MRI ANALYSIS TO DETECT GRAY MATTER TISSUE LOSS IN MULTIPLE SCLEROSIS by KUNIO NAKAMURA Submitted in partial fulfillment of the requirements For the degree of Doctor of Philosophy Dissertation advisor: Elizabeth Fisher, PhD Department of Biomedical Engineering CASE WESTERN RESERVE UNIVERSITY August, 2011 CASE WESTERN RESERVE UNIVERSITY SCHOOL OF GRADUATE STUDIES We hereby approve the thesis/dissertation of Kunio Nakamura ______________________________________________________ Ph.D. candidate for the ________________________________degree *. Andrew M. Rollins (signed)_______________________________________________ (chair of the committee) Elizabeth Fisher ________________________________________________ Bruce D. Trapp ________________________________________________ David L. Wilson ________________________________________________ ________________________________________________ ________________________________________________ June 10, 2011 (date) _______________________ *We also certify that written approval has been obtained for any proprietary material contained therein. To my mother, my father, and my wife for their love, patience and support. Table of Contents Table of Contents .............................................................................................................. 1 List of Tables ..................................................................................................................... 4 List of Figures.................................................................................................................... 5 Acknowledgements ........................................................................................................... 8 List of Abbreviations ........................................................................................................ 9 Abstract............................................................................................................................ 11 Chapter 1 Introduction............................................................................................. 13 1.1 Overview of Multiple Sclerosis ........................................................................ 13 1.2 Clinical Features of MS .................................................................................... 14 1.2.1 Symptoms and Diagnosis.........................................................................................14 1.2.2 MS Disease Course ..................................................................................................15 1.2.3 Clinical Measures of Disability................................................................................17 1.2.4 MS Treatment...........................................................................................................18 1.3 Pathology in MS ............................................................................................... 19 1.3.1 Focal Pathology in White Matter .............................................................................19 1.3.2 Diffuse Pathology in White Matter ..........................................................................21 1.3.3 Pathology in Gray Matter.........................................................................................22 1.4 Imaging Markers in MS.................................................................................... 25 1.4.1 Conventional MRI in MS.........................................................................................26 1.4.2 Advanced MRI to Detect GM Abnormality.............................................................28 1.5 Brain Atrophy in MS ........................................................................................ 35 1.6 Gray Matter Atrophy in MS.............................................................................. 37 1.6.1 Volumetric Gray Matter Atrophy.............................................................................38 1.6.2 Cortical Thickness Measurements in MS.................................................................42 1.7 Objectives ......................................................................................................... 44 Chapter 2 Gray Matter Segmentation Algorithm.................................................. 46 2.1 Introduction....................................................................................................... 46 2.1.1 MRI Format and Viewing ........................................................................................46 2.1.2 Background ..............................................................................................................47 2.1.3 Overview of Segmentation Algorithm .....................................................................49 2.2 Segmentation Algorithm................................................................................... 51 2.2.1 Image Correction......................................................................................................51 2.2.2 Fuzzy C-means Clustering Method..........................................................................54 2.2.3 Anatomic Probability Map.......................................................................................55 2.2.4 Morphologic Probability Map..................................................................................57 2.2.5 Partial Volume Correction .......................................................................................59 2.3 Validation.......................................................................................................... 60 2.3.1 Accuracy Test with Simulated MRI.........................................................................60 2.3.2 Accuracy Test with Manually Traced Real MRIs....................................................61 2.3.3 Reproducibility Test.................................................................................................64 2.3.4 Comparison to Other Segmentation Methods ..........................................................65 2.3.5 Sensitivity to Lesion Size.........................................................................................67 2.4 Discussion......................................................................................................... 70 1 2.4.1 Segmentation Method ..............................................................................................70 2.4.2 Validation Tests .......................................................................................................71 2.4.3 Conclusion ...............................................................................................................74 Chapter 3 Measurement of Gray Matter Atrophy in MS..................................... 75 3.1 Introduction....................................................................................................... 75 3.2 Materials and Methods...................................................................................... 75 3.2.1 Subjects ....................................................................................................................75 3.2.2 MRI ..........................................................................................................................77 3.2.3 Image Analysis.........................................................................................................77 3.2.4 Statistical Analysis...................................................................................................78 3.3 Results............................................................................................................... 79 3.3.1 Baseline Characteristics ...........................................................................................79 3.3.2 Group Comparison of Gray Matter Atrophy............................................................80 3.3.3 Clinical Correlation of Gray Matter Atrophy...........................................................81 3.3.4 Predictors of Gray Matter Atrophy ..........................................................................84 3.4 Discussion......................................................................................................... 84 Chapter 4 Cortical Longitudinal Atrophy Detection Algorithm.......................... 88 4.1 Introduction....................................................................................................... 88 4.1.1 Background ..............................................................................................................88 4.1.2 Overview of CLADA...............................................................................................91 4.1.3 Deformable Model Format and Viewing .................................................................92 4.2 Algorithm Description...................................................................................... 93 4.2.1 Image Acquisition ....................................................................................................93 4.2.2 Pre-processing..........................................................................................................93 4.2.3 Registration and Averaging......................................................................................95 4.2.4 Segmentation............................................................................................................97 4.2.5 Deformable Model ...................................................................................................98 4.2.6