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)
Principal Investigator:
Dr. David E. Kuhl
Project started in: 1979
Project Funding Information:
Project received funding in Fiscal Year 1997.
Project used human subjects in Fiscal Year 1997.
Funding Sources:
In the fiscal year we studied 22 subjects under this grant at an estimated cost of $1850 per subject and 24 subjects at an estimated cost of $3000 per subject.
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 2
Protocol/Subproject # 1
Protocol/Subproject Identifier: 94-283
IRB Review:
Type of Review: Full Board
Most Recent Approval: September 25, 1997
IRB Approval Number: 94-283
Number of Human Subjects who participated in this project/protocol during
09/24/96 - 09/25/97: 24
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 anticipated 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 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.
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 and 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 complications. Risks are kept to a minimum by employing an 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 an aseptic technique by experienced personnel.
Written informed consent is obtained from all subjects following an in-depth verbal description of all techniques to be employed. In the case of questionable mental competence, the subject's legal guardian or next-of-kin provides written informed consent. A physician is always available for further clarification if necessary.
No subject is personally identified in any write-ups associated with any of our projects. All subjects' records are kept confidential to the extent provided by federal, state and local law.
IRB Review:
Type of Review: Full Board
Most Recent Approval: May 15, 1997
IRB Approval Number: 94-440
Number of Human Subjects who participated in this project/protocol during
05/14/96 - 05/15/97: 22
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 the 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 & 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 min 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 an 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 an aseptic technique by experienced personnel.
Written informed consent is obtained from all subjects following an in-depth verbal description of all techniques to be employed. In the case of questionable mental competence, the subject's legal guardian or next-of-kin provides written informed consent. A physician is always available for further clarification if necessary.
No subject is personally identified in any write-ups associated with any of our projects. All subjects' records are kept confidential to the extent provided by federal, state and local law.
Project Identifier: UMH-86-NS24896
Project Title:
Emission Computed Tomography of Local Cerebral Function
Principal Investigator:
Dr. David E. Kuhl
Project started in: 1986
Project Funding Information:
Project received funding in Fiscal Year 1997.
Project used human subjects in Fiscal Year 1997.
Funding Sources:
We studied 43 subjects under this grant for the fiscal year and we estimate a cost of $2500 per subject studied.
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 4
Protocol/Subproject # 1
Protocol/Subproject Identifier: 95-462
IRB Review:
Type of Review: Full Board
Most Recent Approval: April 03, 1997
IRB Approval Number: 95-462
Number of Human Subjects who participated in this project/protocol during
FY 1997 (10/1/96 - 9/30/97): 1
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
The specific aim of this project is to determine in vivo with emission tomography the temporal and spatial sequence of declines in cerebral cholinergic enzyme activity and cholinergic terminal integrity in normal aging. The hypotheses to be tested are as follow:
1. In normal aging, cholinergic enzyme loss will always precede and exceed cholinergic terminal loss both in severity and in extent.
2. In normal aging, there will be an age-dependent decline in hippocampal cholinergic enzyme activity, but not in cholinergic terminal integrity.
RADIOACTIVE SUBSTANCES AND EXPOSURE
Subjects will have a transmission scan to determine tissue attenuation factors. The exposure from this procedure is less than 2 mR to the brain and lens of the eye and it does not exceed dosimetry limits.
Subjects will be injected intravenously with 36 mCi of [11C]N-methyl piperidinol propionate (PMP).
INVOLVEMENT OF SUBJECTS
A. PET Imaging Procedures
OPTION A (PMP - Single Dose)
1. Subjects will be studied lying supine, immobile in a basal state with eyes and ears unoccluded.
2. A catheter will be placed in the radial artery for the withdrawal of blood samples to permit quantification of the PET data.
3. An intravenous catheter will be placed in the contralateral arm for the administration of radiopharmaceuticals.
4. A bolus of [11C]PMP, containing 36 mCi and < 25 µg PMP, will be administered intravenously.
5. 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 radiopharmaceutical dose and scan timing and duration will be optimized to produce an accurate estimate of receptor density while minimizing radiation absorbed dose to the subject. The collection of data will terminate 60 minutes after injection.
6. Arterial blood samples will be collected following the injection of [11C]PMP 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, and 60 minutes following injection. The arterial concentration of [11C]PMP will be determined by chromatographic analysis of the blood samples.
7. Venous and arterial lines will be removed and the subject will be instructed to consume additional fluids for the remainder of the day prior to their release from the PET Suite.
8. The PET data will be analyzed according to a compartmental model derived and validated in our laboratory.
OPTION B (PMP - Fractionated Dose)
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 the radial artery for the withdrawal of blood samples to permit quantification of the PET data.
3. An intravenous catheter will be placed in the contralateral arm for the administration of radiopharmaceuticals.
4. A bolus of [11C]PMP containing less than 25 µg PMP will be administered intravenously.
5. 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 radiopharmaceutical dose and scan timing and duration will be optimized to produce an accurate estimate of receptor density while minimizing radiation absorbed dose to the subject. The collection of data will terminate 60 min after injection.
6. Arterial blood samples will be collected following the injection of [11C]PMP 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, and 60 minutes following injection. The arterial concentration of [11C]PMP will be determined by chromatographic analysis of the blood samples.
7. Following decay of the first imaging dose, a second study consisting of steps 4 - 6 above will be initiated. Behavioral conditions may be altered or maintained to evaluate the effects of tracer delivery and precision of method, respectively.
8. The total cumulative dose will not exceed 36 mCi. Less than 25 µg PMP will be administered.
9. The PET data will be analyzed according to a compartmental model derived and validated in our laboratory.
B. ANCILLARY MEASUREMENTS
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.
Neuropsychometric testing may be performed. This series of tests measures memory, attention, concentration and perception. This testing will take approximately four hours.
RISKS
Low-level radiation exposure: The biologic effects of this level of exposure are judged to be minimal.
Cannulation of the radial artery: The likelihood of a complication from short-term percutaneous cannulation of the radial artery is small (substantially less than 1 in 1000).
Cannulation of a cutaneous vein: The likelihood and severity of a complication (infectious, hemorrhagic) are minimal.
Idiosyncratic/allergic reaction to the study radiopharmaceuticals: The likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered.
MRI: injury due to migration of ferromagnetic foreign bodies or prostheses, or induced dysfunction of electrical prostheses (pacemakers, etc.); the likelihood of adverse reactions will be minimized by interviewing and excluding from study all subjects with vascular clips, pacemakers or other contraindicated prostheses.
Written informed consent is obtained from all subjects following an in-depth verbal description of all techniques to be employed. In the case of questionable mental competence the subject's legal guardian or next-of-kin provides written informed consent. A physician is always available for further clarification if necessary.
No subject is personally identified in any write-ups associated with any of our projects. All subjects' records are kept confidential to the extent provided by federal, state and local law.
IRB Review:
Type of Review: Full Board
Most Recent Approval: April 03, 1997
IRB Approval Number: 95-537
Number of Human Subjects who participated in this project/protocol during
FY 1997 (10/1/96 - 9/30/97): 28
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
The first specific aim of this project is to determine in vivo with emission tomography the temporal and spatial sequence of declines in cholinergic terminal integrity in early Alzheimer's disease (AD). This will be determined by single photon emission computed tomography (SPECT) after the intravenous administration of [123I]iodobenzovesamicol ([123I]IBVM).
The second specific aim is to determine if cholinergic and dopaminergic positron emission tomography (PET) measures permit patients with early Diffuse Lewy Body Disease (DLBD) to be distinguished from patients with early AD. The hypotheses to be tested are as follow:
1. Antemortem, when dementia is only questionable or mild, a subset of Suspect DLBD subjects will be distinguished from other Suspect or Probable AD subjects by a characteristic combination of clinical signs, behavioral measurements, and SPECT/PET-demonstrated severity of temporal cholinergic and caudate dopaminergic deficits.
2. Postmortem examination will confirm the diagnoses of DLBD and AD in the Suspect DLBD subset and in the larger Probable AD group.
RADIOACTIVE SUBSTANCES
Between 8 and 10 mCi of 123I-5-iodobenzovesamicol, code name [123I]IBVM, a radiolabelled presynaptic, cholinergic vesicle ligand will be injected intravenously.
Up to 36 mCi of [11C] N-methyl piperidinol propionate (PMP) will be injected Intravenously.
The internal whole body exposure from the radiopharmaceuticals mentioned in above, is as follow:
[123I]IBVM: 0.040 rad/mCi [11C]PMP: 0.006 rad/mCi
External exposure will result from transmission scanning during the PET imaging session for measurement of tissue attenuation factors. We estimate the absorbed dose during a typical 10 minute transmission scan as less than 2.0 mR. This additional exposure, to head (brain and lens of eye), does not exceed imposed limits.
INVOLVEMENT OF HUMAN SUBJECTS
PET Imaging
Subjects will have had nothing to eat for at least three hours prior to the PET study.
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 of one arm 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]PMP, containing up to 36 mCi and less than 25 µg, will be administered intravenously.
Brain activity will be determined with a series of sequential emission scans lasting up 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 PMP, will be analyzed to determine the transport and binding of the tracer. The catheters will be removed and the subject will be released. Subjects will be instructed to increase their fluid intake and to void frequently for the remainder of the day.
SPECT Imaging
Prior to the injection of [123I]iodobenzovesamicol ([123I]IBVM) subjects will be given super-saturated potassium iodide (SSKI) orally to block absorption of radioactivity in the thyroid gland. SSKI will be given for three days following the injection of [123I]IBVM.
An intravenous catheter will be placed in a vein of one arm for the administration of the radiotracer. [123I]IBVM, containing up to 8 - 10 mCi will be administered. The catheter will be removed.
Brain activity will be determined with SPECT scans in as many as (3) one hour imaging sessions. These sessions will take place immediately after injection and/or at three to four hours after injection and/or at 22 hours after injection.
Subjects will be scanned in a supine position and will be made as comfortable as possible for imaging. An oral laxative will be dispensed for the subject to take after the injection of [123I]IBVM to help lower radiation exposure to the bowel.
ANCILLARY MEASUREMENTS
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.
Genetic testing will be performed in some instances on an additional blood sample. Ideally this blood sample will be obtained from a venous or arterial catheter placed for the PET or SPECT imaging session. This sample will be about four tablespoons in volume.
RISKS
Low-level radiation exposure: The biologic effects of this level of exposure are judged to be minimal.
Cannulation of the radial artery: The likelihood of a complication from short-term percutaneous cannulation of the radial artery is small (substantially less than 1 in 1000).
Cannulation of a cutaneous vein: The likelihood and severity of a complication (infectious, hemorrhagic) are minimal.
Idiosyncratic/allergic reaction to the study radiopharmaceuticals: The likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered.
MRI: injury due to migration of ferromagnetic foreign bodies or prostheses, or induced dysfunction of electrical prostheses (pacemakers, etc.); the likelihood of adverse reactions will be minimized by interviewing and excluding from study all subjects with vascular clips, pacemakers or other contraindicated prostheses.
Written informed consent is obtained from all subjects following an in-depth verbal description of all techniques to be employed. In the case of questionable mental competence, the subject's legal guardian or next-of-kin provides written informed consent. A physician is always available for further clarification if necessary.
No subject is personally identified in any write-ups associated with any of our projects. All subjects' records are kept confidential to the extent provided by federal, state and local law.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 31, 1997
IRB Approval Number: 97-128
Number of Human Subjects who participated in this project/protocol during
FY 1997 (10/1/96 - 9/30/97): 12
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES and METHODOLOGY:
The goal of this project is to validate further the [11C]PMP-PET method which we are developing as a means of imaging in vivo the cerebral distribution of the cholinergic enzyme acetylcholinesterase (AChE). We will test the ability of the scan method to measure the expected transient inhibition of cerebral AChE activity by the FDA-approved therapeutic anticholinesterase agent donepezil (Aricept). AD patients will be scanned before and after Aricept therapy; treatment is for patient care, not research. In the PMP method, the radiolabeled N-methylpiperidyl ester serves as an in vivo AChE substrate and is hydrolyzed to a hydrophilic product which is subsequently trapped locally in the brain according to the distribution of enzyme activity. We have already validated the method in animals (Kilbourn 95) and have applied it to normal human controls and AD patients. Scan-determined distribution of AChE activity matches closely reports of postmortem histochemistry. Expected AChE decline was found in AD cortex. Physostigmine infusion produced a scan-measurable AChE inhibition of 30-50%, matching inhibition reported for experimental treatment of AD patients.
The [11C]PMP-PET method should be useful in early Alzheimer's disease, both to identify the pathophysiology and to monitor the development of new therapy. The cholinergic system has long been implicated in memory, and loss of cholinergic function, including AChE, is a hallmark of Alzheimer's disease. Our understanding of the pathogenesis of these disorders will be advanced if a method permitting the direct testing of these hypotheses early in the course of disease is developed. This may permit subsequent studies on the mechanisms of the action of existing symptomatic therapies, and may lead to development of new therapies directed at preventing nerve damage or restoring function following selective nerve injury. Finally, such studies ultimately lead to more specific diagnostic criteria, and, thus, more effective treatment of some of these disorders. An accurate in vivo method for measuring AChE would provide a new and valuable method for determining the changes of this enzyme function in disease, and provide a method for evaluation of new preventative or therapeutic strategies.
IONIZING RADIATION:
Subjects will have a 10 - 15 minute transmission scan performed for measurement of attenuation factors for the PET scan. The transmission scan utilizes Ge-68 rods which contain less than or equal to 10 mCi . The additional exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects will receive [11C] N-methyl piperidinol propionate (PMP), a methylated derivative of desmethyl precursor, for each of the PET imaging sessions. PMP is a substrate for acetylcholinesterase (AChE), and is readily cleaved in vitro to propionic acid and N-methyl piperidinol. In vivo [11C]PMP is a substrate for AChE, and in the brain the radioactive product [11C]-methyl piperidinol, is retained in the tissue. Regional brain distributions in mice and monkeys show a pattern which highly correlates with the regional distribution of AChE activity in vitro. In both the brain and blood of mice, after 20 minutes, essentially all radioactivity is in the form of the hydrolysis product.
For each of the PET imaging sessions performed, 18 mCi of [11C]PMP, containing < 25 micrograms, will be administered intravenously over 30 seconds. The PET images will be coupled with an arterial input function to generate quantitative images for analysis in this research study.
The effective dose equivalent (EDE) from each [11C]PMP PET scan is ~0.6 rem. This project is currently approved for each subject to receive as many as three PET scans resulting in a cumulative EDE of ~1.8 rem. This exposure is equivalent to the exposure received from ~2.3 CT exams of the chest. The cumulative exposure from three [11C]PMP PET scans is ~ one-third that allowed to a radiation worker in one year. This risk is similar to other every day risks, such as driving a car. Although there are no direct benefits to the subjects involved in this research study, it may ultimately lead to an improved understanding of chemical brain alterations and/or lead to a method for early diagnosis and possible treatment of cognitive diseases in the future.
INVOLVEMENT OF HUMAN SUBJECTS
Criteria for Inclusion of Subjects: 40 years of age or older; diagnosed with AD or a related dementing disorder; no other significant current illness; ability to give informed consent; to clinically receive Donepezil.
Criteria for Exclusion of Subjects: pregnancy; breast feeding.
Patient Preparation and Set-up
1. Subjects will be recruited from the Department of Neurology at the University of Michigan Hospital.
2. Subjects will have AD or a related dementing disorder.
3. Subjects will be scheduled to clinically receive Donepezil, an acetylcholinesterase (AChE) inhibitor.
4. Subjects will undergo a baseline PET scan before the clinical administration of Donepezil and a second PET scan will be performed 4 to 8 weeks after the administration of Donepezil.
4. The PET study will be explained verbally to the subject and written informed consent will be obtained. This will be done in the Division of Nuclear Medicine before each of the PET scans.
5. The subject will be positioned on the PET imaging table in a supine position.
6. A catheter will be placed in the radial artery for the withdrawal of blood samples to permit quantification of the PET data.
7. An intravenous catheter will be placed in the contralateral arm for the administration of N-[11C]methylpiperidinyl propionate ([11C]PMP), the PET radiopharmaceutical.
8. The subject will be positioned in the PET scanner as comfortably as possible.
PET Imaging Procedures
1. A dose of 18 mCi of [11C]PMP, containing less than 25 micrograms, will be injected intravenously.
2. A series of dynamic PET scans will be initiated with duration increasing from 30 seconds to 10 minutes over an 80 minute imaging period.
3. Timed samples of arterial plasma will be collected at increasing time intervals to determine the concentration curve of tracer. Samples will range in volume from 1 ml to 3 ml. A total of 50 ml will be withdrawn during the PET scan.
4. At the end of the PET imaging session arterial and venous lines will be removed.
5. The subject will be asked to void and will then be released.
6. The PET data will be analyzed to determine the relative uptake in various brain regions. Kinetic compartmental modeling will be applied to the data to generate quantitative images.
7. Four to eight weeks after the clinical administration of Donepezil the subject will return for a follow-up PET scan. The same procedure will be followed.
8. If it is clinically determined that a subject is not responding to Donepezil the dosage may be increased. If this occurs, the subject will return for a third PET scan 4 to 8 weeks after the increase. The same procedure as described in steps 1 through 6 above will be followed.
Ancillary Measurements
Genetic testing will be performed in some instances on an additional blood sample. Ideally, this blood sample will be obtained from a venous or arterial catheter placed for the PET or SPECT imaging session. This sample will be about four tablespoons in volume.
Seven ml of venous blood will be withdrawn for the determination of plasma AChE. Ideally, this blood sample will be obtained from a venous or arterial catheter placed for the PET or SPECT imaging session.
There is a potential risk to subjects because of the low-level radiation exposure that will result from the administration of the PET radioisotope [11C]PMP. The biologic effects of this level of exposure are judged to be minimal. There are no alternatives to the use of PET for the noninvasive delineation of acetylcholinesterase.
There is a potential risk associated with the 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). We have utilized this procedure for PET imaging protocols for over 10 years without serious complication. There are no alternative procedures to obtain the arterial tracer input functions necessary for quantification of the PET data.
There is a potential risk associated with the cannulation of a cutaneous vein. The likelihood and severity of a complication (infectious, hemorrhagic) are minimal. There is no alternative to intravenous access for the administration of radiotracers for PET imaging.
There is the potential for an idiosyncratic/allergic reaction to the study radiopharmaceuticals. The likelihood of a reaction to tracer administration is low due to the small chemical amounts of tracer administered. There are no alternatives to the use of these radiopharmaceuticals for the PET measurements to be made.
No subject will be personally identified in any write-ups or analyses associated with this project.
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 24, 1997
IRB Approval Number: 97-313
Number of Human Subjects who participated in this project/protocol during
FY 1997 (10/1/96 - 9/30/97): 2
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES & METHODOLOGY
The specific aim of this project is to determine in vivo with emission tomography the temporal and spatial sequence of declines in cerebral cholinergic enzyme activity and cholinergic terminal integrity in normal aging. The hypotheses to be tested are as follow:
1. In normal aging, cholinergic enzyme loss will always precede and exceed cholinergic terminal loss both in severity and in extent.
2. In normal aging, there will be an age-dependent decline in hippocampal cholinergic enzyme activity, but not in cholinergic terminal integrity.
The above hypotheses will be tested using [11C]N-methyl piperidinol propionate (PMP) PET imaging. [18F] fluorodeoxyglucose (FDG) PET imaging will be performed for anatomic comparison.
AChE is an enzyme responsible for metabolic cleavage of the neurotransmitter acetylcholine. The cholinergic system has long been implicated in memory, and losses of cholinergic function, including AChE, are a hallmark of Alzheimer's disease, an important neurodegenerative disease. Our understanding of the pathogenesis of these disorders will be advanced if a method permitting the direct testing of these hypotheses early in the course of disease is developed. This may permit subsequent studies on the mechanism(s) of action of existing symptomatic therapies, and may lead to the development of new therapies directed at preventing nerve damage or restoring function following selective nerve injury. Finally, such studies ultimately lead to more specific diagnostic criteria, and, thus, more effective treatment for some of these disorders. An in vivo method for measuring AChE would provide a new and valuable method for determining the changes of this enzyme function in disease, and provide a method for evaluation of new preventative or therapeutic strategies.
IONIZING RADIATION
Subjects will have a 10 - 15 minute transmission scan performed for measurement of attenuation factors for the PET scan. The transmission scan utilizes Ge-68 rods which contain less than or equal to 10 mCi . The additional exposure from this procedure is estimated to be less than 20 mR to the brain and lens of the eye.
Subjects will receive [11C] N-methyl piperidinol propionate (PMP), a methylated derivative of desmethyl precursor, for the first PET imaging session. PMP is a substrate for acetylcholinesterase (AChE), and is readily cleaved in vitro to propionic acid and N-methyl piperidinol. In vivo [11C]PMP is a substrate for AChE, and in the brain the radioactive product [11C]-methyl piperidinol, is retained in the tissue. Regional brain distributions in mice and monkeys show a pattern which highly correlates with the regional distribution of AChE activity in vitro. In both brain and blood of mice, after 20 minutes essentially all radioactivity is in the form of the hydrolysis product.
Eighteen (18) mCi of [11C]PMP, containing < 25 micrograms, will be administered intravenously over 30 seconds. The PET images, obtained over an 80 minute imaging period, will be coupled with an arterial input function to generate quantitative images for analysis in this research study. Next, subjects will be injected intravenously with [18F]FDG, a non-metabolizable glucose analog. Administration of the [18F]FDG will occur over 30 seconds. Imaging will begin 30 minutes after administration and continue for 30 minutes.
INVOLVEMENT OF HUMAN SUBJECTS
We will study 30 normal subjects over the age of 18. Subjects will be male or female in gender. Subjects will be recruited by written advertisement. A pre-screen to determine subject eligibility will be performed by a telephone conversation. Eligible subjects will undergo a brief neurologic examination to rule out any underlying illness or disorder.
Subjects will be studied with positron emission tomography (PET) to determine cerebral glucose metabolism and acetylcholinesterase (AChE) activity. The radiopharmaceuticals will be administered intravenously. [11C]PMP will be administered first and PET imaging will begin immediately and continue for 80 minutes. Blood samples will be removed at increasing intervals throughout this imaging session. Withdrawal of these samples will be through a catheter in the radial artery. These samples are needed to generate an arterial input function for the generation of quantitative PET images. [18F]FDG will then be administered. PET imaging will begin 30 minutes after injection and will take approximately 30 minutes to complete. No arterial samples will be withdrawn for this portion of the study. It is our intent to complete the [11C]PMP and [18F]FDG scans in a single four hour session. If necessary the [18F]FDG scan can be performed on a separate day. No hospitalization, clinic visits or long-term follow-up is planned.
POTENTIAL RISKS
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). We have utilized this procedure for PET imaging protocols for over 10 years without serious complication. There are no alternative procedures to obtain the arterial tracer input functions necessary for quantification of the PET data.
Arterial cannulation is performed by an individual trained and experienced in the technique. Local anesthesia and sterile technique are utilized to minimize discomfort and the risk of infection. 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. These measures have never been necessary in our institution following short-term radial cannulations as utilized in PET imaging protocols.
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. There is no alternative to intravenous access for the administration of radiotracers for PET imaging. 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.
Low-level radiation exposure
The biologic effects of this level of exposure are judged to be minimal. There are no alternatives to the use of PET for noninvasive determinations of regional glucose metabolism and distribution of AChE.
The radiation doses arising from these studies are within the range of commonly-utilized diagnostic studies. 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. 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.
Idiosyncratic/allergic reaction to the study radiopharmaceuticals
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 "crash cart". In the unlikely event of a severe allergic response, the subject will be hospitalized for observation following initial emergency treatment.
No subject will be personally identified during the analysis or write-up of any data resulting from this project.
Project Identifier: UMH-87-DE-FG02-87ER60561
Project Title:
Advancing PET Science for New Measures of Brain Function
Principal Investigator:
Dr. David E. Kuhl
Project started in: 1987
Project Funding Information:
Project received funding in Fiscal Year 1997.
Project did not use human subjects in Fiscal Year 1997.
Explanation:
We have started a new grant period. We are currently developing new radiotracers and novel tracer kinetic and data analysis techniques for our new research focus. We have not studied any human subjects with these new techniques.
Funding Sources:
The funds received ($496218) are direct and indirect funds received for the development of new radiotracers and kinetic and data analysis techniques.
Project does not involve use of multiple protocols/subprojects.
IRB Review:
Type of Review: Full Board
Number of Human Subjects who participated in this project/protocol during
the Last Reporting Period for this Project: 0
Type of Human Subjects Involvement:
In this project, new PET radiotracers and new methodology and data analysis techniques were developed. These new techniques were used in the project UMH-79-NS15655 "Positron Emission Tomography (PET) Study of the Biochemistry and Metabolism of the Central Nervous System (CNS)" and project UMH-86-NS24896 "Emission Computed Tomography of Local Cerebral Function".
We are currently developing new radiotracers and novel tracer kinetic and data analysis techniques for our new research focus. During this past year no human studies have been done in this project and no IRB approvals are currently in use. In the coming year of the current DOE funding period, we do plan on studying human subjects.