DOI:10.2214/AJR.05.1301
AJR 2006; 186:291-296
© American Roentgen Ray Society
Good Things Come in Small Packages: A Review of the Proceedings of the 2005 Academy of Molecular Imaging Meeting
James M. Provenzale1
1 Department of Radiology, Duke University Medical Center, Box 3808, Durham, NC
27710.
Received August 1, 2005;
accepted after revision August 12, 2005.
Address correspondence to J. M. Provenzale.
Keywords: molecular imaging • neuroimaging • PET • PET/CT
Introduction
The 2005 annual conference of the Academy of Molecular Imaging (AMI), held
in Orlando, Florida, on March 18-23, 2005, was a unique forum in which various
types of advances in the fields of molecular diagnostics and therapeutics were
highlighted. The AMI consists of four institutes, each representing a
different facet of molecular imaging. The Institute for Molecular Imaging
represents basic scientists in such fields as molecular and cell biology,
chemistry, physics, and molecular genetics. The Society for Non-Invasive
Imaging in Drug Development represents scientists from academic institutions
and industry working in molecular imaging for drug development and testing.
The Institute for Clinical PET represents clinical scientists, practicing
physicians, and technologists involved in the clinical practices of PET,
PET/CT, SPECT, and other imaging sciences related to molecular imaging. The
Institute for Molecular Technologies represents corporations involved in
invention, manufacture, and provision of molecular imaging devices, products,
and services.
Thus, the AMI represents a broad spectrum of individuals and institutions
concentrated in various types of molecular imaging, ranging from widely
accepted practices already in widespread use (e.g., PET and SPECT) to
innovative and experimental imaging methods. This article reports some of the
novel molecular imaging techniques discussed at the conference that, while
still in the various stages of development, may eventually be of clinical
importance to radiologists.
Imaging of Alzheimer's Disease
Over the past 2 decades, one of the major emerging applications of PET has
been in the development of biochemical markers to assess CNS diseases. Recent
developments along these lines were reviewed by Daniel Silverman of the
University of California, Los Angeles, in his presentation, "Future of
Neuronuclear Imaging in the Practice of Medicine." Silverman noted some
of the important advantages of PET agents for interrogating CNS disease
processes, including biochemical sensitivity, versatility, high
signal-to-background ratio, and analysis using absolute quantification
methods.
One of the most widely used roles of imaging of the CNS is clinical
evaluation of Alzheimer's disease based on the sensitivity of
18F-FDG PET for detection of early Alzheimer's disease. Silverman
addressed the issue of Alzheimer's disease imaging in detail and also
discussed some of the newer applications of 18F-FDG PET for
diseases associated with cognitive decline other than Alzheimer's disease
(e.g., study of cognitive effects of chemotherapy in tumor patients). In
addition, Silverman discussed the utility of some of the newer nuclear imaging
agents for neurologic disease in general. In particular, he noted the
potential of 3'-deoxy-3'-18F-fluorothymidine (18F-FLT),
a recently developed PET tracer designed to image tumor cell proliferation,
for evaluation of brain tumors.
An even more innovative development in molecular imaging for Alzheimer's
disease was outlined by Joseph Poduslo of the Mayo Clinic College of Medicine
in his presentation, "MRI of Individual Amyloid Plaques in Alzheimer's
Disease: Development of Contrast Agents and Imaging Methodology." In
this presentation, MR techniques for direct visualization of the senile (i.e.,
amyloid) plaques that are characteristic of Alzheimer's disease were
highlighted. Poduslo outlined the use of MRI to visualize senile plaques in
transgenic mice that develop amyloid plaques similar to those seen in humans.
Contrast enhancement of the plaques is performed using gadopentetate
dimeglumine-aminohexanoic acid that is covalently linked to a derivative of
human amyloid-ß peptide. Development of a similar technique in humans
might allow earlier diagnosis of Alzheimer's disease and provide a
quantitative method for assessment of Alzheimer's disease therapies.
On a similar note, Poduslo and colleagues have also developed methods for
imaging plaques that do not depend on administration of contrast agents (Figs.
1A,
1B,
1C,
1D,
1E, and
1F). By imaging transgenic mice
at 9.4 T using a pulse sequence based on adiabatic pulses, individual plaques
can be depicted using either a spin-echo sequence or a T2*-weighted
gradient-echo sequence [1].
Although imaging at such high field strengths is not performed in humans, this
finding offers a method for noninvasively following disease progression in
small animal models and for measuring the effects of agents directed against
Alzheimer's disease. Specifically, this technique may enable an understanding
of how various therapies affect the disease, for example, by decreasing the
size of preexistent plaques, inhibiting formation of new plaques, or some
other mechanism [1].
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Fig. 1A —Depiction of amyloid plaques of Alzheimer's disease using high-field
MRI in transgenic mouse model. (Reprinted with permission from
[1]) Coronal T2-weighted image
of in vivo specimen shows amyloid plaques as subtle foci of hypointense signal
intensity. Region of interest has been placed over hippocampus. Series of
images from in vivo imaging was spatially registered with those obtained from
ex vivo images and histologic slices (see B).
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Fig. 1B —Depiction of amyloid plaques of Alzheimer's disease using high-field
MRI in transgenic mouse model. (Reprinted with permission from
[1]) Enlarged image of tissue
outlined by region of interest in A shows multiple foci of hypointense
signal intensity thought to represent amyloid plaques. Numbered arrows
represent identical spatial coordinate positions in common space derived from
spatial registration of in vivo images, ex vivo images, and histologic slices
(see D).
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Fig. 1C —Depiction of amyloid plaques of Alzheimer's disease using high-field
MRI in transgenic mouse model. (Reprinted with permission from
[1]) Coronal T2-weighted image
of ex vivo specimen shows better definition of amyloid plaques shown in
A. Region of interest has been placed over hippocampus.
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Fig. 1D —Depiction of amyloid plaques of Alzheimer's disease using high-field
MRI in transgenic mouse model. (Reprinted with permission from
[1]) Enlarged image of tissue
outlined by region of interest in C shows multiple foci of hypointense
signal intensity thought to represent amyloid plaques. Note that better
depiction of plaques is present on ex vivo image than on in vivo image shown
in B.
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Fig. 1E —Depiction of amyloid plaques of Alzheimer's disease using high-field
MRI in transgenic mouse model. (Reprinted with permission from
[1]) Image of mouse brain
stained with thioflavin S for fluorescence microscopy of ß-amyloid
plaques that has been spatially matched to brain slices seen in A and
C. Region of interest has been placed over hippocampus. Scale bar
represents 500 µm.
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Fig. 1F —Depiction of amyloid plaques of Alzheimer's disease using high-field
MRI in transgenic mouse model. (Reprinted with permission from
[1]) Image showing area within
region of interest shown in E depicts fluorescent-labeled
ß-amyloid plaques. Coordinate system indicates that hypointense foci
shown in B and D represent plaques. Scale bar represents 200
µm.
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Imaging of Stem Cell Migration
As interest in stem cell therapy has grown, a need for tracking stem cell
migration has arisen. Such tracking can be performed by a number of methods.
Joseph Frank of the National Institutes of Health delivered a presentation,
"MRI of Cell Tracking," that described the use of MRI to track
spatial migration of stem cells and other types of cells (such as
lymphocytes), which can be accomplished by incorporating moieties that are
visible on MRI, such as superparamagnetic iron oxide (SPIO) particles, into
cells. Incorporation of SPIO particles into cells can be accomplished by
complexing the particles to transfection agents
[2]. Important features of the
approach used by Franks' group are that it is straightforward, does not
require novel synthesis or co-valent bonding of antibodies or proteins to the
dextran coating of the SPIO particles, and uses Food and Drug
Administration-approved materials
[3].
It is important to note that this process does not have any short- or
long-term toxicity and does not alter the physiologic properties of the cells,
such as their functional/metabolic properties or their capacity for
differentiation. Using techniques such as these, Frank and coworkers
[2] have been able to track
migration of stem cells for a variety of purposes, such as to monitor
migration of T cells in experimental autoimmune encephalomyelitis in mice (a
mouse model of relapsing-remitting multiple sclerosis)
[4] and to directly detect
ongoing angiogenesis within tumors
[5] (Figs.
2A and
2B). Targeted delivery may even
be accomplished using an external magnet to guide migration to selected sites,
which opens intriguing possibilities for delivery of cellular-based gene
therapy or immune therapy as part of repair, replacement, and treatment
strategies [6].
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Fig. 2A —Use of stem cells labeled with superparamagnetic iron oxide
nanoparticles to directly detect ongoing angiogenesis within tumors.
(Reprinted with permission from
[5]) Coronal spin-echo image of
tumor in control mouse in which labeled stem cells have not been infused shows
tumor (arrows) as subtle region of abnormal signal intensity.
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Fig. 2B —Use of stem cells labeled with superparamagnetic iron oxide
nanoparticles to directly detect ongoing angiogenesis within tumors.
(Reprinted with permission from
[5]) Coronal spin-echo image of
tumor in mouse in which labeled stem cells have been infused shows tumor
(arrows) as ring of hypointense signal within periphery of tumor,
indicating regions of angiogenesis.
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Targeted MR Contrast Agents for Imaging of Angiogenesis
In his presentation, "Nanoparticle Targeting of
ß3," Gregory Lanza, of Washington
University School of Medicine, described a multimodal platform technology for
molecular imaging that can be used across imaging techniques such as
sonography, nuclear medicine, and MRI. The vehicle consists of a
lipid-encapsulated perfluorocarbon nanoparticle. The native particle can be
used for imaging using sonography, or the particle can be conjugated with
gadolinium particles for MRI or radionuclide tracers for nuclear imaging. The
conjugation process greatly increases the contrast agent payload. For
instance, Lanza reported conjugation of 94,000 gadolinium molecules per
particle. This approach overcomes the primary limitation of MRI for molecular
imaging—low signal contrast. Thus, the interpreter can take advantage of
MRI's inherently high spatial resolution. In addition, strategies that further
increase the signal contrast, such as spacing gadolinium molecules from the
outer surface of the nanoparticles to increase water interactions, were
described.
Lanza also described a modulation of the nanoparticles that allows
selective targeting for angiogenesis imaging. Various ligands can be added to
the surface of the nanoparticles against specific targets such as angiogenic
features, fibrin, and collagen. A specific example provided by Lanza was
targeting against ß3-integrin, which is
expressed on the luminal aspect of angioblasts in neovasculature, thereby
rendering the nanoparticles a contrast agent directed against angiogenesis
[7]
(Fig. 3). The particles can
also be loaded with therapeutic agents that allow the particles to be used as
an antiangiogenesis agent. Imaging using this model can be performed on a
1.5-T scanner, thereby raising the possibility that imaging could be performed
in a clinical environment rather than solely on the very high field strength
MR scanners often used for small animal imaging.
Contrast-Enhanced Sonography for Assessment of Angiogenesis
The possibility of using sonography for molecular imaging has strong appeal
because it is a relatively inexpensive, portable imaging technique that is
frequently used in imaging-guided interventional procedures. Alexander
Klibanov of the University of Virginia School of Medicine provided a
presentation on the use of contrast particles that are specifically targeted
to diseased tissue such as tumors using ligands bound to the sonography
contrast agents. Klibanov discussed at length the use of gas-filled
microbubbles for targeted imaging of tumors by means of targeting of receptors
on intravascular entities, for example, receptors on the inner surface of the
endothelial cell layer of vasculature
[8]. Gas-filled microbubbles
are preferred to liquid-core microemulsions and liposomes because they offer
the highest acoustic impedance mismatch and highest backscatter signals
[8].
The upper size limit of such microbubbles for use as an intravascular
contrast agent is defined by the diameter of capillaries—approximately
several micrometers [8]. Such
contrast agents are, therefore, not diffusible and remain confined to the
vascular compartment (unlike standard MRI contrast agents)
[9]. The biodistribution, in
vivo behavior, and low risk of safety concerns with such agents have been
described in detail by Klibanov in various publications
[8,
9]. Although the sensitivity of
sonography to detect gas-filled microbubbles is reported to be quite high,
additional imaging and postprocessing techniques can be used to further
improve the target-to-background ratio.
One such technique is image subtraction, in which sonographic images using
low-intensity ultrasound beams are obtained after administration of targeted
contrast microbubbles and again a few seconds later after destruction of the
microbubbles using high-intensity ultrasound beams
[8]. Another image is then
obtained using low-intensity ultrasound beams, and the two images are then
coregistered to make contrast material deposition more apparent (Figs.
4A,
4B, and
4C).
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Fig. 4A —In vitro illustration using microbubbles targeted to
streptavidin-coated petri dish showing method for postprocessing of in vivo
contrast-enhanced sonography images. (Reprinted with permission from
[8]) Sonographic image of
microbubbles adhering to petri dish using low-intensity ultrasound beam
(mechanical index of 0.1) shows microbubbles as echogenic layer
(arrow).
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Fig. 4B —In vitro illustration using microbubbles targeted to
streptavidin-coated petri dish showing method for postprocessing of in vivo
contrast-enhanced sonography images. (Reprinted with permission from
[8]) Sonographic image showing
a high-intensity ultrasound beam (arrow; mechanical index of 1.5)
being applied to destroy same microbubbles depicted in A.
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Fig. 4C —In vitro illustration using microbubbles targeted to
streptavidin-coated petri dish showing method for postprocessing of in vivo
contrast-enhanced sonography images. (Reprinted with permission from
[8]) Sonographic image using
low-intensity ultrasound beam (mechanical index of 0.1, same as that used to
obtain A), which was obtained within seconds after A shows
destruction of microbubbles as evidenced by their absence (arrow).
This image is then subtracted from image shown in A to increase
conspicuity of microbubbles.
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In his presentation, Klibanov discussed the use of contrast-enhanced
sonography using microbubbles to depict tumor angiogenesis by using the
microbubbles conjugated to echistatin, which is a protein that binds with high
affinity to ß3-integrin (and which has
been described earlier in this review as a target for MR contrast agents).
Such techniques would provide a direct measurement of angiogenesis as opposed
to the indirect measurement using hemodynamic parameters such as blood
volume.
Klibanov and colleagues have also used such microbubbles to assess
angiogenesis in the setting of ischemia and assess proangiogenic therapies
[10]. For instance,
microbubbles of this type have been used to monitor
ß3-integrin expression in a rodent model
of limb ischemia in which hind-limb ischemia was produced by iliac artery
ligation [10]. Untreated
animals with hind-limb ischemia were seen to have marked reductions in blood
flow and oxygen tension within the affected limb that partially remitted
within a few weeks. These untreated animals were found to have intense signal
from integrin-targeted microbubbles within affected tissue (Figs.
5A,
5B, and
5C).
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Fig. 5A —Use of contrast-enhanced sonography using microbubbles targeted
against integrin (marker of neovascularity) to assess angiogenesis after
experimental creation of limb ischemia in rodent model and treatment with
proangiogenic substance, fibroblast growth factor-2. In these images, red and
yellow indicate high retention fraction of integrin-targeted microbubbles and
green and blue reflect low retention fraction. (Reprinted with permission from
[10]) Color-coded
contrast-enhanced sonography image in control tissue (i.e., no ischemia) shows
very low retention fraction of microbubbles, indicating low levels of
angiogenesis.
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Fig. 5B —Use of contrast-enhanced sonography using microbubbles targeted
against integrin (marker of neovascularity) to assess angiogenesis after
experimental creation of limb ischemia in rodent model and treatment with
proangiogenic substance, fibroblast growth factor-2. In these images, red and
yellow indicate high retention fraction of integrin-targeted microbubbles and
green and blue reflect low retention fraction. (Reprinted with permission from
[10]) Color-coded
contrast-enhanced sonography image in ischemic tissue in untreated animal
shows relatively modest retention fraction of microbubbles, indicating
moderate angiogenic response to ischemia.
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Fig. 5C —Use of contrast-enhanced sonography using microbubbles targeted
against integrin (marker of neovascularity) to assess angiogenesis after
experimental creation of limb ischemia in rodent model and treatment with
proangiogenic substance, fibroblast growth factor-2. In these images, red and
yellow indicate high retention fraction of integrin-targeted microbubbles and
green and blue reflect low retention fraction. (Reprinted with permission from
[10]) Color-coded
contrast-enhanced sonography image in ischemic tissue in animal treated with
fibroblast growth factor-2 shows very high retention fraction of microbubbles,
indicating strong angiogenic response to ischemia.
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In the treatment group of rodents, sustained-release capsules containing
the proangiogenic substance fibroblast growth factor-2 were implanted within
muscle perfused by the common iliac artery at the time of arterial ligation.
The subsequent signal from integrin-targeted microbubbles within ischemic
muscle was even more intense and was more prolonged than in control animals
(Figs. 5A,
5B, and
5C). The differences in signal
intensity in the two groups of animals correlated well with differences in
immunofluorescent staining for
ß3-integrin in arterioles in affected
tissue.
Conclusion
The 2005 Academy of Molecular Imaging meeting provided a wide range of
insights into the future of diagnosis and therapeutics using molecular
techniques. Some of the techniques reviewed here (e.g., 18F-FLT for
brain tumor imaging) are likely to be used in the clinical setting in the near
future. Other techniques are still in the experimental stage, but they stand
as examples for radiologists of the exciting developments being made in the
rapidly expanding field of molecular imaging. For those interested in learning
of more recent advances in the field of molecular imaging, the 2006 meeting of
the Academy of Molecular Imaging will be held March 26-29 in Orlando,
Florida.
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Introduction
Imaging of Alzheimer's Disease
