3 Genes and Disease

Brain Imaging Henry N. Wagner, Jr. Brain Imaging: The Chemistry of Mental Activity Henry N. Wagner, Jr., MD Professor of Environmental Health Sciences Johns Hopkins Bloomberg School of Public Health Professor Emeritus of Medicine and Radiology Johns Hopkins School of Medicine Baltimore, MD, USA ISBN 978-1-84800-307-1 e-ISBN 978-1-84800-308-8 DOI: 10.1007/978-1-84800-308-8 British Library Cataloguing in Publication Data Library of Congress Control Number: 2008940826 © Springer-Verlag London Limited 2009 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored, or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specifi c statement that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer Science + Business Media springer.com Dedication To all the wonderful students, technologists and faculty in Nuclear Medicine at Johns Hopkins 1958–2008. v Foreword A Grand Design Imaging the human brain has captured the imagination of the general public more than almost any scientifi c advance of my recollection. The ability to visualize in great detail the soft tissue of the brain substance has revolutionized clinical neuroscience and permitted early and noninvasive diagnosis for all sorts of brain diseases. More fascinating has been the use of imaging techniques to elucidate brain function. Magnetic resonance imaging can be used to monitor general activity in different parts of the brain. For me, however, the use of radioactive isotopes to visualize metabolism in intact humans is in some ways more important. One underlying strategy refl ects work of Louis Sokoloff at the National Institutes of Health (NIH). In the mid-1970s he assessed glucose use with the nonmetabolized derivative 2-deoxyglucose. With the advent of positron emission tomography (PET) scanning, positron-emitting derivatives of 2-deoxyglucose were used to evaluate glucose use in the human brain. I remember well the excitement surrounding the early PET scanning with 2-deoxyglucose. Medical institutions throughout the country invested many millions of dollars in cyclotrons and PET scanners. Besides the expensive equipment, a staff of chemists was required to rapidly synthesize the short-lived positron emitting ligands, and physicists were necessary to nurture the temperamental cyclotrons. Accustomed to simple, inex- pensive, low-maintenance biochemical technology, I regarded the 2-deoxyglucose PET scanning enterprise as too much fuss for too little payoff. In the early 1970s, Henry Wagner came to visit with me. He wished to apply to the NIH for funding to purchase all the goodies necessary to commence PET scanning. Numerous institutions across the country were jumping on the bandwagon, all doing similar 2-deoxyglucose monitoring. Henry eschewed copycat science and sought some- thing innovative. He had read of our research labeling receptors for opiates and neurotransmitter receptors by the reversible binding of small drug-like ligand molecules. He asked for help in formulating a proposal to the NIH to label appropriate drugs with positron emitting isotopes to monitor receptors in humans. I was fascinated by the chal- lenge and eager to help. For the grant application, one of the principal tasks was calculat- ing various aspects of drug disposition, which would infl uence whether enough receptor-bound drug could accumulate to permit imaging through the skull. My faculty colleague Michael Kuhar had collaborated with me some initial receptor studies. His bachelor degree was in physics and his Ph.D. was in biophysics, so Michael had the mathematical skills to address the underpinnings of a successful grant application. vii viii Foreword The grant was submitted, funded, and PET labeling of receptors in humans worked. I recall vividly the ecstasy of Mike and Henry when the fi rst images of dopamine receptors were obtained. Henry insisted on being the fi rst experimental subject. This led to a peculiar observation. Dopamine receptors are most highly concentrated in the caudate nucleus that contains the terminals of the major dopamine pathway that degenerates in Parkinson’s disease. Repeated images indicated a major discrepancy between the right and left caudate of Henry’s brain. Might he have a selective aberration of dopamine receptors in one side of the brain? With subsequent imaging of other receptors, the abnormality persisted. Presumably, Henry’s brain has compensated for the anomaly as he is a well coordinated individual. I became personally involved with the PET scanning effort when it came time to image opiate receptors. Although the PET scanning team didn’t really need me, Henry felt it appropriate to include me as a collaborator and participant in the initial identifi cation of opiate receptors. As was usual, Henry was the initial experimental subject. I served as the “anesthesiologist.” One of the critical tasks in imaging receptors is to evaluate non- specifi c binding, the portion of the administered drug that is not associated with the receptor but linked to other tissue components. This can be estimated by administering a nonradioactive drug that displaces the radioligand from its receptor. In this case, we used the classic opiate receptor antagonist naloxone. To ensure that enough naloxone was administered to displace the radioligand from opiate receptors, the pharmacologists recommended administering 100 times the naloxone dose typically given to a patient suffering from a heroin overdose. Some years ago, we had discovered that high concen- trations of naloxone blocked receptors for the inhibitory neurotransmitter GABA and would thus be predicted to cause convulsions. I had long since forgotten about that study, but it all came back to me when I began pumping the naloxone into Henry. Instead of his usual carefree, joking demeanor, Henry became irritable, anxious, and shaky. I was terrifi ed that we were going to trigger a convulsion. Fortunately, naloxone is very short lived. Henry’s “panic” subsided within a couple of minutes. The imaging was highly successful and many studies of opiate receptors in humans ensued. I resolved never again to insinuate myself into execution of the clinical study without knowing an awful lot about what was going on. I relate the above-mentioned anecdotes to convey the essence of Henry Wagner—a brilliant, incisive, creative, and audacious investigator. Although these elements are on display in this ambitious volume, rather than just providing reminiscences of his experi- ence in using nuclear medicine to study the brain, he provides an overarching mantle in which to appreciate all the things we can learn from imaging the brain. He commences with an explanation of neurotransmitters with a special focus on serotonin, the neurotransmitter most linked to emotional behavior. He even provides a crash course in molecular biology and how genetic malfunctions lead to disease. He provides an over- view of how mental function can be abstracted from the molecular interface of diverse neurotransmitters in discrete brain regions. Most importantly, he provides a sophisti- cated yet readily understood description of the underpinnings of radioactivity and how a series of investigators, going back to the days of Pierre and Marie Curie, worked out the use of radiolabeled chemicals as tracers. It has long been my feeling that too few people appreciate the critical role of radiotracers in the revolution in biochemistry and molecular biology that characterize the second half of the 20th century. Without such Foreword ix tracers it would never have been possible to map the major metabolic pathways in the body. The breakthroughs in molecular genetics derived heavily from the use of radio- isotopes. All of our own work identifying neurotransmitter receptors would never have been possible without the use of drugs and neurotransmitters labeled very selectively with isotopes. Henry seamlessly integrates descriptions of diverse imaging techniques with a wide range of mental states and diseases that have been investigated by PET scanning. He links these into a coherent view of the molecular underpinnings of brain function. For example, he describes his own research in 1950 on the effects of the drug bulbocapnine, which mimics the motor manifestations of catatonic schizophrenia. He then shows how cocaine, which enhances the effects of dopamine, can block the actions of bulbocapnine. He relates these fi ndings to the catatonia of postencephalitic Parkinson’s disease, which is dramatically reversed by the increased formation of dopamine after treatment with L-dopa. He links these observations to what he has learned about dopamine systems by using PET scanning. Henry writes with a degree of lucidity and enthusiasm that renders the volume acces- sible both to the specialist and the educated lay public. We are in the debt to Henry Wagner for conveying to us his remarkable life’s work and transforming insights. Solomon H. Snyder Baltimore, MD Acknowledgement To Judy Buchanan for her help in correcting the page proofs. xi Contents Foreword . vii 1 A Molecular Theory of Disease . 1 2 The Master Molecule . 7 3 Genes and Disease . 9 4 From Brain to Mind . 17 5 The Early Days . 27 6 A Molecular Theory of Mental Disease . 35 7 The Physics of Radioactivity .

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