Evaluation of Hahn, CPMG, and Combined Spin Echo Analysis at 8 Tesla MRI DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Chastity Diane Shaffer Whitaker, M.S. * * * * THE OHIO STATE UNIVERSITY 2004 APPROVED BY DISSERTATION COMMITTEE: Professor Petra Schmalbrock, Advisor Professor Douglas Scharre Professor David Beversdorf Advisor Professor Philip Smith Biophysics Program Copyright by Chastity DS Whitaker 2004 ABSTRACT Magnetic Resonance Imaging is a non-invasive technique that has been developed for its excellent depiction of soft tissue contrasts. Instruments capable of ultra-high field strengths, ≥7 Tesla, were recently engineered and have resulted in higher signal-to-noise and higher resolution images. Total iron content within the brain is not homogenous. Age and a number of neurological conditions (such as Alzheimer’s, Parkinson’s, Multiple Sclerosis, etc.) may influence the distribution. The ability to non-invasively detect the distribution of iron may be useful for diagnosis and for assessment of the effectiveness of treatments. Iron is also capable of indirectly influencing the signal in an MRI study by dephasing spins. This may then lead to an increase in relaxation rates. However, the standard transverse relaxation rate is not the most sensitive measure of iron content and other methods, such as gradient echo, are plagued with artifacts (example: air-tissue susceptibility signal loss and distortion). To increase the sensitivity of high field spin echo analysis to the distribution of iron content, we have analyzed Hahn and CPMG spin echoes with the Carr and Purcell spin echo signal equation. This resulted in an intrinsic T2 ii that describes the relaxation of the tissues and a susceptibility and diffusion dependent term (γ2G2D) that may be correlated with paramagnetic content. Experimentation includes the accuracy of Hahn, CPMG, and Combined Spin echo calculations in an inhomogeneous B1 field and the influence of macromolecular content on T2 and γ2G2D. We also examined Alzheimer’s disease using in vitro, in situ, and in vivo subjects with these techniques. Independent correlation to iron content is accomplished with ICP-Mass Spectroscopy. We found that reliable relaxation measurements are found within image regions of ±20° of a nominal 90° flip angle. The paramagnetic content is linear with intrinsic T2 values quadratic with γ2G2D. Gradient and diffusion effects are not independent and a static regime model may be appropriate for describing γ2G2D. In vitro imaging of brain material results in similar relaxation rates to in situ imaging if the tissue is imaged immediately following autopsy. iii Dedicated to Steve & Beverly Shaffer and Matthew & Caleb Whitaker iv ACKNOWLEDGMENTS Be forewarned - this is going to take a while. First, of course, I would like to thank my parents, Steve and Beverly Shaffer. Without them, I would never have accomplished all that I have. Their belief in me, that I can do anything that I put my mind to, has pushed me in continuing in those rough times when quitting sounded so easy. Their faith in God has set an example to me of how believing in him to provide all that you need. Also to my brother, Steven. His youthful point-of-view always reminds me that life is suppose to be fun and that problems always seem bigger than they really are. Steven has a passion for life and friends that I admire so much. Next there are my in-laws. Charles and Shirley have always included me and made me feel as though I was naturally part of the family. There was never any doubt on their part as to what my future holds, and that I would do exactly what I had set my mind to. My sister-in-law, Amy, whose energy is beyond anything I have ever seen. She exhausts me just watching her bounce and chatter about. That energy will be a great benefit as she begins to shape young minds. Finally, Chad & Chrissy, for their dedication to their profession of saving v lives and always providing helpful second opinions for medical concerns. You two will make great parents when you decide the time is right. To my advisor, Petra Schmalbrock, who had taken me in when I was academically ‘homeless’ and in desperate need of finding someone to be my mentor. You have taken a chance on me and I hope that I have not disappointed (besides the conservative view points and desire to be one of those awful lawyer types). Just remember to have faith in people. My partner in crime and statistical crutch – Martina Pavlicova. You have an amazing ability focus on the final goal (not the current crisis) and have an incredible intelligence. You will be extremely successful, I’m quite sure. To the department of Radiology, the staff (Heidi, Gail, Bill, Lindsey) and physicians (Chakeres, Slone, Christoforidis, Borekas) who have always provided help and information when needed, I’m eternally grateful. Drs. Scharre and Beversdorf – the two of you have always been there for my work. Even when things were not going as well as we anticipated, you stood by my work and kept offering to help in any way possible. I truly appreciated all that you have done. But who can forget some of my most ‘favorite’ people ever? Trong-kha Truong, Chad Mitchell, Ryan Gilbert, Johannes Heverhagen, and Jim Ibinson. We have suffered together, cried together (well, you have listened to me cry), cursed, laughed, etc, etc. Who can count all of the fru-fru (or cheap-a-chino) that we have drank, chocolate that Chad has (I mean we have) eaten, or number of times we have beat the RF lab printer? Your friendships will always be one of vi my fondest memories of the graduate school experience and I can only pray that you all have the success and happiness that you deserve. TKT – just remember to speak out more. I know it is hard, I deal with it everyday. Chad, you have such a strong faith and conviction. You are an inspiration to maintaining your beliefs and strong sense of family. ‘The Doctor Is In…5¢ please,’ should be on the couch near Ryan’s office. Or perhaps, ‘Will fix Ebay lemons.’ Thanks for your optomism. I will only say thanks to Johannes so that there is not further suspicion to contribute to TKTs MS Windows desktop. Finally, Jim (and your ‘big, happy family’). The four of you have given Matt, Caleb, and I so much help and advice throughout the last year. I miss living so close to you guys!! We will eventually call a truce on the competition of number of degrees…maybe. Then there are those silent partners that we already miss so dearly. Drs Algaze and Ibrahim have shown that attaining the PhD is possible if you can endure. Hendrik and Klauss were always available for a run to the Café Oasis, happy hour at Don Pablos, or just a chat. I miss you all. The support of the Biophysics program was phenomenal. Susan Hauser is so dedicated to the success of every student, and we take her for granted every day. Thanks so much for all for always dropping your work just to find that 999 number for me the day that my schedule is due. Dr. Clanton is one of the most positive and supportive directors that I have seen. You strive to help each one of us succeed and usually at the expense of added stress to your life. I’m so happy that you are allowing yourself to pass on some of the resonsibilities to other members of the faculty. vii Now, for the two most important men in my life. Caleb, you are just a few months old, but you have made such an impact on my life. Never before have I felt so many emotions and so much love – maybe it is all the hormones, anti- depressants, and alcohol talking, but I’m sure maternal instinct has something to do with it. That silly person that I use to be when I did not want children never knew what it meant to feel fulfillment in life, until recently. I pray that I do not disappoint you as a parent, do not embarrass you too much in front of your friends, provide a safe and happy home, and do not cause so much damage that years of therapy cannot cure. If you are anything like your father and I then you will surely understand the sarcasm in that statement. And Matt…you always ask me why I love you. I never know how to put it into words – imagine that I don’t know what to say. You are my source of strength and self-confidence. While I act like a feminist with everyone else, you know exactly how weak and frail I am. You are so supportive, loving, understanding, and intelligent. And I strive to make our life together happier than the day before. Finally, to my Father in Heaven. I know I disappoint you often, but you have an everlasting love and forgiveness. Please do not give up on me. viii VITA June 12, 1977…………………..…………Born – Morgantown, WV 1999…………………………………………B.S. Chemistry & Biology, Bridgewater College, Bridgewater, VA 1999-2000………………………………….Graduate Teaching Assistant 2000-present……………………………….Research Assistant, The Ohio State University 2002…………………………………………Graduate Teaching Assistant 2003…………………………………………M.S. Biophysics, The Ohio State University PUBLICATIONS 1. Whitaker CDS (2001) What Recourse? – Liability for Managed-care Decisions and the Employee Retirement Income Security Act. Review of Mariner W. N Engl J Med. 2000;343:592-596. Journal of Allied Health 30(2) 133.