ORIGINAL RESEARCH
ADULT BRAIN
Longitudinal Mixed-Effect Model Analysis of the Association
between Global and Tissue-Specific Brain Atrophy and Lesion
Accumulation in Patients with Clinically Isolated Syndrome
M. Varosanec, T. Uher, D. Horakova, J. Hagemeier, X N. Bergsland, M. Tyblova, Z. Seidl, M. Vaneckova, J. Krasensky, M.G. Dwyer,
E. Havrdova, and R. Zivadinov
ABSTRACT
BACKGROUND AND PURPOSE: The relationship between lesion formation and brain atrophy development in the early phase of multiple
sclerosis is unclear. We investigated the association between new lesion accumulation and brain atrophy progression in patients with
clinically isolated syndrome over 48 months.
MATERIALS AND METHODS: Patients with clinically isolated syndrome (n ⫽ 210) were evaluated with 1.5T MR imaging at baseline and at
6, 12, 24, 36, and 48 months as part of a multicenter observational study of early administration of intramuscular interferon -1a. Mixedeffect model analyses, adjusted for age, sex, and treatment status, investigated the association between accumulation of contrastenhancing and T2 lesions and brain-volume percent changes in a 48-month period.
RESULTS: In patients with clinically isolated syndrome, the average whole-brain volume decreased 2.5%, the mean lateral ventricle volume
increased 16.9%, and a mean of 7.7 new/enlarging T2 lesions accumulated over the follow-up period. Patients with clinically isolated syndrome
who showed greater percentages of change in whole-brain, white and gray matter, cortical, and lateral ventricle volumes over the follow-up
period had more severe lesion outcomes at baseline (all P ⬍ .007). There were significant associations between decreased individual brain-volume
measures at baseline and greater percentages of change during follow-up (P ⬍ .05). We found a significant association between the total
cumulative number of new/enlarging T2 lesions and the evolution of whole-brain (P ⬍ .001), lateral ventricle (P ⫽ .007), gray matter and thalamic
(P ⫽ .013), subcortical deep gray matter (P ⫽ .015), and cortical (P ⫽ .036) volumes over the follow-up period.
CONCLUSIONS: Lesion accumulation and brain-volume changes occur simultaneously in the early phase of clinically isolated syndrome.
More severe lesion and brain-volume outcomes at baseline were associated with greater development of brain atrophy over the follow-up
period in patients with clinically isolated syndrome.
ABBREVIATIONS: CIS ⫽ clinically isolated syndrome; CE ⫽ contrast-enhancing; EDSS ⫽ Expanded Disability Status Scale; LV ⫽ lesion volume; SDGM ⫽ subcortical
deep gray matter
M
ultiple sclerosis is a chronic inflammatory demyelinating
disease that affects the central nervous system. Approximately 85% of patients with MS begin with the relapsing-remit-
Received October 31, 2014; accepted after revision December 26.
From the Buffalo Neuroimaging Analysis Center (M.V., T.U., J.H., N.B., M.G.D., R.Z.),
Department of Neurology, University at Buffalo SUNY, Buffalo, New York; Department of Neurology and Center of Clinical Neuroscience (T.U., D.H., M.T., E.H.) and
Department of Radiology (Z.S., M.V., J.K.), Charles University in Prague, First Faculty
of Medicine and General University Hospital, Prague, Czech Republic; and IRCCS
“Santa Maria Nascente” (N.B.), Don Gnocchi Foundation, Milan, Italy.
The Observational Study of Early Interferon -1a Treatment in High Risk Subjects
after CIS (SET) study was supported by Czech Ministries of Education and Health
(NT13237-4/2012, PRVOUK-P26/LF1/4, RVO-VFN64165/2012) and Biogen Idec.
Please address correspondence to Robert Zivadinov, MD, PhD, FAAN, Buffalo Neuroimaging Analysis Center, MRI Clinical Translational Research Center, Department
of Neurology, School of Medicine and Biomedical Sciences, University at Buffalo,
100 High St, Buffalo, NY 14203; e-mail: rzivadinov@bnac.net
ting form.1 This event consists of an episode of neurologic disturbance known as a clinically isolated syndrome (CIS). The risk of
progression to clinically definite MS is highest within the first 5
years of the initial event.
The development of brain atrophy is a well-known feature of
MS.2 The general loss of brain tissue in MS derives from focal and
diffuse damage, including loss of myelin and axons and Wallerian
neurodegeneration.3 In recent years, there has been an increased
focus on GM pathology in MS. This surge has been triggered by
new histochemical and MR imaging techniques that enable improved detection of GM pathology.4 Recent studies have shown
that global and regional GM atrophy at the first clinical event in
patients with CIS is associated with conversion to clinically definite MS.5-8
GM pathology in MS has become a focal point of research
Indicates open access to non-subscribers at www.ajnr.org
Indicates article with supplemental on-line photo.
http://dx.doi.org/10.3174/ajnr.A4330
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since the discovery that GM atrophy can predict clinical outcomes
better than WM pathology.9-11 Weak-to-modest associations between the development of regional brain atrophy and changes in
lesion number and lesion volume (LV) suggest that newly detected lesions, as well as progressive tissue damage in pre-existing
lesions, contribute only partially to the loss of overall brain tissue.12,13 At this time, the importance of lesion formation in relation to brain atrophy development is unclear, especially at the
earliest clinical stages of MS.
Against this background, the aim of the present study was to
investigate the relationship between new/enlarging lesion formation and brain atrophy progression over 48 months in patients
with CIS who presented with their first clinical event.
MATERIALS AND METHODS
Study Population
This was an investigator-initiated, multicenter, prospective, observational clinical study in patients with CIS in which we investigated the evolution of clinical and MR imaging outcomes over
24 and 48 months.5,14-17
Inclusion criteria were age between 18 and 55 years and enrollment into the study within 4 months of the first clinical event.
Criteria included diagnostic MR imaging showing ⱖ2 T2-hyperintense lesions, an Expanded Disability Status Scale (EDSS) score
of ⱕ3.5, and ⱖ2 oligoclonal bands in the CSF at the screening visit
before the start of treatment. Exclusion criteria were a second
relapse before the baseline examination, missing or invalid clinical or MR imaging follow-up information after the baseline examination, and pregnancy. Clinical visits were performed every 3
months, and disability, as measured by the EDSS, was assessed
every 6 months. MR imaging was performed at baseline and at 6,
12, 24, 36, and 48 months.
All patients received the same treatment at baseline, which
included 30 g of intramuscular interferon -1a once per week.
Necessary adjustments were made in the treatment for patients
who presented with no or limited treatment effects, including the
development of 2 relapses, a 6-month sustained EDSS progression of 1 point, or other clinical reasons. Each study subject was
treated with 3–5 g of methylprednisolone after the first symptom
before study entry, and a baseline MR imaging examination was
performed at least 30 days after administration of the steroid.
During the study, relapses were treated with 3–5 g of methylprednisolone.
The local ethics committees approved the study protocol, and
each study subject gave written informed consent.
MR Imaging Acquisition and Analysis
MR imaging was performed at baseline and at 6, 12, 24, 36, and 48
months with a standardized protocol using the same 1.5T MR
imaging scanner (Gyroscan; Philips Healthcare, Best, the Netherlands). Axial brain images were obtained by using FLAIR with a
section thickness of 1.5 mm (TR, 11,000 ms; TE, 140 ms; TI, 2600
ms; matrix size, 256 ⫻ 181; flip angle, 90°). Axial T1-weighted 3D
T1 images were acquired with a section thickness of 1 mm (TR, 25
ms; TE, 5 ms; matrix size, 256 ⫻ 204; flip angle, 30°). The FLAIR
and 3D T1 images were contiguous. In addition, each patient
underwent a postcontrast T1 spin-echo scan with a section thick1458
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ness of 3 mm, 5 minutes after contrast injection of a single dose of
0.1 mmol/kg of Gd-DTPA (TE, 12 ms; TR, 450 ms).
The image analysis included the cumulative number of new
and enlarging T2 lesions, defined as the overall number of new
and enlarging T2 lesions, and the cumulative number of contrast-enhancing (CE) lesions between all time points from
baseline to 48 months. All lesion measures were performed by
a single analyst (M.G.D.) who was blinded to the disease status
of the patients. T2 and CE LVs were calculated by applying a
semiautomated contouring-thresholding technique in Jim
software (http://www.xinapse.com).18
Baseline whole-brain, GM, WM, cortical, and lateral ventricle
volumes were calculated by using FSL Structural Imaging Evaluation of Normalized Atrophy Cross-sectional (SIENA/X; http://
fsl.fmrib.ox.ac.uk/fsl/fslwiki/SIENA).19 Subcortical deep gray
matter (SDGM)— defined as the thalamus, globus pallidus, putamen, caudate, nucleus accumbens, hippocampus, and amygdala—volume was calculated by using the FMRIB Integrated Registration and Segmentation Tool (FIRST; http://fsl.fmrib.ox.ac.uk/fsl/
fslwiki/FIRST).20 All brain-volume measures were performed by a
single analyst (N.B.) who was blinded to the disease status of the
patients. Each baseline tissue volume was normalized for head size by
using a skull-constrained registration to the standard MNI 152 template. Longitudinal percent changes in whole-brain, GM, WM, cortical, and lateral ventricle volumes were obtained by using direct
methods of atrophy measurement. Briefly, whole-brain volume
changes were measured by using the SIENA technique,21 whereas
GM, WM, and lateral ventricle changes were calculated by using a
longitudinal regularization of a hidden Markov random field
model.22 Absolute and percent volume changes for the SDGM and
thalamus at each time point were calculated.
Statistical Analysis
SPSS (version 21; IBM, Armonk, NY) and Statistica (version 10;
StatSoft, Tulsa, Oklahoma) were used for all analyses. Because of
non-normal distribution of the data, as assessed by using the Kolmogorov–Smirnov method, T2 and CE LVs and lesion numbers
were logarithmically transformed.
Longitudinal linear mixed-effect models were used with random intercept for patients and adjusted for age, sex, and treatment status to describe temporal associations between baseline
and follow-up MR imaging measures. Separate longitudinal linear mixed-effect models with a random intercept for patients,
with interaction with time, were used to describe temporal associations between changes in individual MR imaging measures
over the 48 months. The analyses included percent change values
for whole-brain, GM, WM, lateral ventricle, cortical, SDGM, and
thalamic volumes for each time point.
Mixed-effect model analyses investigated the association between MR imaging lesion outcomes, including the cumulative T2
and CE lesion activity, absolute T2 and CE LV changes, CE positivity (general occurrence of CE lesions during the study period),
and the evolution of MR imaging brain volumetric percentage
measures of global and tissue-specific volumes over 48 months.
The first mixed-effect model explored the association between
the number of T2 and CE lesions, T2 and CE LVs, and CE positivity at baseline as the independent predictor variables with re-
spect to the dependent outcome variables, which were global and
tissue-specific brain-volume percent changes over the 48 months.
To minimize the potential confounding effect of baseline brain
volumes, we performed an additional confirmatory analysis adjusted also for baseline brain volumes.
After this analysis, we investigated the relationship between
baseline MR imaging brain volumetric measures (independent
variables) and the evolution of global and tissue-specific brainvolume percent changes over the 48 months (dependent
variables).
Finally, we analyzed the association between lesion activity
and brain-volume changes over the whole study period by comparing the total cumulative T2 and CE lesion activity and absolute
T2 and CE LV changes over the 48 months with global and tissuespecific brain-volume percent changes over the same time period.
To minimize the potential effect of baseline brain volume and LV,
we performed an additional confirmatory analysis adjusted also
for baseline brain volume and LV.
The results of the mixed-effect model analyses are presented
for the whole study population. The Benjamini–Hochberg correction was used to minimize the false-discovery rate, and P values
of ⬍.05 are considered significant.23
Table 1: Demographic, clinical, and MRI lesion and brain
volumetric measures in patients with CIS over a 48-month period
(n ⴝ 210)a
Measure
Patient Data
No. (%) female
139 (66)
Age at onset, y
28.7 ⫾ 7.9
Time to baseline, days
81.9 ⫾ 23.7
EDSS at baselineb
1.7 ⫾ 0.7; 1.5 (0.0–3.5)
EDSS at 48 mob
1.8 ⫾ 0.9; 1.5 (0.0–6.5)
Cumulative no. of
Total new T2 lesions
7.7 ⫾ 14.4; 3.0
New T2 lesions
5.8 ⫾ 10.7; 2.0
Newly enlarging T2 lesions
1.9 ⫾ 4.6; 0.0
Cumulative no. of new CE lesions
1.5 ⫾ 6.1; 0.0
T2 lesion volume absolute change, mL ⫺0.08 ⫾ 3.6; ⫺0.1
CE lesion volume absolute change, mL ⫺0.07 ⫾ 0.3; 0.0
WB volume, % change
⫺2.5 ⫾ 2.1; ⫺2.0
GM volume, % change
⫺2.3 ⫾ 2.3; ⫺2.0
WM volume, % change
⫺1.7 ⫾ 2.1; ⫺1.4
Cortical volume, % change
⫺2.8 ⫾ 2.2; ⫺2.6
Lateral ventricle volume, % change
16.9 ⫾ 14.2; 14.3
Total normalized SDGM volume,
⫺3.6 ⫾ 3.6; ⫺3.1
% change
Thalamic volume, % change
⫺4.6 ⫾ 4.2; ⫺4.0
Note:—WB indicates whole brain.
Unless otherwise indicated, all data are reported as mean ⫾ standard deviation;
median.
b
Data in parentheses are ranges.
a
RESULTS
Demographic, Clinical, and MR Imaging Characteristics
Overall, 210 patients with CIS underwent clinical and MR imaging assessments and were included in the analysis over the 48
months of this study. Demographic, clinical, and MR imaging
global and tissue-specific volumes and lesion characteristics over
the 48 months are shown in Table 1. The mean age at onset was
28.7 years, and the median baseline EDSS score was 1.5. An average total of 7.7 new T2 lesions were accumulated over 48 months.
Global and tissue-specific brain-volume percent changes showed
average decreases of 2.5% in whole-brain, 2.8% in cortical, and
4.6% in thalamic volumes and an average increase of 16.9% in
lateral ventricle volumes.
Mixed-Effect Model Analysis Using Baseline Lesion
Measures as Independent Outcome Variables and BrainVolume Evolution Measures as Dependent Outcome
Variables
Table 2 shows the relationship between baseline lesion measures
and the evolution of brain-volume percent changes over the 48
months. Patients with CIS who showed greater percent changes in
whole-brain, WM, GM, cortical, and lateral ventricle volumes
over the 48 months had a greater lesion activity at baseline (all P ⬍
.007). The percent change in thalamic volume over the 48 months
was associated with greater baseline T2 LV and lesion number
(P ⱕ .001) and baseline CE lesion number (P ⫽ .018), whereas the
percent change in SDGM volume was associated only with greater
baseline CE lesion number (P ⫽ .029).
Patients with CIS with the highest number of CE lesions at baseline progressed the most in whole-brain, cortical, and lateral ventricle
volume changes over the 48 months (all P ⬍ .0001) (Fig 1). The
association was somewhat less pronounced for thalamic volume
(P ⫽ .018).
Similarly, patients with CIS with the highest number of T2
lesions at baseline progressed the most in cortical, thalamic,
and lateral ventricle volume changes (all P ⬍ .0001), and there
was also an association with the whole-brain volume progression (P ⫽ .01) (Fig 2).
The effects of baseline T2 and CE lesion numbers and T2 LV
on whole-brain, WM, GM, cortical, and lateral ventricle volume
changes persisted (all P ⬍ .008) even when adjusting the analyses
for baseline brain volumes. In this confirmatory analysis, the percent change in thalamic volume over the 48 months was associated with greater baseline T2 LV and lesion number (P ⬍ .001)
and baseline CE lesion number (P ⫽ .004), whereas the percent
Table 2: Relationship between MRI lesions at baseline and evolution of MRI brain volumetric measures in patients with CIS over a
48-month perioda
MRI Brain Volume % Changes Over 48 mo
MRI Lesions at Baseline
T2 LV
T2 LN
CE positivity
CE LN
CE LV
WB
0.001b
.010b
⬍.001b
⬍.001b
⬍.001b
WM
.001b
.001b
.007b
⬍.001b
.001b
GM
⬍.001b
⬍.001b
.004b
⬍.001b
⬍.001b
Cortical
.004b
⬍.001b
.002b
⬍.001b
⬍.001b
Lateral Ventricle
⬍.001b
⬍.001b
⬍.001b
⬍.001b
⬍.001b
SDGM
.133
.243
.292
.029b
.101
Thalamus
⬍.001b
⬍.001b
.517
.018b
.234
Note:—WB indicates whole brain; LN, lesion number.
a
All data are reported as P values corrected by the Benjamini–Hochberg procedure. Associations between MRI measures were tested by using mixed-model analysis.
b
P ⬍ .05.
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FIG 1. Mixed-effect model analysis of global and tissue-specific brain-volume percent changes over 48 months (dependent variables) and
number of CE lesions at baseline (independent variable). For better visualization, the CE lesions were categorized into different baseline number
groups, including 0, 1, 2–3, and ⬎3 lesions. The Benjamini–Hochberg method was used to minimize the false-discovery rate, and P values of ⬍.05
were considered significant.23
change in SDGM volume was associated with greater baseline T2
LV (P ⫽ .01) and baseline CE lesion number (P ⫽ .013).
Mixed-Effect Model Analysis Using Baseline Brain
Volumetric Measures as Independent Outcome Variables
and Brain-Volume Evolution Measures as Dependent
Outcome Variables
Table 3 shows the relationship between normalized baseline
brain-volume measures and associations with their percent
changes over 48 months. There were significant associations between decreased individual brain-volume measures at baseline
and their greater percent changes over the follow-up period (P ⬍
.05). Of all the explored brain-volume measures, only greater enlargement of lateral ventricles showed a consistent association
with a decrease in most of the brain-volume measures at baseline
(P ⬍ .013).
Mixed-Effect Model Analysis Using Evolution of Lesion
Measures as Independent Outcome Variables and BrainVolume Measures as Dependent Outcome Variables
We performed a mixed-effect model analysis to evaluate the associations between longitudinal changes of lesion variables with respect to brain-volume percent changes over 48 months. The results revealed a significant association between the total
cumulative number of new/enlarging T2 lesions and the evolution of whole-brain (P ⬍ .001), lateral ventricle (P ⫽ .007), GM
and thalamic (P ⫽ .013), SDGM (P ⫽ .015), and cortical (P ⫽
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.036) volumes (Table 4 and On-line Fig 1). No significant differences were found between absolute changes in T2 LV (On-line Fig
2), cumulative CE lesion number, or absolute CE LV changes and
the evolution of global and tissue-specific brain-volume measures
over the 48 months.
The relationship between total cumulative number of new/
enlarging T2 lesions and whole-brain, GM, cortical, lateral
ventricle, subcortical deep GM, and thalamic volume changes
persisted (all P ⬍ .016), even when adjusting analyses for the
baseline brain volume and LV. In this confirmatory analysis,
no significant differences were found between absolute
changes in T2 LV and the evolution of global and tissue-specific brain-volume measures over the 48 months.
DISCUSSION
In this prospective, longitudinal, observational study of highrisk patients with CIS for development of clinically definite MS
treated with interferon -1a,5,14-17 we investigated the association of brain-volume changes in relation to the formation of
new T2 and CE lesions and their volumes over the 48-month
study period.
Using mixed-effect model analysis in which global and tissue-specific volumes changes were used as dependent outcome
variables and MR imaging lesions at baseline as independent
predictors, the progression of brain-volume measures was significantly associated with higher CE and T2 lesion numbers,
FIG 2. Mixed-effect model analysis of global and tissue-specific brain-volume percent changes over 48 months (dependent variables) and
number of T2 lesions at baseline. For better visualization, the T2 lesions were categorized into different baseline number groups, including 1–5,
6 –9, 10 –15, and ⬎15 lesions. The Benjamini–Hochberg method was used to minimize the false-discovery rate, and P values of ⬍.05 are
considered significant.23
Table 3: Relationship between MRI brain volumetric measures at baseline and evolution of changes over a 48-month period in patients
with CISa
MRI Brain Volume % Changes Over 48 mo
MRI Brain Volumetric
Measures at Baseline
Normalized WB volume
Normalized WM volume
Normalized GM volume
Normalized cortical volume
Normalized lateral ventricle volume
Total normalized SDGM volume
Normalized thalamic volume
WB
.712
.591
.881
.847
.066
.032b
.115
WM
.004b
⬍.001b
.794
.774
.156
.710
.578
GM
.426
.711
.049b
.075
.935
.177
.243
Cortical
.299
.904
.075
.040b
.587
.291
.291
Lateral Ventricle
⬍.001b
.001b
.004b
.007b
.013b
.394
.343
SDGM
.182
.588
.069
.192
.342
.042b
.038b
Thalamus
.174
.254
.248
.343
.769
.457
⬍.001b
Note:—WB indicates whole brain.
a
All data are reported as P values corrected by the Benjamini-Hochberg procedure. Associations between MRI measures were tested by using mixed-model analysis.
b
P ⬍ .05.
Table 4: Relationship between evolution of MRI lesion and brain volumetric measures over a 48-month perioda
MRI Brain Volume % Changes Over 48 mo
Longitudinal MRI
Lesion Measures
Total cumulative T2 LN
T2 LV absolute change
Total cumulative CE LN
CE LV absolute change
WB
⬍.001b
.115
.394
.360
WM
.517
.444
.182
.936
GM
.013b
.234
.489
.399
Cortical
.036b
.456
.795
.802
Lateral Ventricle
.007b
.861
.341
.160
SDGM
.015b
.717
.193
.769
Thalamus
.013b
.659
.489
.843
Note:—WB indicates whole brain; LN, lesion number.
a
All data are reported as P values corrected by the Benjamini-Hochberg procedure. Associations between MRI measures were tested by using mixed-model analysis with
interaction with time.
b
P ⬍ .05.
CE and T2 LVs, and CE positivity. The impact of baseline
lesion number and LV on global and tissue-specific brain-volume changes persisted, even when adjusting the analyses for
baseline brain volumes. These findings suggest that more se-
vere lesion outcomes at baseline are associated with greater
development of brain atrophy over the follow-up period in
patients with CIS. A possible explanation for these findings is
that diffuse inflammation in the WM and GM is responsible
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for accelerated tissue loss that occurs from the earliest disease
stages.9,11,13,24
Exploring the relationship between accumulation of new/enlarging CE and T2 lesions and global and tissue-specific volumetric changes over 48 months, we found a significant association
between the total cumulative number of new/enlarging T2 lesions
and the evolution of whole-brain, lateral ventricle, GM, thalamic,
SDGM, and cortical volumes. The relationship between lesion
accumulation and brain-volume changes over 48 months persisted, even when adjusting the analyses for baseline brain volume
and LV. These results suggest that lesion accumulation and brainvolume changes occur simultaneously in the early phase of the
disease. Other studies showed an additional correlation between
T2 LV and brain-volume changes during early treatment
phases.25 In our study, however, absolute change of T2 LV was not
associated with the progression of brain atrophy measures over
the follow-up period, but this finding has to be interpreted with
caution, given that over the 48 months of our study, the T2 LV
remained stable. Overall, these results suggest that measurement
of cumulative accumulation of new/enlarging T2 lesions may be a
more sensitive marker of disease activity in patients with CIS than
the accumulation of T2 LV.
While the CE lesion number and LV at baseline showed significant associations with the evolution of brain-volume changes
over the 48 months, no significant associations between cumulative CE lesions or CE LV absolute changes and the evolution of
brain-volume measures over the follow-up period were found in
this study. The impact of acute inflammation on the evolution of
brain-volume changes remains unclear at this time.26-30 The transient nature of CE lesions can be better captured by using frequent
serial scanning, which may not be feasible in long-term studies.26,27 The findings from this study support the notion that brain
atrophy and active inflammation may occur simultaneously, and
that monitoring the accumulation of new/enlarging T2 lesions
can better reflect this relationship than monitoring CE lesions.
Patients with CIS who presented with lower individual brainvolume measures at baseline showed greater percent changes over
the follow-up period. This is an interesting result, because it suggests
that, along with the predictive value of baseline lesion burden, the
baseline brain volume is also a reliable predictor of future brainvolume changes and therefore of disease progression.31 Lower baseline brain volumes found in this study can reflect more aggressive
disease ongoing even before the first clinical manifestation.32
The results from this study indicate that the association between
accumulation of new/enlarging T2 lesions and development of
whole-brain atrophy and enlargement of lateral ventricles was stronger than the association with the GM volume measures. The close
association between lateral ventricular enlargement and accumulation of T2 lesions in patients with CIS was previously reported.33
Other mechanisms at work, including an effect of altered CSF flow
pulsatility, may be considered when interpreting these findings.34
There is evidence that approximately 40% of patients with CIS
have cortical lesions according to histopathologic examination.35
They occur early in patients with CIS and increase in number and
size over time.36 These lesions are characterized pathologically by
demyelination and microglial activation.37,38 Therefore, compared with WM lesions, inflammation is not as prominent and
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breakdown of the blood-brain barrier occurs less frequently with
GM lesions.38 Assessment of cortical atrophy was proposed as an
indirect marker of cortical pathologic assessment over time.4 The
use of advanced MR imaging sequences, such as double inversion
recovery,39 can enhance the detection of the number and volume
of cortical lesions. We did not apply this sequence; therefore, a
somewhat weaker association between accumulation of T2 lesions
and the evolution of cortical volume changes in the current study
should be interpreted in light of the technical limitations of the
MR imaging study protocol.
A strength of this study is the use of a mixed-effect model, which
provides the ability to assess the interaction of 2 variables at multiple
time points while including covariates. However, there are also several limitations to the present study. It is well known that high-dose
intravenous corticosteroid,40 interferon ,41 or natalizumab42 treatment leads to a temporary reduction in brain volume, mainly from
WM volume loss,42 a phenomenon described as pseudoatrophy.43
Because all the patients in this study were treated with interferon
-1a, the rate of brain-volume changes could have been influenced
by the anti-inflammatory effect of the drug over the first 6 months of
the study period. However, it is less likely that these medications
would have impacted significantly on brain-volume changes over the
48 months in the present study. In addition, MR imaging scans were
performed at least 30 days after high-dose intravenous corticosteroid
administration.
Even though this was a longitudinal serial MR imaging study, it is
difficult to establish causality between lesion formation and atrophy
progression without using more sophisticated microstructural imaging methods or histopathology; therefore, only inferences about an
association are presented. Another approach for determining causes
and effects would be to investigate pathologic processes in specific
regions, and experimental animal model studies may be more suited
for investigation of this relationship. More frequent MR imaging
could also provide greater ability to investigate the relationship between lesion accumulation and brain atrophy progression at the earliest clinical stages of MS.
CONCLUSIONS
We have demonstrated the utility of longitudinal mixed-effect
model analysis approaches in the study of patients with CIS, and
we have shown that lesion accumulation and brain-volume
changes occur simultaneously in the early phase of the disease.
More severe LV and lower brain volume at baseline are associated
with greater development of brain atrophy over the follow-up
period in patients with CIS.
Disclosures: Mihael Varosanec—RELATED: Grant: The SET study was supported by
Czech Ministries of Education and Health (NT13237-4/2012, PRVOUK-P26/LF1/4,
RVO-VFN64165/2012) and Biogen Idec.* Thomas Uher—UNRELATED: Grants/
Grants Pending: Biogen Idec*; Payment for Lectures (including service on speakers
bureaus): Biogen Idec; Travel/Accommodations/Meeting Expenses Unrelated to
Activities Listed: Biogen Idec,* Genzyme*; Other: Received financial support for
conference travel and honoraria from Biogen Idec. Dana Horakova—RELATED:
Grant: The SET study was supported by Czech Ministries of Education and Health
(NT13237-4/2012, PRVOUK-P26/LF1/4, RVO-VFN64165/2012) and Biogen Idec*;
UNRELATED: Received compensation for travel, speaker honoraria, and consultant
fees from Biogen Idec, Novartis, Merck Serono, Bayer Schering, and Teva and support for research activities from Biogen Idec. Michaela Tyblova—RELATED: Grant:
The SET study was supported by Czech Ministries of Education and Health (NT132374/2012, PRVOUK-P26/LF1/4, RVO-VFN64165/2012) and Biogen Idec*; UNRELATED:
received compensation for travel and honoraria from Biogen Idec, Sanofi Aventis,
Teva, Novartis, and Merck Serono. Zdenek Seidl—RELATED: Grant: Biogen Idec.
Manuela Vaneckova—RELATED: Grant: RVO-VFN64165/2012*; Fees for Participation in Review Activities such as Data Monitoring Boards, Statistical Analysis, Endpoint Committees, and the Like: Biogen Idec; Consultancy: Biogen Idec, Novartis,
Merck Serono, and Teva; Grants/Grants Pending: RVO-VFN64165/2012*; Payment
for Development of Educational Presentations: Biogen Idec, Novartis, Merck Serono, and Teva; Other: Received compensation for speaker honoraria and consultant
fees from Biogen Idec, Novartis, Merck Serono, and Teva and support for research
activities from Biogen Idec. Jan Krasensky—RELATED: Support for Travel to Meetings for the Study or Other Purposes: Biogen Idec; Other: Received financial support
for research activities from Biogen Idec. Michael Dwyer—UNRELATED: Consultancy: Claret Medical, EMD Serono, Comments: Study consulting by Claret Medical,
and served on scientific advisory board for EMD Serono; Grants/Grants Pending:
Novartis International,* Comments: Grant support for new software development.
Eva Havrdova—RELATED: Grant: Biogen Idec*; UNRELATED: Consultancy: Biogen
Idec, Genzyme, Novartis, Roche, Teva, Merck, and Receptos; Payment for Lectures
(including service on speakers bureaus): Biogen Idec, Genzyme, Novartis, Teva, and
Merck; Other: Received speaker honoraria and consultant fees from Biogen Idec,
Merck Serono, Novartis, Genzyme, and Teva and support for research activities from
Biogen Idec and Merck Serono. Robert Zivadinov—RELATED: Grant: Biogen Idec*;
UNRELATED: Consultancy: Novartis, Claret Medical, Genzyme, and Teva; Grants/
Grants Pending: Novartis,* Claret Medical,* Genzyme,* and Teva*; Payment for
Development of Educational Presentations: Genzyme; Other: Received financial
support for research activities from Teva Pharmaceuticals, Biogen Idec, Claret Medical, Genzyme, Novartis, and Greatbatch and received personal compensation from
Biogen Idec, Novartis, Genzyme, Claret Medical, and EMD Serono for speaking and
consultant services. *Money paid to the institution.
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