Week 5. Basics and clinical uses of MR spectroscopy.
1. 2012.10.30.
COURSE FAQ
Forthcoming lectures:
16. October – „IGT lecture”
23. October – NO LECTURE, holiday
30. October – MR Spectroscopy
6. November – PET + Final Test
In vivo MR spectroscopy
Test:
- Basic imaging techniques, what are they Ervin Berényi
- 5-10 easy, simple choice questions
- If November 6. is not good for everyone, I will organize extra András Jakab
time for getting the short test done
Study material:
Lecture material will be distributed in PDF 2 wks before the
test.
Diagnostic neuroimaging modalities
CT – Computed Tomography Structural MRI
Brain anatomy Fine brain anatomy
Stereotactic reference frame Vascular structure
Intra-operative imaging Diffusion, perfusion MRI
modalities, open MRI, low- Fine pathological
field information
Positron Emission
MR Spectroscopy
Tomography PET
Brain metabolism
Brain metabolism
Biochemical mapping
Brain function
Electro encephalography,
Functional MR imaging fMRI
LORETTA,
Brain function
Magnetoencephalography
Take home message about MR
spectroscopy
• Performing NMR experiments for an
image pixel
• Spectrum of brain chemicals, i.e.
metabolites.
metabolites Diagnose their alterations
alterations.
• Display, measure:
– Choline
– Creatine
– N-acetyl-aspartate
– Lactate
– Lipids
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2. 2012.10.30.
History of MR imaging Nobel prizes
1977 EPI Mansfield – Nobel prize, 2003
1977. Július 3. 4:45 First human MR Damadian
image • Otto Stern (1988-1969) • Isidor Isaac Rabi
• 1943 – “proton magnetic (1898-1988)
1975 NMR Fourier Ernst – Nobel, 1991 spin discovery” • 1944 – “developing a
Zeugmatography method to examine the
1973 g g p y
Zeugmatography Lauterbur - Nobel, 2003
, magnetic properties of
protons b nuclear
by l
1972 Cancer detection Damadian, US Patent 3,789,832 resonance”
with NMR
60’s-70’s Relaxometry of Hazlewood, Damadian, Ling…
living tissue
60’s Spectroscopy Ernst – Nobel, 1991
1946 NMR Bloch, Purcell – Nobel 1952
phenomenon
The first 1H NMR spectrum of
The Birth of NMR water
• 1952 – Felix Bloch & Edward Mills Purcell
• “for the precision measurements on nuclear magnetic resonance”
(1905-1983)
(1912-1997)
Stanford Harvard
Bloch, F.; Hansen, W. W.; Packard, M. The nuclear induction experiment. Physical Review (1946), 70 474-85.
474-
Magnetic resonance imaging
NMR spectroscopy
(MRI !)
• Richard Ernst • 2003 – Paul Lauterbur & Sir Peter Mansfield
• 1991 – “developing high
resolution NRM spectroscopy”
(1929-2007) (1933-)
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Lauterbur’s 1973 Nature paper
Damadian’s pattern from 1972
Indomitable Damadian and the coil
1977.
0,05-0,1 T
Szupravezető
54,43 kg
Damadian, Minkoff, Goldsmith
The first pathological case
The first MR image of a human
1977. Július 3. 4:45, Minkoff
Physiol. Chem. & Phys., 10:285-87, 1978.
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First pathological case – lung
Basics of MR spectroscopy
cancer
• Nuclei of atoms bear a physical property
called a spin.
• All moving charged bodies create a
moving,
magnetic field around themselves
• Nuclei with spins act as small magnets
Physiol. Chem. & Phys, 10:285-87, 1978.
Basics of MR spectroscopy Basics of MR spectroscopy
• If a nuclei is in a different
• In the presence of a strong external microenvironment, its resonant
magnetic field, nuclei spins are oriented frequency is altered
and show precession with a well-
defined frequency • This means that atomic bonds and
• This is the Larmor frequency which is neighbouring atoms determine the
proportional to the strength of the resonance frequencies (Chemical Shift)
external field
• One can depict it using a spectrum,
• This is the resonance frequency of the where each peak represents a specific
given nucleus atom is a specific bond
Chemical shift
1951
Ethanol 1H NMR spectrum
Arnold, J.T., S.S. Dharmatti, and M.E. Packard, J. Chem. Phys., 1951. 19: p. 507.
19:
Modern ethanol spectrum
spectrum
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Free Induction Decay Processing for MRS
FT
FT
Where can MRS be used? Different types of MRS
• Volume selective MRS
• MRS Imaging (MRSI) - metabolite mapping
• Proton MRS – Proton (H1)
– Brain • NAA map
• Cho map
– Prostate • Cr map
– Liver • Lac map
• Citrate map (prostate)
• Phosphorus MRS – Phosphor (P31)
– Liver • Pi map
• PCr map
– Heart • ATP subtypes
– Muscles – C13
• Pl. hyperpolarized imaging
Single Volume Localization Single Volume Localization
RF Image selected in
Localized spectra is
obtained from a single
vivo spectroscopy,
Gx volume of interest (VOI) ISIS
Localization is achieved by
y Po nt
Point resolved
RF sequential selection of spectroscopy,
three orthogonal slices
PRESS
Gy The size and location of
VOI can be easily Stimulated echo
RF
controlled acquisition mode,
Anatomic 1H images are STEAM
used for localizing the VOI
Gz
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6. 2012.10.30.
Point Resolved Spectroscopy, PRESS Stimulated Echo Acquisition Mode, STEAM
180° 180° 90° 90° 90°
90°
RF
RF
Gx
Gx
Gy Gy
Gz Gz
TE1/2 (TE1+TE2)/2 TE2/2 TE/2 TM TE/2
Three slice-selective 90o pulses form a stimulated
A slice-selective 90o pulse is followed by two slice- echo from a single voxel.
selective 180o refocusing pulses
Achieves localization within a single acquisition
Achieves localization within a single acquisition
Only half of the available signal is obtained
Suitable for signals with long T2 – 1H MRS
Can achieve shorter TE than PRESS
Effects of MR Parameters on Single Voxel Spectroscopy: Overview
PRESS spectra
Simplicity
Repetition Time, TR Flexibility in voxel size and position
Number of Signal Averages Accurate definition of VOI
Echo Time, TE Excellent shim and spectral resolution
Voxel Size Many voxels within the same dataset
Chemical Shift Imaging CSI Spectral Map
Multiple localized Display of all spectra
90°
spectra are obtained
simultaneously from a Underlying reference
RF
set of voxels spanning image shows voxel
the region of interest position
G
slice Uses same phase- Individual spectra can be
encoding principles as displayed enlarged
G imaging Spectral map can be
y
No gradient is applied archived together with
during data collection, so the reference image and
G
z spectral information is the CSI grid
preserved
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CSI Data Analysis MR spectroscopic imaging,
Chemical shift imaging (CSI)
Normal Tumor
NAA Cho
Cho Crt
Necrosis
Image showing voxel position
Spectrum from a voxel
Primer Progressiv Aphasia CSI: Overview
Advantages
Acquisition of multiple voxels
NAA/Cho NAA Metabolite images, spectral maps, peak
information maps, and results table
Many voxels within the same dataset
Disadvantages
Large volume – more difficult to shim
Cho Cre Voxel bleeding
Large datasets
Important Nuclei for Biomedical MR Important Nuclei for Biomedical MR
1H – Neurotransmitters, amino acids, membrane
Nucleus Spin γ, MHz/T Natural Relative constituents
Abundance Sensitivity
2H – Perfusion, drug metabolism, tissue and cartilage
1H 1/2 42.576 99.985 100 structure.
2H 1 6.536 0.015 0.96 13C – Glycogen, metabolic rates, substrate preference,
3He 1/2 32.433 .00013 44 drug metabolism, etc.
metabolism etc
13C 1/2 10.705 1.108 1.6 19F – Drug metabolism, pH, Ca2+ and other metal ion
17O 3/2 5.772 0.037 2.9 concentration, pO2, temperature, etc
19F 1/2 40.055 100 83.4 23Na – Transmembrane Na+ gradient, tissue and cartilage
23Na 3/2 11.262 100 9.3 structure.
31P 1/2 17.236 100 6.6 31P – Cellular energetics, membrane constituents, pHi,
39K 3/2 1.987 93.08 .05 [Mg2+], kinetics of creatine kinase and ATP
hydrolysis.
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Brain 1-H MRS
water
N-acetyl aspartate
1H MR Spectroscopy
Creatine
Choline
(lactate/
lipid)
5.0 4.0 3.0 2.0 1.0
ppm
Important 1H Signals Important 1H Signals
N-Acetyl aspartate (NAA) Choline (Cho), choline compounds
•NAA is a neuronal marker
•Cho compounds are
2.02, CH3 and indicates density and
O CH3 3.24, CH3 involved in phospholipid
2.52, CH2 viability of neurons.
CH3-C-NH-CH-CH2-COOH 3.56, CH2 metabolism of cell
2.70, CH2 •It is decreased in glioma, CH3-N-CH2-CH2-OH
4.07, CH2 membrane.
CH2-COOH 4.40, CH ischemia and degenerative CH3
•Increase Cho mark tumor
diseases.
tissue or multiple sclerosis
plaques
Creatine (Cr), phosphocreatine (PCr) •Cr is a marker of aerobic
Glutamate (Glu), glutamine (Gln)
energy metabolism
•Cr signal is constant even •Glu is a neurotransmitter,
NH HOOC-CH2-CH2-CH-COOH
with pathologic changes Gln a regulator of Glu
3.04, CH3
NH2-C-N-CH2-COOH and may be used as a NH2 2.1, CH2 metabolism
3.93, CH2
CH3 control value 2.4, CH2 •It is hardly possible to
• However, isolated cases NH2-CH2-CH2-CH-COOH 3.7, CH detect their signals
of Cr deficiency may occur sepratly. The signals are
NH2
in children jointly designated “Glx”.
Important 1H Signals Neurochemical pathways & neuro-MRS
Lactate (Lac) •Lactate is the final
product of glycolysis
CH3-CH-COOH 1.33, CH3 •It can be detected in
OH 4.12, CH ischemic/hypoxic tissue
and tumors indicating lack
of oxygen
Taurine (Tau)
•Cells examination indicates
3.27, NCH2
NH2-CH2-CH2-S-OH taurine synthesis in
3.44, SCH2
astrocytes
Myo-inositol (Ins)
•Ins marks glia cells in
PO4- brain
PO4-
PO4- PO4- 3.56, CH •It is decreased in hepatic
encephalopathy and
elevated in Alzheimer’s
PO4-
PO4- disease.
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9. 2012.10.30.
A normal brain MR spectrum The effect of echo time on the spectra
Mitochondrial myopathy Quantitative MRS
• Metabolit ratios
• Cr is stable, we compare metabolites to
this
• Contralateral – CSI
• Water as reference signal (proton cc ≈ 77-
88 M)
• Water content
• External reference (not so practical)
TE 144 ms TE 288 ms
Proton spectrum metabolites Quantitativ MRS Fantom - QA
• Components:
– 12,5 mM NAA
– 10 mM Cr
– 3 mM Cho, 12,5 mM Glu
, ,
– 7,5 mM mI
– 5 mM Lac
• 50 mM-os foszfát pufferben (7,2 pH; 1%
Magnevist; 0,1% Na-azide)
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The proton MR spectrum varies Age related changes of the
by age proton spectrum
MRS indications for newborns Neonatal hypoxia
• Hypoxia, but normal UH, CT, MRI, SPECT,
PET
• No contraindications
• Lactate is elevated, NAA & Cr reduced
• Sensitivity: high
• Specificity: lower, developmental disorders
affect it as well
Shaken Baby Syndrome MRS in infants - indications
• Normal UH, CT, MRI, SPECT, PET
• No contraindications
• Lactat elevated, NAA and Cr reduced
• Specificity is extremely high in a few
diseases:
– Canavan disease: NAA⇑
– Frahm-Hanefeld Sy: Cr ⇓
– Phenylketonuria : Phenylalanin⇑
– Nonketotic hyperglycinemia: glycine ⇑
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MELAS
(Mitochondrial Encephalopathy with Lactic Acidosis and Stroke like
lesion) MR spectroscopy (MRS) chemical shift
imaging in stroke
Regionális variabilitás:
legérintettebb az
Occipitális lebeny
Metabolic disfunction
of mitochondria in
vessels
Changes in MRS in stroke MRS and CSI in tumors
• NAA is reduced, Lac elevates
• NAA is most reduced after 30
hours
• Lactate is detected in chronic
ischaemia (degragation)
• Lactate is also present (DDG)
– Mitochondrial diseases
– Demyelinisation
– Visual cortex excitation
Oligodendroglioma
Oligodendroglioma
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Metabolic profile of gliomas Recurrent astrocytoma
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• High Cho, Low NAA and no
• High Choline 1 2
3 lipids
– Tumor cells
• 2: Infiltrtive tumor is marked
• Low Choline
by Cho
– Centrum –
necrosis • 3 solid t
3: lid tumor – hi h grade
high d
transformation is marked by
• Normal Cho
Lac++
– Vasogen oedema
• 4: Early necrosis – lipid sign
is present
Hearshen et al. In Clinical MR Neuroimaging. Cambridge Univ Press. Page 310.
Bizzi et al. In Clinical MR Neuroimaging. Cambridge Univ Press. Page 306-307. Croteau et al. Neurosurgery. 2001. 49:823-829
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Radiation necrosis (brain
tumors) MRS in brain meningeomas
2
1
• Cho, Cr and NAA reduced
• NAA is not present in non-
• Low lipide signal neurogenic tumors
• Cho/NAA ≈ 1 • Alanine is found
• Similar
Si il to necrosis i • Elevated Choline means
• Biopsy may be necessary, aggressivity
or monitor the grow
• DDG: recurrent/residual
tumor!!!!!!!!
Hearshen et al. In Clinical MR Neuroimaging. Cambridge Univ Press. Page 311.
Rock et al. Neurosurgery. 2002. 51(4):912-919
Variability of brain tumors’ spectra
Defining tumor subtypes using
mathematical analysis (ICA)
Howe et al. Magn Reson Med. 2003. 49:223-232 Szabo de Edelenyi et al. Anal Chim Acta. 2005. 544:36-46
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Nosologic imaging INTERPRET
(International Network for Pattern Recognition of Tumours
Using MR Spectroscopy)
• EU funded research for
making MRS diagnostic
simpler
• Protocoll (methodical) consent
• 800 sample database
• Automatic analysis
• Computer aided diagnostic
tool
Szabo de Edelenyi et al. Nature Medicine. 2000. 6:1287-89 http://azizu.uab.es/INTERPRET/ Arjan W. Simonetti PhD Thesis 2004.
Tumefact Mulitple Sclerosis Abscessus vs. tumor
Abscessus GBM
• Similar appearance to tumors,
gliomas, BUT DD:
Tu: NAA ↓↓, Perf ↑↑;
Acetate
mI/Cr↑↑,
MS: mI/Cr↑↑ Diff ↓↓
Ac: 1.92 ppm
• Diffuse methabolic changes Succinate
• Acute-chronic plaques Suc: 2.4 ppm
• Recurrent remittent (RR) – Suc Aspartate
Progressive secondary (PR) Asp:2,6 ppm
form
Szabo de Edelenyi et al. Nature Medicine. 2000. 6:1287-89 Nakaiso et al. Neurol Med Chir. 2002. 42:346-348
Juvenile SLE MRS in epilepsy
Psychiatrical symptoms Cr/NAA map
MRS early diagnosis, before
MR lesions are apparent:
Cho ↑; NAA/Cr ↓
Contralateral
Lesion
Steens et al. Ann Rheum Dis. 2003. 62:583-586 Hetherington et al. Magn Reson Imaging. 1995. 13:1179
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Mitocondrial myopathy Primer Progressiv Aphasia
NAA/Cho NAA
Cho Cre
TE 144 ms TE 288 ms
Summary: the main advantages
Problems of clinical MRS
of clinical MRS
• One must STANDARDIZE the
• In vivo biochemical diagnosis – acquisition
• Patterns of metabolites help us to: – reading
– Radiological reports
– Monitor therapy
• Reproducibility is not high
– Progression-regression
• Absolute quantification is problematic
– Prognostic possibilities (i.e. tumors, • Sedation (pediatric or non-cooperative)
Alzheimer)
• Team work is necessary (radiologist,
physicist, biochemist, etc.)
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