Download Mapping Metabolic Activity with Hyperpolarized

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Hyperpolarization is the nuclear spin polarization of a material
far beyond thermal equilibrium conditions.1 In MR imaging
research, hyperpolarization is used to increase the number of
nuclei in one spin orientation, which increases the polarization
level, in order to increase the signal generated by a sample.
Researchers are using hyperpolarized
Published studies have shown the
Carbon 13 ( C) MR to map metabolic
feasibility of imaging the C signal
activity in the heart and in tumors and
in pre-clinical animal studies.2,3,4 In
to probe the activities of a specific
2013, the first human imaging study
metabolic pathway using an injected
evaluating the safety and feasibility
substrate, pyruvate. Hyperpolarized 13C
of hyperpolarized 13C pyruvate was
pyruvate is an investigational drug;
successfully conducted on 31 patients
and imaging 13C requires additional
with prostate cancer.5 This study
investigational MR components, such
has further energized the research
as specialized coils and software.
community and several leading
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academic institutions are pursuing
human studies with hyperpolarized 13C.
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Imaging metabolism
of the heart
Researchers at Sunnybrook Research
Institute have recently published their
first human study of four subjects
utilizing hyperpolarized 13C MR in the
heart6, led by Charles Cunningham, PhD,
Senior Scientist, Physical Sciences at
Sunnybrook Research Institute and an
Associate Professor, Department of
Medical Biophysics, at the University
of Toronto. This feasibility study was
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Tech Trends
Mapping Metabolic Activity
with Hyperpolarized Carbon 13
Figure 1. (A) [1-13C] pyruvate;
(B) 13C-bicarbonate. Initial
imaging results using HP-13C
metabolic imaging of the human
heart demonstrating feasibility.
A
B
Images courtesy of
Sunnybrook Research Institute.
conducted to demonstrate that this
study. And, his research is generating a
The images show the different regions
type of imaging could be successfully
higher image quality than he expected,
of the heart and the metabolic
performed. Ultimately, the goal is
which he says further demonstrates
conversion of pyruvate to CO2 and
to help clinicians understand how
the feasibility of C metabolic imaging.
then to bicarbonate, Professor
metabolism plays a role in heart failure
With continued improvements in
Cunningham explains. The bicarbonate
in order to help guide treatment.
scanner hardware and software,
signal is an indicator of how much
Professor Cunningham is very excited
metabolic flux there is of pyruvate in
that in the near future he will be able to
the mitochondrial metabolic pathways.
improve spatial resolution and visualize
This information is potentially very
beyond what he has currently captured.
useful, he adds.
“Detecting early changes in metabolism
could be used to individualize
treatments,” Professor Cunningham
says. “Cardiologists are treating
patients with the same drugs, but
13
“We’ve been very focused on the
For example, it is not known how
some respond while others don’t. It is
imaging aspect, rather than the
metabolism changes as heart failure
possible there are imaging markers—
spectrum. We’re imaging metabolites
progresses. 13C MR imaging could
metabolism being a promising
with good spatial resolution,” he
potentially help identify when these
one—that can help clinicians tailor
explains. “We can see the bicarbonate,
metabolic changes are happening. “If
treatments to the patient.”
which is produced after injecting
we could predict which patients are
the contrast agent, reflective of the
going to do worse and treat them
metabolism in the mitochondria in the
accordingly, then that could make a
Since MR is routinely used to
image cardiac patients, Professor
Cunningham believes it is very feasible
difference in outcomes,” Professor
heart muscle.”
Cunningham says.
to add a 10-minute 13C MR scan to the
Thus far, pyruvate is the only metabolite
that has been used in human studies.
While Dr. Cunningham believes other
Charles Cunningham, PhD,
agents will also be investigated in the
is a Senior Scientist of Physical Sciences at
Sunnybrook Research Institute in Toronto,
and an Associate Professor in the
Department of Medical Biophysics at the
University of Toronto.
GEHEALTHCARE.COM/MR
future, hyperpolarized 13C pyruvate
is the first probe to be investigated
in humans.
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Figure 2. Example of cardiac-gated,
slice-selective pulse-and-acquire
human 13C spectra following
administration of hyperpolarized
[1-13C] pyruvate. (A) shows
10 seconds and (B) 25 seconds
after injection.
Figure courtesy of the
University of Oxford.
Understanding normal
changes in the heart7
At the University of Oxford, Damian
Tyler, PhD, Associate Professor of
Physiological Metabolism, has
been studying real-time myocardial
hearts using hyperpolarized 13C. Over
the past 10 years, his work has moved
from translational to pre-clinical and
now into humans.
“The first study we are undertaking
in humans is trying to observe and
understand normal changes in how
the heart uses fuels to make energy,”
Professor Tyler explains. “Overnight,
when we are fasting, the heart switches
to primarily using the fats stored in the
body, whereas when we have a meal, it
switches back to sugars.”
This work can have implications in
There is another key aspect of this work
first few patients, and the initial results
that Professor Tyler can extrapolate
match the pre-clinical studies that he
into clinical practice that would benefit
has conducted. In the pre-clinical
patients. “A key question that we can’t
studies, when the subject is fasting
answer well with current techniques
and the heart is using fat, there is
is in patients with stress-induced
not much conversion into CO2. When
chest pain whether they would benefit
eating, more of that pyruvate is turned
from revascularization. Would that
into CO2 and bicarbonate. Professor
restoration of blood flow to that region
Tyler and his group have measured
of the heart improve their health?”
the balance between the use of sugars
and fats.
While Professor Tyler points out that
MR, SPECT, and CT are all good at
“We can expand this to diabetics, who
measuring perfusion, it is challenging
have a much stronger preference for
for these modalities to measure or
using fats than sugar because of the
image an area of the heart that is
lack of insulin in Type I diabetes and
ischemic or not getting enough blood
the insensitivity to insulin in Type II
and oxygen, which can lead to cell
diabetes. These patients are less
damage or cell death.
able to take sugar up into cells and
therefore less able to turn sugar in
CO2,” Professor Tyler says.
understanding metabolism in people
with Type I and Type II diabetes, for
example. 13C is a unique tool to do that
non-invasively and in vivo, he says.
Damian Tyler, PhD,
Associate Professor of Physiological Metabolism,
University of Oxford.
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metabolism in normal and diseased
Professor Tyler’s group has scanned the
answer to diagnosing and stratifying
imaging could also assist with clinical
cardiac patients. That is where
drug trials. Pharma is interested in
hyperpolarized 13C could add clinical
knowing whether or not a drug has
benefit,” Professor Tyler adds.
hit its target early in the development
stage. For some drugs, there is a very
Cancer therapy monitoring
7
Oncology is another clinical area
where hyperpolarized 13C research is
GE Healthcare’s SPINlab™
underway in human subjects.
Kevin M. Brindle, FMedSci, Professor,
Department of Biochemistry and
“The beauty of hyperpolarized 13C is that
it can directly measure metabolism,
and only cells that are alive can
metabolize,” he continues. “So we can
potentially better stratify if patients
should be revascularized.”
The other areas where Professor Tyler
sees benefits include monitoring drug
therapies for cancer and potentially
identifying genetic alterations that
Cancer Research UK Cambridge
Institute, University of Cambridge, is
leading a group at the Institute seeking
to find new imaging techniques for
detecting early treatment response and
for monitoring disease progression.
“It is clear that functional imaging, in our
rapid metabolic effect, and that’s what
Professor Brindle is hoping to visualize
with hyperpolarized 13C.
However, Professor Brindle explains
that it is important to note these
changes can indicate whether a
drug has hit its target, but they don’t
necessarily indicate outcomes—such
as, did the drug kill the tumor cell? His
group is developing another Dynamic
Nuclear Polarization tracer, fumarate,
that they hope will show whether the
cell died. So a metabolic response
can show the drug hit the target and
case metabolic imaging, can provide
then downstream, another tracer
a much earlier indication of treatment
can indicate whether the treatment
response,” Professor Brindle says.
killed the cell. Ultimately, that’s the
Metabolic changes can occur within
information that is important to
history or genetic predisposition to
24-48 hours of treatment, he adds.
clinicians, Professor Brindle adds.
cardiomyopathy, or sudden cardiac death.
Cancer is a genetically heterogeneous
In a pre-clinical animal study, the
disease: not all patients with a similar
team has had success in visualizing
type of tumor or cancer respond in
early evidence of disease progression
the same way to the same therapy. In
in a pancreatic tumor model. Now,
may exist in people with a family
“If we can combine our traditional
cardiac MR study with the metabolic
imaging, and then add perfusion, we
could have a strong one-stop-shop
addition to helping monitor treatment
Professor Brindle and his team
response in the clinic, metabolic
are embarking on a study using
hyperpolarized 13C metabolic imaging
Kevin M. Brindle, FMedSci,
Professor, Department of Biochemistry and
Cancer Research UK Cambridge Institute,
University of Cambridge.
“
The gain in sensitivity using hyperpolarized 13C
is huge. We are talking about a 10,000-fold gain
and that, in any scientific technique, is clearly
a paradigm-shifting event. It allows you to see
things that you would never have seen before.
„
Professor Kevin M. Brindle
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“
The beauty of hyperpolarized 13C is that it can directly
measure metabolism, and only cells that are alive can
metabolize, so we can potentially better stratify if
patients should be revascularized.
„
Professor Damian Tyler
for therapy monitoring in humans with
clearly a paradigm-shifting event. It
aiming to do with this work is change
lymphoma, glioblastoma, breast, and
allows you to see things that you would
clinical practice, but we are a long way
ovarian cancers. They have imaged one
never have seen before.”
from that right now. We are just taking
patient and expect to image several
more in the next few months.
Cambridge is using spiral EPI-based
acquisitions and spatial spectral pulses
The challenge with C, he explains, is
for selective excitations of individual
the short lifetime of the polarization,
resonances. One of the key advantages
and therefore fast imaging sequences
is that spectra have relatively few
must be employed to address this. “The
signals and that is important when
polarization is very short-lived, only a
rapidly acquiring a series of images.
13
20-30 second half-life, so we only have
2-3 minutes to get everything done—
the patient, have it travel through the
blood stream to the target, and then
collect the imaging data very quickly,”
Professor Brindle says.
clinical information can we get, and
that’s where we are at. I have no doubt,
based on the pre-clinical studies and
the first published human clinical
trial, that we can image this signal in
patients. We have some idea of what
However, there is an enormous
we can do with the technique, and now
benefit: “The gain in sensitivity using
we are looking to test that in the clinic.
hyperpolarized 13C is huge. We are
talking about a 10,000-fold gain and
that, in any scientific technique, is
“We are at the beginning of this journey,”
Professor Brindle adds. “What we are
References
1. Ardenkjaer-Larsen JH, Fridlund B, Gram A, et al. Increase in
signal-to-noise ratio of > 10,000 times in liquid-state NMR.
Proc Natl Acad Sci U S A 2003;100(18):10158-10163.
2. Rider OJ, Tyler DJ. Clinical Implications of Cardiac
Hyperpolarized Magnetic Resonance Imaging. Journal
of Cardiovascular Magnetic Resonance 2013, 15:93.
http://jcmr-online.com/content/15/1/93.
3. Rodrigues TB, Serrao EM, Kennedy BWC, Hu D-E, Kettunen
MI, Brindle KM. Magnetic resonance imaging of tumor
glycolysis using hyperpolarized C-13-labeled glucose.
Nat Med 2014;20(1):93-97.
4. Serrao EM, Kettunen MI, Rodrigues TB, et al. MRI with
hyperpolarised [1-13C] pyruvate detects advanced pancreatic
preneoplasia prior to invasive disease in a mouse model.
Gut 2016;65:465–475.
5. N
elson SJ, Kurhanewicz J, Vigneron DB, et al. Metabolic
Imaging of Patients with Prostate Cancer Using
Hyperpolarized [1-13C]Pyruvate. Sci Transl Med
2013;5(198):198ra108.
6. Cunningham CH, Lau JY, Chen AP, et al. Hyperpolarized 13C
Metabolic MRI of the Human Heart: Initial Experience.
Circulation Research, Sept 2016. Published ahead of print.
http://dx.doi.org/10.1161/CIRCRESAHA.116.309769.
7. H
yperpolarized C-13 pyruvate and other hyperpolarized
C-13 substrates may only be used for human applications
under an approved research study (IND or equivalent). MR
data collection (including images and/or spectra) involving
hyperpolarized C13 compounds may require investigational
MR coils and MR system software.
Dr. Charles Cunningham, PhD, is a Senior Scientist of Physical Sciences at Sunnybrook Research Institute in Toronto, and an Associate Professor in the
Department of Medical Biophysics at the University of Toronto. He received his PhD in medical biophysics from the University of Toronto.
Sunnybrook Research Institute (SRI) is a fully affiliated research and teaching hospital with the University of Toronto. Research spans three Toronto-based
campuses: Sunnybrook Health Sciences Centre, Holland Musculoskeletal Centre and St. John’s Rehab. Total research funding for 2014/2015 was $96.6 million.
Kevin M. Brindle, FMedSci, is a Professor in the Department of Biochemistry and Cancer Research UK Cambridge Institute at the University of Cambridge.
The primary aim of his laboratory is to develop clinically applicable imaging methods that can be used to detect early tumor responses to treatment. Through
a partnership with GE Healthcare, his team is developing nuclear spin hyperpolarization as a novel tool for molecular imaging.
The University of Cambridge is a collegiate public research university in Cambridge, England. Founded in 1209, Cambridge is the second-oldest university
in the English-speaking world and the world’s fourth-oldest surviving university.
Damian Tyler, PhD, is an Associate Professor of Physiological Metabolism at the University of Oxford. He earned his MSci in Medical Physics and his doctorate
from the University of Nottingham. He is a British Heart Foundation Senior Research Fellow and a Tutorial Fellow in Medicine at Somerville College. He’s also an
associate member of the Cardiac Metabolism Research Group (CMRG) and leads the Oxford Metabolic Imaging Group.
Oxford University Medical School is the medical school of the University of Oxford. It is a component of the Medical Sciences Division, and teaching is carried
out in its various constituent departments. The Medical School was ranked 1st in the world by the 2016 Times Higher Education rankings of Universities for
Pre-Clinical, Clinical and Health Studies.
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Tech Trends
from injecting the labeled material into
“The key question now is what useful
the first steps in that direction.”