2012.10.30.

1

COURSE FAQ

Forthcoming lectures:16. October – „IGT lecture”23. October – NO LECTURE, holiday30. October – MR Spectroscopy6. November – PET + Final Test

Test:- Basic imaging techniques, what are they- 5-10 easy, simple choice questions- If November 6. is not good for everyone, I will organize extra

time for getting the short test done

Study material:Lecture material will be distributed in PDF 2 wks before thetest.

In vivo MR spectroscopy

Ervin BerényiAndrás Jakab

Diagnostic neuroimaging modalities

CT – Computed TomographyBrain anatomyStereotactic reference frame

Structural MRIFine brain anatomyVascular structure

Diffusion, perfusion MRIFine pathologicalinformation

Intra-operative imagingmodalities, open MRI, low-field

Positron EmissionTomography PETBrain metabolismBrain function

Functional MR imaging fMRIBrain function

Electro encephalography, LORETTA, Magnetoencephalography

MR SpectroscopyBrain metabolismBiochemical mapping

Take home message about MR spectroscopy

• Performing NMR experiments for an image pixel

• Spectrum of brain chemicals, i.e. metabolites Diagnose their alterationsmetabolites. Diagnose their alterations.

• Display, measure:– Choline– Creatine– N-acetyl-aspartate– Lactate– Lipids

2012.10.30.

2

History of MR imaging

1973 Zeugmatography Lauterbur - Nobel, 2003

NMR FourierZeugmatography

1975

1977. Július 3. 4:45 First human MR image

Ernst – Nobel, 1991

Damadian1977 EPI Mansfield – Nobel prize, 2003

1946

60’s

Bloch, Purcell – Nobel 1952

Spectroscopy

NMR phenomenon

Ernst – Nobel, 1991

60’s-70’s Relaxometry of living tissue

Hazlewood, Damadian, Ling…

Cancer detectionwith NMR

Damadian, US Patent 3,789,832

g g p y ,

1972

Nobel prizes

• Isidor Isaac Rabi(1898-1988)

• 1944 – “developing a method to examine themagnetic properties of

b l

• Otto Stern (1988-1969)• 1943 – “proton magnetic

spin discovery”

protons by nuclearresonance”

The Birth of NMR

• 1952 – Felix Bloch & Edward Mills Purcell• “for the precision measurements on nuclear magnetic resonance”

(1905-1983) (1912-1997)Stanford Harvard

The The firstfirst 11H NMR H NMR spectrumspectrum of of waterwater

Bloch, F.; Hansen, W. W.; Packard, M. Bloch, F.; Hansen, W. W.; Packard, M. The nuclear induction experiment.The nuclear induction experiment. Physical Review (1946), 70 474Physical Review (1946), 70 474--85. 85.

NMR spectroscopy

• Richard Ernst • 1991 – “developing high

resolution NRM spectroscopy”

Magnetic resonance imaging(MRI !)

• 2003 – Paul Lauterbur & Sir Peter Mansfield

(1929-2007) (1933-)

2012.10.30.

3

Damadian’s pattern from 1972 Lauterbur’s 1973 Nature paper

Indomitable1977.0,05-0,1 TSzupravezető54,43 kg

Damadian, Minkoff, Goldsmith

Damadian and the coil

The first MR image of a human

1977. Július 3. 4:45, Minkoff

The first pathological case

Physiol. Chem. & Phys., 10:285-87, 1978.

2012.10.30.

4

First pathological case – lungcancer

Physiol. Chem. & Phys, 10:285-87, 1978.

Basics of MR spectroscopy

• Nuclei of atoms bear a physical propertycalled a spin.

• All moving charged bodies create aAll moving, charged bodies create a magnetic field around themselves

• Nuclei with spins act as small magnets

Basics of MR spectroscopy

• In the presence of a strong externalmagnetic field, nuclei spins are orientedand show precession with a well-defined frequencydefined frequency

• This is the Larmor frequency which isproportional to the strength of theexternal field

• This is the resonance frequency of thegiven nucleus

Basics of MR spectroscopy• If a nuclei is in a different

microenvironment, its resonantfrequency is altered

This means that atomic bonds and• This means that atomic bonds and neighbouring atoms determine theresonance frequencies (Chemical Shift)

• One can depict it using a spectrum, where each peak represents a specificatom is a specific bond

EthanolEthanol 11H NMR H NMR spectrumspectrum

Chemical shift1951

Modern ethanol spectrModern ethanol spectrumum

Arnold, J.T., S.S. Dharmatti, and M.E. Packard, J. Chem. Phys., 1951. Arnold, J.T., S.S. Dharmatti, and M.E. Packard, J. Chem. Phys., 1951. 1919: p. 507. : p. 507.

2012.10.30.

5

Free Induction Decay

FT

FT

Processing for MRS

Where can MRS be used?

• Proton MRS– Brain– Prostate– Liver

• Phosphorus MRS– Liver– Heart– Muscles

Different types of MRS• Volume selective MRS• MRS Imaging (MRSI) - metabolite mapping

– Proton (H1)• NAA map• Cho map• Cr map• Cr map• Lac map• Citrate map (prostate)

– Phosphor (P31)• Pi map• PCr map• ATP subtypes

– C13

• Pl. hyperpolarized imaging

Single Volume Localization

RF

Gx

Localized spectra is obtained from a single volume of interest (VOI)Localization is achieved by

RF

Gy

RF

Gz

ysequential selection of three orthogonal slicesThe size and location of VOI can be easily controlledAnatomic 1H images are used for localizing the VOI

Image selected in vivo spectroscopy, ISIS

Point resolved

Single Volume Localization

Po nt resolved spectroscopy, PRESS

Stimulated echo acquisition mode, STEAM

2012.10.30.

6

RF

GxGyGz

90°180° 180°

Point Resolved Spectroscopy, PRESS

(TE1+TE2)/2TE1/2Gz

TE2/2

A slice-selective 90o pulse is followed by two slice-selective 180o refocusing pulsesAchieves localization within a single acquisitionSuitable for signals with long T2 – 1H MRS

90° 90° 90°

RF

Gx

Gy

Gz

Stimulated Echo Acquisition Mode, STEAM

TE/2 TE/2TM

Gz

Three slice-selective 90o pulses form a stimulated echo from a single voxel.Achieves localization within a single acquisitionOnly half of the available signal is obtainedCan achieve shorter TE than PRESS

Effects of MR Parameters on PRESS spectra

Repetition Time, TRNumber of Signal AveragesEcho Time, TEVoxel Size

Single Voxel Spectroscopy: Overview

Simplicity

Flexibility in voxel size and position

Accurate definition of VOI

Excellent shim and spectral resolution

Many voxels within the same dataset

RF

90°

Chemical Shift Imaging

Multiple localized spectra are obtained simultaneously from a set of voxels spanning the region of interest

Gslice

G y

G z

Uses same phase-encoding principles as imaging

No gradient is applied during data collection, so spectral information is preserved

Display of all spectra

Underlying reference image shows voxel position

CSI Spectral Map

Individual spectra can be displayed enlarged

Spectral map can be archived together with the reference image and the CSI grid

2012.10.30.

7

CSI Data Analysis

Image showing voxel position

Spectrum from a voxel

MR spectroscopic imaging,Chemical shift imaging (CSI)

TumorNormal

Cho

Necrosis

NAA

CrtCho

Primer Progressiv Aphasia

NAA/Cho NAA

Cho Cre

CSI: Overview

Advantages

Acquisition of multiple voxels

Metabolite images, spectral maps, peak information maps, and results table

Many voxels within the same dataset

Disadvantages

Large volume – more difficult to shim

Voxel bleeding

Large datasets

Nucleus Spin γ, MHz/T Natural Abundance

Relative Sensitivity

1H 1/2 42.576 99.985 1002H 1 6.536 0.015 0.96

3He 1/2 32.433 .00013 44

Important Nuclei for Biomedical MR

13C 1/2 10.705 1.108 1.617O 3/2 5.772 0.037 2.919F 1/2 40.055 100 83.4

23Na 3/2 11.262 100 9.331P 1/2 17.236 100 6.639K 3/2 1.987 93.08 .05

1H – Neurotransmitters, amino acids, membrane constituents

2H – Perfusion, drug metabolism, tissue and cartilage structure.

13C – Glycogen, metabolic rates, substrate preference, drug metabolism etc

Important Nuclei for Biomedical MR

drug metabolism, etc.19F – Drug metabolism, pH, Ca2+ and other metal ion

concentration, pO2, temperature, etc23Na – Transmembrane Na+ gradient, tissue and cartilage

structure.31P – Cellular energetics, membrane constituents, pHi,

[Mg2+], kinetics of creatine kinase and ATP hydrolysis.

2012.10.30.

8

1H MR Spectroscopy

Brain 1-H MRS

CholineCreatine

N-acetyl aspartatewater

5.0 4.0 3.0 2.0 1.0ppm

Choline (lactate/lipid)

•NAA is a neuronal marker and indicates density and viability of neurons. •It is decreased in glioma, ischemia and degenerative diseases.

N-Acetyl aspartate (NAA)

CH3-C-NH-CH-CH2-COOHO

CH2-COOH

2.02, CH32.52, CH22.70, CH24.40, CH

Important 1H Signals

Creatine (Cr), phosphocreatine (PCr)

NH2-C-N-CH2-COOHCH3

NH3.04, CH33.93, CH2

•Cr is a marker of aerobic energy metabolism•Cr signal is constant even with pathologic changes and may be used as a control value• However, isolated cases of Cr deficiency may occur in children

•Cho compounds are involved in phospholipidmetabolism of cell membrane.•Increase Cho mark tumor tissue or multiple sclerosis plaques

Choline (Cho), choline compounds

3.24, CH33.56, CH24.07, CH2

CH3-N-CH2-CH2-OH

CH3

CH3

Important 1H Signals

plaquesGlutamate (Glu), glutamine (Gln)

2.1, CH22.4, CH23.7, CH

•Glu is a neurotransmitter, Gln a regulator of Glumetabolism•It is hardly possible to detect their signals sepratly. The signals are jointly designated “Glx”.

HOOC-CH2-CH2-CH-COOH

NH2

NH2-CH2-CH2-CH-COOH

NH2

•Lactate is the final product of glycolysis•It can be detected in ischemic/hypoxic tissue and tumors indicating lack of oxygen

Lactate (Lac)

1.33, CH34.12, CH

Taurine (Tau)•Cells examination indicates

CH3-CH-COOH

OH

Important 1H Signals

3.27, NCH23.44, SCH2

•Cells examination indicates taurine synthesis in astrocytes

NH2-CH2-CH2-S-OH

PO4-

PO4-

PO4- PO4

-

PO4-

PO4-

Myo-inositol (Ins)

3.56, CH

•Ins marks glia cells in brain •It is decreased in hepatic encephalopathy and elevated in Alzheimer’s disease.

Neurochemical pathways & neuro-MRS

2012.10.30.

9

A normal brain MR spectrum The effect of echo time on the spectra

Mitochondrial myopathy

TE 144 ms TE 288 ms

Quantitative MRS

• Metabolit ratios• Cr is stable, we compare metabolites to

this• Contralateral – CSI• Water as reference signal (proton cc ≈ 77-

88 M)• Water content• External reference (not so practical)

Proton spectrum metabolites Quantitativ MRS Fantom - QA

• Components:– 12,5 mM NAA– 10 mM Cr– 3 mM Cho, 12,5 mM Glu, ,– 7,5 mM mI– 5 mM Lac

• 50 mM-os foszfát pufferben (7,2 pH; 1% Magnevist; 0,1% Na-azide)

2012.10.30.

10

The proton MR spectrum variesby age

Age related changes of theproton spectrum

MRS indications for newborns

• Hypoxia, but normal UH, CT, MRI, SPECT, PET

• No contraindicationsNo contraindications• Lactate is elevated, NAA & Cr reduced• Sensitivity: high• Specificity: lower, developmental disorders

affect it as well

Neonatal hypoxia

Shaken Baby Syndrome MRS in infants - indications• Normal UH, CT, MRI, SPECT, PET• No contraindications• Lactat elevated, NAA and Cr reduced• Specificity is extremely high in a few

diseases:– Canavan disease: NAA⇑– Frahm-Hanefeld Sy: Cr ⇓– Phenylketonuria : Phenylalanin⇑– Nonketotic hyperglycinemia: glycine ⇑

2012.10.30.

11

Canavan disease

ARAspartoacylasedeficiency

Hypotonia,seizure,Macrocephalia

NAA Spasticity,blindness

Death (age:4)

Frahm - Hanefeld syndrome(Guanidinoacetate methyl transferase deficiency)

(Total Cr absence)

Arginin is administered

Creatinin is administered

Phenylketonuriaphenylalanine hydroxylase deficiency

AD recessiveMental retardationChoreoatetosisSeizures (25 %)HyperreflexiaHyperactivitySpasticus paraplegia

MRSShort echo time:Phe 7.3 ppmMonitoring therepy!

Alexander disease(fibrinoid leukodystrophia)

Rosenthal fibers

Ventrodorsal

Spasticity, seizures

Leukodystrophies

Metachromatic LD Adrenoleukodystrophy

Adrenal insuff. - ALD variant

Leigh’s diseaseMitochondrial diseaseFirst year:HypotoniaAtaxiaOphthalmoplegiaPtosisDysphagia

Lac (1.33) és Ala (1.48) ↑↑

Dysphagia

T2Nucleus caudatusNucleus lentiformisPeriaquaeductálisNucleus dentatusThalamusCerebellaris pedunculus

2012.10.30.

12

MELAS(Mitochondrial Encephalopathy with Lactic Acidosis and Stroke like

lesion)

Regionális variabilitás:legérintettebb az Occipitális lebeny

Metabolic disfunctionof mitochondria inof mitochondria invessels

MR spectroscopy (MRS) chemical shift imaging in stroke

Changes in MRS in stroke

• NAA is reduced, Lac elevates• NAA is most reduced after 30

hoursLactate is detected in chronic• Lactate is detected in chronicischaemia (degragation)

• Lactate is also present (DDG)– Mitochondrial diseases– Demyelinisation– Visual cortex excitation

MRS and CSI in tumors

OligodendrogliomaOligodendroglioma

2012.10.30.

13

Metabolic profile of gliomas

• High Choline– Tumor cells

• Low Choline– Centrum –

necrosis• Normal Cho

– Vasogen oedema

Bizzi et al. In Clinical MR Neuroimaging. Cambridge Univ Press. Page 306-307.

Recurrent astrocytoma

• High Cho, Low NAA and no lipids

• 2: Infiltrtive tumor is markedby Cho3 lid t hi h d

1 23

4

• 3: solid tumor – high gradetransformation is marked byLac++

• 4: Early necrosis – lipid signis present

Croteau et al. Neurosurgery. 2001. 49:823-829

Hearshen et al. In Clinical MR Neuroimaging. Cambridge Univ Press. Page 310.

Radiation necrosis (braintumors)

• Cho, Cr and NAA reduced• Low lipide signal• Cho/NAA ≈ 1

Si il i

1

3

2

• Similar to necrosis• Biopsy may be necessary,

or monitor the grow• DDG: recurrent/residual

tumor!!!!!!!!

Rock et al. Neurosurgery. 2002. 51(4):912-919

Hearshen et al. In Clinical MR Neuroimaging. Cambridge Univ Press. Page 311.

MRS in brain meningeomas

• NAA is not present in non-neurogenic tumors

• Alanine is found• Elevated Choline means

aggressivity

Variability of brain tumors’ spectra

Howe et al. Magn Reson Med. 2003. 49:223-232

Defining tumor subtypes usingmathematical analysis (ICA)

Szabo de Edelenyi et al. Anal Chim Acta. 2005. 544:36-46

2012.10.30.

14

Nosologic imaging

Szabo de Edelenyi et al. Nature Medicine. 2000. 6:1287-89

INTERPRET(International Network for Pattern Recognition of Tumours

Using MR Spectroscopy)

• EU funded research formaking MRS diagnosticsimpler

• Protocoll (methodical) consent• 800 sample database• Automatic analysis• Computer aided diagnostic

tool

Arjan W. Simonetti PhD Thesis 2004.http://azizu.uab.es/INTERPRET/

Tumefact Mulitple Sclerosis

• Similar appearance to tumors, gliomas, BUT DD:Tu: NAA ↓↓, Perf ↑↑;MS: mI/Cr↑↑ Diff ↓↓MS: mI/Cr↑↑, Diff ↓↓

• Diffuse methabolic changes• Acute-chronic plaques• Recurrent remittent (RR) –

Progressive secondary (PR) form

Szabo de Edelenyi et al. Nature Medicine. 2000. 6:1287-89

Abscessus vs. tumorAbscessus GBM

Acetate

Nakaiso et al. Neurol Med Chir. 2002. 42:346-348

Ac: 1.92 ppmSuccinateSuc: 2.4 ppmAspartateAsp:2,6 ppm

Suc

Juvenile SLEPsychiatrical symptomsMRS early diagnosis, beforeMR lesions are apparent:Cho ↑; NAA/Cr ↓

Contralateral

Lesion

Steens et al. Ann Rheum Dis. 2003. 62:583-586

MRS in epilepsyCr/NAA map

Hetherington et al. Magn Reson Imaging. 1995. 13:1179

2012.10.30.

15

Mitocondrial myopathy

TE 144 ms TE 288 ms

Primer Progressiv Aphasia

NAA/Cho NAA

Cho Cre

Summary: the main advantagesof clinical MRS

• In vivo biochemical diagnosis• Patterns of metabolites help us to:

– Monitor therapyMonitor therapy– Progression-regression– Prognostic possibilities (i.e. tumors,

Alzheimer)

Problems of clinical MRS

• One must STANDARDIZE the– acquisition– reading– Radiological reports

• Reproducibility is not high• Absolute quantification is problematic• Sedation (pediatric or non-cooperative)• Team work is necessary (radiologist,

physicist, biochemist, etc.)