Organisation und Infrastruktur der translationalen Forschung am FZ Jülich

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1 Mitglied der Helmholtz-Gemeinschaft Organisation und Infrastruktur der translationalen Forschung am FZ Jülich N. Jon Shah, Director Institute of Neuroscience and Medicine 4 Forschungszentrum Jülich GmbH Jülich Germany

2 Institute of Neuroscience and Medicine Structural und Functional Organisation of the Brain Prof. Dr. K. Amunts Molecular Organisation of the Brain Prof. Dr. K. Zilles Cognitive Neurology Prof. Dr. G.R. Fink Medical Imaging Physics Prof. Dr. N.J. Shah Neuromodulation Prof. Dr. Dr. P. A. Tass Nuclear Chemistry Prof. Dr. H.H. Coenen Architektonics and brain function Prof. Dr. K. Amunts Transmittersreceptors Prof. Dr. K. Zilles MR Physics Prof. Dr. N.J. Shah System Medicine Prof. Dr. Dr. P. A. Tass Radionuclei Development Dr. B. Scholten Morphometry and image analysis Prof. Dr. U. Pietrzyk Molecular Neuroimaging Prof. Dr. A. Bauer PET Prof. Dr. H. Herzog Neurotechnology PD Dr. C. Hauptmann Radiopharmacology Dr. D. Bier Structure of Synapses Prof. Dr. J. Lübke Brain tumours Prof. Dr. K.-J. Langen Mathematical Neuroscience PD Dr. O.V. Popovych Radiotracer Development Dr. D. Holschbach Functional neuronal circuits Prof. Dr. D. Feldmeyer MEG Prof. Dr. N.J. Shah Radiotracer Production Dr. J. Ermert Dr. K. Hamacher

3 Forschungsziele Analyse der Struktur und der funktionellen Prozesse des Gehirns (organismische Ebene), der Nerven- und Sinneszellen (zelluläre Ebene) sowie der für Signalübertragung relevanten Moleküle (molekulare Ebene), um Organisationsprinzipien sowie normale und pathologisch veränderte Mechanismen des Nervensystems zu verstehen, und neue Diagnoseverfahren und Therapien für neurologische und psychiatrische Erkrankungen zu entwickeln.

4 Forschungsprogramme und Methoden Hirnforschung an Gesunden und Kranken zur Analyse neurologischer und psychiatrischer Erkrankungen Entwicklung neuer bildgebender Techniken und selektiver Radiotracer für das Neuroimaging mit MRT, PET, SPECT und MEG, sowie fluoreszenzmarkierter Biomoleküle und anderer Verfahren für das zelluläre Imaging und die biophysikalische Strukturanalyse Entwicklung neuer Therapien wie z.b. bedarfsgesteuerte Tiefenhirnstimulation, elektrische oder chemische Neuromodulation

5 Vom Radioisotop zur Hirndiagnose Radionuklidproduktion Teilchenbeschleuniger Radiotracerherstellung Pharmakologische Evaluierung Syntheseautomat In vitro Autoradiographie Qualitätskontrolle/GMP 3 mv / UV1 H -86 C T "00 01'00 02'00 03'00 04'00 05'00 06'00 07'00 08'00 09'00 min H 12,0 CPS *1000 C C11 T ] 10,0 C 1 8,0 1 [ 6,0 4,0 2,0 PET-Aufnahme Anwendung beim Menschen Radiochromatographie

6 Concept for Translational Research Research RESEARCH 9.4T MR Animal 9.4T MRI- PET Human TransFOR Research/Clinical 4T Human Clinical 3T MRI-PET Human Clinical Clinical 3T Human Clinical 1.5T Human

7 9.4T Animal Scanner in Jülich

8 3T MR-PET Scanner in Jülich 3T MR-PET

9 Reseach Scanners in Jülich 1.5 T 3 T 4 T

10 MRI Quantitative Shah *Gras Novel Contrasts Oros Sodium Romanzetti Pracht Diffusion Shah Maximov 9.4T MR- PET Shah Keil Petersen Fiege Grinberg *Kaffanke Abbas Kemper *Kupriyanova Kubach Lindemeyer *Ullisch Hardware Felder Geschewski *Celik Besançon Sequences Stöcker Kaffanke (50%) Pflugfelder Vahedipour Brenner Stirnberg

11 Imaging the Living Brain Ultra High-Field MRI Quantitative Imaging (T1, T2*, Water, 23 Na, 17 O) Animal Imaging (Home-built, Syngo-based 9.4T) Brain Connectivity (DTI+fibre tracking as well as PLI) Sodium Imaging Hybrid MR-PET (3T MR-PET, 9.4T MR-PET) Molecular and Cellular PET Novel Tracers / Receptor (PET) Neurodegeneration MRI Highlights

12 Current MRI Anatomy Molecular Imaging Function Sensitivity/Specificity Temporal Clinical Utility Spatial High Very Good Good Low Very Low Clinical Availability Technological Maturity Development Prospects

13 Current PET Anatomy Molecular Imaging Function Sensitivity/Specificity Temporal Clinical Utility Spatial High Very Good Good Low Very Low Clinical Availability Technological Maturity Development Prospects

14 Hybrid MR-PET Molecular Imaging Anatomy Function Sensitivity/Specificity Temporal Clinical Utility Spatial High Very Good Good Low Very Low Clinical Availability Technological Maturity Development Prospects

15 Hybrid-Imaging Molecular level: Neurotransmission driven by neurotransmitters and receptors or modulated by drugs Domain of PET Systemic level: Complex neural functions Localization and analysis of complex neural mechanisms Domain of fmri

16 Biochemical Communication at the Synapse modulated by internal neurotransmitters or drugs Domain of PET Centers of cerebral data processing Domain of fmri

17 Introduction Current commonly combined use of PET and MRI T 1 -MRI: morphology 11 C-Flumazenil-PET: benzodiazepine-receptors fmol/ml

18 Cerebral gliomas: PET with O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) completes MRI based diagnosis Preoperative determination of tumor extent in FET-PET and MRI MRI: Sensitivity: 96 % Specificity: 53 % MRI+FET: 93 % 94 % Match Pauleit et al. Brain 2005 Mismatch

19 Multiparametric Imaging with MR-PET

20 Industry - FZJ - BICW Pharma FZJ 9.4T MRI-PET Neuro- Imaging Neurology Psychiatry A-B-C-D Biomed.

21 Mitglied der Helmholtz-Gemeinschaft High-Resolution / High- Definition Anatomy

22 In vivo anatomical imaging at 1.5T with 0.6mm 3 isotropic resolution MP-RAGE, 10 separate scans coregistered and complex averaged off-line. Whole brain coverage. Shortest acquisition time: 3min:38s

23 In vivo high resolution anatomy (0.6mm 3 ) at 1.5T

24 Mitglied der Helmholtz-Gemeinschaft MRI Sequence Development

25 Imaging Brain Anatomy MP-SAGE a new MRI sequence for high resolution and high contrast human brain imaging Comparison to the standard approach (MP-RAGE) MP-RAGE MP-SAGE Stöcker T, Shah NJ. MP-SAGE: a New MP-RAGE Sequence with Enhanced SNR & CNR for Brain Imaging Utilising Square-Spiral Phase Encoding and Variable Flip Angles. Magnetic Resonance in Medicine 2006, Vol 56 (4):

26 High Field DTI A new theoretical description of the spin-dephasing for single-shot STEAM provides higher SNR: a) Standard single-shot STEAM measurement with a constant flip angle (α=20 ) b) Standard single-shot STEAM measurement with a variable flip angle approach (VFA) c) New single-shot STEAM sequence with VFA for shaping a constant echo train d) New single-shot STEAM sequence with an optimised VFA approach for an exponentially decaying echo train e) Spin- Echo EPI image is strongly affected by susceptibility-induced artefacts. Last column provides correct SNR comparison! results at 4 Tesla

27 High Field DTI A new theoretical description of the spin-dephasing for single-shot STEAM provides higher SNR. results at 4 Tesla: undistorted FA maps in sub-cortical brain regions Stöcker, Kaffanke, and Shah. Whole Brain Single-Shot STEAM DTI at 4 Tesla, Magnetic Resonance in Medicine, in revision

28 New results: parallel transmit / selective excitation Single channel: Multi channel: True 3D selective pulses: Solving a HUGE linear system Using FZJ supercomputers Examples below need 65 GB of RAM Simulation result: (JEMRIS) 8 Tx channels 3D checkerboard 4 Tesla result: 8 Tx channel pseudo set up 3D selective excitation of a homogenous box

29 Mitglied der Helmholtz-Gemeinschaft Sodium Imaging at 4T

30 in vivo sodium imaging of a healthy 4T Conical SPRITE (acq time ~ 15min) Romanzetti et al. 2006

31 in vivo sodium imaging of a healthy 4T Conical SPRITE (acq time ~ 15min) Romanzetti et al. 2006

32 Conclusions Need high fields 4T, 9.4T SPRITE with efficient k-space trajectories and acquisition of multiple FID points Sensitive to fast-decaying relaxation components Clinical acquisition times feasible (~15min) Direct quantitative measure of 23 Na concentration Conical SPRITE 5x5x10 mm 3 voxel volume Conical-SPRITE is feasible in vivo

33 Mitglied der Helmholtz-Gemeinschaft Quantitative Imaging Enables Translational Research

34 How to do Translational Studies: an Example Development of Quantitative MRI TAPIR (T 1 mapping of Partial Inversion Recovery) T 2* mapping Extension to mapping of water

35 Introduction Measurement of T 1 in vivo Detection of tissue abnormalities High in-plane resolution combined with whole-brain coverage Quantitative VBM Fast acquisition: reduction of image artefacts clinically useful

36 Implementation TAPIR (T 1 mapping of Partial Inversion Recovery) Shah et al.,; US Patent No.: 6,803,762 Shah et al., NeuroImage: (5): Steinhoff et al., Magn. Reson. Med.: 46(1) Zaitsev, et al; Magn. Reson. Med.: 49(1) Shah et al., Hepatology: : Tapir: any perissodactyl mammal of the genus Tapirus. of South and central America and SE Asia, having an elongated snout, threetoed hind legs, and four-toed forelegs.

37 Phantom Results FLASH T1 Map 500ms<T 1 <3s Acquisition parameters: T R =13ms; T E= 1.9ms; TI=30ms; TD=3s; α=6 ; 4 slices; 48 time points; ; FoV=250mm; slice-thickness = 8mm; interleaved

38 TAPIR: In vivo T 1 Mapping Large number of points affords reconstruction of accurate maps Multi-exponential fitting is feasible T 1 mapping enables quantitative measurement of water content. S(t) = M 0 {1-2exp(t/T 1 )} life is not so simple! Shah et al.,; US Patent No.: 6,803,762 Shah et al., NeuroImage: (5): Steinhoff et al., Magn. Reson. Med.: 46(1) Zaitsev, et al; Magn. Reson. Med.: 49(1) Shah et al., Hepatology: :

39 TAPIR Results in vivo Typical T 1 GM: 1000±25ms Typical T 1 WM: 600 ±90ms Acquisition parameters: T R =13ms; T E =1.9 / 2.7 / 3.5ms; TI=30ms; TD=3s; α=8 ; 4 slices; 48 time points; 256 2, FoV=230mm, slice-thickness = 5mm; interleaved Shah, Steinhoff, and Zaitsev; US Patent No: 6,8,762 Shah et al., NeuroImage: (5): Steinhoff et al., Magn. Reson. Med.: 46(1) Zaitsev et al., Magn. Reson. Med.: 49(6)

40 Validation of TAPIR Representative in vivo T 1 maps from 9-echo TAPIR Zatisev, Steinhoff, Zilles and Shah. Proc. ISMRM 2002

41 Mansfield: 1984 Spectroscopic Imaging (EPSI) Mitglied der Helmholtz-Gemeinschaft T 2* Mapping

42 Phantom and in vivo Results

43 Mitglied der Helmholtz-Gemeinschaft Water Mapping

44 Water Content Mapping Why? Normal Brain Water Content Highly Regulated How? T 1 Maps from TAPIR; T 2 * Maps from QUTE What is it good for? Oedema Monitoring of Therapy Voxel-Based Morphometry with Water Content

45 Water Content Mapping All Corrections No RX Sensitivity No Flip Angle Correction Tubes filled with different mixtures of (doped) normal water H 2 O and heavy water D 2 O. Heavy water is not MR visible at the proton resonance frequency! MR Measured /24/ Phantom Water Content [%] Excellent agreement (<1.5%) between known mixing ratio and MR measured water content Neeb et al., Intern. Congr. Series, 2004 Neeb et al., 13 th ISMRM, 2005 Neeb et al., NeuroImage

46 Water Content in Grey/White Matter HE I => HE0

47 Water Content in Grey Matter Neeb et al., Neuroimage 2006b

48 Water Content in Grey/White Matter In Controls Neeb et al., 2006a, NeuroImage

49 Age Dependence of H 2 O Content Neeb et al., Neuroimage 2006b

50 Water Content Mapping in vivo Neeb, Zilles, and Shah. 2006, submitted

51 Water Content Mapping in Tumours

52 Mitglied der Helmholtz-Gemeinschaft Hepatic Encephalopathy Measurement of the Effects of Manganese Deposition and Low-Grade Cerebral Oedema Non-Invasively

53 Water Content 1.5T C5 putamen putamen thalamus Hepatic Encephalopathy grade HE 0 Hepatic Encephalopathy grade HE II Shah et al., US Patent No.: 6,803,762 Shah et al., NeuroImage: (5): Steinhoff et al., Magn. Reson. Med.: 46(1) Zaitsev et al; Magn. Reson. Med.: 49(1) Shah et al., German Patent No.: Shah et al., Hepatology: : Neeb H, Shah NJ. Magn Reson Med (1): Neeb H, Zilles K, Shah NJ. NeuroImage (3): Neeb H, Zilles K, Shah NJ. NeuroImage (3): Shah et al., (3):706-17

54 White Matter Water Content in HE Shah NJ et al., Neuroimage. 2008;41(3):

55 White Matter Water Content and Therapy HE I => HE0 Shah NJ et al., Neuroimage. 2008;41(3):

56 Water Content HE 0 HE II Shah NJ et al., Neuroimage. 2008;41(3): /24/2009

57 Water Content Mapping in HE White Matter CONTROL 70.8±0.48 HE ±0.44 SHE 71.6±0.45 HE I 72.9±0.66 Shah NJ et al., Neuroimage. 2008;41(3): /24/2009 HE II 72.8±0.17 (Mean±S.E.M.)

58 HE Grade vs. H 2 O content Significant correlation between HE grade and water content Frontal and Occipital WM Putamen Globus Pallidus Posterior Limb of the Internal Capsule Shah NJ et al., Neuroimage. 2008;41(3): /24/2009

59 Mitglied der Helmholtz-Gemeinschaft New Directions for Translation: MR-PET at 3T and 9.4T

60 M.Schwaiger, S.Ziegler, et al., 2005 MR instead of CT in PET/CT?

61 The combination of MR and PET in one scanner allows the simultaneous and complementary use of these modalities Siemens

62 Avalanche photo diodes (APD) vs. photo multiplier tubes (PMT) PMT APD Magnetically PMT sensitive APD insensitive Size mm dia. 5x5 mm Gain Up to 10 6 Up to 200 Risetime ~1 ns ~5 ns

63 Installed in Jülich in autumn 2008: MAGNETOM Trio with a BrainPET

64 18 F in Hoffman 3D brain phantom 30 min 18 F-PET Simultaneous T1 MPRAGE Fusion

65 Our first human MR-PET images Brain tumour studied with 18 F-fluoro-ethyl-tyrosine (FET)

66 Mitglied der Helmholtz-Gemeinschaft Building of the Infrastructure

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84 Conclusions The MR-BrainPET allows simultaneous scanning! Artefacts seen in the first images have been reduced Qualitative PET imaging shows excellent resolution Quantitative PET is to be achieved 9.4T MR scanner functional Sodium single channel Tx, 8 channel Rx built JEMTIS simulation environment demonstrated

85 Thanks to: Acknowledgments H. Herzog, L. Tellmann, B. Marx, E. Rota Kops, J. Scheins, and C. Weirich (Juelich) K.J. Langen, G.Stoffels, J. Kaffanke (Juelich) A. Oros, J. Felder, T. Stöcker, K. Vahedipour (Juelich) L. Byars, C. Michel, M. Schmand, E. Rummert (Siemens, Knoxville) J. Kampmeier, M. Fenchel (Siemens, Erlangen) BMBF

86 Thank you for your attention!!