Magnetic Resonance Imaging in Multiple Sclerosis
Magnetic Resonance Imaging and Spectroscopy
Functional/Metabolic Imaging in the Brain
Development and Evaluation of Magnetic Resonance Contrast Agents
Magnetic Resonance Imaging in Experimental Allergic Encephalomyelitis and Remyelination
Multimodality Radiological Image Processing System
INTRAMURAL
RESEARCH PROJECT
Z01 CL-90001-08 LDRR
October 1, 1999 to September 30, 2000
Title of Project:
Magnetic Resonance Imaging in Multiple Sclerosis
Principal Investigator:
J.A. Frank, M.D. (Senior Investigator)
LDRR, CC, NIH
Bethesda, MD 20892
Other Personnel:
N. Richert, M.D., Ph.D., LDRR
C. Bash, M.D., LDRR
J. Ostuni, Ph.D., LDRR
B.K. Lewis, B.A., LDRR
T. Howard, B.S., LDRR (CRADA)
J. Patel, B.S., LDRR (CRADA)
Collaborating Units:
NIB, NINDS (H. McFarland, M.D.)
Cephalon, Inc. (CRADA)
Novartis, Inc. (CRADA)
Staff-Years:
4.0
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: The focus of this project is the use of magnetic resonance imaging to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by various immunomodulatory treatments such as Insulin-like growth factors (rhIGF-1), and altered peptide ligand (APL) and to monitor the natural history of MS. Magnetization transfer (MT) imaging which is sensitive to the amount of bound and free water in the white matter and indirectly reflects myelination was also used to evaluate these patients. MT region of interest (ROI) analysis of individual enhancing or non-enhancing lesions reveals that there is no difference in the pattern of MS lesion recovery either when a lesion develops during the natural history of the disease or receiving INFB-1b. However, there does appear to be a faster improvement in the MTR recovery towards baseline when enhancing lesions occur in association with a clinical exacerbation requiring treatment with intravenous steroids. These results would indicate that closure of the blood brain barrier with steroids is associated with a decrease in the ratio of free to bound water within a MS lesion that is detected as a change in MTR. MTR studies performed of MS lesions in patients receiving rhIGF-1 suggest that a similar recovery pattern as observed with steroids which would be consistent with the proposed anti-inflammatory effects of this agent.
The rhIGF-1 study closed in 1999 after enrollment of a total of seven MS patients, who completed the open-labeled baseline trial design with contrast enhancing lesions as primary outcome measure. The results of this study indicated that rhIGF-1 was safe and well tolerated in all patients and that further analysis of the primary and secondary outcome measures are still ongoing to determine therapeutic efficacy. A second open-labeled baseline versus treatment trial is evaluating Altered Peptide Ligand (APL) as a treatment for relapsing-remitting MS patients. APL is thought to interfere with binding of T-cells to antigen presenting cells and induce tolerance in MS patients. This trial was put on hold after three of seven patients developed clinical adverse effects of APL that were correlated to findings on MRI examination. Further immunologic-imaging evaluations of the patients following the cessation of APL therapy are underway in order to develop a better understanding of the mechanism of action of this approach to treating MS.
INTRAMURAL
RESEARCH PROJECT
Z01 CL-90002-06 LDRR
October 1, 1999 to September 30, 2000
Title of Project:
Magnetic Resonance Imaging and Spectroscopy
Principal Investigator:
J.H. Duyn, Ph.D.
LDRR, CC, NIH
Bethesda, MD 20892
Other Personnel:
J. Frank, M.D., LDRR
M. Yongbi, Ph.D., LDRR
B. Lewis, B.A., LDRR
Collaborating Unit:
CBDB, NIMH (J.V. Der Veen, Ph.D.)
Staff-Years:
1.75
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: Significant improvements and developments in fast scanning techniques for functional magnetic resonance (MR) imaging of the brain have occurred during the past year. We have been able to migrate all rapid imaging and spectroscopic imaging techniques to the 3 Tesla MR units. Improvements in signal to noise are observed with MR based spin tagging perfusion to detect cerebral blood flow and clinical studies are being performed comparing the results of functional imaging studies at 1.5 Tesla and 3.0 Tesla.
Evaluation of a newly developed proton spectroscopic imaging (MRSI) involves the acquisition of cerebral metabolites without suppression of the water signal. MRSI without water suppression revealed high degree of coefficient of variation of between 5 to 13 percent for intrasubject and intersubject comparisons which is an improvement over standard MRSI techniques which use water suppression. Improvements in this new non-water suppressed MRSI technique will allow for the addition of a second echo which may be used to segment the signal originating from cerebral spinal fluid versus intracellular water and provide some information about the relaxation properties of the signals from cerebral metabolites.
INTRAMURAL
RESEARCH PROJECT
Z01 CL-90003-06 LDRR
October 1, 1999 to September 30, 2000
Title of Project:
Functional/Metabolic Imaging in the Brain
Principal Investigators:
J.A. Frank, M.D. (Senior Investigator)
J.H. Duyn, Ph.D. (Investigator)
LDRR, CC, NIH
Bethesda, MD 20892
Other Personnel:
K. St. Lawrence, Ph.D., LDRR
J. Ostuni, Ph.D., LDRR
B.K. Lewis, B.A., LDRR
M. Yongbi, Ph.D., LDRR
C. Tan, Ph.D., LDRR
Collaborating Unit:
CBDB, NIMH (A. McLaughlin, Ph.D.)
Staff-Years:
3.25
Human Subjects:
x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: Functional and metabolic magnetic resonance imaging (MRI) techniques have been rapidly evolving and have tremendous potential for clinical brain disorders research. Clinical activation functional fMRI studies are performed at 1.5 and at 3.0 Tesla using blood oxygenation level dependent (BOLD) contrast method and arterial spin tagging (AST) techniques. Reproducible alterations cerebral blood flow (CBF) have been performed having healthy controls inhale carbogen at 6 percent carbon dioxide with an approximate increase of 20 to 30 percent in CBF. These preliminary studies will allow us to perform pharmacological challenges and demonstrate the effects on CBF over multiple trials and doses that presently can not be performed using standard imaging techniques. Because of improvements in pulse sequences and phase array head coils for the 1.5 Tesla, single event functional MRI trials using AST pulse sequences can be performed. The results of these preliminary studies indicate that changes in CBF can be detected within 1 second when the healthy control performs a sensorimotor task. Future work will focus on improving the AST pulse sequences with background suppression to provide coverage over the whole head and also move the techniques to higher field strengths.
INTRAMURAL
RESEARCH PROJECT
Z01 CL-90004-07 LDRR
October 1, 1999 to September 30, 2000
Title of Project:
Development and Evaluation of Magnetic Resonance Contrast Agents
Principal Investigator:
J.A. Frank, M.D. (Senior Investigator)
LDRR, CC, NIH
Bethesda, MD 20892
Other Personnel:
J. Bulte, Ph.D., LDRR
L.H. Bryant, Ph.D., LDRR
Collaborating Units:
ROB, NCI (M. Brechbiel, Ph.D.)
Univ. of Wisconsin (Ian Duncan, D.V.M.)
Temple Univ. (T. Douglas, Ph.D.)
Staff-Years:
2.25
Human Subjects:
(a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: STAR BURST dendrimers (D) and ultra-small iron oxide particles (USPIOs) were developed as cellular tags in molecular imaging. A series of high generation (G) dendrimers (G=5, 7, 9, 10) was conjugated to 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetate (DOTA), and gadolinium (III) ion was added to the 1/T1 and 1/T2 NMR dispersion profile for generations 5 through 10 dendrimer DOTA complexes. There is an increase in proton relaxation enhancement (PRE) effect from G 5 through G 7, which levels off at generations 9 and 10. Biodistribution studies in rodents using radiolabeled gadolinium 153 chelated to the DOTA-dendrimer complex reveals dose dependent effect for blood half-life and tissue distribution. Cellular labeling was accomplished by incubating G9DOTA-Gd with cells in culture with magnetic resonance imaging of the cells along with fluorescence studies indicating that G9DOTA-Gd was in the cytoplasm of cells. Adding transfection agents in solution with G9DOTA-Gd provided evidence for a molecular switch by altering the PRE properties by shielding other inner-sphere interaction of water with the last coordination site of gadolinium in the DOTA chelate. This served to "turn off" the PRE effects of MR contrast agent, and the switch could be turned on with a change in pH. Further work is planned to determine if the macromolecular contrast agent with a switch can be incorporated into cells and turned on by changing metabolic processes in the cell.
A new class of iron-oxide-based contrast agents, in which the traditional dextran coating was replaced with dendrimers, are known as magnetodendrimers (MD). MD are a T2 star shortening susceptibility contrast agent that are more efficient at shortening the T2 relaxation times of solution compared with other iron-oxide-based agents. The MD also can be used as molecular label, as the dendrimers are used as transfection agents and therefore the MD can easily be incorporated into the cytoplasm of various cell cultures, including malignancy and stem cells, by simple incubation. Alteration in the PRE properties can be demonstrated, along with identification of iron oxide in cells, using Prussian blue staining on histology. Further work is planned to determine the duration that the MD labels will remain visible using in vivo MR imaging techniques.
INTRAMURAL
RESEARCH PROJECT
Z01 CL-90005-05 LDRR
October 1, 1999 to September 30, 2000
Title of Project:
Magnetic Resonance Imaging in Experimental Allergic Encephalomyelitis and Remyelination
Principal Investigator:
J.A. Frank, M.D. (Senior Investigator)
LDRR, CC, NIH
Bethesda, MD 20892
Other Personnel:
E.K. Jordan, D.V.M., LDRR
J. Bulte, Ph.D., LDRR
B.K. Lewis, B.A., LDRR
Collaborating Units:
NIB, NINDS (H. McFarland, M.D.)
Univ. of Wisconsin (I. Duncan, D.V.M.)
NIMH (R. Saunders, D.Phil.)
Staff-Years:
3.0
Human Subjects:
(a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: Magnetic resonance imaging (MRI) scans were performed in myelin- deficient animals in which magnetically labeled progenitor oligodendrocytes were implanted into the spinal cord. Three-dimensional MR microscopy (MRM) was performed ex vivo on the spinal cords with 78 micron isotropic resolution at 4.7 Tesla. MR microscopy showed extensive migration (up to 8.4 mm) of magnetically labeled grafted cells, particularly in the area of the dorsal column. MR images were correlated with histopathologic staining for iron, myelin, astrocytes, and microglia. Both the Prussian blue and myelin staining closely matched the area of contrast enhancement seen on the MR images (Bulte et al PNAS 1999; 96:15256-61). Magnetically labeled precursor oligodendrocytes have also been implanted in the brains of dysmyelinated rats and cell proliferation and migration has also been noted at clinically relevant magnetic resonance imaging 1.5 Tesla units which indicates the possibility of in vivo monitoring the migration and function of neural transplanted stem cells.
Serial MRI studies performed in the marmoset model experimental autoimmune encephalomyelitis (EAE) are being used as part pre-clinical evaluation of new therapies for multiple sclerosis (Jordan, et al., American Journal of Neuroradiology 1999;20:965-76). The serial MRI studies have demonstrated week to week changes in the number and distribution of EAE lesions. MRI stereotactic directed biopsy techniques have been perfected that will allow us to biopsy EAE lesion for histopathologic and microarray analysis to reveal the immunologic, cellular, and biochemical microenvironment of the EAE lesion.
INTRAMURAL
RESEARCH PROJECT
Z01 CL-90006-09 LDRR
October 1, 1999 to September 30, 2000
Title of Project:
Multimodality Radiological Image Processing System
Principal Investigator:
R.L. Levin, Sc.D. (Senior Investigator)
DRD, CC, NIH
Bethesda, MD 20892
Other Personnel:
None
Collaborating Units:
Sensor Systems, Inc. (J. Solomon; I. Heaton)
MedData Research (J. Plum; R. Momenan, Ph.D.)
Staff-Years:
1.0
Human Subjects:
(a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors (a2) Interviews
Summary of Work: During this year, the MRIPS Archive and Retrieval System (MARS) collected over 6 million digital images produced in the Diagnostic Radiology Department, Nuclear Medicine Department, and the in vivo NMR Research Center. These data can be retrieved using the industry standard DICOM (Digital Imaging and Communication) format to workstations and PCs throughout NIH. Currently, data from MARS is being migrated over to the Clinical Center's new PACS (Picture Archiving and Communication System).
A new version of MEDx 3.3 was released this year; including a DICOM wrapper for synthetic or processed MR images. This new DICOM wrapper will allow inclusion of fMRI datasets into the PAC system and thereby should allow for access of these functional or metabolic maps to clinicians in the Clinical Center. A perfusion module was also added to MEDx in order to facilitate the determination of relative cerebral blood volume, relative cerebral blood flow, and mean transit time maps.
Index:
Annual Report of Clinical Research Activities FY 2000
Home
| Public/Patients
|
Professionals/Scientists | Staff
| Contact
Us | Site
Map | Search
For more
information about the Clinical Center,
e-mail occc@cc.nih.gov, or call Clinical
Center Communications, 301-496-2563.
NIH Clinical Center
National Institutes of Health
Bethesda, Maryland 20892-7511