NMR in Physiology and Biomedicine

465 Pages·1994·22.118 MB·English

by  Robert J. Gillies (Eds.)

N MR in Physiology
and Biomedicine
Edited by
Robert J. Gillies
Departments of Biochemistry,
Physiology, and Radiology
Arizona Health Sciences Center
University of Arizona
Tucson, Arizona
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Library of Congress Cataloging-in-Publication Data
NMR in physiology and biomedicine / edited by Robert J. Gillies,
p. cm.
Includes bibliographical references and index.
ISBN 0-12-283980-3 (hardcover)
1. Nuclear magnetic resonance spectroscopy. 2. Magnetic resonance
imaging. 3. Physiology, Experimental. I. Gillies, Robert J.
[DNLM: 1. Nuclear Magnetic Resonance. 2. Magnetic Resonance
Imaging. WN 445 N38 1994]
QP519.9.N83N685 1994
612'.01585-dc20
DNLM^)LC
for Library of Congress 94-930
CIP
PRINTED IN THE UNFIED STATES OF AMERICA
94 95 96 97 98 99 QW 9 8 7 6 5 4 3 2 1
Contributors
Numbers in parentheses indicate the pages on which the authors' Stephen John Blackband (119), MRI Centre, Hull Royal
contributions begin. Infirmary, Hull HU3 2JZ, United Kingdom, and De­
partment of Radiology, Johns Hopkins Hospital, Bal­
Jeffry R. Alger (151), Department of Radiological Sci­
timore, Maryland 21205
ences, University of California, Los Angeles, Los
Angeles, California 90024 Kevin M. Brindle (237), Department of Biochemistry,
University of Cambridge, Cambridge CB2 IQW,
E. Raymond Andrew (1), Department of Radiology,
United Kingdom
University of Florida, Gainesville, Florida 32610
Robert J. Bache (413), Department of Medicine (Car­ Rodney D. Brown III (57), IBM T. J. Watson Research
diovascular Section), and Center for Magnetic Reso­ Center, Yorktown Heights, New York 10598
nance Research, University of Minnesota Medical
Paul Canioni (373), University of Bordeaux II, and Insti­
School, Minneapolis, Minnesota 55455
tute of Cellular Biochemistry, 33077 Bordeaux,
Jimmy D. Bell (221), NMR Unit, Hammersmith Hospi­ France
tal, London W12 OHS, United Kingdom
Britton Chance (405), Department of Biochemistry and
David Bendahan (389), Centre de Resonance Magnιti­
Biophysics, University of Pennsylvania, Philadelphia,
que Biologique et Mιdicale (CRMBM), Facultι de
Pennsylvania 19104
Mιdecine, 13005 Marseille, France
Patrick J. Cozzone (389), Centre de Resonance
Michal Bental (295), Department of Physiology, Univer­
Magnιtique Biologique et Mιdicale (CRMBM), Fa­
sity of Pennsylvania, School of Medicine, Philadel­
cultι de Mιdecine, 13005 Marseille, France
phia, Pennsylvania 19104
Zaver M. Bhujwalla (311), Division of NMR Research, Delphine Davis (185), Department of Radiology, Johns
Department of Radiology, Johns Hopkins University Hopkins University Medical School, Baltimore,
School of Medicine, Baltimore, Maryland 21205 Maryland 21205
XI
xu Contributors
Hadassa Degani (329), Department of Chemical Phys­ Seong-Gi Kim (137), Center for Magnetic Resonance
ics, Weizmann Institute of Science, 76100 Rehovot, Research, University of Minnesota Medical School,
Israel Minneapohs, Minnesota 55455
Carol Deutsch (295), Department of Physiology, Uni­ Seymour H. Koenig (57), IBM T. J. Watson Research
versity of Pennsylvania, School of Medicine, Philadel­ Center, Yorktown Heights, New York 10598
phia, Pennsylvania 19104 Denis Le Bihan (43), Department of Diagnostic Radiol­
Jutta Ellermann (137), Center for Magnetic Resonance ogy, The Warren G. Magnuson Clinical Center, Na­
Research, University of Minnesota Medical School, tional Institutes of Health, Bethesda, Maryland
Minneapohs, Minnesota 55455 20892
Jeffrey L. Evelhoch (209), Department of Internal Medi­ Robert E. London (263), Laboratory of Molecular Bio­
cine, Wayne State University School of Medicine, De­ physics, National Institute of Environmental Health
troit, Michigan 48201 Sciences, National Institutes of Health, Research Tri­
angle Park, North Carolina 27709
Arthur H. L. From (413), Department of Medicine (Car­
diovascular Section), and Center for Magnetic Reso­ Craig R. Malloy (439), Department of Radiology and
nance Research, University of Minnesota Medical Internal Medicine, Rogers Magnetic Resonance Cen­
School, and Minneapolis Veteran's Administration ter, University of Texas Southwestern Medical Cen­
Medical Center, Minneapolis, Minnesota 55417 ter, Dallas, Texas 75235
Alexandra M. Fulton (237), Department of Biochemis­ Kevin McCully (405), Division of Geriatric Medicine,
try, University of Cambridge, Cambridge CB2 IQW, Medical College of Pennsylvania, Philadelphia, Penn­
United Kingdom sylvania 19129
Edna Furman-Haran (329), Department of Chemical K. A. McGovern (279), Department of Radiology/On­
Physics, Weizmann Institute of Science, 76100 Re­ cology, University of Arizona, Tucson, Arizona
hovot, Israel 85724
Michael Garwood (137), Center for Magnetic Reso­ Ravi Menon (137), Center for Magnetic Resonance Re­
nance Research, University of Minnesota Medical search, University of Minnesota Medical School,
School, Minneapolis, Minnesota 55455 Minneapolis, Minnesota 55455
Jerry D. Glickson (311), Division of NMR Research, Hellmut Merkle (137), Center for Magnetic Resonance
Department of Radiology, Johns Hopkins University Research, University of Minnesota Medical School,
School of Medicine, Baltimore, Maryland 21205 Minneapohs, Minnesota 55455
Qiuhong He (311), Division of NMR Research, Depart­ Dieter J. Meyerhoff (169), Department of Radiology,
ment of Radiology, Johns Hopkins University School University of California, San Francisco, San Fran­
of Medicine, Baltimore, Maryland 21205 cisco, Cahfornia 94143
Kristy Hendrich (137), Center for Magnetic Resonance Chrit T. W. Moonen (185), In Vivo NMR Research
Research, University of Minnesota Medical School, Center, BEIP, NCRR, National Institutes of Health,
Minneapolis, Minnesota 55455 Bethesda, Maryland 20892
Richard Hinke (137), Center for Magnetic Resonance Michal Neeman (101), Department of Hormone Re­
Research, University of Minnesota Medical School, search, Weizmann Institute of Science, Rehovot
Minneapohs, Minnesota 55455 76100, Israel
Edward Hsu (119), Department of Biomedical Engi­ Seiji Ogawa (137), Biological Computation Research
neering, Johns Hopkins Hospital, Baltimore, Mary­ Department, AT&T Bell Laboratories, Murray Hill,
land 21205 New Jersey 07974
Xiaoping Hu (137), Center for Magnetic Resonance Re­ H. G. Parkes (221), Upjohn Limited, Crawley, West
search, University of Minnesota Medical School, Sussex RHIO 2NJ, United Kingdom
Minneapolis, Minnesota 55455 Joel Posner (405), Division of Geriatric Medicine, Medi­
Thomas Jue (199), Department of Biological Chemistry, cal College of Pennsylvania, Philadelphia, Pennsylva­
University of California, Davis, Davis, California nia 19129
95616 N. E. Preece (221), Royal College of Surgeons, Unit of
Gregory Karczmar (25), Department of Radiology, Uni­ Biophysics, Institute of Child Health, London WCIN
versity of Chicago, Chicago, Illinois 60637 3EH, United Kingdom
Contributors XIU
Bjσrn Quistorff (373), Panum Institute, University of Kamil Ugurbil (137, 413), Departments of Medicine
Copenhagen, NMR Center, Copenhagen 2200, Den­ (Cardiovascular Section), Radiology, and Biochemis­
mark try, and Center for Magnetic Resonance Research,
University of Minnesota Medical School, Minneapo-
Sabrina Μ. Ronen (329), Institut Curie, Section Biolo­
hs, Minnesota 55455
gie, 91405 Orsay, France
Krista Vandenborne (405), Department of Rehabilita­
Douglas I. Rothman (353), Magnetic Resonance Center,
tion Medicine, University of Pennsylvania, Philadel­
Yale University, New Haven, Connecticut 06510
phia, Pennsylvania 19104
Α. Dean Sherry (439), Department of Chemistry, Uni­
Peter C. M. van Zijl (185), Department of Radiology,
versity of Texas at Dallas, Richardson, Texas 75083,
Johns Hopkins University Medical School, Baltimore,
and Department of Radiology, Rogers Magnetic Res­
Maryland 21205
onance Center, University of Texas Southwestern
Medical Center, Dallas, Texas 75235 Janna P. Wehrle (311), Division of NMR Research, De­
partment of Radiology, Johns Hopkins University
Dikoma C. Shungu (311), Division of NMR Research,
School of Medicine, Baltimore, Maryland 21205
Department of Radiology, Johns Hopkins University
School of Medicine, Baltimore, Maryland 21205 Simon-Peter Williams (237), Department of Biochemis­
Laurel O. Sillerud (101), Life Sciences Division, Los Ala­ try, University of Cambridge, Cambridge CB2 IQW,
mos National Laboratory, Los Alamos, New Mexico United Kingdom
87544
Jianyi Zhang (413), Department of Medicine (Cardio­
Charles S. Springer, Jr. (75), Departments of Chemistry vascular Section), and Center for Magnetic Reso­
and Radiology, State University of New York at nance Research, University of Minnesota Medical
Stony Brook, Stony Brook, New York 11794 School, Minneapolis, Minnesota 55455
Foreword
The continuous excitement of NMR research since imaging (MRI) has advanced in the traditionally rapid
its discovery in 1946 has been a source of wonder and NMR takeover of a field, in vivo spectroscopy (MRS)
dehght. It has changed its focus many times, moving has marched slower, clearing, as if by hand, small areas,
into new fields of applications where it has often become in contrast to the prairie fire engulfment sparked by
the method of choice. MRI. In part, the slow advance of MRS is relative, and
At first Blumbergen, Purcell, and Pound used NMR its practitioners have been at times embarrassed by its
to study nuclear spin relaxation, the very process whose slow climb into the sacred circle of medically useful
absence had interfered with Gorter's early attempts to techniques, techniques for which patients would be au­
observe the resonance. The physics of spins and their thorized to pay. Meetings addressing in vivo MRS, if
relaxation continues to excite researchers after half a not quite piggybacked upon an MRI event, would not
century, although it does not carry the startling novelty be held in fashionable hotels and in dazzlingly expensive
that I encountered when Ed Purcell spoke about NMR cities, but would, by themselves, have slogged away in
to the Physics Department at Columbia University in New England prep schools, otherwise abandoned for
1947. Chemical shifts and coupling discovered in the the summer. Poor but honest, those meetings would
early 1950s transformed chemistry, and plots of NMR have accommodated attempts to understand and de­
chemical papers versus time have increased super- scribe physiological processes in the body—localized to
linearly for more than 40 years. Biochemistry, geology, organs and basically studying normal events. At these
mineralogy, and enzymology have all been opened up obscure Gordon Conference type meetings, MRS practi­
further by the magic wand of the nuclear resonance tioners were rarely challenged by a question commonly
phenomena. Now, this book consolidates advances and confidently asked in the large ballrooms of expen­
made in the highly defended territories of in vivo struc­ sive hotels (where the challenged speaker has been try­
ture and activity. ing to follow his own slides of metabolic pathways, be­
Two decades ago the first NMR experiments re­ cause of the oblique angle they make from the offcenter
vealed the potential in vivo importance of spectroscopy speaker's podium, attached as he/she is to an immov­
and imaging. Since then, while magnetic resonance able microphone and a technical laser pointer), "When
xv
XVI Foreword
can w^e expect clinical reimbursement tor this proce­ formation available from cellular extracts to understand
dure?" At this point answers vary. Some speakers fall the control of flux. At present, molecular genetics has
into the trap and start apologizing for merely under­ reached a basic understanding of control when the end
standing or discovering some natural event. Others point of a pathway of gene expression is phosphoryl­
strain, extrapolate, and optimistically predict a certain ation of a protein. However, studies by in vivo NMR
number of years. Rarely does the speaker bite the bullet have shown that enzyme phosphorylation in the well-
and throw the question back with a query as to whether understood glycolytic pathways, and in the gluconeo­
increased medical charges should be the goal of bio­ genic pathways, does not occur at control points but
medical research. instead occurs further down the pathway. The enzymes,
In the present volume Bob Gillies has collected re­ phosphofructokinase and glycogen synthase, both long
ports from an excellent group of in vivo MRS practi­ considered to be the control points, are phosphorylated
tioners who have directed their efforts toward testing and dephosphorylated, in synchrony with flux changes;
hypotheses in order to obtain basic physiological and however, they are responding to controlled changes in
biochemical information. The present volume, while flux, not controlling those changes.
giving the opportunity to view the state of the field and This leads to the need, in the near future, for a more
its accomplishments, encourages us to consider the quantitative conceptual understanding of control that
larger question: "What do we see as the future of the will guide the difficult experiments needed to provide
physiologically oriented research described by its elo­ quantitative answers. Fortunately, such a theoretical
quent contributors?" framework exists in the little appreciated work on con­
Without retreating from the position that advances trol theory developed primarily by Kacser. He defined a
in basic understanding are the basis of future medical control coefficient for an enzyme in a pathway as the
applications, this particular discussion can describe, sep­ fractional change in flux per fractional change in en­
arately, the immediate consequences for science and zyme activity. A value of unity means the enzyme is the
medicine. For the basic sciences it is my expectation that controlling step, in accordance with existing qualitative
in vivo NMR will reawaken excitement in intermediary ideas. However, values less than unity for different steps
metabolism and systemic physiology. These were the in the pathway will show the contribution of these steps.
main areas of interest in biochemistry and physiology Do we really need to understand the control of flux
until approximately three decades ago, when they began in a pathway any more quantitatively than we do? My
to be replaced by interest in molecular genetics and bio­ answer is that such control is needed as a basis for future
physics. The information becoming available from in knowledge and for efficient medical applications. Cer­
vivo NMR will begin to revitalize these fields by raising tainly medical diagnosis and treatment desperately
the possibilities of understanding the control of meta­ need such knowledge. Does pH really slow down gly­
bolic fluxes in vivo. In biochemistry, classical extraction colysis in vivo} Are tumors acidic? Does this have conse­
methods, combined with isotopic labels, discovered a quences for tumor metabolism? What are the mecha­
panoply of control mechanisms which could exist in nisms of insulin control of glucose metabolism and how
vivo, Allosteric control, gene expression, covalent phos­ are they imposed in diabetes? How does exercise inter­
phorylations, compartmentation, and product inhibi­ act with insulin in the control of glucose metabolism?
tion are some of the well-established control mecha­ What are the energetic consequences of hypoxia versus
nisms. Faced with such a great variety of possible ischemia in heart or brain? How do these perturbations
controls, often with several possibilities established for a of the pathways increase rates of irreversible damage?
particular pathway, pre-NMR research in the field did In short, in vivo NMR studies of metabolism offer
not uniquely determine the actual control mechanism. the prospect of reviving scientific interest in the control
As a result, controlling steps in pathways are pictured of pathways, since the method can provide results that
with various arrows, products, and conditions such as will answer these important questions more exactly than
pH and energy status, all of which are described as exer­ previously possible.
cising control. All this is pictured, seemingly, without When we turn to the second area, that is, direct
the realization that the plurality of controls implies un­ medical applications from the study of patients, we of­
certainty about the actual quantitative control. To es­ ten find that more conceptual advances are needed.
tablish the actual nature of the control of flux through a NMR has established a niche for its usefulness in deal­
pathway it is necessary to have the kind of information ing with diseases affecting energetics. Certainly, ad­
that is now available from in vivo NMR. In vivo deter­ vances in understanding the recovery of brain, heart,
minations of pH, flux, futile cycling, energy status, con­ and kidney after ischemia will profit from future in vivo
centrations of allosteric effectors, and metabolites must measurements which should help evaluate therapy. Dis­
be made simultaneously in combination with all the in­ eases of metabolic impairment, such as diabetes, will
Foreword XVll
continue to be studied by in vivo NMR with advances in how studies of brain metabolism have lately become
understanding and treatment. Energetic states during refocused as a result of independent NMR advances in
exercise and sports can be evaluated by in vivo NMR in functional MRI and of input from PET studies. For
unique ways. In all of these conditions in vivo NMR some years, it has been a concern to those making MRS
spectroscopy will continue to build on existing under­ measurements of brain metabolism by developing meth­
standing and should, in favorable cases, lead to paradig­ ods for measuring CMRO2 and CMR glucose, that the
matic changes. energy supply, described by these parameters, was very
There are different problems raised by diseases remote from the actual brain work of neuronal dis­
where our present understanding has not yet led to charge. Happily, these two directions are being brought
a means of incorporating MRS results. Energetic and together by the discovery of functional MRI, which now
metabolic diseases have profited more from the many in allows metabolic measurements to be located accurately
vivo MRS studies than have tumors, strokes, Alz­ in the functional regions. This leads to the near future
heimers, AIDS, dementia, and MS. In general, these possibility of resolving questions raised by PET studies
studies, particularly Ή MRS, have taken the approach about the energetic requirements of the human visual
of looking for phenomenological differences between cortex during visual stimulation. This fusion of local­
normal and diseased tissue with the hope of finding di­ ized, functional MRI and MRS promises that many
agnostic information. What then is their future? A sug­ questions about the magnitude of brain energy require­
gestion can be made, following a 1991 summary plenary ments during activation, and the mechanism by which
talk at SMRM by my colleague Doug Rothman. Given this energy is supplied, will soon be answered.
the sudden abundance of novel information obtained by Hence, even in the most recalcitrant directions
Ή and NMR of these brain disorders, and the rela­ where progress is slow and biomedical relevance seems
tively slow progress being made fitting these data into far away, the plenitude of quantitative, reliable NMR
the existing knowledge, perhaps in the future we would data, otherwise unobtainable, having helped create such
be better served by taking a more research-oriented ap­ strong progress in many cases encourages us to expect
proach. Scientists could use these NMR measurements that MRS is helping to create the biochemistry, physiol­
in conjunction with appropriate animal and cellular ogy, and medicine of the future.
models, as well as other noninvasive methods, to extend
our understanding of the disease process. I cannot pre­ Robert Shulman
dict these new directions, but I can give the example of Yale University
Preface
This is an exciting time to be associated with the new windows on old problems. Thus, a major aim of
field of in vivo biological magnetic resonance. The past this book is to introduce nuclear magnetic resonance
decade has been one of tremendous expansion, both in methods and apphcations to the working physiologist.
terms of the numbers of researchers in the field and in The chapters of this book have been written at a level
terms of the diverse applications of this powerful tech­ that should be accessible to all researchers, regardless of
nique. In previous years, this technology has always their area of expertise. To maintain the timeliness of this
been one of "promise," wherein most research efforts book, current capabilities and future directions have
were expended in proving principles and not in discov­ been emphasized, at the expense of historical review.
ering new biological concepts or biomedical applica­ Such a book comes into being only through the ef­
tions. The articles in this book prove, without a doubt, forts of many people. First, I must thank Bob Shulman,
that the promise of this technology is being fulfilled. for readily agreeing to write the foreword and helping
The purpose of this book is twofold. First, it aims to me in every way possible during my career. Second, I
comprehensively review the entire field of in vivo biolog­ thank Joe Hoffman. Although he may not know it, this
ical magnetic resonance. Because the field is expanding book would never have gotten off the ground without
at a rapid rate, such a book is timely and needed. There­ his initial efforts and foresight. Third, I thank my wife,
fore, it should serve to update and expand the working Christine, and my daughters, Julia and Jessica, for those
knowledge of practicing researchers in in vivo biological hours I spent with my computer and not with them.
magnetic resonance. Second, and equally important, the Finally, this book is dedicated to my mother, Joyce, and
applications of biological NMR are making inroads into to the memory of my father, Hugh William Gillies, who
areas that are historically the bailiwick of physiologists: lived with diabetes for over 50 years.
for example, cardiac physiology, neurophysiology, renal
physiology, microcirculation, cellular physiology, he­ Robert J. Gillies
patic physiology, and others. These applications provide Tucson, Arizona
xix
£ Raymond Andrew
Introduction to
Nuclear Magnetic
Resonance
I. INTRODUCTION from the interaction between atomic nuclei, as found in
all forms of matter, and a magnetic field. This interac­
Nuclear magnetic resonance (NMR) is a remark­ tion is not a strong one; compared with many other
ably versatile phenomenon. Discovered in 1946 (Bloch, areas of physics NMR signals are relatively weak and
Hansen, and Packard, 1946, Purcell, Torrey, and Pound, must be sought delicately and husbanded with care.
1946) it was initially important in physics but soon also However, this relative weakness of NMR is also a
became an essential analytical and structural technique source of its strength, enabling NMR to probe materials
in chemistry. It swept across the disciplines to biochem­ and living systems without significantly disturbing them
istry and physiology and on to medicine where it is now and thus yielding detailed information in a noninvasive
firmly established as a standard modality of diagnostic manner.
investigation and research. There have been applications Our starting point therefore is the atomic nucleus.
in fields as diverse as archeology, oil prospecting, and
veterinary science; few areas of scientific endeavor re­
main untouched by NMR. In this chapter we provide an II. MAGNETIC PROPERTIES
introduction to NMR, in the context of physiology and OF ATOMIC NUCLEI
medicine, particularly for those readers with little pre­
vious acquaintance with the subject. For further discus­ Many atomic nuclei possess an intrinsic angular
sion of basic principles of NMR the reader is referred to momentum or spin. The largest measurable component
Harris (1983), Slichter (1990), Abragam (1961), and of this angular momentum is M, where / is called the
Ernst, Bodenhausen, and Wokaun (1987) in order of nuclear spin number and h is the natural unit of angular
increasing difficulty. momentum, given by ^/Ιττ, where h is Planck's con­
NMR may be regarded as a branch of spectroscopy, stant.
though not all its applications are strictly spectroscopic, The principal constituents of atomic nuclei are pro­
operating in the radiofrequency region of the electro­ tons and neutrons, collectively nucleons. Protons and
magnetic spectrum broadly from 0 to 10^ Hz. It arises neutrons have almost the same mass, so the number of
NMR in Physiology and Biomedicine
Copyright © 1994 by Academic Press, Inc. All rights of reproduction in any form reserved.