2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 1 Development of Complex Curricula for Molecular Bionics and Infobionics Programs within a consortial* framework** Consortium leader PETER PAZMANY CATHOLIC UNIVERSITY Consortium members SEMMELWEIS UNIVERSITY, DIALOG CAMPUS PUBLISHER The Project has been realised with the support of the European Union and has been co-financed by the European Social Fund *** **Molekuláris bionika és Infobionika Szakok tananyagának komplex fejlesztése konzorciumi keretben ***A projekt az Európai Unió támogatásával, az Európai Szociális Alap társfinanszírozásával valósul meg. PETER PAZMANY CATHOLIC UNIVERSITY SEMMELWEIS UNIVERSITY sote_logo.jpg dk_fejlec.gif INFOBLOKK 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 2 Biomedical Imaging (Orvosbiológiai képalkotás) (MRI a diagnosztikában) LAJOS R. KOZÁK Peter Pazmany Catholic University Faculty of Information Technology www.itk.ppke.hu CLINICAL MRI METHODS Basics of MR Spectroscopy (MRS) MRS or nuclear magnetic resonance (NMR) spectroscopy is one of the earliest MR-based method. It operates on the magnetic resonance principle: • Nuclei in the tissues of the body can become radio transmitters and receivers if they are in an external magnetic field. • The resonance frequency depends on the strength of the magnetic field B and a constant called gyromagnetic ratio (.) • The .is unique for each specific isotope. The values of .are sufficiently different that isotopes can be separated easily with tuning the frequency of excitation. • Variations of the magnetic field strength result in variations of resonance frequency . 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 3 www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Basics of MR Spectroscopy (MRS) The gyromagnetic ratio (.) is the constant term of the equation; it depends only on the isotope to be measured: • stable isotopes that contain an odd numer of protons and/or neutrons have an intrinsic magnetic moment and thus susceptible to RF excitation Nuclei Unpairedp+ Unpairedn0 Net spin .[MHz/T] 1H 1 0 1/2 42.58 13C 0 1 1/2 10.71 19F 0 1 1/2 40.08 23Na 2 1 3/2 11.27 31P 0 1 1/2 17.25 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 4 www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Basics of MR Spectroscopy (MRS) The magnetic field (B) is the technical term of the equation: • the main field (B0) is used to introduce the basic alignment • gradients (GX, GY, GZ) are used for spatial encoding (MRI, localized MR spectroscopy) • B is affected by the chemical environment:• the distribution of electrons in the chemical bonds introduce local field inhomogeneities, and thus local differences in resonance frequency 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 5 B0 GX, GY, GZ chemical composition www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Basics of MR Spectroscopy (MRS) The distribution of electrons in the chemical bonds lead to various shielding effects • Weak shielding is present when a nucleus draws the e-from the proton:• Strong magnetic field • Higher resonance frequency • Where the shielding remains stronger:• Weak magnetic field • Lower resonance frequency 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 6 acetaldehyde.png www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods 1H MR Spectrum of cholin The peaks corresponding to protons are shifted according to the chemical environment 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 7 www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods MRS acquisition MRS sequences are spin echo sequences, TE strongly influences the resulting spectrum. Single voxeltechniques: • PRESS (Point RESolved Spectroscopy)• Higher SNR • Less precisely defined voxels • STEAM (Stimulated Echo Acquisition Mode)• About half the SNR of PRESS • More precise voxels • Less demanding technologically Multi voxeltechnique: • CSI (Chemical Shift Imaging) 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 8 The spectrum depends on: • Magnetic field • TE : echo time • TR : repetition time • the region of the brain • the patient’s age, etc. www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods MRS quality criteria • Volume • as big as possible, at least: 1 cm3 • Max 20% partial volume • No contact with• CSF • bone marrow fat • air in sinuses • No patient movement • Magnetic field inhomogeneities < 10 Hz FWHM • MRS measurement before contrast material (CM) administration • about 10% choline decrease after CM administration 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 9 The concentration of H2O is about 10000 times higher than that of metabolites, this is reflected in the MRS signal. To have equal SNR for the metabolites 10000 times bigger voxels are needed. Moreover, water signal has to be suppressed. www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Normal compounds with 1H MRS Large signals at long TE N-acetyl aspartate (NAA) Creatine (Cr) and phosphocreatine (PCr) Cholines (Cho) Glycerophosphocholine (GPC) Phosphocholine (PC), free choline (Cho) Large signals at short TE Glutamate (Glu) Glutamine (Gln)Myo-inositol (mI) Small signals (short or long TE) N-Acetyl aspartylglutamate (NAAG), aspartate Taurine, betaine, scyllo-inositol, ethanolamine Threonine Glucose, glycogen, purine nucleotides Histidine 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 10 www.itk.ppke.hu Pathological compounds with 1H MRS Long TE Lactate (Lac) Hydroxy-butyrate, acetone Succinate, pyruvate Alanine Glycine Short TE Galactitol, Lipids Macromolecules Phenylalanine Exogenous compounds (short or long TE) Propan-1,2-diol Mannitol Ethanol Methyl sulfonylmethane(MSM) Biomedical Imaging: ClinicalMRI Methods Clinical significance of specific compounds N-acetyl aspartate(NAA)~2.00 pmm • neuron specific amino acid derivative • reflectsthehealthof neurons(neuronalmarker) • decreased in neurodegenerative processes • decreasedinlargenecrotictumors • elevatedin Canavandisease Creatine/Phosphocreatine(Cr, PCr)~3.00 ppm • a reservoir for high energy phosphate for generation of adenosine triphosphate[ATP]energy metabolite • the most stable metabolite in the brainusually used as a reference peak to generate NAA/Cr and Cho/Cr ratiosforquantification 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 11 Choline(Cho)~3.25 ppm • membrane phospholipidmetabolite • associated with glialcell membrane integrity (cell membrane marker) • elevatedin malignant tumors • elevatedinischemia • elevatedininflammations• canbe usedtomonitor multiplesclerosis www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Clinical significance of specific compounds Lactate (Lac)~1.33 ppm • indicateshypoxiaand/ orglycolysis • elevatedininfarcts • elevatedinabscesses • elevatedinmitochondrialdisorders • elevatedinmalignanttumors • elevatedinmultiplesclerosis plaques Lipids~0.9-1.4 ppm • indicatetissuenecrosis • elevatedin e.g. metabolic disturbances 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 12 Glutamate/Glutamine (Glu/Gln)~2.1-2.5 ppm • excitatory neurotransmitter • elevatedinstroke • elevatedinlymphoma • elevatedinhypoxia Myo-inositol(mI)~3.56 ppm • cell membrane marker (shows cell destruction)/intracellular transmitter • elevatedinAlzheimer’s • elevatedindiabetes • elevatedinrecoveredhypoxia Specific metabolites • metabolic diseases • can be very specific, e.g. in nonketotichyperglycinemia www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Clinical indications of MRS Oncology • Neuro-oncology • Haemato-oncology Inflammations • Meningo-encephalitis • ADEM • MS • Abscess • Differential diagnosis: stroke Metabolic diseases Neonatology 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 13 Oncology is the main indication for MRS • differential diagnosis: tumor vs. inflammation • tumor dignity assessment • tumor inhomogeneity assessment • assessing residual / recidive tumors• choline at least 40-60% higher than in the norm. side • Post radiation masses• all of the typical metabolites strongly decreased, but still present • Postoperative gliosis • all of the typical metabolites are absent MRS is a non invasive in vivo „biopsy” www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Differentiating viable and necrotic parts of tumor metastasis Metastasis of pulmonary origin 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 14 Cho ^ Lac/Lip ^^ Tumor Necrosis www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Patientexamination@ MRKK, imagescourtesyof G Rudas, MD, PhD. Gliomain the brainstem 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 15 Cho Cr NAA Scar tissue Tumor Cho Cr NAA Tumor 3 mo follow-up www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Patientexamination@ MRKK, imagescourtesyof G Rudas, MD, PhD. Neonatology example: diagnosis of hypoxic ischemic encephalopathy (HIE) 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 16 Normal HIE 6000 2000 www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Patientexamination@ MRKK, imagescourtesyof G Rudas, MD, PhD. SENSE SpectroCSIprovides spectra in multiple voxels. The lactate/lipid peak is indicative of metastasis in this case. 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 17 SENSE Spectro_C Lac/Lip Metastasis www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Patientexamination@ MRKK, imagescourtesyof G Rudas, MD, PhD. 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 18 www.itk.ppke.hu Future of MRS / research applications Quantitative MRS e.g. Marlianiet al., AJNR, 2010 MR spectroscopy is done after calibration with either • internal endogenous marker • external reference • LC-model software Multinuclear MRS e.g. Lyooet al., Psychiatry Res, 2003 Specific hardware for simultaneous 1H, 13C, 19F, 31P, MRS spectroscopy measurements • 31P: measuring ATP, i.e. energy accessibility and consumption • 19F: not present in the human body, but numerous drugs contain F• information on drug distribution / kinetics • monitoring cytostatictherapy MRS thermometrye.g. Zhu et al., MRM, 2008 Linear relationship between the 1H MR resonance frequency of tissue water and the tissue’s temperature. Biomedical Imaging: ClinicalMRI Methods MRI contrast agents MRI contrast agents alterT1, T2, or T2* of various tissues, resulting in changes of image contrast. Contrast agents are useful for the detection of tumors, infection, inflammation, infarction and lesions. MRI contrast materials are called contrast “agents” since it is the effect that the magnetic properties of the contrast agent has on the relaxation of tissues that is imaged,and not the contrast material itself. 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 19 www.itk.ppke.hu X-ray contrast media Barium and iodine compounds are used to enhance contrast in x-ray procedures. These compounds are referred to as contrast “media” since their presence appears directly on the images. Biomedical Imaging: ClinicalMRI Methods MRI contrast agents Endogenous • e.g. hemoglobin • BOLD contrast, see fMRI chapter• dexyhemoglobin is diamagnetic • deoxyhemoglobin is paramagnetic Exogenous • Paramagnetic agents have positive magnetic susceptibility due to the presence of one or more unpaired electrons• Gd3+ • Dy3+ • Fe2+ • Mn3+ 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 20 Exogenous cont’d • Ferromagnetic agents are solids with crystalline structures that develop small magnetic domains. When placed in an external magnetic field (B0), the multitude of magnetic domains will align with the field and retain magnetism when removed from B0• Fe • Ni • Co • Superparamagnetic agentsare smaller solid particles each of which develop a “single domain”. The domains align with B0; but do not retain the alignment after being removed from B0• Magnetite (Fe3O4) www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods MRI contrast agents Positive contrast agents (relaxation agents) • cause hyperintensity on T1 weighted images • the presence of a positive agent stimulates an increase in spin flip transitions resulting in reduced T1 values and increased brightness on T1 weighted images • cause hypointensity on T2 weighted images because of susceptibility effects The most common positive contrast agent is the paramagnetic gadolinium (Gd). 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 21 Negative contrast agents (shift agents, chemical shift agents or frequency agents) • cause hypointensityon T2weighted images • produce substantial magnetic inhomogeneitydue to magnetic susceptibility • magnetic inhomogeneityperturbs the Larmorfrequency of protons, resulting in a loss of phase coherence and reduced T2values Dysprosium (Dy) is also paramagnetic but acts to reduce T2 or T2* without affecting T1. www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods MRI contrast agents Safety considerations Most of the agents appropriate for contrast enhanced MRI are toxic metals, therefore they are usually used in a chelatedform. Gadolinium • in its pure form can bind to membranes, transport proteins, enzymes, etc. in the lungs, liver, bones and spleen. • small amount of pure metallic Gdcan cause liver necrosis • chelationshields the toxic metal ion from direct interaction with the tissues • chelationmay also change susceptibility effects 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 22 Chelates are cleared from the body via glomerular filtration. If the glomerular filtration rate is decreased, e.g. due to kidney disease, toxic metals can slowly be released from the chelates and cause toxicity. Nephrogenic systemic fibrosis is a possible complication which is highly correlated with the use of Gd contrast agents in patients with kidney disease. www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods MRI contrast agents Clinical applications Mostly Gd-chelates are used, chelation differs between pharmaceuticals. Some brands are: Magnevist (Bayer-Schering), Ultravist (Bayer-Schering), Optimark (Covidien), ProHance (Bracco), etc. Contrast enhanced MRI • Central nervous system tumors (diagnosis, differential diagnosis) • Gd-chelates do not pass the blood-brain barrier if the barrier is distrupted the contrast agent accumulates in the tissue • Angiography • MR perfusion (see later) • etc. 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 23 Contrast enhancement in case of a malignant brain tumor (glioblastoma multiforme). Red arrows represent CA enhancement in the lesion, while the blue arrow represent a physiological enhancement in the venous sinus. T1W CE T1W Patientexamination@ MRKK, imagescourtesyof G Rudas, MD, PhD. www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods MR Perfusion(Perfusion Weighted Imaging, PWI) Perfusion • the delivery of oxygen and nutrients to the cells via capillaries • Identifiedwith blood flow • measured in milliliters per minute per 100 g of tissue 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 24 Measuring perfusion • Dynamic susceptibility contrast (DSC) imaging in the brain• GD-chelatecontrast agent • Arterial spin labeling• See ASL chapter www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods DSC imaging in the brain • injection of a bolus of Gd-chelatecontrast agent• Gd-chelatesdo not cross the healthy blood-brain barrier • the paramagnetic Gdcauses signal drop at in the vicinity of the bolus on T2W images • the labeled bolus spreads trough the circulation • the intensity change during the first pass represents perfusion 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 25 pwi1.png Based on a figure from P Barsi, MD, PhD www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods DSC imaging Sequences • Gradient-Echo EPI (GRE-EPI)• High signal drop • Sensitive to capillaries & larger vessels • Spin-Echo EPI (SE-EPI)• Signal drop only 25% of GRE-EPI • Sensitive mainly to capillaries For a detailed account on technical aspects, see Wu et al., NeuroimagClinN Am, 2005 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 26 pwi2.png www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Perfusion calulation • Baseline determination• starting point • endpoint • Concentration-time curve calculation • Curve fitting 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 27 pwi3.png www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Perfusion parameters • Time to arrival (TTA, [s])• time when the contrast agent reaches the tissue • Time to peak (TTP, [s])• time of peak concentration • Mean transit time (MTT, [s])• the average time required for any given particle to pass through the tissue, following an idealised input function • Relative cerebral blood volume (rCBV, [ml/100g, %/100g])• the volume of distribution of the Gd-chelate during its first passage through the brain 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 28 pwi4.png www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods Clinical applications of MR Perfusion Cerebrocascular diseases • acute stroke • stenosis (decrease in vessel diameter) Tumors • differential diagnosis • grading 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 29 Other indications • Trauma • Dementia • Epilepsy, etc www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods PWI in stroke • Changes seen almost immediately after the ischemic event• more sensitive than conventional MRI • Perfusion findings often more extensive than those on DWI in early stroke• PWI more accurately reflects the amount of tissue under ischemic conditions in the hyperacuteperiod than DWI • abnormal PWI results correlate with an increased risk of stroke • PWI -DWI = tissue at risk 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 30 PWI and tumors • many tumors have high rCBV • regions of increased rCBVcorrelate with areas of active tumor • heterogeneous patterns of perfusion suggest high grade • radiation necrosis typically demonstrates low rCBV • Lesion characterization may be possible• meningeomashave very high CBV in contrast to Schwannomas www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods PWI in other diseases Dementias • Perfusion parameters correlate well with PET and SPECT findings in Alzheimer’s disease Traumatic brain injury • focal rCBVdeficits correlate with cognitive impairment Schizophrenia • decreased frontal lobe rCBV 2011.10.04.. TÁMOP –4.1.2-08/2/A/KMR-2009-0006 31 PWI future applications Perfusion weighted MRI using the dynamic susceptibility imaging principle poses a risk due to the contrast agents used. Arterial spin labeling (see the ASL chapter) can eliminate this risk and opens the possibility to serial perfusion measurements for the • follow-up of therapy, e.g. in stroke, traumatic brain injury, etc. • follow-up of disease-related perfusion changes, e.g. in dementias www.itk.ppke.hu Biomedical Imaging: ClinicalMRI Methods