Outline
Proton Magnetic
Resonance Spectroscopy
Magnetic Resonance: Analytic
Analytic, Biochemical and
Imaging Techniques - HST584J
February 24th 2010
Eva-Maria Ratai, Ph.D.
Department of Radiology MGH
A. A. Martinos Center for Biomedical Imaging
Email: [email protected]
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling or Spin – Spin Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
¾ MRS other than brain
¾ MRS other than 1H
Proton MR Signal –
Why?
Spectral content of brain MR signal
¾ Spectroscopy gives us a glimpse into the neurochemical state of the brain
water
¾ Diagnostics
• Metabolic changes in pathology may not be apparent from anatomic
images
• Metabolic changes may precede anatomic changes
¾ Differentiate among different diseases
• e.g. grade and classify tumor types by MRS patterns
¾ Monitoring therapeutic treatments
• e.g. Radiation necrosis and tumor recurrence look the same in
conventional images, very different metabolically
fat
ppm
¾ Understand pathogenesis of diseases
Frequency
Proton MRS Signal -
Why do protons in different chemicals have
slightly different MR frequencies?
Spectral content of brain MR signal
water
suppressed
water
Larmor frequency : ω L = γB0
NAA
Cho
5
4
3
2
1
0
PPM
Water Signal is 10,000 x
greater than that of other
metabolites
5
4
3
Cr
Cr2
2
B0: external magnetic field
γ: gyromagnetic ratio
Ch
Cho
NAA
1
Cr
0
PPM
Chemical Selective Saturation
(CHESS)
5
4
3
2
1
PPM
1
Electronic Shielding
Shielding of electrons around the nucleus
Electrons are induced to circulate around
the nucleus about the direction of the
applied magnetic field B0
Larmor frequency : ω L = γB0
NAA
Cho
Cr2
5
4
2
1
ωL = γ Beff
B eff = (1 − σ )B 0
σ : shielding constant
PPM
Arises from secondary magnetic field produced by
circulation of the electrons in the molecule.
γ ⋅ B0
2π
γ
νi =
B0 (1 − σ i )
2π
r
e2 2 r
r B0 sin 2 θ
4 me
ν0
= −Δσ
ν0 ≈
γ ⋅ B0
2π
θ is the angle between r and B0
Nucleus is exposed to an effective field that is somewhat smaller than the applied
field B0
Beff = B0 − σ ⋅ B0
Beff = B0 (1 − σ )
σ = shielding constant
Reference Standards and Solvents
• Measure resonance frequencies relative to that of a standard chemical
• Shielding is directly related to the electron density surrounding the
nucleus and by the position of the nucleus in the molecule.
• Resonance frequency are proportional to magnitude of B0
• This relationship makes it difficult to compare NMR spectra taken
on spectrometers operating at different field strengths.
• Absolute magnitude of shielding constant would require a precise
knowledge of both B0 and resonance frequency
• Not feasible to measure magnetic field with this precision
• Feasible to measure small differences in frequencies under
constant field.
Δν
e r
B0
2 me
which for a single electron at a distance r from the nucleus is given by:
μ=−
Chemical Shifts
νi =
r
ω=
There will be an associated induced magnetic moment μi
Cr
3
Angular velocity:
“Electronic
Shielding”
Shielding
Operator frequency
1) Tetramethy silane (TMS): resonances at low frequency (why), single sharp
peak, inert, soluble in most organic solvents, volatile.
Arbitrarily placed at 0 ppm
2) 2,2 dimethyl –2- silapentane –5 sulfonic acid
The ppm scale: Chemical shift δ
δ=
ν Sample − ν ref
⋅ 106 ppm
ν ref
• The δ are positive if the sample absorbs to high frequency of the reference
absorption
• Note by designating the shift as a fraction of B0 we make it field independent
δ = σ ref − σ sample ⋅ 106 ppm
Chemical Shifts
Chemical Shift
Chemical shift – expressed in units at parts per million (ppm) on a δ
scale which appears along the bottom of the spectra.
Chemical shift differences (in Hz) increase when B0 increases
νi =
γ
2π
B0 (1 − σ i )
Shielding is directly related to the
electron density surrounding the
nucleus and by the position of the
nucleus
uc eus in the
t e molecule.
o ecu e
Increasing Frequency at
fixed B0
deshielding
shielding
The electron density of the hydroxyl
proton is less because oxygen is more
electronegative than the carbon
Illustrated by d of methyl halides:
CH3F < CH3Cr < CH3Br < CH3I
4.26
3.05
2.68
2.16
2
Outline
Quantification
1
3
2
• The intensity of absorption (the area under the peak) is
proportional to concentration of the nucleus
• Still valid for comparisons between different molecules
• This makes NMR spectroscopy a quantitative tool
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
Spin-Spin coupling
Dipolar coupling
Total field seen by proton A depends on whether
proton B is “spin-up” or “spin-down”
B0
• Secondary environmental effect
• Superimposed on the chemical shift
• J coupling – measured in Hz, does not depend on
magnetic field
• Interaction between nuclear spins through electrons
Spin-Spin Coupling
Spin-Spin Coupling
Energy
Energy
A↓ B↓
νB
A↓ B↑
νA
A↓ B↓
3
A↓ B↑
νA
Typical for
C-H or
H-C-C-H
J = 0
νA
J < 0
νB
Typical for
H-C-H
3
2
1
J > 0
Δm = ±1
4
νB
A↑ B↑
1
J > 0
νB
A↑ B↓
νB
A↑ B↑
Δm = ±1
4
2
A↑ B↓
A and B are 2
non-equivalent
protons
Proton B
Proton A
Typical for
C-H or
H-C-C-H
J = 0
νA
J < 0
νB
Typical for
H-C-H
3
Spin-Spin Coupling
Spin-Spin Coupling
Energy
A↓ B↓
4
A↓ B↑
3
2
A↑ B↓
A↑ B↑
1
J > 0
Δm = ±1
J = 0
J < 0
Typical for
C-H or
H-C-C-H
• Two NMR active nuclei can also interact with each other via electrons (Fermions).
• With Pauli's exclusion principle, it will be required to have electrons in any
molecular orbital to have spins antiparallel to each other.
• Fermi contact term: magnetic interaction between an electron inside an atomic
nucleus and that nucleus. This term relies on the probability of finding an electron
at the site of the two coupled nuclei.
Typical for
H-C-H
Multiplicity
Spin-Spin Coupling
Distance has an effect on spin spin splitting.
Peak splitting is not observed among chemically equivalent protons
H-C-H, which is called geminal coupling. 12-15Hz
H-C-C-H, which is called vicinal coupling 0-5 Hz
Unsaturation can promote splitting over longer distances, for example in
substituted benzenes.
• The Height ratio for the splitting pattern ( for spin ½ nuclei) will follow the
numbers in Pascal's triangle.
•
•
•
•
•
• The resonance for a set of protons will be split (M
for multiplicity) into M = 2nI+1 peaks where n = # of
equivalent protons on adjacent carbons and I =
nuclear spin.
• The N+1 Rule
• For nuclei where I = ½ (e.g. 1H, 13C, 31P, 19F, 195Pt),
this equation collapses to M = N+1.
Ex vivo vs. in vivo NMR spectra
High resolution brain extract spectrum
Cr, PCr
1H
NMR @ 600 MHz (14T)
Cr
Ex vivo NMR
spectrum of human
WM brain extracts
measured @ 14T (600
MHz) with single pulse
sequence (TR=20 s,
NS=64).
Ex vivo liquid state, can measure
precisely…
- Well separated
- Easy to quantify
NAA
Cr
Lac
Cho
PCho
GPC
MI
MI Glu
MI MI
Gln
Tau
Myoinositol
Tau
Gly
Cho
Suc
Glu/
Gln
Glu/
Gln
Lac
NAA
MI
4.0
Gln
Glu
Glu
GABA
GSH Asp
3.5
3.0
2.5
2.0
1H MRS from the
WM acquired with a
singe voxel PRESS
sequence
(TR/TE=2300/30,
NS=160) at 3.0T
MRI scanner.
Lac
NAA
Cr
NAA,
Gln
NAAG
+ Glu
Gln
Glu
NAA,
Asp
Ace,
GABA
δ / ppm
NAA
Val
Cho Cr
Cr
MI
Glx
PPM
δ / ppm
4
1H
NMR spectroscopy
identifies different cell types
Brain Cells
Neurons
Astrocytes
Oligodendrocytes
Microglia
g
Other immune cells
Endothelial cells
Blood cells
Neurons
Astrocytes
news-info.wustl.edu/images/2002/synapse.jpg
Urenjak, J Neurosci,1993
Outline
Regional Variation
NAA
Cho Cr
White Matter
Pons
Cerebellum
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
Spin echo
TE = 144 ms
Voxel size 8 cc
Ref.: Nouha Salibi
N-Acetylaspartate
NAA and neurons
in Alzheimer’s Disease
N-Acetylaspartate (NAA):
Peak at 2 ppm
~10 mmol/kgww
Found in neurons in the adult brain
Marker of neuronal density and
viability
Precursor for neurotransmitter NAAG
Participates in formation of myelin
lipids (Acetyl source)
Regulates protein synthesis
Storage of aspartate
Regulates Osmosis
H
H
H
Ref.: Zimmerman
Decrease in NAA
Loss / injury of neurons
Replaced by tumor
Hypoxia
Demyelination
Increase in NAA
Canavan’s disease
Neuronal Counts by Stereology
vs. NAA
Cheng et al. Magn Reson Imaging 2002
5
SIV Macaque in vivo MRS:
Acute Changes
Paradox: NAA Change Reversible!
7
1.00
5
7
2.0x10
00
0.0
0
5
10
15
20
Days Post Inoculation
25
30
0
-5
-10
*
-15
-20
0
5
10
15
20
25
30
Days Post Inoculation (dpi)
Plasma Viral Loads NAA/Cr Changes
in the frontal cortex
NAA/Cr Mea
asured Ex-vivo
¾ Multiple sclerosis
¾ Epilepsy
¾ Stroke
St k
¾ HIV- associated neurologic disease
(NeuroAIDS)
10
7
4.0x10
% Changes NAA/Cr
Pla
asma Viral Load (Eq./mL)
6.0x10
• Reliable Marker of Neuronal Injury
• Sensitive to early, reversible injury
• Late, correlates with neuronal number
Total Creatine (Cr):
Creatine and Phosphocreatine
Peak at 3 ppm (also at 3.9ppm)
Energy metabolism (generation
of ATP), PCr acts as a reservoir
for the generation of ATP
ATP + Cr
ADP + PCr
PCr
Cr + Pi
Good internal standard
Thought to remain unchanged in
most diseases and with age
5–10 mmol/kgww
H
H
H
Glycerol
Phosphocholine
Phosphocholine
Decreased in high grade
astrocytomas
MI
Glu/
Gln
0.65
160 180 200 220 240 260 280 300 320 340
Synaptophysin
Greco et al. MRM 2004
Lentz et al, Radiology 2005
• Cho is an umbrella term for
several soluble components of
brain myelin and fluid-cell
membranes
• Resonance at 3.2 ppm
• Normally not soluble
• Pathological
P th l i l alterations
lt ti
iin
membrane turnover (tumor,
leukodystrophy, multiple
sclerosis) result in a massive
increase in MRS-visible Cho
Myo-Inositol (MI):
• Peak at 3.5-3.6 ppm
• Visualized at short TE
• 4 to 8 mmol/kgww
• Glial specific
• Elevation may reflect gliosis
• Proposed inflammatory marker
NAA
GPC
3.22
3 T in vivo
0.70
Myo--Inositol
Myo
PC
Cho Cr
080
0.80
0.75
Changes in neuroAIDS
Choline
Total Choline
1–2 mmol/kgww
0.85
• Elevated Cho also seen in
developing brain
Choline
Ref. : Zimmerman
rs = 0.72
p = 0.013
0.90
Choline
Creatine
H
0.95
Cho
3.20
3.18
14 T ex vivo
• Important marker in grading
tumors:
Low: in high grade tumors
High: in low grade tumors
• High in Alzheimer
ppm
Ref. : Zimmerman
6
Glutamate/Glutamine/GABA
Lipids
Glu
H
• Lipids (CH2) = 0.8 – 1.5
ppm (and 2 ppm)
• Contamination by
subcutaneous fat from
the skull
skull.
• Breakdown of tissue
• In brain tumors, where
lipids indicate necrosis
• Seen in myelin
destruction (MS)
H
H
H
Glu + Gln = Glx
• Peaks at 2.1 – 2.5 ppm (left
shoulder of NAA)
• Glu: amino acid acting as
excitatory neurotransmitter ~12
mmol/kgww
• Gln: precursor and storage form
of glutamate located in astrocytes
• GABA: amino acid acting as
inhibitory neurotransmitter
Ref. : Zimmerman
Outline
Lactate
Lactate (Lac):
Doublet at 1.3 ppm
<0.5 mmol/kgww
Peak is inverted at TE of 144 ms (135 ms)
(due to spin coupling or J coupling)
Distinguish lactate from lipids
H
Elevation of lactate:
Produced by anaerobic metabolism
Found in tumors containing zones of
necrosis
Hypoxia, infarction
Mitochondrial diseases, seizures
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
T2 Decay of Metabolites
Long TE, TE = 144 ms
•
•
•
•
1.0
NAA
T2 = 435 ms
0.8
S
i
g
n
a
l
0.6
Cho
M xy
M xy max
T2
)
Parietal White Matter
T2 = 377 ms
0.4
(
= exp − TE
Cr
T2 = 205 ms
Reduced number of metabolites
Less baseline distortion
Easy to process and analyze
Lactate (1.3 ppm) and alanine (1.5 ppm) (doublets)
are inverted - easier to differentiate between these
p
metabolites and lipids/macromolecules
NAA
0.2
0.0
0
500
1000
1500
Cho Cr
2000
Lac
TE ( ms)
Linewidth of spectrum in frequency domain is dependant
on T2 (relaxation time).
Ref.: Salibi
7
T2 Relaxation: Short TE, TE = 35 ms
T1 Relaxation
More metabolites:
• Lipids and macromolecules
• Glutamine (Gln) and glutamate (Glu) = Glx
• Myo-Inositol (MI)
(
)
Mz
=1 − exp − TR
T1
M0
T1 Relaxation times for selected resonances at 1.5 T in
the occipital lobe:
• Lactate, methyl group: 1.55 s
• NAA, methyl group: 1.45 s
• Cr, amines: 1.55 s
• Cho, amines: 1.15 s
Water Suppression
Parameter - TR
water
Ideally > 3s
If TR is long (> 3s) SNR improves, quantification improves
However, if TR is long, exam time increases
Typical TR values are 1-3 s
water
suppressed
NAA
Cho
Cr2
Cr
fat
Spectra sensitive to T1:
TR = 1.5 s
TR = 3 s
TR = 4.5 s
5
8 cc voxel, TE = 30 ms
•
•
•
1.5T, 8 cc, TE = 30 ms, occipital lobe
Ref.: Salibi
Chemical shift selective imaging technique which destroys the unwanted
signal component by means of a selective 90 degree excitation pulse
and a subsequent magnetic field gradient
Prior to imaging of wanted components.
RF
Gx
G slice
3
2
1
We are not able to detect any of the metabolite signals if we don’t suppress the water
signal.
This can be accomplished by chemical selective saturation (CHESS) pulse on the
water signal at 4.7 ppm. Suppression by a factor of 1,000 – 10,000 can be achieved
The CHESS sequence uses a frequency-selective 90 pulse to selectively excite the
water signal, followed by a spoiler gradient to dephase the resulting magnetization.
The sequence, which normally precedes the main pulse sequence, may be repeated
several times with gradients applied in different directions to increase its
effectiveness.
CHESS Water Suppression
90°
4
PPM
•
Water Suppression
No water suppression With water suppression 2nd WS after data acq.
10 ms RF pulse with gaussian shape
and a 20 ms period for spoiler gradients
time
FT
FT
FT
Leaves the spin system in a state where no net magnetization of
unwanted component is retained while the wanted component
remains entirely unaffected in the form of z-magnetization.
• A second water suppression is achieved by subtraction the
water signal at 4.7 ppm from the rest of the spectrum.
8
Outline
Localization Techniques
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
To measure MR spectra in vivo we have to be
able to control the spatial origin of the
detected signal
Single voxel: use selective excitation pulse to
localize a relatively small voxel
Multivoxel arrays of spectra (spectroscopic
images) can be obtained in 1D, 2D or 3D
Step one: excite a slice
Bo
y
Slice Profiles
• A slice selective gradient is applied to the
sample volume along with an RF excitation
pulse
• While the grad. is on, excite only band of
frequencies
B Field
d
Signal inten. (w/ z gradiient)
RF
t
z
Gz
Bo + Gz z
v
B1 (ω ) = ∫ B1 (t ) e
− iω t
t
dt
= ∫ B1 (t ) [cos(ω t ) − i sin(ω t )dt ]
0
Bandwidth : Δω = γ GΔz
Re al [ B1 (ω )] = B1
ω
B
Position : z = L − 0
γG G
Im[ B1 (ω )] = − B1
slice thickness : Δz =
Slice Profiles
ω
t
0
Frequency : ω L = γ (B0 +Gz )
Δv
0
τ
1/τ
τ
z
Bo
τ
⎧ B for 0 ≤ x ≤ τ
B1 (t ) = ⎨ 1
⎩0 otherwise
pulse duration t ∝
sin ωτ
1
1
=
Δω spectral width
ω
sin 2 ωτ
0.5ωτ
Δω
γ G
Single Voxel Spectroscopy: intersection
of 3 slice selective excitations
z
Selective pulse with a sinc
envelope is applied for
infinite long duration
However, rf pulse durations
are limited (2-10 ms)
Truncated sinc pulse
Truncated and filtered
sinc pulse
y
x
A
B
C
Slice A: rf pulse + gradient in the x direction
Slice B: 2nd rf pulse + gradient in y direction
Slice C: 3rd rf pulse + gradient pulse in z direction
9
Spin Echo
PRESS
Rotating frame
Point Resolved Spectroscopy
Uses double spin echo with slice
selects
CHESS 90°
z
y
RF
Gx
s
y
180x(+)
Grad order of
slice select is
arbitrary…
-x
-x
s
t = 2TE
Echo
z
z
Gy
y
f
x
x
time
Gz
z
-x
180°
180°
t =TE
z
90x
y
y
f
ADC
TE1/2
TE1/2
TE2/2
TE2/2
Echo
STEAM
Spin Echo
-x
-x
-y
y
-y
y
-y
x
r
M (τ ) = M 0 yˆ cos(Ωτ )e −τ / T2 +
r
M (0 + ) = M 0 yˆ
y
x
+ M 0 xˆ sin( Ωτ )e −τ / T2
-x
Time = 2τ
r
M (τ + t ) = M 0 e −τ +t / T2 ⋅
[− yˆ cos(Ωτ ) ⋅ cos(Ωτ )
time
Gy
y
ADC
− yˆ sin(Ωτ ) ⋅ sin(Ωτ )]
x
x
TE/2
90x
z
τ
90x
f
y
s
After Mixing
time T
90x
z
-x
2τ+T
-x
-x
y
y
r
M (τ ) = M 0 yˆ cos((Ωτ )e −τ / T2 +
r
M (0 + ) = M 0 yˆ
r
M (90 0 + ) = − M 0 zˆ cos(Ωτ )e −τ / T2 +
+ M 0 xˆ sin(Ωτ )e −τ / T2
+ M 0 xˆ sin( Ωτ )e −τ / T2
Mixing timezT
z
90x
2τ+T
z
z
y
-x
y
y
y
y
z
-x
-x
-x
z
-x
-x
y
y
90x
z
τ
-x
y
z
-x
-x
TE/2
Stimulated Echo
z
z
TM
Echo
r
M (2τ ) = − M 0 yˆ
Stimulated Echo
90x
90°
Gz
-y
− xˆ cos(Ωτ ) ⋅ sin(Ωτ )
+ xˆ sin(Ωτ ) ⋅ cos(Ωτ )
y
90°
RF
Gx
r
M (180 0 + ) = − M 0 yˆ cos((Ωτ )e −τ / T2 +
+ M 0 xˆ sin(Ωτ )e −τ / T2
-x
-y
Stimulated Echo Acquisition Mode
3 slice selective 90º pulses form a “stimulated” echo from
that region.
CHESS 90°
x
Time = τ + t
Time = (180x)+ -x
Time = τ
Time = 0+ (90x)
r
M (τ + T ) = − M 0 zˆ cos(Ωτ )e −τ / T2 e −T / T1
r
M (τ + T + 90 0 + ) = M 0 yˆ cos(Ωτ )e −τ / T2 e −T / T1
y
r
M (2τ + T ) = M 0 e −τ / T2 e −T / T1
yˆ cos(Ωτ ) cos(Ωτ )
xˆ cos(Ωτ ) cos(Ωτ )
10
PRESS
STEAM
J Coupling during a spin echo
Advantages:
Shortest TE (good for low T2*
species)
Excellent slice selection
profiles
Excellent water suppression
can be
b achieved
hi
d
Advantages:
Higher sensitivity: 2-fold
gain over STEAM
Æ Good SNR or faster
scan
Disadvantages:
T2 losses are more
pronounced
Poorer slice profiles on
180 pulses
Disadvantages:
The stimulated echo has 50%
signal loss
Æ Lower SNR / longer scan
times
J
90y
z
τ = π/2J
z
y
τ
z
y
z
y
x
y
ν=-J/2 ν
x
x
ν=+J/2 ν
ν
σ2
Starts out just like the previous spin echo example…
J Coupling during a spin echo
J
90y
z
J Coupling during a spin echo
J
z
y
90y
z
y
τ = π/J
z
y
z
y
y
ν=-J/2 ν
x
x
ν
σ2
180x
x
ν=+J/2 ν
τ = π/J
z
180x
y
ν=+J/2 ν
x
ν=+J/2 ν
z
z
τ = 2π/J
y
ν=+J/2 ν
x
x
x
ν
σ2
z
y
ν=-J/2 ν !!! Direction reversed !!!
ν=-J/2 ν
x
ν
J Coupling – TE Dependence
x
x
ν=-J/2 ν !!! Direction reversed !!!
Echo?
ν
y
Echo inverted
Spectroscopic Imaging
5
1x10
TE 30 ms
at 3T
5
1x10
Lactate (Lac)
4
8x10
1.3 ppm
7 Hz J-coupling – doublet
4
6x10
4
4x10
Spectroscopic Imaging (SI) / Chemical Shift
Imaging (CSI) can collect the spectra data of
a whole grid of many voxels.
4
2x10
0
4
-2x10
4
5
1x10
TE 70 ms
8x10
4
8x10
4
6x10
TE 144 ms
4
6x10
TE 288 ms
4
5x10
4
4x10
4
6x10
4
4x10
4
3x10
4
4x10
4
2x10
4
2x10
4
2x10
4
1x10
0
0
4
-2x10
0
4
-2x10
4
-1x10
11
Spatial Localization in MR Imaging
Field of View (FOV)
Selected Slice
Gs
Z
Phase Enc
coding Direction
Loc of spins in a 3D volume
Spatial Localization in MR Imaging
Spatial localization is done by phase encoding
in one, two or three dimensions
CSI sequence is similar to an imaging
sequence, but with no readout gradient
pp y g during
g data collection
applying
•
•
Frequency Encoding Direction
Volume selective 2D CSI
Volume selective 2D CSI
Phase Encodin
ng (16 steps)
FOV
y
ROI
16 phase encoding steps
in the x and y directions
over the entire FOV of
16 cm × 16 cm
1 voxel = 1 cm
voxel
Phase Encoding (16 steps)
RF excitation of 6 x 7
(6 cm x 7 cm) ROI
defined on a 1 cm
axial slice of the brain
16 x16 = 256 acquisitions
CHESS 90°
180°
180°
RF
Gx
time
Gy
Gz
ADC
TE1/2
TE1/2
TE2/2
TE2/2
Echo
x
Volume Selective 2D CSI
Spectroscopic Imaging: Data Display
Acquisition time = NEX · n PE(x) · n PE(y) · TR
NEX = number of repeated acquisitions (1 - 2)
n PE (x,y) = number of phase encoding steps (8, 12, 16, 24,
32)
Spectral maps
Individual
voxel
Metabolite
images
TR = repetition time (1000 – 3000 ms)
Acquisition time = 1 · 16 · 16 · 1.5 s
Acquisition time = 6.4 min
Intensities displayed are
proportional to particular
metabolite signal strength
12
Outline
Metabolite Maps
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
Courtesy Oded Gonen
Clinical Applications
¾ Brain Tumors
MGH
Large quantitative changes Value in individual patients
¾ Inborn Errors of Metabolism
Occasionally large enough
y be useful for clinical
may
management in some
individual patients
¾ Ischemia
¾ Epilepsy
¾ Neurodegenerative Diseases
¾ Psychiatric Diseases
More subtle changes: most
meaningful in assessing
groups of patients or
possibly individual patients
who have serial MRS studies
Grading of Brain Tumors
11 Clinical Scanners:
50 – 190 MR Spectroscopy
exams/month
Grading Tumors
• Avoid biopsy
• Classification of Astrocytomas
– LGA: Low grade astrocytoma (WHO grade I + 2) normal or slightly
increased cellularity, mild anaplasia
– AA: Anaplastic astrocytoma (WHO grade 3) hypercellularity,
moderate anaplasia
– GBM: Glioblastoma (WHO grade 4) necrotizing tissue surrounded
by anaplastic cells
An increase in the Cho ratios
are generally correlated with
increase in tumor malignancy.
Mean and SD (vertical lines) of normalized spectra obtained at TE 136 ms
Howe et al. MRM 2003 and Majos et al. AJNR 2004
13
Radiation Necrosis vs.
Recurrent Tumor
Grading Tumors
[MI]
FSE T2
FLAIR
T1 Post Contrast
CBV
Mean and SD (vertical lines) of normalized spectra obtained at TE 35 ms
Howe et al. MRM 2003 and Majos et al. AJNR 2004
Radiation Necrosis vs.
Recurrent Tumor
*
*
Radiation Necrosis vs.
Recurrent Tumor
*
MRS shows high choline peaks
- consistent with active cellular turnover and
membrane metabolism
Radiation Necrosis vs.
Recurrent Tumor
FSE T2
FLAIR
T1 Post Contrast
CBV
Radiation Necrosis vs.
Recurrent Tumor
Important Ratio:
Chobiopsy site/Crbiopsy site
Chobiopsy site/Crcontralateral
*
MRS shows lipids consistent with necrosis
Ratai and Gonzalez, MRI of the Brain and Spine, 2008, edited by Scott W. Atlas
Rabinov JD, et al. Radiology 2002
14
Inborn Errors of Metabolism
MR spectra with age
• MRS is valuable in pediatric brain disorders
that are due to inborn errors of metabolism
• These include
Spectra from Occipital Gray Matter
MI
Cho
Cr
NAA
– Leukodystrophies (degeneration of myelin in the
phospholipid layer insulating the axon of a neuron)
– Mitochondrial disorders
– Enzyme defects that cause an absence or
accumulation of metabolites
Holshouser et al. Radiology 1997
X-linked Adrenoleukodystrophy (X-ALD)
MRI and MRS in childhood X-ALD
cerebral nonprogressive
• MRI depicts the
demyelinating
lesion
• Hereditary neurodegenerative disease
• Accumulation of very long chain fatty acids (VLCFA)
• extending from the
splenium symmetrically
into the periventricular
wm
• Acute form in the childhood: inflammatory demyelination
• Chronic form in the adulthood: axonal loss in spinal cord
- however, also demyelinating lesions
cerebral progressive
• MRS predicts
lesion progression
• Cho/NAA: increased
with cell and
membrane turnover
even in NAW
• Not possible to predict phenotype by mutation analysis or
biochemical assays
Eichler et al. Neurology 2002
Creatine Deficiency
Canavan Disease
• Mutation in the enzyme aspartoacylase (ASPA) results in the inability to
catabolize NAA
• Leads to fatal leukodystrophy/mental retardation/loss of previously
acquired motor skills
12 month later
NAA ↑
NAA ↑↑
2.5 y/o child with mental
retardation, seizures and
speech delay
15
Ischemic Injury
Creatine Deficiency after treatment
Lactate (1.3 ppm)
1,2-propandiol (1.1 ppm) phenobarbitol
day 1
After 3 month of supplementation of
creatinemonohydrate
Outline
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
Mitochondrial Disorder
Problems and Solutions
¾ MRS is more sensitive to B0 field inhomogeneities than MRI –
requires Shimming to correct
¾ Voxel Location
¾ Patient Motion
ea part
pa t of
o the
t e spectrum
spect u (area
(a ea u
under
de tthe
e cu
curve
e~
¾ Real
proportional to the number of protons) - a phase correction
¾ Chemical Shift Artifact - spatial misregistration when
converting the MR signals from the frequency to the spatial
domain.
¾ Absolute Quantification
¾ Low SNR / low spatial resolution
Shimming
Phasing
• Field homogeneity
• “Shimming” - adjusting the magnetic
field to make it more homogeneous.
• Signal linewidth “FWHM” from prescan should be 7 Hz or less (SV),
11 Hz or less ((MV))
water
Cho&Cr
NAA
4 month
day 7
15 hr old male baby, born with apnea, question of seizure activity – HIE
Real
“absorption”
Imaginary
"dispersion"
When peaks
are out of
phase …
16
The Right ROI Location
Very Selective Saturation Pulses
¾ Proximity to sinuses can result in signal broadening and
susceptibility artifacts
¾ Iron in basal ganglia causes susceptibility broadening
¾ Proximity to scull can result in a contaminating lipid signal
¾ Signal contamination from adjacent tissue
Less contamination from adjacent tissue
Difficult locations
Contains paranasal sinus
Hurd, R., Magn Reson Med. 2000
Signal to Noise Ratio
1cm3
2cm3
4cm3
Signal to noise ratio
SNR = N acquisitions
8cm3
Full Scale
•
•
•
•
Spectrum with 32 scans
TR = 1.5 s
32 scans: 48 s
To obtain twice as good
S/N: 128 scans
• 128 scans: 3.2 min
Fixed Scale
• Spectrum with 128 scans
• Volume: 2 × 2 × 2 cm = 8 ccm
• To obtain the same S/N with
a 1 × 1 × 1 cm = 1 ccm
• How many scans?
8^2 as many scans
64 x 128 = 8192 scans
3.4 h
Signal ∝
TE = 30 ms, TR = 1500 ms, 128 averages, 3.2 min
• With increasing field – higher Signal
• Magnetic homogeneity and T2* increase with decreasing voxel
size
SNR ∝ Volume
NV ⋅ γ 2 ⋅ B0
T
Ref.: Salibi
Spatial Resolution
Increased Signal to Noise Ratio at
higher Magnetic Field Strengths
Lesion too small for MRS
• Most 2D 1H-MRS studies have been
performed with a spatial resolution of 1 cm3
or more.
• Higher-resolution SI can allow the separation
between different anatomical structures
1.5T
N ⋅ γ 2 ⋅ B0
Signal ∝ V
T
NV : Number of Spins
γ : gy
gyromagnet
g ic ratio
B0 : magnetic field
• Nonhuman primates provide excellent model
systems for the pathogenesis of neurological
diseases and their response to treatments
• Its much smaller size, 80 cm3 versus 1250 cm3,
however requires proportionally higher spatial
resolution
3T
T :Temperature
Linear increase in signal with
field strength
if T1 and T2 relaxation times,
coil and system losses and
RF penetration effects,
do not change significantly
7T
17
High Resolution MRSI at 7T
a
High Resolution MRS
b
6 cm ,
×16 C
SI
NAA
NAA
3.4 cm
Cr
0.05 cm3
VOI =4 cm
FOV =
1.5 cm
× 4 HS
I
V OI =
4 cm
FOV = 6 cm, ×16 CSI
Cho
2.6 cm
6 cm
Cr
O
VOI =3.5 cm
3
FOV = 6 cm, ×16 CSI
ƒ 3D MRSI pulse sequences with 2D (CSI) 16 x 16 phase encoding
ƒ 1D Hadamard spectroscopic imaging (HSI) resulting in 4 slabs in z
ƒ isotropic spatial resolution at (0.375 cm)3=0.05 cm3 in 25 min.
Cho
axial metabolic
maps
3.5
3.0
2.5
ppm
2.0
1.5
Resulting in these spectra that still show good SNR at resolution of 0.05 cm3 or 50 μL
Gonen O,Liu S, Goelman G, Ratai E, Lentz M, Pilkenton S. and González R.G. MRM 2008
Chemical Shift Misregistration
Higher spectral resolution
[email protected]
For slice selection: position depends on resonance frequency.
PRESS:
TE/TR=35/3000
NA: 256
water
NAA
Cho
Cho
Only overlap
has both NAA
and Cho
MRS@7 0T
[email protected]
STEAM:
TE/TR=15/3000;
NA: 256
ω L B0
−
γ G γG
Δω P − P
Δz =
γG
z=
NAA
ppm
1.5 ppm
2.7 ppm
NAA
Δω P − P = 2.0 ppm − 3.2 ppm = 1.2 ppm
at 1.5T : 1.2 ppm ⋅ 64 MHz = 77 Hz
at 7T : 1.2 ppm ⋅ 300 MHz = 360 Hz
Outline
¾ Introduction
¾ Shielding Effect - Chemical Shift
¾ J-Coupling
¾ Detectable Metabolites and their Significance
¾ Acquisition Parameters
¾ Localization Techniques
¾ Clinical Applications
¾ Problems + Solutions
¾ MRS other than brain
¾ MRS other than 1H
Prostate Spectroscopy
¾ The human prostate is the most commonly diseased of all internal
organs with the highest frequency of cancer and of benign
hyperplasia.
¾Cancers of the same histologic grade do not all behave uniformly
and their response to hormonal, radiation and chemotherapy is
unpredictable.
¾Available techniques (transrectal ultrasound, CT, MRI) cannot
differentiate quiescent cells and necrotic debris from proliferating
neoplastic cells.
¾Combination of 3-D proton MRS and high resolution MRI determining
the presence, degree, and extent of prostatic malignancy and benign
hyperplasia and their response to therapy.
18
Prostate Spectroscopy
Prostate Spectroscopy
Prostate MRS /
Control Spectra
Prostate MRS /
Tumor Spectra
While healthy prostate
tissue demonstrates high
l
levels
l off citrate
it t and
d low
l
levels of choline.
Prostate cancer shows
high levels of choline
choline.
Sensitivity / Specificity
80%/80%
1H
31P
MRS in other organs
• Prostate
• Muscle (fat – triglicerides,
Cho, Cr, PCr)
• Bone marrow (water and
lipids)
p ) ; leukemia
• Breast (fat/water = 0.3;
Cho)
• Liver
• Heart
Difficulties:
• Inhomogeneous line
broadening
• Large lipid signals
• Physiological motion
•
•
•
•
Spectroscopy
Cellular energy metabolism
Larger chemical shift (30 ppm) than 1H (4 ppm)
Lower sensitivity
Brain, muscle, liver and heart
PCr: high energy phosphate
storage compound (brain,
(brain muscle)
PME and PDE: membrane
phospholipids
↑PME: rapid tissue growth,
tumors
Energy metabolims:
ATP → ADP + Pi + Energy
PCr + ADP ←→ Cr + ATP
13C
•
•
•
•
Spectroscopy
Natural abundance 1.1% - Sensitivity: 1.6%
Advantages:
Large chemical shift range (200 ppm)
Large number of metabolic peaks that are well
separated
• Enrich substrates that are metabolized in living cells
for observing pathways / measuring metabolic rates
in vivo
• 13C MRS of glycogen
• 13C MRS labeled glucose
Thank you
very much!
Questions and comments:
Email: [email protected]
19