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: 4
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 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
We studied 27 subjects in the fiscal year under this grant 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: 2
Protocol/Subproject # 1
Protocol/Subproject Identifier: 94-283
IRB Review:
Type of Review: Full Board
Most Recent Approval: May 16, 1996
IRB Approval Number: 94-283
Number of Human Subjects who participated in this project/protocol during
05/16/95 - 05/16/96: 4
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 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 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.
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 30, 1996
IRB Approval Number: 94-440
Number of Human Subjects who participated in this project/protocol during
05/30/95 - 05/30/96: 4
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 & 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 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.
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 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
We studied 90 subjects under this grant for the fiscal year and we estimate a cost of $2200 per subject studied.
Project involves use of multiple protocols/subprojects.
Number of protocols/subprojects associated with this project: 5
Protocol/Subproject # 1
Protocol/Subproject Identifier: 88-395
IRB Review:
Type of Review: Full Board
Most Recent Approval: February 08, 1996
IRB Approval Number: 88-395
Number of Human Subjects who participated in this project/protocol during
02/08/95 - 02/08/96: 5
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 various stages of cognitive impairment. Initially, patients studied in this project were required to show a cognitive decline during the previous 6 months prior to study in order to be entered into the project. Groups will include patients diagnosed 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 quite 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 [15O]H2O. A few blood samples will be used to determine arterial plasma levels of (cold) glucose, pO2, pCO2, and 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 <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 ~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 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.
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: September 19, 1996
IRB Approval Number: 92-201
Number of Human Subjects who participated in this project/protocol during
09/19/95 - 09/19/96: 28
Type of Human Subjects Involvement:
OBJECTIVES
[123I]IBVM 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 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 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.
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: September 19, 1996
IRB Approval Number: 95-462
Number of Human Subjects who participated in this project/protocol during
09/19/95 - 09/19/96: 24
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 preceed 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 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: November 16, 1995
IRB Approval Number: 95-537
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 27
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 25, 1996
IRB Approval Number: 96-234
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 6
Type of Human Subjects Involvement:
Internal administration of radioactive substances to human subjects.
OBJECTIVES
The goal 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 reversible anticholinesterase agent physostigmine. 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 approximately 15 normal human controls and 8 AD patients (Kuhl in press). Scan-determined distribution of AChE activity matches closely reports of postmortem histochemistry and the expected AChE decline was found in AD cortex. The proposed physostigmine infusion matches those reported for experimental treatment of AD patients (Christie 82, Becker 91, Asthena 95). It is expected to produce a scan-measurable AChE inhibition of 30-50%.
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 hall mark 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 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 AND RADIOACTIVE SUBSTANCES
Subjects will be injected intravenously with 36 mCi of [11C] N-methyl piperidinol propionate (PMP), a methylated derivative of desmethyl precursor. This activity will be administered in two fractionated doses. Internal whole body exposure from the radiopharmaceutical is 0.21 rad/36 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 20 mR. This additional exposure, to head (brain and lens of eye), does not exceed imposed limits.
HUMAN SUBJECT INVOLVEMENT
Patient Preparation and Set-up
1. Subjects will have a brief medical/neurologic examination to rule out any
underlying illness.
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 physostigmine and N-[11C]methylpiperidinyl propionate
([11C]PMP), the PET radiopharmaceutical.
4. The subject will be positioned in the PET scanner as comfortably as possible
in a supine position.
B. PET Imaging Procedures
1. A dose of 18 mCi of [11C]PMP 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 to determine the
concentration curve of tracer.
4. At the completion of the first PET scan, subjects will be given 2.5 mg of
methscopolamine bromide orally. This medication is expected to reduce
peripheral autonomic reactions of physostigmine.
5. A blood pressure cuff and EKG electrodes will be placed for the monitoring of
vital
signs.
6. One hour after the administration of methscopolamine bromide, the subject
will receive intravenous infusion of 1.5 mg physostigmine salicyclate in 100 ml
saline, given at a uniform controlled rate over a period of 60 minutes. The
physostigmine infusion will be discontinued if there is the appearance of severe
nausea, vomiting or headache.
7. Immediately after cessation of the physostigmine infusion, when
acetylcholinesterase inhibition should be zero, a second dose of 18 mCi of
[11C]PMP will be injected intravenously.
8. The total cumulative dose of [11C]PMP will not exceed 36 mCi (+ 10 %) and
will contain less than 25 µg methylpiperidinyl propionate.
9. A series of dynamic PET scans will be initiated with duration increasing from
30 seconds to 10 minutes over an 80 minute imaging period.
10. Timed samples of arterial plasma will be collected to determine the
concentration curve of tracer.
11. The PET data will be analyzed first qualitatively to determine the relative
uptake in various brain regions. If the data permit, preliminary kinetic
compartmental modeling will be applied to determine the sensitivity of tracer
distribution to tissue delivery versus enzymatic cleavage.
12. At the end of the second PET imaging session, arterial and venous lines will
be removed as well as other monitoring devices provided the subject is not
experiencing any discomfort or adverse effects.
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.
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-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 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
We studied 15 subjects for this project at a cost of $2050 per subject.
Project does not involve use of multiple protocols/subprojects.
Protocol/Subproject Identifier: 89-457
IRB Review:
Type of Review: Full Board
Most Recent Approval: July 11, 1996
IRB Approval Number: 89-457
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 15
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.
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-93-N149310462
Project Title:
Working Memory as Revealed by Positron Emission Tomography (PET)
Principal Investigator:
Dr. John Jonides
Project started in: 1993
This project ended in Fiscal Year 1996.
Project Funding Information:
Project received funding in Fiscal Year 1996.
Project used human subjects in Fiscal Year 1996.
Funding Sources:
We studied 31 subjects under this grant during the fiscal year and we estimate a cost of $1750 per subject studied.
We studied 31 subjects at the cost of $1870 per subject.
Total Funding: $112,220
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: July 11, 1996
IRB Approval Number: 89-457
Number of Human Subjects who participated in this project/protocol during
FY 1996 (10/1/95 - 9/30/96): 62
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.
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.