organisation und infrastruktur der translationalen ... · organisation und infrastruktur der...

Mitg

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Hel

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aft

Organisation und Infrastrukturder translationalen Forschung am

FZ Jülich

N. Jon Shah, DirectorInstitute of Neurosci ence and Medicine – 4

Forschungszentrum Jülich GmbH52425 Jülich

Germany

Institute of Neuroscience and Medicine

Architektonicsand brain functionProf. Dr. K. Amunts

Structural und Functional

Organisation of the Brain

Prof. Dr. K. Amunts

Morphometryand image analysisProf. Dr. U. Pietrzyk

Cognitive NeurologyProf. Dr. G.R. Fink

Medical ImagingPhysics

Prof. Dr. N.J. Shah

MR PhysicsProf. Dr. N.J. Shah

PETProf. Dr. H. Herzog

Brain tumoursProf. Dr. K.-J. Langen

MolecularOrganisation of the Brain

Prof. Dr. K. Zilles

Transmitters-receptors

Prof. Dr. K. Zilles

Structureof Synapses

Prof. Dr. J. Lübke

MolecularNeuroimaging

Prof. Dr. A. Bauer

Functional neuronal circuits

Prof. Dr. D. Feldmeyer

System MedicineProf. Dr. Dr. P. A. Tass

NeurotechnologyPD Dr. C. Hauptmann

NeuromodulationProf. Dr. Dr. P. A. Tass

MathematicalNeuroscience

PD Dr. O.V. Popovych

Nuclear ChemistryProf. Dr. H.H. Coenen

RadionucleiDevelopmentDr. B. Scholten

Radio-pharmacology

Dr. D. Bier

RadiotracerDevelopment

Dr. D. Holschbach

RadiotracerProductionDr. J. Ermert

Dr. K. HamacherMEG

Prof. Dr. N.J. Shah

Analyse der Struktur und der funktionellenProzesse des Gehirns (organismischeEbene), der Nerven- und Sinneszellen(zelluläre Ebene) sowie der fürSignalübertragung relevanten Moleküle(molekulare Ebene),

um Organisationsprinzipien sowienormale und pathologisch veränderteMechanismen des Nervensystems zuverstehen, und

neue Diagnoseverfahren und Therapien fürneurologische und psychiatrischeErkrankungen zu entwickeln.

Forschungsziele

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

Forschungsprogramme und Methoden

Vom Radioisotop zur Hirndiagnose

Radionuklidproduktion

Radiotracerherstellung

Qualitätskontrolle/GMP

Pharmakologische Evaluierung

Anwendung beim Menschen

C11

2,0

4,0

6,0

8,0

10,0

12,0 CPS *1000

[11C]TCH 346

00"00 01'00 02'00 03'00 04'00 05'00 06'00 07'00 08'00 09'00 min

UV1

00"00 01'00 02'00 03'00 04'00 05'00 06'00 07'00 08'00 09'00 min

-94

-93

-92

-91

-90

-89

-88

-87

-86

-85mV /1000

TCH 3

Teilchenbeschleuniger

Syntheseautomat

Radiochromatographie

In vitro Autoradiographie

PET-Aufnahme

Concept for Translational Research

Research/Clinical4T

Human

Clinical 3T

MRI-PET Human

Clinical 3T

Human

Clinical 1.5T

Human

9.4T MR Animal

9.4T MRI-PET

Human

RESEARCH

TransFOR

Research

Clinical

9.4T

Ani

mal

Sca

nner

in

Jülic

h

3T MR-PET

3T MR-PET Scanner in Jülich

Res

each

Sca

nner

s in

Jül

ich

1.5

T3

T

4 T

Quantitative

Shah*Gras

Keil

Abbas

Lindemeyer

Sequences

StöckerKaffanke (50%)

Pflugfelder

Vahedipour

Brenner

Stirnberg

Diffusion

ShahMaximov

Grinberg

*Kupriyanova

Novel Contrasts

OrosPetersen

Kemper

Sodium

RomanzettiPracht

Fiege

9.4T MR-PET

Shah*Kaffanke

Kubach

*Ullisch

Hardware

FelderGeschewski

*Celik

Besançon

MRI

Imaging the Living Brain

Ultra High-Field MRI Quantitative Imaging (T1, T2*, Water, 23Na, 17O)

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

Current MRI

Anatomy

Function

Temporal

Spatial

Development Prospects

Technological Maturity

Clinical Availability

Clinical Utility

Sensitivity/Specificity

Molecular Imaging

HighVery GoodGoodLowVery Low

Current PETAnatomy

Function

Temporal

Spatial




Clinical Utility


Molecular Imaging


Hybrid MR-PET

Anatomy

Function

Temporal

Spatial




Clinical Utility


Molecular Imaging


Localization and analysis of complex neuralmechanismsDomain of fMRI

Molecular level:

Neurotransmissiondriven by neurotransmitters and receptorsor modulated by drugsDomain of PET

Systemic level:Complex neuralfunctions

Hybrid-Imaging

Centers of cerebraldata processingDomain of fMRI

Biochemical Communication at the Synapse

modulated byinternal neurotransmitters or drugs

Domain of PET

Introduction

T1-MRI:morphology

86

66

54

43

22

fmol/ml

33

75

11C-Flumazenil-PET:benzodiazepine-receptors

Current commonly combined use of PET and MRI

Cerebral gliomas:PET with O-(2-[ 18F]fluoroethyl)-L-tyrosine (FET)completes MRI based diagnosis

Mismatch

Match

Preoperative determinationof tumor extent in FET-PET and MRI

MRI:Sensitivity: 96 %Specificity: 53 %

MRI+FET:93 %94 %

Pauleit et al. Brain 2005

Mul

tipar

amet

ricIm

agin

gw

ithM

R-P

ET

Industry - FZJ - BICW

NeurologyPsychiatry

A-B-C-D

9.4TMRI-PET

Neuro-Imaging

FZJ

Pharma

Biomed.

Mitglied der Helmholtz-Gemeinschaft

Hig

h-R

esol

utio

n / H

igh-

Def

initi

on A

nato

my

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

In v

ivo

high

res

olut

ion

anat

omy

(0.6

mm

3 ) a

t 1.5

T


MR

I Seq

uenc

e D

evel

opm

ent

MP-SAGE a new MRI sequence for high resolutionand high contrast human brain imaging

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):824-834.

Comparison to the standard approach (MP-RAGE)

MP-SAGEMP-RAGE

Imaging Brain Anatomy

A new theoretical description of the spin-dephasing for single-shot STEAM provides higher SNR:

High Field DTI

results at 4 Tesla

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:undistorted FA maps in sub-cortical brain regions

A new theoretical description of the spin-dephasing for single-shot STEAM provides higher SNR.

High Field DTI

Stöcker, Kaffanke, and Shah. Whole Brain Single-Shot STEAM DTI at 4 Tesla, Magnetic Resonance in Medicine, in revision

New results:parallel transmit / selective excitation

4 Tesla result:•8 Tx channel pseudo set up•3D selective excitation of a homogenous box

Simulation result:(JEMRIS)•8 Tx channels•3D checkerboard

Single channel:

Multi channel:

True 3D selective pulses:

•Solving a HUGE linear system•Using FZJ supercomputers•Examples below need 65 GB of RAM


Sod

ium

Imag

ing

at 4

T

in vivo sodium imaging of a healthy volunteer @ 4T

Conical SPRITE (acq time ~ 15min)

Romanzetti et al. 2006

ConclusionsConclusions

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 23Na concentration

Conical-SPRITE is feasible in vivo

Conical SPRITE 5x5x10 mm3

voxel volume


Qua

ntita

tive

Imag

ing

Ena

bles

T

rans

latio

nal R

esea

rch

Development of Quantitative MRI TAPIR (T1 mApping of Partial Inversion

Recovery) T2

* mapping Extension to mapping of water

How to do Translational Studies: an Example

Introduction

Measurement of T1 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

Implementation

TAPIR (T1 mApping of Partial Inversion Recovery)

Shah et al.,; US Patent No.: 6,803,762

Shah et al., NeuroImage: 2001 14(5): 1175-85

Steinhoff et al., Magn. Reson. Med.: 46(1) 131-140 2001

Zaitsev, et al; Magn. Reson. Med.: 49(1) 1121-1132 2003

Shah et al., Hepatology: 2003 38: 1219-26

Tapir: any perissodactyl mammal of the genus Tapirus …. of South and central America and SE Asia, having an elongated snout, three-toed hind legs, and four-toed forelegs.

500ms<T1<3s

Phantom Results

FLASH

Acquisition parameters:

TR=13ms; TE=1.9ms; TI=30ms; TD=3s; α=6°; 4 slices; 48 time points; 2562; FoV=250mm; slice-thickness = 8mm; interleaved

T1 Map

TAPIR: In vivo T1 Mapping

Large number of points affords reconstruction of accurate maps

Multi-exponential fitting is feasible

T1 mapping enables quantitative measurement of water content.

S(t) = M0 {1-2exp(t/T1)}

… life is not so simple!

Shah et al.,; US Patent No.: 6,803,762



Zaitsev, et al; Magn. Reson. Med.: 49(1) 1121-1132 2003

Shah et al., Hepatology: 2003 38: 1219-26

1 4 7 12 35

Acquisition parameters:

TR=13ms; TE=1.9 / 2.7 / 3.5ms; TI=30ms; TD=3s; α=8°; 4 slices; 48 time points; 2562, FoV=230mm, slice-thickness = 5mm; interleaved

Typical T1 WM: 600 ±90ms

Typical T1 GM: 1000±25ms

TAPIR Results in vivo

Shah, Steinhoff, and Zaitsev; US Patent No: 6,8,762



Zaitsev et al., Magn. Reson. Med.: 49(6) 1121-32 2003

Validation of TAPIR

Zatisev, Steinhoff, Zilles and Shah. Proc. ISMRM 2002

Representative in vivo T1 maps from 9-echo TAPIR


T2*

Map

ping

Man

sfie

ld: 1

984

Spe

ctro

scop

ic Im

agin

g (E

PS

I)

Phantom and in vivo Results


Wat

er M

appi

ng

Water Content Mapping

Why? Normal Brain Water Content Highly Regulated

How? T1 Maps from TAPIR; T2

* Maps from QUTE

What is it good for? Oedema Monitoring of Therapy Voxel-Based Morphometry with Water Content

11/24/2009

50 60 70 80 90 100Phantom Water Content [%]

50

60

70

80

90

100

MR

Measured

All CorrectionsNo RX SensitivityNo Flip Angle Correction

Tubes filled with different mixtures of (doped) normal water H2O and heavy water D2O. Heavy water is not MR visible at the proton resonance frequency!

Excellent agreement (<1.5%) between known mixing ratio and MR measured water content

Neeb et al., Intern. Congr. Series, 2004 Neeb et al., 13th ISMRM, 2005 Neeb et al., NeuroImage 2006 31 1156-1168

Water Content Mapping

Wat

er C

onte

nt in

Gre

y/W

hite

Mat

ter

HE

I =

> H

E0

Neeb et al., Neuroimage 2006b 29 910-922

Water Content in Grey Matter

Neeb et al., 2006a,NeuroImage 31 1156-1168

Water Content in Grey/White MatterIn Controls

Neeb et al., Neuroimage 2006b 29 910-922

Age Dependence of H2O Content

Neeb, Zilles, and Shah. 2006, submitted

Water Content Mapping in vivo

Wat

er C

onte

nt M

appi

ng in

Tum

ours

Mitg

lied

der

Hel

mho

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emei

nsch

aft

HepaticEncephalopathy

Measurement of the Effects ofManganese Depositionand Low-Grade CerebralOedema Non-Invasively

Shah et al., Hepatology: 2003 38: 1219-26Neeb H, Shah NJ. Magn Reson Med. 2006 56(1):224-9. Neeb H, Zilles K, Shah NJ. NeuroImage. 2006 31(3):1156-68. Neeb H, Zilles K, Shah NJ. NeuroImage. 2006 29(3):910-22.Shah et al., 2008 41(3):706-17

C5

Water Content Mapping @ 1.5T

Hepatic Encephalopathy grade HE 0

Shah et al., US Patent No.: 6,803,762Shah et al., NeuroImage: 2001 14(5): 1175-85Steinhoff et al., Magn. Reson. Med.: 46(1) 131-140 2001Zaitsev et al; Magn. Reson. Med.: 49(1) 1121-1132 2003Shah et al., German Patent No.: 10028171

Hepatic Encephalopathy grade HE II

putamen putamen

thalamus

White Matter Water Content in HE

Shah NJ et al., Neuroimage. 2008;41(3):706-17.

White Matter Water Content and Therapy

HE I => HE0


11/24/2009

HE 0 HE II

Water Content Mapping @1.5T


11/24/2009

White MatterCONTROL70.8±0.48

HE 071.1±0.44

SHE 71.6±0.45

HE I72.9±0.66

HE II72.8±0.17

(Mean±S.E.M.)

Water Content Mapping in HE


11/24/2009

Significant correlation between HE grade and water content

• Frontal and Occipital WM

• Putamen

• Globus Pallidus

• Posterior Limb of the Internal Capsule

HE Grade vs. H2O content



New

Dire

ctio

ns fo

r T

rans

latio

n:M

R-P

ET

at 3

T a

nd 9

.4T

MR instead of CT in PET/CT ?

M.Schwaiger, S.Ziegler, et al., 2005

The combination of MR and PET in one scanner allows the

simultaneous and complementary use of these modalities

Siemens

Avalanche photo diodes (APD)

vs. photo multiplier tubes (PMT)

PMT APDAPDPMT

insensitiveMagnetically sensitive

~5 ns~1 nsRisetime

Up to 200Up to 10 6Gain

5x5 mm10-52 mm dia.Size

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

30 min 18F-PET

SimultaneousT1 MPRAGE

Fusion

18F in Hoffman 3D brain phantom

Our first human MR-PET images

Brain tumour studied with 18F-fluoro-ethyl-tyrosine (FET)


Bui

ldin

g of

the

Infr

astr

uctu

re


Bu

ildin

g P

rogr

ess

14

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

Acknowledgments

Thanks to:

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

Tha

nkyo

u

for

your

atte

ntio

n!!

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