Clinical Applications of magnetic
resonance spectroscopy
Peter B. Barker, D.Phil.
Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins
University School of Medicine, and the Kennedy Krieger Institute, Baltimore, MD, USA
Information Content of Proton Brain Spectra
Compounds detectable (at
either long or short echo times):
Normal
NAA
Cho
Cr
• N-Acetyl Aspartate (NAA):
Axons, neurons, dendrites
• Creatine + Phosphocreatine (Cr):
Energy metabolites
• Cholines (Cho):
TE 280 ms
Ischemic Brain
Lac
Glial cells, active demyelination
• Lactate (Lac):
Anaerobic glycolysis, ischemia
PPM 4.0
3.0
2.0
1.0
Compounds detectable at short echo times (< ~35 ms)
•
•
•
Myo-inositol (mI) - glial cells, demyelination, osmolyte (?)
Glutamate + Glutamine (Glx)
Lipids
NAA
TE = 35 msec
Cho
Cr
mI
“Glx”
Lipids
PPM
4.0
3.0
2.0
1.0
• Other Compounds normally •
present (if you look closely!)
• NAAG, Aspartate
• Taurine, Scyllo-Inositol
• Betaine, Ethanolamine*
• Purine Nucleotides*
• Histidine*
• Glucose (Glycogen?)
• Compounds observed using
“Spectral Editing”
• GABA
•
• Ascorbic acid
• Glutathione
• ‘Macromolecules’ *
* - Short TE only
Compounds which may be detectable
under abnormal/pathological
conditions
•
β-Hydroxy-butyrate, acetone
•
Phenylalanine (PKU) *
•
Galactitol, Ribitol, Arabitol
•
Succinate, pyruvate
•
Alanine
•
Glycine
•
Valine, leucine, isoleucine
•
Threonine?
Exogenous Compounds
•
Propan-1,2-diol
•
Mannitol
•
Ethanol
•
MSM - methylsulfonylmethane
The Developing Brain:
Parietal White Matter
Kreis et al. MRM 30: 424-437 (1993)
Occipital Gray Matter
Normal Aging
30 year old
69 year old
NAA
Putamen
Cho
Cho
Cr
Cr
Frontoparietal
Gray Matter
PPM 4.0
3.0
NAA
Putamen
Frontoparietal
Gray Matter
2.0
1.0
PPM 4.0
3.0
2.0
1.0
Normal Aging: mM Concentrations
14
*
*
*
‡
10
NAA
Cho
6
2
20-40
(N=20)
4
>65 yrs
(N=20)
*
3
* *
*
*
‡
*
2
1
1
2
3
4
5
6
ISMRM 2002. #1318 Horska et al.
7
8
9
10
11
12
BRAIN REGION
13
14
15
16
17
* significant effect of age p<0.05
‡ p<0.06
Neurobiol Aging. 2009 Mar;30(3):353-63.
Epub 2007 Aug 23.
MR Spectroscopic Imaging (MRSI)
T1
Cho
Gray Matter
Frontal White
Matter NAA
NAA
- Lateral
ChoCr
Cho
Cr
Frontal Gray Matter
- Mesial Semiovale
Centrum
Cr
NAA
Posterior Gray Matter
- Lateral
Parietal White Matter
Posterior Gray Matter
- Mesial
PPM
4.0
3.0
2.0
1.0
MRSI in the brainstem and cerebellum
T1 MRI
3
2
1
3
Pons
Cerebellar
Hemisphere
2
Vermis
1
Cho
Cr
NAA
7 Tesla 2D SENSE MRSI
NAA
NAA
Cr
GSH/MM
Cr
Cho
NAA
Glx mI
Glu
Asp Gln
Tau
PPM
4.0
3.0
2.0
1.0
32-channel Multi-slice 2D-MRSI, 0.7 cm3, SENSE=2x1.5, TE=34ms, 7x7x15 mm, ~13 min
All of the following metabolites may be
detected in long echo time proton
spectroscopy of the brain except:
0%
0%
0%
0%
0%
1.
2.
3.
4.
5.
Choline
Phosphocreatine
Lactate
Myo-Inositol
Glycine
10
Answer:
All of the following metabolites may be detected
in long echo time proton spectroscopy of the
brain except:
1. Choline
2. Phosphocreatine
3. Lactate
4. myo-inositol
5. Glycine
In vivo proton MR spectroscopy of the human brain.
Barker PB, Lin DD. Prog NMR Spect 2006;49:99-128
During the 1st 2 years of life, the following
metabolic changes occur in the brain
0%
0%
0%
0%
0%
1.
2.
3.
4.
5.
NAA and choline increase
NAA increases and myo-inositol decreases
NAA increases, and choline and creatine decrease
NAA and creatine increase
Lactate increases
10
Answer:
During the 1st 2 years of life, the following
metabolic changes occur in the brain
a. NAA and choline increase
b. NAA increases and myo-inositol decreases
c. NAA increases, and choline and creatine
decrease
d. NAA and creatine increase
e. Lactate increases
Development of the human brain: in vivo quantification of metabolite and water
content with proton magnetic resonance spectroscopy. Kreis R, Ernst T, Ross BD.
Magn Reson Med. 1993;30(4):424-37
In the normal adult brain, which of the
following is true?
0%
1.
0%
2.
NAA/creatine ratio is higher in gray matter than white
matter
Choline is higher in posterior brain regions than frontal
0%
3.
The brain stem has high levels of creatine
0%
4.
5.
The cerebellum has high levels of creatine
Deep and cortical gray matter have the same spectral
appearance
0%
10
Answer:
In the normal adult brain, which of the following is true?
a. NAA/creatine ratio is higher in gray matter than
white matter
b. Choline is higher in posterior brain regions than
frontal
c. The brain stem has high levels of creatine
d. The cerebellum has high levels of creatine
e. Deep and cortical gray matter have the same
spectral appearance
Mapping of brain metabolite distributions by volumetric proton MR spectroscopic
imaging (MRSI). Maudsley AA, Domenig C, Govind V, Darkazanli A, Studholme
C, Arheart K, Bloomer C. Magn Reson Med. 2009;61(3):548-59
Normal
Brain
Astrocytoma Gr II
Choline Metabolic Pathways
All Cases, r2 = .32
GBM only, r2 = .76
Glioblastoma Multiforme (High Grade Tumor)
FLAIR
Cho
Right
T1
Cho
Cr
NAA
NAA
Lac
Left
PPM
4.0
3.0
2.0
1.0
Riedy and Barker ASNR Washington DC 2003
Glioblastoma Multiforme (High Grade Tumor)
FLAIR
Cho
Cr
NAA
Cho
T1 Post-Gd
NAA
Cr
Cho
NAA
Cr
PPM 4.0
3.0
2.0
1.0
PPM 4.0
3.0
2.0
1.0
Riedy and Barker ASNR Washington DC 2003
Oligodendroglioma - (Grade II)
FLAIR
R. Contralateral NAA
Cho
Cr
L. Lesion
PPM 4.0
3.0
2.0
1.0
Riedy and Barker ASNR Washington DC 2003
Brain Tumor Metabolite Concentrations
(milliMolar)
Choline
NAA
6.0
10.0
9.0
5.0
8.0
7.0
4.0
6.0
3.0
5.0
4.0
2.0
3.0
2.0
1.0
1.0
0.0
0.0
Oli 2 Ast 2 Oli 3
GBM
GBM
GBM
GBM
Oli 2 Ast 2 Oli 3
GBM GBM GBM GBM
LESION
CONTRALATERAL
Riedy and Barker ASNR Washington DC 2003
(pure and mixed)
astrocytomas
(INN Besta n=58)
Dr Alberto Bizzi, Instituto Neurologica Carlo Besta’, Milan, Italy
Outlier
G.A. - 64
H-MRSI
T1-wi pre-Gd
Cho
Cr
T2-wi
NAA
Lip
T1-wi post-Gd
Dr Alberto Bizzi, Instituto Neurologica ‘Carlo Besta’, Milan, Italy
G.A. - 64
H-MRSI
Outlier
Oligo WHO II
colorazione EE
T2WI
Brain Tumor Diagnosis
F.A. Howe et al., Magnetic Resonance in Medicine 49:223–232 (2003)
Brain Tumor Diagnosis
Lactate +
Alanine +
Lipids
F.A. Howe et al., Magnetic Resonance in Medicine 49:223–232 (2003)
Brain Lesion Diagnosis: Malignant vs. Benign
Hypotheses:
• Benign lesions will have lower Cho than
malignant
• Benign lesions will have lower rCBV than
malignant
• Combined measurement of Cho and rCBV will
have higher sensitivity/specificity than either
alone
Hourani, Horská, Barker et al. AJNR 2008;29(2):366-372
Primary CNS Lymphoma
FLAIR
T1+ Gd
rCBV
1.Right parietal
NAA
Cho
Cr
1
Cho
2
Cr
NAA
2. Lesion
PPM 4.0
3.0
2.0
1.0
Meningoencephalitis
1.Right frontal NAA
FLAIR
1
T1+ Gd
rCBV
2
Cho
Cr
Cho
Cr
NAA
2. Lesion
PPM 4.0
3.0
2.0
1.0
Results - Sensitivity and Specificity
Discriminant function analysis
MRSI:
Perfusion:
93.3% correct
80.0% correct
Cut-off value analysis:
NAA/Cho < 0.61
84.1% sensitivity, 86.1% specificity
rCBV > 1.5
77.8% sensitivity, 91.7% specificity
Area under curve
0.86
0.92
0.96
Combined MRSI+PWI
72.2% sensitivity, 91.7% specificity
Hourani, Horská, Barker et al. AJNR 2008;29(2):366-372
But there are still outliers.. infiltrating, low grade glioma
FLAIR
Cho
Cr
Contralateral
NAA
Cho
Cr
CBV
NAA
T1+Gd
Lesion
PPM
4.0
3.0
2.0
1.0
F 3 yr old, complex partial seizures
Tumefactive MS Lesion
Cho
FLAIR
NAA
CBV
Lesion Cho
Lac
T1 Post Gd
Lac
PPM
4.0
3.0
2.0
1.0
41 year old male
Which of the following statements is
false?
0%
2.
The level of Cho generally increases with the increasing
grade of a glial brain tumor
Lipids are elevated in glioblastoma multiforme
0%
3.
Lipids are elevated in metastatic brain tumors
0%
4.
myo-Inositol is elevated in anaplastic astrocytoma
0%
5.
N-acetyl aspartate in decreased in all brain tumors
0%
1.
10
Answer:
Which of the following statements is false?
a.
The level of Cho generally increases with the
increasing grade of a glial brain tumor
b.
Lipids are elevated in glioblastoma multiforme
c.
Lipids are elevated in metastatic brain tumors
d.
myo-Inositol is elevated in anaplastic astrocytoma
e.
N-acetyl aspartate in decreased in all brain
tumors
Correlation of myo-inositol levels and grading of cerebral astrocytomas. Castillo
M, Smith JK, Kwock L. AJNR Am J Neuroradiol. 2000 Oct;21(9):1645-9
Which of the following features can be used to
reliably distinguish tumefactive demyelinating
lesions from glioblastoma multiforme (GBM)
0%
0%
0%
0%
0%
1.
2.
3.
4.
5.
Low NAA
High Cho
High lactate
High lipid
None of the above
10
Answer:
Which of the following features can be used to reliably
distinguish tumefactive demyelinating lesions from
glioblastoma multiforme (GBM)
a.
Low NAA
b.
High Cho
c.
High lactate
d.
High lipid
e.
None of the above
Intra-axial brain masses: MR imaging-based diagnostic strategy--initial
experience. Al-Okaili RN, Krejza J, Woo JH, Wolf RL, O'Rourke DM, Judy KD,
Poptani H, Melhem ER. Radiology. 2007;243(2):539-50
Effects of Treatment: Radiation
Necrosis vs. Tumor Recurrence
Tumor Regrowth/ Radiation Necrosis
Normal Brain
Necrosis
Recurrent Tumor
Preul et al. Can. J. Neurol. Sci. 1998; 25: 13-22
Radiation Necrosis
Rock JP, Hearshen D, Scarpace L, Croteau D, Gutierrez J, Fisher JL et al.
Correlations between magnetic resonance spectroscopy and image-guided
histopathology, with special attention to radiation necrosis.
Neurosurgery 2002; 51:912-9; discussion 919-20
Recurrent Tumor
FLAIR
NAA
FDG
Cho
Lac
Radiation Necrosis
2/99 Pre-treatment
Pre-treatment
Post-treatment
3/00 Post-treatment
T1
R. Frontal
Anaplastic Astrocytoma
Cho
Post-treatment
PET
Courtesy of Dr David Hearshen, Henry Ford Hospital, Detroit, MI
Astrocytoma - Recurrent tumor or Radiation Necrosis?
FLAIR
T1 Post Gd
A
Cho Cr
A
NAA
C
B
B
* Lipid *
Cho
NAA
C
PPM 4.0
3.0
2.0
1.0
Astrocytoma - FDG-PET/CT
MRS in Brain Tumors: Summary
• Diagnosis - overlap
• Tumor Grading – low vs. high
• Malignant vs. Benign
• Evaluation of treatment response
• Comparison to other modalities
(PWI/PET)
“Mitochondrial Diseases” - disorder of TCA
cycle metabolism
• Heterogeneous group of
inherited disorders
• Manifest in childhood or
early adulthood
• Effect muscle, brain, optic
and other organ systems
• Often associated with
lactic acidosis
• Definitive diagnosis can
be difficult in some cases
Mitochondrial Encephalopathy with Lactic
Acidosis and Stroke like Episodes (MELAS)
Lin, Crawford and Barker, AJNR 24; 33-41 (2003)
Methylmalonic Acidemia (M 14 yrs, mut-)
Isoleucine, valine, threonine
Proprionic acid
Methylmalonic acid
Methylmalonyl
CoA mutase,
Adenosyl
cobalamine
Succinate
Trinh, Melhem and Barker, AJNR Am J Neuroradiol 22:831–833, 2001
Complex II (Succinate Dehydrogenase) Deficiency
T2
Succ
White Matter
Cr
Cho
NAA
Lac
PPM
Succ
PPM
3.0
3.0
2.0
2.0
1.0
1.0
Gray Matter
PPM
PPM
3.0
3.0
2.0
2.0
1.0
1.0
Provided by Dr Alberto Bizzi, Istituto Nazionale Neurologico “Carlo Besta”, Milan, Italy
Lactate Elevation in Suspected Mitochondrial
Disease
• 63% sensitivity, high (~100%) specificity in some
studies, depending on inclusion/exclusion criteria*
• Lactate often highest (or only seen) in ventricular
CSF
• May depend on stage of disease
• Lactate best visualized on long TE (e.g. 140 or 280
msec) MRS
*Lin, Crawford and Barker, AJNR 24; 33-41 (2003)
Which of the following statements about
mitochondrial diseases (MD) is true?
0%
1.
Lactate is best detected in ventricular CSF
0%
2.
Lactate is best detected in the brain
3.
Lactate is always seen in brain lesions associated with
MD, but not normal appearing brain
Lactate is only elevated in mitochondrial diseases, and
not other metabolic diseases
Brain lactate levels are well correlated with serum
lactate levels
0%
0%
4.
0%
5.
10
Answer:
Which of the following statements about mitochondrial
diseases (MD) is true?
a.
Lactate is best detected in ventricular CSF
b.
Lactate is best detected in the brain
c.
Lactate is always seen in brain lesions
associated with MD, but not normal appearing brain
d.
Lactate is only elevated in mitochondrial
diseases, and not other metabolic diseases
e.
Brain lactate levels are well correlated with serum
lactate levels
Cerebral lactic acidosis correlates with neurological impairment in MELAS.
Kaufmann P, Shungu DC, Sano MC, Jhung S, Engelstad K, Mitsis E, Mao X,
Shanske S, Hirano M, DiMauro S, De Vivo DC. Neurology. 2004;62(8):1297-302
Summary – MRS in Metabolic Diseases
• Some rare diseases have specific, pathognomic
metabolic patterns
• Succinate dehydrogenase
• Creatine deficiency
• Non-ketotic hyperglycinemia
• Leukodystrophies, others…
• More commonly non-specific metabolic changes
related to underlying tissue pathophysiology
• NAA decreased – neuroaxonal loss/dysfunction
• Cho elevation in active demyelination
• Lactate increased in anaerobic glycolysis
Acknowledgments
Johns Hopkins/Kennedy Krieger Inst.
Tom Crawford
Alena Horská
Roula Hourani
Doris Lin
Marty Pomper
Gerard Reidy
Peter van Zijl
Istituto Carlo Besta, Milan, Italy
Alberto Bizzi