1. MRI-Based Assessment of Neovasculariation in Carotid Plaque – A Novel Risk Marker for Plaque Rupture Lawrence L. Wald, Ph.D. MGH Martinos Center for Biomedical Imaging Michael Jerosch-Herold, PhD Brigham & Women’s Hospital

2. Novel Risk Predictors for Plaque Vulnerability Systemic Markers / Risk Factors –Blood lipids, C-reactive protein, fibrinogen Plaque-specific markers –Hemodynamic predictors E.g. wall shear stress –Plaque neovascularization

3. Neovascularization of Carotid Plaque Neovascularization of the vessel wall appears to be a consistent feature of inflamation and atherosclerotic plaque development.Neovascularization of the vessel wall appears to be a consistent feature of inflamation and atherosclerotic plaque development. Due to their potential to promote intra- plaque hemorrhage and subsequent cholesterol deposition and plaque growth, plaque microvessels are considered markers of plaque vulnerability.Due to their potential to promote intra- plaque hemorrhage and subsequent cholesterol deposition and plaque growth, plaque microvessels are considered markers of plaque vulnerability.

4. 3T Imaging of Carotid Plaque 3D T1W imaging of plaque morphology

5. New 3.0 T Bilateral 8-Channel Carotid Array and Head- Holder for Reynold Carotid Study Coil mounted on a frame with head-holder consists of two curved paddles MGH Design Wiggins/Wald Reference: Hinton-Yates et al., TMRI 2007 8- Coils = pair of four 4.8 cm loops Head Holder

6. Patient Characteristics N=33Age71±9 Male 16 (48%) Diabetes 11 (33%) Hypertension 21 (64%) Smoking 6 (18%) History of CV disease 17 (52%) Prior MI 4 (12%) TIA/Stroke 5 (15%) Symptomatic 10 (30%)

7. MRI Protocol for Dynamic Contrast Enhancement T1-weighted 3D fast gradient echo –TR/TE/flip angle: 4.3/2.3 ms/ 20° –3 mm slices –In-plane resolution: 0.7 x 0.7 mm –Time per dynamic view: 14 s With new 8-element neck phased array the time per dynamic view is reduced to 10 s.

8. Image Analysis Carotid bifurcation was used as landmark to match MRI, PET, and CEA specimensCarotid bifurcation was used as landmark to match MRI, PET, and CEA specimens MRI: High resolution T1 and T2 spin echo images were used to identify plaque and to match with the CEA specimen.MRI: High resolution T1 and T2 spin echo images were used to identify plaque and to match with the CEA specimen. FDG PET: ROIs were drawn around the CCA and/or ICA at a slice location matching the MRI-defined plaque and CEA specimen levels, using the anatomic landmarks from the CT scan of the PET/CT study.FDG PET: ROIs were drawn around the CCA and/or ICA at a slice location matching the MRI-defined plaque and CEA specimen levels, using the anatomic landmarks from the CT scan of the PET/CT study. Quant FDG uptake: For each slice, the arterial Standardized Uptake Value was calculated as the mean pixel activity within the ROI using a standard approachQuant FDG uptake: For each slice, the arterial Standardized Uptake Value was calculated as the mean pixel activity within the ROI using a standard approach –SUV LBM = tissue activity (  Ci/mL) / injected activity (mCi) / LBM (kg) The arterial SUV (was corrected for blood activity by normalizing it to the average blood SUV estimated from the jugular vein to produce a blood-corrected arterial SUV (arterial tissue-to-background ratio)The arterial SUV (was corrected for blood activity by normalizing it to the average blood SUV estimated from the jugular vein to produce a blood-corrected arterial SUV (arterial tissue-to-background ratio) mm mm

9. Isotropic resolution of 0.6 mm SPACE sequence for plaque morphology

10. FDG-PET Co-Registered to Carotid MRI

11. Image Analysis and Determinatin of First Order Capillary Transfer Rate Constant Contrast-Enhancement in Carotid Wall

12. Kinetic Modeling (Kety-Schmidt Model) Arterial Input Venous Outflow Tissue Extraction (K trans ) vbvbvbvb Model Parameters Determined by Optimization v p vascular volume K trans First order blood-to-tissue transfer rate constant Measured in vessel lumen Δ C t = v p * Δ C p + K trans C p VascularPermeability

13. Plaque Edema on T2 SPACE and K trans 03630993-R

14. K trans Area under Signal Curve (2 min. post injection) T2 SPACE P-NCHLS High K trans in plaque at carotid bifurcation

15. Correlation Between FDG PET and MR Ktrans R=0.463 P=0.017

16. ECA ICA lumen ICA plaque K trans map of ICA wall and plaque P-NCHLS-R Area under SI curve (AUC) (2 min. window) Complex ICA Plaque Dark-Blood T2-w SPACE

17. Plaque Edema and Ktrans 16549180-R Ktrans - ICASPACE (T2w) ICA

18. Correspondence between regions with high SI on T2 SPACE and K trans map of ICA wall P-BSHTT-left K trans map T2 SPACE above carotid bifurcation T2 SPACE

19. Association between Signal Intensity Level in Carotid Wall with T2 SPACE and K trans Perfusion Parameter

20. Correlation of MRI Parametric Maps with Histology

21. Macrophage Density by Ktrans Categories R=0.80 P=0.03

22. Plans 3 accepted abstracts for May 2010 ISMRM conference –“High Resolution 3D Carotid Plaque Perfusion Mapping and its Association with T2 Hyperintensity” –“3D Isotropic Non-contrast Approach for the Assessment of Carotid Arteries Stenosis at 3T” –“T1 Contrast in MPRAGE for Carotid Plaque Imaging” Enrollment of more patients scheduled for endarterectomy for comparison with plaque pathology Future sponsored studies

23. Acknowledgements Co-Investigators: Larry Wald (Co-PI), Raymond Kwong, Marcelo Di Carli Support through Partners Radiology Research Award