Quantitative MRI of the Brain: Measuring Changes Caused by Disease

Quantitative MRI of the Brain: Measuring Changes Caused by Disease

by Paul Tofts (Editor)


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Product Details

ISBN-13: 9780470847213
Publisher: Wiley
Publication date: 10/03/2003
Pages: 650
Product dimensions: 7.70(w) x 10.02(h) x 1.69(d)

About the Author

Professor Paul Tofts has worked on the physical aspects of quantitative brain imaging since the early days of clinical NMR. He was the first to measure in-vivo concentrations of metabolites, and to use dynamic imaging to measure blood-brain barrier permeability and extra-cellular space in multiple sclerosis.

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Quantitative MRI of the Brain

Measuring Changes Caused by Disease

John Wiley & Sons

Copyright © 2003

Paul Tofts
All right reserved.

ISBN: 0-470-84721-2

Chapter One


1.1.1 Measurement Science and MRI
Come Together

Measurement science has been around a long time;
MRI has been around for about 20 years. This
book is about the blending of the two paradigms.

We have come to expect to be able to measure
certain quantities with great accuracy, precision
and convenience. Instruments for mass, length and
time are all conveniently available, and we expect
the results to be reproducible when measured
again, and also to be comparable with measurements
made by others in other locations. In the
human body we expect to measure some parameters
(height, weight, blood pressure) ourselves,
recognizing that some of these parameters may
have genuine biological variation with time. More
invasive measurements (e.g. blood alcohol level
or blood sugar level) are also expected to have a
well-defined normal range, and to be reproducible.
In physics, chemistry, electrical engineering and
manufacturing there is a strong tradition of measurement,
international agreements on standards,
and training courses for laboratory practitioners.
International standards of mass, length and time
have been in existencefor many years. Secondary
standards have been produced which can be traced
back to the primary standards. National and international
bodies provide coordination.

As individual scientists we may have a passionate
desire to use our talents for the benefit of
mankind, preferring to devote our energy to finding
better ways of helping our fellow humans to
be healthy than to improving weapons for their
destruction. In this context, developing measurement
techniques in MRI constitutes a perfect application
of traditional scientific skills to a modern

MRI is now widespread, and accepted as the
imaging method of choice for the brain (and
for many body studies). It is generally used in
a qualitative way, with a radiologist interpreting
(reporting) film hardcopy on a light box. Many
MRI machines now have independent workstations
connected to the scanner and the database of MR
images, which enable and encourage simple quantitative
analysis of the images in their numerical
(i.e. digital) form. However the data collection procedure
often prevents proper quantification being
carried out; machine parameters such as transmitter
gain, flip angle value (and its spatial variation),
receiver gain and image scaling may all be acceptable
for qualitative analysis, but cause irreversible
confusion in images to be quantified. Researchers
may be unaware of good practice in quantification,
and collect or analyse data in an unsuitable way,
even though the MRI machine is capable of more.

The process of quantifying, or measuring,
parameters in the brain necessarily takes more
time and effort than a straightforward qualitative
study. More MRI scanner time is needed, and
considerable physics development effort and
computing resources may be needed to set up
the procedure. In addition, analysis can be very
time-consuming, and support of the procedure is
required to measure and maintain its reliability
over time. Procedures have to be found which
are insensitive to operator influence (whether in
the data collection or image analysis) and to
scanner imperfections (such as radiofrequency
nonuniformity from a particular head coil), which
provide good coverage of the brain in a reasonable
time, and which are stable over study times which
may extend to decades.

The benefits of quantification are that fundamental
research into biological changes in disease,
and their response to potential treatments, can proceed
in a more satisfactory way. Problems of bias,
reproducibility and interpretation are substantially
reduced. MRI can move from a process of picture-taking,
where reports are made on the basis of
unusually bright, dark, small or large objects, to
a process of measurement, in the tradition of scientific
instrumentation, where a whole range of
quantities can be tested to see whether they lie
in a normal range, and whether they have changed
from the time of a previous examination.

In this book, the intention is to merge these
two traditions, or paradigms, of measurement and
of MRI to form the field of quantitative MRI, or
qMRI. The MRI measurement process is analysed,
often in great detail. Limits to accuracy and precision
are identified as far as possible, with the intention
of identifying methods that are reliable and yet
practical in a clinical MRI scanning environment.
The biological meaning of the many MR parameters
that are available is explored, and many clinical
examples are given where MR parameters are
altered in disease. Often these changes have been
observed qualitatively, and they serve to encourage
us to improve the measurement techniques,
in order that more subtle effects of disease can
be seen earlier than is currently possible, and in
tissue that is currently thought to be normal as
judged by conventional MRI. The ideal is to obtain
push-button (turnkey) techniques for each of the
many MR parameters in this book, such that an
MRI radiographer (technologist) can measure each
of these parameters reliably and reproducibly with
a minimum of human training or intervention, in
the same way that we can currently step onto a
weighing machine and obtain a digital readout of
our mass. In the case of qMR the output would
be considerably richer, perhaps showing images of
abnormal areas (computed from large databases of
normal image datasets), changes from a previous
MRI exam, possible interpretations (diagnoses),
and an indication of certainty for each piece of
information. The advances in the pre-scan and the
spectroscopy MR procedures, which used to be
very time-consuming and operator-dependent and
are now available as fully automated options, show
how this might be possible.

Thus MRI may be undergoing a paradigm shift
in how it is viewed and used. In the past it was
used for forming qualitative images (the 'happy-snappy
MRI camera', taking pictures); in the future
it may be increasingly used as a scientific instrument
to make measurements of clinically relevant
quantities. The dichotomy can be seen in
this book. Clinical descriptions will often speak of
signal hyperintensity in a sequence with a particular
weighting, whilst elsewhere (idealized) physical
measurement methods are described, with talk
of localized concentration values, normal ranges,
age and gender effects, and reproducibility. As
measurement becomes more precise, and analysis
enables clinically relevant information to be
extracted from myriad information, it will become
possible in principle to make measurements on an
individual patient to characterize the state of their
tissue, guiding the choice of treatment and measuring
its effect. The issues involved in bringing
qMR into the radiological clinic are well summarized
in an Editorial in the American Journal of
(McGowan, 2001).

As part of this ongoing paradigm shift, our
view of what MRI can tell us is changing.
When it started, information was largely anatomical
(anatomical MRI), in the sense that relatively
large structures would be observed. Changes in
their geometric characteristics (usually size), compared
with normal subjects or a scan carried out in
previous weeks or months, would be noted. Quantitative
examples would be volume and atrophy.
Functional MRI (fMRI) claimed the complementary
ground, studying short-term changes in tissue
arising from carrying out particular (neural)
functions. Micro-structural MRI occupies a third
role, as shown in this book. Many MR parameters
[such as diffusion, magnetization transfer ratio
(MTR), spectroscopy] show structural changes in
tissue arising from damage caused by disease.
To observe these changes directly would require
imaging resolution of the order of 1-100 µm,
since they generally involve a variety of biological
changes at the cellular level. These can
be observed by pathologists in post-mortem tissue,
using optical or electron microscopy and
special staining techniques (histopathology). This
resolution is much finer than the spatial resolution
of MRI (which is about 1 mm). However
changes at the microscopic level (e.g. in cellular
structure) give changes in the MR parameters
(e.g. in water diffusion); these can be
observed at coarser spatial resolution (of about
1 mm). Thus structural changes of sizes well
below those that would be called anatomical
can be detected. In addition, the concentrations
of chemical compounds (metabolites) in cells,
and their changes, can be measured with spectroscopy.
The physiological permeability of the
endothelial membrane around blood vessels can
be measured using dynamic imaging of gadolinium
(Gd)-contrast agent. These micro-structural
changes are generally more quantitative than fMRI
in terms of their reproducibility and how well
we can relate them to underlying physiological

These changes may occur both in a 'lesion',
which is tissue seen at post-mortem and in conventional
MRI to be visibly different from the
surrounding tissue, and in the 'normal-appearing'
tissue, which appears normal at post-mortem and
in conventional MRI. Lesions are usually described
as 'focal', meaning that the change is localized to
a relatively small area (a few mm or cm) with
a distinct boundary; thus its different brightness
in an image distinguishes it from the surrounding
tissue (considered normal). In contrast, a diffuse
change may extend over more area, has no distinct
boundary, and is harder to detect by simple visual
observation of the image. Diffuse changes are often
well characterized by quantification, since it is the
absolute value of quantities within the area that is
measured, without reference to surrounding tissue,
or the need for a distinct boundary.

1.1.2 Limits to Progress

It may appear that qMR research proceeds under its
own impetus. However the current state and rate of
progress in developing reliable qMR methodology
are determined by several factors: MRI manufacturers,
research institutions, pharmaceutical companies,
computer technology and publicly funded
research councils.

MRI machine manufacturers (vendors) will take
on some of the measurement procedures over time,
incorporating them into their research and development
programmes, and then offering themas turnkey
(push-button) products. The speed of this process
is driven by demand from clinical purchasers, by
whether competing manufacturers offer such facilities,
and by whether public medical funding bodies
such as the US Food and Drugs Administration
(FDA) is likely to approve reimbursement of the
cost of such procedures from medical insurance policies.
The existence of a large and growing installed
base of high-quality, reliable and ever improving
MRI machines, primarily designed for routine clinical
use, largely in environments where they can be
run as parts of profitable businesses, has enabled and
encouraged the development on these machines of
qMR techniques, which are still of interest to only a
minority of users.

Research institutions have particular structural
strengths and weaknesses. Brain qMR needs input
from chemists, computer scientists, neurologists,
physicists, radiologists and statisticians. There may
be good career support for those applying methods
to study clinical problems, but none for those
basic scientists inventing and developing the methods.
There may be a clash of paradigms or traditions
between those who have been educated
in a hierarchical environment where asking questions
is considered to be irrelevant or subversive,
and those who consider asking questions to be
an absolute basic necessity of undertaking modern
high-quality scientific research. The availability of
talented researchers in turn depends on how much
value is placed on science in society, schools and
universities, and whether appropriate postgraduate
training opportunities exist. The International Society
for Magnetic Resonance in Medicine (ISMRM)
is a powerful force bringing together researchers
from different institutions who are working on similar
methodologies, through both its journals and
its scientific meetings.

The demand from pharmaceutical companies
and neurologists for qMR measurements to be used
in drug trials is large and likely to increase (Miller,
2002; Filippi and Grossman, 2002; Filippi et al.,
2002; McFarland et al., 2002). The traditional
double-blind placebo-controlled phase III trial
involves many patients (typically 100-1000), who
are studied for several years in order to obtain
enough statistical power to determine whether a
drug is effective. The large sample size is needed
to deal with the variability of disease in the absence
of treatment, and the imperfect treatment effect
(which may vary according to patient subgroup).
Such trials typically cost several US$100 million.
qMR can potentially make more efficient
use of such financial investments by shortening
the duration of such trials, by identifying treatment
failures early on in the testing process and
by allowing the use of smaller sample sizes. If
there is no observed biological effect from the
treatment, it may be considered unlikely that the
drug is working (this will depend on the particular
way the drug has been postulated to act).
For example, if a potential treatment for multiple
sclerosis (MS) showed no effect on all the
MR measures that are known to be abnormal in
MS, it would probably be dropped in favour of
other drugs. With new biotechnology and gene-based
treatments being developed, the number of
candidate drugs for evaluation will increase by a
large factor, and traditional trials will become too
expensive and slow to evaluate all of them. Thus
direct in vivo qMR observation of treatment effect
will become increasingly valued.

The rapid increase in power and availability
of computing technology has also been key
in enabling data acquisition and image analysis
techniques to be realized. Numerically designed
magnets, coils and radiofrequency pulses, digital
receivers and rapid image registration and analysis
have all changed the way that MRI is carried

The resources available from pharmaceutical
companies to drive the process of developing
and supporting reliable qMR measures may
exceed those available from traditional publicly
funded research sources. Traditional research
council sources have been willing to support
the application of qMR methods to study
particular diseases, but often unwilling to support
the development of new quantitative methods,
sometimes claiming that MRI manufacturers
should be doing this.

1.1.3 Using this Book

This book can be used in many ways. Those interested
in each MR parameter can read each chapter
in turn. Physicists will be more interested in the
details on how to implement measurement techniques
for that parameter, and what can go wrong
in a practical situation.


Excerpted from Quantitative MRI of the Brain

Copyright © 2003 by Paul Tofts.
Excerpted by permission.
All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.
Excerpts are provided by Dial-A-Book Inc. solely for the personal use of visitors to this web site.

Table of Contents

List of Contributors
List of Reviewers
Section 1: the measurement process
Concepts in Quantification (Paul Tofts)
Section 2: pandora's box of MR parameters PD (Paul Tofts)
T1 (Penny Gowland, Val Stevenson)
T2 (Phil Boulby, Fergus)
Blood vessel permeability (Geoff Parker, Anwar Padhani)
Diffusion (Claudia Wheeler-Kingshott, Gareth Barker, Mark van Buchem & Stefan Steens
Magnetisation transfer (Paul Tofts, Stefan Steens, Mark van Buchem)
Spectroscopy (Paul Tofts, Adam Waldman)
BOLD fMRI (Peter Jezzard, Nick Ramsay)
Perfusion and blood volume using bolus-tracking (Richard Kennan et al)
Perfusion using spin labelling (Laura Parkes, John Detre)
Section 3: the biology
Biological meaning of MR parameters (Bruno Brochet, Klaus Petry, Vincent Dousset)
Section 4: analysing images
Image registration (John Ashburner, Tina Good (Catriona))
Volume and Atrophy (Geoff Parker, Declan Chard)
Histograms (Jamshid Dehmeshki, Gerard Davies, Paul Tofts)
Image analysis - shape and texture (Bill Crum)
Section 5; where are we going?
The future (Paul Tofts)
Appendix 1 - Greek Alphabet
Appendix 2 - Contributors and reviewers

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