Transcript Multinuclear MR Spectroscopy and Spatial Localization

Spatial Localization and
Multinuclear MR Spectroscopy
Techniques
Navin Bansal, Ph.D.
Associate Professor and Director of MR Research
Proton MR Image
 MR images contain
anatomical information
based on the distribution
of protons and the relative
proton relaxation rates in
various tissues
 MR images are based on
proton signals from water
and fat
MR Spectrum
 MR spectroscopy
determines the presence
of certain chemical
compounds
 Stress, functional
disorders, or diseases can
cause the metabolite
concentration to vary
 Metabolite concentrations
are low, generating ~10,000
times less signal intensity
than the water signal
Chemical Shift
1H

The electron cloud around each
nuclei shields the external
magnetic field

Because of differences in
electron shielding, identical
nuclei resonate at different
frequencies

The resonance frequency in the
presence of shielding  is
expressed as:
MR spectra
-CH3
-OH
, ppm
2
1
0

= (1- )Bo
Where  is the gyromagnetic
ratio and Bo is the external
magnetic field strength
Chemical Shift

The frequency shift increases with field strength. For example,
shift difference between water and fat
(water - fat)
at 1.5 T is 255 Hz
at 3.0 T is 510 Hz
 = (water - fat) 106/Bo, in ppm units
water-fat is 3.5 ppm independent of field strength

By convention
o Signals of weakly shielded nuclei with higher frequency are
on the left
o Signals of more heavily shielded nuclei with lower frequency
are on the right

Chemical shift of water is set to 4.7 ppm at body temperature
MR Spectrum: Peak Characteristics
1H
MR Spectrum from Brain
Water Signal
Metabolite Signals
Spatial Localization
Surface Coil Localization
 Simple surface coil acquisition
 Depth Resolved Surface Coil Spectroscopy,
DRESS
Single Volume Localization
 Image Selected In Vivo Spectroscopy, ISIS
 Point Resolved Spectroscopy, PRESS
 Stimulated Echo Acquisition Mode, STEAM
Multiple Volume Acquisition
 Chemical Shift Imaging, CSI
Surface Coil Acquisition
A simple loop of wire and associated
circuit tuned to the desired
frequency are placed directly over
the tissue of interest to obtain
spectra
A surface coil
Advantages
 Easy to build and does not require
specialized pulse sequence
RF
Pulse-acquire sequence
 Superb SNR and filling factor
Disadvantages
 Must be close to region of interest
 Changing ROI is difficult
 Inhomogeneous RF field
Spin Echo Imaging Sequence
90°
180°
90°
RF
Gz
Gy
Gx
TE
TR
Depth Resolved Surface Coil
Spectroscopy, DRESS
A disk-shaped slice is excited parallel
to the surface coil with a frequency
selective RF pulse in the presence of a
gradient.
Advantages
 Relatively simple
 Suppresses signal from superficial
tissue
RF
Gslice
 Multi-slice acquisition, SLIT-DRESS
Disadvantages
 T2 loss
 Partial Localization
Single Volume Localization
RF
Gx
RF
Gy
RF
Gz
 Localized spectra is
obtained from a single
volume of interest (VOI)
 Localization is achieved by
sequential selection of
three orthogonal slices
 The size and location of
VOI can be easily
controlled
 Anatomic 1H images are
used for localizing the VOI
Single Volume Localization
Image selected in
vivo spectroscopy,
ISIS
Point resolved
spectroscopy,
PRESS
Stimulated echo
acquisition mode,
STEAM
Image Selected In Vivo Spectroscopy ISIS
One Dimensional
180o
Slice inversion
90o
No inversion
RF
Gslice
Subtraction
Two acquisitions with and without inversion of a
selected slice are obtained and subtracted
3D ISIS
90°
RF
RF
RF
RF
RF
RF
RF
RF
1
180°
90°
2
90°
180°
3
4
5
180°
90°
180°
180°
90°
180°
180°
90°
180°
180°
90°
180°
6
7
90°
180°
180°
8
Gx
Gy
Gz
T1
T1
T1
+
-
+
+
+
-
 A set of eight pulse
sequences with one,
two, or three slice
selective inversion
pulses are used
 The signal is localized
to a VOI by adding
signals from sequences
1, 5, 6, and 7 and
subtracting signals
from 2, 3, 4, and 8.
Image Selected In Vivo Spectroscopy, ISIS
Advantages
 No T2 loss –
31P
MRS
 Less sensitive to gradient imperfections
 Can be used with a surface coil
Disadvantages
 Dynamic range
 Subtraction error due to motion
Point Resolved Spectroscopy, PRESS
180°
180°
90°
RF
Gx
Gy
Gz
TE1/2
(TE1+TE2)/2
TE2/2
 A slice-selective 90o pulse is followed by two sliceselective 180o refocusing pulses
 Achieves localization within a single acquisition
 Suitable for signals with long T2 – 1H MRS
Stimulated Echo Acquisition Mode, STEAM
90°
90°
90°
RF
Gx
Gy
Gz
TE/2
TM
TE/2
 Three slice-selective 90o pulses form a stimulated
echo from a single voxel.
 Achieves localization within a single acquisition
 Only half of the available signal is obtained
 Can achieve shorter TE than PRESS
Effects of MR Parameters on
PRESS spectra
 Repetition Time, TR
 Number of Signal Averages
 Echo Time, TE
 Voxel Size
Effect of Repetition Time (TR)
TR = 1500 ms
TR = 5000 ms
NAA
Cho Cr/PCr
Cr/PCr
Effect of Signal Averaging
8 Averages
64 Averages
256 Averages
Effect of Voxel Size
1 cc
2 cc
4 cc
8 cc
Effect of Echo Time, TE
TE = 144 ms
TE = 288 ms
Short TE 1H Brain Spectrum
Healthy volunteer
Additional Peaks
Glx
2.05-2.45 ppm
3.6 - 3.8 ppm
mI
3.56
ppm
Glucose
3.43
3.8
ppm
ppm
And more
The Lactate Doublet
Tumor spectra: showing no NAA,  Cho,  mI,  lactate
Lipids and
lactate
Inverted
lactate
Upright
lactate
Single Voxel Spectroscopy: Overview
 Simplicity
 Flexibility in voxel size and position
 Accurate definition of VOI
 Excellent shim and spectral resolution
 Many voxels within the same dataset
Chemical Shift Imaging
90°
RF
G
G
G
slice
y
z
 Multiple localized
spectra are obtained
simultaneously from a
set of voxels spanning
the region of interest
 Uses same phaseencoding principles as
imaging
 No gradient is applied
during data collection, so
spectral information is
preserved
CSI Spectral Map
 Display of all spectra
 Underlying reference
image shows voxel
position
 Individual spectra can be
displayed enlarged
 Spectral map can be
archived together with
the reference image and
the CSI grid
CSI Data Analysis
Image showing voxel position
Spectrum from a voxel
Spectral Map and Metabolite Images
NAA
NAA/Cho
CSI: Overview
Advantages
 Acquisition of multiple voxels
 Metabolite images, spectral maps, peak
information maps, and results table
 Many voxels within the same dataset
Disadvantages
 Large volume – more difficult to shim
 Voxel bleeding
 Large datasets
Multinuclear MR Spectroscopy
Important Nuclei for Biomedical MR
Nucleus
Spin
, MHz/T
Natural
Abundance
Relative
Sensitivity
1H
1/2
42.576
99.985
100
2H
1
6.536
0.015
0.96
3He
1/2
32.433
.00013
44
13C
1/2
10.705
1.108
1.6
17O
3/2
5.772
0.037
2.9
19F
1/2
40.055
100
83.4
23Na
3/2
11.262
100
9.3
31P
1/2
17.236
100
6.6
39K
3/2
1.987
93.08
.05
Important Nuclei for Biomedical MR
1H
– Neurotransmitters, amino acids, membrane
constituents
2H
– Perfusion, drug metabolism, tissue and cartilage
structure.
13C
– Glycogen, metabolic rates, substrate preference,
drug metabolism, etc.
19F
– Drug metabolism, pH, Ca2+ and other metal ion
concentration, pO2, temperature, etc
23Na
31P
– Transmembrane Na+ gradient, tissue and cartilage
structure.
– Cellular energetics, membrane constituents, pHi,
[Mg2+], kinetics of creatine kinase and ATP
hydrolysis.
1H
MR Spectroscopy
1H
MR Spectra of the Brain
Short TE
NAA
Cr
Glx Ins
Cho
Glx
Lipids
Cr
ppm
4.5
3.5
3.0
2.5
2.0
1.5
1.0
0.5
Important 1H Signals
N-Acetyl aspartate (NAA)
O
CH3-C-NH-CH-CH2-COOH
CH2-COOH
2.02, CH3
2.52, CH2
2.70, CH2
4.40, CH
Creatine (Cr), phosphocreatine (PCr)
NH
NH2-C-N-CH2-COOH
CH3
3.04, CH3
3.93, CH2
•NAA is a neuronal marker
and indicates density and
viability of neurons.
•It is decreased in glioma,
ischemia and degenerative
diseases.
•Cr is a marker of aerobic
energy metabolism
•Cr signal is constant even
with pathologic changes
and may be used as a
control value
• However, isolated cases
of Cr deficiency may occur
in children
Important 1H Signals
Choline (Cho), choline compounds
CH3
CH3-N-CH2-CH2-OH
CH3
3.24, CH3
3.56, CH2
4.07, CH2
•Cho compounds are
involved in phospholipid
metabolism of cell
membrane.
•Increase Cho mark tumor
tissue or multiple sclerosis
plaques
Glutamate (Glu), glutamine (Gln)
HOOC-CH2-CH2-CH-COOH
NH2
NH2-CH2-CH2-CH-COOH
NH2
2.1, CH2
2.4, CH2
3.7, CH
•Glu is a neurotransmitter,
Gln a regulator of Glu
metabolism
•It is hardly possible to
detect their signals
sepratly. The signals are
jointly designated “Glx”.
Important 1H Signals
Lactate (Lac)
•Lactate is the final
product of glycolysis
CH3-CH-COOH
1.33, CH3
4.12, CH
OH
Taurine (Tau)
NH2-CH2-CH2-S-OH
3.27, NCH2
3.44, SCH2
Myo-inositol (Ins)
PO4
PO4
PO4-
PO4
-
PO4-
PO4-
•Cells examination indicates
taurine synthesis in
astrocytes
•Ins marks glia cells in
brain
-
•It can be detected in
ischemic/hypoxic tissue
and tumors indicating lack
of oxygen
3.56, CH
•It is decreased in hepatic
encephalopathy and
elevated in Alzheimer’s
disease.
31P
MR Spectroscopy
31P
MR Spectra of Normal Tissue
4
Muscle
2
3
6
1
4
7
Heart
7
Liver
65
6 5
Kidney
3
6
4
4
7 6 5
4
2
3
3
3
1
2
2
2
1
1
1
Brain
10
0
ppm
-10
-20
1.
-ATP
2.
-ATP
3.
-ATP
4.
PCr
5.
PDE
6.
Pi
7.
PME
Important
31P
Adenosine triphosphate (ATP)
-16.5
-7.8
-2.7
-ATP
-ATP
-ATP
Phosphocreatine (PCr)
0
PCr
Signals
ATP is the energy currency in
living systems
- and -ATP have
contributions from ADP, NAD
and NADH
-ATP is uncontaminated and
used for quantification
PCr is used for storing energy
and converting ADP to ATP
It is absent in liver, kideny and
red cells
It is used as an internal
reference for chemical shift
Important
Inorganic Phosphate (Pi)
3.7 to 5.7
Pi
31P
Signals
•Pi is generated from
hydrolysis of ATP and
increased in compromised
tissue
•Its chemical shift is sensitive
to pH
Phosphomonoester (PME)
5.6 to 8.1
PME
•PME signal contains
contribution from membrane
constituents and glucose-6phosphate and glycerol-3
phosphate.
•It is elevated in tumors
Phosphodiester (PDE)
0.6 to 3.7
PDE
•PME signal contains
contribution from membrane
constituents
Measurement of pH by
31P
MRS
Pi
PME
30
20
10
PCr
ATP
0
-10
Shift, ppm
H2PO4-  HPO42- + H+
-20
pKa = 6.75
  obs -  H PO 

pH = pka + log  
 HPO -  obs 
2
4
2-
4
Effect of Exercise on
31P
MRS
Detection of myocardial infarctions by
31P-MR spectroscopy
Beer et al., J Magn Reson Imaging. 2004;20:798-802.
A Lesson from 31P MRS
Tumor Microenvironment
Poor Vascularization
and Perfusion
Tumors are
expected
to be acidic
Hypoxia
Anaerobic Glycolysis
Aerobic Glycolysis
Increased Acid Production
pH of Tumors and Normal Tissue
Electrode Measurements
A: pH POT
pH
5.6
Skeletal Muscle
Brain
Skin
Glioblastomas
Astrocytomas
Meningiomas
Brain Metastases
Malignant Melanomas
Sarcomas
Mammary Ca.
Adenocarcenomas
Squamous Cell Ca.
6.0
6.4
6.8
7.2
7.6
 Normal
 Tissue

pH of Tumors and Normal Tissue
MRS Measurements
B: pH
pH
5.6
6.0
6.4
6.8
7.2
7.6
NMR
Skeletal Muscle
Brain
Skin
Heart
Sarcomas
Squamous Cell Ca.
Mammary Ca.
Brain Tumors
Non-Hodgkin Lymp.
Misc Tumors
 Normal
 Tissue

Bansal, et al.
23Na
MR
Spectroscopy and Imaging
Biological Importance of Sodium
 Sodium and other ions are
inhomogeneously distributed across the
cell membrane.
 A transmembrane sodium gradient
reflects a dynamic equilibrium between
Na+-K+ ATPase versus passive or
mediated flux.
 The sodium gradient may be altered in
certain diseased states.
Bansal, et al.
Biomedical 23Na NMR
 23Na is the second most sensitive nucleus
for biomedical NMR.
 Intra- and extracellular sodium resonate at
the same frequency.
 Two approaches to distinguish between
different sodium pools:
Paramagnetic Shift Reagents
Multiple Quantum Filters
Bansal, et al.
23Na
Na+e
Shift Reagents
Na+e
Na+e
Na+i
Na+i
Na+e
Na+e
SR
SR Na+e
Na+e
SR
SRs are
membrane
impermeable
negatively
charged chelates
of a lanthanide
metal ion. They
interact with
extracellular Na+,
causing its signal
to be shifted
away from
intracellular Na+.
Action of a
Typical Shift Reagent
With SR
Nae
Nai
10
0
Without SR
10
ppm
Nai + Nae
0
ppm
23Na
Shift Reagents
O
P
O
O
P
O
O
O
O
O
P
O
O
O
O
O
O
O
Dy
O
O
O
O
P
O
Dy(PPP)27-
N
O
O
O
P
O
P
O
Dy
N
O
O
N
O
O
O
O
P
N
O
DyTTHA3-
P
O
O
N
O
O
P
O
O
O
P
O
Tm
O
N
N
N
TmDOTP5-
O
O
O
In Vivo 23Na Spectra after TmDOTP5- Infusion
Ext
9L Glioma
Int
Muscle
Heart
Liver
Brain
Urine
x5
ppm
Kidney
40
30
20
10
0
-10
Bansal, et al.
Nai in Perfused RIF-1 Tumor Cells
Significance: ** p < 0.01 (with vs without EIPA)
Relative Nai Signal Intensity
200
37 oC
45 oC
**
180
**
160
**
37 oC
w/o EIPA
with EIPA
140
120
produced a 6070% increase in
Nai+.
 The
EIPA
100
80
 Hyperthermia
-10 -20 -10 0
10 20 30 40 50 60 70 80
increase in
Nai+ is mainly due
to an increase
Na+/H+ antiporter
activity
Time, min
Bansal, et al.
Multiple-Quantum Filters
MQFs depend only on the relaxation
properties of 23Na. Thus, they do not
produce any known physiological
perturbation to the biological system and
cab be applied to humans.
Disadvantages
• Low signal-to-noise ratio
• Some Nae+ contribution
Bansal, et al.
MQ Filtered
23Na
NMR
 “Transiently bound” Na+ can pass through a MQ filter.
|-3/2>
|-1/2>
|1/2>
|3/2>
SQ outer
SQ inner
SQ outer
“Free” Na+
DQ
TQ
DQ
“Transiently Bound” Na+
 Concentration of macromolecules within the
cytoplasm is relatively high while the extracellular
milieu is largely aqueous.
SQ and TQ Filtered 23Na Spectra
of a Phantom
Aqueous
Agarose
40 mM
TmDOTP5-
SQ
ppm
50
10%
Agarose
TQ
0
-50
ppm
50
Agarose
0
-50
Bansal, et al.
Composition of Tissue Compartments
200
m Eq/L H2O
180
HCO3
Cl -
Nonelectrolytes
160
H2CO3
Nonelectrolytes
HCO3-
140
-
H2CO3
HCO3-
HPO4-2
K+
120
100
Na+
Na+
Cl -
80
Cl -
60
Na+
40
20
0
SO4-2
Mg+2
K+
Ca+2
HPO4-2
SO4-2
Organic
acids
Protein
Blood
plasma
Ca+2
Mg+2
K+
Interstitial
fluid
HPO4-2
SO4-2
Organic
acids
Protein
Protein
Mg+2
Intracellular
fluid
H2CO3
3D MQF 23Na Imaging Pulse Sequence
RF
Readout
Phase
Encoding 1
Phase
Encoding 2
PD
(100 ms)
TAU ()
(3 ms)
DELTA ()
(3 µs)
TE
(4 ms)
3D SQ and TQF 23Na MRI of a Live Rat
SQ
TQF
Caronal Sections
SQ and TQF 23Na MRI of Rat In vivo
Effect of CCl4 Treatment
Control
saline
lung
CCl4 Treated
bladder
SQ
agarose
heart
kidney
TQF
Liver