administered intravenously.
5. Brain activity will be measured with a series of sequential emission scans
taken over 60 minutes.
6. Arterial blood samples (total of less than 30 ml) will be withdrawn to
determine tracer time-activity curve.
7. The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of flumazenil, will be
analyzed to determine the transport and binding of the tracer.
8. This procedure will be repeated after surgical intervention or liver
transplant.
RADIOACTIVE SUBSTANCES
Subjects will be injected intravenously with up to 50 mCi of [11C] flumazenil, a radiolabeled antagonist of the benzodiazepine binding site of the CNS GABA receptor -CL channel membrane complex.
INVOLVEMENT OF HUMAN SUBJECTS
Subjects will undergo PET imaging, as described above, at baseline and after intervention. Medical records will be used for collection of ancillary information. No other procedures will be performed exclusively for the purpose of this research.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered, the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
IRB Review:
Type of Review: Full Board
Most Recent Approval: December 01, 1994
IRB Approval Number: 91-418
Number of Human Subjects in the Last Reporting Period for this Project: 28
(Reporting periods vary.)
Type of Human Subjects Involvement:
OBJECTIVES
Gamma-amino-butyric acid (GABA) is the most prevalent inhibitory chemical transmitter in the mammalian brain. The neuronal receptors for GABA have been purified and studied at the molecular level, where benzodiazepines have been shown to augment GABA responses. The benzodiazepines act at a recognition site ("receptor") which allosterically modifies the binding of GABA to its receptor. Postmortem radioligand binding studies have demonstrated alterations in benzodiazepine receptors in a number of diseases. In addition, benzodiazepines are used in the therapy of several neurologic and psychiatric disorders. Preliminary studies on the in vivo distribution of the benzodiazepine radioligand [11C]flumazenil in young normal volunteers indicate that its regional brain distribution volume, as determined with positron emission tomography, bears close correspondence to the regional distribution of receptors found in postmortem in vitro studies. In the present proposal, we will explore the ability of tracer kinetic modeling to detect patterns of [11C]flumazenil delivery and receptor binding in normal subjects and in patients with neurologic or psychiatric diseases.
METHODOLOGY, RADIOACTIVE SUBSTANCES AND HUMAN INVOLVEMENT
A. Clinical Evaluation
Clinical diagnosis will be established by a physician (usually a neurologist or psychiatrist) experienced in the evaluation of patients with the disorder under investigation. A clinical diagnosis will be established for all subjects prior to the investigational procedures.
B. PET Imaging Procedures
PET imaging with [11C]flumazenil may be combined with determination of cerebral blood flow (CBF) or cerebral glucose metabolism (CMRglu) for ancillary physiologic characterization of cerebral function. In addition, the administration of flumazenil may consist of one or two injections, either during the same imaging session or separated by a longer interval (i.e., a second imaging session at a later time). One of three imaging options will be employed: A) [11C]Flumazenil alone; B) [11C]Flumazenil in combination with [15O]H2O; or C). [11C]Flumazenil in combination with [18F]fluorodeoxyglucose. The protocols below indicate the relationships of the ancillary scans to the flumazenil imaging session(s) and the dosimetry and maximal dosages of the radiopharmaceuticals are given separately for each option.
Option A (Flumazenil alone)
1) Subjects will be studied lying supine, immobile, in a basal state with eyes
and ears unoccluded, or during controlled auditory, visual, or somatosensory
stimulation.
2) A catheter will be placed in a radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
3) An intravenous catheter will be inserted in an arm for the administration of
radiopharmaceuticals.
4) A bolus of [11C]flumazenil, containing up to 50 mCi and 27 µg, will be
administered intravenously. In some instances, the dose may be fractionated
between a bolus and a subsequent infusion, the total of which will not excede
the above limits.
5) Brain activity will be determined with a series of sequential emission scans
over 60 to 90 min.
6) Arterial blood samples (total of 40 ml or less) will be withdrawn to
determine the tracer time-activity curve.
7) The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of flumazenil, will be
analyzed to determine the transport and binding of the tracer.
8) The injection of flumazenil may be repeated during the same session after
decay of the first dose (90-120 min later), or on a subsequent day, following
interval change in therapy or in physiologic/pharmacologic state. The total
cumulative radioisotopic dose of [11C]flumazenil administered in these sessions
will be less than 50 mCi.
Option B (Flumazenil in combination with CBF)
1) Subjects will be studied lying supine, immobile, in a basal state with eyes
and ears unoccluded, or during controlled auditory, visual, or somatosensory
stimulation.
2) A catheter will be placed in a radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
3) An intravenous catheter will be inserted in an arm for the administration of
radiopharmaceuticals.
4) A bolus of [15O]H2O, containing up to 100 mCi, will be injected
intravenously and arterial blood samples (less than 20 ml total) and sequential
emission brain scans will be obtained over the following 6 min to determine
CBF.
5) A bolus of [11C]flumazenil, containing up to 40 mCi and 27 µg, will be
administered intravenously. In some instances, the dose may be fractionated
between a bolus and a subsequent infusion, the total of which will not excede
the above limits.
6) Brain activity will be determined with a series of sequential emission scans
over 60 to 90 min.
7) Arterial blood samples (total of 40 ml or less) will be withdrawn to
determine the tracer time-activity curve.
8) The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of flumazenil, will be
analyzed to determine the transport and binding of the tracer. Comparison with
CBF will allow estimation of the relative contributions of blood-brain-barrier
permeability versus blood flow to overall flumazenil transport, and will permit
correlation of transport changes (between groups or between physiologic states
in the same individual) with CBF changes.
9) The injections of [11C]flumazenil and [15O]H2O may be repeated during the
same session after decay of the first dose (90-120 min later), or on a
subsequent day, following interval change in therapy or in
physiologic/pharmacologic state. The radiotracer amounts administered in these
sessions will be subject to the cumulative total radioisotopic limits of 40 mCi
of [11C]flumazenil and 200 mCi of [15O]H2O.
Option C (Flumazenil in combination with CMRglu)
1) Subjects will be studied lying supine, immobile, in a basal state with eyes
and ears unoccluded, or during controlled auditory, visual, or somatosensory
stimulation.
2) A catheter will be placed in a radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
3) An intravenous catheter will be inserted in an arm for the administration of
radiopharmaceuticals.
4) A bolus of [11C]flumazenil, containing up to 25 mCi and 27 µg, will be
administered intravenously. In some instances, the dose may be fractionated
between a bolus and a subsequent infusion, the total of which will not excede
the above limits.
5) Brain activity will be determined with a series of sequential emission scans
over 60 to 90 min.
6) Arterial blood samples (total of 40 ml or less) will be withdrawn to
determine the tracer time-activity curve.
7) The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of flumazenil, will be
analyzed to determine the transport and binding of the tracer.
8) Following decay of the flumazenil (60 to 90 min post-injection), a bolus of
[18F]fluorodeoxyglucose containing up to 10 mCi will be administered
intravenously. Arterial blood samples (less than 30 ml total) will be collected
for calculation of CMRglu. The cerebral distribution of tracer will be
determined by emission scanning beginning 30 min post injection for a total of
two sequential 20-30 min periods.
C. Ancillary Measurements
1) Structural/anatomic brain imaging will be performed in some instances with
the use of magnetic resonance (MRI). Standard T1 and T2 weighted images are
obtained in orientation to match the PET scan data. The imaging session is
usually less than 1 hr in duration.
2) Neuropsychological testing will be performed in some subjects to establish
the presence of disease- or drug-related changes in function. In addition,
elderly normal subjects may undergo screening neuropsychological testing to
exclude subtle memory abnormalities which may go undetected on routine
neurologic examination.
3) Electroencephalography (EEG) will be performed in association with
flumazenil imaging in some instances. This will allow correlation of the
binding with the presence or absence of epileptogenic or seizure activity in
patients with epilepsy, or with the effects of drugs on the EEG in cases of pre-
and post-therapeutic studies. Aside from the time required for electrode
placement (usually less than 30 min), the imaging session will not be altered by
EEG recording.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
IRB Review:
Type of Review: Full Board
Most Recent Approval: June 15, 1995
IRB Approval Number: 92-350
Number of Human Subjects in the Last Reporting Period for this Project: 5
(Reporting periods vary.)
Type of Human Subjects Involvement:
OBJECTIVES
Previous research has shown that a decrease in benzodiazepine receptor binding occurs in the hippocampi of refractory temporal lobe epilepsy patients. It has been proposed that this is a selective process affecting the GABA neuronal population only. However, the pathology of specimens from resected temporal lobes in medically refractory epilepsy patients has demonstrated mesial temporal sclerosis. The co-localization of benzodiazepine receptors and muscarinic cholinergic receptors on intrinsic neurons in the hippocampus has previously been determined. [11C]Flumazenil(FMZ) and [11C]N-methyl piperidyl benzilate(NMPB) are radiopharmaceuticals which are antagonists of benzodiazepine receptors and muscarinic cholinergic receptors, respectively. Our hypothesis is that the neurons of the hippocampal region undergo nonselective destruction, and that by utilizing [11C]FMZ and [11C]NMPB we will observe similar decreases in binding of each agent.
METHODOLOGY, RADIOACTIVE SUBSTANCES AND HUMAN INVOLVEMENT
A. Clinical Evaluation
Clinical diagnosis will be established by a neurologist experienced in the evaluation of patients with epilepsy. A clinical diagnosis of medically refractory partial epilepsy will be established for all subjects prior to the investigational procedures.
B. PET Imaging Procedures
PET imaging with [11C]FMZ will be combined with [11C]NMPB. The patient will receive one injection of the [11C]FMZ followed by a complete series of PET images. The patient will then receive an injection of [11C]NMPB followed by a second series of PET images.
FMZ in Combination with NMPB Protocol
1. Subjects will have electroencephalogram (EEG) scalp electrodes placed either
immediately prior to the PET imaging or within the previous 12-24 hours to
monitor for seizures.
2. Subjects will be studied lying supine, immobile in a basal state with eyes
and ears unoccluded or during controlled auditory, visual or somatosensory
stimulation.
3. A catheter will be placed in the radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
4. An intravenous catheter will be placed in the contralateral arm for the
administration of radiopharmaceuticals.
5. A bolus of [11C]FMZ, containing up to 25 mCi and 27 µg, will be administered
intravenously.
6. Brain activity will be determined with a series of sequential emission scans
over 60 to 90 min.
7. Arterial blood samples (total of 40 ml or less) will be withdrawn to
determine the tracer time-activity curve.
8. The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of FMZ, will be
analyzed to determine the transport and binding of the tracer.
9. The injection of FMZ will be followed by an injection of [11C]NMPB after
decay of the [11C]FMZ (90-120 min later).
10. A bolus of [11C]NMPB containing up to 40mCi and less than 15 µg will be
administered intravenously.
11.Brain activity will be monitored with sequential PET scans of increasing
duration from 30 seconds initially to a maximum of 20 min per scan. Greater
than 1,000,000 counts per frame of data will be obtained. The collection of
data will terminate 110 min after injection.
12.Arterial blood samples will be collected following the injection of
[11C]NMPB for determination of the arterial input curve. A total of 40 ml or
less of blood will be collected. Samples will be collected at 10 second
intervals for 2 minutes, then at 1 minute intervals for 10 minutes, and finally
at 12, 15, 20, 30, 45, 60, 90 and 110 minutes following injection. The arterial
concentration of [11C]NMPB will be determined by chromatographic analysis of the
blood samples.
13.The PET data will be analyzed according to a compartmental model derived and
validated in our laboratory.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 14, 1994
IRB Approval Number: 94-244
Number of Human Subjects in the Last Reporting Period for this Project: 8
(Reporting periods vary.)
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
The goal of this project is to investigate the feasibility of delineating terminals of aminergic neurons in the brain on the basis of specific binding sites located on presynaptic vesicles. 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 shorter duration of effect. We have investigated the use of [11C]tetrabenazine for localization of aminergic nerve terminals in vivo by positron emission tomography, but quantitation of the distribution of that radioligand is limited by the in vivo production of radiolabeled metabolites. The goal of the present project is to determine feasibility of quantitative imaging of presynaptic dopamine terminals in the striatum using [11C]dihydrotetrabenazine, a radioligand designed not to have radiolabeled metabolites in vivo. Our preclinical animal studies indicate that dihydrotetrabenazine should be an improved radioligand for determination of dopamine terminals.
METHODOLOGY, RADIOACTIVE SUBSTANCES AND HUMAN INVOLVEMENT
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
normal controls 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 radiopharmaceutical and withdrawal of plasma samples, respectively.
4) A dose of 18 mCi of [11C]dihydrotetrabenazine, containing less than 50 µg
will be injected intravenously.
5) A series of dynamic PET scans will be initiated with duration increasing from
30 seconds to 10 minutes over a one hour imaging period.
6) Timed samples of arterial plasma will be collected to determine the
concentration curve of tracer.
7) The PET data will be analyzed first qualitatively to determine the relative
uptake in striatum versus other brain areas with much lower levels of
presynaptic aminergic nerve terminals. If the data permit, preliminary kinetic
compartmental modeling will be applied to determine the sensitivity of tracer
distribution to tissue delivery versus vesicular binding.
8) In some instances, a repeat study (steps 4 through 7) may be performed within
60 min of the first to investigate the precision of the scanning procedure. In
this instance, the total cumulative dose of [11C]dihydrotetrabenazine will not
exceed 18 mCi.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
IRB Review:
Type of Review: Full Board
Most Recent Approval: April 20, 1995
IRB Approval Number: 94-283
Number of Human Subjects in the Last Reporting Period for this Project: 2
(Reporting periods vary.)
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
Postmortem analyses of human neurodegenerative disorders including Parkinson's disease (PD) have revealed decreases in neurochemical markers of dopaminergic neurons. These observations are interpreted as reflecting specific losses of synaptic terminals arising from chemically-defined monoaminergic brain stem neurons. In the present project, we will investigate the relationship between striatal monoaminergic innervation and PD with the use of positron emission tomography (PET). The relationship between disease severity and loss of dopaminergic indices will be evaluated, as will the controversial relationship between PD and isolated (essential) tremor (ET) in elderly patients. Finally, we will evaluate the longitudinal loss of striatal dopaminergic innervation in PD, and assess the possible beneficial effects of monoamine oxidase inhibitor therapy.
Specific aim 1: To determine the loss of striatal monoaminergic vesicle content in patients with early PD in comparison with elderly normal subjects and patients with ET. Subjects will be studied with [11C]dihydrotetrabenazine (DTBZ) and with [11C]flumazenil (FMZ), to quantify monoaminergic vesicle and benzodiazepine binding sites, respectively. There is current disagreement as to the relationship between ET and PD, particularly with regard to the risk of developing PD in patients with isolated postural tremor. We have determined an age-associated increase in the cerebellar benzodiazepine binding in elderly normals studied with FMZ, and hypothesize that ET may constitute an exaggeration of this process, on the basis of functional studies implicating the cerebellum in its generation.
Specific aim 2: To determine the relationship between the loss of striatal monoaminergic vesicle content and the severity of PD. Patients with advanced stages of PD will be studied with DTBZ and analyzed in comparison to early stage PD patients. Based on the prevailing hypotheses, it is anticipate that early PD will be associated with over 50 to 75% depletion of striatal dopamine terminals. Advanced PD is anticipated to result from further loss of DTBZ binding, reflecting even greater depletion of terminals. As observed in postmortem and prior PET imaging studies, we anticipate a progression of dopamine terminal loss with earliest and most severe involvement of the posterior putamen, and least severe involvement of the anteroventral striatum.
Specific aim 3: To determine the loss of striatal monoaminergic vesicles over time in subjects with early PD. Subjects with early PD will be followed longitudinally over three years, to determine the relationship between disease severity and dopamine terminal integrity within individuals. A parallel group of normal subjects will be studied longitudinally to determine whether the rate of progressive loss of presynaptic dopamine terminals is accelerated in PD.
Specific aim 4: To examine striatal muscarinic cholinergic receptors in PD patients with complicated L-dopa responses as a marker of intrinsic reorganization. Although the primary pathology in PD affects extrastriatal catecholaminergic neurons, there is data supporting intrinsic striatal changes in PD, which may ultimately limit the efficacy of symptomatic therapy. We will examine the binding of [11C]NMPB to striatal muscarinic receptors in PD patients with uncomplicated L-dopa responsiveness in comparison to patients with complicated L-dopa responses as an indicator of intrinsic striatal organization.
METHODOLOGY, RADIOACTIVE SUBSTANCES AND HUMAN INVOLVEMENT
1) EXPERIMENT 1: Longitudinal Evaluation Of Monoaminergic Terminals
Twenty normal control subjects and 40 subjects with PD will participate in this study. Subjects will have had a neurologic/physical examination prior to enrollment in this project.
Scan Session #1: [11C]DTBZ + [11C]FMZ
Subjects will be studied lying supine, immobile in a basal state with eyes and ears unoccluded. A catheter will be placed in the radial artery for the withdrawal of blood samples to permit quantification of the PET data. An intravenous catheter will be placed in the contralateral arm for the administration of radiopharmaceuticals. [11C]DTBZ, containing up to 10 mCi and less than 50 µg, will be administered intravenously. Brain activity will be determined with a series of sequential emission scans lasting from 30 to 60 minutes after injection. Arterial blood samples (total of 40 ml or less) will be withdrawn to determine the tracer time-activity curve. The PET images, together with the arterial blood curve and a physiologic compartmental model describing the cerebral distribution of DTBZ, will be analyzed to determine the transport and binding of the tracer. After allowing for the clearance and decay of [11C]DTBZ, a dose of [11C]FMZ containing up to 24 mCi and less than 27 µg will be administered intravenously. Brain activity will be monitored with sequential PET scans of increasing duration. The collection of data will terminate 60 minutes after injection. Arterial blood samples will be collected following the injection of [11C]FMZ for determination of the arterial input curve. A total of 40 ml or less of blood will be collected. The PET data will be analyzed according to a compartmental model derived and validated in our laboratory. The catheters will be removed and the subject will be released.
Scan Session #2: [11C]DTBZ + [11C]NMPB
After an interval of two years the subjects will return for the second session. The neurologic/physical examination will be repeated. Subjects will be studied lying supine, immobile in a basal state with eyes and ears unoccluded. A catheter will be placed in the radial artery for the withdrawal of blood samples to permit quantification of the PET data. An intravenous catheter will be placed in the contralateral arm for the administration of radiopharmaceuticals. [11C]DTBZ, containing up to 10 mCi and less than 50 µg, will be administered intravenously. Brain activity will be determined with a series of sequential emission scans lasting from 30 to 60 minutes after injection. Arterial blood samples (total of 40 ml or less) will be withdrawn to determine the tracer time-activity curve. The PET images, together with the arterial blood curve and a physiologic compartmental model describing the cerebral distribution of DTBZ, will be analyzed to determine the transport and binding of the tracer. After allowing for the clearance and decay of [11C]DTBZ, a dose of [11C]NMPB containing up to 25 mCi and less than 15 µg will be administered intravenously. Brain activity will be monitored with sequential PET scans of increasing duration. The collection of data will terminate 60 min after injection. Arterial blood samples will be collected following the injection of [11C]NMPB for determination of the arterial input curve. A total of 40 ml or less of blood will be collected. The PET data will be analyzed according to a compartmental model derived and validated in our laboratory. The catheters will be removed and the subject will be released.
EXPERIMENT 2: Benzodiazepine Receptors and Monoaminergic Terminals in Essential Tremor
Twenty subjects with ET will participate in this study. Subjects will have had a neurologic/physical examination prior to enrollment in this project. Subjects will be studied lying supine, immobile in a basal state with eyes and ears unoccluded. A catheter will be placed in the radial artery for the withdrawal of blood samples to permit quantification of the PET data. An intravenous catheter will be placed in the contralateral arm for the administration of radiopharmaceuticals. [11C]DTBZ, containing up to 10 mCi and less than 50 µg, will be administered intravenously. Brain activity will be determined with a series of sequential emission scans lasting from 30 to 60 minutes after injection. Arterial blood samples (total of 40 ml or less) will be withdrawn to determine the tracer time-activity curve. The PET images, together with the arterial blood curve and a physiologic compartmental model describing the cerebral distribution of DTBZ, will be analyzed to determine the transport and binding of the tracer. After allowing for the clearance and decay of [11C]DTBZ, a dose of [11C]FMZ containing up to 24 mCi and less than 27 µg will be administered intravenously. Brain activity will be monitored with sequential PET scans of increasing duration. The collection of data will terminate 60 min after injection. Arterial blood samples will be collected following the injection of [11C]FMZ for determination of the arterial input curve. A total of 40 ml or less of blood will be collected. The PET data will be analyzed according to a compartmental model derived and validated in our laboratory. The catheters will be removed and the subject will be released.
EXPERIMENT 3: Monoaminergic Terminals and Muscarinic Receptors in Advanced PD
Forty subjects with PD will participate in this study. Subjects will have had a neurologic/physical examination prior to enrollment in this project. Subjects will be studied lying supine, immobile in a basal state with eyes and ears unoccluded. A catheter will be placed in the radial artery for the withdrawal of blood samples to permit quantification of the PET data. An intravenous catheter will be placed in the contralateral arm for the administration of radiopharmaceuticals. [11C]DTBZ, containing up to 10 mCi and less than 50 µg, will be administered intravenously. Brain activity will be determined with a series of sequential emission scans lasting from 30 to 60 minutes after injection. Arterial blood samples (total of 40 ml or less) will be withdrawn to determine the tracer time-activity curve. The PET images, together with the arterial blood curve and a physiologic compartmental model describing the cerebral distribution of DTBZ, will be analyzed to determine the transport and binding of the tracer. After allowing for the clearance and decay of [11C]DTBZ, a dose of [11C]NMPB containing up to 25 mCi and less than 15 µg will be administered intravenously. Brain activity will be monitored with sequential PET scans of increasing duration. The collection of data will terminate 60 min after injection. Arterial blood samples will be collected following the injection of [11C]NMPB for determination of the arterial input curve. A total of 40 ml or less of blood will be collected. The PET data will be analyzed according to a compartmental model derived and validated in our laboratory. The catheters will be removed and the subject will be released.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 27, 1995
IRB Approval Number: 94-440
Number of Human Subjects in the Last Reporting Period for this Project: 4
(Reporting periods vary.)
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
The pathophysiology of hyperkinetic movement disorders is incompletely understood. This lack of knowledge is an obstacle to the development of better symptomatic therapies. We will explore the pathophysiology of hyperkinetic movement disorders using positron emission tomography (PET) with ligands aimed at striatal muscarinic cholinergic receptors and striatal dopamine terminals. We hypothesize that dystonias are characterized by excessive cholinergic neurotransmission and down-regulation of striatal cholinergic receptors. We predict decreased muscarinic cholinergic receptor binding and will test this hypothesis using [11C]NMPB. In Tourette's syndrome, we hypothesize that there is excessive striatal dopaminergic innervation and excessive striatal cholinergic neurotransmission. We predict increased density of striatal dopaminergic terminals and decreased striatal cholinergic receptor binding. We will test these predictions with [11C]DTBZ and [11C]NMPB. We hypothesize that the degree of dopaminergic innervation is an important determinant of the type of movement disorder suffered by Huntington's disease (HD) patients with marked rigidity resulting from degeneration of dopaminergic neurons. We will test this hypothesis by correlating character of the movement disorder with the results of the [11C]DTBZ scans. We predict significantly diminished [11C]DTBZ binding in rigid but not in choreic HD patients. We will examine striatal muscarinic cholinergic receptors in Parkinson's disease (PD) patients with complicated L-dopa responses as a marker of intrinsic striatal reorganization. Although the primary pathology in PD affects extrastriatal catecholaminergic neurons, there is data supporting intrinsic striatal changes in PD, which may ultimately limit the efficacy of symptomatic therapy.
METHODOLOGY, RADIOACTIVE SUBSTANCES AND SUBJECT INVOLVEMENT
PET imaging will be performed with [11C]DTBZ, [11C]NMPB, or [11C]DTBZ and [11C] NMPB.
[11C]DTBZ alone
1. Subjects will have had a neurologic/physical examination prior to enrollment
in this project.
2. Subjects will be studied lying supine, immobile in a basal state with eyes
and ears unoccluded.
3. A catheter will be placed in the radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
4. An intravenous catheter will be placed in the contralateral arm for the
administration of radiopharmaceuticals.
5. A dose of [11C]DTBZ, containing 18 mCi and less than 50 µg, will be
administered intravenously during the PET imaging session.
6. Brain activity will be determined with a series of sequential emission scans
lasting from 30 to 60 minutes after injection.
7. Arterial blood samples (total of 40 ml or less) will be withdrawn to
determine the tracer time-activity curve.
8. The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of DTBZ, will be
analyzed to determine the transport and binding of the tracer.
[11C]NMPB alone
1. Subjects will have had a neurologic/physical examination prior to enrollment
in this project.
2. Subjects will be studied lying supine, immobile, in a basal state with eyes
and ears unoccluded.
3 A catheter will be placed in the radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
4. An intravenous catheter will be placed in the contralateral arm for the
administration of radiopharmaceuticals.
5. A dose of [11C]NMPB containing 40 mCi and less than 15 µg will be
administered intravenously.
6. Brain activity will be monitored with sequential PET scans of increasing
duration from 30 seconds initially to a maximum of 10 min per scan. The
collection of data will terminate 110 min after injection.
7. Arterial blood samples will be collected following the injection of [11C]NMPB
for determination of the arterial input curve. A total of 40 ml or less of
blood will be collected. The arterial concentration of [11C]NMPB will be
determined by chromatographic analysis of the blood samples.
8. The PET data will be analyzed according to a compartmental model derived and
validated in our laboratory.
[11C]DTBZ and [11C]NMPB
1. Subjects will have had a neurologic/physical examination prior to enrollment
in this project.
2. Subjects will be studied lying supine, immobile, in a basal state with eyes
and ears unoccluded.
3. A catheter will be placed in the radial artery for the withdrawal of blood
samples to permit quantification of the PET data.
4. An intravenous catheter will be placed in the contralateral arm for the
administration of radiopharmaceuticals.
5. [11C]DTBZ, containing 10 mCi and less than 50 µg, will be administered
intravenously during the PET imaging session.
6. Brain activity will be determined with a series of sequential emission scans
lasting from 30 to 60 minutes after injection.
7. Arterial blood samples (total of 40 ml or less) will be withdrawn to
determine the tracer time-activity curve.
8. The PET images, together with the arterial blood curve and a physiologic
compartmental model describing the cerebral distribution of DTBZ, will be
analyzed to determine the transport and binding of the tracer.
9. After allowing for the clearance and decay of [11C]DTBZ, a dose of [11C]NMPB
containing up to 25 mCi and less than 15 µg will be administered
intravenously.
10. Brain activity will be monitored with sequential PET scans of increasing
duration from 30 seconds initially to a maximum of 10 min per scan. Greater
than 1,000,000 counts per frame of data will be obtained. The collection of
data will terminate 110 minutes after injection.
11. Arterial blood samples will be collected following the injection of
[11C]NMPB for determination of the arterial input curve. A total of 40 ml or
less of blood will be collected. The arterial concentration of [11C]NMPB will
be determined by chromatographic analysis of the blood samples.
12. The PET data will be analyzed according to a compartmental model derived and
validated in our laboratory.
Structural/anatomic brain imaging will be performed in some instances with the use of magnetic resonance (MRI). Standard T1 and T2 weighted images are obtained in orientation to match the PET scan data. The imaging session is usually less than 1 hr in duration.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
Project Identifier: UMH-86-NS24896
Project Title:
Emission Computed Tomography of Local Cerebral Function
Principle Investigator:
Dr. David E. Kuhl
Project started in: 1986
Project Funding Information:
Project received funding in Fiscal Year 1995.
Project used human subjects in Fiscal Year 1995.
Funding Sources:
We studied 22 subjects under this grant for the fiscal year and we estimate a cost of $2200 per subject studied.
Total Funding: $134,400
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2
Protocol/Subproject # 1
Protocol/Subproject Identifier: 88-395
IRB Review:
Type of Review: Full Board
Most Recent Approval: March 23, 1995
IRB Approval Number: 88-395
Number of Human Subjects in the Last Reporting Period for this Project: 5
(Reporting periods vary.)
Type of Human Subjects Involvement:
OBJECTIVES
Studies measuring cerebral glucose metabolic rate and cerebral blood flow will be performed on elderly normal controls and on patients in various stages of cognitive impairment. Initially, patients studied in this project were required to show a cognitive decline during the 6 months prior to study in order to be entered into the project. Groups will include patients diagnosed with possible Alzheimer's disease (poss. AD), probable Alzheimer's disease (prob. AD), and isolated memory impairment (IMI). More recently, additional patient groups including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and normal pressure hydrocephalus (NPH). The primary objectives of the project include determining whether there is an early pattern of glucose metabolism in patients suspected of having early Alzheimer's disease that will be useful in predicting whether or not they will eventually go on to develop Alzheimer's disease. Another objective is to compare the dementia in Alzheimer's disease with that of Parkinson's patients that develop dementia.
METHODOLOGY
Subjects will be studied lying supine, immobile in a basal state with their eyes open, ears unoccluded, in a quiet room. A radial artery catheter will be inserted for the purpose of withdrawing arterial blood samples at specified times throughout the scan in order to measure the concentration of injected tracer in the arterial plasma. A venous line will also be inserted for administration of [18F]fluorodeoxyglucose (FDG) and/or [Oxygen-15] H2O. A few blood samples will be used to determine arterial plasma levels of (cold) glucose, Oxygen pressure (pO2), carbon dioxide pressure (pCO2), and hydrogen pressure (pH). Blood hematocrit will also be measured.
For cerebral blood flow scans, a bolus of 50-80 mCi of [15O]H2O will be administered intravenously. Brain activity will be measured with the PET scanner as a dynamic sequence of scans of 6 minutes duration. Arterial blood sampling, removing less than 15ml of blood will be performed to determine the arterial input function of [15O]H2O. The PET scan and arterial input function data will be analyzed by a tracer kinetic model to produce functional or parametric images of both cerebral blood flow (given as ml of blood per gram of tissue per minute) and brain water partition coefficient (given as ml of blood per gram of tissue) using methods developed in our laboratories.
For cerebral glucose metabolic rate scans, a bolus of 10 mCi of [18F]FDG will be administered intravenously. A 30 minute incorporation period occurs following injection prior to the initiation of PET scanning. Brain activity will be measured as a static set of images beginning at the 30 minute time point and continuing for the next 30-50 minutes. Arterial blood sampling, removing approximately 30-40 ml of blood will be performed throughout the study, in order to determine the arterial input function of [18F]FDG. The PET scan and arterial input function data will be analyzed by a mathematical approximation for a kinetic model, yielding functional or parametric images of the metabolic rate of glucose (given as mg of glucose per gram of tissue per minute).
RADIOACTIVE SUBSTANCES
Subjects will receive as many as two injections of [15O]H2O, with up to 80 mCi per injection, and one injection of 10 mCi of [18F]FDG.
INVOLVEMENT OF SUBJECTS
Subjects (both normal and patient) will have a medical and neurologic examination performed by a trained neurologist to rule out any occult abnormalities. This will take approximately 30-60 minutes. The PET imaging procedure may take up to three hours. MRI and/or computed tomography (CT) scanning will have already been performed as part of the patient's routine care and diagnosis and will not be performed exclusively for the purposes of this research project.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
IRB Review:
Type of Review: Full Board
Most Recent Approval: September 28, 1995
IRB Approval Number: 92-201
Number of Human Subjects in the Last Reporting Period for this Project: 17
(Reporting periods vary.)
Type of Human Subjects Involvement:
OBJECTIVES
[123I]IBVM (iodobenzovesamicol) is a newly developed radiotracer that was designed to bind selectively to the intraneuronal storage vesicles of cholinergic nerve endings. Preclinical studies in small animals have confirmed that [123I]IBVM does indeed serve as a highly specific marker for cerebral cholinergic neurons(1). Chromatographic analysis of brain radioactivity revealed only parent tracer (2). The marked accumulation and prolonged retention of [123I]IBVM in cholinergic neuron rich regions of the brain, such as the striatum and cerebral cortex, give expectations that high quality tomographic images should result when SPECT (single photon emission computed tomography) is applied for study of the human brain. This radiotracer is expected to define the density of presynaptic cholinergic neurons not only in the brain, but also in the heart and stomach, permitting scintigraphic assessments of these organs in living patients. In each instance, the kinetic behavior of the tracer will be established using mathematical models to derive quantitative indices of cholinergic nerve densities in various anatomic zones.
METHODOLOGY, RADIOACTIVE SUBSTANCES AND HUMAN INVOLVEMENT
1. A physical, neurologic and/or neuropsychometric exam will be performed prior
to the study to assure patient/subject eligibility.
2. Blood, urine and/or fecal samples may be obtained to confirm dosimetry data
and human biodistribution of IBVM.
3. Prior to the injection of [123I]IBVM subjects will be given super saturated
potassium iodide (SSKI) orally to block absorption of radioactivity in the
thyroid gland.
4. A radial artery and/or peripheral vein will be catheterized.
5. 10 mCi of [123I]IBVM will be injected by vein.
6. Continuous imaging will be started immediately after injection and will
continue for one hour.
7. Arterial blood samples may be withdrawn during the imaging session to
determine a tracer time-activity curve.
8. The images and the arterial input function will be analyzed to determine
transport and tracer binding.
9. Additional discrete imaging sessions of approximately two hours each will
take place at 2, 6 and 24 hours post injection.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Potential idiosyncratic reaction to administered radiopharmaceuticals. At
the levels administered the risk of reaction is judged to be minimal. A "crash
cart" is readily available in the PET imaging area as are qualified persons
trained to handle such emergencies.
4. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.
Project Identifier: UMH-93-N149310462
Project Title:
Working Memory as Revealed by Positron Emission Tomography (PET)
Principle Investigator:
Dr. John Jonides
Project started in: 1993
Project Funding Information:
Project received funding in Fiscal Year 1995.
Project used human subjects in Fiscal Year 1995.
Funding Sources:
We studied 51 subjects under this grant during the fiscal year and we estimate a cost of $1750 per subject studied.
Total Funding: $287,750
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 1
Protocol/Subproject # 1
Protocol/Subproject Identifier: 89-457
IRB Review:
Type of Review: Full Board
Most Recent Approval: June 01, 1995
IRB Approval Number: 89-457
Number of Human Subjects in the Last Reporting Period for this Project: 51
(Reporting periods vary.)
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
Using measurements of cerebral blood flow with [Oxygen-15]H2O during both "activation" and "control" conditions we will determine cerebral blood flow (CBF) changes attributable to the "activation" condition. Regions of the brain that exhibit changes are then assumed to be associated with the particular brain function required to perform the "activation" task. The purpose of using normal subjects is 1) to validate that the "activation" and "control" conditions are appropriate tasks for probing a particular aspect of brain function and 2) some of the project's aims are to study the normal (not diseased) human brain.
The purpose of using these subjects is not to determine the pattern of uptake and distribution of [O-15]H2O in normal controls. Every newly proposed pair of "activation" and "control" tasks has the purpose of studying a particular aspect of brain function (such as cognition, memory, speech and language formulation, visual/spatial processing) and requires a new set of control data.
The specific aim of this project is to study the mechanisms of memory in the normal functioning human brain. Five groups of normal subjects will be studied. These groups will attempt to 1) determine brain regions involved in simple spatial working memory, 2) differentiate effects on brain activation from left vs. right visual field presentation of information, 3) study effects of difficulty of the memory task, 4) study effects of the duration of the memory period required by the task, and 5) measure effects when a spatial orientation task is included in addition to memory task.
METHODS, RADIOACTIVE SUBSTANCES AND HUMAN INVOLVEMENT
To examine rapidly changing states in brain function (lasting 1- 5 min) such as those associated with sensory and most cognitive tasks, O-15-water will be used to sequentially measure CBF. Previous work in this area has employed a bolus injection and a single 40 second PET scan for this measurement. We plan, however, to examine several protocols which will combine various methods of injection (bolus, ramp, and/or continuous infusion) with dynamic PET data acquisition to determine the best statistical measure of CBF.
All subjects will have an intravenous antecubital line placed for radiotracer injection and then be positioned in the PET scanner. Some subjects will have a radial artery catheter placed as well for measurements of radiotracer blood activity.
A series of PET measurements of CBF will be obtained over a period up to 3 hours. Each measurement will begin with establishment of the mental state (see below), then infusion of O-15-water (40 - 90 mCi) and initiation of dynamic PET scanning (from 1 up to 6 minutes of data collection). In certain subjects arterial blood samples will be drawn through a continuous blood sampler for quantitative CBF calculations. After allowing for the decay of O-15 the PET CBF measurement will be repeated (up to 20 times, or a maximum of 400 mCi) depending on the number of mental states to be examined.
One of three general mental states will be established just prior to and maintained during all PET measurements. 1) A control state: Eyes closed, ears partially plugged, and the subject instructed to rest and "think of nothing in particular". 2) A sensory state: Consisting of either somatosensory (hand vibration, thermal, or light touch), auditory (words, word-like sounds, white-noise, etc.), and/or visual (words, shapes , colors, etc.) stimuli. 3) Cognitive task state: Subject responding (internally or externally) to sensory stimuli. Rules of response can be simple (e.g., reading aloud a visually presented word) or more complex (e.g., silently counting the number of times a red square is seen among a pattern of red circles).
MRI studies: In selected subjects an MRI study of the head will be obtained after completion of the PET study. To obtain both gray matter/white matter distinction and brain/CSF distinction, two different pulse sequence acquisitions may be run, lasting a total of 45 minutes.
RISKS
1. Low-level radiation exposure. At the levels used, the effects are judged to
be minimal.
2. Arterial catheterization - unexpected bleeding, thrombosis, vasospasm, or
infection at the site of radial artery puncture. This procedure has been used
for over 10 years in our PET facility without serious complication. Risks are
kept to a minimum by employing aseptic technique by experienced personnel.
3. Venous catheterization - infection. Risks are kept to a minimum by employing
aseptic technique by experienced personnel.