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Overview of
non-invasive imaging
in rodents
10/2003
Kathy Gabrielson
Goals for this lecture
•  Introduce the multiple non-invasive imaging
modalities used in animal research for human
diseases
•  Provide examples
•  Present advantages
•  Introduce you to JHU faculty contacts for these
imaging techniques
Advantages of non-invasive
imaging in rodent studies
Less animals are used when assessing multiple time points.
Animals can be used as their own controls pre-experiment
Reduce costs- reduce time
Allow better in vivo understanding of disease mechanism in
vivo
Imaging can be quantitative and less subjective
These imaging modalities are established methods used for
human disease assessment
Imaging modalities
reviewed
•  Ultrasound/echocardiography- cardiovascular function and
structure
•  MRI- structure, linked to NMR for biochemistry
•  CT- structure
•  PET -metabolism or gene expression
•  SPECT- metabolism or gene expression
•  Optical - Fluorescence or photon imaging- gene expression
Ultrasound
imaging
Reduction and Refinement application
with non-invasive imaging
•  Longitudinal monitoring of the progression of a disease
•  For example:
•  10 week experiment- the design is to sample 10 mice each
week for an endpoint (histopathology). N=100
•  Similar 10 week experiment- (echocardiography) design- to
monitor heart function- 10 mice are evaluated each week
through out the 10 week period N=10
•  Advantage - Reduction of mice needed for a single experiment
(90%)
Ultrasound
M-mode of the left ventricle
mouse
Y-axis distance from transducer
X- time
M-mode sound wave is focused
in a beam similar to this probe
through the heart
rat
Progressive Cardiomyopathy in Doxorubicin
treated mouse
Week 3
Week 5
Week 7
control doxorubicin
Week 8
M-mode of the left ventricle
Magnetic Resonance
imaging
MRI Applications
•  Imaging can be linked to biochemistry-example, MR
guided spectroscopy, rgweiss@rad.jhu.edu
•  Physiology can be evaluated- tumor vessel volume
and permeability, zaver@mri.jhu.edu
•  Structure/anatomy evaluated-, white and grey matter
structure, susumu@mri.jhu.edu
Magnetic resonance imaging
MRI- Application in rodents
•  Intrinsic contrast allows imaging of:
hydrocephalus- ventricles are dilatedinfarct/stroke
White matter vs grey matter
•  Contrast agents are used to improve image quality
Gd-diethyenetriamine penta-acetic acid
contrast agents can be linked to antibodies to target
specific cells
Imaging set up
MRI
MRI example 2
PCr
[β -P]ATP
RV
LV
Pi
20 PPM
10
• Chacko et al Am J Physiol (2000) 279:H2218
0
-10
-20
Computer-assisted
tomography
CT
Computer-assisted
tomography
CT
•  3D x-ray technique
•  3D mouse images with 100 x 100 x 100 micron
resolution obtained in a few minutes
•  Contrast generated by differences in tissue
absorption –
Instrumentation -MicroCT and MicroPET
CT
PET
NIH
Overlay of CT and PET images
Both Imaging modalities complement each other
CT Resolution = 200 microns
PET Resolution = 1.8 mm
250 g Rat
brain
muscle
ribs
heart
Sagittal Slice
heart
Coronal Slice
PET imaging
Movie of rat in PET
gantry
Positron emission tomographyapplications
•  Ability to tract labeled molecules, at the level of the whole
animal
to study transport, metabolism, excretion,
pharmacokinetic and pharmacodynamic time course
•  Neuroreceptor imaging
•  Metabolism-glucose analog 18F 2-DG
tumor metabolism
•  Gene expression
lung tumor xenograph in nude ratExamination of cell metabolism using
Positron emission tomography
•  Images show the uptake
and distribution of the
labeled 18FDG in the
lung permitting analysis
and localization of tumor
metabolic function
[11C]Raclopride for D2DR in rat striatum
High specific
activity stud
y
Blocking study
(1 mg/kg cold RAC)
SPECT Imaging
MicroSPECT Systems
at JHU
JHU Prototype
MicroSPECT System1
1Division of Medical Imaging Physics
Department of Radiology
Coronal Images of the Mouse’s Chest (slice 21-60)
80 sec/view, image matrix size = 80x80, voxel size = 0.35 mm3
OS-EM 6 iterations, subset =8, Butterworth filter fc=0.3 cycle/pixel, order=8
Optical imaging
•  Uses a label that produce light or fluorescence when
stimulated
•  bioluminescence (luciferase-luciferin) or fluorescence
(green fluorescent protein)
•  novel photon detection system that allows quantitative
whole-body imaging of bioluminescence generated by
the luciferase reporter
Bioluminescence Imaging:
Luciferase
Days after PC-3M-luc inoculation
C Contag, Neoplasia 2000; 2:41
MRI
CT
PET/SPECT
optical
US
noninvasive
√
√
√
√
√
longitudinal
√
√
√
√
√
Reduction of animals
√
√
√
√
√
Image time/animal
30 minutes to
hours
minutes
30 minutes
minutes
minutes
resolution
0.05mm
0.5 mm
1.5mm
0.5mm
< 0.05mm
sensitivity
uM-mM
nM
nM
structure
√
√
√
√
function
NMR
√
√
√
quantitative
√
√
√
√
√
√
radioactivity
Light
fluorescence
√
√
Gene expression
modality
magnetic field
cost
$50/hour
anesthesia
√
X-ray
$150/ animal
√
√
Sound
waves
$50/animal
√
Advantages of imaging to
improve rodent studies
Less animals are used when assessing multiple time points.
Animals are used as their own controls pre-experiment
Reduce costs- reduce time
Allow better in vivo understanding of disease mechanism
Imaging can be quantitative and less subjective
These imaging modalities are established methods used for
human disease assessment
Imaging contacts
at JHU
•  PET-SOM, Marty Pomper,
•  SPECT- SOM, Ben Tsui, SOPH Jonathan Links
•  MRI- SOM, Zaver Bhujwalla, Susumu Mori
•  MRI-NMR Vadappuram Chacko, Bob Weiss
•  Optical, Dianne Griffin, John Isaacs, David Johns
•  Ultrasound, Kathy Gabrielson and James Weiss
•  In Vivo Cellular Molecular Imaging Center
http://icmic.rad.jhmi.edu
Review reference
•  ILAR (2001) 42:187-262 ) entire issue dedicated to
imaging
Acknowledgements
Dr. Marty Pomper, JHU Radiology, PET
Dr. Susumu Mori, JHU Radiology, MRI
Dr. Wayne Mitzner, JHU, SOPH, EHS, CT
Dr. Benjamin Tsui, JHU Radiology, SPECT
Dr. Jonathan Links, JHU,SOPH, EHS, SPECT
Dr. Zaver Bhujwalla, JHU, Radiology, MRI
Dr. Bob Weiss, JHU, SOM, MRI,NMR
BRB- imaging
facility
•  State of the art multi-modality
imaging facility will open early
2004 in the JHU School of
Medicine Broadway Research
Building