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Assessment of Normal-Appearing White and Gray Matter in Patients With Primary Progressive Multiple Sclerosis
A Diffusion-Tensor Magnetic Resonance Imaging Study
Marco Rovaris, MD;
Marco Bozzali, MD;
Giuseppe Iannucci, MD;
Angelo Ghezzi, MD;
Domenico Caputo, MD;
Enrico Montanari, MD;
Antonio Bertolotto, MD;
Roberto Bergamaschi, MD;
Ruggero Capra, MD;
Giovanni Luigi Mancardi, MD;
Vittorio Martinelli, MD;
Giancarlo Comi, MD;
Massimo Filippi, MD
Arch Neurol. 2002;59:1406-1412.
ABSTRACT
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Background Diffusion-tensor magnetic resonance imaging is sensitive to the more
destructive aspects of multiple sclerosis (MS) evolution occurring outside
and within T2-visible lesions and, as a consequence, holds promise for providing
a more complete picture of primary progressive (PP) MS–related tissue
damage than conventional magnetic resonance imaging.
Objective To improve our understanding of PPMS by assessing the extent of occult
pathological features in the normal-appearing white and gray matter of the
brain using diffusion-tensor magnetic resonance imaging.
Methods Ninety-six patients with PPMS, 47 patients with secondary progressive
(SP) MS, and 44 healthy control subjects were studied. T2-hyperintense and
T1-hypointense lesion volumes were calculated, and the volume of the whole
brain tissue was measured. Diffusion-tensor magnetic resonance imaging scans
were postprocessed and analyzed to obtain the mean diffusivity and fractional
anisotropy histograms from the brain and from the normal-appearing white and
gray matter in isolation.
Results The mean T2-hyperintense and T1-hypointense lesion volumes were lower
in patients with PPMS than in patients with SPMS, while the mean absolute
brain volumes were similar in the 2 groups. The average lesion diffusivity
was significantly higher in patients with SPMS than in patients with PPMS
(P<.001). Histogram-derived metrics of the brain
tissue and normal-appearing white and gray matter were significantly different
between patients with PPMS and healthy subjects (range, P = .004 to <.001). Average diffusivity values were significantly
higher in patients with SPMS than in patients with PPMS for all the tissues
studied (range, P = .001 to <.001). Fractional
anisotropy histogram–derived quantities did not significantly differ
between the 2 patient groups (range, P = .94 to .03).
Conclusion This study confirms that, in patients with PPMS, normal-appearing white
and gray matter are not spared by disease-related pathological processes,
although they are affected to a lesser degree than in patients with SPMS.
INTRODUCTION
THE MECHANISMS underlying multiple sclerosis (MS) evolution in patients
with the primary progressive (PP) form of the disease are poorly understood.1 Despite the accumulation of irreversible neurological
deficits, the burden and activity of lesions on T2-weighted and gadolinium-enhanced
magnetic resonance imaging (MRI) scans of the brain are, on average, lower
in patients with PPMS than in patients with relapsing-remitting or secondary
progressive (SP) MS.2-7
That the pathological features of PPMS lesions consist of a predominant loss
of myelin and axons with only mild inflammatory components8
can, at least partially, explain the relative paucity of conventional MRI-detectable
activity3-4 and the discrepancy
between clinical and MRI findings.
Several pieces of evidence9-11
have suggested that diffuse brain damage, which goes undetected when using
conventional MRI, may be a relevant component of PPMS pathological features.
All these studies are based on the use of quantitative MRI techniques, with
increased specificity to the most destructive aspects of MS pathological features
and increased sensitivity for the detection of subtle MS-related changes occurring
in the normal-appearing white matter (NAWM). The severity of NAWM damage correlates
with MS irreversible disability better than MRI-derived measures of macroscopic
lesion burden do.11 More recently, the importance
of gray matter pathological features in patients with MS has also been emphasized.12-14 Again, conventional
T2-weighted MRI scans underestimate the burden of MS lesions located in the
brain gray matter,12 as shown by several studies
using fast fluid-attenuated inversion recovery,15-16
gadolinium-enhanced,17 magnetization transfer, 18-20 or diffusion-tensor
(DT) MRI.18-19,21
Diffusion-tensor MRI is sensitive to pathological processes that, by
modifying the integrity of tissues, result in loss of restricting barriers
to water molecular motion and tissue anisotropy.22
Measures derived from DT MRI include the mean diffusivity
(), which is affected by cellular size and integrity,23 and the fractional anisotropy (FA), which reflects
the degree of alignment of cellular structures within fiber tracts24 and their structural integrity. By creating histograms
of
and FA values from the corresponding
brain maps, an estimation of MS-related damage can be achieved.25-28
Diffusion-tensor histogram–derived metrics differ between patients with
MS and healthy subjects, and among patients with MS with varying disease phenotypes
and clinical disability.25-28
In addition, using a technique based on FA thresholding to segment the white
and gray matter on
maps of the brain,18 information on the presence and extent of MS abnormalities
can be obtained from each of these 2 compartments separately.
In the present study, DT MRI was used to assess the presence and severity
of normal-appearing gray matter (NAGM) and NAWM damage in a large sample of
patients with PPMS and to compare their damage with that of age-matched healthy
subjects and of a group of patients with SPMS with similar clinical characteristics.
PATIENTS AND METHODS
PATIENTS
Patients with PPMS were consecutively selected from the populations
attending the MS clinics in the participating centers. To be included, patients
had to be corticosteroid free for at least 3 months before study enrollment.
The disease course was classified according to the criteria of Lublin et al,29 and other neurological conditions were carefully
excluded by performing the appropriate investigations.30
Patients were classified as having definite, probable, or possible PPMS.30 At enrollment, all patients underwent a complete
neurological examination, with rating of the Expanded Disability Status Scale
(EDSS) scores.31 This was done by a single
observer who was unaware of the MRI results, on the same day of the MRI session.
Ninety-six patients with PPMS (female-male ratio, 57:39) were studied. Eighty-one
patients were affected by definite and 15 by probable PPMS.30
Patients with probable PPMS had either negative cerebrospinal fluid (CSF)
examination findings and positive MRI findings (n = 13); negative CSF examination
findings, equivocal MRI findings, and abnormal visual evoked potentials (n
= 1); or positive CSF examination findings, negative MRI findings, and abnormal
visual evoked potentials (n = 1). Seventy patients with PPMS had a spinal
cord presentation at disease onset, while 26 had a unifocal (n = 21) or multifocal
(n = 5) presentation, with motor (n = 8), visual (n = 4), cerebellar (n =
12), brainstem (n = 4), or sensory (n = 2) disturbances. Their mean age was
50.3 (range, 25-69) years, their median disease duration was 10.0 (range,
1-26) years, and the median EDSS score was 6.0 (range, 2.5-7.5). Seventy-two
patients with PPMS were not undergoing any immunomodulatory or immunosuppressive
treatment at study enrollment, 12 were treated with methotrexate, 7 were treated
with azathioprine, and 5 were treated with pulses of intravenous mitoxantrone
hydrochloride.
Forty-four healthy volunteers (female-male ratio, 25:19; mean age, 50.1
[range, 32-66] years) who were similar in sex and age to the PPMS group served
as control subjects. None of the healthy volunteers had experienced previous
episodes of neurological dysfunction, hypertension, diabetes mellitus, or
other disorders potentially affecting the central nervous system, and all
had completely normal neurological examination findings. A second control
group consisted of 47 patients with clinically definite MS (female-male ratio,
31:16), with an SP disease course,29 who were
consecutively referred to the MS clinics in the participating centers. To
be included, patients with SPMS had to be relapse- and corticosteroid-free
for at least 3 months before study enrollment. Their mean age was 47.4 (range,
31-61) years, their median disease duration was 16.0 (range, 3-29) years,
and the median EDSS score, assessed by the same rater and with the same modalities
as for patients with PPMS, was 6.0 (range, 3.5-8.0). At enrollment, 23 patients
with SPMS were untreated, 14 were treated with interferon beta-1b, 8 were
treated with pulses of intravenous mitoxantrone, and 2 were treated with glatiramer
acetate.
All of the subjects signed a written informed consent form before study
enrollment, and the study was approved by the local ethical committees.
IMAGE ACQUISITION
Using a 1.5-T system, the following pulse sequences were acquired: (a) dual-echo turbo spin-echo (repetition time, 3300 ms;
echo time, 16 ms (first echo) and 98 ms (second echo); and echo train length,
5); (b) T1-weighted conventional spin-echo (repetition
time, 768 ms; and echo time, 14 ms); and (c) pulsed-gradient
spin-echo echo-planar (interecho spacing, 0.8; and echo time, 123 ms), with
diffusion gradients applied in 8 noncollinear directions, chosen to cover
3-dimensional space uniformly. The duration and maximum amplitude of the diffusion
gradients were 25 ms and 21 mT/m (mT indicates millitesla), respectively,
giving a maximum b factor in each direction of 1044 s/mm2. To optimize
the measurement of diffusion, only 2 b factors were used32
(b1  0 and b2 = 1044 s/mm2). Fat saturation
was performed using a 4-radiofrequency pulse binomial pulse train to avoid
chemical shift artifacts. Twenty-four contiguous axial slices, with a 5-mm
thickness, a 192 x 256 matrix size, and a 188 x 250-mm field of
view were obtained for dual-echo and T1-weighted scans. For pulsed-gradient
spin-echo echo-planar scans, 10 axial slices with a 5-mm thickness, a 128
x 128 matrix size, and a 250 x 250-mm field of view were acquired,
with the same orientation as the other scans and the second-last caudal slice
positioned to match exactly the central slices of these sets.
IMAGE ANALYSIS
Two experienced observers (M.R. and M.B.), without knowing to whom the
scans belonged, identified by consensus the hyperintense lesions on proton
density–weighted scans and the hypointense lesions on T1-weighted scans.
T2-weighted images were always used to increase confidence in lesion identification.
On proton density– and T1-weighted images, total lesion volumes (LVs)
were measured by a single observer, using a local thresholding technique for
lesion segmentation.33 On T1-weighted images,
the absolute volumes of the whole brain were measured using a segmentation
technique based on signal intensity thresholding and characterized by a high
intraobserver reproducibility.34
From DT MRI scans,
and FA maps were
created and coregistered to the dual-echo images following a method described
elsewhere.18, 35-37
Lesion outlines on proton density–weighted images were automatically
transferred onto the coregistered
and
FA images, and the area and
and FA of
each lesion were measured. Then, for each patient, the average lesion
and FA, weighted by lesion area,36
were calculated.
Normalized histograms of
and FA
maps were created as previously described.26
For all the histograms, the average
and
FA values were calculated, as were the heights and locations of their peaks.
Diffusivity histograms were derived from the brain tissue (including T2-visible
MS lesions and normal-appearing tissue), NAWM, and NAGM. To obtain
histograms of NAWM and NAGM, MS lesion outlines from T2-weighted
scans were automatically transferred onto the coregistered
maps and then nulled out. The segmentation of NAWM and NAGM
from the resulting
maps was obtained using
an automated technique based on FA thresholding, which has been previously
validated in healthy controls and in patients with MS.18
Because FA maps were used for the segmentation of NAWM and NAGM, FA histograms
were derived only from the brain tissue.
STATISTICAL ANALYSIS
Group comparisons were assessed using the Mann-Whitney test for nonparametric
data or the t test for parametric data. After Bonferroni
correction, significant P values were P<.004 for comparisons between patients with PPMS and healthy controls
and P<.003 for comparisons between patients with
PPMS and those with SPMS.
Univariate correlations were assessed using the Spearman rank correlation
coefficient. Composite MRI scores38 were generated
using a linear combination of MRI variables, which were chosen a priori based
on biological considerations. The first score included MRI measures of macroscopic
lesion burden and intrinsic lesion damage (ie, T2-hyperintense LV, T1-hypointense
LV, and average lesion
). The second score
was composed by average brain, NAWM, and NAGM
(ie, by measures reflecting diffuse tissue damage). A third score
included quantities reflecting MS tissue damage within and outside T2-visible
lesions (ie, average lesion, NAWM, and NAGM
).
The weight of each MRI variable resulted from the coefficients estimated by
a linear regression model, with EDSS score as the dependent variable. The
magnitude and the significance of the correlation between composite MRI scores
and EDSS score were evaluated by a nonparametric Spearman rank correlation
analysis, because EDSS score does not satisfy the assumptions of continuity
and normality for a valid inference in linear regression models. For all the
correlations, P<.05 was considered significant.
Statistical analysis was performed using a statistical package (Statistical
Product and Service Solutions, version 9.0; SPSS Inc, Chicago, Ill).
RESULTS
Nine or more T2-hyperintense lesions30
were seen on the scans from 88 (92%) of the 96 patients with PPMS and on the
scans from all patients with SPMS; fewer lesions (range, 2-8) were visible
in the remaining patients with PPMS. In the patients with PPMS, median T2-hyperintense
and T1-hypointense LVs were 11.3 (25th-75th percentile range [PR], 4.5-30.4)
mL and 2.5 (25th-75th PR, 0.4-7.1) mL, respectively. In the patients with
SPMS, the corresponding quantities were 26.4 mL (25th-75th PR, 16.0-38.6 mL; P<.001 vs patients with PPMS, Mann-Whitney test) and
4.5 mL (25th-75th PR, 2.6-9.1 mL; P = .004 vs patients
with PPMS, Mann-Whitney test), respectively. The median values of average
lesion
and FA were 1.07 (25th-75th PR,
0.98-1.16) mm2/s per 10-3 and 0.26 (25th-75th
PR, 0.23-0.28) in patients with PPMS and 1.26 (25th-75th PR, 1.14-1.37) mm2/s per
10-3 and 0.23 (25th-75th PR, 0.20-0.27) in
patients with SPMS, respectively. The average lesion
was significantly higher in patients with SPMS than in patients with
PPMS (P<.001, Mann-Whitney test).
The mean (SD) values of brain volume were 1094.8 (113.5) mL in patients
with PPMS, 1155.4 (89.3) mL in healthy subjects, and 1096.1 (117.8) mL in
patients with SPMS. In patients with PPMS, the mean brain volume was significantly
lower than in healthy subjects (P = .001, t test), while no significant differences were found between patients
with PPMS and those with SPMS (P = .95).
Table 1 and Table 2 report the mean values of histogram-derived quantities from
brain tissue, NAWM, and NAGM (Figure 1)
in patients with PPMS, healthy controls, and patients with SPMS. All the differences
remained statistically significant after adjusting for brain volume.
Table 3 reports the correlations between
DT MRI–derived metrics and T2-hyperintense or T1-hypointense LV; the
strongest correlation was that between average brain
and T2-hyperintense LV (r = 0.74, P<.001).
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Table 1. and FA Histogram-Derived
Metrics of the Brain Tissue From All Study Subjects*
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Table 2.
Histogram-Derived
Metrics of the NAWM and NAGM From All Study Subjects*
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Average mean diffusivity () histograms of the
normal-appearing white matter (A) and the normal-appearing gray matter
(B) from healthy control subjects, patients with primary progressive
multiple sclerosis (PPMS), and patients with secondary progressive
multiple sclerosis (SPMS). Compared with healthy controls, a
reduction of the histogram peak height (which reflects the amount of
"truly" normal tissue) can be observed for the patients with PPMS
and SPMS, and is more pronounced in the latter group.
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Table 3. Univariate Correlations Between Quantities Derived From DT
MRI and T2-Hyperintense or T1-Hypointense LVs in 96 Patients With PPMS*
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No significant correlations were found between EDSS score and any MRI-
or DT MRI–derived variable (range, P = .99
to .26). No significant differences in any of the MRI-derived quantities were
found between patients with PPMS with spinal cord presentation and those with
other clinical presentations (range, P = .86 to .09).
Patients with PPMS with an EDSS score of 6.0 or greater (n = 53) did not differ
significantly from those with lower scores (n = 43) for their brain MRI or
DT MRI characteristics (range, P = .92 to .06).
In patients with PPMS, none of the 3 composite MRI scores was significantly
associated with clinical disability (P = .59, .50,
and .42 for the first, second, and third score, respectively). In 26 patients
with clinical presentations other than spinal cord syndromes, moderate, albeit
statistically not significant, correlations were found between EDSS score
and average brain, NAWM, and NAGM
(r values were 0.32, 0.26, and 0.41, respectively) (P = .14, .26, and .06, respectively). In the same subgroup,
the composite MRI score, including average lesion, NAWM, and NAGM
, was significantly associated with disability (r = 0.45, P = .04).
COMMENT
The clinical characteristics of our sample of patients with PPMS are
similar to those of other populations enrolled in previous large-scale studies,5-6 but the predominance of patients with
definite PPMS is likely to be the explanation for the relatively higher brain
T2-hyperintense LV we found compared with those previously reported.5-7 A diagnosis of definite
PPMS actually requires the presence of either at least 9 brain T2-hyperintense
lesions or 4 to 8 brain lesions when spinal cord lesions are detected.30 Consistent with the results of another study,6 we found that brain T1-hypointense LVs did not differ
significantly between patients with PPMS and those with SPMS, thus indicating
that the overall burden of macroscopic lesions affected by severe tissue damage39 may overlap in the 2 progressive forms of MS. However,
the average
of T2-visible lesions was
significantly higher in patients with SPMS than in those with PPMS. These
findings suggest that, when only a binary classification of MS lesions as
either T1 hypointense or T1 isointense is performed, relevant information
about the pathological heterogeneity of "black holes" is inevitably lost.39 Our results also prompt speculations on how intrinsic
lesion MS pathology may have a different functional impact in patients with
the progressive forms of the disease. Given the greater amount of tissue that
is involved by T2-visible lesions in patients with SPMS, in these patients
the severity of intrinsic lesion damage might play an important role in the
accumulation of irreversible disability. This agrees with longitudinal data
showing a continuous increase of tissue damage within newly formed lesions
in patients with SPMS.40 On the contrary, the
few T2-visible lesions and the observation that the severity of intrinsic
tissue damage within individual lesions is lower in patients with PPMS than
in patients with SPMS suggest that other factors in addition to the presence
of lesions affected by marked tissue disruption should act in determining
the dynamics of PPMS evolution.
Brain
and FA histogram analysis
confirmed the presence of diffuse abnormalities in patients with PPMS, for
whom the histographic quantities were all significantly lower than those of
healthy subjects. Admittedly, the DT MRI acquisition scheme we used allowed
us to obtain limited brain coverage. Nevertheless, we covered a large portion
of the central brain, where most of the MS abnormalities are typically located.
The severity of brain tissue damage was, however, greater in patients with
SPMS than in those with PPMS. Although patients with PPMS showed a significant
decrease of brain parenchymal volume vs healthy controls, the results of group
comparisons for
and FA
histogram–derived
quantities did not change after correcting for this factor, thus indicating
that the observed changes are not attributable to the inclusion of pixels
with significant partial volume effects from the CSF. The correlation we found
between T2-hyperintense LVs and average brain
or FA suggests that, at least partially, wallerian degeneration of
axons that are transverse to macroscopic lesions41
might contribute to MRI-undetectable brain abnormalities in patients with
PPMS. Nevertheless, given the paucity of T2-visible lesions in patients with
PPMS, the occurrence of multiple discrete lesions beyond the resolution of
conventional scanning should also be considered. This important issue should
be addressed by future postmortem studies because, to our knowledge, no pathological
data are available supporting the presence of more diffuse occult damage in
patients with PPMS than in those with other MS phenotypes.
Although much of the examined brain tissue is constituted of NAWM and,
as a consequence, diffuse NAWM damage is likely to be the major contributor
to the observed histogram changes, recent studies19-20
have suggested that gray matter damage is not a negligible aspect of PPMS
pathological features. For this reason, after removal of T2-visible lesions,
we obtained
histograms from the NAWM and
NAGM separately.
In a previous study,18 it was demonstrated
that a segmentation process based on FA thresholding allows accurate separation
between white and gray matter, based on their different microstructural properties.
That this segmentation technique works properly in healthy subjects and in
patients with MS is indicated by the previous finding that the mean ratios
between pixels attributed to NAGM and those attributed to NAWM were similar
in these 2 samples, and by the lack of significant differences between region
of interest–based and histographic analysis of DT MRI characteristics
from the NAGM and NAWM of patients with MS.18
We found that NAWM and NAGM
histogram–derived
quantities were different between patients with PPMS and age-matched healthy
subjects. Again, tissue damage in both of the compartments seemed to be more
pronounced in patients with SPMS than in patients with PPMS.
Our finding of NAWM
abnormalities
is consistent with those of other magnetization transfer MRI and magnetic
resonance spectroscopy studies,9-11
showing that tissue damage occurs outside T2-visible lesions in patients with
PPMS. Although these results indicate a net loss and disorganization of structural
barriers to water molecular motion in the NAWM, we can only speculate on the
possible pathological substrates, and postmortem correlative studies are needed
to clarify this issue. Nevertheless, valuable information can be derived from
DT MRI studies of other neurological conditions. Increased values have been described in the brain tissue and NAGM
from patients with Alzheimer disease,42 which
can be considered a condition characterized by diffuse degenerative brain
changes. Increased has also been found
in patients with cerebrovascular abnormalities, such as leukoaraiosis,43 systemic lupus erythematosus,44
and cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy.45 Although the magnitude
of DT MRI histogram abnormalities observed in our patients is less pronounced
than in patients with Alzheimer disease,42
most of the subtle pathological changes known to occur in the NAWM from patients
with MS, including diffuse astrocytic hyperplasia, patchy edema, perivascular
infiltration, and abnormally thin myelin and axonal loss,46
have the potential to determine increased
values.
Several observations12-14
have recently emphasized the potential role of gray matter tissue damage in
patients with MS. Studies with positron emission tomography47
and quantitative18-21
MRI techniques have consistently shown functional and structural abnormalities
in the NAGM of patients with MS. In a postmortem study,48
gray matter MS lesions had a reduced amount of inflammation when compared
with those located in the white matter of the same patients, thus supporting
the hypothesis that MS pathological features might follow different patterns
in these 2 tissue compartments. Our results confirm that, in patients with
PPMS, the brain NAGM is not spared by the pathological process. There are
at least 2 factors that may contribute to the increased values found in the NAGM of patients with PPMS. First, there
is the presence of discrete MS lesions, which may go undetected when using
T2-weighted imaging.12, 49-50
That demyelinated regions of the cerebral cortex from patients with MS harbored
transected dendrites, transected axons, and apoptotic neurons48
also suggests that T2-undetectable cortical lesions might provoke a significant
increase of gray matter . Second, an alternative,
but not mutually exclusive, explanation of the observed changes might be the presence of wallerian degeneration
of gray matter neurons, secondary to the damage of fibers that are transverse
to MS white matter lesions.41 However, the
modest correlation we observed between macroscopic lesion load and average
NAGM suggests that such a mechanism is
likely to account only for a limited part of DT MRI findings from the NAGM.
Because the results of NAGM histogram analysis did not change after correcting
for brain volume, we conclude that, even though in patients with PPMS and
SPMS, due to the presence of brain atrophy, pixels with significant partial
volume effect from the CSF might have been introduced in the gray matter pixel
pool, such a factor is likely not to affect NAGM a great deal.
Disappointingly, we did not find any significant correlation between
DT MRI–derived measures and EDSS score. This might be because of the
limitations of EDSS score, including that it is heavily weighted toward locomotor
disability,31 which is likely to be largely
dependent on the amount of spinal cord damage. Accordingly, conventional and
magnetization transfer MRI studies5-6,51
have suggested that a prevalent involvement of the cervical cord might, at
least partially, explain the discrepancy between brain MRI and clinical findings
in patients with PPMS. In this study, the absence of imaging data from the
cervical cord might, therefore, account for the poor clinical and MRI correlations.
Interestingly, when the subgroup of patients with PPMS with clinical presentations
other than a spinal cord syndrome was considered in isolation, we found a
stronger correlation between the EDSS score and a composite MRI score based
on measures of tissue damage within and outside T2-visible lesions. The paucity
of the correlation between NAWM/NAGM pathological features and disability
might also be secondary to the interpatient variability of adaptive cortical
reorganization, with the potential to limit the clinical impact of structural
PPMS damage, as shown by recent functional MRI studies.52-53
AUTHOR INFORMATION
Accepted for publication May 3, 2002.
Author contributions: Study
concept and design (Drs Rovaris, Ghezzi, Caputo, Montanari, Bertolotto,
and Filippi); acquisition of data (Drs Bozzali, Iannucci,
Ghezzi, Caputo, Montanari, Bertolotto, Bergamaschi, Capra, Mancardi, and Martinelli); analysis and interpretation of data (Drs Rovaris, Bozzali,
Iannucci, Bergamaschi, Capra, Mancardi, Comi, and Filippi); drafting of the manuscript (Dr Rovaris); critical
revision of the manuscript for important intellectual content (Drs
Bozzali, Iannucci, Ghezzi, Caputo, Montanari, Bertolotto, Bergamaschi, Mancardi,
Martinelli, Comi, and Filippi); statistical expertise
(Drs Bozzali, Bergamaschi, and Filippi); obtained funding (Drs Ghezzi, Capra, Mancardi, Comi, and Filippi); administrative, technical, and material support (Drs Rovaris, Iannucci,
Caputo, Montanari, Bertolotto, and Martinelli); study supervision (Dr Filippi).
This study was supported in part by grant 2000/R/37 from Fondazione
Italiana Sclerosi Multipla, Genoa, Italy; and by grant ICS030.5/RF00.79 from
the National Ministry of Health, Rome, Italy.
We thank Maria Pia Sormani, PhD, for her help in conducting the statistical
analysis.
Corresponding author and reprints: Massimo Filippi, MD, Neuroimaging
Research Unit, Department of Neuroscience, Scientific Institute and University
Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy (e-mail: filippi.massimo{at}hsr.it).
From the Neuroimaging Research Unit (Drs Rovaris, Bozzali, Iannucci,
and Filippi) and the Clinical Trials Unit (Drs Martinelli and Comi), Department
of Neuroscience, Scientific Institute and University Ospedale San Raffaele,
Milan; the Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate (Dr
Ghezzi); the Departments of Neurology, Scientific Institute Don Gnocchi, University
of Milan, Milan (Dr Caputo), Ospedale di Orbassano, Orbassano (Dr Bertolotto),
and Spedali Civili, University of Brescia, Brescia (Dr Capra); the Multiple
Sclerosis Center, Ospedale di Fidenza, Fidenza (Dr Montanari); and the Departments
of Neurological Sciences, Scientific Institute C. Mondino, University of Pavia,
Pavia (Dr Bergamaschi), and University of Genoa, Genoa (Dr Mancardi), Italy.
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