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• There are numerous metabolites found in the human
• Fortunately, only several of them occur in significant
quantities and are useful in proton spectroscopic
• There is evidence that the normal metabolites in the
brain vary with according to the patient's age.
• The changes are most noticeable during the first
three years of life.
• Most of the metabolites
are involved in energy
• Presented here is a
diagram of the major
in the energy
• Detection of frequency dependent signals from
• Interpretation is based on identity of chemical
• Baseline normal spectra - constant
• Concentration of each metabolites alter in a
reproducible pattern - Abnormal spectra =
• Cho - Cell membrane turn over
• Cr - Energy marker -Reference
• NAA - Neuronal cell marker
• mI - Osmolyte
• Lactate - Anerobic state - NOT SEEN
IN NORMAL BRAIN
NAA Regional Variations
• NAA peak – Highest due to N acetyl group
• Marker of neuronal / axonal viability and
• Evenly distributed in Cerebral hemisphere
• Less in hippocampus and cerebellum
• NAA - Neuronal marker
• Decreases with loss of neuronal integrity.
• Energy stores.
• Cr 1 - 3.0 ppm
• Cr 2 - 3.9 ppm
• Marker of intact brain Energy Metabolism.
• Reference for interpretation of ratio.
• Higher in grey matter than white matter
• Higher in thalamus and cerebellum
• Cho - 3.2 ppm
• Present in Cell membrane
• Cell membrane turnover
• Choline released during disease from pool
• Choline - Increased with increased cellular
• Elevated in tumors and inflammation
Choline Regional Variations
• Slightly higher in white matter than gray
• Higher in thalamus and cerebellum
• More choline in pons and terminal zones
• Cell Volume Regulator - Osmolyte
• mI - 3.5 ppm ; 4.0 ppm.
• Present in astrocytes
• Astrocyte /glial marker - Product of myelin
• Accelerated glycolysis /Anaerobic glycolysis
• Lac - 1.3 ppm – Doublet
• Inverts with TE 144 or 135 ms
• Normal in preterm / term infants & CSF
• Lip 1 - 0.9 ppm; Lip 2 - 1.3 - 1.4 ppm
• Broad based
• Sign of brain injury
• Normally Bound - Not seen
• Seen when there is cell death and cell membrane
• Indicates necrosis and / or disruption of myelin
• Difficult to differentiate from macromolecules
• Non significant lipid – from scalp contamination
NORMAL H BRAIN SPECTRA
• A spectrum of the metabolites is plotted on a two
– The horizontal axis represents the frequencies (chemical
shifts) and the vertical axis represents the concentration of
• The frequencies are plotted with reference to a
– The reference compound most often used is
tetramethylsilane (TMS). The chemical shifts are now
expressed as parts per million (ppm).
• This approach allows for consistent spectra
regardless of the field strength.
• It also provides a standardization of the spectrum .
– TMS is assigned a chemical shift of zero ppm and it lies to
the far most right hand .
– The far left end is occupied by water approximately 4.7
– The area under a peak is contributed by the concentration
of that metabolites.
– Therefore, higher or wider peak results from higher
• The 1H-MRS spectrum of major metabolites in a
normal brain is shown in Fig 1 below:
Major Metabolites in the Brain
• NAA is the marker of neuronal density and viability.
– It is present in both gray and white matter and the difference in
concentration is not clinically significant.
– NAA is detected by the its N-acetyl methyl group.
– Its concentration appears to decrease with any brain insults such as
infection, ischemic injury, neoplasm, and demyelination process.
• NAA is not in found in tumors outside the central nervous
system (CNS) such as meningioma.
• NAA is the tallest peak in the proton MR spectrum and it is
assigned at 2.0ppm. Additional smaller peaks may be seen at
2.6 and 2.5 ppm.
• Elevation of NAA is rare and may be found in hyperosmolar
state and axonal recovery.
• The choline peak receives contribution from
glycerophosphocholine, phosphocholine, and
– It is the precursor of acetyl choline and
– Acetylcholine is an important neurotransmitter and the
latter is an integral part of cell membrane synthesis.
• Disease processes affecting the cell membrane and myelin can
lead to the release of phosphatidylcholine.
• Thus, elevation of choline can be seen during ischemic injury,
neoplasm or acute demyelination diseases.
• Many brain tumors will lead to elevated choline peak,
presumably associated with their increased cellularity and
compression of surrounding brain tissue.
• Choline is the second largest peak and assigned to 3.2 ppm.
• The Cr peak receives contribution mainly from creatine, and creatine
– Note that phospocreatine supplies phosphate to adenosine diphosphate (ADP)
to form adenosine triphosphate (ATP) with the release of creatine.
• The overall level of total creatine in normal brain is fairly constant.
– Reduced Cr level may be seen in pathologic processes such as neoplasm,
ischemic injury, infection or some systemic diseases.
– Most metastatic tumors to the brain do not produce creatine since they do
not possess creatine kinase.
– Therefore, metastatic tumors should be suspected if there is an absence of a Cr
peak in the proton spectrum.
• Cr is the third highest peak and is assigned to 3.03 ppm. It is usually seen
next to the right of choline. An additional peak occurs near 4 ppm but is
usually suppressed with water.
• Lactate has a molecular structure of CH3-COH2-CO2.
• Lactate levels in the brain are normally are very low or
absent. When oxygen supply is depleted, the brain switches to
anaerobic respiration for which one end product is lactate.
• Therefore, elevated lactate peak is a sign of hypoxic tissue.
– Low oxygen supply can result from decreased oxygen supply or
increased oxygen requirement.
– The former may be seen in vascular insults, or hypoventilation and the
latter may be seen in neoplastic tissue.
• Resonance of lactate consists of two distinct peak (doublet)
due to J-J coupling.
• Lactate peak also occurs at two different locations.
– The lower field peak (a doublet) occurs at approximately 1.32 ppm.
– The other peak (a quartet) is seen at 4.1 ppm and this is very close to
the water peak.
• usually suppressed during data processing.
• The lactate peak at lower frequency field show a peak
inversion for different TE's.
– This property serves as an excellent confirmation for the presence of
lactate. The lactate peak is above the baseline at TE of 270 ms and
below the baseline at TE of 136 ms. The inversion arises from the
weak J-J coupling from the CH3 and CH protons. The coupling constant
J is 7Hz.
• Myo-Inositol is a glucose-like metabolite and it
involves primarily in hormone-sensitive
neuroreception. It is found mainly in astrocytes and
helps to regulate cell volume.
• Elevated level of mI would be seen where there is
glial cell proliferation as in gliosis.
– Depressed level of mI would be seen processes causing
glial cell destruction , as in neoplasm, infection or ischemic
injury. The main mI peak is assigned to 3.56 ppm and
additional peak may be seen at 4.06 ppm.
• Lipids are often in composition of triglycerides, phospholipids,
and fatty acids.
• These substances are incorporated into cell membranes and
– Lipid peak should not be seen unless there is destructive process of the
brain including necrosis, inflammation or infection.
– Lipids have a very short T1 relaxation time and are normally not seen
unless short TEs are utilized.
• The proton lipid peaks occur at several frequencies including 0.8, 1.2, 1.5
and 6.0 ppm.
• Lipid resonance at 1.2 ppm can sometimes obscure the lactate peak at
• Fat in the cranium can contaminate the true disease process if the voxels
are placed too close the cranium.
Glutamate and Glutamine (Glx)
• Glutamate is an excitatory neurotransmitter in
• Glutamine and glutamate resonate closely
• Their sum is often designated as Glx and is
assigned between 2.1 and 2.5 ppm.
• Glutamine is astrocyte marker
• Glutamate – Neurotransmiter - neurotoxin in
• Main ammonia intake route
• Elevated - In hypoxia, ischemia, recovering
• Its not a grave prognostic finding like lactate
• Understood by identifying important
metabolites and quantifying them.
• Comparing with normal and benign
tissues, we can understand metabolite
markers and grade them.
Alteration of metabolites in Brain Tumors
• Decreased or absence of N – Acetyl Aspartate (NAA) (Non-
neuronal and NAA is only found in neurons)
• Decreased Creatine
• Increased Choline
• Appearance of Lactate (Anaerobic glycolysis)
• Myo-Inositol may distinguish hemangiopericytomas from
• Glutamine and Glutamate are prominent in meningiomas
• Is it a tumour
• GBM/ Metz/ Abscess?
• ? Oligodentroglioma?
• D/D -Stroke, Focal cortical dysplasia,
Herpes and Neoplasm
• ^ Cho – Neoplasm
• Always exclude Demylination - ^ Cho
• Multivoxel PRESS sequence with intermediate
TE -for elevation of Cho in enhancing rim and
in peri-lesional T2 hyperintensity
• If Cho is elevated in both areas - GBM
• Elevated in rim; N –Around - Metz
• Detection of peptides and amino acids in Short
TE - Pyogenic abscess
• Cho/NAA ratio - Most sensitive
index for tumor cell density and
• Marker of tumor infiltration
• High Cho/NAA and Cho/Cr - Fast
growing and high grade neoplasm
• High Creatine levels in grade II
gliomas- malignant transformation
and poor survival
• High Cho -Pediatric brain tumors
Oligo dentro glioma
Sky-rocketing Choline - high cellular density
MR perfusion:Increased- rCBV- high capillary density
low level of angiogenesis
• High Cho - High tumor cell density & high vascular
• Low Cho and elevation of lipids - Necrosis.
• Cho higher enhancing rim -may be the faster growing
side of the tumor.
• Vasogenic edema -Normal Cho and slightly decreased
Spectra of active demyelination indistinguishable from
MR perfusion may be helpful.
41y focal seizure
Tumefactive multiple sclerosis
• Alanine (Ala) doublet at 1.4 ppm
• Elevation of Cho
• Presence of Lac at 1.3 ppm.
• Absent NAA - Non-neural origin.
• Ala -30–40% of Meningioma
• Mobile lipid and high Cho -
43 y Focal deficit
• Normal -1 Infiltrative -2
• Solid -3 Early necrotic -4
• All with high Cho/ Cr >1.7
• High Cho, very low NAA and no lipid -Solid
• Small Lac without lipid may be early indicator
of transformation to high grade.
• 51y M, GBM Rx RT.
• Reduced Cho, NAA and
Cr relative to normal brain
• Localized decreased NAA - few hours of ischemia.
• Very low or absent – chronic infarcts.
• Lac is elevated in acute stroke due to anaerobic glycolysis in
• Creatine and Choline may change in acute and chronic stroke.
• Lipid - Reflect necrosis.
• MRS is added value to diffusion and perfusion
Occlusion of the left ICA /MCA @ 24 h
Left - Elevated Lac and near absent NAA
With in 24 hr
Follow-up @ 1 wk
absence of NAA
Lac in infarct region.
High Cho in peri
Follow-up @ 5 m
high Cho in WM
Lipid + in infarcted
right basal ganglia.
large amount of amino acids -1, lactate -2, alanine -3, acetate -4,acetoacetate -5
Inv Of AA,0.9 ppm, Lac, 1.33 ppm, and Ala, 1.47 ppm peaks
• Similar on MRI.
• Tuberculous abscesses - only Lac and lipid signals @
0.9 and 1.3 ppm; No amino acids
• Lipid peaks –In Both tuberculoma and pyogenic
• Amino acid signals helps to discriminate pyogenic
from tuberculous abscess
• @ 135 TE Inv of AA- 0.9 ppm
Tuberculous vs Pyogenic abscesses
TE 35, only Lip and Lac at 1.3 ppm.
TE 135 spectrum, phase reversal & reduction in signal
Findings are due to interstitial edema; MRS - Non-specific.
• TE 135 proton MR spectrum
from core of abscess - inverted
AA and Lac peaks.
• Multiple signal (*) @ 3.6–3.8
MRS with TE 35 - Lac at 1.33 ppm,
acetate at 1.92 ppm, and succinate at 2.4
@TE 135 - Lac and Ala at 1.5 ppm show
phase reversal while Ace and Suc show
• Spectroscopy may be of value in the large
cysticercus cyst without visible scolex, where
differential diagnosis includes brain abscess
and cystic metastases.
• In vivo MRS shows acetate, succinate and Lac.
• Presence of Cr depending on whether the
lesion is in the vesicular or colloid stage
• Reductions in NAA and increases in Cho, mI
in both lesional and normal appearing brain
• Toxoplasmosis Vs lymphoma
– Toxoplasmosis -Very large lipid signals
– Lymphoma -Large lipid (smaller than toxo)
-High Cho (not seen in toxo).
Multiple sclerosis - Axonal damage - Decreased NAA
Demyelination - Increased mI, Cho.
Acute MS plaques - Decreased NAA and Cr in large plaques
Increased mI, Cho and Lac
Chronic plaque - Cr and Lac return quickly to normal,
Cho - months to return to normal
NAA -may or may not recover to normal.
Tumefactive demyelination may be similar to neoplasm (elevated Cho, Lac,
decreased NAA) –Perfusion useful.
Monophasic Acute Disseminated Encephalo Myelitis - Mild, reversible NAA
reductions without changes in other metabolites - Good prognosis.
• Long TE spectra in acute and chronic MS
– Both - Elevated Cho and reduced NAA
– Only acute lesion - Elevated lactate
• Short TE spectra from acute lesion and normal
brain for comparison
– Increased mI, choline, and lipids, slightly
decreased Cr and NAA.
Acute Vs Chronic Plaque
• During acute phase- focal increases in Cho and Lac
and decreases in NAA, Cr.
• 15 m later - Reduction of lesion and normalization of
Cho, Cr, and Lactate. NAA- partial recovery.
• Help in localize and characterize epileptogenic
• Helps in lateralizing in temporal lobe epilepsy
• @35TE: Decreased NAA, Increased Cho and
mI - Gliosis
• MRS may help to characterize epileptogenic
lesions visible on MRI (aggressive vs. indolent
Reduced NAA signal and increased Cho
and mI signals- Gliosis
Helpful in identification of seizure focus in
refractory pts with normal MR
Reversible with time - transient neuronal
Bilateral metabolic changes, associated with
poor post-op seizure outcome
Aging and dementia
• Aging - Cho and Cr increase and NAA stable
• AD – Reduced NAA and High mI
• NAA/Cr and mI/Cr ratios correlate with
cognitive function in AD, and this correlation
is more significant with NAA/mI ratios.
• WM NAA/Cr is lower in VaD –than AD
• Progression of AD - Regional
elevation of mI/Cr levels in
• mI/Cr and NAA/Cr - useful for
predicting and monitoring
• Neuronal dysfunction & cell death.
• Metabolite changes in idiopathic Parkinson’s
disease are inconsistent.
• Multiple system atrophy -reduction in NAA
and NAA/Cr ratio when compared with IPD.
• Lactate increased in Huntington’s disease.
Traumatic brain injury
• Conventional CT and MR – major role
• High lactate levels - Poor outcome.
• Visible Lac in normal appearing brain
soon after injury - Poor outcome
• Fall in NAA - Continue for months after
the initial insult.
• Most common leukodystrophy in children
• Zones- demylination, inflamm, gliosis
• MRI often precede clinical symptoms showing
symmetrical WM lesions in parietal and
• MRS - Onset of demyelination and extent of
WM damage, information for Hemo Stem Cell
Inborn errors of metabolism
• Canavan and Salla disease show an elevated NAA
• Maple syrup urine disease -Branched-chain amino
acids at 0.9 ppm.
• Phenylketonuria -Small phenylalanine signal at
7.36ppm (i.e. downfield of water)
• Non-ketotic hyperglycinemia -Glycine at 3.55 ppm
(use long TE to distinguish from mI)
Canavan’s disease- AR
• Deficiency of aspartoacylase an enzyme that
deacetylates NAA, Increased free acetate
• Hypotonia and macrocephaly
• Symmetrical confluent subcortical WM T2
prolongation & Centripetal spread
• Bilateral involvement of globi pallidi, thalami,
cerebellum and brainstem
NAA is elevated in posterior
sub cortical WM (1) that is
hyper intense on T2 image;
NAA is near normal levels in
(2) is relatively spared by
Maple syrup urine disease
• Deficiency of branched-chain -keto acid dehydrogenase,
catalyzing essential branched-chain amino acids (BCAA)
isoleucine, leucine and valine.
• Hypertonia and hypotonia, irregular respiration and apnea
• Diffusion restriction compatible with cytotoxic edema in pons,
midbrain, pallidi, thalami, cerebellar, and periventricular WM
• Abnormal peak at 0.9 ppm due to accumulation of lactate
(Lac) and loss of NAA
• Prognostic value & monitor response to Rx / diet
• TE 136 ms- avoids lipids
Elevation of Lac (1.3 ppm) and of the methyl group of BCAA/BCKA (0.9
After therapy at day 12 the two abnormal peaks have disappeared.
• Phe hydroxylase def
• Periatrial and periventricular WM symmetrical
• Calcifications bilaterally in the globi pallidi
and frontal subcortical regions
• Elevated Phe signal at 7.36 ppm
• Highly elevated glycine in the CSF and
absence of ketoacidosis
• Large glycine peak at 3.55 ppm
• Long TE is necessary to distinguish glycine
resonance from that of mI at 3.56 ppm which
is normally high in neonates
abnormal elevation of Gly at 3.55 ppm with a Gly/Cr ~ 1.
Progressive decrease of Gly during treatment with a protein restriction diet
• Diffuse symmetrical hyperintensity and
volume loss in WM
• mild Lac accumulation in WM, with moderate
NAA and mild Cho and Cr signal losses
Multivoxel TE 136 ms at centrum semiovale level