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Laboratory of Diagnostic Radiology Research
The Laboratory of Diagnostic Radiology Research (LDRR) was transferred this fiscal year from the Office of the Director, NIH into the newly formed Imaging Sciences Program. LDRR does not have a traditional clinical component role in the Clinical Center and was formed as a result of a congressional mandate in 1989 to establish a research program in Radiology at the NIH. LDRR's mission is to serve as a focal point and training program promoting basic and clinical research in medical imaging and related fields.
LDRR has two main objectives: 1.) to train U.S. or permanent resident radiologist and nuclear medicine M.D.s and Ph.D.s to teach techniques and skills used to perform "Imaging Research" not readily available at other academic institutions; and 2.) to focus its efforts in the areas of Magnetic Resonance Imaging (MRI), Magnetic Resonance Spectroscopy (MRS), molecular imaging using novel contrast agents or techniques, image processing, and the development of new approaches in order to achieve these goals.
A summary of FY '98s clinical and basic research accomplishments follow:
- Dr. Nancy Richert, in collaboration with Dr. Henry McFarland's group, NINDS, demonstrated using Magnetization Transfer (MT) MRI techniques preliminary evidence that Interferon Beta-1b does not seem to protect normal appearing white matter from continued subacute injury in Relapsing Remitting Multiple Sclerosis (RRMS) patients.
- Dr. John Ostuni in LDRR has tested a mathematical model that allows for the direct comparisons and identification of differences between the MT characteristics of multiple sclerosis (MS) patients and healthy controls. This mathematical transformation will provide important insight into how treatment affects the MT histogram of MS patients. It also will allow for direct comparison in multi-Institute trials in which different MT pulse sequences are used. We also determined that cerebral atrophy on MRI appears to be slowed in RRMS patients receiving Interferon Beta-1b over a period of 2 years of treatments compared to a natural history study of the individual's disease.
- LDRR initiated two Phase II clinical trials based upon a cross over design in RRMS patients. MRI measures of RRMS disease activity, such as number and volume of Blood Brain Barrier (BBB) disruption, volume of white matter lesion load, MT ratio histograms, and MRS imaging, are monitored monthly during 6-month baseline natural history periods and then subsequently for a period of 6 to 9 months after treatment is initiated. LDRR also started treatment trials using recombinant insulin-like growth factor-1, which has been shown to close the BBB and induce remyelination in experimental rodent models of MS, and altered peptide ligand, which blocks one with interaction of T-cells and antigen presenting cells. We expect to have complete enrollment for both studies by mid-1999.
- Using MR microscopic imaging techniques, we have detected white matter lesions in acute experimental allergic encephalomyelitis (EAE) in the SJL mouse model of 100 microns in diameter. These studies employed ultrasmall superparamagnetic iron oxide particles (MION-46L) as a MR contrast agent. The MR characteristics of hypomyelination were investigated in a springer spaniel dog (SSD) model. We observed that hypomyelination resulted in a diffusely homogeneous hyperintense signal in the white matter of these animals compared to age-matched controls. In addition, MT imaging revealed a significant shift in ratio of bound to free water in the white matter probably reflecting the degree and number of myelin wraps around axons. Future plans with Dr. Ian Duncan, University of Wisconsin, are to label fetal oligodendrocytes, transplant these into SSD pups to induce remyelination, monitor remyelination by MRI, and correlate results to histopathology.
- Dr. Jeff Duyn, the head of the Advanced MR Development area of LDRR, and his team have made significant improvements in fast imaging techniques for functional MRI (fMRI) and proton multislice MRS Imaging (MRSI). LDRR was able to obtain a twofold increase in scan speed as a result of improvements in single shot spiral imaging in combination with new prototype gradient amplifiers added onto LDRR's 1.5 Tesla MR unit. LDRR can now acquire, using echo shifted trapezoidal spiral techniques, 30 slice locations/sec in comparison to 7 to 8 slices/sec obtained using the clinical MR units. This technique will allow for increased temporal resolution in cerebral activation studies and dynamic contrast studies used to measure cerebral perfusion. LDRR has also developed a new proton MRSI technique that does not require water suppression. This will allow for direct intra- and inter-subject comparisons of normalized cerebral metabolic levels in healthy controls and patients with cerebral nervous system pathology. This new pulse sequence will aid in the validation of MRSI results and provide the basis for future clinical trials using a measure of cerebral metabolites as an outcome measure.
- LDRR continued its collaborative studies of fMRI with Dr. Weinberger's group from NIMH on healthy controls, patients with schizophrenia, and their age-matched siblings. Over 60 individuals with schizophrenia and controls have been evaluated using fMRI techniques with various neurophysiological paradigms. The results strongly suggest a functional disturbance in the cortical motor circuitry of patients with schizophrenia compared with controls. Schizophrenic patients and their siblings were also found to have significant reductions in hippocampal n-acetyl aspartate levels as compared with aged-matched healthy controls using MRSI techniques. These results may suggest that this pattern of neurochemical abnormality may represent a brain "phenotype" associated with schizophrenia. Furthermore, work will be required to verify these results using the new MRSI pulse sequence that allows for quantitation of cerebral metabolites.
- In order to integrate fMRI into clinical decision making schemes, for the purpose of improved patient care, LDRR developed an interactive fMRI examination with specific applications towards physiological interviews and the study of cerebral physiology. LDRR developed a technical hardware and software solution that allows for capture of raw data from the MRI unit on-the-fly, and performs the reconstruction, registration and statistical analysis; and displays the results within seconds after completion of an fMRI examination. It presently takes 6 to 8 hours to process and analyze an fMRI data set. Plans are to incorporate this system onto the NIH systems and the Suburban-NIH MRI facility to be used as part of a brain attack protocol for treatment of acute strokes.
- LDRR has synthesized and quantitated the NMR relaxation properties of large molecular weight STAR BURST Dendrimers covalently bonded to Gadolinium DOTA. These compounds were found to be useful as intravascular contrast agents, which are more efficient at altering tissues and relaxation properties, thereby changing MR signal intensities. In addition, these dendrimer Gadolinium DOTA complexes have large numbers of available binding sites for attaching monoclonal antibodies or other molecules that can attach to specific antigens or receptors on cells. Preliminary work on characterizing the biodistribution and cellular uptake of the dendrimer Gadolinium DOTA contrast agents to cells is under way.
- LDRR has also labeled two different monoclonal antibodies to endothelia cell antigens with ultrasmall superparamagnetic iron oxide particles (MION-46L) and has been able to demonstrate, using NMR relaxometry and imaging, the uptake of MION-46L into cells. MION-46L has been attached to monoclonal antibodies for vascular endothelial growth factor and intracellular adhesion molecule receptor. There are additional plans to see if the monoclonal antibody MION-46L combination can be targeted to a specific antigen expressed on endothelial cells and to use MR imaging to identify the areas of uptake in tumors or in inflammation. In addition, a MION-46L monoclonal antibody to transferring receptor has been made. It will be used to shuttle the MR contrast agent into cells such as oligodendrocytes, which in turn can be used for transplantation into the central nervous system as part of an attempt to monitor remyelination in experimental systems.
- LDRR's Multimodality Radiological Image Processing (MRIPS) group collects and stores all digital imaging data (i.e., Computerized Tomography (CT), MRI, Computerized Radiography (CR)) in the DRD, In Vivo NMR Research Center, and LDRR for use by NIH scientists. The MRIPS group was able to deploy DICOM-compliant buffer machines that facilitate the automatic movement of data from various scanners into the new image data registry. Together with the daily collection of all CR, CT, and MRI exams at NIH, we are now collecting over 8 gigabytes of images per day. Moreover, MEDx version 3.0 was released, which provides imaging to scientists on campus.