diffusion physics

Diffusion Physics

H2O in the body is always in random motion due to thermal agitation

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Detecting Diffusion with MRI - Intravoxel Incoherent Motion

Ellingson et al., Concepts in MR, 2008

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson, Concepts in MR, 2008

Detecting Diffusion with MRI - Intravoxel Incoherent Motion

Detected DWI Signal

MRI Signal w/o Diffusion Sensitivity

Variability inPhase of “Tagged” H2O Level of Diffusion Weighting

Diffusion Coefficient

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Proton on H2O

Image Voxel = t1

= t2

= t3

MR

I Sig

nal

Diffusion Time (or level of diffusion weighting)

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

• Apparent diffusion coefficient (ADC) measured clinically reflects extracellular water• ADC is dependent on tumor cell density

(Ellingson, 2010; Sugahara, 1999; Lyng, 2000; Chenevert, 2000; Gaurain, 2001; Nonomura, 2001; Guo, 2002; Chen, 2005; Hayashida, 2006; Manenti, 2008;

Kinoshita, 2008

Cell Density (hypercellular) = ADC Cell Density (hypocellular) = ADC

Diffusion MR Characteristics of theCentral Nervous System

Viable Tumor (Dark)

Necrotic Core

Edema

ADC Map

From: Ellingson, J Magn Reson Imaging, 2010B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Diffusion MRI During Successful Cytotoxic Therapy

From: Ross, Mol Cancer Ther, 2003B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

The Functional Diffusion Map (fDM)(Moffat, 2005; 2006; Hamstra, 2005; 2008; Ellingson, 2010)

From: Ellingson, JMRI, 2010

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Early Detection of Brain Tumor Growth

T1+C

FLAIR

fDMs

HypercellularRegions (Blue)

Contrast-Enhancement(white)

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

fDMs in Brain Tumor Progression

T1+C

FLAIR

fDM

3 mo. 6 mo. 9 mo. (Onset of symptoms)

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

From: Ellingson, ISMRM, 2009; SNO, 2009B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

fDMs in Progressive Disease (PD)

Hypercellularity

Hypercellularity

Hypercellularity

Positive Tumor Response to TreatmentDay 89 Day 180 Day 237 Day 298

HypercellularTumor

Hypocellular“Treated” Tumor

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson, ISMRM, 2009; SNO, 2009

From: Ellingson, ISMRM, 2009; SNO, 2009B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

fDM Results in Stable/Responding Disease (SD/RD)

Hypocellularity Hypocellularity

Hypocellularity

From: Ellingson, ISMRM, 2009; SNO, 2009B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

fDMs May Reflect Molecular/Genetic Phenotypes

MGMT(+) MGMT(+) MGMT(+)MGMT(-) MGMT(-) MGMT(-)

(n = 50 Total Patients)

Spearman Corr. Coeff. R = 0.4350, P = 0.0016

Clinical fDM Sensitivity/Specificity

WHO Grade

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson BM et al., ISMRM, 2010

(n = 50 Total Patients)

Pearson Corr. Coeff.R2 = 0.8586, P < 0.0001

Clinical fDM Sensitivity/Specificity

Neurological Status

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson BM et al., ISMRM, 2010

fDMs as an early biomarker for cytotoxic and new anti-angiogenic treatments

From: Ellingson BM, J Neuroonc, 2010B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Volumetric Analysis of fDMs as an early biomarker for cytotoxic and new anti-angiogenic treatments

From: Ellingson BM, J Neuroonc, 2010

fDMs detect PD > 2 months before recurrence

Bevacizumab Temozolomide

fDMs predict survival and progression better than age and tumor grade!

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Better Defining ADC Thresholds for Classification

From: Ellingson, JMRI, 2010

ADC =

95%

C.I.

NAW

M

ADC =

95%

C.I.

NAGM

ADC =

95%

C.I.

NAW

M+N

AGM

ADC =

95%

C.I.

NAW

M+N

AGM+C

SF

Different ADC thresholds reflect different sensitivity/specificity to growing tumor

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Better Defining ADC Thresholds for Classification

From: Ellingson, JMRI, 2010

Different ADC thresholds reflect different sensitivity/specificity to growing tumor

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Graded fDMs Allow Visualization and Quantification of Growing Tumor

+ Hypercellular+ Hypocellular

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Biological Calibration

From: Ellingson, JMRI, 2010

Graded fDMs Allow Better Visualization of Growing Tumor

+ Hypercellular+ Hypocellular

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Graded fDMs Allow Better Visualization of Growing Tumor

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Hyp

erc

ellu

lar

Hyp

oce

llula

r

Macrophages& Inflammatory Cells

Demyelination

Graded fDMs in Differential DiagnosisTumor vs. Demyelination

Biopsy Diagnosis = Demyelination (Multiple Sclerosis)

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Graded fDMs can distinguish radiation necrosis from tumor

Hyp

erc

ellu

lar

Hyp

oce

llula

r

T1+

CF

LAIR

Gra

ded

fDM

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Diffusivity Mismatch Index (DMI) predicts survival

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson, Clin Cancer Res, 2010, Submitted

Diffusivity Mismatch Index (DMI) predicts survival

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson, Clin Cancer Res, 2010, Submitted

Cell Invasion, Migration, and Proliferation Level Estimates = CIMPLE Maps

• Higher-order changes in ADC over time and space• Allows us to map estimates of invasion and proliferation

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson, Magn Reson Med, 2010, Accepted

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Whole Brain CIMPLE Maps & 18F-FDOPA PET

From: Ellingson, Magn Reson Med, 2010, Accepted

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Whole Brain CIMPLE Maps & 18F-FDOPA PET

-10Cell Proliferation

[1/yr]

10

CIMPLE Maps Pre-Tx Post-Tx Recurrence

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 From: Ellingson, Cancer Imaging, 2010, Submitted

CIMPLE Maps(Doubling Times)

Doubling Time

Days 3650

Within physiologic range of doubling times:

• 22 days (GBM) - 556 days (WHO II)

Blankenberg et al, AJNR, 2005

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

CIMPLE Maps(Doubling Times)

Doubling Time

Days 3650

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Doubling Time (Days)

50< 10 403020

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Mean proliferation at start of treatment predicts survival(defined from time of CIMPLE map) N = 26

From: Ellingson, Cancer Imaging, 2010, Submitted

Conclusions

• Diffusion MRI is sensitive to cell density

• Functional diffusion maps (fDMs) reflect voxel-by-voxel changes in cellularity

• fDM kinetics are useful for individual patient monitoring

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

• Graded fDMs allow for degree of cellularity to be visualized and quantified (biological basis)

• Graded fDMs can distinguish radiation necrosis from tumor recurrence

• CIMPLE maps allow visualization and quantification of invasion and proliferation rates

Conclusions

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Radiology• Whitney Pope, M.D., Ph.D.• Dieter Enzmann, M.D.• Jonathan Goldin, M.D.• MedQIA

Neurology/Neuro-Oncology• Timothy Cloughesy, M.D.• Albert Lai, M.D., Ph.D.

Neurosurgery• Linda Liau, M.D.• Bob Shafa, M.D.• Antonio DeSalles, M.D.

Pathology• Paul Mischel, M.D.• Bill Yong, M.D.

Thank You!

B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010

Radiology• Kathleen Schmainda, Ph.D.• Scott Rand, M.D., Ph.D.

Neurology/Neuro-Oncology• Mark Malkin, M.D.• Jennifer Connelly, M.D.

Neurosurgery• Wade Mueller, M.D.• Shekar Kurpad, M.D., Ph.D.