Brain atrophy in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) has traditionally been considered to be primarily an inflammatory demyelinating disorder affecting the white matter. Nowadays it is recognized as both an inflammatory and a neurodegenerative condition involving the white and grey matter. Grey matter atrophy occurs in the earliest stages of MS, progresses faster than in healthy individuals, and shows significant correlations with cognitive function and physical disability; indeed, brain atrophy is the best predictor of subsequent disability and can be measured using magnetic resonance imaging (MRI). There are a number of MRI methods for measuring global or regional brain volume, including cross-sectional and longitudinal techniques. Preventing brain volume loss may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article summarizes the knowledge on brain volume in MS.

Full text

American Journal of Psychiatry and Neuroscience
2015; 3(3): 40-49
Published online March 30, 2015 (http://www.sciencepublishinggroup.com/j/ajpn)
doi: 10.11648/j.ajpn.20150303.11
ISSN: 2330-4243 (Print); ISSN: 2330-426X (Online)
Brain atrophy in Multiple Sclerosis
Rugilo Carlos
1
, Seifer Gustavo
2, 3
, Kuperman Gaston
3
, Villa Andrés María
2
1
Department of Neurology, British Hospital, Buenos Aires, Argentina
2
Department of Neurology, José María Ramos Mejía Hospital, Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina
3
Department of Medicine, Novartis Argentina
Email address:
seifergustavo@yahoo.com.ar (G. Seifer)
To cite this article:
Rugilo Carlos, Seifer Gustavo, Kuperman Gaston, Villa Andrés María. Brain atrophy in Multiple Sclerosis. American Journal of Psychiatry
and Neuroscience. Vol. 3, No. 3, 2015, pp. 40-49. doi: 10.11648/j.ajpn.20150303.11
Abstract:
Multiple sclerosis (MS) has traditionally been considered to be primarily an inflammatory demyelinating disorder
affecting the white matter. Nowadays it is recognized as both an inflammatory and a neurodegenerative condition involving the
white and grey matter. Grey matter atrophy occurs in the earliest stages of MS, progresses faster than in healthy individuals,
and shows significant correlations with cognitive function and physical disability; indeed, brain atrophy is the best predictor of
subsequent disability and can be measured using magnetic resonance imaging (MRI). There are a number of MRI methods for
measuring global or regional brain volume, including cross-sectional and longitudinal techniques. Preventing brain volume loss
may therefore have important clinical implications affecting treatment decisions, with several clinical trials now demonstrating
an effect of disease-modifying treatments (DMTs) on reducing brain volume loss. In clinical practice, it may therefore be
important to consider the potential impact of a therapy on reducing the rate of brain volume loss. This article summarizes the
knowledge on brain volume in MS.
Keywords:
Multiple Sclerosis, Brain Atrophy, Brain Volume Loss
1. Introduction
Multiple sclerosis (MS) is a chronic disorder of the central
nervous system (CNS), characterized pathologically by
multifocal areas of inflammation and demyelination in the
brain and spinal cord that evolve over time, and clinically by a
variable course. Most patients develop significant locomotor
disability in 15-20 years after onset [1-4]. In approximately
85% of patients who develop MS, clinical onset is
characterized by an acute episode of neurological deficit due
to a single lesion within the CNS, and is known as a clinically
isolated syndrome (CIS) [2, 3].
While long recognized as a feature of late stages and/or
particularly severe MS, brain volume loss (atrophy) was
recently recognized and understood as occurring early in the
majority of patients with MS even in CIS and radiological
isolated syndrome (RID) patients [5-8]. (Figure 1) It was
thought to reflect the underlying permanent neuronal damage,
and is associated with irreversible disease progression and
clinical disability [5, 7, 9]. Both, gray matter (GM) and white
matter (WM) appear to manifest neurodegeneration, as
reflected by tissue atrophy [10-12] and it may be, at least in
part, independent of the degree of active inflammation
associated demyelination. This has led to considerable interest
in the development of protective strategies aimed at
preventing degeneration of axons, and thereby slowing or
halting the progression of disability in MS.
Atrophy measures are already becoming standard in many
MS treatment trials [5]. Atrophy measures are complementary
to conventional magnetic resonance imaging (MRI) measures
of gadolinium enhancement, T1 hypointense and T2
hyperintense lesion volume.
In contrast to MRI-visible lesions, CNS atrophy is believed
to reflect the net effect of severe and potentially irreversible
processes such as demyelination and axonal loss.
Measurement of the size of CNS structures may provide an
indication of the total amount of tissue damage that has
occurred up to a given point in time.
Figure 1. Evolution in time of the pathophysiology of MS.

41 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
2. Pathophysiology of Atrophy in MS
First of all it is important to understand that the pathology
underlying atrophy is the result of multiple mechanisms, and
these mechanisms may not be constant over time in
individuals and populations. [13] More and less aggressive
variations may be associated with disease phenotype and,
possibly, histopathology types [14-17]. Disease phenotypes
and lesions at various stages are responsible of composite of
(transient) volume-gaining (edema by inflammatory
demyelination) and volume-losing processes obtained by MRI
volumetry. Inflammation and its transiently increased volume
effects can confound the interpretation of atrophy measures
after successful treatment, when treatment reduces the
inflammatory CNS volume, causing a pseudoatrophy [18, 19].
When axonal injury occurs, several potential mechanisms
could explain the amplifying functional and structural
consequences, the latter resulting in additional volume loss.
These include Wallerian degeneration (axonal distal segment)
and retrograde or anterograde transneuronal degeneration [20,
21].
Na+ channels and axonal degeneration
The available evidence suggests that Na+ channels are
important participants in axonal degeneration in MS. Nav1.6
are the predominant Na+ channel isoform found in axonal
membranes in the CNS in mature nodes of Ranvier [22, 23].
When an axon is demyelinated acquires higher and diffuse
expression of Nav1.6 producing a persistent Na+ current that
can drive the Na+–Ca2+ exchanger to operate in a reverse
mode, importing Ca2+ and triggering secondary cascades and
axonal damage [23, 24]. In addition, NO-induced
mitochondrial damage, changes in mitochondrial gene
expression, and hypoxia/ischaemia due to perivascular
inflammation seem to contribute to axonal energy failure,
which in turn leads to loss of function of Na+/K+ ATPase and
impaired ability of the axon to maintain resting potential and
to export Na+ [25, 26]. Great Ca2+ influx into the axon
triggers calcium-induced calcium release from internal stores,
and the activation of NO synthase, proteases and lipases.
Nav1.6 channels are also involved in the activation of
microglia and macrophages, which contribute to the
production of NO, and in phagocytosis by these cells [27].
It is also possible that some axons degenerate in MS in the
absence of demyelination. Therefore, if the inadequacy of ATP
supply in MS occurs in neurons in which axons are not
demyelinated, the axons might be suffered Ca2+-mediated
injury [26, 27].
3. Methods for Measuring Brain Atrophy
The MRI methods available to measure brain volume fall
into two main categories: longitudinal or cross-sectional
segmentation-based (cross-sectional) and registration-based
(longitudinal) techniques. Longitudinal methods measure
change in brain volume over time by comparing two MRI
scans acquired at different time points [28]. Cross-sectional
methods measure brain volume at a single time point using a
single MRI scan (Table 1).
Segmentation techniques can measure the whole brain
volume or any specific brain structure. Within the
segmentation-based method is the BPF, which measure the
ratio between brain parenchymal tissue with the total
intracranial volume (cerebrospinal fluid and brain tissue). BPF
is an automatic method that takes into account the variability
of head size [29]. The quantitative two dimensional measures
of lateral or third ventricular volume/width can be used easily
in daily practice [30].
In the registration-based method, serial scans of the patients
are compared, the SIENA is an automatic method
registration-based with longitudinal purpose and limited
regional analysis. SIENAX is its cross sectional variant [31].
The other method is the voxel-based morphometry (VBM)
which allows the entire brain to be explored regional with
cross sectional or longitudinal purposes [32, 33].
BPF and SIENA are the most frequently used methods to
measure brain volume in clinical practice and in MS trials
[34-36].
Table 1. Most common MRI methods to measure brain volume loss in MS.
Ventricular volumes (VV)
Structural Image Evaluation, using Normalisation of Atrophy (SIENA)
Structural Image Evaluation, using Normalisation of Atrophy - cross
sectional (SIENAX)
Brain Parenchymal Fraction (BPF)
Voxel-Based Morphometry (VBM)
4. Which is the Annual Rate of Atrophy
and is Stable Process over Time
As healthy people age, brain volume decreases as part of a
normal process. It has been estimated that this rate of annual
brain volume loss in healthy subjects ranges from 0.1% to
0.3% [34, 37]. Studies have shown that the rate of brain
volume loss in patients with MS is higher, ranging from 0.5%
to 1.3% annually [12, 38-42].
The rate of brain atrophy in an individual patient may be
affected by a number of factors, MS phenotype, toxic agents,
genetic factors and the presence of MS inflammatory lesions.
Patients with the apolipoprotein E-ε4 genotype showed an
annual increase in brain volume loss five times higher than in
patients without this genotype [43], although other studies
could not show this relation with brain atrophy [44].
The estimates of brain atrophy rates have varied between
studies when compared different MS subtypes. Many studies
have shown higher or similar [9, 38, 41, 45, 46] atrophy
progression in secondary progressive MS (SPMS) patients
when compared to those at earlier stages of MS. De Stefano et
al, [39] found heterogeneity in percent brain volume change
(PBVC) across MS subtypes and different stage disease.
Interestingly, however, this heterogeneity disappeared when
PBVC values were corrected for the baseline normalized brain
volume (NBV). This suggests that the rate of atrophy
progression is very similar in the different MS subtypes and, at
late disease stages, does not seem to show nonlinear

American Journal of Psychiatry and Neuroscience 2015; 3(3): 40-49 42
progression [9] or a true acceleration [39]. For the patients
with CIS, brain atrophy rates are greater in patients who are
worsening clinically. This indicate that measures of brain
atrophy should have relevance on clinical progression.
Perhaps measures of gray matter atrophy could show
correlation with measures of cognitive impairment [47, 48].
5. How Early Begins the Atrophy and
which is the Gray Matter Damage
MS was traditionally considered to be primarily a white
matter disorder, it has become apparent during the last decade
that brain atrophy and specially grey matter atrophy, occurs
from the earliest stages. Many studies support the idea of an
early onset of whole brain atrophy, specially grey matter
atrophy, in the first year after CIS and predicts conversion in
MS [49-51].
Filippi et al [40] found that in early MS, mean whole brain
NAA was reduced by 22% compared with healthy controls (p
< 0.0001) and this change did not correlate with T2-lesion
volume (diffuse damage). This finding suggests that
widespread irreversible axonal pathology is independent of
MRI-detectable inflammation and is present at early stages of
disease, perhaps even before diagnosis [40, 52, 53].
Brain atrophy rates are higher in those CIS patients who
subsequently develop MS compared with those who remain
CIS [50, 53-55]. In the ETOMS (Early Treatment of Multiple
Sclerosis) trial, a difference in median annual PBVC was
found between patients who developed clinical definitive MS
(CDMS) versus patients who did not (0.92% and 0.56%,
respectively) [56]. Pérez-Miralles et al [57] also found similar
results, those patients with a second attack had larger PBVC
change (-0.65% versus +0.059%; p < 0.001) concluding that
global brain and grey matter volume loss occurred within the
first year after a CIS and predicts conversion to MS.
Several studies show that gray matter volume loss in MS
occurs early in the disease, both deep gray (eg. thalamus) as
well as the cortical gray matter [58-60]. Dalton et al [54]
showed that progressive gray matter, and not white matter
atrophy, was seen in the population progressing to a diagnosis
of MS after a CIS and is related to physical disability and
cognitive impairment.
It was reported that neocortical atrophy was a prominent
feature of relapsing remitting MS (RRMS), and suggested that
neocortical atrophy occurs in the earliest stages of MS and is
even seen when white matter lesion accumulation is minimal
[12, 39, 57, 59]. Many studies have shown that in MS patients
there is diffuse cortical atrophy and thinning of the cerebral
cortex. Sailer et al. [61] showed that the mean overall
thickness of the cortical ribbon in MS patients was 2.30 mm,
compared with 2.48 mm in healthy controls. In addition,
patients with severe disability and/or long-standing course
showed marked focal thinning of the motor cortex (mean 2.35
mm vs 2.74 mm) [61]. Other studies of early MS showed
greater atrophy of gray matter than of white matter [51, 59,
62].
It has been shown that the normalised thalamic volume in
MS patients was decreased by an average of 17%, compared
with healthy controls, and the mean width of the third
ventricle was increased by two-fold [11].
It is unknown whether these losses are due to focal or more
diffuse gray matter pathology, nor the relative contribution of
direct axonal injury nor retrograde degeneration [61, 63, 64].
The pattern of cortical atrophy in patients with RRMS were
found in the anterior cingulate cortex, the insula and the
transverse temporal gyrus [65]. This pattern differs from that
seen in normal ageing, in which, the atrophy occurs mainly in
the primary motor and premotor cortices, the prefrontal cortex
and the calcarine cortex [66].
6. Clinical Signification
One of the MRI measures that have been proposed to assess
MS progression (physical and cognitive disability) is the
estimation of brain and spinal atrophy [5, 41, 48, 67-71]. Due
to a relative short follow-up periods of 6 months to 3 years,
previous longitudinal studies in MS have not shown consistent
or strong relation between brain atrophy and disability [30, 72,
73].
Gray matter atrophy correlates and predicts both physical
and cognitive disability in MS patients [74-78].
Fisher et al [6] showed the relation between atrophy
progression and later neurologic disability, suggesting that
atrophy progression during RRMS is clinically relevant and
may be used as useful marker for disease progression. Amato
et al. have shown that in patients with radiological isolated
syndrome, 27.6% of patients have signs of cognitive
impairment similar to those of RRMS [79]. Fisniku et al [80]
showed that GM, but not WM, fraction correlated with
expanded disability status scale (p < 0.001) and MS
Functional Composite scores (p < 0.001). Corpus Callosum
(CC) atrophy was associated with cognitive impairment
measured with the verbal fluency test (VFT), Symbol Digit
Modalities Test (SDMT) and Paced Auditory Serial Addition
Test (PASAT). The atrophy of the anterior CC segment was
significantly associated with fatigue severity and poor
outcome in the long-term memory test [81]. Using various
cognitive tests, localized cortical atrophy in the prefrontal,
parietal, temporal and insular regions has been associated with
deficits in verbal memory, information processing speed and
attention [82, 83]. Sailer et al. [61] showed significant
negative correlations between Expanded Disability Status
Scale (EDSS) scores and global cortical thickness (p= 0.011)
and the mean thickness of the motor cortex (p= 0.001).
Similary, in a case-control study there were significant
negative correlations between EDSS scores and the thickness
of the right parahippocampal (p ≤0.01), left lateral occipital (p
≤0.01) and left postcentral cortex (p≤0.001), and between
EDSS scores and the volumes of the right caudate (p ≤0.01)
and right nucleus accumbens (p ≤0.01) [84]. Rudick et al. [85]
found a correlation between progression of grey matter
atrophy and Multiple Sclerosis Functional Composite (MSFC)
scores, but not between atrophy and EDSS scores.

43 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
Cognitive impairment, affecting attention, memory and
information processing speed, may be present in up to 70% of
MS patients [86, 87], and within first years in the disease [88].
In a study of patients with RRMS, the cognitive impairment
was correlated with significantly smaller normalised brain
volumes and normalised neocortical grey matter volumes than
those with normal cognition [89]. Cortical atrophy appears to
be a good predictor of cognitive impairment, because even
mild impairment has been shown to be associated with
significant cortical thinning [90]. Significant correlations have
also been reported between cognitive impairment and
thalamic atrophy [91].
The deep gray matter volumes (basal ganglia and especially
the thalamus) are correlated with disability and cognitive
impairment, with information processing speed [91, 92],
fatigue [81, 93] and EDSS scores [94, 95].
7. Treatments
In general, prospective studies with interferon- (IFN) β and
glatiramer acetate (GA) have shown limited and inconsistent
evidence for a beneficial effect on brain atrophy (Table 2).
Table 2. Brain volume outcomes
Treatment Phase Duration Clinical type n Results
Placebo controlled trials
IFN-ß 1b SC Phase III 5 years CIS 468 NS
IFN-ß 1b SC Phase III 3 years SPMS 718 NS
IFN-ß 1a IM Phase III 2 years RRMS 172 NS
IFN-ß 1a SC Phase III 2 years CIS 309 NS
GA Phase III 1.5 years RRMS 207 SIG
GA Phase III 5 years CIS 409 SIG (early vs delayed tx)
Natalizumab Observational 2 years RRMS 39 SIG (WM)
Natalizumab Phase III 2 years RRMS 942 NS
Fingolimod Phase III 2 years RRMS 1272 SIG
Laquinimod Phase III 2 years RRMS 1331 SIG
Laquinimod Phase III 2 years RRMS 1106 SIG
Teriflunomide Phase III 2 years RRMS 1088 NS
DMF Phase III 2 years RRMS 540 SIG (bid), NS (tid)
DMF Phase III 2 years RRMS 681 NS
Active comparator controlled trials
IFN-ß 1b SC (vs GA) Phase III 3.5 years RRMS 2244 NS
IFN-ß 1a IM (dose comparison) Phase III 3 years RRMS 189 SIG
GA (vs INF ß) Post hoc 2 years RRMS 86 SIG (GM)
GA (vs IFN ß) Retrospective 5 years RRMS 275 SIG
Daclizumab (vs IFN, GA) Post hoc 11 years RRMS 70 SIG
Natalizumab (vs IFN ß) Pilot study 1.5 years RRMS 26 SIG
Alemtuzumab (vs IFN-ß 1a SC) Phase II 3 years RRMS 334 SIG
Alemtuzumab Phase III 2 years RRMS 840 SIG
Alemtuzumab Phase III 2 years RRMS 581 SIG
Fingolimod Phase III 1 year RRMS 1292 SIG
bid: twice daily, CIS: clinically isolated syndrome, DMF: dimethyl fumarate, GA: glatiramer acetate, GM: grey matter, IFN: interferon, IM: intramuscular, NS:
not significant, SIG: significant, RRMS: relapsing remitting MS, SPMS: secondary progressive MS, tid: three times daily, WM: white matter
Today we know that the pathophysiology of MS involves
inflammation, neurodegeneration and the failure of the repair
mechanisms. Classically the disease modifying treatments
have controlled the inflammatory component of the disease.
Recently, various trials have begun to evaluate the rate of
brain volume loss have yielded mixed results for the reasons
mentioned above.
The need of drugs not only against the inflammatory
process is obvious, but also we need drugs that prevent or
reduce the progression of brain atrophy and/or facilitate the
repair mechanisms.
Currently, there is no disease modifying therapy available
that completely stop the evolution from RRMS to the
progressive phase of the disease.
Zivadinov et al, [96] investigated the effects of intravenous
methylprednisolone on brain atrophy and disability
progression of 88 patients with RRMS. Patients received
either pulsed intravenous methylprednisolone (IVMP) (1

American Journal of Psychiatry and Neuroscience 2015; 3(3): 40-49 44
g/day for five days with oral prednisone taper) every four
months for three years and then every six months for two
subsequent years, or IVMP (1 g/day for five days with oral
prednisone taper) only for relapses, without other disease
modifying drugs. At the end of the five-year period, treatment
with pulsed IVMP significantly slowed development of T1
black holes (p < 0.0001), slowed brain atrophy and disability
progression (p = 0.003) [96].
For subcutaneous interferon β 1a, [97] [61], a study of 519
patients over two years with relapsing MS, found no treatment
effect. For IFN β 1b (8 MIU subcutaneous) in relapsing MS,
no large trial data are available.
In study of 227 patients with relapsing MS no atrophy was
detected with GA, over the nine-month double-blind phase of
the study [18].
In TEMSO trial changes of brain volume did not differ
significantly among the three study groups (teriflunomide 7
mg vs placebo, p=0.19; teriflunomide 14 mg vs placebo
p=0.35) [98].
Dimethyl fumarate (BG-12) presents inconsistent data
relating to the decrease in brain volume loss in the two
published trials against placebo. In the CONFIRM study the
difference fail to reach statistical power [99]. In the DEFINE
study the difference was significant in the 240 mg twice daily
arm, but not in 240 mg three times daily arm [100].
Decreases in brain atrophy in RRMS patients have also
been reported with laquinimod [101].
Fingolimod have shown consistent data about decrease
brain volume loss in its three pivotal trials and their extensions
(Figure 2). In FREEDOMS trial, [102] fingolimod
significantly reduced the brain volume loss over 2 years,
compared with placebo (relative reduction, 35%; p<0.001), in
the FREEDOMS II [103] trial patients given placebo had
increased brain volume loss compared with those given
fingolimod at months 6, 12, and 24 (relative reduction, 33%;
p<0.001), and in the TRANSFORMS trial, [104] fingolimod
treatment resulted in a significantly lower rate of brain atrophy
than intramuscular IFNβ-1a (relative reduction, 32%;
p<0.001).
Figure 2. Brain volume loss in phase III trials of Fingolimod (*p=0.05, **p=0.01, ***p=0.001).
8. Conclusion
MS was historically considered as an inflammatory disease
of the white matter (focal damage). Today there is much
evidence that supports, in addition, the affection of the gray
matter and neurodegenerative mechanisms, which are at least
partially independent of the inflammation.
The atrophy of the GM develops faster than WM atrophy
and predominates in early disease stages. The
neurodegenerative mechanism, produces permanent damage
and appears to correlate with physical and cognitive disability
of the patient.
Given this, it is vital the early treatment of MS with drugs
that control the inflammatory component and reduce the rate
of brain volume loss.
Conflict of Interests
Dr. Gustavo Seifer is Medical Scientific Liaison (MSL) for
Novartis Argentina.
Dr. Gaston Kuperman is Medical Manager for Novartis
Argentina.
References
[1] A. Compston, and A. Coles, "Multiple sclerosis," Lancet, vol.
359, no. 9313, pp. 1221-31, 2002.
[2] D. Miller, F. Barkhof, X. Montalban, A. Thompson, and M.
Filippi, "Clinically isolated syndromes suggestive of multiple
sclerosis, part 2: non-conventional MRI, recovery processes,
and management," Lancet Neurol, vol. 4, no. 6, pp. 341-8,
2005.

45 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
[3] D. Miller, F. Barkhof, X. Montalban, A. Thompson, and M.
Filippi, "Clinically isolated syndromes suggestive of multiple
sclerosis, part I: natural history, pathogenesis, diagnosis, and
prognosis," Lancet Neurol, vol. 4, no. 5, pp. 281-8, 2005.
[4] J. H. Noseworthy, C. Lucchinetti, M. Rodriguez, and B. G.
Weinshenker, "Multiple sclerosis," N Engl J Med, vol. 343, no.
13, pp. 938-52, 2000.
[5] J. H. Simon, "Brain and spinal cord atrophy in multiple
sclerosis: role as a surrogate measure of disease progression,"
CNS Drugs, vol. 15, no. 6, pp. 427-36, 2001.
[6] E. Fisher, R. A. Rudick, J. H. Simon, G. Cutter, M. Baier, J. C.
Lee, D. Miller, B. Weinstock-Guttman, M. K. Mass, D. S.
Dougherty, and N. A. Simonian, "Eight-year follow-up study of
brain atrophy in patients with MS," Neurology, vol. 59, no. 9,
pp. 1412-20, 2002.
[7] D. H. Miller, F. Barkhof, J. A. Frank, G. J. Parker, and A. J.
Thompson, "Measurement of atrophy in multiple sclerosis:
pathological basis, methodological aspects and clinical
relevance," Brain, vol. 125, no. Pt 8, pp. 1676-95, 2002.
[8] H. Vrenken, M. Jenkinson, M. A. Horsfield, M. Battaglini, R. A.
van Schijndel, E. Rostrup, J. J. Geurts, E. Fisher, A. Zijdenbos,
J. Ashburner, D. H. Miller, M. Filippi, F. Fazekas, M. Rovaris,
A. Rovira, F. Barkhof, and N. de Stefano, "Recommendations
to improve imaging and analysis of brain lesion load and
atrophy in longitudinal studies of multiple sclerosis," J Neurol,
2012.
[9] N. C. Fox, R. Jenkins, S. M. Leary, V. L. Stevenson, N. A.
Losseff, W. R. Crum, R. J. Harvey, M. N. Rossor, D. H. Miller,
and A. J. Thompson, "Progressive cerebral atrophy in MS: a
serial study using registered, volumetric MRI," Neurology, vol.
54, no. 4, pp. 807-12, 2000.
[10] M. Wylezinska, A. Cifelli, P. Jezzard, J. Palace, M. Alecci, and
P. M. Matthews, "Thalamic neurodegeneration in
relapsing-remitting multiple sclerosis," Neurology, vol. 60, no.
12, pp. 1949-54, 2003.
[11] A. Cifelli, M. Arridge, P. Jezzard, M. M. Esiri, J. Palace, and P.
M. Matthews, "Thalamic neurodegeneration in multiple
sclerosis," Ann Neurol, vol. 52, no. 5, pp. 650-3, 2002.
[12] N. De Stefano, P. M. Matthews, M. Filippi, F. Agosta, M. De
Luca, M. L. Bartolozzi, L. Guidi, A. Ghezzi, E. Montanari, A.
Cifelli, A. Federico, and S. M. Smith, "Evidence of early
cortical atrophy in MS: relevance to white matter changes and
disability," Neurology, vol. 60, no. 7, pp. 1157-62, 2003.
[13] J. H. Simon, "Brain atrophy in multiple sclerosis: what we
know and would like to know," Mult Scler, vol. 12, no. 6, pp.
679-87, 2006.
[14] C. F. Lucchinetti, W. Bruck, M. Rodriguez, and H. Lassmann,
"Distinct patterns of multiple sclerosis pathology indicates
heterogeneity on pathogenesis," Brain Pathol, vol. 6, no. 3, pp.
259-74, 1996.
[15] M. Filippi, M. A. Rocca, F. Barkhof, W. Bruck, J. T. Chen, G.
Comi, G. DeLuca, N. De Stefano, B. J. Erickson, N. Evangelou,
F. Fazekas, J. J. Geurts, C. Lucchinetti, D. H. Miller, D.
Pelletier, B. F. Popescu, and H. Lassmann, "Association
between pathological and MRI findings in multiple sclerosis,"
Lancet Neurol, vol. 11, no. 4, pp. 349-60, 2012.
[16] N. Evangelou, G. C. DeLuca, T. Owens, and M. M. Esiri,
"Pathological study of spinal cord atrophy in multiple sclerosis
suggests limited role of local lesions," Brain, vol. 128, no. Pt 1,
pp. 29-34, 2005.
[17] G. C. DeLuca, G. C. Ebers, and M. M. Esiri, "Axonal loss in
multiple sclerosis: a pathological survey of the corticospinal
and sensory tracts," Brain, vol. 127, no. Pt 5, pp. 1009-18,
2004.
[18] M. Rovaris, G. Comi, M. A. Rocca, J. S. Wolinsky, M. Filippi,
and G. European/Canadian Glatiramer Acetate Study,
"Short-term brain volume change in relapsing-remitting
multiple sclerosis: effect of glatiramer acetate and
implications," Brain, vol. 124, no. Pt 9, pp. 1803-12, 2001.
[19] A. Vidal-Jordana, J. Sastre-Garriga, F. Perez-Miralles, C. Tur,
M. Tintore, A. Horga, C. Auger, J. Rio, C. Nos, M. C. Edo, M. J.
Arevalo, J. Castillo, A. Rovira, and X. Montalban, "Early brain
pseudoatrophy while on natalizumab therapy is due to white
matter volume changes," Mult Scler, vol. 19, no. 9, pp. 1175-81,
2013.
[20] M. P. Coleman, and V. H. Perry, "Axon pathology in
neurological disease: a neglected therapeutic target," Trends
Neurosci, vol. 25, no. 10, pp. 532-7, 2002.
[21] C. Bjartmar, and B. D. Trapp, "Axonal degeneration and
progressive neurologic disability in multiple sclerosis,"
Neurotox Res, vol. 5, no. 1-2, pp. 157-64, 2003.
[22] J. H. Caldwell, K. L. Schaller, R. S. Lasher, E. Peles, and S. R.
Levinson, "Sodium channel Na(v)1.6 is localized at nodes of
ranvier, dendrites, and synapses," Proc Natl Acad Sci U S A, vol.
97, no. 10, pp. 5616-20, 2000.
[23] M. J. Craner, J. Newcombe, J. A. Black, C. Hartle, M. L.
Cuzner, and S. G. Waxman, "Molecular changes in neurons in
multiple sclerosis: altered axonal expression of Nav1.2 and
Nav1.6 sodium channels and Na+/Ca2+ exchanger," Proc Natl
Acad Sci U S A, vol. 101, no. 21, pp. 8168-73, 2004.
[24] M. J. Craner, T. G. Damarjian, S. Liu, B. C. Hains, A. C. Lo, J.
A. Black, J. Newcombe, M. L. Cuzner, and S. G. Waxman,
"Sodium channels contribute to microglia/macrophage
activation and function in EAE and MS," Glia, vol. 49, no. 2,
pp. 220-9, 2005.
[25] K. J. Smith, and H. Lassmann, "The role of nitric oxide in
multiple sclerosis," Lancet Neurol, vol. 1, no. 4, pp. 232-41,
2002.
[26] R. Dutta, J. McDonough, X. Yin, J. Peterson, A. Chang, T.
Torres, T. Gudz, W. B. Macklin, D. A. Lewis, R. J. Fox, R.
Rudick, K. Mirnics, and B. D. Trapp, "Mitochondrial
dysfunction as a cause of axonal degeneration in multiple
sclerosis patients," Ann Neurol, vol. 59, no. 3, pp. 478-89,
2006.
[27] S. G. Waxman, "Axonal conduction and injury in multiple
sclerosis: the role of sodium channels," Nat Rev Neurosci, vol.
7, no. 12, pp. 932-41, 2006.
[28] A. Giorgio, M. Battaglini, S. M. Smith, and N. De Stefano,
"Brain atrophy assessment in multiple sclerosis: importance
and limitations," Neuroimaging Clin N Am, vol. 18, no. 4, pp.
675-86, xi, 2008.
[29] R. A. Rudick, E. Fisher, J. C. Lee, J. Simon, and L. Jacobs,
"Use of the brain parenchymal fraction to measure whole brain
atrophy in relapsing-remitting MS. Multiple Sclerosis
Collaborative Research Group," Neurology, vol. 53, no. 8, pp.
1698-704, 1999.

American Journal of Psychiatry and Neuroscience 2015; 3(3): 40-49 46
[30] J. H. Simon, L. D. Jacobs, M. K. Campion, R. A. Rudick, D. L.
Cookfair, R. M. Herndon, J. R. Richert, A. M. Salazar, J. S.
Fischer, D. E. Goodkin, N. Simonian, M. Lajaunie, D. E. Miller,
K. Wende, A. Martens-Davidson, R. P. Kinkel, F. E.
Munschauer, 3rd, and C. M. Brownscheidle, "A longitudinal
study of brain atrophy in relapsing multiple sclerosis. The
Multiple Sclerosis Collaborative Research Group (MSCRG),"
Neurology, vol. 53, no. 1, pp. 139-48, 1999.
[31] S. M. Smith, Y. Zhang, M. Jenkinson, J. Chen, P. M. Matthews,
A. Federico, and N. De Stefano, "Accurate, robust, and
automated longitudinal and cross-sectional brain change
analysis," Neuroimage, vol. 17, no. 1, pp. 479-89, 2002.
[32] J. Ashburner, and K. J. Friston, "Voxel-based
morphometry--the methods," Neuroimage, vol. 11, no. 6 Pt 1,
pp. 805-21, 2000.
[33] C. D. Good, I. S. Johnsrude, J. Ashburner, R. N. Henson, K. J.
Friston, and R. S. Frackowiak, "A voxel-based morphometric
study of ageing in 465 normal adult human brains,"
Neuroimage, vol. 14, no. 1 Pt 1, pp. 21-36, 2001.
[34] F. Barkhof, P. A. Calabresi, D. H. Miller, and S. C. Reingold,
"Imaging outcomes for neuroprotection and repair in multiple
sclerosis trials," Nat Rev Neurol, vol. 5, no. 5, pp. 256-66, 2009.
[35] F. Barkhof, and M. Filippi, "MRI--the perfect surrogate marker
for multiple sclerosis?," Nat Rev Neurol, vol. 5, no. 4, pp. 182-3,
2009.
[36] R. A. Bermel, and R. Bakshi, "The measurement and clinical
relevance of brain atrophy in multiple sclerosis," Lancet Neurol,
vol. 5, no. 2, pp. 158-70, 2006.
[37] A. F. Fotenos, M. A. Mintun, A. Z. Snyder, J. C. Morris, and R.
L. Buckner, "Brain volume decline in aging: evidence for a
relation between socioeconomic status, preclinical Alzheimer
disease, and reserve," Arch Neurol, vol. 65, no. 1, pp. 113-20,
2008.
[38] E. Pagani, M. A. Rocca, A. Gallo, M. Rovaris, V. Martinelli, G.
Comi, and M. Filippi, "Regional brain atrophy evolves
differently in patients with multiple sclerosis according to
clinical phenotype," AJNR Am J Neuroradiol, vol. 26, no. 2, pp.
341-6, 2005.
[39] N. De Stefano, A. Giorgio, M. Battaglini, M. Rovaris, M. P.
Sormani, F. Barkhof, T. Korteweg, C. Enzinger, F. Fazekas, M.
Calabrese, D. Dinacci, G. Tedeschi, A. Gass, X. Montalban, A.
Rovira, A. Thompson, G. Comi, D. H. Miller, and M. Filippi,
"Assessing brain atrophy rates in a large population of
untreated multiple sclerosis subtypes," Neurology, vol. 74, no.
23, pp. 1868-76, 2010.
[40] M. Filippi, M. Bozzali, M. Rovaris, O. Gonen, C. Kesavadas, A.
Ghezzi, V. Martinelli, R. I. Grossman, G. Scotti, G. Comi, and A.
Falini, "Evidence for widespread axonal damage at the earliest
clinical stage of multiple sclerosis," Brain, vol. 126, no. Pt 2, pp.
433-7, 2003.
[41] N. F. Kalkers, N. Ameziane, J. C. Bot, A. Minneboo, C. H.
Polman, and F. Barkhof, "Longitudinal brain volume
measurement in multiple sclerosis: rate of brain atrophy is
independent of the disease subtype," Arch Neurol, vol. 59, no.
10, pp. 1572-6, 2002.
[42] R. Zivadinov, J. Sepcic, D. Nasuelli, R. De Masi, L. M.
Bragadin, M. A. Tommasi, S. Zambito-Marsala, R. Moretti, A.
Bratina, M. Ukmar, R. S. Pozzi-Mucelli, A. Grop, G. Cazzato,
and M. Zorzon, "A longitudinal study of brain atrophy and
cognitive disturbances in the early phase of relapsing-remitting
multiple sclerosis," J Neurol Neurosurg Psychiatry, vol. 70, no.
6, pp. 773-80, 2001.
[43] R. M. Vigeveno, O. T. Wiebenga, M. P. Wattjes, J. J. Geurts,
and F. Barkhof, "Shifting imaging targets in multiple sclerosis:
from inflammation to neurodegeneration," J Magn Reson
Imaging, vol. 36, no. 1, pp. 1-19, 2012.
[44] O. Fernandez, J. C. Alvarez-Cermeno, R. Arroyo-Gonzalez, L.
Brieva, M. C. Calles-Hernandez, B. Casanova-Estruch, M.
Comabella, V. de las Heras, J. A. Garcia-Merino, M. A.
Hernandez-Perez, G. Izquierdo, J. E. Meca-Lallana, D.
Munoz-Garcia, J. Olascoaga, C. Oreja-Guevara, J. M. Prieto, L.
Ramio-Torrenta, A. Rodriguez-Antiguedad, L. Romero-Pinel,
F. Sanchez, N. Tellez, M. Tintore, X. Montalban, and E. g. Post,
"Review of the novelties presented at the 27th Congress of the
European Committee for Treatment and Research in Multiple
Sclerosis (ECTRIMS) (I)," Rev Neurol, vol. 54, no. 11, pp.
677-91, 2012.
[45] M. Rovaris, G. Comi, M. A. Rocca, M. Cercignani, B. Colombo,
G. Santuccio, and M. Filippi, "Relevance of hypointense
lesions on fast fluid-attenuated inversion recovery MR images
as a marker of disease severity in cases of multiple sclerosis,"
AJNR Am J Neuroradiol, vol. 20, no. 5, pp. 813-20, 1999.
[46] M. Rovaris, F. Agosta, M. P. Sormani, M. Inglese, V. Martinelli,
G. Comi, and M. Filippi, "Conventional and magnetization
transfer MRI predictors of clinical multiple sclerosis evolution:
a medium-term follow-up study," Brain, vol. 126, no. Pt 10, pp.
2323-32, 2003.
[47] M. P. Amato, E. Portaccio, B. Goretti, V. Zipoli, M. Battaglini,
M. L. Bartolozzi, M. L. Stromillo, L. Guidi, G. Siracusa, S.
Sorbi, A. Federico, and N. De Stefano, "Association of
neocortical volume changes with cognitive deterioration in
relapsing-remitting multiple sclerosis," Arch Neurol, vol. 64,
no. 8, pp. 1157-61, 2007.
[48] M. P. Amato, L. Razzolini, B. Goretti, M. L. Stromillo, F. Rossi,
A. Giorgio, B. Hakiki, M. Giannini, L. Pasto, E. Portaccio, and
N. De Stefano, "Cognitive reserve and cortical atrophy in
multiple sclerosis: a longitudinal study," Neurology, vol. 80, no.
19, pp. 1728-33, 2013.
[49] J. I. Rojas, L. Patrucco, C. Besada, L. Bengolea, and E.
Cristiano, "[Brain atrophy in clinically isolated syndrome],"
Neurologia, vol. 25, no. 7, pp. 430-4, 2010.
[50] M. Di Filippo, V. M. Anderson, D. R. Altmann, J. K. Swanton,
G. T. Plant, A. J. Thompson, and D. H. Miller, "Brain atrophy
and lesion load measures over 1 year relate to clinical status
after 6 years in patients with clinically isolated syndromes," J
Neurol Neurosurg Psychiatry, vol. 81, no. 2, pp. 204-8, 2010.
[51] M. Tiberio, D. T. Chard, D. R. Altmann, G. Davies, C. M.
Griffin, W. Rashid, J. Sastre-Garriga, A. J. Thompson, and D. H.
Miller, "Gray and white matter volume changes in early RRMS:
a 2-year longitudinal study," Neurology, vol. 64, no. 6, pp.
1001-7, 2005.
[52] H. Lassmann, "Brain damage when multiple sclerosis is
diagnosed clinically," Lancet, vol. 361, no. 9366, pp. 1317-8,
2003.
[53] C. M. Dalton, P. A. Brex, R. Jenkins, N. C. Fox, K. A. Miszkiel,
W. R. Crum, J. I. O'Riordan, G. T. Plant, A. J. Thompson, and D.
H. Miller, "Progressive ventricular enlargement in patients with
clinically isolated syndromes is associated with the early
development of multiple sclerosis," J Neurol Neurosurg
Psychiatry, vol. 73, no. 2, pp. 141-7, 2002.

47 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
[54] C. M. Dalton, D. T. Chard, G. R. Davies, K. A. Miszkiel, D. R.
Altmann, K. Fernando, G. T. Plant, A. J. Thompson, and D. H.
Miller, "Early development of multiple sclerosis is associated
with progressive grey matter atrophy in patients presenting
with clinically isolated syndromes," Brain, vol. 127, no. Pt 5,
pp. 1101-7, 2004.
[55] K. T. Fernando, M. A. McLean, D. T. Chard, D. G. MacManus,
C. M. Dalton, K. A. Miszkiel, R. M. Gordon, G. T. Plant, A. J.
Thompson, and D. H. Miller, "Elevated white matter
myo-inositol in clinically isolated syndromes suggestive of
multiple sclerosis," Brain, vol. 127, no. Pt 6, pp. 1361-9, 2004.
[56] M. Filippi, M. Rovaris, M. Inglese, F. Barkhof, N. De Stefano,
S. Smith, and G. Comi, "Interferon beta-1a for brain tissue loss
in patients at presentation with syndromes suggestive of
multiple sclerosis: a randomised, double-blind,
placebo-controlled trial," Lancet, vol. 364, no. 9444, pp.
1489-96, 2004.
[57] F. Perez-Miralles, J. Sastre-Garriga, M. Tintore, G. Arrambide,
C. Nos, H. Perkal, J. Rio, M. Edo, A. Horga, J. Castillo, C.
Auger, E. Huerga, A. Rovira, and X. Montalban, "Clinical
impact of early brain atrophy in clinically isolated syndromes,"
Mult Scler, 2013.
[58] M. Quarantelli, A. Ciarmiello, V. B. Morra, G. Orefice, M.
Larobina, R. Lanzillo, V. Schiavone, E. Salvatore, B. Alfano,
and A. Brunetti, "Brain tissue volume changes in
relapsing-remitting multiple sclerosis: correlation with lesion
load," Neuroimage, vol. 18, no. 2, pp. 360-6, 2003.
[59] D. T. Chard, C. M. Griffin, G. J. Parker, R. Kapoor, A. J.
Thompson, and D. H. Miller, "Brain atrophy in clinically early
relapsing-remitting multiple sclerosis," Brain, vol. 125, no. Pt 2,
pp. 327-37, 2002.
[60] J. Sastre-Garriga, G. T. Ingle, D. T. Chard, L. Ramio-Torrenta,
D. H. Miller, and A. J. Thompson, "Grey and white matter
atrophy in early clinical stages of primary progressive multiple
sclerosis," Neuroimage, vol. 22, no. 1, pp. 353-9, 2004.
[61] M. Sailer, B. Fischl, D. Salat, C. Tempelmann, M. A. Schonfeld,
E. Busa, N. Bodammer, H. J. Heinze, and A. Dale, "Focal
thinning of the cerebral cortex in multiple sclerosis," Brain, vol.
126, no. Pt 8, pp. 1734-44, 2003.
[62] D. T. Chard, C. M. Griffin, W. Rashid, G. R. Davies, D. R.
Altmann, R. Kapoor, G. J. Barker, A. J. Thompson, and D. H.
Miller, "Progressive grey matter atrophy in clinically early
relapsing-remitting multiple sclerosis," Mult Scler, vol. 10, no.
4, pp. 387-91, 2004.
[63] D. Kidd, F. Barkhof, R. McConnell, P. R. Algra, I. V. Allen, and
T. Revesz, "Cortical lesions in multiple sclerosis," Brain, vol.
122 ( Pt 1), pp. 17-26, 1999.
[64] L. Bo, C. A. Vedeler, H. I. Nyland, B. D. Trapp, and S. J. Mork,
"Subpial demyelination in the cerebral cortex of multiple
sclerosis patients," J Neuropathol Exp Neurol, vol. 62, no. 7, pp.
723-32, 2003.
[65] A. Charil, A. Dagher, J. P. Lerch, A. P. Zijdenbos, K. J. Worsley,
and A. C. Evans, "Focal cortical atrophy in multiple sclerosis:
relation to lesion load and disability," Neuroimage, vol. 34, no.
2, pp. 509-17, 2007.
[66] D. H. Salat, R. L. Buckner, A. Z. Snyder, D. N. Greve, R. S.
Desikan, E. Busa, J. C. Morris, A. M. Dale, and B. Fischl,
"Thinning of the cerebral cortex in aging," Cereb Cortex, vol.
14, no. 7, pp. 721-30, 2004.
[67] N. A. Losseff, S. L. Webb, J. I. O'Riordan, R. Page, L. Wang, G.
J. Barker, P. S. Tofts, W. I. McDonald, D. H. Miller, and A. J.
Thompson, "Spinal cord atrophy and disability in multiple
sclerosis. A new reproducible and sensitive MRI method with
potential to monitor disease progression," Brain, vol. 119 ( Pt
3), pp. 701-8, 1996.
[68] A. Minneboo, B. Jasperse, F. Barkhof, B. M. Uitdehaag, D. L.
Knol, V. de Groot, C. H. Polman, and J. A. Castelijns,
"Predicting short-term disability progression in early multiple
sclerosis: added value of MRI parameters," J Neurol Neurosurg
Psychiatry, vol. 79, no. 8, pp. 917-23, 2008.
[69] H. Kearney, M. Rocca, P. Valsasina, L. Balk, J. Sastre-Garriga, J.
Reinhardt, S. Ruggieri, A. Rovira, C. Stippich, L. Kappos, T.
Sprenger, P. Tortorella, M. Rovaris, C. Gasperini, X. Montalban, J.
Geurts, C. Polman, F. Barkhof, M. Filippi, D. Altmann, O.
Ciccarelli, D. Miller, and D. Chard, "Magnetic resonance imaging
correlates of physical disability in relapse onset multiple sclerosis
of long disease duration," Mult Scler, 2013.
[70] L. Hofstetter, Y. Naegelin, L. Filli, P. Kuster, S. Traud, R.
Smieskova, N. Mueller-Lenke, L. Kappos, A. Gass, T. Sprenger,
I. K. Penner, T. E. Nichols, H. Vrenken, F. Barkhof, C. Polman,
E. W. Radue, S. J. Borgwardt, and K. Bendfeldt, "Progression
in disability and regional grey matter atrophy in
relapsing-remitting multiple sclerosis," Mult Scler, 2013.
[71] M. Muller, R. Esser, K. Kotter, J. Voss, A. Muller, and P.
Stellmes, "Third ventricular enlargement in early stages of
multiple sclerosis is a predictor of motor and
neuropsychological deficits: a cross-sectional study," BMJ
Open, vol. 3, no. 9, pp. e003582, 2013.
[72] N. A. Losseff, L. Wang, H. M. Lai, D. S. Yoo, M. L.
Gawne-Cain, W. I. McDonald, D. H. Miller, and A. J.
Thompson, "Progressive cerebral atrophy in multiple sclerosis.
A serial MRI study," Brain, vol. 119 ( Pt 6), pp. 2009-19, 1996.
[73] I. T. Redmond, S. Barbosa, L. D. Blumhardt, and N. Roberts,
"Short-term ventricular volume changes on serial MRI in
multiple sclerosis," Acta Neurol Scand, vol. 102, no. 2, pp.
99-105, 2000.
[74] M. Calabrese, F. Rinaldi, P. Grossi, and P. Gallo, "Cortical
pathology and cognitive impairment in multiple sclerosis,"
Expert Rev Neurother, vol. 11, no. 3, pp. 425-32, 2011.
[75] D. Horakova, T. Kalincik, J. B. Dusankova, and O. Dolezal,
"Clinical correlates of grey matter pathology in multiple
sclerosis," BMC Neurol, vol. 12, pp. 10, 2012.
[76] M. Calabrese, D. Seppi, C. Romualdi, F. Rinaldi, S. Alessio, P.
Perini, and P. Gallo, "Gray matter pathology in MS: a 3-year
longitudinal study in a pediatric population," AJNR Am J
Neuroradiol, vol. 33, no. 8, pp. 1507-11, 2012.
[77] N. D. Chiaravalloti, and J. DeLuca, "Cognitive impairment in
multiple sclerosis," Lancet Neurol, vol. 7, no. 12, pp. 1139-51,
2008.
[78] M. P. Sanfilipo, R. H. Benedict, B. Weinstock-Guttman, and R.
Bakshi, "Gray and white matter brain atrophy and
neuropsychological impairment in multiple sclerosis,"
Neurology, vol. 66, no. 5, pp. 685-92, 2006.
[79] M. P. Amato, B. Hakiki, B. Goretti, F. Rossi, M. L. Stromillo, A.
Giorgio, M. Roscio, A. Ghezzi, L. Guidi, M. L. Bartolozzi, E.
Portaccio, N. De Stefano, and R. I. S. M. S. S. G. Italian,
"Association of MRI metrics and cognitive impairment in
radiologically isolated syndromes," Neurology, vol. 78, no. 5,
pp. 309-14, 2012.

American Journal of Psychiatry and Neuroscience 2015; 3(3): 40-49 48
[80] L. K. Fisniku, D. T. Chard, J. S. Jackson, V. M. Anderson, D. R.
Altmann, K. A. Miszkiel, A. J. Thompson, and D. H. Miller,
"Gray matter atrophy is related to long-term disability in
multiple sclerosis," Ann Neurol, vol. 64, no. 3, pp. 247-54,
2008.
[81] O. Yaldizli, I. K. Penner, K. Frontzek, Y. Naegelin, M. Amann,
A. Papadopoulou, T. Sprenger, J. Kuhle, P. Calabrese, E. W.
Radu, L. Kappos, and A. Gass, "The relationship between total
and regional corpus callosum atrophy, cognitive impairment
and fatigue in multiple sclerosis patients," Mult Scler, 2013.
[82] K. Morgen, G. Sammer, S. M. Courtney, T. Wolters, H.
Melchior, C. R. Blecker, P. Oschmann, M. Kaps, and D. Vaitl,
"Evidence for a direct association between cortical atrophy and
cognitive impairment in relapsing-remitting MS," Neuroimage,
vol. 30, no. 3, pp. 891-8, 2006.
[83] S. D. Roosendaal, K. Bendfeldt, H. Vrenken, C. H. Polman, S.
Borgwardt, E. W. Radue, L. Kappos, D. Pelletier, S. L. Hauser,
P. M. Matthews, F. Barkhof, and J. J. Geurts, "Grey matter
volume in a large cohort of MS patients: relation to MRI
parameters and disability," Mult Scler, vol. 17, no. 9, pp.
1098-106, 2011.
[84] D. P. Ramasamy, R. H. Benedict, J. L. Cox, D. Fritz, N.
Abdelrahman, S. Hussein, A. Minagar, M. G. Dwyer, and R.
Zivadinov, "Extent of cerebellum, subcortical and cortical
atrophy in patients with MS: a case-control study," J Neurol Sci,
vol. 282, no. 1-2, pp. 47-54, 2009.
[85] R. A. Rudick, J. C. Lee, K. Nakamura, and E. Fisher, "Gray
matter atrophy correlates with MS disability progression
measured with MSFC but not EDSS," J Neurol Sci, vol. 282, no.
1-2, pp. 106-11, 2009.
[86] M. P. Amato, G. Ponziani, G. Siracusa, and S. Sorbi, "Cognitive
dysfunction in early-onset multiple sclerosis: a reappraisal after
10 years," Arch Neurol, vol. 58, no. 10, pp. 1602-6, 2001.
[87] S. M. Rao, G. J. Leo, L. Bernardin, and F. Unverzagt,
"Cognitive dysfunction in multiple sclerosis. I. Frequency,
patterns, and prediction," Neurology, vol. 41, no. 5, pp. 685-91,
1991.
[88] B. I. Glanz, C. M. Holland, S. A. Gauthier, E. L. Amunwa, Z.
Liptak, M. K. Houtchens, R. A. Sperling, S. J. Khoury, C. R.
Guttmann, and H. L. Weiner, "Cognitive dysfunction in
patients with clinically isolated syndromes or newly diagnosed
multiple sclerosis," Mult Scler, vol. 13, no. 8, pp. 1004-10,
2007.
[89] M. Calabrese, F. Agosta, F. Rinaldi, I. Mattisi, P. Grossi, A.
Favaretto, M. Atzori, V. Bernardi, L. Barachino, L. Rinaldi, P.
Perini, P. Gallo, and M. Filippi, "Cortical lesions and atrophy
associated with cognitive impairment in relapsing-remitting
multiple sclerosis," Arch Neurol, vol. 66, no. 9, pp. 1144-50,
2009.
[90] M. Calabrese, F. Rinaldi, I. Mattisi, P. Grossi, A. Favaretto, M.
Atzori, V. Bernardi, L. Barachino, C. Romualdi, L. Rinaldi, P.
Perini, and P. Gallo, "Widespread cortical thinning
characterizes patients with MS with mild cognitive
impairment," Neurology, vol. 74, no. 4, pp. 321-8, 2010.
[91] M. K. Houtchens, R. H. Benedict, R. Killiany, J. Sharma, Z.
Jaisani, B. Singh, B. Weinstock-Guttman, C. R. Guttmann, and
R. Bakshi, "Thalamic atrophy and cognition in multiple
sclerosis," Neurology, vol. 69, no. 12, pp. 1213-23, 2007.
[92] S. Batista, R. Zivadinov, M. Hoogs, N. Bergsland, M.
Heininen-Brown, M. G. Dwyer, B. Weinstock-Guttman, and R.
H. Benedict, "Basal ganglia, thalamus and neocortical atrophy
predicting slowed cognitive processing in multiple sclerosis," J
Neurol, vol. 259, no. 1, pp. 139-46, 2012.
[93] M. Calabrese, F. Rinaldi, P. Grossi, I. Mattisi, V. Bernardi, A.
Favaretto, P. Perini, and P. Gallo, "Basal ganglia and
frontal/parietal cortical atrophy is associated with fatigue in
relapsing-remitting multiple sclerosis," Mult Scler, vol. 16, no.
10, pp. 1220-8, 2010.
[94] M. Calabrese, F. Rinaldi, I. Mattisi, V. Bernardi, A. Favaretto, P.
Perini, and P. Gallo, "The predictive value of gray matter
atrophy in clinically isolated syndromes," Neurology, vol. 77,
no. 3, pp. 257-63, 2011.
[95] M. A. Rocca, S. Mesaros, E. Pagani, M. P. Sormani, G. Comi,
and M. Filippi, "Thalamic damage and long-term progression
of disability in multiple sclerosis," Radiology, vol. 257, no. 2,
pp. 463-9, 2010.
[96] R. Zivadinov, R. A. Rudick, R. De Masi, D. Nasuelli, M.
Ukmar, R. S. Pozzi-Mucelli, A. Grop, G. Cazzato, and M.
Zorzon, "Effects of IV methylprednisolone on brain atrophy in
relapsing-remitting MS," Neurology, vol. 57, no. 7, pp. 1239-47,
2001.
[97] D. W. Paty, D. K. Li, U. M. M. S. Group, and I. M. S. S. Group,
"Interferon beta-lb is effective in relapsing-remitting multiple
sclerosis. II. MRI analysis results of a multicenter, randomized,
double-blind, placebo-controlled trial. 1993 [classical article],"
Neurology, vol. 57, no. 12 Suppl 5, pp. S10-5, 2001.
[98] P. O'Connor, J. S. Wolinsky, C. Confavreux, G. Comi, L.
Kappos, T. P. Olsson, H. Benzerdjeb, P. Truffinet, L. Wang, A.
Miller, M. S. Freedman, and T. T. Group, "Randomized trial of
oral teriflunomide for relapsing multiple sclerosis," N Engl J
Med, vol. 365, no. 14, pp. 1293-303, 2011.
[99] R. J. Fox, D. H. Miller, J. T. Phillips, M. Hutchinson, E.
Havrdova, M. Kita, M. Yang, K. Raghupathi, M. Novas, M. T.
Sweetser, V. Viglietta, K. T. Dawson, and C. S. Investigators,
"Placebo-controlled phase 3 study of oral BG-12 or glatiramer
in multiple sclerosis," N Engl J Med, vol. 367, no. 12, pp.
1087-97, 2012.
[100] R. Gold, L. Kappos, D. L. Arnold, A. Bar-Or, G. Giovannoni, K.
Selmaj, C. Tornatore, M. T. Sweetser, M. Yang, S. I. Sheikh, K.
T. Dawson, and D. S. Investigators, "Placebo-controlled phase
3 study of oral BG-12 for relapsing multiple sclerosis," N Engl
J Med, vol. 367, no. 12, pp. 1098-107, 2012.
[101] G. Comi, D. Jeffery, L. Kappos, X. Montalban, A. Boyko, M. A.
Rocca, M. Filippi, and A. S. Group, "Placebo-controlled trial of
oral laquinimod for multiple sclerosis," N Engl J Med, vol. 366,
no. 11, pp. 1000-9, 2012.
[102] L. Kappos, E. W. Radue, P. O'Connor, C. Polman, R. Hohlfeld,
P. Calabresi, K. Selmaj, C. Agoropoulou, M. Leyk, L.
Zhang-Auberson, P. Burtin, and F. S. Group, "A
placebo-controlled trial of oral fingolimod in relapsing multiple
sclerosis," N Engl J Med, vol. 362, no. 5, pp. 387-401, 2010.
[103] P. A. Calabresi, E. W. Radue, D. Goodin, D. Jeffery, K. W.
Rammohan, A. T. Reder, T. Vollmer, M. A. Agius, L. Kappos, T.
Stites, B. Li, L. Cappiello, P. von Rosenstiel, and F. D. Lublin,
"Safety and efficacy of fingolimod in patients with
relapsing-remitting multiple sclerosis (FREEDOMS II): a
double-blind, randomised, placebo-controlled, phase 3 trial,"
Lancet Neurol, vol. 13, no. 6, pp. 545-56, 2014.

49 Rugilo Carlos et al.: Brain atrophy in Multiple Sclerosis
[104] J. A. Cohen, F. Barkhof, G. Comi, H. P. Hartung, B. O. Khatri,
X. Montalban, J. Pelletier, R. Capra, P. Gallo, G. Izquierdo, K.
Tiel-Wilck, A. de Vera, J. Jin, T. Stites, S. Wu, S. Aradhye, L.
Kappos, and T. S. Group, "Oral fingolimod or intramuscular
interferon for relapsing multiple sclerosis," N Engl J Med, vol.
362, no. 5, pp. 402-15, 2010.