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Laboratory of Diagnostic Radiology Research
Project numbers
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
MRI in Experimental Allergic Encephalomyelitis and Remyelination
Multimodality Radiological Image Processing System
INTRAMURAL RESEARCH PROJECT Z01 CL-90001-06 LDRR
October 1, 1997 to September 30, 1998
Title of Project: Magnetic Resonance Imaging in Multiple Sclerosis
Principal Investigator: J.A. Frank, M.D. (Senior Investigator)
LDRR, CC, NIH, Bethesda, MD 20892
Others Personnel: N. Richert, M.D., Ph.D., LDRR
C. Bash, M.D., LDRR
J. Ostuni, Ph.D., LDRR
B.K. Lewis, B.A., LDRR
M.C. Zierak, B.S., LDRR (CRADA)
R. Kwok, LDRR (CRADA)
Collaborating Units: NIB, NINDS (H. McFarland, M.D.)
Cephalon, Inc. (CRADA)
Novartis, Inc. (CRADA)
Staff-Years: 4
Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. The focus of our project is the use of magnetic resonance imaging (MRI) to understand the pathophysiology of multiple sclerosis (MS) and to determine whether disease activity is altered by treatment with Interferon Beta 1b (IFNB1b), Insulin-like Growth Factors (rhIGF-1), and Altered Peptide Ligand (APL). In the IFNB1b treatment trial, 33 MS patients were followed for a minimum of 2 years with the following observations: 1) The majority of patients treated with IFNB1b show an immediate decrease in the number of blood brain barrier openings (enhancing lesions). This effect of IFNB1b is not sustained, however, and after 24 months of treatment there is a steady increase in enhancing lesions. 2) Cumulative white matter disease or Bulk White Matter Lesion Load (BWMLL) was reduced by approximately 15 percent after 6 to 18 months of treatment and then increased despite the relatively low number of new lesions. 3) Cerebral atrophy which occurs at a rate of about 1 to 2 percent per year in untreated MS patients is prevented by IFNB1b during a period of 18 to 24 months. 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. Whole brain histogram analysis of MT ratios in a cohort of MS patients showed that the histogram peak (Hp) of 0.25 ± 0.01 and histogram mean (Hm)=0.21 ± 0.01 were statistically lower than in control subjects with Hp of 0.27 ± 0.01 (p=0.008) and Hm of 0.23 ± 0.01 (p=0.016) respectively. When histograms were analyzed by quartiles, voxels with low MTR in Qrt 1 (MTR 0-0.124) increased during the baseline period and correlated with BWMLL (r=0.65). IFNB1b had no effect on MTR during the first 6 months of treatment. These results support the findings that IFNB1b acts primarily as a cytostatic agent in the brain and, despite a dramatic response by a decreasing number of contrast enhancing lesions, that the disease process probably continues at a subacute level. These findings appear to occur independent of whether an individual develops significantly elevated Neutralizing Antibodies (NAb) titers to IFNB1b. Only 4/11 patients who developed NAb had sustained elevated titers. Further studies are under way in a small cohort of MS patients to see if MRI-documented disease activity can be used to predict NAb development to biomodulating therapies.
Two clinical MRI-based baseline-versus-treatment trials were started to evaluate the effect of rhIGF-1 (which stimulates oligodendrocyte proliferation) and the effect of APL (which is thought to interfere with the binding of T-cells to antigen presenting cells) on MR measures of disease activity. Phase II studies will be used to determine the effects of these drugs on contrast-enhancing lesion frequency as a primary outcome measure, with BWMLL and MTR histograms as secondary outcome measures. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-90002-04 LDRR
October 1997 to September 30, 1998
Title of Project: Magnetic Resonance Imaging and Spectroscopy
Principal Investigator: J.H. Duyn, Ph.D. (Investigator)
LDRR, CC, NIH, Bethesda, MD 20892
Others Personnel: J. Frank, M.D., LDRR
Collaborating Units: CBDB, NIMH (J.V. Der Veen, Ph.D.)
Staff-Years: 0.75
Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. Significant improvements and developments in fast scanning techniques for functional magnetic resonance (MR) imaging of the brain were achieved by the addition of new prototypic scaleable gradient amplifiers to the MR unit. For Echo planar imaging and spiral scanning, the prototype system increased the duty cycle from 25 to 50 percent, resulting in a twofold improvement in scan speed. These improvements allowed our group to develop and test a new echo-shifted trapezoidal spiral sequence that acquired 30 slice locations/second (compared with 18 slices/second for single-shot spiral imaging) with comparable T2* weighting and temporal shot-to-shot stability to other single-shot techniques. This will allow LDRR to perform signal event based functional MRI studies or dynamic contrast studies of the whole head at 1-second temporal resolution. This will provide valuable information for the timing of activation and neural connections between activated regions of the central nervous system. In addition, post-processing strategies were evaluated and published that allowed for effective and straightforward correction of amplifier nonlinearities. These strategies are currently being implemented as a standard feature for all our fast scanning studies.
This significant new development in proton spectroscopic imaging (MRSI) involves the acquisition of metabolic data without suppression of the water signal using a multislice long echo time sequence. MRSI without water suppression uses the high dynamic range that recently became available with state-of-the-art MRI instrumentation. This new technique will allow for reliable quantitation of the concentration of brain metabolites by using the water signal as a reference. With this approach, corrections can be made to effect the instrumental variation and subject motion on the measured metabolite intensities. In addition to the hardware demands, it requires dedicated post-processing techniques of the data, involving reliable time-domain fitting routines. A prototype software spectroscopic imaging analysis package has been developed, which has demonstrated robust operation on normal volunteers. These developments should lead to the detection of Choline, Creatine, N-Acetyl aspartate and Lactate, with improved sensitivity and improved reliability. This is expected to be important in diagnosis and treatment planning, as well as the characterization of a number of diseases and neurologic abnormalities. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-90003-04 LDRR
October 1997 to September 30, 1998
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
Others Personnel: K. St. Lawrence, Ph.D., LDRR
J. Ostuni, Ph.D., LDRR
B.K. Lewis, B.A., LDRR
Collaborating Units: CBDB, NIMH (V.S. Mattay, M.D.; A. McLaughlin, Ph.D.; D. Weinberger, M.D.)
IRP, NIDA (E. London, Ph.D.; S. Grant, M.D.)
Staff-Years: 2.25
Human Subjects: x (a) Human subjects (b) Human tissues (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. Functional and metabolic magnetic resonance imaging (MRI) techniques have been rapidly evolving and have tremendous potential for clinical brain disorders research. Clinical activation functional magnetic resonance imaging (fMRI) studies are performed at 1.5 Tesla using the blood oxygenation level dependent (BOLD) contrast method and arterial spin tagging (AST) techniques. We have examined healthy controls, patients with schizophrenia, and their siblings using motor tasks of varying complexity and cognitive tasks of increasing working memory load. The results of these studies in over 60 patients strongly suggest that there is functional disturbance in the cortical motor circuitry of patients with schizophrenia compared with healthy controls. Patients with schizophrenia are unable to recruit as focal a response as normal subjects, even to a simple, automatic sequential finger movement task. Patients also showed greater ipsilateral activation in the primary sensorimotor and lateral premotor regions. These abnormalities were exacerbated as the complexity of the task increased.
Using AST techniques, LDRR studied the activation of memory circuits in cocaine addicts as they view cocaine versus control-related cues in a single step-wise paradigm. The purpose of the study is to better understand the role environmental cues play in eliciting drug craving in addicts. No activation associated change in cerebral blood flow (CBF) was observed in volunteers, whereas six of nine cocaine addicts showed minimal (n= 4) changes in CBF. Significant increases in CBF in two cocaine addicts was observed primarily centered in the extrastriatal cortices that could be related to visual cues involving cocaine and its use.
These fMRI studies and others on patients with primary brain tumors were facilitated by using a newly developed real-time analysis package for fMRI and dynamic contrast studies. This new system allows for an interactive fMRI-based Physiological Interview. The investigator can review processed and statistically evaluated activation maps within 20 to 50 seconds after the completion of the MRI acquisition, while the subject is in the scanner in order to take advantage of the experimental conditions.
Multislice 1H MR Spectroscopic Imaging (1H MRSI) studies performed in schizophrenic patients have continued to show low N-Acetyl aspartate (NAA) concentrations in the dorsolateral prefrontal cortex and are predictive of higher D-2 binding potential in the basal ganglia. Patients with schizophrenia and their siblings also had significant reductions in hippocampal NAA as compared with controls. These results may suggest that this pattern of neurochemical abnormality may represent a brain "phenotype" associated with schizophrenia. 1H MRSI was also performed in HIV-positive patients who are receiving Interleukin 2 (IL2) therapy whose side effects include decrease in cognitive function and dementia. Patients evaluated off and on IL2 showed a significant correlation between post-IL2 reductions in NAA/CRE in the prefrontal cortex and impaired performance on the mean digit span subscale. These results suggest neuronal integrity of prefrontal cortex correlates with working memory impairment in HIV-positive adults treated with IL2. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-90004-05 LDRR
October 1, 1997 to September 30, 1998
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
Others Personnel: J. Bulte, Ph.D., LDRR
L.H. Bryant Ph.D., LDRR
Collaborating Units: NIB, NINDS (R. Brooks, Ph.D.)
ROB, NCI (O. Gansow, Ph.D.; M. Brechbiel, Ph.D.)
University of Wisconsin (I. Duncan, D.V.M.)
Staff-Years: 2.25
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. STAR BURST Dendrimers (D), and Ultra Small Iron Oxide Particles (USPIO) were developed for possible cellular tags in molecular imaging. A series of high generation (G) dendrimers (G=5, 7, 9, 10) were conjugated to DOTA and Gadolinium (III) ion was added to the macromolecules. The 1/T1 and 1/T2 NMR Dispursion profiles were measured at 23 degrees C and the 1/T1 ion relaxivity increased from 30 mM-1s-1 for the G=5 to 35 mM-1s-1 for the G=7, with plateau at 36 mM-1s-1 for the G=9 and G=10 D. A similar plateau was observed for 1/T2 with values of 36 mM-1s-1 for G=5, 42 mM-1s-1 for G=7, and 45 mM-1s-1 for the G=9 and G=10 Ds. This "saturation" of ion relaxivity for high generation dendrimers occurred over the entire frequency range studied. The 1/T1 and 1/T2 relaxivities decreased with temperature and for each generation of D studied, implying that slow water exchange of bound water molecules with the bulk solvent limits the relaxivity. This suggests that there is an increase in the rotational correlation times associated with higher generations of dendrimer and, therefore, these large macromolecules do not show significant increases in the ion relaxivity. The total molecular relaxivities increased from 2880 mM-1s-1 for the G=5 to 66960 mM-1s-1 for the G=10 dendrimer. Studies of the G=7, 9, and 10 GdDOTA dendrimers are planned in the rodent along with magnetic resonance imaging to characterize the biodistribution and blood clearance of these macromolecules.
Ultra small iron oxide particles, as specific targeting agents to cerebral endothelial markers for transferring receptor (Tfr), were used to tag the rat oligodendrocyte precursor cell line CG-4 with MION-46L. Using the periodate-oxidation/borohydride-reduction method, mouse anti-rat Tfr monoclonal antibodies (MoAb) OX-26 is covalently linked to the contrast agent MION-46L. The Tfr has been used as a shuttle vector to deliver macromolecules into cells via direct internalization of the Tfr-ligand complex. Incubation of the CG-4 in situ for 48 hours with OX-26-MION46-L in tissue culture medium demonstrated that the CG-4 were packed with magnetic nanoparticles as determined by NMR relaxometry and Prussian Blue staining. CG-4-labeled cells had a viability greater than 95 percent and at 7 days was greater than 80 percent. Further experiments using different amounts of contrast agent and different cellular densities are planned as well as obtaining transmission electron micrographs of the magnetically-labeled CG-4 cells. OX-26-MION-46L preparations will be implanted into a hypomyelinated rat model. Plans are to perform MR imaging following labeled CG-4 implantation and correlate with histopathological staining to determine the degree of cellular migration and remyelination. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-90005-03 LDRR
October 1, 1997 to September 30, 1998
Title of Project: MRI in Experimental Allergic Encephalomyelitis and Remyelination
Principal Investigator: J.A. Frank, M.D. (Senior Investigator)
LDRR, CC, NIH, Bethesda, MD 20892
Other Personnel: N. Richert, M.D., Ph.D., LDRR
E.K. Jordan, D.V.M, LDRR
J. Bulte, Ph.D., LDRR
S. Xu, Ph.D., LDRR
B.K. Lewis, B.A., LDRR
Collaborating Units: NIB, NINDS (H. McFarland, M.D.)
Varmus Lab, NCI (E. Holland, M.D.) (Glioma)
KE, NHLBI (M. Burg, M.D.) (Prostate Cancer)
MC, NHLBI (R. Adelstein, M.D.) (Myosin Deficient)
University of Wisconsin (I. Duncan, D.V.M.)
Staff-Years: 3.5
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. Magnetic resonance imaging (MRI) scans were performed on three Shaking Springer Spaniel Dogs (SD), a large animal model, that has significant diffuse hypomyelination of axons. Various MR imaging measures including single voxel spectroscopic imaging and magnetization transfer imaging were performed in the SD's of 6 weeks, 1 year, and 2 years of age along with age-matched control animals. Clearly delineated MRI findings were observed on routine imaging techniques including evidence of hydrocephalus as a result of white matter (WM) thinning in all SDs compared with normal controls. Hypomyelination resulted in a diffusely homogeneous hyperintensity to be observed in all white matter in the SD. Single voxel long and short echo time spectroscopy demonstrated essentially no differences in ratios of choline to creatine, n-acetylaspartate (NAA) to choline, or NAA to creatine between the two groups of animals. Magnetization transfer ratios and histograms revealed a significant shift in mean and peak MTR histogram at three different MT pulse offset frequencies to lower values in shaking dogs compared with age-matched controls. These results indicate that there is less of a magnetization transfer effect occurring in the SD compared with normal and is most likely a direct result of fewer myelin wraps around axons. The combination of a decrease in cerebral volume, along with an increase in T2 signal intensity characteristics, normal proton spectroscopy, and lower MTR ratio in the white matter of the SD compared with control animals would suggest that amount of myelin and its architecture are important contributors to the MRI appearance in the WM and that MRI may be useful in monitoring the extent of remyelination following transplantation with oligodendrocytes. Studies are planned to implant the SD with fetal oligodendrocytes for longitudinal MRI studies in an attempt to characterize remyelination of axons. As part of this oligodendrocyte transplantation study, we plan to magnetically label the oligodendrocytes using monoclonal antibodies to the transferring receptor that is conjugated to iron oxide particles to see if we can enhance the sensitivity of MR to the extent of remyelination.
The MR research in the SJL EAE model detected early lesions of approximately 100 microns in diameter, and enabled us to observe signal intensity changes associated with the treatment effect in EAE mice. Based on this, several preliminary MR microscopy (MRM) studies were performed to understand the results of the phenotypic expression in genetic alterations in the animal models. MRM in transgenic mice, deficient in a single myosin gene, showed the early development of hydrocephalus prior to skeletal abnormalities. Therefore, MRM could clearly differentiate these animals from the control wild type. The MRM imaging techniques were applied to several other transgenic animal rodent models including a spontaneous prostate cancer model and viral-induced glioblastoma model and allowed for identification and characterization of some of the genetic alterations produced in these animals. (Return to project list)
INTRAMURAL RESEARCH PROJECT Z01 CL-90006-07 LDRR
October 1, 1997 to September 30, 1998
Title of Project: Multimodality Radiological Image Processing System
Principal Investigator: R.L. Levin, D.Sc. (Senior Investigator)
DRD, CC, NIH, Bethesda, MD 20892
Others Personnel: D. Collier, R.T., DRD, CC
Collaborating Units: Sensor Systems, Inc (J. Solomon; H. Tavakoli; T. Ellmore)
Sytel Corporation, (J. Plum; P. Gosakan; S. Nevet)
Meddata (Reza Momenan, Ph.D.)
Staff-Years: 2
Human Subjects: (a) Human subjects (b) Human tissues x (c) Neither
(a1) Minors
(a2) Interviews
Summary of Work: In FY '97, LDRR was transferred from the Office of Director, NIH to the Clinical Center. Over 250 NIH clinicians, researchers, and other staff are using the Multimodality Radiological Image Processing System (MRIPS) file servers, data registry, and image processing software packages provided by this section. This year's accomplishments by MRIPS are as follows. MRIPS deployed new DICOM-compliant buffer machines that facilitate the automatic movement of data from various scanners into the MRIPS Data Registry. Together with the daily collection of all of the computerized radiography, computerized tomography, and magnetic resonance examinations being conducted at NIH, this corresponds to the acquisition and storage of over 8 gigabytes of image data per day by MRIPS. MRIPS activated an automatic multitier migration and retrieval system to move image data back and forth between disk-based, optical-based, and tape-based storage. MRIPS deployed Version 3.0 of the MEDx II image visualization and analysis packages on five different platforms (e.g., Sun SPARC, DEC Alpha, HP PA_RISC, SGI MIPS, and LINUX).
Version 3.0 of MEDx has a complete DICOM-compliant query/retrieve backend and the following new features, most of which were added at the request of the NIH intramural community or supplied by Sensor Systems: Integration of Statistical Parametric Mapping, SPM '96; Threshold Option in Statistics (i.e., only performs statistics on pixels above a threshold); Interactive Display Range (i.e., as user drags slider bar, the display range is modified); Interactive Segmentation Viewer (i.e., strips brain from skull and scalp); Bounds check and Auto Scale/Offset option for Convert (i.e., auto-compute gain and offset when converting between data types); Multiple Graphics/Slice for 3D Contours (i.e., allows for multiple graphics per slice when contouring a bifurcating structure); Annotated Lightbox (i.e., allows display of image information on each slice of the image); Region Growing can create a graphic and uses thresholds (i.e., user can choose to modify the image based on region growing or just create a graphic); Wavelet Transform (i.e., adds various wavelet transformation models); API Function for Adding a User Transform; API function for adding a User Dictionary; Attenuation Options for Rendering (i.e., allows maximum intensity projections to use attenuation factors); Interactive Colorwash (i.e., Colorwash is now updated in real-time); ROI Extensions to functional MRI; and No Result Viewer Option for API Functions (i.e., cancels result viewers from being displayed when running a script). A new tutorial for MRIPS/MEDx has been introduced and courses have started on how to use MEDx for image analysis.
The future plans for MRIPS include: continue to facilitate the exchange of medically related images by permitting data from multiple sources to be accessed from a single archive, independent of the original format or source of the data; enhance the current MEDx package by adding features and functions requested by the NIH ICs; and explore the possibility of extending the current package to nonradiological images, such as electron micrographs and histopathological images. (Return to project list)