Download Magnetic Resonance Imaging and Spectroscopy

Chapter 10 (pp 139-167) of Multiple Sclerosis 2 - Blue Books of Practical Neurology, vol. 27. J.H Noseworthy, W.I. McDonald (eds.). Elsevier Science (USA), 2003.
Magnetic Resonance Imaging and Spectroscopy: Insights into the Pathology and
Pathophysiology of Multiple Sclerosis.
Zografos Caramanos†, A. Carlos Santos†*, and Douglas L. Arnold†
†
Magnetic Resonance Spectroscopy Unit, Montreal Neurological Institute, McGill University, Montreal, Canada
* Department of Clinical Medicine Imaging Center, Ribeirao Preto Medical School, University of Sao Paulo, Brazil
1.
INTRODUCTION
Since the time that Ormerod, du Boulay, and McDonald wrote
their chapter on the neuroimaging of multiple sclerosis (MS ) for the
first edition of this volume1, continuing advances in the field of
magnetic resonance (MR) and MR imaging (MRI) have made
tremendous impacts in our understanding of this disease2. Over the
last few years, findings from (i) “conventional” MRI techniques
[e.g., T 2-weighted imaging, proton-density-weighted imaging, and
T 1-weighted imaging] – as well as those from (ii) more-recently
developed “non-conventional” MRI techniques [e.g.,
magnetization-transfer imaging (MTI), diffusion-weighted imaging
(DWI), diffusion-tensor imaging (DTI), proton magnetic resonance
spectroscopy (1H-MRS ), and functional MRI (fMRI)] and (iii)
MRI-based estimates of brain and spinal cord atrophy – have
converged with findings from other areas of MS research (e.g.,
histopathological and clinical research) in order to give us a more
comprehensive picture of MS pathology and pathophysiology.
Given that a number of excellent reviews have been written on this
topic in recent years3-9, the purpose of the present chapter is to
describe some of the MRI techniques that are most-commonly used
in the study of MS and to summarize some of the main aspects of
our MRI-based understanding of MS. First, however, we will
briefly review some of the relevant aspects of our current
understanding of the pathology and pathophysiology of MS.
1.1. THE PATHOLOGY AND PATHOPHYSIOLOGY OF MULTIPLE
S CLEROSIS
The pathological hallmark of MS is the presence of
demyelinating lesions (also referred to as MS plaques) within the
central nervous system (CNS ) that are disseminated in both space
and time10. Acute and sub-acute plaques are associated with acute
inflammation and myelin breakdown. Chronic plaques are welldemarcated areas within the white matter that are hypocellular and
characterized by myelin loss and astrocytic scar-formation11.
Although usually described as being “relatively spared,” axons are
injured and their density is decreased in both these types of
demyelinating lesions.
The overt, symptomatic “attacks” of MS that signal the usual
initial “relapsing-remitting” (RR) stage of the disease are generally
attributed to focal inflammation, which is associated with axonal
injury and demyelination that result in slowing and/or blockade of
axonal conduction. Conversely, the remission of symptoms during
this stage is generally attributed to a combination of (i) the
resolution of inflammation, (ii) the insertion of new sodium
channels across demyelinated segments of axons, and (iii) the
remyelination of axons. The majority of patients will eventually
enter a “secondary-progressive” (S P) stage of the disease in which
there is progressive neurological disability that is speculated to
result from (i) the eventual failure of remyelination, (ii) gliosis, and
(iii) irreversible axonal injury and degeneration. Indeed, as reviewed
by Rieckmann and Smith12 and by Bjartmar and Trapp13, MS is no
longer viewed as simply being a disease of inflammation and
demyelination of the white matter: rather, axonal degeneration and
neuronal damage throughout the brain are now accepted as being
prominent features of MS – even early on in the disease.
1.2. S OME RECENT MRI-BASED INSIGHTS INTO MULTIPLE
S CLEROSIS
As we will soon see, insights into the pathology and
pathophysiology of MS have been greatly advanced by information
obtained using MRI. For example, it is now evident that the socalled “normal-appearing” white matter (NAWM, i.e., white matter
that appears normal on gross pathological examination or on
conventional MRI) in patients with MS is, in fact, far from normal;
this is true both on appropriate histological analysis 14; 15, as well as
on non-conventional MRI measures including MTI16, DWI17,
DTI18, and 1H-MRS19; 20. Indeed, further changes in patients’
NAWM may become visible on these measures months – if not
years – before the lesions associated with their MS become
detectable on conventional MRI: this is true for MTI21, DWI22, and
1
H-MRS23; 24.
In addition to this pathology of NAWM, there is now growing
evidence for a significant involvement of the normal-appearing grey
matter (NAGM) of the cerebral cortex in MS. Again, this is true
both on histological analysis 25; 26, as well as on non-conventional
MRI measures including MTI16; 27; 28, DWI29, and 1H-MRS30; 31.
Furthermore, there is now evidence from fMRI for adaptive cortical
reorganization in patients with MS in the absence of neurological
impairment: a finding which suggests that the extent of corticofunctional pathology is greater than that which is manifest
clinically 20; 32-34. Finally, there is also now MRI-based evidence that
brain and spinal cord atrophy (which reflect destructive, irreversible
pathology) are common – even early on in the course of the
disease35.
Page 1 of 18
Of course, all of these aforementioned MR measures that have
contributed to our increased understanding of MS are only surrogate
markers for different aspects of the pathological changes that
accompany the disease. In order to better appreciate what changes
in these MR surrogates mean, we will now review some of the MR
techniques that are currently being used to study MS – first the
conventional ones and then the non-conventional ones. We will then
go on to review some of the findings regarding MRI-based analyses
of cerebral atrophy in patients with MS.
2.
CONVENTIONAL MAGNETIC RESONANCE IMAGING
TECHNIQUES
The conventional MRI techniques used to study MS patients
produce images that reflect the physico-chemical state of protons
that are present mainly in the water in the tissue that is being
imaged. Contrast in such images is derived primarily from tissuespecific differences in the relaxation times, T1 (i.e., the time
constant for the recovery of magnetization in the direction of the
magnetic field) and T2 (i.e., the time constant for the decay of
magnetization in the plane perpendicular to the magnetic field). (For
a review of MRI theory and applications see Gadian36).
These conventional MRI techniques include (i) T 2-weighted
imaging, (ii) proton-density-weighted imaging, (iii) fluid-attenuated
inversion-recovery imaging, (iv) standard T 1-weighted imaging, and
(v) gadolinium-enhanced T 1-weighted imaging – each of which is
described below. Figure 10-1 presents examples of images obtained
using these techniques in patients with MS.
2.1. T2-WEIGHTED IMAGING
MR images are T 2-weighted by allowing more time for signal
decay to occur due to T 2 relaxation during a relatively-long echo
time (TE). Signals from water protons located in tissues associated
with longer T 2 values decay less during a long TE; because of this,
such tissues appear hyperintense on T 2-weighted images relative to
tissues with shorter T 2 values.
T 2 is prolonged in most pathologies that are associated with (i)
inflammatory edema or tissue destruction (i.e., pathologies that
increase bulk water that has less interaction with macromolecules)
or (ii) gliosis in the white matter of the brain. For these reasons, MS
lesions are hyperintense on T 2-weighted scans both in the early
stages of the disease (i.e., when inflammation is most prominent) as
well as in the later stages of the disease (i.e., when tissue injury and
gliosis are more prominent).
2.1.1. T2-Weighted Imaging of Multiple Sclerosis
Consistent with well-known pathological observations, the T 2weighted MR appearance of MS (see Figure 10-1) is primarily one
of multiple, hyperintense white-matter lesions with periventricular
predominance37. (See Narayanan et al38 for an example of the
probabilistic mapping of MS lesions). Because of their exquisite
sensitivity to subtle changes in water, T 2-weighted hyperintensities
can even identify regions of brain tissue that appear normal on gross
pathology and that are only associated with a very subtle
infiltration of inflammatory cells 39.
2.1.1.1. Evolution of T 2-Weighted Hyperintense Lesions
New lesions that are seen on T 2-weighted imaging [or on
proton-density-weighted imaging (see below)] have a characteristic
evolution40. Typically, they reach a maximum size in approximately
four weeks, decrease in size over the next six to eight weeks, and
leave a residual T 2-weighted abnormality37 that is a permanent
record of tissue injury 5. For this reason, the total lesion volume that
can be measured on such scans is often used as a surrogate measure
of disease burden in MS. Furthermore, changes across time in the
number and volume of lesions that are visible on T 2-weighted
imaging can be used as indicators of disease activity and of response
to treatment. It should be noted, however, that such changes in
volume consist partly of inflammatory edema that eventually
resolves with an associated decrease in the volume of T 2-weighted
abnormality41.
2.1.1.2. Clinical Significance of T 2-Weighted Hyperintense Lesions
Although the relationship between T 2-weighted imaging
abnormalities and abnormal findings on histological examination is
strong37; 39, the correlation between total cerebral T 2-weighted lesion
load and clinical disability at any given time is only modest42; 43.
Nevertheless, the predictive value of T 2-weighted lesions for the
future development of clinically-definite MS is strong – particularly
over the long term. For example, Brex et al44 recently published the
latest results of an ongoing, longitudinal study that had, at that
point, followed a group of 71 patients for 14 years from the time of
their initial episode of presumed CNS-demyelination. They found
that clinically-definite MS eventually developed in 44 of the 50
patients with T 2-weighted lesions at presentation (but in only 4 of
21 patients that had presented with normal MRI). Furthermore, the
number and the volume of T 2-weighted lesions at baseline, as well
as the change in lesion volume over the first 5 years, correlated
significantly with the patients’ degree of long-term disability as
measured by the EDSS (i.e., Kurtzke’s Expanded Disability Status
Scale45). The latter correlations were, however, of only moderate
strength – suggesting that, on its own, T 2-weighted lesion data
cannot be used to make strong predictions about the prognosis in a
patient that is known to have MS.
The modest correlation seen between T 2-weighted lesion load
and concurrent clinical disability may be explained by several
factors: (i) the lack of pathological specificity of T 2-weighted
abnormality, (ii) the fact that neurological disability is not easy to
quantify and that the instruments used to do so (primarily the
EDSS) are limited in their scope (e.g., the EDSS is based primarily
on ambulatory ability), (iii) the fact that lesions in different CNS
locations would be expected to correlate differently with disabilities
in different spheres of CNS function (e.g., cerebral lesion-load is
only weakly related to the sensorimotor dysfunction that results
from spinal cord lesions – a dissociation that increases as the MS
disease process progresses 46), and (iv) the fact that lesions may not
be the only pathology responsible for disability, particularly late in
the disease when a neurodegenerative process may develop 13. The
correlation between T 2-weighted lesion volume and disability is also
weakened by (v) the potential of the brain to functionally adapt to
injury 20; 32-34 and (vi) the fact that focal lesions have diffuse
consequences 19; 38. Thus, it is not surprising that it has been difficult
to demonstrate a strong, direct effect of the localization of cerebral
Page 2 of 18
T 2-weighted lesions on specific EDSS-measured functional
impairments47. Nevertheless, there are examples of specific
functional deficits that have been shown to correlate with the T 2weighted lesion load that is present in the region of the CNS
associated with those particular functions (e.g., olfactory
function48, sustained complex-attention and verbal workingmemory 49, and visual function50).
Centrum Semiovale
T2-weighted image
PD-weighted image
T1-weighted image
Gd-enhanced image
PD-weighted image
T1-weighted image
Gd-enhanced image
Lateral Ventricles
T2-weighted image
Figure 10-1. Cross-sectional slices through the centrum semiovale (top) and the lateral ventricles of a patient with multiple sclerosis (MS) as
seen on T 2-weighted, proton-density-weighted (PD), T 1-weighted, and gadolinium-enhanced T 1-weighted images. Of note at the level of the
centrum semiovale: (i) many of the hyperintense lesions that can be seen on the T 2- and PD-weighted images are also seen as hypointensities
on the T 1-weighted images and (ii) two of these lesions are still active and inflammatory (as evidenced by the ring-like Gd-enhancement). Of
note at the level of the lateral ventricles: (i) it is difficult to discriminate between the periventricular lesions and cerebrospinal fluid (CSF) on
the T 2-weighted image, (ii) it is easy to discriminate between the periventricular lesions and the CSF on the PD-weighted image; (ii) the extent
of T 2- and PD-weighted hyperintensity is much more extensive than the hypointensities seen on the T 1-weighted images; and (iii) there are
no active, inflammatory lesions at this level (as evidenced by the lack of Gd-enhancement). (Images are courtesy of the Canadian MS/BMT
Study Group).
2.1.1.3. T2-Weighted Hypointensities
In addition to the T 2-weighted white-matter hyperintensities
that we have dealt with thus far, grey-matter hypointensity on T 2weighted imaging of patients with MS (which is thought to reflect
pathologic iron deposition and brain degeneration) has also been
described51 and shown to be related to clinical status52; 53 and
prognosis 54 in MS.
2.2. PROTON -DENSITY-WEIGHTED IMAGING
Because both lesions and cerebrospinal fluid (CSF) are
hyperintense on T 2-weighted images, the discrimination of
periventricular lesions can be difficult. One way of increasing this
discrimination is to acquire images with, so-called, “proton-density
weighting” 55. Such images do not actually reflect the density of
protons; they do, however, have intermediate T 1- (see below) and
Page 3 of 18
T 2-weightings that, as shown in Figure 10-1, result in the CSF
appearing dark (because its long T 1 value predominates over its long
T 2) and lesions appearing bright (because their long T 2 values
predominate over their relatively shorter T 1).
2.3. FLUID-ATTENUATED INVERSION -RECOVERY IMAGING
Another means of increasing contrast between CSF and lesions
is through the use of fluid-attenuated inversion-recovery (FLAIR)
images 55. This approach involves the use of an inversion pulse to
suppress the signal arising from bulk water in the CSF 56. FLAIR
images provide both (i) better discrimination between ventricular
CSF and the periventricular T 2-weighted-hyperintensities that are
associated with MS lesions and (ii) increased contrast for lesions –
particularly for those that are cortical or juxtacortical57.
2.4. T1-WEIGHTED IMAGING
T 1-weighted images are produced by shortening the TR (i.e., the
amount of time between successive repetitions of water-proton
excitation) and, thereby, allowing less time for water to regain its
equilibrium magnetization. Water protons in tissues with a
relatively short T 1 recover more quickly and produce more signal at
relatively-short TR than do those in tissues with a longer T 1.
Protons in bulk water (e.g., in CSF, or in tissue that is associated
with either extracellular edema or with a loss of structural integrity)
have a long T 1 and, as shown in Figure 10-1, appear hypointense on
T 1-weighted sequences.
T 1-weighted images are less sensitive to changes in either watercontent or gliosis than are T 2-weighted images. Nevertheless, acute,
inflammatory lesions can sometimes be associated with so much
edema that they can show substantial T 1-weighted hypointensity.
Chronic T 1-weighted hypointensities are, however, much more
specific indicators of tissue destruction than are T 2-weighted
hyperintensities 58-60. The term “black hole” has been used to
describe hypointense lesions on T 1-weighted images 61. Given the
fact, however, that this term is typically used to imply an
association with irreversible tissue destruction, use of the term is
probably best reserved for lesions that are chronically-hypointense
on T 1-weighted imaging. Only about 30% of new T 2-weighted
lesions will evolve into chronic black holes 62.
2.4.1. T1-Weighted Imaging of Multiple Sclerosis
Given the increased pathological specificity associated with T 1weighted hypointensity, it is not surprising that lesions that show
this feature on T 1-weighted imaging are more strongly correlated to
disability in MS than are lesions that are T 1-isointense43; 59; 61. In a
recent study, Cid et al63 examined the relationship between RR-MS
patients’ (i) degree of lesion hypointensity on T 1-weighted imaging
obtained at the time of an MS relapse, (ii) change in EDSS score
between the time of the relapse and one month later, and (iii)
amount of neuronal apoptosis induced on neuronal cultures by CSF
obtained at the time of the relapse. They found a strong relationship
between T 1-weighted lesion hypointensity and both (i) poor
recovery from relapse and (ii) the amount of neuronal apoptosis
induced by the CSF.
weighted imaging can be increased with the injection of a chelated
form of gadolinium (Gd), which interacts with water so as to
shorten its T 1 relaxation time. Normally, Gd does not cross the
blood-brain barrier (BBB). However, focal inflammation in the CNS
– as occurs during an MS attack – is often associated with an
“opening” of the BBB65. This opening allows Gd to pass through in
a manner that is graded depending upon (i) the extent of the
associated increase in BBB permeability, (ii) the dose of Gd
administered, and (iii) the interval between Gd-injection and T 1weighted MR acquisition (i.e., the time available for the Gd to leak
across the BBB)66; 67.
2.5.1. Gd-Enhanced T1-Weighted Imaging of Multiple
Sclerosis
The acute inflammatory process that was described above is
transient. As a result, Gd only causes MS lesions to enhance for
two to six weeks after they become detectable by conventional
MRI 66; 68. Thus, a useful role for Gd-enhanced T 1-weighted imaging
is to help distinguish recently-appearing, inflammatory lesions from
ones that are more chronic (and no longer associated with sufficient
inflammation to result in Gd enhancement). Indeed, MRI
assessment of disease activity in MS is often based upon the
number of Gd-enhancing lesions that are seen within a T 1-weighted
scan. The majority of enhancing lesions are “nodular,” but about
25% of lesions show “ring-like” enhancement 69. Such ring-enhancing
lesions are associated with a more-severe clinical outcome and it has
been suggested that they reflect a more-destructive pathology 70.
Most lesions that are Gd-enhancing on T 1-weighted images
continue to be detectable on T 2-weighted images after the acute
inflammation (and, thus, the Gd-enhancement) have resolved.
Conversely, it is generally believed that (i) most T 2-weighted
lesions in the central white matter of MS patients are associated
with an initial, variable period of Gd-enhancement on T 1-weighted
imaging and (ii) Gd-enhancing lesions and T 2-weighted lesions
represent two different stages of a single pathological process.
There is evidence, however, to suggest that some of the lesions on
T 2-weighted images can develop independently of Gdenhancement 71 – perhaps because of (i) ongoing low-grade
inflammation that is not detected with Gd-enhancement or (ii)
mechanisms other than inflammation that are responsible for
progression in some existing lesions.
2.5.1.1. Clinical Significance of Gd-Enhancement
About 50% of patients with MS will have at least one Gdenhancing lesion at any given time. Surprisingly, in what is referred
as the “clinico-radiological paradox,” a large proportion of these
lesions are not associated with clinical manifestations: indeed, on
average, Gd-enhancing lesions occur about ten times more
frequently than clinical relapses 3; 72; 73. Despite the striking
difference between the frequency of new Gd-enhancing lesions and
the frequency of clinical exacerbations, there is still, however, a
strong relationship between them74. Furthermore, the number of
enhancing lesions on a single scan is (i) predictive of subsequent
relapse-rate and (ii) is correlated with both subsequent enhancinglesion activity and change in T 2-weighted lesion load75.
2.5. GADOLINIUM-ENHANCED T1-WEIGHTED IMAGING
As reviewed by Rovaris and Filippi64, signal intensity on T 1-
Although the presence of one or more Gd-enhancing brain
Page 4 of 18
lesions is predictive of conversion to clinically definite MS76, Gdenhancement is not a strong predictor of the development of
cumulative impairment or EDSS-measured disability74. These
findings are consistent with the hypothesis that different
pathogenetic mechanisms may be responsible for (i) the occurrence
of relapses and (ii) the development of long-term disability.
MT(on)
MT(off)
with saturation pulse
B
A
3.
% MTr Image
without saturation pulse
B
A
[1-(MTon / MToff)] x 100
B
A
NON-CONVENTIONAL MAGNETIC RESONANCE
IMAGING TECHNIQUES
Even though the aforementioned conventional-MRI techniques
have allowed us to image MS lesions with much greater sensitivity,
these techniques are not capable of fully characterizing and
quantifying the extent of tissue damage in patients with MS. A
number of recently-developed MR techniques are better suited for
such a role. These techniques include: (i) MTI, (ii) DWI, (iii) DTI,
(iv) 1H-MRS, and (v) fMRI – each of which are, in turn, described
below.
Figure 10-2. Examples of T 1-weighted images obtained during a
magnetization transfer (MT) study of a patient with multiple
sclerosis. Images are obtained both with (Mton) and without
(MToff) the presence of a saturation pulse, and MT ratios are
calculated as shown. Note that the MToff image is just a
standard T 1-weighted image and MTR values are more reduced
in lesions that are more hypointense on this image (e.g.,
compare A and B). (Images are courtesy of Dr. G.B. Pike).
3.1. MAGNETIZATION -TRANSFER IMAGING
Protons associated with molecules that are large and less mobile
than water (e.g., the macromolecules that make up cell membranes)
have a very short T 2 and are not visible on conventional MRI; this
is because their signals decay completely before conventional MRI
data is acquired. The effect of these protons can, however, be
observed indirectly by the phenomenon of magnetization transfer
(MT)77. In MTI, appropriate radio-frequency pulses are applied to
selectively saturate the magnetization of the bound protons. This
saturated magnetization is then naturally exchanged with those
protons that are found in the relatively “mobile” protons of CSF,
extracellular water, and intracellular water (i.e., the protons that are
normally observed by MRI). This transfer of saturated
magnetization to the MRI-observable, free-water pool results in a
reduction of the signal intensity from the observable protons to a
degree that depends upon (i) the nature and density of the
macromolecules at a given location and (ii) their interaction with
bulk water. In the white matter of the CNS, the MT effect is
dominated by the large surface area of myelin, and changes in MT
are considered more specific for demyelination78; 79 than are changes
in either T 2 or T 1 relaxation times. It should be noted that MT is
also sensitive to changes in bulk water that are associated with
edema80-82 as well as to macromolecular changes associated with
injury to other cell types (e.g., axons60; 83). Thus, changes in MT
should not be considered pathologically specific.
An important advantage of MTI is that it can be easily
quantified by calculating the magnetization-transfer ratio (MTR),
which is the relative MRI signal intensity measured in the absence
of a saturating pulse compared to the intensity that is measured in
the presence of a saturating pulse (see Figure 10-2). A low MTR
indicates less exchange of magnetization between tissue
macromolecules and the surrounding water molecules.
3.1.1. MTI of Multiple Sclerosis
MTR values are typically reduced in MS lesions in a manner
that is consistent with the degree of T 1-weighted hypointensity60; 84;
85
, which, as we have seen, is related to tissue destruction; thus,
lesions that are larger and more destructive have lower MTR values
than lesions that are smaller and less destructive. Furthermore,
greater reductions in MTR values are seen in lesions that are more
inflammatory 86. In addition to the MTR changes observed in MS
lesions, numerous studies have also reported decreased MTR in the
NAWM of MS patients compared to the white matter of healthy
normal controls 21; 85; 87-89. Greater decreases in MTR are found in
patients with SP-MS than in patients with RR-MS90-92, and these
decreases are related to both increasing EDSS-measured disability43;
93
and increasing cognitive impairment 94.
3.1.1.1. Temporal Evolution of Lesions on MTI
Because MTI produces very reproducible MTR values for a
given pulse sequence, it can be used to quantify the pathological
evolution of MS lesions over time. Such longitudinal MTI studies
have shown that, even before the detection of lesions is possible on
proton-density- or T 2-weighted images, MTR values have begun to
decline in the NAWM that is found at these locations21; 95; 96. Then,
as lesions begin to demonstrate Gd-enhancement on T 1-weighted
imaging, there is an explosive decrease in the lesional MTR values
due to a combination of inflammatory edema and demyelination;
this may be followed by either (i) a stabilization of lesional MTR
values at these lower levels, (ii) a recovery of lesional MTR values
several weeks after the initial decrease, or, in a small number of
lesions, (iii) a continuing decrease in local MTR values 97-99. The
recovery of MTR or its continued decline may be related,
respectively, to remyelination or to chronic activity of lesions.
Thus, MTR provides a potentially powerful tool for exploring
lesion evolution in MS.
3.1.1.2. Clinical Significance of MTI
The fact that MTR focal abnormalities in NAWM develop
Page 5 of 18
before the appearance of lesions implies that MTI might provide
information that could predict the future evolution of MS. This has
led to the assessment of the predictive value of MTI in MS. For
example, the prognostic value of MTI was recently examined by
Santos et al100,who found that mean NAWM-MTR values were
able to successfully predict whether or not levels of disability
would increase at five-year follow-up in patients with relativelylong-standing MS; importantly, MTR values within these
individuals’ T 2-weighted lesions could not predict such changes. In
a related study of patients with a clinically-isolated syndrome
suggestive of MS, Iannucci et al101 found that MTR values at the
time of presentation were significant predictors of the development
of clinically-definite MS within the next 25-42 months (although
not as strong predictors as these patients’ presenting T 2-weighted
lesion volumes). On the other hand, Brex et al102 found that mean
NAWM-MTR values in a similar group of patients could not
predict whether these individuals would go on to have MS in the
following 12 months (at which point, these newly-diagnosed MS
patients still had normal NAWM-MTR). Thus, while it is clear that
MTI has prognostic value in MS, further studies are necessary to
better characterize its strengths and limitations.
As reviewed by Filippi and Inglese106, the pathology associated
with MS modifies the water self-diffusion characteristics in the
CNS by altering the geometry and/or the permeability of structural
barriers that are found therein. The application of DWI techniques
to the study of MS is appealing in that they can provide a
quantitative estimate of the degree of fiber disruption and, thus,
potentially provide information on the mechanisms that lead to
irreversible disability in this disease.
3.2.1. DWI of Multiple Sclerosis
DWI studies have consistently shown that the ADC107; 108 and
of water is (i) higher in MS lesions than in NAWM (see
D
Figure 10-3) and (ii) higher in acute lesions than in chronic lesions.
Such studies have also consistently demonstrated that mean D
values are increased in the NAWM of MS patients compared to
those observed in the white matter of healthy normal controls – a
finding that hold true in the brain17; 110; 111, the spinal cord112, and
the NAGM 16.
109
PD-Weighted Image
Mean Diffusivity Image
Fractional Anisotropy Image
3.1.1.3. MTI of Normal-Appearing Grey Matter
As mentioned in the introduction, there is now an increasing
appreciation that, at the microscopic level, there is substantial
lesional pathology of the NAGM in patients with MS25; 26. The
lesions in NAGM are associated with much less inflammation and
demyelination than are the lesions in the white matter26. Perhaps
related to this, as well as to their size and to their location (i.e.,
adjacent to CSF), these lesions in the NAGM are largely undetected
by current conventional MRI techniques. Thus, it is important that,
in addition to the MTI changes in the lesional and normal-appearing
white matter of patients with MS, reductions in MTR values have
also been found in the NAGM of patients with MS relative to
normal controls 16; 27; 28. Together, these findings suggest that the
pathological process that is at work in the brains of patients with
MS is very diffuse and is not tissue-specific.
3.2. DIFFUSION -WEIGHTED IMAGING
As reviewed by Cercignani and Horsfield103, DWI allows for the
in vivo measurement of the diffusion of water in the CNS due to
Brownian motion. Because both the axolemma and the myelin
sheath restrict water diffusion in nerve fibers104, pathological
processes (such as those at work in MS) that modify the integrity
of such tissues can result in a loss of restricting barriers and,
thereby, increase the so-called “apparent diffusion coefficient”
(ADC) of water.
The ADC is a measure of the random displacement of water
molecules in a particular direction. Because of the restricting entities
that are found in biological tissues, ADC values in the CNS are
lower than the diffusion coefficient of pure water (hence the term
“apparent diffusion coefficient of water”). A measure of diffusion
that is independent of the orientation of structures is provided by
the mean diffusivity index, D . Also referred to as the directionallyaveraged ADC (or ADCavg) or trace, D is the average of the ADCs
measured in three orthogonal directions. (For a review of DWI
theory and applications see, for example, Schaefer et al105).
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**
Figure 10-3. Cross-sectional slices through the lateral ventricles
of a patient with multiple sclerosis as seen on proton-densityweighted (PD), diffusion-weighted, and diffusion-tensor
imaging (which is reviewed in the next section). The asterisks
point out the lesions that are seen as (i) hyperintensities on
PD-weighted imaging, (ii) increased mean diffusivity ( D )
values on diffusion-weighted imaging, and (iii) decreased
fractional anisotropy (FA) values on diffusion-tensor imaging.
(Images are courtesy of J.S.W. Campbell).
D values have been shown to correlate with individual MS
patients’ EDSS scores 113-116 and disease durations114-116.
Furthermore, D values are higher in patients with SP-MS than in
those with RR-MS116; 117. Increases in lesional D values correlate
with hypointensity on T 1-weighted images 116, and ring-enhancing
lesions on Gd-enhanced T 1-weighted images have higher mean D
values than do nodular-enhancing lesions118 – a pattern that
corresponds to reported histopathological differences between these
types of lesions70.
Interestingly, individual patients’ D values are not significantly
related to their MTR values 119 and are only moderately related to
decreases in their 1H-MRS-measured NA/Cr values 120 (the relevance
of which is explained in the section on 1H-MRS below). These
findings suggest that MTI provides information about different
aspects of brain pathology in MS than do these other two imaging
techniques (i.e., MTI and 1H-MRS).
Page 6 of 18
3.2.1.1. Temporal Evolution of Lesions on DWI
Serial DWI studies have also been used in order to investigate
the changes in NAWM that precede the development of acute MS
lesions. For example, Rocca et al121 found that regions of NAWM
that would subsequently become Gd-enhancing lesions had a
significant increase in their mean D values starting six weeks prior
to the appearance of enhancement. Furthermore, Werring et al22,
who acquired a years’ worth of monthly DWI scans in MS
patients, observed (i) a steady and moderate increase in mean
NAWM D values that was followed by (ii) a rapid and marked
increase at the time of Gd-enhancement and (iii) a slow decay after
the end of enhancement. These two studies suggest that new focal
lesions that are associated with an eventual breakdown of the BBB
are preceded by subtle, progressive alterations in tissue integrity
that are below the resolution of conventional MRI. Interestingly,
Werring et al22 also found that there was a mild increase in the mean
D values of NAWM regions that were contralateral and
homologous to the NAWM regions that evolved into Gd-enhancing
lesions (but that themselves did not become lesional) – a finding
that supports the concept that structural damage in lesions can
cause disturbances in connected areas of NAWM 122.
3.3. DIFFUSION -TENSOR IMAGING
The ADC of water in biological tissue that has a regular and
ordered microstructure depends upon the direction along which it is
measured (i.e., it is anisotropic)103. Thus, D (which has a
magnitude but no direction) does not provide a complete
description of the diffusion phenomenon. A full characterization
can, however, be obtained in terms of a tensor (i.e., a matrix of
numbers) that describes the diffusion of water in three dimensions.
From such a tensor it is possible to derive an index of diffusion
anisotropy – the most commonly-used index being that of fractional
anisotropy (FA123; 124). FA values obtained using DTI reflect the
degree of cellular-structure alignment within the tissue that is being
imaged.
In the normal brain, FA images show a marked difference
between (i) grey matter and CSF (which are both virtually
isotropic) and (ii) white matter (which has a variable degree of
anisotropy)125. Maximum FA values are found in white-matter
regions that are characterized by a strongly-ordered parallel
arrangement of fibers, whereas much lower values are found in
regions where white matter fibers have incoherent orientations or
where fiber-bundles cross. In DTI voxels that are normally full of
highly-ordered fibers, a relative decrease in diffusion anisotropy
could signal structural disintegration within the CNS and could be
used to detect both focal damage to major neuronal pathways as
well as remote damage resulting from Wallerian degeneration126. It
should be noted that DTI would be expected to be less sensitive to
such damage in voxels that contained less-ordered tissue or that
contained crossing fibers.
3.3.1. DTI of Multiple Sclerosis
Results similar to those found using DWI have also been found
using DTI in patients with MS. For example, as shown in Figure
10-3, DTI measures of FA have been shown to be decreased in the
NAWM of patients with MS18; 29; 126; 127 and to be even more
decreased in lesions18; 126; 127 – the greatest FA decreases typically
being found in the most destructive (i.e., T 1-weighted hypointense)
lesions18; 126; 127. Similar to the D findings described above119, there
is also a lack of relationship between individual MS patients’ FA
values and their MTR values 128; 129 – further suggesting that
diffusion imaging and MTI provide somewhat independent
measures of brain pathology in MS. Interestingly, whereas
significant negative relationships have been found between
individuals’ EDSS scores and their FA values 18; 29; 127, abnormalities
in FA have not yet been found in RR-MS at the very early stages of
their disease130 and mean FA difference have not yet been found
between different MS subgroups16; 18; 29. If this is not simply the
result of a low sensitivity of DTI for detecting structural damage,
this would imply that the disability in RR-MS has a basis more in
dysfunction than in loss of structural integrity.
3.4. PROTON MAGNETIC RESONANCE S PECTROSCOPY
None of the water-based imaging methods that we have
reviewed so far can provide pathological specificity for injury to a
particular cell type. Pathological specificity for injury to neurons
and neuronal processes (i.e., axons and dendrites) can, however, be
provided by quantification of the neuronal marker compound, Nacetylaspartate (NAA) using 1H-MRS131.
1
H-MRS is fundamentally different from the water-protonbased MRI techniques that we have discussed thus far in that it
records signals that arise from protons in metabolites that are
present in brain tissue at concentrations approximately one
thousand times lower than that of tissue water132. Whereas the
signal-to-noise ratio and image resolution that is possible with these
metabolite-based images is much lower than that for water-based
images, the resulting images can provide chemico-pathological
specificity that is not possible with conventional MR images. The
various approaches to in vivo 1H-MRS include: (i) single-voxel 1HMRS studies (in which proton spectra are acquired from a single
volume) and (ii) 1H-MRS imaging (1H-MRSI) studies [in which
proton spectra are obtained from multiple volume elements (i.e.,
voxels) at the same time].
3.4.1.1.
1
H-MRS Metabolites of Interest
As shown in Figure 10-4, the water-suppressed, localized 1HMRS spectrum of the normal human brain that is recorded at
relatively-long echo times (usually 136 - 272 ms) reveals three
major resonance peaks [the locations of which are expressed as the
difference in parts per million (ppm) between the resonance
frequency of the compound of interest and that of a standard
compound (i.e., tetramethylsilane)]. These peaks are commonly
ascribed to the following metabolites: (i) tetramethyl amines (Cho),
which resonate at 3.2 ppm and are mostly choline-containing
phospholipids that participate in membrane synthesis and
degradation; (ii) creatine and phosphocreatine (Cr), which resonate
at 3.0 ppm and play an important role in energy metabolism; and
(iii) N-acetyl groups (NA), which resonate at 2.0 ppm and are
comprised primarily of the neuronally-localized NAA. A fourth
peak usually arising from either the methyl resonance of lactate
(LA) or lipids (which both resonate at 1.3 ppm), is normally onlybarely visible above the baseline noise but can be detected in certain
pathological conditions. Spectra acquired at shorter echo times (e.g.,
30 ms) are better for detecting resonances that have a short T 2 (e.g.,
Page 7 of 18
lipids and inositol). Unfortunately, such short-T 2 1H-MRS records
broad, overlapping signals that complicate the quantification of such
spectra.
Normal Control
Patient with MS
NA
[1] NWM
[1] NAWM
NA/Cr = 3.83
Cho/Cr = 1.30
NA/Cr = 2.86 NA
Cho/Cr = 1.84
Cho
Cho
Cr
Cr
1
1
[2] NWM
2
NA/Cr = 3.04
Cho/Cr = 1.14
[2] Lesion
NA
2
NA/Cr = 1.91
Cho/Cr = 1.12
NA
Cho
Cr
Cho
Cr
Figure 10-4. Proton-density-weighted magnetic resonance
images through the centrum semiovale and the results of
proton magnetic resonance spectroscopic imaging (1H-MRSI)
in a normal control subject and in a patient with multiple
sclerosis. The superimposed grid in each image represents
individual 1H-MRSI voxels, and the large, thick, white box
represents the entire 1H-MRSI volume of interest for that
individual. The smaller, numbered boxes represent voxels of
normal-appearing white matter (NAWM) and lesional brain
tissue in the patient and normal white matter (NWM) in the
normal control subject. The 1H-MRSI spectra from within
each of these voxels is shown to the right of each image. The
areas under the NA and Cho peaks (normalized to Cr) are
shown above each spectrum. The spectra have been scaled so
that the Cr peak in each of them has the same height. Note (i)
the decrease in NA/Cr values from the patient’s NAWM voxel
relative to the NWM voxels in the control subject, (ii) the even
greater decrease in lesional NA/Cr, and (iii) the increased
Cho/Cr in the patient’s NAWM voxel, which may be
predictive of a soon-to-appear lesion in that location.
The simplest approach to the quantitation of 1H-MR spectra is
to normalize the NA and Cho signal intensities to the signal
intensity from Cr in the same voxel131. Of course, this latter method
does not provide absolute quantification and, importantly, the
resulting measures of relative concentration are only valid if the underlying pathology does not substantially affect the local
concentration of Cr. Thus, it is important that Cr concentrations are
relatively constant throughout normal brain tissue and that they
have also been shown to be relatively constant in both the
lesions133; 134 and the NAWM 134-136 of patients with MS. It should
be noted , however, that Cr values have been shown to decrease in
acute133 and severely-hypointense lesions136: thus, it is
inappropriate to normalize within-lesion NA and Cho values to
within-lesion Cr values in either acute lesions or T 1-weighted black
holes.
The limitations of ratio-based quantitation can be overcome by
the various methods of semi-absolute quantification that have been
developed137; 138. Unfortunately, such methods have their own
limitations; for example, (i) they are dependent on many
assumptions, (ii) they can be difficult to carry out, and (iii) they
tend to have more variance than those based on ratios
3.4.2.
1
H-MRS of Multiple Sclerosis
The resonance intensity that is ascribed to NAA is, arguably,
the most important 1H-MRS signal in the characterization of MS
pathology because NAA is localized exclusively within neurons and
neuronal processes such as axons and dendrites 139; 140. Although
NAA has been found in cell cultures of oligodendroglial cell
lineage 141; 142, this appears to be a phenomenon that is limited to cell
cultures. Indeed, the specificity of NAA as an axon-specific marker
in vivo, even in the presence of injury and significant density of
oligodendroglial cell precursors, has been confirmed in a recent
biochemical and immunohistochemical study of rat optic nerve
transection143. Furthermore, the validity of NAA as a surrogate for
axonal density in MS has been confirmed in studies that correlated
(i) findings from in vivo 1H-MRSI and histopathological analysis of
cerebral biopsy specimens144 and (ii) findings from HPLC and
histopathological analysis of spinal cord biopsy specimens145.
3.4.2.1. NA/Cr
1
H-MRSI-measured NA/Cr values have been used to quantify
neuronal and axonal integrity in vivo in the brains of patients with
MS for over a decade now146; 147. 1H-MRS studies have shown that
periventricular NA/Cr values are low in both the lesions and, to a
lesser extent, the NAWM of patients with MS19; 122; 147; 148. Patients
with SP-MS are more affected than those with RR-MS19; 149.
Interestingly, however, this latter finding seems to be related more
to NA/Cr differences in NAWM than in lesions19. Importantly, just
as with MTI and DWI, 1H-MRSI-measured values of NA/Cr within
the cortical NAGM of patients with MS have also been shown to
be decreased relative to those in the cortical grey matter of healthy
normal controls 30; 31.
Decreases in MS patients’ periventricular-NA/Cr values
are strongly related to both their disease duration and their EDSS
scores 149. Importantly, the correlation between patients’ EDSS
scores and their periventricular NA/Cr values is as strong, or
stronger, than that of any other MRI measure150 – a relationship
that becomes even stronger when EDSS scores are correlated with
estimates of NA/Cr in pure periventricular NAWM 19; 20. In addition
to correlating with patient’s EDSS scores (which are greatly
influenced by a patients’ ambulatory status), periventricular-NA/Cr
values in MS patients have also been shown to be strongly related
to their cognitive abilities 151.
3.4.2.2. Other Metabolites
In addition to NA, several other 1H-MRS resonance intensities
are also important in understanding the MS disease process. For
example, 1H-MRS-observed Cho and lipid peaks are thought to
provide important information regarding myelin breakdown in the
MS disease process23; 148. Furthermore, the presence of myoinositol has been proposed as a marker of glial cells and gliosis 30.
3.4.2.3. Temporal Evolution of Lesions on 1H-MRS
As with MTI and DWI, the earliest abnormalities that are
visible on 1H-MRS occur months before the appearance of Gdenhanced or T 2-weighted lesions. For example, regions of NAWM
that will go on to become lesions have been shown to be associated
with locally-increased levels of both Cho24 and lipids23 – both of
which are markers of abnormality in cell membranes. As newly-
Page 8 of 18
developing lesions become detectable on conventional MRI, they
are associated with focal inflammation, demyelination, and axonal
injury – pathological processes that result in decreases to NA/Cr
values 148; 152-154, further increases to Cho/Cr values 148; 152-154, and
acutely-increased LA/Cr values 148.
Importantly, these NA-related decreases may persist
chronically – particularly in the core of chronic lesions148. On the
other hand, the presence of LA is more common in lesions that are
Gd-enhancing154 and seems to resolve within weeks148. Increases in
Cho/Cr are pronounced in Gd-enhancing lesions153; 154 and may
remain elevated for years148, but eventually return to normal136; 148.
3.4.2.4. Spatial Distribution of 1H-MRSI Pathology
Changes in 1H-MRSI metabolites are greatest in the core of
lesions and decrease with increasing distance from their center148.
Importantly, they do not end at the edge of the T 2-weighted
abnormality but extend into the surrounding NAWM 148. For
example, in the hyper-acute phase of the lesion (i.e., when it is still
expanding), both the decrease in NA/Cr and the increase in Cho/Cr
can be found around the lesion in the NAWM that is well beyond
the expanding T 2-weighted abnormality. It is still not clear if the
NAWM abnormalities in patients with MS result from (i) the sum
of the remote effects of focal, lesional pathology or (ii) an
independent process that is more diffuse.
been shown to be even more related to FA and NA/Cr values that
are measured specifically within the periventricular NAWM 20 –
implying that NAWM changes are more specifically related to
functional change than those in non-segmented periventricular brain
tissue (which contains NAWM, NAGM, and lesions). This reorganized cortico-motor activation has been found in regions of the
brain that are usually only activated in the execution of morecomplex motor tasks – suggesting that such activation reflects, at
least in part, disinhibition of latent motor pathways that are
“recruited” to limit any functional impairment related to the tissue
damage associated with MS157. Individual patients’ levels of
activation within these recruited areas have been shown to be
related to their (i) EDSS scores, (ii) disease duration, (iii) extent and
number of spinal cord lesions, (iv) brain and spinal-cord MTR, (v)
whole-brain D , and (vi) and whole-brain FA157. Together, these
findings suggest that compensation due to adaptive cortical changes
can contribute to sustaining motor functions during the early stages
of MS; as a result, the actual extent of cortico-functional pathology
in patients with MS may be greater than that which is clinically
evident.
Normal Control
MS Patient 1
w/ Low Disability, Normal NA/Cr
MS Patient 2
w/ Low Disability, Low NA/Cr
3.5. FUNCTIONAL MAGNETIC RESONANCE IMAGING
fMRI is another MR technique that differs fundamentally from
the others discussed so far. For example, the blood-oxygen level
dependent method of fMRI (a widely-used approach to such an
analysis) exploits the fact that hemoglobin and deoxyhemoglobin are
magnetically different such that hemoglobin shows up better on
MRI images than does deoxyhemoglobin155. Brain activation is
associated with increased blood flow and greater blood oxygenation
that, in turn, produce an increased MR signal. fMRI involves (i) the
acquisition of a series of such MR images of the brain in quick
succession and (ii) the statistical analysis of these images in order to
quantify subtle changes in the functional state of the brain across
time.
Figure 10-5. Examples of fMRI activation maps (in white)
obtained during a simple finger-flexion motor task and
registered on to anatomical MR images for a normal control
subject, a multiple sclerosis (MS) patient with normal
periventricular NA/Cr, and an MS patient with abnormallylow periventricular NA/Cr. Both patients were able to perform
the task without difficulty and had low disability ratings. Note
the larger, bilateral extent of functional activation in the patient
with low NA/Cr. (Images are courtesy of Dr. P.M.
Matthews).
3.5.1. fMRI of Multiple Sclerosis
Thus far, fMRI has been used in patients with MS to study
abnormal patterns of brain activation that occur during the
performance of simple motor tasks20; 32-34; 156; 157. These studies
have shown that, as with other forms of brain injury, there is
adaptive cortical reorganization in patients with MS as evidenced
by extended, bilateral activation in motor-related regions (as
opposed to the more-constrained, mostly-unilateral activation that
is seen in normal controls during the tasks that have been used in
these studies).
Reddy et al156 combined findings from fMRI of a simple fingerflexion task with those from 1H-MRSI. As shown in Figure 10-5,
they demonstrated that the extent of this functional reorganization
[as expressed in the form of a lateralization index (LI) that reflected
the degree of bilateral versus unilateral functional-activation] was
strongly related to the presence of axonal injury (as measured by
decreased periventricular NA/Cr on 1H-MRSI). LI values have since
4.
MR-BASED ASSESSMENT OF BRAIN ATROPHY
Atrophy of the brain or spinal cord at post mortem examination
is one of the pathological hallmarks of irreversible CNS damage. As
reviewed by Simon35, with the advent of MRI, it is now possible to
assess CNS atrophy in vivo using a variety of measures that
include, for example, (i) ventricular enlargement, (ii) grey- and
white-matter volumes, and (iii) the use of more-global measures
such as (a) the brain parenchymal fraction (BPF, i.e., the ratio of
brain parenchymal volume to the total volume within the surface
contour of the brain)158 or (b) BICCR (i.e., the ratio of brain
parenchymal volume within the surface contour of the inner table of
the skull)159.
Page 9 of 18
4.1.1. Atrophy in Multiple Sclerosis
CNS atrophy in patients with MS has been documented since
the original autopsy examinations of such individuals – with
atrophy having been shown to reflect (i) injury and loss of both (a)
neurons and their processes and (b) oligodendrocytes and the
myelin that they produce, as well as (ii) changes in the supporting
matrix that result from the contraction of glial tissue35. Until
recently, such atrophy has generally been thought of as occurring
late in the disease35; this view has changed, however, with the
development of neuroimaging techniques that have demonstrating
atrophy in the majority of patients with MS – even at very early
stages of the disease158; 160; 161.
4.1.1.1. Clinical Significance of CNS Atrophy
The average amount of accumulated spinal cord atrophy has
been shown to be greater in patients with SP-MS than in patients
with RR disease162-165. Similarly, as a group, SP-MS patients have
also been shown to have smaller brain volumes, and larger lateral
ventricles, than RR-MS patients159; 166 (see Figure 10-6).
Normal Control
Patient with RR-MS
Patient with SP-MS
Figure 10-6. Cross-sectional slices through the lateral ventricles
of a normal control subject, a patient with relapsing-remitting
multiple sclerosis (RR-MS), and a patient with secondaryprogressive multiple sclerosis (SP-MS) as seen on T 2-weighted
imaging. Note (i) the high degree of atrophy seen even in the
early stage of the disease (as evidenced visually by the
ventricular enlargement in the RR-MS patient as compared to
the control subject) and (ii) the even-greater degree of atrophy
that is seen in the secondary-progressive stage of the disease
(as evidenced visually by the sulcal enlargement, the decreased
volume of the white- and grey-matter, and the furtherincreased ventricular enlargement in the SP-MS patient).
Brainstem and upper-spinal-cord atrophy have been shown to
be strongly correlated with EDSS scores in patients with MS164; 167.
This may, in part, be due to the fact that atrophy in these regions
can be related to Wallerian degeneration following damage to the
cerebrum, to the spinal cord, or to both. Moderate correlations have
also been found between individuals’ EDSS scores and their degrees
of (i) callosal atrophy 42; 168, (ii) cerebral white-matter atrophy 162,
and (iii) ventricular enlargement 42; 169-172. On the other hand,
correlations between EDSS scores and brain-parenchyma-based
estimates of atrophy have been variable – ranging from strong158; 159;
173
to non-significant 115; 174; 175. It should be noted that MRI
measures of brain volume and atrophy have been also shown to be
significantly related to the presence of depression176, impaired
quality of life177, and cognitive decline173; 178 in patients with MS.
4.1.1.2. Rate of Atrophy
Brain atrophy develops at a remarkably-high rate in patients
with MS35. For instance, Fox et al179 showed that (i) the yearly rate
of cerebral atrophy in their MS group (0.8% per year) was over
twice that of normal controls (0.3%) and (ii) the yearly rate of
ventricular enlargement in patients was almost five times greater
than in the controls (1.6 versus 0.3 cc per year). Furthermore,
Simon et al180 studied 85 RR-MS patients with mild-to-moderate
disability over the course of two years and found that (i) the
volume of the lateral ventricles increased at a rate of 5.5% per year
and (ii) the area of the corpus callosum decreased at a rate of 4.9%
per year. The course of cerebral atrophy in these patients was
related to prior inflammatory disease activity as indicated by the
presence of Gd-enhancing, T 1-weighted lesions at baseline. Analysis
of a subset of these patients (n=72) found a yearly decrease of
0.61% in their BPF, which translated to a yearly loss of
approximately 8 cc per year158.
There is some preliminary evidence to suggest that the rate of
atrophy in patients with RR-MS differs from that in patients with
SP-MS in a region-specific manner181; 182. For example, SP-MS
patients seem to have a significantly-faster rate of atrophy around
the ventricles than patients with RR-MS – suggesting a greater
relative volume change along the long projection tracts182. On the
other hand, the rate of spinal cord atrophy has been reported to be
faster in patients with RR-MS164. These findings suggest that CNS
atrophy may not be a uniform process and that different regions
may have distinct responses to disease progression.
4.1.1.3. Relationship of Atrophy to Other MRI Measures
As might be expected, CNS atrophy in patients with MS has
been shown to be related to many of the other MRI-measures that
we have reviewed in this chapter. For example, patients’
supratentorial brain volumes have been shown to be significantly
related to their load of hypointense lesions on T 1-weighted
imaging183; 184. Similarly, patients’ numbers of Gd-enhancing T 1weighted lesions have been shown to be well-correlated with an
increase in their ventricular size166; 185 – especially in patients with a
high proportion of ring-enhancing lesions185. Furthermore, in two
related longitudinal studies, Luks et al172 found that patients’ total
numbers of new Gd-enhancing lesions were related to their monthly
changes in ventricular volume, and Simon et al180 found that the
degree of cerebral atrophy observed over a two-year period (as
indicated by ventricular enlargement and callosal atrophy) was
greater for patients that had entered their trial with Gd-enhancing
lesions. It should be noted, however, that not all studies have found
a relationship between Gd-enhancement and atrophy 186.
The relationship of atrophy with T 2-weighted lesion load has
also been somewhat inconsistent. For example, whereas some
groups have found a significant relationship between their patients’
T 2-hyperintense lesion load and their (i) degree of ventricular
enlargement 162, (ii) callosal atrophy 162, and (iii) overall brain
volume90, others have been unable to find a significant relationship
with their patients’ supratentorial brain volumes 183; 184.
Page 10 of 18
The relationship between cerebral atrophy and the newer, nonconventional MRI measures seems to be more consistent. For
example, brain volume has been shown to correlate with both (i)
MTR values within normal-appearing brain tissue90 and (ii) D
values within the brain parenchyma115. Furthermore, Collins et al159
found that cerebral atrophy (as measured by BICCR values) was
correlated with periventricular axonal injury (as measured by
decreases in 1H-MRSI NA/Cr values) in their group of patients
with SP-MS. BICCR values in their group of mildly-disabled
patients with RR-MS were not reduced relative to their normal
control group, even though this group of patients did have
significantly reduced NA/Cr values. Together, these findings suggest
that microscopic and biochemical changes in the brains of patients
with MS are related to the decreases in brain volume that are found
in such individuals; importantly, however, there seems to be a
decoupling between axonal damage and atrophy in the very early
stages of the disease.
4.1.1.4. Caveats
It should be noted that current MRI analysis techniques allow
for the measurement of small changes in volume on the order of
0.2% of total brain volume – changes of magnitude that are much
smaller than those that can be identified on gross pathological
examination. Thus far, it has been tempting to (i) assume that these
small changes in brain volume have the same pathological
significance as gross atrophy post mortem and (ii) suggest that they
provide a measure of a specific pathological feature such as axonal
loss. Unfortunately, it is not clear that this is always the case: for
example, myelin loss, glial- and matrix-related changes, as well as
shifts in water distribution all occur in MS and may be associated
with volume changes of this magnitude. Although it is clear that
volume measurements must contribute in some way to estimating
the full extent of irreversible axonal damage in MS, further
investigations are required to understand the precise pathological
significance of atrophy and the mechanisms that contribute to its
progression.
5.
SUMMARY AND CONCLUSIONS
MS, consistent with the emerging view that the pathology in this
disease is relatively diffuse and not specifically tied to the white
matter. Importantly, the amount of such microscopic, pathological
change in any individual patient is highly related to their degree of
concurrent disability and is also related to future changes in their
disability. Second, certain pathological changes in NAWM can
foreshadow the appearance of the focal lesions that are classically
associated with MS. Third, there is significant cortico-functional
reorganization that takes place in the brains of patients with MS; a
reorganization that, at least at the early stages of the disease, seems
to have the potential to be functionally-adaptive and compensate
for some of the effects of the ongoing neuropathological processes
that are associated with the disease. Fourth, all of these changes are
occurring in parallel with the progressive CNS atrophy, even in the
early course of the disease.
Although findings from MRI have taught us much about the
MS disease process over the sixteen years since the publication of
the first edition of this volume, we still have much to learn about
the spatial and temporal dynamics of the lesional and non-lesional
pathological tissue that characterizes the MS brain. It is the hope
and goal of the present authors that a multimodal, multiparametric
approach to the analysis of longitudinal data obtained from a
combination of conventional and non-conventional imaging
techniques will become commonplace. Such an approach still has
much to teach us about the spatial and temporal characteristics of
the MS disease process, and the knowledge that it will provide us
with will undoubtedly lead to better methods of treating and
monitoring MS.
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