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CA<strong>MR</strong>T / ACMDTT, May 30, 2014<br />
Edmonton, Alberta
James N. Scott MD MSc FRCPC<br />
Clinical Associate Pr<strong>of</strong>essor<br />
Neuroradiology<br />
Diagnostic Imaging & Clinical Neurosciences<br />
Faculty <strong>of</strong> Medicine, University <strong>of</strong> Calgary<br />
Foothills Medical Centre<br />
Partner EFW Radiology
• Define <strong>the</strong> basic <strong>brain</strong> metabolites observed<br />
• Illustrate some common clinical applications <strong>of</strong> <strong>MR</strong>S<br />
• Examine <strong>the</strong> typical <strong>MR</strong>S patterns in different <strong>brain</strong><br />
pathologies
<strong>MR</strong> <strong>Spectroscopy</strong> is Different<br />
Than Conventional <strong>MR</strong>I<br />
• <strong>MR</strong>I and <strong>MR</strong>S use <strong>the</strong> frequency <strong>of</strong> <strong>the</strong> <strong>MR</strong> signal to encode<br />
different in<strong>for</strong>mation<br />
• <strong>MR</strong>I provides spatial imaging<br />
• <strong>MR</strong>S provides chemical in<strong>for</strong>mation
When To Add <strong>Spectroscopy</strong> ?<br />
• Indications on study requisition<br />
• Imaging abnormalities identified on <strong>MR</strong> exam<br />
• <strong>MR</strong> technologist discretion<br />
• Discussion with <strong>MR</strong> radiologist
Clinical Applications <strong>of</strong> <strong>MR</strong>S<br />
• Development / Myelin Maturation<br />
• Neurodegenerative Diseases<br />
• Metabolic Diseases<br />
• Stroke / Cerebral Infarction<br />
• Hypoxic Ischemic Encephalopathy<br />
• Epilepsy<br />
• Encephalitic / Systemic Disease<br />
• Demyelination<br />
• Infections<br />
• HIV and AIDS<br />
• Intracranial Neoplasms<br />
• Head Injury<br />
• Neurocutaneous Syndromes<br />
• Psychiatric Disorders
Main Cerebral Metabolites<br />
Short Echo Times (TE 30/35)<br />
• Myoinositol<br />
• Glutamate & Glutamine<br />
• Lactate<br />
• Lipids<br />
Intermediate or Long Echo Times (TE 135/144 or TE 270)<br />
• N-acetylaspartate<br />
• Choline (& phosphorylcholine + glycerophosphorylcholine)<br />
• Creatine (& phosphocreatine)<br />
• Lactate
Main Cerebral Metabolites<br />
NAA<br />
TE 30<br />
TE 135<br />
Cho<br />
mI<br />
Cr<br />
Glx<br />
4.0<br />
3.0 2.0 1.0 ppm<br />
4.0<br />
3.0 2.0 1.0 ppm<br />
Creatine is <strong>of</strong>ten used as internal standard to measure o<strong>the</strong>r<br />
peaks against
N-Acetylaspartate (NAA)<br />
• primary peak ! = 2.0 ppm<br />
• Amino acid found in mature neurons and axons<br />
• Function is as yet undefined<br />
• Marker <strong>for</strong> neuronal and axonal integrity<br />
• Can be detected as early at 16 weeks gestation<br />
• With normal myelination <strong>the</strong>re is a rapid rise in NAA levels:<br />
! dendritic proliferation & ! synaptic density<br />
• Decreased NAA in pathologies with neuronal loss / damage<br />
2.0
Choline (Cho)<br />
• ! = 3.2 ppm<br />
• Found in both glia and neurons<br />
• Structural component <strong>of</strong> all cell membranes, including<br />
myelin<br />
• Reflects cellular proliferation<br />
• Infers in<strong>for</strong>mation about myelination and cell membrane<br />
turnover<br />
3.2
Creatine (Cr)<br />
• primary peak ! = 3.0 ppm<br />
• Creatine pool (creatine & phosphocreatine)<br />
• Found in neurons and glia<br />
• Involved in cellular ATP metabolism<br />
• Considered most stable cerebral metabolite<br />
3.0<br />
• Used as internal standard to measure o<strong>the</strong>r peaks against
Lactate (Lac)<br />
• primary peak ! = 1.3 ppm<br />
• Not measurable in normal functioning <strong>brain</strong> tissue<br />
• End product <strong>of</strong> glycolysis & indicates anaerobic metabolism<br />
• Lactate accumulates in:<br />
! necrosis & many neoplasms (especially higher grade)<br />
! stroke & seizure activity<br />
! mitochondrial defect or injury<br />
! inflammatory demyelination & infection<br />
1.3
Lipids<br />
• multiple peaks within ! = 0.8 to 1.3 ppm<br />
• Indicates necrosis and/or disruption <strong>of</strong> myelin sheath<br />
in white matter<br />
• Commonly seen due to voxel contamination from fat<br />
(eg., scalp)<br />
• Lipids may obscure o<strong>the</strong>r peaks (eg, lactate)<br />
• Best seen at short TE 35/35<br />
0.8-1.3
Myoinositol (mI)<br />
• ! = 3.6 ppm<br />
• Located primarily in astrocytes<br />
• Absent in neurons<br />
3.6<br />
• Considered important “osmolyte” or cell volume regulator<br />
• Marker <strong>for</strong> gliosis and reactive astrocytosis<br />
• Dominant peak in newborn, decreases rapidly by 6 months<br />
<strong>of</strong> age<br />
• Best seen at short TE 30/35
Glutamate & Glutamine (Glx)<br />
• ! = 2.1 to 2.5 ppm<br />
• Glutamate is an excitatory neurotransmitter<br />
• Glutamate is converted to glutamine (primarily found in<br />
astrocytes)<br />
• Conversion system can be overwhelmed in some hepatic<br />
diseases<br />
• Best seen at short TE 30/35<br />
2.1-.5
Single vs. Multivoxel Localization ?<br />
Lesion<br />
What ? Where ?
Normal Cerebral Maturation<br />
26 wk EGA preterm term newborn 2 month old 6 month old<br />
Cho<br />
NAA<br />
• In preterm infants, higher Cho levels reflect very early<br />
myelination<br />
• Cho levels normalize between 8 months and 2 years
Normal Cerebral Maturation<br />
1 year old 2 year old 7 year old<br />
30 year old<br />
• Gradual rising NAA/Cr after birth reflects neuronal maturation<br />
• After 2 years, <strong>the</strong> spectral pattern in children will be nearly<br />
identical to that <strong>of</strong> adults
Abnormal Development & Metabolic<br />
Consider adding <strong>MR</strong>S in developmental delay, metabolic, and<br />
unexplained neuromuscular disorders<br />
Place voxel in WM abnormality & “normal” WM <strong>for</strong> comparison<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• Low NAA<br />
• Excess lactate<br />
• Metabolic pr<strong>of</strong>iles unique to several common disorders:<br />
! ! NAA (Canavan’s disease)<br />
! ! Glx & " mI (Ornithine transcarbamylase (OTC) deficiency<br />
! ! mI (Metachromatic leukodystrophy)<br />
! """ Creatine (creatine deficiency syndromes)<br />
! Phenylalanine (Phenylketonuria)
Creatine Deficiency Syndromes<br />
6 y.o. male, developmental delay<br />
TE 144<br />
# Cr<br />
3.0 1.3<br />
Severe creatine deficiency or depletion, no cerebral lactate
Creatine Deficiency Syndromes<br />
Genetics confirmed X-linked creatine transporter deficiency<br />
39 y.o. mo<strong>the</strong>r - unaffected<br />
12 y.o. male, Index case<br />
TE 144<br />
# Cr<br />
9 y.o. sister - unaffected<br />
3.0<br />
3.0<br />
3.0
Metachromatic Leukodystrophy<br />
6 y.o. male, cognitive decline, loss <strong>of</strong> developmental milestones<br />
mI<br />
TE 35<br />
3.6<br />
TE 144<br />
3.2 2.0 1.3
Epilepsy – Temporal Lobe<br />
Place voxels along both hippocampal planes<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• " NAA, NAA/creatine, & NAA/(Cho + Cr) indicating neuronal loss<br />
and/or dysfunction<br />
• ! mI indicating reactive gliosis<br />
• ! Lactate & lipids $ within first 24 hours after seizure, may last <strong>for</strong> as<br />
long as 7 days
Epilepsy – Temporal Lobe<br />
NAA/Cho + Cr is most useful parameter in mesial TLE:<br />
• NAA/(Cho + Cr) < 0.71 is considered pathologic<br />
• Sensitivity <strong>of</strong> <strong>MR</strong>S to lateralize lesion is 85-92%<br />
• Asymmetry Index (AI) > 11% can lateralize epileptogenic focus<br />
• Bilateral <strong>MR</strong>S abnormalities in up to 50% TLE patients<br />
• When NAA/(Cho + Cr) is reduced in both hippocampi, index used<br />
<strong>for</strong> lateralization is halved to 5.5%<br />
Goal is to lateralize epileptogenic lesion and convert a “non-lesional”<br />
into a “lesional” <strong>MR</strong> exam
<strong>MR</strong> <strong>Spectroscopy</strong> in Hippocampal Sclerosis<br />
18 y.o. male, refractory right temporal lobe epilepsy with obvious right<br />
hippocampal sclerosis on structural <strong>MR</strong> imaging<br />
TE 135<br />
NAA<br />
= 0.20<br />
(Cho + Cr)<br />
AI = 52.3%<br />
NAA<br />
(Cho + Cr)<br />
= 0.42
<strong>MR</strong> <strong>Spectroscopy</strong> in Hippocampal Sclerosis<br />
46 y.o. male, chronic left temporal lobe epilepsy, increased left<br />
hippocampal T2/FLAIR signal without hippocampal atrophy<br />
TE 135<br />
NAA<br />
(Cho + Cr)<br />
= 0.61<br />
NAA<br />
= 0.39<br />
(Cho + Cr)<br />
AI = 22.0%
<strong>MR</strong> <strong>Spectroscopy</strong> in Hippocampal Sclerosis<br />
27 y.o. female, nocturnal seizures x 5 yrs, left mesial temporal lobe seizures on<br />
EEG but with normal anatomical <strong>MR</strong> imaging<br />
TE 135<br />
NAA<br />
(Cho + Cr)<br />
= 0.67<br />
NAA<br />
= 0.59<br />
(Cho + Cr)<br />
AI = 8.0%
Amygdaloid Sclerosis<br />
55 y.o. female, anterior right temporal lobe seizures with prominent fear and<br />
panic semiology<br />
TE 30<br />
3.6<br />
Place TE 30/35 single voxel (~ 1.5 x 1.5 cm) over each amygdala<br />
Lateralized % myoinositol (3.6 ppm) to “gliotic” amygdala
Neuro-Oncology<br />
Common Indications:<br />
• Differentiate neoplastic vs. non-neoplastic lesion<br />
• Establish etiology – primary neoplasm vs. metastasis<br />
• Suggest histologic grade<br />
• Assess tumor boundaries<br />
• Indicate preferred biopsy target(s)<br />
• Assess <strong>the</strong>rapeutic response (recurrence, post-RT necrosis)<br />
• Differing roles <strong>for</strong> single- and multi-voxel sampling
Brain Neoplasm<br />
Place SV at edge <strong>of</strong> enhancement, or CSI to<br />
cover mass and surrounding parenchyma<br />
• Intermediate TE 135 is most useful<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• " NAA (NAA implies CNS origin)<br />
• ! Choline (main metabolite to be assessed in neoplasms)<br />
• " Creatine<br />
• ! Lactate<br />
• ! Lipids
Brain Neoplasm<br />
Differential Diagnosis <strong>of</strong> Tumor Grading:<br />
• Lower NAA occurs in higher-grade tumors<br />
• Higher choline is found in high-grade tumors<br />
• ! myoinositol in low-grade (benign) > high-grade tumors<br />
• Higher lactate found in high-grade tumors (ischemia)<br />
• Lipids are typically found in high-grade tumors with necrosis<br />
• Reduction <strong>of</strong> all metabolites (+/- lipids/lactate) is indicative <strong>of</strong><br />
radiation necrosis
Mixed Oligoastocytoma<br />
WHO grade II<br />
TE 135<br />
NAA<br />
+Gd<br />
Residual NAA implies CNS origin (i.e., not metastatic)
Oligodendroglioma<br />
WHO grade II<br />
NAA<br />
TE 30<br />
Cho/NAA & Cho/Cr both increase with cellular density and mitotic index<br />
Often increased mI in low grade tumors at short TEs
Glioblastoma Multi<strong>for</strong>me<br />
WHO grade IV<br />
T2W<br />
!!! Choline, ! lipids & lactate, and " NAA from necrosis<br />
Peri-insular ! choline represents ‘infiltrative’ edema and tumor
Always Review <strong>MR</strong>S Alongside Structural Images<br />
Example: Central Neurocytoma<br />
Cho<br />
TE 30<br />
TE 135<br />
Lactate<br />
NAA<br />
Some benign tumors have ‘aggressive & hypermetabolic’ spectra
Meningioma<br />
WHO grade II<br />
TE 30<br />
TE 135<br />
Alanine<br />
! Alanine (doublet at 1.4 ppm inverts at TE 135)<br />
No NAA<br />
!! Choline<br />
Alanine
Primary Neoplasm vs. Metastases<br />
Place multivoxel (TE 135) to sample <strong>the</strong> enhancing<br />
lesion and its “perilesional edema”<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• Absent or """ NAA and Cr suggestive <strong>of</strong> metastatic lesion<br />
• ! choline within both metastatic lesion and glioma<br />
• ! choline in “perilesional edema” suggests infiltrating tumor
Metastatic Adenocarcinoma<br />
Lung Primary Malignancy<br />
Cho<br />
TE 135<br />
# Cr<br />
# NAA<br />
3.0 2.0<br />
No NAA implies tumor is <strong>of</strong> non-CNS origin<br />
Avoid including cystic component in voxel
Metastatic Squamous Cell Carcinoma<br />
Lung Primary Malignancy<br />
*<br />
TE 135<br />
*<br />
Metastatic perilesional “vasogenic” edema lacks ! choline (*)
! Cho<br />
TE 135<br />
Malignant Glioma<br />
WHO grade III<br />
! Cho<br />
‘Infiltrative’ or ‘cellular’ edema shows ! choline from infiltrating tumor
Preferred Biopsy Target(s)<br />
Use multi-voxel <strong>MR</strong>S (TE 135) over lesion<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• Identify area with greatest increase in Cho levels<br />
• ! Cho indicates areas <strong>of</strong> ‘higher cellularity’<br />
• Biopsy should show high tumor infiltration
Malignant Mixed Oligoastrocytoma<br />
WHO grade III<br />
!! Cho<br />
! Choline indicates areas <strong>of</strong> higher cellularity and tumor grade
Inflammatory Demyelination vs. Neoplasm<br />
37 y.o. female, subacute progressive right-sided hemiparesis, enhancing left<br />
hemispheric mass lesion<br />
Cho<br />
TE 30<br />
NAA<br />
TE 135<br />
mI<br />
3.2<br />
2.0<br />
3.2<br />
2.0<br />
! Choline, " NAA, ! lactate and myoinositol<br />
Demyelination spectra may look very similar to neoplasm
Cerebral Abscess vs. Neoplasm<br />
35 y.o. female, progressive headache, right-sided weakness<br />
TE 135<br />
AAs<br />
DWI +Gd<br />
1.3 0.9<br />
Doublet peak at 0.9 ppm inverts at TE 135<br />
! Cytosolic Amino Acids from proteolytic activity <strong>of</strong> PMN leukocytes<br />
Amino acid peak may be masked by lipid peaks at TE 30<br />
O<strong>the</strong>r peaks from voxel including adjacent <strong>brain</strong> parenchyma
Assessing Therapeutic Response<br />
Use multi-voxel <strong>MR</strong>S over lesion<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• Identify residual or recurrent tumor<br />
• Differentiate residual or recurrent tumor from post-treatment<br />
abnormality (i.e., radiation necrosis)<br />
! Evidence RT necrosis typically observed within 6 months<br />
! Absent or """ NAA, Cho, Cr, mI<br />
! ! lipid and lactate levels
Radiation-Induced Necrosis<br />
Stereotactic Radiosurgery-Targeted Metastatic Breast Cancer Metastasis<br />
Baseline 6 mos post SRT 8 mos post SRT<br />
Lipids<br />
""" NAA, Cho, Cr, and !!! lipids with treatment-related necrosis
Stroke and Cerebral Ischemia<br />
Place SV voxel (TE 135) in lesion, or over basal ganglia in<br />
suspected diffuse hypoxic ischemic injuries<br />
Major Findings on 1 H <strong>MR</strong>S:<br />
• ! Lactate (most sensitive & earliest finding)<br />
• " NAA<br />
• occasional ! Glutamate<br />
• ! Lipids<br />
• Reality is that <strong>MR</strong>S has little <strong>practical</strong> role in adult stroke as<br />
DWI / PWI is faster and more specific<br />
• <strong>MR</strong>S is useful in suspected pediatric hypoxic ischemic injury
Hypoxic Ischemic Encephalopathy<br />
Term infant, suspected perinatal HIE<br />
TE 135<br />
1.3<br />
Lactate<br />
<strong>MR</strong>S can confirm HIE, as ! lactate may be only clue within first 48 hours
Hypoxic Ischemic Encephalopathy<br />
Term infant, seizures, no <strong>brain</strong>stem reflexes<br />
TE 135<br />
Lactate<br />
1.3<br />
1.1<br />
Propan-1,2-diol<br />
Beware iatrogenic peak at 1.1 ppm (related to seizure medication)
Hypoxic Ischemic Encephalopathy<br />
Term infant, seizures, possible perinatal twin-twin HIE<br />
TE 135<br />
1.1<br />
Propan-1,2-diol<br />
No increased lactate or <strong>MR</strong>/<strong>MR</strong>S evidence <strong>of</strong> HIE
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