BRAIN MR SPECTROSCOPYRadiologist Le Thi Kim Ngoc
Introduction of MRS Magnetic Resonance Spectroscopy (MRS) :ananalytical method in chemistry that enables theidentification and quantification of metabolites insamples. Differs from conventional Magnetic ResonanceImaging (MRI): spectra provide physiological andchemical information instead of anatomy
Introduction MR spectra may be obtained from different nuclei :1H(proton), 23Na (sodium), 31P (phosphorus). Themost common nuclei : 1H (proton) (easier to performand higher signal-to-noise) Proton MRS : within 10-15 minutes, + conventional MRimaging protocols. Monitor biochemical changes in neurologic disease Interpretation : be correlated with the MR images beforemaking a final diagnosis
Physical Basis Conventional MRI: 0.2 to 3T. MRS: to detect weak signals from metabolites, ahigher strength field is required (1.5T or more). Higher field strength units have the advantage:higher signal-to-noise ratio (SNR), betterresolution and shorter acquisition times
BASIC PHYSICALPRINCIPLES H-MRS: the chemical shift properties of the atom When a tissue is exposed to an external magneticfield, its nuclei will resonate at a frequency (f) that isgiven by the Larmor equationf = γBo gyromagnetic ratio (γ) is a constant of eachnuclear species the external magnetic field (Bo) and the localmicroenvironment.
BASIC PHYSICALPRINCIPLES interactions of nuclei with the surroundingmolecules - change in the local magnetic field -change on the spin frequency of the atom (aphenomenon called chemical shift) The value of this difference in RF gives informationabout the molecular group carrying H and isexpressed in parts per million (ppm).
The MR spectrum the x axis-metabolitefrequency inppm accordingto the chemicalshift the y axis thatcorresponds tothe peakamplitude
BASIC PHYSICAL PRINCIPLES The resonant frequencies of protons : 10 MHz (0.3T) - 300 MHz (7 T) At 1.5 T, the metabolites :63,000,000 and64,000,000 Hertz- parts per million (ppm). NAA at2.0 ppm and other metabolites fall into their properpositions on the spectral line the ppm scale :it readsfrom right to left
Techniques Anatomical images-select a volume ofinterest (VOI)-spectrum will beacquired different techniques:single- and multi-voxelimaging using bothlong and short echotimes (TE)
Single-Voxel Spectroscopy signal is obtained from a voxelpreviously selected, in 3D Two techniques for acquisitionof SVS H-MRS spectra:pointed-resolved spectroscopy(PRESS) and stimulated echoacquisition mode (STEAM). PRESS - mostly used SVStechnique : doubles SNR, betterspectral quality, more artifact STEAM - shorter than PRESS(short TE and precise volumeselection is needed), lower SNRthan PRESS.
Multivoxel technique obtain simultaneously manyvoxels and a spatialdistribution of the metaboliteswithin a single sequence Instead of the anatomicalinformation ( conventionalMRI), the MRS signal results ina spectrum of metabolites withdifferent frequencies The same sequences used forSVS (STEAM or PRESS) 1D, 2Dor 3D to sample the k-space
SVS vs MRSI SVS : high quality spectrum, a short scan time, and goodfield homogeneity, usually obtained with short TE sincelonger TE has decreased signal due to T2 relaxation.SVS is used to obtain an accurate quantification of themetabolites but spectrum in a limited brain region MRSI is spatial distribution but the quantification of themetabolites is not as precise when using MRSI techniquebecause of voxel bleeding. Therefore,MRSI can be usedto determinate spatial heterogeneity.
Short TE vs long TE MRS with different TEs that result in distinct spectra Short TE: 20 - 40 ms, higher SNR and less signal loss,more metabolies peaks, such as myoinositol andglutamine-glutamate ( not detected with long TE) .Sincemore peaks are shown on the spectrum, overlap inquantifying the peaks of metabolites. Long TEs, from 135 to 288 ms: worse SNR, moresimple spectra due to suppression of some signals.Thus, the spectra are less noisy but have a limitednumber of sharp resonances.
Short TE vs long TEFig. 8. Spectrum obtained with TE = 30ms (A) and TE = 135ms (B). Note the inverted lactatepeak (doublet) with long TE acquisition and the more number of sharps resonance with short TE.Cho– choline; Cr- creatine NAA– N-acetylaspartate; Ins dd1– myoinositol.
Technique The single voxel, short TE, to make the initial diagnosis, becausethe signal-to-noise is high and all metabolites are represented. Multi-voxel, long TE, to further characterize different regions of amass and to assess brain parenchyma around or adjacent to themass. Multi-voxel, long TE techniques are also used to assessresponse to therapy and to search for tumor recurrence
Water Suppression MRS-visible brain metabolites : low concentration in braintissues. Water : the most abundant-spectrum is much higher thanthat of other metabolites (the signal of water is 100.000times greater than that of other metabolites) To avoid high peak from water to be superimpose on thesignal of other brain metabolites- water suppressiontechniques The most commonly used technique is chemical shiftselective water suppression (CHESS) which pre-saturateswater signal Other techniques : Variable Pulse power and OptimizedRelaxation Delays (VAPOR) and Water suppressionEnhanced Through T1 effects (WET).
Fig. 9. Water signal suppressing with CHESS. Spectrum before CHESS(A) and after CHESS (B). CHESS reduces signal from water by a factor of1000 allowing brain metabolites to be depicted on the spectrum.
Artifacts MRS is prone to artifacts: Motion, poor water or lipidsuppressions, field inhomogeneity, eddy currents, andchemical shift displacement .. One of the most important factors: the homogeneity ofthe magnetic field. Poor field homogeneity : a lower SNRand broadening of the width of the peaks. For brain MRS, some regions are more susceptible tothis artifact: near bone structures and air tissue-interfaces. Therefore placement of the VOI should beavoided near areas such as anterior temporal and frontallobes. Paramagnetic devices
Higher Fields H-MRS Higher field MRI (3T, 7T and above): better SNR andfaster acquisitions factor which are important in sickpatients that cannot hold still H-MRS is more sensitive to magnetic fieldinhomogeneity: artifacts due to eddy currents andChemical shift displacement Receiver coils: The use of multiple radiofrequency:higher local sensitivity and results in higher SNR.These coils also allow a more extended coverage ofthe brain.
Spectra H-MRS allows the detection of brain metabolites. The metabolite changes: structural abnormalities.MRS can demonstrate abnormalities before MRI does Spectral variations according to the technique, patientage, and brain region.
Spectra 1H spectra of metabolites areshown on x and y axes. The x, horizontal, axis: thechemical shift of themetabolites (ppm) increasesfrom R to L The y, vertical, axis: signalamplitude of the metabolites.The height of metabolic peakrefers to a relativeconcentration and the areaunder the curve to metaboliteconcentration
Main brain metabolites:N-acetyl aspartate (NAA) Peak of NAA is the highestpeak in normal brain. N-acetyl aspartate : 2.02ppm NAA is exclusively found inthe nervous system in bothgrey and white matter. It isa marker of neuronal andaxonal viability and density.
Main brain metabolites: NAA Absence or decreased concentration of NAA is asign of neuronal loss or degradation. Neuronal destruction from malignant neoplasms andmany white matter diseases result in decreasedconcentration of NAA. In contrast, increased NAA is nearly specific forCanavan disease. NAA is not demonstrated in extra-axial lesions such as meningiomas or intra-axialones originating from outside of the brain such asmetastases.
Main brain metabolites: Creatine (Cr) The peak of Cr spectrum is at3.02 ppm.. Cr is a marker of energeticsystems and intracellularmetabolism. Concentration of Cr isrelatively constant, the moststable cerebral metabolite - asan internal reference forcalculating metabolite ratios. However, there are regionaland individual variability in Crconcentrations.
Main brain metabolites: Cr In brain tumors: reduced Cr. On the other hand,gliosis may cause minimally increased Cr dueto increased density of glial cells (glialproliferation).
Main metabolites: Choline Its peak is assigned at3.22 ppm represents the sum ofcholine and choline-containing compounds Cho is a marker ofcellular membraneturnover (phospholipidssynthesis anddegradation) reflectingcellular proliferation
Main metabolites: Cho Cho = Tumor marker or cell Active tumor growth :increase in Cho, since there isabove-normal production of cells, persistent Choelevation. In tumors, Cho levels correlate withdegree of malignancy reflecting of cellularity Other processes can release or increase Chobesides tumor; multiple sclerosis or infarctions.(from gliosis or ischemic damage to myelin) orinflammation (glial proliferation). Hence elevatedCho is nonspecific. This can be a transient effect.
Main metabolites: Lactate Lactate (lactic acid) is seenas a doublet (two peaksclose to one another) at1.33 ppm and is a by-product of anaerobicmetabolism. Lipids resonate at the 0.9to 1.2 ppm range. Both are released with celldestruction or synthesizedin necrosis.
Main metabolites: Lactate Lip and Lac peaks are absent under normal conditions Lactate and lipid : present in aggressive diseaseprocesses. Lac is a product of anaerobic glycolysis - anaerobicmetabolism : cerebral hypoxia, ischemia, seizures andmetabolic disorders (especially mitochondrial ones). Increased Lac signals also occur with macrophageaccumulation (e.g. acute inflammation). Lac also accumulates in tissues with poor washout suchas cysts, in abscess, normal pressure hydrocephalus,and necrotic and cystic tumors
Main metabolites: Lipid Lipids: cell membranes, notvisualized on long TE (very shortrelaxation time) There are two peaks of lipids: at1.3 ppm and 0.9 ppm Absent in the normal brain,(lipids may result from impropervoxel selection- adjacent fattytissues) Lipid peak: cellular membranebreakdown or necrosis such asin metastases or primarymalignant tumors.
Main metabolites:Myoinositol (Myo) Myo: is a simple sugar, at3.56 ppm. Myo isconsidered a glial marker(primarily synthesized inglial cells) Myo may represent aproduct of myelindegradation. Elevated Myo: proliferationof glial cells ininflammation, in gliosis,astrocytosis and inAlzheimer’s disease
Main metabolites:Alanine (Ala) Ala is an amino acid, doubletcentered at 1.48 ppm. Thispeak is located above thebaseline in spectra obtainedwith short/long TE and invertsbelow the baseline on withTE= 135-144 msec . Its peak may be obscured byLac (at1.33 ppm). The function of Ala is uncertain Increased concentration of Ala: oxidative metabolism defects.In tumors: elevated level of Alais specific for meningiomas.
Main metabolites:Glutamate-Glutamine (Glx) Glx : complex peaks =glutamate (Glu) + Glutamine(Gln) + gamma-aminobutyricacid (GABA), assigned at2.05-2.50 ppm. These metabolite peaks aredifficult to separate at 1.5 T. Glu is an important excitatoryneurotransmitter Elevated concentration of Glnis found in a few diseasessuch as hepaticencephalopathy
Obsevable Proton Metabolitesppm Metabolite Properties0,9-1,4 Lipid Product of brain destruction1,3 Lactat Product of an aerobic glycolysis2,0 NAA Neuronal maker2,2-2,4 Glutamine/GABANeurotransmitter3,0 Creatine Energy Metabolism3,2 Choline Cell membrane maker3,5 Myo-inositol Glial cell maker, osmolyte hormone receptormechanisim1,2 Ethanol Triplet1,48 Alanine Present in meningioma3,4&3,8 Glucose Increased in diabete3,8 Manitol Rx for increased ICP
Regional variations of thespectra Metabolites may varies from brain regions:white and grey matters, supra and infratentorial The Cho concentrations are higher in whitematter than in gray matter but Cr is higher ingrey matter NAA are not significantly different in W and G The cerebellar levels of Cho are higher thanthe supratentorial levels
Developmental variations.Spectra in pediatrics Newborn : low NAA, high Cho, and high Myo levels onMR spectroscopy As age ↑ , NAA and choline-containing compounds andMyo become ↓. NAA reflects brain maturation ,correlates with myelination These metabolites gradually approach the adult patternby 1 to 2 year, is practically constant by 4 years of age Creatine and phosphocreatine are constant - referencevalues A small amount of Lac may be seen in newborn brains
Spectra in elderly With aging, the Cho concentration ingray matter is signiﬁcantly increased. Ongoing reseach
Clinical Application Brain Tumors Radiation injury Human Immunodeficiency Virus(HIV)Infection Degenerative Disorders of theElderly:Alzheimer and Parkinson Diseases Inborn Error of Metabolism Hepatic Encephalopathy Cerebral Ischemia
Some Innovative Applications of MRSpectroscopy Measurement of Psychoactive Drugs Neurofibromatosis Type 1 Cerebral Heterotopias Multiple Sclerosis
MR spectroscopy of neoplasm Brain tumors are currently the main applicationof H-MRS, used as a complement toconventional MRI, along with other advancedtechniques Brain tumors : confirming the diagnosis, gradingthe malignancy, and distinguishing radiationnecrosis from residual/recurrent neoplasm
MRS in brain tumor: TE and Voxel The most relevant parameter : TE- Short TE : more peaks than long TE, differential diagnosis ofbrain masses and for grading tumors. Myo is a marker for lowgrade gliomas, only seen on short TE .- Longer TEs: a limited number of peaks making it easier toanalyze.- Long TEs varying from 135-140ms also invert peaks of Lacand Ala. This inversion is important for differentiating betweenthese peaks and lipids since they commonly overlap The accuracy of MRS is greatest in voxels at the enhancingedge of a lesion, avoiding areas of necrosis, hemorrhage,calcification, or cysts.
MRS in brain tumor: MRSI and SVS MRSI is preferable to SVS : spatial distribution, aspectrum of a lesion and the adjacent tissues,tumor heterogeneity. However, MRSI is generallycombined with long TE SVS is faster, using both long and short TEs. TheVOI should be placed within the mass, avoidingcontamination from adjacent tissues. An identicalVOI must be positioned on the homologous regionof the contralateral hemisphere for comparison
MRS in brain tumor The typical H-MRS spectrumfor a brain tumoris one of highlevel of Cho, lowNAA and minorchanges in Cr
MRS in brain tumor: Cho Elevation of Cho is seen in all neoplastic lesions. Cho increase : cellular membrane turnover whichreflects cellular proliferation, correlated with cell density. Cho peak is usually higher in the center of a solidneoplastic mass and decreases peripherally. Cho signalis consistently low in necrotic areas Diagnosis and progression of tumor, treatmentresponse. The degree of elevation of Cho correlateswith the histologic grade of malignancy and is helpful indistinguishing tumors from non-neoplastic diseaseprocesses.
MRS in brain tumor: NAA and Cr Decrease NAA. This metabolite is a neuronalmarker : destruction and displacement ofnormal tissue. Absence of NAA in an intra-axial tumorgenerally implies an origin outside of thecentral nervous system (metastasis) or a highlymalignant tumor that has destroyed all neuronsin that location. Cr : slightly variable in brain tumors. It changesaccording to tumor type and grade.
MRS in brain tumor Cho elevation is usually evidencedbyincrease in Cho/NAA or Cho/Cr ratios,rather than its absolute concentration. Absolute Cho concentration issusceptible to many errors Therefore, Cho/NAA and Cho/Cr ratios areaccurate for establishing Cho levels inbrain neoplasms.
MRS in differentiaton braintumor and others A low grade glioma (LGG) from stroke or focal cortical dysplasia:increased levels of Cho A giant demyelinating plaque usually shows high Cho and low NAAlevels, increase Lac. Cho increase: transient Brain abscess and neoplasms:+ restricted diffusion+ VOI is positioned in the enhancing area - presence of Cho favors aneoplasm.+ VOI is positioned in the cystic area of a lesion: Presence of acetate,succinate, and amino acids (AAs) such as valine, alanine, andleucine in the core of the lesion have high sensitivity for pyogenicabscess. These peaks are not seen in tumors (pyogenic brainabscess that are under antibiotic therapy these peaks may beabsent)
MRS in Glioma Gliomas: the most common neuroepithelial tumors.They originate from glial cells (e.g. astrocytes oroligodentrocytes) Astrocytomas : low grade (grade I and II, benign) andhigh grade (grade III - anaplastic gliomas and IVglioblastoma multiforme - malignant). A typical astrocytoma: ↓NAA, ↓ Cr, and ↑Cho levels,helpful in distinguishing tumors from non-neoplasticdisease processes
MRS in Glioma Lip and Lac peaks are absent under normalconditions. Lipid peak indicates necrosis in malignant tumors. Lac, a product of anaerobic glucolysis andaccumulates in necrotic portions of tumors. Presence of Lip and Lac correlate with necrosis inhigh grade gliomas.An elevated lactate level isfrequently found in high-grade malignancies
MRI in grading brain tumors Accurate grading of gliomas on the basis of MRS alonemay be difficult: MRS + conventional MR+ other advanced MRI techniques(perfusion MRI..) = precise grading.- Conventional MRI: contrast enhancement, surroundingedema, signal heterogeneity, necrosis, hemorrhage andmidline crossing- Perfusion MRI (high rCBV) suggest a high grade.- MRS : Cho, NAA, Cr, Ratio, Myo, Lac, Lip
MRS in grading brain tumors High grade gliomas demonstrate marked elevation of Cho,decreased NAA The degree of elevation of Cho correlates with the histologicgrade of malignancy and is. Cho/Cr, Cho/NAA ↑, thresholdvalues of metabolite ratios for grading of gliomas are not wellestablished. Cho/Cr is the most frequently used ratio: cutoffvalue of 2.5 Presence of Lac and Lip. Myo is high in low grade gliomas and decreases withincreasing grades of tumors. Low grade gliomas : ↑ Myolevels compared with high grade gliomas. This may be due tolow mitotic index in low grade gliomas and, thus, lowermitogens (substances that trigger cell mitosis), results in Myoaccumulation, characteristic of grade II astrocytomas.
Secondary (Metastatic) Neoplasms Typical MRS of secondary neoplasms: ↑ lipid, lactate,and choline and reduced or absent NAA Distinguishing metastases from high-grade primaryneoplasm: Primary neoplasms (infiltrate surroundingbrain tissue). Interrogation of areas outside theenhancing portion of the lesion (the high signalintensity on T2 weighted imaging seen in theperilesional area) demonstrates ↑ Cho/Cr ratio, ↑Cho/NAA ratio only in high grade gliomas.This featureis consistent with the pathological findings of infiltratingtumor cells in areas of edema not seen in metastases.( In one study, a choline/NAA ratio of greater than 1had an accuracy of 100%)
Lymphoma Typical MRS of lymphoma: ↑ lipid, lactate, andcholine and ↓ NAA signal MRS of lymphoma in AIDS patients: mild tomoderately ↑ lactate and lipid signals, along with aprominent choline peak and ↓ NAA, creatine, andmyoinositol signals. This pattern can help indifferentiating lymphoma from toxoplasmosis, whichtypically ↑ lactate and lipid signals but absence ofthe other metabolites in MR spectra
Tumefactive DemyelinatingLesions Typical MRS for tumefactive demyelinatinglesions : ↑ choline peak and ↓ NAA signal ,presence of lactate (difficult to distinguish atumefactive demyelinating lesion from neoplasticlesions at MR spectroscopy) In multiple sclerosis, the spectroscopicabnormalities are not limited to visible lesions,since normal-appearing areas of white matter wereshown to have reduced NAA signal (compared withNAA signals in healthy control subjects). In theearly stages of the disease, an increasedmyoinositol peak may be more apparent in normal-appearing white matter than reduced NAA signal
Encephalitis Typical MRS features for encephalitis: ↑ lactate,choline, and myoinositol and ↓ NAA signal Encephalitis resemble low-grade gliomas, withreduction of the NAA signal and elevation of thecholine and myoinositol peaks A lactate peak is aninconsistent finding After the initial acute phase of encephalitis, gradualnormalization of the MR spectrum in about 1 year
Brain Abscesses Typical MRS of brain abscesses :elevated peaks of aminoacid, lactate, alanine, acetate, pyruvate, and succinateand absent signals of NAA, creatine, and choline Abscesses have a distinct spectroscopic pattern thatallows differentiation from other entities. - elevation of choline and absence of signal from avariety of amino acids, acetate, and succinate :neoplasticprocess, - whereas the other peaks listed above—alanine, acetate,pyruvate, and succinate—favor abscesses Tuberculous abscesses typically have high lipid andlactate peaks. These abscesses have no peaks for aminoacids (leucine, isoleucine, and valine) at 0.9 ppm,succinate at 2.41 ppm, acetate at 1.92 ppm, and alanineat 1.48 ppm, in contrast to pyogenic abscesses, whichhave peaks for all these metabolites
Radiation necrosis A common clinical problem: distinguishing tumorrecurrence from radiation effects ( following surgeryand radiation therapy). ↑ Choline is a marker for recurrent tumor. Radiation change : ↓ NAA, ↓ Creatine, and ↓Choline. If radiation necrosis is present: ↑ lipids andlactate.
MRS : Cerebral Ischemia andInfarction When the brain becomes ischemic - anaerobicglycolysis and lactate accumulates. ↑↑ lactate is the key spectroscopic feature ofcerebral hypoxia and ischemia. Choline ↑ , andNAA and creatine ↓ . If cerebral infarction : lipids ↑
Inborn Error of Metabolism The diagnosis of an inborn error of metabolism: challenging andmainly based on clinical and laboratorial findings,and genetictests. Brain MRI : narrowing the differential diagnosis, establishing afinal diagnosis. Since these disorders are caused by inherited enzymaticdefects, concentrations of some metabolites may be abnormallylow or high. Metabolites with a very small concentration in braintissue are not depicted on H-MRS. In these cases, thespectrum changes usually correspond to a general pathology,such as demyelination or ischemia. On some diseases: H-MRS may identify a specific biomarkerthat helps in the diagnosis
Inborn Error of Metabolism Disorders that have specific H-MRS patterns maymanifest as increase or absence of particularmetabolites. Specific biomarkers can be seen in phenylketonuria(↑ phenylalanine7.36 ppm ), Canavan disease (↑NAA), nonketotic hyperglycinemia (↑ glycine 3.55ppm ), creatine deficiency (↓↓ Cr), and maple syrupurine disease (branched-chain amino acids and ketoacids 0.9 ppm )