INTRODUCTION Noninvasive technique to determine the molecular metabolites

INTRODUCTION  Noninvasive technique to determine the molecular metabolites

INTRODUCTION Noninvasive technique to determine the molecular metabolites in any given living tissue. A method of molecular imaging. In many pathologic processes, metabolic changes precede anatomic changes. Concentration of these metabolites alter in a defined reproducible way in diseased tissue - Abnormal spectra

So, MRS offers a method for early detection of diseases and can influence therapy. Nuclei with odd no of protons and neutrons (atomic mass number) have a magnetic moment and interact with external magnetic field and are observed in MR spectroscopic studies. Ex : 1H, 31P, 13C,19F, 23Na. MRS can detect metabolites in conc. more than 0.1 mM.

PREREQUISITE Basic principles are the same as MRI with following differences: WATER SUPRESSION MR images are reconstructed from entire proton signals from tissue dominated by water and fat protons. Protons from other metabolites do not contribute to imaging because of their negligible conc. In MRS - aim itself is to detect these small metabolites. Most metabolites of clinical interest resonate between resonant frequencies of water and fat. Hence to detect them large signal from water protons needs to be suppressed.

Concentration of water can be 10000 times the concentration of other metabolites. Most frequently used technique - Chemical Shift Selective excitation (CHESS) - reduces water signal by a factor of 1000. (Adequate water suppression if base line is normal.) Factors affecting resonance frequency: Lamda (Gyromagnetic ratio), Field strength,

Chemical environment, Magnetic homogeneity. 1. Gyromagnetic ratio: Fixed for an atom of an element. The gyromagnetic ratio (also sometimes known as the magnetogyric ratio in other disciplines) of a particle or

system is the ratio of its magnetic moment to its angular momentum. The gyromagnetic ratio (MHz/T) for a few commonly measured or imaged isotopes are 1: H-1 F-19 Na-23 P-31 42.58 40.05

11.26 17.24 2. Field strength: So, in homogenous field, Precessional frequency of protons in a given metabolite proportional to chemical shift to the position of metabolic peak. From Larmor equation, = B precessional frequency of any proton is directly proportional to external magnetic field strength. Chemical Shift in Hz will be different at different magnetic field

strengths. Hence, Chemical shift is expressed in terms of ppm ( parts per million ), which remains same for a particular metabolite at all field strengths. Also since Chemical shift is proportional to external magnetic field, smaller CS will not be detected at low field strengths. Field strength of 1.5T or above is required for improved spectral separation and increased SNR. 3. CHEMICAL SHIFT phenomenon: Variation in the resonance frequency of a nuclear spin due to the

chemical environment around the nucleus - Chemical shift. Chemical shift results from the magnetic shielding by the electrons around the nucleus. Chemical shift forms basis of 2 imaging patterns: In phase and out phase imaging: when fat and water are in phase and out of phase so that their signal add or cancel each other respectively. MR spectroscopy: Chemical Shift determines the position of metabolic peak in MRS. For ex: proton in water, fat , NAA will all precess at different frequencies.

Chemical shift results from the magnetic shielding by the electrons around the nucleus. All nuclei in a given molecule are surrounded by an electron cloud. Higher the electron density around a nucleus- more effectively is the nucleus shielded. When placed inside the static

external magnetic field B0, a circulation in the electron cloud surrounding the nucleus is induced such that the induced magnetic field, Bind, is opposite to B0. The opposing magnetic field, Bind, reduces the field experienced by the nucleus- resulting in a shielding of the nucleus from the full strength of the external magnetic field.

Effective magnetic field, Beff, felt by the nucleus is therefore smaller than the applied magnetic field - resulting in a lower resonance frequency of the nucleus: Higher the electron density around a nucleus- more effectively is the nucleus shielded. The strength of the induced magnetic moment depends on the applied magnetic field and the shielding constant, : REMEMBER

In MRS- standard is the resonance of a compound Tetramethylsilane (TMS) - arbitrarily defined as 0 ppm For in vivo MRS - the water resonance is typically used as an internal standard, at 4.7 ppm with regard to TMS 4. Magnetic field homogeneity: MRS requires more homogenous magnetic field than MRI. Since, CS is proportional to external magnetic field, smaller chemical shifts will be misinterpreted and incorrect conc. will be recorded in inhomogenous field. Homogeneity required

MRI - 1 to 10 ppm MRS - 0.1 ppm Magnetic field is made homogenous by SHIMMING LOCALISATION TECHNIQUES IN MRS Two major approaches to localize MRS signal :

Single voxel spectroscopy (SVS) - pulse sequences used are STEAM PRESS ISIS Multivoxel spectroscopy - based on Chemical shift imaging (CSI)

MULTIVOXEL SPECTROSCOPY Based on CSI. (also called MRSI) Signal intensity, peak resonance area can be converted in image format and overlaid onto anatomical MR image. Phase encoding is done in one , two or three dimensions to encode information from multiple voxels simultaneously. Then data are translated to extract chemical shift information from multiple positions using Fourier Transformations.

SVS - Excellent localization, Field homogeneity Excellent Water suppression. Short time. -Generate data from well defined small volume in short time 3 to 6 min. MVS

- Advantage of acquiring multiple spectra in single acquisition. Shown superimposed on MR image. - Long time- upto 12 min - Sensitive to motion artefacts MRI MRS Digitizes signal & generate

images Vs Digitizes signal & generates spectrum Data.analyzed in time domain Data analyzed in frequency domain . Frequencies used to encode space.

. Frequencies used to encode chemistry H2O & Fat predominates Metabolites predominate . All field . strengths

Field strength > 1.5 T Homogeneity Imp (1-10ppm) Field Homogeneity crucial(0.1ppm) No additional shimming Additional shimming

All available signal contribute Selective signal contribute ) STEPS TO OBTAIN MRS 1. Patient positioning and acquisition of MR images for localization2. Selection of MRS parameters : TE TE- 20-30 ms, 135-145 ms , 270 ms Short TE- ALL METABOLITES (Glu, Gln, mI) are visible

Long TE (>135ms) - major brain metabolites - Choline ,Creatine ,NAA, Lactate Thus, Less noise at longer TE. 3. SHIMMING: For narrower metabolic peaks, better spectral resolution and good SNR. 4. Water suppression So that small metabolite peaks are visible. By CHESS technique.

5. MRS data collection, processing and display Done by software. Zero point in spectrum is set at freq. of TMS (tetra methyl silane). INTERPRETATION

Look at the baseline Look at peak separation Identify the Normal & Abnormal Metabolites Assess Metabolite Ratios using Cr as internal reference Should always be based on -ratios of metabolites rather than absolute conc. of individual metabolites -comparison with normal side. NAA Regional Variations

Marker of neuronal / axonal viability and density Adult concentration more in gray matter than white matter. Infant concentration is equal in both. . Evenly distributed throughout the cerebral cortex . Less in hippocampus. . Lesser in cerebellum. NAA Pathological Variations NAA count decreases in brain disorder , resulting in neuronal and axonal loss Ex., neurodegenerative disease ,stroke ,tumor , epilepsy, multiple sclerosis (decreased number of neurons).

NAA concentration increases in Canavans disease (due to deficiency of enzyme N-acetylaspartate cyclase). Creatine + Phosphocreatine =Total Creatine Marker of intact brain Energy Metabolism. Acts as store of ATP.

Used as internal reference as most stable metabolite, Cr =1 Higher in grey matter than white matter (as cell nucleus lies in neuronal body that lie in grey matter) Higher in thalamus and cerebellum than white matter (as they are nuclei / grey matter / neuronal body ) Increased : In trauma, Hypometabolic states. Reduced: Hypoxia, stroke, necrosis, malignant tumor (where it is used up already), in hypermatebolic states- hyperthyroidism

Phosphorylcholine + glycerophosphorylcholine Total Choline Choline is slightly more in white matter than gray but more in thalamus and cerebellum. Concerned with cell membrane turnover. Choline released during disease from the pool. Increased in condition of: myelin breakdown, hypercellular state tumor (increased cell turnover).

Reduced in hepatic encephalopathy, stroke (decreased number of ce and so cell membranes). 4. MYOINOSITOL (mI) First peak : 3.56 ppm Second peak : 4.1 ppm Acts as an osmolyte (cell volume regulator ) Almost exclusively located in astrocytes -- a marker of gliosis. Most dominant peak in newborns and decreases with age. Increases in- Alzheimers disease, frontal lobe dementias (as neuron number deceases and glial cell marker increases),

diabetes, hyperosmolar states. Decreases in - hepatic encephalopathy (edema), stroke, tumor ( as in these cases glial cell also decrease in number). hyponatraemia, osmotic pontine myelinolysis Lactate increases in -: hypoxia, tumor,

Mitochondrial encephalopathy, Canavans disease, Alexanders disease Doublet at 30 ms Persists even after 270 ms Inverts at 144 ms

--.. -.. Lipids : - It is non specific indicator of anaerobic glycolysis. Normally Bound - not seen Seen when liberated in pathological processes -cell death and cell membrane destruction: - high grade tumors with necrosis, - multiple sclerosis, - tuberculomas, - stroke.

. Definitely pathological - indicates necrosis and / or disruption of myelin sheath . Difficult to differentiate from macromolecules . Nonsignificant lipid - contamination of Voxel Of Interest from lipids in scalp. GLUTAMATE Glutamate is excitatory neurotransmitor. Glutamate is a neurotoxin when concentration exceeds that required for neurotransmission Glutamate is elevated : in hypoxia, ischemia, recovering brain.

GLUTAMINE Glutamine is astrocyte marker. Protective function of astrocyte Main ammonia intake route. ALANINE Alanine doublet seen at 1.48 ppm Elevated in meningioma. Valine and leucine are marker of abscess LIMITATIONS

Neurotransmitters are beyond detection (Low concentration) Ach, NE, Dopamine, serotonin (Exceptions - Glycine, Glutamate, Glutamine, GABA) Hormonal messengers are not detected Inositol polyphosphates, c- AMP( Lack of Methyl group) Macromolecules not detected - RNA, DNA (Bound state, Limited Mobility)

Time required, Motion artefacts may make it impossible in some pt Expertise technician CLINICAL APPLICATIONS Brain Prostate Breast Gauchers D: quantification of fat in marrow.

31P MRS: used in herpes encephalitis. Liver Cardiac. BRAIN TUMORS In general show 5 biochemical defects

NAA is decreased destruction/absence of neurons & axons Cr is moderately decreased - Low energy state of tumors Choline is increased - Proliferation of cell membrane Lactate is increased - Increased anaerobic glycolysis Lipid is increased - Necrotic regions or Rx response

- Reduced NAA/Cr ratio, - elevated Cho/Cr ratio I. DIAGNOSIS AND GRADING Grading of glial tumors Cho/ Cr ratio > 2.0 in glioma, bet 1.3 -2.0 in hamartoma ,and less than 1.3 in normal brain

High choline, low NAA, presence of lactate and lipid- correlates with higher grade of malignancy- reflects tumor, hypoxia and necrosis Eg: in GBM. ASTROCYTOMA Myo-ionositol - Marked elevation - Low grade gliomas Normal or absent mI - High grade gliomas NAA levels are low in all astrocytoma, but are lowest in grade-IV

tumors. Choline is always elevated in solid astrocytomata, but is more so in those of higher grades. The presence of lactate generally reflects necrosis and, therefore, a higher degree of malignancy 3. Meningioma Vs

GBM Sometimes may be difficult to differentiate with conventional MR images. On MRS, Meningioma - low NAA (neuron destruction) - Alanine peak . GBM - low NAA , high Lac , lipid peak. - mI increased

MENINGIOMA VS GBM 4. METASTASIS Most useful in solitary lesion. High choline, Decreased - Cr and absent NAA

Astrocytomas also have similar spectra. Differentiated by- sharp margin of mets with no spectroscopic abnormality in the immediate adjacent tissue. Incontrast gliomas - spectroscopic abnormalities extending beyond the enhancing margin of tumor. Glycine level markedly elevated in GBM , ependymoma and medulloblastoma whereas it is low in mets. 5. Lymphoma low NAA and high Cho. Similar to astrocytomas.

MRS helpful in assessing response to treatment successfully treated lymphoma shows progressive decreases in choline and lipids. II. TUMOR EXTENT - EDEMA VS INFILTRATION Both appear hyperintense on T2 and FLAIR. MRS - area of cellular infiltration shows increased Cho and low NAA. - Vasogenic edema does not show any such changes. MRS helps to delineate tumor margins - for complete

tumor resection or planning RT and avoiding it (tumor under Rx.) III. Therapeutic planning for gliomas and predicting response to therapy. IV. Radiation necrosis Vs Tumor recurrence On MRI both appear as heterogeneous mass lesions with enhancement and edema.

On MRS, Tumor recurrence - relative incresed choline levels Radiation necrosis- shows low or absent Cho. RADIATION NECROSIS TUMOUR RECURRENCE V. DIFFERENTIATION OF INTRACRANIAL RING ENHANCING LESIONS

1. Necrotic brain tumors Vs abscess MRS in Pyogenic abscess - shows lactate - amino acid peaks like valine and leucine Necrotic areas of tumors - show only lactate peak Further, anaerobic brain abscesses- acetate and succinate, which are not seen in aerobic ones. PYOGENIC ABSCESS VS BRAIN TUMOUR

2. Pyogenic Vs Tubercular abscess Pyogenic - lipid, lactate and amino acids- valine, leucine Tubercular abcesses - only lipids and lactate TB abscesses vs necrotic tumors Both show only lipids and lactate, but necrotic high grade tumors also show significantly elevated Cho / NAA ratios. 3. NCC Vs Intracranial tuberculoma

NCC- shows an extremely low levels of metabolites. TB- primarily lipid peak at 0.9 and 1.3 ppm (d/t large lipid fraction present in mycobacteria). Recent studies Tuberculomas show inc. Choline and low Cr with Cho/Cr ratio >1 in tuberculomas as compared to NCC. NCC TUBERCULOMA

C. MRS IN EPILEPSY : Conventional MRI - normal in some cases of mesial temporal lobe epilepsy. MRS - metabolic changes that precede imaging findings, like low NAA, NAA/ (Cho+ Cr) in ipsilateral hippocampus. - NAA/Cr - reduced in ipsilateral frontal lobe in frontal lobe epilepsy. 31P MRS- pH and Pi, in involved frontal lobe/ hippocampus.

Changes persist interictally - helps to lateralize epileptic focus. Pre-op planning of epilepsy surgery. VI. NEURODEGENERATIVE DISEASES 1. Alzheimers disease Diagnosis is achieved at autopsy AD vs NPH

MRS AD - Dec. NAA , NAA/Cr in fronto-parietal, temporal lobes and hippocampus - Increased myo-Ionositol is hallmark of AD - mI /Cr increased (help to diff. from other dementia) NPH - NAA/Cr is unchanged. 31 P MRS - Inc. PME, dec. PCr in initial stages of AD. - As dementia worsens, level of PME dec and

PCr inc. NORMAL BRAIN VS ALZHEIMERS VII. MRS in Demyelinating diseases

1. Multiple sclerosis Hyperacute plaques - normal spectrum Acute active plaques - Enhance with Gd-DTPA - Raised lactate and mobile lipids and so called marker peaks in 2.1-2.6 ppm (not seen in children) Chronic plaques - mI (myoinositol).

NAA or NAA/Cr is a good surrogate marker for monitoring of response to treatment in MS. Myo-Ionositol level detected when disease process is severe. AGE VARIATIONS CHILD 2 Days Choline & mI are high, NAA is low Lactate present in preterm and small for date infant, present till 40 weeks

. 2 Months All are roughly equal . 2 Years Adult pattern, increased NAA and low choline F. HEAD TRAUMA: To evaluate tissue viability following trauma. Helps to decide and whether RX is effective. MRS in injured region - highly lactate - due to ischemia NAA, Cr, Cho - due to edema (dilution effect).

Diffuse axonal injury - grossly normal CT - significant NAA/Cr and NAA/Cho in splenium of patients - correlating well with severity of head injury. G. MRS in STROKE Acute strokeNAA and lactate level - in area of infarct.

- Correlates clinically with functional outcome and disability. In ischemic penumbra - lactate without dec in NAA. Chronic infracts - raised lactate levels.(??? Lactate may be present in low level) Leukodystrophies: MRS can detect secondary changes that result from these disorder - help in diagnosis. Ex :

High NAA Canavans disease High phenylephrine (7.3 ppm ) PKU Abnormal lipids Niemann pick disease High glycine ( at ) Non ketotic hyperglycemia. High lactate Mitochondrial disorders HYPOXIC ISCHEMIC INJURY MRI - may be normal in first few days, DWI shows

changes in 2-4 days MRS - Appearance of lactate - Loss of NAA ,Cr - Increase of Glx, Cho . Persistent lactate at 1 yr is poor prognostic sign MRS OF PROSTATE Combined with MRI - To differentiate benign conditions from Ca

prostate - Intraglandular cancer localization and staging - Tumor volume estimation - Assessment of cancer aggressiveness. Pref use endorectal coil. Use 1H MRS, Peaks for choline, creatine and polyamines overlap in regions of healthy prostate tissue. So we consider them together but actually increase in choline is pathological. Citrate is present in normal cells and decreases in cancer and so ratio choline+creatine : citrate is most specific.

Chances of % malignancy if ratio is > than normal > than twice or thrice MRS OF PROSTATE MRS BREAST

1H MRS is commonly used - more sensitive than 31P. Multichannel phased array coil. SVS is more sensitive and commonly used.

Adipose tissue - abundant in breast, absent in brain. Can cause contamination of spectra. Voxel placement most important Placed to cover as much of lesion as possible while excluding surrounding adipose and fibroglandular tissue. Use of long TE 135 to 350 ms To reduce amplitude of lipid and water signals through natural T2 relaxation effects that still allows assessment of pathological lipid signals. t Cho at 3.2ppm-- most important metabolite. To diff benign from malign,

To monitor Rx, APPLICATIONS Benign Vs malignant -Raised tCho in malignant lesions. -Some benign pathologies Fibroadenoma detectable levels of Tubular adenomas tCho at 1.5 T

Lactating subjects THANK YOU - Dr. Azharuddin Syed JR II

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