Diffusion Physics H 2 O in the body is always in random motion due to thermal agitation B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen.

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Presentation transcript:

Diffusion Physics H 2 O 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 in Phase of “Tagged” H 2 O 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 H 2 O Image Voxel  = t 1  = t 2  = t 3 MRI Signal 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 the Central Nervous System Viable Tumor (Dark) Necrotic Core Edema ADC Map From: Ellingson, J Magn Reson Imaging, 2010 B.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, 2003 B.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 Hypercellular Regions (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, 2009 B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 fDMs in Progressive Disease (PD)  Hypercellularity

Positive Tumor Response to Treatment Day 89 Day 180Day 237Day 298 Hypercellular Tumor 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

B.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

From: Ellingson, ISMRM, 2009; SNO, 2009 B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010 fDMs May Reflect Molecular/Genetic Phenotypes MGMT(+) MGMT(-)

(n = 50 Total Patients) Spearman Corr. Coeff. R = , P = Clinical fDM Sensitivity/Specificity WHO Grade B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010From: Ellingson BM et al., ISMRM, 2010

(n = 50 Total Patients) Pearson Corr. Coeff. R 2 = , P < Clinical fDM Sensitivity/Specificity Neurological Status B.M. Ellingson, Ph.D., Dept. of Radiological Sciences, David Geffen School of Medicine at UCLA, 2010From: Ellingson BM et al., ISMRM, 2010

fDMs as an early biomarker for cytotoxic and new anti-angiogenic treatments From: Ellingson BM, J Neuroonc, 2010 B.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 BevacizumabTemozolomide 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. NAWM  ADC = 95% C.I. NAGM  ADC = 95% C.I. NAWM+NAGM  ADC = 95% C.I. NAWM+NAGM+CSF 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

Hypercellular Hypocellular Macrophages & Inflammatory Cells Demyelination Graded fDMs in Differential Diagnosis Tumor 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 Hypercellular Hypocellular T1+C FLAIR Graded 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 & 18 F-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 & 18 F-FDOPA PET -10 Cell 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) 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<

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.