Recent advances in quantitative MR spectroscopy Anke Henning, PhD Institute for Biomedical Engineering, University and ETH Zurich, Switzerland July 2009 MOTIVATION: non-invasive metabolite quantification NAA 3T Cho tCr tCr Ins Glx NAA Glx Gln Courtesy: Dept. of Radiology, University of Bonn, Germany AAPM 2009 – Quantitative MRI and MRS Symposium 1 MOTIVATION: Spectroscopic Imaging NAA NAA Cho Cre Cho AAPM 2009 – Quantitative MRI and MRS Symposium BASIC PRINCIPLE: Larmor frequency B0 f0 = γ* x B0 (γ * = γ ) 2π γ: property of nucleus γ*H = 42.58 Mhz/T γ*P = 17.24 Mhz/T γ*C = 10.71 Mhz/T Lamor frequency 1.5 T 3T 1H 63.86 MHz 127.73 MHz 31P 25.85 MHz 51.7 MHz 13C 16.06 MHz 32.12 MHz AAPM 2009 – Quantitative MRI and MRS Symposium 2 BASIC PRINCIPLE: Chemical Shift H + e - B0 AAPM 2009 – Quantitative MRI and MRS Symposium BASIC PRINCIPLE: Chemical Shift Fat Water H C H H ion bonding hydrogen deprived from electron weak shielding covalent bonding shared electrons strong shielding AAPM 2009 – Quantitative MRI and MRS Symposium 3 BASIC PRINCIPLE: Chemical Shift NAA Spectrum FID Cho Cre NAA Cre f t Cho Frequency domain Time domain FT AAPM 2009 – Quantitative MRI and MRS Symposium BASIC PRINCIPLE: J-coupling 1H SPECTRUM OF LACTATE O OH rest CH H C-C-CH3 CH3 O OH 1:1 1:3:3:1 AAPM 2009 – Quantitative MRI and MRS Symposium 4 BASIC PRINCIPLE: metabolite concentrations AAPM 2009 – Quantitative MRI and MRS Symposium relative QUANTIFICATION area under peak / amplitue of FID estimation of fitting reliability absolute additional influence factors reference standard concentrations in mM AAPM 2009 – Quantitative MRI and MRS Symposium 5 QUANTIFICATION Estimation of area under peak / amplitue of FID: - time domain vs. frequency domain - peak integration - line fitting (JMRUI/AMARES; scanner packages) - fitting of basis spectra (LC Model; JMRUI/QUEST; TDFD Fit ) - considering phase evolution & distortion - considering RF pulses - spatial statistics for MRSI fitting - 2D prior knowledge fitting (ProFit) AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: time vs. frequency domain jMRUI VAPRO SVD TDFDfit LCmodel ProFit AAPM 2009 – Quantitative MRI and MRS Symposium 6 QUANTIFICATION: time vs. frequency domain time domain fitting frequency domain fitting signal truncation can be considered signal truncation can not be considered directly frequency range can not be restricted Æ residual water and lipid signals have to be modeled or suppressed by additional filters frequency range can be restricted Æ residual water and lipid might be considered as baseline fitting of multi-frequency basis spectra is not straight forward fitting of linear combination of multi-frequency basis spectra straight forward no user-dependent prior user-dependent prior knowledge required to initialise fit: frequencies, knowledge required to initialise fit linewidth, phase Ædiscrete time domain model and frequency domain fitting TDFDfit: Slotboom et al; Magn Reson Med. 1998 Jun;39(6):899-911. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: peak integration Problems overlapping peaks baseline phasing -> magnitude spectra -> complex integration depends on shimming AAPM 2009 – Quantitative MRI and MRS Symposium 7 QUANTIFICATION: peak fitting Problems overlapping peaks baseline phasing -> magnitude spectra -> complex integration depends on shimming JMRUI/AMARES; scanner packages AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: Fitting basis spectra Fitting a linear combination of basis spectra LCmodel; TDFDfit; ProFit; jMRUI/QUEST AAPM 2009 – Quantitative MRI and MRS Symposium 8 QUANTIFICATION: macro-molecular baseline De Graaf; In vivo NMR spectroscopy; WILEY 2007 (2nd Edition) Hofmann L et al, Magn Reson Med. 2002 Sep;48(3):440-53. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: “spline fit” (LCModel) insufficient water suppression AAPM 2009 – Quantitative MRI and MRS Symposium 9 QUANTIFICATION: truncation of FID FID(LOVS) MRSI NAA 90° 5.5 ms Cho MM RF Glx Cre GR acquisition delay = truncation of first few points of the FID strong linear phase Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: truncation of FID VAPOR - WS RF 90° * 90° 150 ms 160° 100 ms 90° 122 ms OVS 140° 105 ms OVS 90° 102 ms OVS MRSI 160° 61 ms 160° 67 ms ** GM GP GS FID acquisition Localized by Outer Volume Supression Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. Tkac et al, Magn Reson Med, 41:649-659, 1999. Henning et al, Magn Reson Med 59:40-51, 2008. AAPM 2009 – Quantitative MRI and MRS Symposium 10 QUANTIFICATION: truncation of FID a b Cho c a modulation sidebands b Cre NAA NAA two pulse WS prior OVS VAPOR AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: truncation of FID Ho Non-apodized spectra from individual voxels wr Voxel size: 1 ml; TR = 4500 ms; Acquisition time: 26 min elia ble is t he qua white matter grey matter nti fic NAA ati on WM of GM Cre FI DL NAAG Cre OV mI ChoS scylloI MR GSH Cho NAA Asp S Cre Glx mI GABA Cre Glx NAA NAAG I dGlu ata ? Gln Tau Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium 11 QUANTIFICATION: truncation of FID GSH GABA Gln Glu mI Cho Cre truncation incorporated in the time domain of model spectra NAA Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: truncation of FID Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium 12 QUANTIFICATION: truncation of FID no phase correction prior fitting voxel size: 1 ml phase correction prior fitting (1 cm3) AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: 2D J-resolved MRS Tacq=TE=t1(1) 90° 180° t2 AAPM 2009 – Quantitative MRI and MRS Symposium 13 QUANTIFICATION: 2D J-resolved MRS Tacq=TE=t1(2) 90° 180° t2 AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: 2D J-resolved MRS Tacq=TE=t1(3) 90° 180° t2 AAPM 2009 – Quantitative MRI and MRS Symposium 14 QUANTIFICATION: 2D J-resolved MRS FT along t1 90° 180° same CS evolution different J evolution AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: 2D JPRESS & ProFIT Schulte et al, NMR Biomed 19(2), 255-263 & 264-270, 2006. AAPM 2009 – Quantitative MRI and MRS Symposium 15 QUANTIFICATION: 2D JPRESS & ProFIT ProFit = VAPRO & LCModel time efficient global fit parameters: zeroth-order phase Gaussian line broadening in f2 shift in f1 biexponential phase decay due to eddy currents individual fit parameters: concentration same exponential line-broadening for f1 and f2 shift in f2 model-free regularization robust convergence fit of linear combination of model spectra (discrete, simulated time domain model: max echo sampling pattern considered) Schulte et al, NMR Biomed 19(2), 255-263 & 264-270, 2006. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: COSY & ProFIT Extension of ProFit to other 1D or 2D h sequences ric possible! y es rt u co o , BT I f ity rs e iv Un H ET d an Zu fitting a linear combination of 2-dimensional COSY basis metabolite sets Alexander Fuchs, IBT AAPM 2009 – Quantitative MRI and MRS Symposium 16 QUANTIFICATION Estimation of fitting reliability: - Residue - Cramer-Rao lower bounds (CRLB) - Covariance matrix - CRLB maps for MRSI AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: residue mouse brain, 9.4 T Tkac I et al; ISMRM (2008) 16:1624 Govindaraju et al; ……………….. AAPM 2009 – Quantitative MRI and MRS Symposium 17 QUANTIFICATION: Fisher information matrix Fisher information matrix F= transposition 1 σN 2 ( P T D H DP ) Hermitian conjugation standard deviation of noise model function matrix element: Dij = ∂x i ∂p j model function prior knowledge matrix element: Pmn = parameter ∂p m ∂p n parameter m parameter n model function: exponentially damped, gaussian filtered sinusoids parameters: metabolite prior knowledge (frequencies, coupling constants) De Graaf; In vivo NMR spectroscopy; WILEY 2007 (2nd Edition) AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: CRLB standard deviation of fitting result for parameter i σ p ≥ CRLB p = Fii−1 i i Cramer-Rao Lower bounds inverted Fisher information matrix diagonal elements Tkac I et al; ISMRM (2008) 16:1624. AAPM 2009 – Quantitative MRI and MRS Symposium 18 QUANTIFICATION: CRLB Lac Glc Asc Asp Ala Tau PE scylloI NAAG NAA mI FIDLOVS MRSI @ 7T MM / Lip GSH tCho Glu Gln Cre GABA 1H statistical analysis considers SNR Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: covariance matrix covariance coefficient for parameters m and n ρ mn = Fmn−1 −1 Fmm Fnn−1 off-diagonal elements inverted Fisher information matrices JPRESS @ 3T unambiguous and simultaneous quantification of GABA, Gln, Glu and NAA Walter/Henning/Grimm et al, Archives of General Psychiatry 2009; 66(5):478-486 AAPM 2009 – Quantitative MRI and MRS Symposium 19 QUANTIFICATION: covariance matrix JPRESS COSY cou rt esy of IB T, 1D Un iv e rsi 3T ty and ET HZ u ri ch Fuchs et al, ISMRM (2009) 17: 2406. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: covariance matrix & CRLB maps 1H GM FIDLOVS MRSI @ 7T voxel size: 0.2 ml (6 mm3) WM GM WM GM WM Cor Cortex voxel Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium 20 QUANTIFICATION: covariance matrix 1H FIDLOVS MRSI @ 7T phase correction prior fitting no phase correction prior fitting Ala Asc Asp Cre GABA Glc Gln Glu GPC GSH Lac mI MM/ Lip NAA NAAG PCh PE scylloI Tau Ala Asc Asp Cre GABA Glc Gln Glu GPC GSH Lac mI MM/ Lip NAA NAAG PCh PE scylloI Tau Tau scylloI PE PCh NAAG NAA MM/Lip mI Lac GSH GPC Glu Gln Glc GABA Cre Asp Asc Ala correlation analysis considers spectral overlap at original shim quality Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: CRLB maps no phase correction prior fitting Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium 21 QUANTIFICATION: CRLB maps phase correction prior fitting Henning et al, NMR in Biomedicine (Epub ahead of print), 2009. AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION Additional influence factors: metabolite signal intensity metabolite concentration volume Smet = Cmet x NS x RG x V x ω0 x fsequence x fcoil x fadd # averages receive gain volume fsequence: TE (T2); TR (T1); partial volume effects RF pulses (phase evolution, NOE); gradients (diffusion) fcoil: transmit and receive B1 distribution, power optimization coil load (load dependent resistance of coil) fadd: contributing nuclei per molecule B0 , temperature, pH, conductivity artifacts (f.i. eddy currents; lipid and water) AAPM 2009 – Quantitative MRI and MRS Symposium 22 Relaxation T2 relaxation c met ,corr = fT1 = fT2 = c met fT2 * fT 1 1 − exp(−TR / T1 ) phantom 1 − exp(−TR / T1 ) invivo exp(−TE / T2 ) phantom exp(−TE / T2 ) invivo Or: TR > 5 T1, max Tkac et al; Magn Reson Med 46:451, 2001 TE ultra-short (also for diffusion) AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: IDAP multi-dimensional fitting Basis spectra can be subdived into parts with different T2 relaxation behavior: T2 determination from lineshape analysis. IDAP: Kreis et al, Magn Reson Med 54, 761-768, 2005; .TDFDfit: Slotboom et al; Magn Reson Med. 1998 Jun;39(6):899-911. AAPM 2009 – Quantitative MRI and MRS Symposium 23 RF pulses 90° 3.6 kHz 90° 1.6 kHz 180° 1.6 kHz 180° 0.5 kHz 180° 28.3 kHz 30° 9.1 kHz 90° 0.9 kHz 150° 4.65 kHz AAPM 2009 – Quantitative MRI and MRS Symposium RF pulses 90° 90° 180° 180° excitation & refocusing Glx H2O 0 -200 Cre -400 -600 NAA Lac -800 -1000 AAPM 2009 – Quantitative MRI and MRS Symposium 24 RF pulses pulses and gradients need to be considered in simulations of basis spectra 90° 90° 180° 180° PRESS 7T brain phantom TE = 66 ms AAPM 2009 – Quantitative MRI and MRS Symposium Contributing nuclei per molecule Creatine Choline H3C-N-CH2-COO- CH3 C=NH2+ HO-CH2-CH2-N-CH3 NH2 CH3 2 mM N-Acetylaspartate O O C-CH2-CH-C O NH O C=O CH3 6 mM 12 mM AAPM 2009 – Quantitative MRI and MRS Symposium 25 B1 and B0 inhomogeneity Transmit B1 B0 line broade phase encod De Graaf; In vivo NMR spectroscopy; WILEY 2007 (2nd Edition) AAPM 2009 – Quantitative MRI and MRS Symposium Conductivity, pH and temperature pH = pK A + log( Buchli R.; SMRM (1990) 9:504 δ − δ HA ) δA −δ 2 3 ω water (T ) = γ (1 − χ (T ) − σ (T )) B0 bulk susceptibility electronic shielding De Graaf; In vivo NMR spectroscopy; WILEY 2007 (2nd Edition) AAPM 2009 – Quantitative MRI and MRS Symposium 26 QUANTIFICATION Reference standards: -Internal reference standards (water, creatine) -External reference calibration (simultaneous phantom calibration) -Symmetric phantom calibration -Phantom replacement method (simulation phantom calibration) -ERETIC (Electric reference to assess in vivo concentrations) AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: metabolite ratios tCr (PCr + Cr): 1. Energy Buffer: H + PCr + ADP ⇔ ATP + Cr 2. Energy shuttle: “Energy transport” from production (mitochondria) to energy utilizing sites The CRE peak is stable during activation/exercise and therefore may serve as an internal reference for 1H MRS. AAPM 2009 – Quantitative MRI and MRS Symposium 27 QUANTIFICATION: metabolite ratios pathology healthy or ? relative quantification: ambigious AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: internal water reference assumes stable and known water concentration additional unsuppressed water spectrum needs to be measured from same voxel be sure the same preparation settings are used (e.g. receiver gain & power optimizations, shimming) AAPM 2009 – Quantitative MRI and MRS Symposium 28 QUANTIFICATION: internal references Advantages coil load receive gain settings volume temperatur pH conductivity are considered B1 inhomogeneities power optimization are considered for the same type of nucleus (f.i. internal Disadvantages internal water or reference metabolite concentrations as well as all relaxation times depend on: age voxel composition (f.i. CSF content) and change in pathologies B1 inhomogeneities PO are not considered for different types of nuclei water reference for 1H MRS) (f.i. internal water reference for 31P and 13C MRS) AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: external reference calibration External reference calibration phantom with known concentration B1 variations should be taken into account especially for surface coils be sure the same preparation settings are used (f.i. receiver gain & power optimizations, shimming) AAPM 2009 – Quantitative MRI and MRS Symposium 29 QUANTIFICATION: external reference calibration Advantages Disadvantages known & stable concentration for reference standard known relaxation times for reference standard coil load is directly considered additional reference spectrum needed each time receive gain settings volume temperatur pH conductivity B1 inhomogeneities power optimization relaxation times of in vivo metabolites need to be considered by adjustments or correction factors determined by additional measurements AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: symmetrical phantom calibration Symmetric phantom calibration phantom with known concentration be sure the same preparation settings are used for localized version (f.i. receiver gain & power optimizations, shimming) Buchli et al, MRM (1993) 30: 552-558. AAPM 2009 – Quantitative MRI and MRS Symposium 30 QUANTIFICATION: symmetrical phantom calibration Disadvantages Advantages known & stable concentration for reference standard known relaxation times for reference standard coil load is directly considered B1 inhomogeneities are directly considered if conductivity of phantom is adjusted to in vivo values and PO is not repeated for phantom measurement additional reference spectrum needed each time receive gain volume temperatur pH conductivity relaxation times of in vivo metabolites need to be considered by adjustments or correction factors determined by additional measurements AAPM 2009 – Quantitative MRI and MRS Symposium QUANTIFICATION: phantom replacement method saline make sure to adjust coil load to in-vivo condition by moving the saline tube in or out each time correction for receiver gain is necessary power optimization & shim differences are not considered AAPM 2009 – Quantitative MRI and MRS Symposium 31 QUANTIFICATION: phantom calibration methods Disadvantages Advantages known & stable concentration for reference standard known relaxation times for reference standard coil load (additional reference spectrum needed each time) receive gain settings volume temperatur pH conductivity B1 inhomogeneities PO relaxation times of in vivo metabolites need to be considered by adjustments or correction factors determined by additional measurements AAPM 2009 – Quantitative MRI and MRS Symposium ERETIC: Electric REference To access In vivo Concentrations cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium 32 ERETIC: Fitting with LC Model & TDFD fit cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium ERETIC: Electric REference To access In vivo Concentrations Why ERETIC? 1H MRS @ 1.5T and 3T: reliable reference standard in lesions where water concentration is unknown Æ clinical application 13C & 31P MRS @ 3T & 7T: reliable reference standard Æ no internal reference available Æ water reference is unreliable since transmit and receive fields of water and heavy nucleus are very different at 3T & 7T AAPM 2009 – Quantitative MRI and MRS Symposium 33 ERETIC: optical signal transmission cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium ERETIC: optical vs. electrical signal transmission cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium 34 ERETIC: scaling with coil load cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium ERETIC: stability over time cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium 35 ERETIC: phantom calibration cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium ERETIC: cross validation with internal water reference cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch Heinzer-Schweizer et al, ISMRM 2009: 232 AAPM 2009 – Quantitative MRI and MRS Symposium 36 31P MRS: simultaneous 1H decoupling and ERETIC cou rt esy of IB T, Un iv e rsi ty and ET HZ u ri ch ATP ATP Schweizer et al, ISMRM 2008: 193. AAPM 2009 – Quantitative MRI and MRS Symposium JPRESS & ERETIC ERETIC cou rt MM esy of NAA IB T, Un iv e rsi Cho Cr ty Cr and ET HZ H2O u ri ch in vivo, 3T, GM rich voxel Fuchs et al, ISMRM 2009: 2405. AAPM 2009 – Quantitative MRI and MRS Symposium 37 QUANTIFICATION: ERETIC Advantages known & stable reference standard known relaxation times for calibration metabolites receive gain settings considered coil load directly considered phantom calibration needs to be performed only once Disadvantages volume temperatur pH conductivity B1 inhomogeneities PO relaxation times of in vivo metabolites need to be considered due to adjustments or correction factors determined by additional measurements AAPM 2009 – Quantitative MRI and MRS Symposium IBT spectroscopy group Mateo Pavan Nicola de Zanches Klaas Pruessmann Rolf F. Schulte AAPM 2009 – Quantitative MRI and MRS Symposium 38
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