Clinical correlates of grey matter pathology in
Dana Horakova*†, Tomas Kalincik†, Jana Blahova Dusankova and Ondrej Dolezal
Traditionally, multiple sclerosis has been viewed as a disease predominantly affecting white matter. However, this
view has lately been subject to numerous changes, as new evidence of anatomical and histological changes as
well as of molecular targets within the grey matter has arisen. This advance was driven mainly by novel imaging
techniques, however, these have not yet been implemented in routine clinical practice. The changes in the grey
matter are related to physical and cognitive disability seen in individuals with multiple sclerosis. Furthermore,
damage to several grey matter structures can be associated with impairment of specific functions. Therefore, we
conclude that grey matter damage - global and regional - has the potential to become a marker of disease
activity, complementary to the currently used magnetic resonance markers (global brain atrophy and T2
hyperintense lesions). Furthermore, it may improve the prediction of the future disease course and response to
therapy in individual patients and may also become a reliable additional surrogate marker of treatment effect.
Multiple sclerosis (MS) is known for the great variability
of its clinical presentations, spanning the relapsing-
remitting course with a subsequent secondary progres-
sive phase, primary progressive course and relapsing-
progressive course. The rate of disability accumulation
varies from a lack of disease activity (benign MS) to
rapidly progressing (malignant) MS  with a range of
possible neurological manifestations. Therefore, the view
of MS as a heterogeneous entity resulting from a num-
ber of inter-related etiopathogenetic cascades has been
receiving increasing scientific attention [2-4]. The role
of the immune system is likely to be pivotal in the dis-
ease pathogenesis, however, direct causality is yet to be
established [5,6]. Surrogate markers such as magnetic
resonance imaging (MRI), optic coherent tomography
and susceptibility genes may elucidate the great clinical
variability arising from the complex etiopathogenesis.
On the diagnostic level, these might help to identify the
specific subtypes of disease in individual patients, pre-
dict the future MS course, and develop individually tai-
lored therapeutic regimens [7,8].
The currently available therapies, which are based
mainly on their anti-inflammatory properties, are imper-
fect, with a number of patients showing only sub-opti-
mal control over the MS activity . It is therefore
important that clinicians are able to predict the future
response to treatment in individual patients early after
disease onset in order to allow for the most appropriate
treatment to be chosen . Furthermore, the treat-
ment, once administered, needs to be monitored to ver-
ify its efficacy. In both instances, surrogate markers may
play significant roles [11,12]. Among different surrogate
markers, MRI has been the only one used routinely in
clinical practice. The traditional view of MS as a disease
affecting predominantly white matter (WM) was driven
by the higher sensitivity of the conventional MRI techni-
ques to the WM changes [13-15]. However, these
changes proved to be insufficient to explain the broad
spectrum of neurological and psychological manifesta-
tions of MS satisfactorily [16-22]. Novel MRI techniques
with improved sensitivity to grey matter (GM) changes
[23-28] have shown that the GM damage is more preva-
lent than first estimated [29-34], that it may even pre-
cede development of the WM damage , and that it
is significantly associated with physical and cognitive
impairment [11,12,31,36-47]. The aim of this review is
to summarise the current knowledge of the GM damage
in MS and of its clinical implications.
* Correspondence: email@example.com
† Contributed equally
Department of Neurology and Center of Clinical Neuroscience, Charles
University in Prague, 1st Faculty of Medicine and General University Hospital,
Charles University, Prague, Czech Republic
Horakova et al. BMC Neurology 2012, 12:10
© 2012 Horakova et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and
reproduction in any medium, provided the original work is properly cited.
Assessing grey matter pathology
Both GM atrophy [11,34,38,41,42,44,48] and GM lesions
[29-32,49-52] were demonstrated in cerebral cortex and
deep GM structures using MRI supported by histologi-
cal studies [32,53-56]. A body of work suggested that
GM atrophy occurs early in relapsing-remitting as well
as primary progressive MS [15,38,57-59]. Its progression
was shown to be more prominent compared to WM
atrophy, which is in contrast to some of the earlier
works [12,33,34,44,60]. GM atrophy becomes more evi-
dent with the progression of MS [12,34,36] and in the
chronic stages might even drive total brain atrophy .
Its relation to the WM changes, however, has not been
sufficiently explained [52,61,62]. GM atrophy has been
associated with several MHC II alleles , which are
known genetic risk factors in MS [6,64]. This all implies
that GM atrophy may play an important role in the
pathogenesis of MS.
It is known that GM atrophy is not distributed homo-
geneously. Temporal and frontal cortex (including
motor areas) can be affected predominantly, particularly
early in the disease course [12,33,39,65-70]. The subcor-
tical GM also shows marked atrophy, especially in the
thalamus, basal ganglia (caudate and striatum) and the
infratentorial structures [58,66,71,72]. As a result, cor-
tico-subcortical connections might suffer significant
According to the original pathological study of Brow-
nell and Hughes, GM lesions comprise 26% of all lesions
identified in the central nervous system (CNS) .
Cortical lesions occur early in clinically isolated syn-
drome (CIS) and relapsing-remitting MS, as well as in
primary progressive MS (36%, 64% and 81% of patients,
respectively) and increase in number and size with pro-
gression of the disease [30,31,74]. Cortical lesions are
most common in the frontal and temporal cortex, pre-
dominantly affecting the motor (30-40%) and cingulate
areas (10%) . Among the subcortical GM, the struc-
tures most affected are the thalamus, basal ganglia,
hypothalamus, hippocampus, cerebellum and spinal cord
[76-80]. Compared to WM lesions, inflammation is less
pronounced  and the blood-brain barrier is not dis-
rupted in GM lesions . Interestingly, T-cell mediated
autoimmunity directed against contactin-2, which is pre-
sent specifically within the GM, was identified as a fac-
tor contributing to the GM pathology in MS .
Sensitivity of the conventional MRI methods for GM
lesions is low compared to WM lesions [32,82]. This
improves with alternative techniques, such as double
inversion recovery (DIR) [25,28,83] and its combina-
tion with phase-sensitive inversion recovery , T1-
weighted gradient-recalled-echo  and higher field-
strength MRI [24,26]. Another promising approach is
the combination of the conventional MRI techniques
with magnetisation transfer ratio [73,84]. Furthermore,
diffusion tensor imaging has the potential to uncover
progressive microstructural changes in normal-appear-
ing GM . Functional changes in MS can be exam-
ined using functional MRI to study re-organisation of
the cortex, positron emission tomography to establish
activation of microglia, or continuous arterial spin
labelling to analyse brain perfusion [86-88]. Despite
their promising results, the non-conventional MRI
techniques have so far found only a limited use in rou-
tine clinical practice, partly due to their sparse avail-
ability and high technological and time requirements,
and partly due to limited reproducibility of their out-
Clinical correlates of GM impairment
Abnormalities of GM are present early in CIS [90-95]
and evolve with its progression to definite MS
[11,96-98]. Numerous works have shown that the
changes in GM are closely associated with both physical
disability and cognitive impairment (see Table 1)
GM atrophy It is known that GM atrophy is correlated
with physical disability and its progression (r = 0.47 -
0.59) [12,36,39,102,103]. According to a number of stu-
dies, this relation is stronger than that of WM matter
changes [33,57,67,99,100]. Fisniku and co-workers
showed that GM atrophy, unlike WM atrophy,
[Expanded Disability Status Scale (EDSS) > 3] .
This view is further supported by the fact that the GM
atrophy rate is accelerated upon conversion from CIS
to the relapsing-remitting and secondary progressive
stages (3.4× and 14× the normal rates, respectively),
while WM atrophy remains stable throughout the MS
course (3× the normal rate) [11,12]. The association of
GM atrophy with disability becomes even stronger in
primary progressive MS . All this suggests that the
GM changes could be more representative of the pro-
gressive damage to the CNS and the resulting physical
disability than the WM damage. However, it is worth
noting that also some contrasting results have been
reported . These opposing conclusions may relate
to inequalities in studied cohorts, such as differences
in disease stages or subtypes.
GM lesions Apart from the GM atrophy, cortical and
subcortical inflammatory (T2 hyperintense) GM lesions
also contribute to the overall disability in MS [104,105].
They show mild correlation with EDSS and moderate
correlation with its changes in time . Similar to the
atrophy, primary progressive MS shows more pro-
nounced accumulation of the GM lesions, parallel with
accumulation of the physical disability . On the
Horakova et al. BMC Neurology 2012, 12:10
Page 2 of 10
other hand, in a benign form of MS with only a modest
disability after long disease duration, the GM lesions are
T2 hypointense lesions have also been reported in MS.
They may represent iron deposits and foci of brain
degeneration [107,108], predominantly located within
the thalamus, striatum and rolandic cortex [107-109].
Similar to the T2 hyperintense lesions, T2 hypointense
[43,109-111] as well as cognitive impairment , and
are predictive of future brain atrophy [108,113].
with physical disability
Regional GM changes Among the regional GM
changes, it is in particular the cortical atrophy which is
thought to be associated with physical disability
[13,15,33,100]. However, structural changes within the
thalamus could also play role in the accumulation of
disability . It was suggested that MS-associated fati-
gue could be secondary to the regional atrophy of the
fronto-parietal cortex, striatum and thalamus [115-118]
as well as the higher overall GM lesion burden [69,119].
On the other hand, impaired gait may be associated
with the damage to the dentate nucleus . Another
Table 1 Selected works studying grey matter changes and their relations to physical and cognitive impairment in MS
Study Patients Follow-
Dalton et al.,
58 CIS3 GMFDecrease in GMF was higher in patients who converted to CDMS (-3.3%) than in
those who did not (-1.1%).
Fisher et al.,
4 BPF, GMF,
GMF decrease was more pronounced in patients compared to HC:
CIS converting to RRMS, 3.4×; RRMS, 8.1×; RRMS converting to SPMS, 12.4×; SPMS,
WMF decrease was 3× higher in all patient sub-groups than in HC.
Fisniku et al.,
GMF but not WMF correlated with EDSS (r = 0.48) and MSFC sub-scores (r = 0.59).
Horakova et al.,
5GMV, PBVCDecline in PBVC and GMV were the strongest MRI predictors of disability progression.
Calabrese et al.,
2GMF, cortical lesions
Baseline volume of cortical lesions correlated with EDSS (r = 0.48) and its change
over 2 years (r = 0.38).
Calabrese et al.,
4Regional atrophyAtrophy of the superior frontal gyrus, thalamus, and cerebellum predicted
independently conversion from CIS to CDMS.
al., 2011 
GMVGMV was lower in SPMS than RRMS, and was the strongest independent predictor of
physical disability and cognitive impairment.
Amato et al.,
GMVCortical atrophy was found in cognitively impaired but not in cognitively preserved
patients, and was correlated with a poorer performance on tests of verbal memory,
attention, and verbal fluency.
Amato et al.,
Decrease in cortical volume was significantly higher in cognitively deteriorating than
in stable or improving patients (-43 ml vs. -18 ml).
al., 2007 
GMFFrontal atrophy was associated with impaired memory (auditory/verbal, visual
episodic and working).
al., 2007 
1 PP MS
thalamic volumeThalamic volume was 17% lower in the MS group than in HC, and was associated
with impaired cognitive performance (r = 0.51-0.72) and physical disability (r = 0.32).
Calabrese et al.,
Higher number and volume of cortical lesions and lower volume of neocortical grey
matter were seen in cognitively impaired vs. cognitively preserved patients.
BPF, brain parenchymal fraction; CDMS, clinically definite multiple sclerosis; CIS, clinically isolated syndrome; EDSS, Expanded Disability Status Scale; GMF, grey
matter fraction; GMV, grey matter volume; HC, healthy controls; MS, multiple sclerosis; MSFC, Multiple Sclerosis Functional Composite; NCV, normalised cortical
volume; PBVC, percentage brain volume change; RRMS, relapsing-remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; WMF, white matter
Horakova et al. BMC Neurology 2012, 12:10
Page 3 of 10
co-morbidity of MS - restless legs syndrome - is prob-
ably related to the changes in the cervical spinal cord
, where demyelination of GM is more extensive
than that of WM . Apart from the routinely evalu-
ated signs of the physical disability, the GM lesions are
likely to contribute to the increased epileptic activity
 which occurs in 2.9% of patients with MS (i.e. its
prevalence is 3-6× higher compared to healthy popula-
tion) [122-124]. Yet, it is not known whether the sever-
ity of physical impairment is proportional to the GM
lesion volume or if it depends more on the topography
of the focal GM damage.
GM reorganisation Besides the limited regenerative
capacity of the CNS , adaptation of neural net-
works represents important compensatory mechanism
of the damaged CNS. Cortical reorganisation, as shown
by a number of studies with functional MRI, occurs
early in MS, but its extent varies greatly among patients.
It can be visualised as a non-normal cortical activation
pattern, elicited by standardised motor and cognitive
tasks [126-133]. For instance, during motor processing,
recruitment of higher (supplementary) areas may be
seen even with simple movements in MS patients but
not in healthy subjects [129,130,134]. Similar functional
reorganisation takes place in the cervical spinal cord
. This can be interpreted as compensation for
damage inflicted by the demyelination and neuronal
loss. It is possible that more extensive (or efficient) com-
pensation and axonal regeneration contribute to a less
severe course of MS and slower accumulation of the
CNS structural damage [106,134].
Evaluation of disability Research of functional out-
comes of the structural changes in MS depends on the
ability of clinicians to quantify physical and cognitive
impairment in MS patients. Two scales, EDSS and
Multiple Sclerosis Functional Composite (MSFC), have
been used most commonly to evaluate the physical
impairment in clinical practice and in research. Both
of these scales quantify the extent of disability only
imperfectly . For EDSS, this is attributed to sub-
optimal inter-rater reproducibility, lack of weighted
functional sub-scores and omission of psychological
assessment , while for MSFC, this is due to prac-
tice effects, variations in reference populations, omis-
sion of visual assessment and lack of accepted
definition of a clinically meaningful change .
EDSS mainly evaluates the physical component of the
impairment, with the emphasis on ambulation, asses-
sing the cognitive impairment only marginally. On the
other hand, MSFC is a more complex scale with objec-
tive evaluation of ambulation (timed 25-foot walk test),
fine motor skills (9-hole peg test) and cognition (3-sec-
ond Paced Auditory Serial Addition Test). It was sug-
gested that MSFC may better correlate with GM
atrophy than EDSS [12,36]. Furthermore, it is possible
that EDSS is more sensitive to disability progression in
patients with mild physical disability, while being less
sensitive to the progression in patients with more
severe disability . This raises concerns about the
value of EDSS in secondary progressive MS. In any
case, instruments assessing the physical disability reli-
ably at all stages and in all courses of MS are critical
for accurate evaluation of the descriptive and prognos-
tic value of the GM changes.
Cognitive impairment is highly prevalent in MS, affect-
ing 40-65% of patients with all disease courses and in all
its clinical stages . Although the character and
severity of the cognitive impairment vary widely among
the patients, information processing speed, attention,
recent and long-term memory, executive functions and
visuospatial abilities seem to be the most affected
domains, whereas general intelligence, language and cer-
tain aspects of memory (short-term capacity and impli-
cit memory) are spared, and overt dementia is rare in
MS [141-143]. In addition, in patients with disease onset
before the age of 18, impairment of expressive language
and visuomotor integration were described . This
suggests that even in young patients the damage to the
CNS may exceed its plasticity. Overall, the extreme
variability of the cognitive impairment may depend on
several factors, such as patient age, gender, age at dis-
ease onset, level of education and cognitive reserve
GM vs. WM changes Even though significant correla-
tions between the amount and the regions of the WM
atrophy vs. the degree and pattern of cognitive impair-
ment were shown , studies failed to explain the full
array of cognitive impairment by the WM damage only
. A range of specific cognitive deficits, such as
memory impairment, low information processing speed
and attention deficits, could be better explained by the
cortical GM lesions rather than the subcortical WM
lesions . Changes in the GM might therefore add
to our understanding of the causality of the cognitive
impairment in MS. For example, more widespread atro-
phy and hypometabolism of GM can be found in the
cognitively impaired patients than in those cognitively
intact [149,150]. Moreover, it is of interest that the cog-
nitive impairment is more prominent at the time of con-
version from the relapsing-remitting to the secondary
progressive course [151,152], which is also marked by
accelerated degeneration of the cerebral GM . In
fact, a number of works provided evidence of a strong
association between GM impairment (lesions and atro-
phy) and global or selective cognitive disability in MS
[40,68,101,142,149,153], which may imply a causative
Horakova et al. BMC Neurology 2012, 12:10
Page 4 of 10
Regional GM changes A pattern of widespread cortical
thinning was found in cognitively impaired patients
with relapsing-remitting MS [149,154]. Even a cortical
variant of MS was described in those with the cognitive
impairment among the initial manifestations of MS
[155,156]. It was shown that neocortical atrophy is
relatedto the impairment
[40,65,68,153], visual episodic and working memory
, verbal fluency [40,101], attention/concentration
 and processing speed [65,70,157]. It may also be
responsible for subtle personality changes observed in
MS patients, such as disinhibition and euphoria
[153,158]. More specifically, atrophy of the prefrontal,
precentral and superior parietal cortex is related to the
decreased processing speed and impaired calculation
abilities . Left frontal atrophy occurs in patients
with impaired auditory/verbal memory, while right
frontal atrophy is related to impaired visual episodic
and working memory . Atrophy of the mesial tem-
poral cortex is associated with decreased processing
speed and impaired episodic and verbal memory
[159,160]. Atrophy of the subcortical GM structures
can be evaluated either directly or indirectly - using
enlargement of the third ventricle as a marker [68,154].
Of the subcortical GM, the most relevant are the atro-
phy, structural changes and altered metabolism of the
thalamus, which are linked with deterioration in multi-
ple cognitive domains [114,144,150,154,157,161,162].
Compared to GM atrophy, there is considerably less
evidence to support contribution of demyelinating
lesions of GM to cognitive impairment. The volume of
the cortical lesions shows only a modest association
with cognitive impairment, while an increase in the
lesion volume seems to be moderately associated with
cognitive deterioration [31,37,163,164]. More specifically,
lesions in the medial frontal and temporal cortex seem
to correlate with impaired memory .
Overall, it can be speculated that the cognitive decline
observed in MS patients results from focal inflammatory
lesions and widespread GM loss. Despite the fact that
the neuropsychological profiles of MS patients cannot
be defined as either purely “cortical” or “subcortical”
, it is likely that it is the impairment of the cortical
GM which determines the level and character of cogni-
of verbal memory
GM as a surrogate marker
Objective indicators of MS activity as well as predictors
of future disease course and treatment efficacy applic-
able in individual patients are crucial for making appro-
priate therapeutic decisions in routine clinical practice.
A number of works have addressed these issues, and
several markers, both clinical and paraclinical, have been
suggested [7,21,166-169]. Yet, accuracy of the MRI
markers, particularly when used in individual patients, is
only limited [16,170,171].
Marker of MS activity
According to the existing evidence, changes in GM
might represent a reliable marker of disease activity and
of CNS damage. The relatively less pronounced inflam-
mation within GM is likely to result in lesser fluctua-
tions of its changes triggered by the relapsing
inflammatory activity . Moreover, focal oedema and
treatment-associated pseudoatrophy, which may mask
the changes reflecting the activity of MS, are known to
be less evident in GM [172,173]. Therefore GM lesions
and atrophy, rather than WM changes, might better
reflect long-term changes which drive the accumulation
of disability .
In fact, assessment of GM lesions improves the speci-
ficity and accuracy of MRI diagnostic criteria . At
the same time, GM atrophy correlates closely with the
progression of CISto
[11,12,39,176]. Furthermore, both GM lesions and GM
atrophy can be used to predict this conversion [96,175].
Long-term accumulation of disability is also predicted
by the diffuse changes in the GM [36,177]. It can be
speculated that an even better prognostic value may be
achieved with assessment of regional GM atrophy.
Monitoring of treatment efficacy
For the reasons discussed above, the impairment of GM
has the potential to become an important marker of the
efficacy of immunomodulatory remedies . On the
other hand, the less inflammatory nature of GM damage
[51,178,179] and better preservation of the blood-brain
barrier within altered GM  may diminish the
response of GM to immunomodulatory therapy. Calabr-
ese and co-workers demonstrated a decrease in accumu-
lation of GM lesions and cortical atrophy in patients
treated with disease modifying drugs, and reported a
more pronounced effect of subcutaneous interferon b
compared to intramuscular interferon b and glatiramer
acetate . Zivadinov and co-authors observed ame-
liorated progression of GM atrophy in patients treated
with interferon b . In contrast, Benfeldt and co-
workers reported more pronounced atrophy in the
fronto-temporal, cingulate and cerebellar cortex in
patients treated with interferon b. It is therefore appar-
ent that more work evaluating the effect of immunomo-
dulation on the changes in GM is required.
The growing body of evidence supports the view of MS
as a disease not only of WM but also of GM. The
mechanisms responsible for the inter-individual varia-
tion in the extent of GM and WM pathology are largely
unknown, and their identification will significantly con-
tribute to the understanding of the MS etiopathogenesis.
Horakova et al. BMC Neurology 2012, 12:10
Page 5 of 10
On the diagnostic level, GM atrophy and lesions provide
information complementary to the conventional MRI
variables and further improve correlation between the
radiological and clinical variables [118,183]. Thus, GM
pathology may not only serve as a new marker for the
existing immunomodulatory therapies but may also pro-
vide a potential target for novel therapies.
CIS: clinically isolated syndrome; CNS: central nervous system; EDSS:
Expanded Disability Status Scale; GM: grey matter; MRI: magnetic resonance
imaging; MS: multiple sclerosis; MSFC: Multiple Sclerosis Functional
Composite; WM: white matter
DH prepared the Introduction and Physical disability sections and Table 1,
and reviewed the manuscript. TK prepared the Physical disability section and
Table 1, and edited and reviewed the manuscript. JBD prepared the
Cognitive impairment section and reviewed the manuscript. OD prepared the
Assessing grey matter pathology section and reviewed the manuscript. All
authors read and approved the final manuscript.
Dana Horakova has received speaker honoraria and consultant fees from
Biogen Idec, Merck-Serono, Bayer Shering and Teva, as well as support for
research activities from Biogen Idec.
Tomas Kalincik has received compensation for travel and honoraria from
Biogen Idec, Sanofi Aventis, Teva and Merck-Serono.
Jana Blahova Dusankova has received speaker honoraria and compensation
for travel from Biogen Idec, Bayer Shering, Merck-Serono and Novartis.
Ondrej Dolezal has received speaker honoraria and compensation for travel
from Biogen Idec, Merck-Serono and Novartis.
The authors have received financial support from the Czech Ministry of
Health [MSM 0021620849].
Received: 17 September 2011 Accepted: 7 March 2012
Published: 7 March 2012
1. Weiner HL: The challenge of multiple sclerosis: how do we cure a
chronic heterogeneous disease? Ann Neurol 2009, 65(3):239-248.
2.Compston A, Coles A: Multiple sclerosis. Lancet 2008, 372(9648):1502-1517.
3.Derfuss T, Parikh K, Velhin S, Braun M, Mathey E, Krumbholz M, Kumpfel T,
Moldenhauer A, Rader C, Sonderegger P, et al: Contactin-2/TAG-1-directed
autoimmunity is identified in multiple sclerosis patients and mediates
gray matter pathology in animals. Proc Natl Acad Sci USA 2009,
4.Lassmann H, van Horssen J: The molecular basis of neurodegeneration in
multiple sclerosis. FEBS letters 2011.
5.Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H,
Schmidbauer M, Laursen H, Sorensen PS, Lassmann H: The relation
between inflammation and neurodegeneration in multiple sclerosis
brains. Brain 2009, 132(Pt 5):1175-1189.
6.IMSGC: Genetic risk and a primary role for cell-mediated immune
mechanisms in multiple sclerosis. Nature 2011, 476(7359):214-219.
7.Rio J, Comabella M, Montalban X: Predicting responders to therapies for
multiple sclerosis. Nat Rev Neurol 2009, 5(10):553-560.
8.Sormani MP, Bonzano L, Roccatagliata L, De Stefano N: Magnetic
resonance imaging as surrogate for clinical endpoints in multiple
sclerosis: data on novel oral drugs. Mult Scler 2011, 17(5):630-633.
9.Havrdova E, Galetta S, Stefoski D, Comi G: Freedom from disease activity
in multiple sclerosis. Neurology 2010, 74(Suppl 3):S3-7.
10.Hartung HP, Montalban X, Sorensen PS, Vermersch P, Olsson T: Principles
of a new treatment algorithm in multiple sclerosis. Expert Rev Neurother
11.Dalton CM, Chard DT, Davies GR, Miszkiel KA, Altmann DR, Fernando K,
Plant GT, Thompson AJ, Miller DH: Early development of multiple sclerosis
is associated with progressive grey matter atrophy in patients
presenting with clinically isolated syndromes. Brain 2004, 127(Pt
Fisher E, Lee JC, Nakamura K, Rudick RA: Gray matter atrophy in multiple
sclerosis: a longitudinal study. Ann Neurol 2008, 64(3):255-265.
Chard DT, Griffin CM, Parker GJ, Kapoor R, Thompson AJ, Miller DH: Brain
atrophy in clinically early relapsing-remitting multiple sclerosis. Brain
2002, 125(Pt 2):327-337.
Ge Y, Grossman RI, Udupa JK, Babb JS, Nyul LG, Kolson DL: Brain atrophy
in relapsing-remitting multiple sclerosis: fractional volumetric analysis of
gray matter and white matter. Radiology 2001, 220(3):606-610.
Sastre-Garriga J, Ingle GT, Chard DT, Ramio-Torrenta L, Miller DH,
Thompson AJ: Grey and white matter atrophy in early clinical stages of
primary progressive multiple sclerosis. Neuroimage 2004, 22(1):353-359.
Barkhof F: The clinico-radiological paradox in multiple sclerosis revisited.
Curr Opin Neurol 2002, 15(3):239-245.
Comi G, Filippi M, Martinelli V, Sirabian G, Visciani A, Campi A, Mammi S,
Rovaris M, Canal N: Brain magnetic resonance imaging correlates of
cognitive impairment in multiple sclerosis. J Neurol Sci 1993, 115(Suppl):
Thorpe JW, Kidd D, Moseley IF, Kenndall BE, Thompson AJ, MacManus DG,
McDonald WI, Miller DH: Serial gadolinium-enhanced MRI of the brain
and spinal cord in early relapsing-remitting multiple sclerosis. Neurology
Simon JH, Jacobs LD, Campion MK, Rudick RA, Cookfair DL, Herndon RM,
Richert JR, Salazar AM, Fischer JS, Goodkin DE, et al: A longitudinal study
of brain atrophy in relapsing multiple sclerosis. The Multiple Sclerosis
Collaborative Research Group (MSCRG). Neurology 1999, 53(1):139-148.
Fox NC, Jenkins R, Leary SM, Stevenson VL, Losseff NA, Crum WR, Harvey RJ,
Rossor MN, Miller DH, Thompson AJ: Progressive cerebral atrophy in MS: a
serial study using registered, volumetric MRI. Neurology 2000,
Zivadinov R, Stosic M, Cox JL, Ramasamy DP, Dwyer MG: The place of
conventional MRI and newly emerging MRI techniques in monitoring
different aspects of treatment outcome. J Neurol 2008, 255(Suppl
Rudick RA, Fisher E, Lee JC, Simon J, Jacobs L: Use of the brain
parenchymal fraction to measure whole brain atrophy in relapsing-
remitting MS. Multiple Sclerosis Collaborative Research Group. Neurology
Bagnato F, Butman JA, Gupta S, Calabrese M, Pezawas L, Ohayon JM, Tovar-
Moll F, Riva M, Cao MM, Talagala SL, et al: In vivo detection of cortical
plaques by MR imaging in patients with multiple sclerosis. AJNR Am J
Neuroradiol 2006, 27(10):2161-2167.
Geurts JJ, Blezer EL, Vrenken H, van der Toorn A, Castelijns JA, Polman CH,
Pouwels PJ, Bo L, Barkhof F: Does high-field MR imaging improve cortical
lesion detection in multiple sclerosis? J Neurol 2008, 255(2):183-191.
Geurts JJ, Pouwels PJ, Uitdehaag BM, Polman CH, Barkhof F, Castelijns JA:
Intracortical lesions in multiple sclerosis: improved detection with 3D
double inversion-recovery MR imaging. Radiology 2005, 236(1):254-260.
Kangarlu A, Bourekas EC, Ray-Chaudhury A, Rammohan KW: Cerebral
cortical lesions in multiple sclerosis detected by MR imaging at 8 Tesla.
AJNR Am J Neuroradiol 2007, 28(2):262-266.
Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA:
Improved identification of intracortical lesions in multiple sclerosis with
phase-sensitive inversion recovery in combination with fast double
inversion recovery MR imaging. AJNR Am J Neuroradiol 2007,
Pouwels PJ, Kuijer JP, Mugler JP, Guttmann CR, Barkhof F: Human gray
matter: feasibility of single-slab 3D double inversion-recovery high-
spatial-resolution MR imaging. Radiology 2006, 241(3):873-879.
Brownell B, Hughes JT: The distribution of plaques in the cerebrum in
multiple sclerosis. J Neurol Neurosurg Psychiatry 1962, 25:315-320.
Calabrese M, Rocca MA, Atzori M, Mattisi I, Bernardi V, Favaretto A,
Barachino L, Romualdi C, Rinaldi L, Perini P, et al: Cortical lesions in
primary progressive multiple sclerosis: a 2-year longitudinal MR study.
Neurology 2009, 72(15):1330-1336.
Horakova et al. BMC Neurology 2012, 12:10
Page 6 of 10
31.Calabrese M, Rocca MA, Atzori M, Mattisi I, Favaretto A, Perini P, Gallo P,
Filippi M: A 3-year magnetic resonance imaging study of cortical lesions
in relapse-onset multiple sclerosis. Ann Neurol 2010, 67(3):376-383.
Geurts JJ, Bo L, Pouwels PJ, Castelijns JA, Polman CH, Barkhof F: Cortical
lesions in multiple sclerosis: combined postmortem MR imaging and
histopathology. AJNR Am J Neuroradiol 2005, 26(3):572-577.
De Stefano N, Matthews PM, Filippi M, Agosta F, De Luca M, Bartolozzi ML,
Guidi L, Ghezzi A, Montanari E, Cifelli A, et al: Evidence of early cortical
atrophy in MS: relevance to white matter changes and disability.
Neurology 2003, 60(7):1157-1162.
Horakova D, Cox JL, Havrdova E, Hussein S, Dolezal O, Cookfair D,
Dwyer MG, Seidl Z, Bergsland N, Vaneckova M, et al: Evolution of different
MRI measures in patients with active relapsing-remitting multiple
sclerosis over 2 and 5 years: a case-control study. J Neurol Neurosurg
Psychiatry 2008, 79(4):407-414.
Pirko I, Lucchinetti CF, Sriram S, Bakshi R: Gray matter involvement in
multiple sclerosis. Neurology 2007, 68(9):634-642.
Fisniku LK, Chard DT, Jackson JS, Anderson VM, Altmann DR, Miszkiel KA,
Thompson AJ, Miller DH: Gray matter atrophy is related to long-term
disability in multiple sclerosis. Ann Neurol 2008, 64(3):247-254.
Calabrese M, Agosta F, Rinaldi F, Mattisi I, Grossi P, Favaretto A, Atzori M,
Bernardi V, Barachino L, Rinaldi L, et al: Cortical lesions and atrophy
associated with cognitive impairment in relapsing-remitting multiple
sclerosis. Arch Neurol 2009, 66(9):1144-1150.
Chard DT, Griffin CM, Rashid W, Davies GR, Altmann DR, Kapoor R,
Barker GJ, Thompson AJ, Miller DH: Progressive grey matter atrophy in
clinically early relapsing-remitting multiple sclerosis. Mult Scler 2004,
Chen JT, Narayanan S, Collins DL, Smith SM, Matthews PM, Arnold DL:
Relating neocortical pathology to disability progression in multiple
sclerosis using MRI. Neuroimage 2004, 23(3):1168-1175.
Amato MP, Bartolozzi ML, Zipoli V, Portaccio E, Mortilla M, Guidi L,
Siracusa G, Sorbi S, Federico A, De Stefano N: Neocortical volume decrease
in relapsing-remitting MS patients with mild cognitive impairment.
Neurology 2004, 63(1):89-93.
Sastre-Garriga J, Ingle GT, Chard DT, Cercignani M, Ramio-Torrenta L,
Miller DH, Thompson AJ: Grey and white matter volume changes in early
primary progressive multiple sclerosis: a longitudinal study. Brain 2005,
Valsasina P, Benedetti B, Rovaris M, Sormani MP, Comi G, Filippi M:
Evidence for progressive gray matter loss in patients with relapsing-
remitting MS. Neurology 2005, 65(7):1126-1128.
Tjoa CW, Benedict RH, Weinstock-Guttman B, Fabiano AJ, Bakshi R: MRI T2
hypointensity of the dentate nucleus is related to ambulatory
impairment in multiple sclerosis. J Neurol Sci 2005, 234(1-2):17-24.
Tiberio M, Chard DT, Altmann DR, Davies G, Griffin CM, Rashid W, Sastre-
Garriga J, Thompson AJ, Miller DH: Gray and white matter volume
changes in early RRMS: a 2-year longitudinal study. Neurology 2005,
Smith SM, Zhang Y, Jenkinson M, Chen J, Matthews PM, Federico A, De
Stefano N: Accurate, robust, and automated longitudinal and cross-
sectional brain change analysis. Neuroimage 2002, 17(1):479-489.
Zivadinov R, Grop A, Sharma J, Bratina A, Tjoa CW, Dwyer M, Zorzon M:
Reproducibility and accuracy of quantitative magnetic resonance
imaging techniques of whole-brain atrophy measurement in multiple
sclerosis. J Neuroimaging 2005, 15(1):27-36.
Simon JH, Schiffer RB, Rudick RA, Herndon RM: Quantitative determination
of MS-induced corpus callosum atrophy in vivo using MR imaging. AJNR
Am J Neuroradiol 1987, 8(4):599-604.
Tedeschi G, Lavorgna L, Russo P, Prinster A, Dinacci D, Savettieri G,
Quattrone A, Livrea P, Messina C, Reggio A, et al: Brain atrophy and lesion
load in a large population of patients with multiple sclerosis. Neurology
Kidd D, Barkhof F, McConnell R, Algra PR, Allen IV, Revesz T: Cortical lesions
in multiple sclerosis. Brain 1999, 122(Pt 1):17-26.
Kutzelnigg A, Lassmann H: Cortical lesions and brain atrophy in MS. J
Neurol Sci 2005, 233(1-2):55-59.
Peterson JW, Bo L, Mork S, Chang A, Trapp BD: Transected neurites,
apoptotic neurons, and reduced inflammation in cortical multiple
sclerosis lesions. Ann Neurol 2001, 50(3):389-400.
52.Wegner C, Esiri MM, Chance SA, Palace J, Matthews PM: Neocortical
neuronal, synaptic, and glial loss in multiple sclerosis. Neurology 2006,
Chard D, Miller D: Grey matter pathology in clinically early multiple
sclerosis: evidence from magnetic resonance imaging. J Neurol Sci 2009,
Wylezinska M, Cifelli A, Jezzard P, Palace J, Alecci M, Matthews PM:
Thalamic neurodegeneration in relapsing-remitting multiple sclerosis.
Neurology 2003, 60(12):1949-1954.
Roosendaal SD, Bendfeldt K, Vrenken H, Polman CH, Borgwardt S,
Radue EW, Kappos L, Pelletier D, Hauser SL, Matthews PM, et al: Grey
matter volume in a large cohort of MS patients: relation to MRI
parameters and disability. Mult Scler 2011, 17(9):1098-1106.
Sormani M, Stromillo ML, Battaglini M, Signori A, De Stefano N: Modelling
the distribution of cortical lesions in multiple sclerosis. Mult Scler 2011.
Khaleeli Z, Cercignani M, Audoin B, Ciccarelli O, Miller DH, Thompson AJ:
Localized grey matter damage in early primary progressive multiple
sclerosis contributes to disability. Neuroimage 2007, 37(1):253-261.
Sepulcre J, Sastre-Garriga J, Cercignani M, Ingle GT, Miller DH,
Thompson AJ: Regional gray matter atrophy in early primary progressive
multiple sclerosis: a voxel-based morphometry study. Arch Neurol 2006,
Audoin B, Davies G, Rashid W, Fisniku L, Thompson AJ, Miller DH: Voxel-
based analysis of grey matter magnetization transfer ratio maps in early
relapsing remitting multiple sclerosis. Mult Scler 2007, 13(4):483-489.
Quarantelli M, Ciarmiello A, Morra VB, Orefice G, Larobina M, Lanzillo R,
Schiavone V, Salvatore E, Alfano B, Brunetti A: Brain tissue volume changes
in relapsing-remitting multiple sclerosis: correlation with lesion load.
Neuroimage 2003, 18(2):360-366.
Pomeroy IM, Jordan EK, Frank JA, Matthews PM, Esiri MM: Diffuse cortical
atrophy in a marmoset model of multiple sclerosis. Neurosci Lett 2008,
Geurts JJ, Stys PK, Minagar A, Amor S, Zivadinov R: Gray matter pathology
in (chronic) MS: modern views on an early observation. J Neurol Sci 2009,
Zivadinov R, Uxa L, Bratina A, Bosco A, Srinivasaraghavan B, Minagar A,
Ukmar M, Benedetto S, Zorzon M: HLA-DRB1*1501, -DQB1*0301,
-DQB1*0302, -DQB1*0602, and -DQB1*0603 alleles are associated with
more severe disease outcome on MRI in patients with multiple sclerosis.
International review of neurobiology 2007, 79:521-535.
Zivadinov R, Uxa L, Zacchi T, Nasuelli D, Ukmar M, Furlan C, Pozzi-Mucelli R,
Tommasi MA, Locatelli L, Ulivi S, et al: HLA genotypes and disease severity
assessed by magnetic resonance imaging findings in patients with
multiple sclerosis. J Neurol 2003, 250(9):1099-1106.
Benedict RH, Zivadinov R, Carone DA, Weinstock-Guttman B, Gaines J,
Maggiore C, Sharma J, Tomassi MA, Bakshi R: Regional lobar atrophy
predicts memory impairment in multiple sclerosis. AJNR Am J Neuroradiol
Prinster A, Quarantelli M, Orefice G, Lanzillo R, Brunetti A, Mollica C,
Salvatore E, Morra VB, Coppola G, Vacca G, et al: Grey matter loss in
relapsing-remitting multiple sclerosis: a voxel-based morphometry study.
Neuroimage 2006, 29(3):859-867.
Sailer M, Fischl B, Salat D, Tempelmann C, Schonfeld MA, Busa E,
Bodammer N, Heinze HJ, Dale A: Focal thinning of the cerebral cortex in
multiple sclerosis. Brain 2003, 126(Pt 8):1734-1744.
Tekok-Kilic A, Benedict RH, Weinstock-Guttman B, Dwyer MG, Carone D,
Srinivasaraghavan B, Yella V, Abdelrahman N, Munschauer F, Bakshi R, et al:
Independent contributions of cortical gray matter atrophy and ventricle
enlargement for predicting neuropsychological impairment in multiple
sclerosis. Neuroimage 2007, 36(4):1294-1300.
Riccitelli G, Rocca MA, Forn C, Colombo B, Comi G, Filippi M: Voxelwise
assessment of the regional distribution of damage in the brains of
patients with multiple sclerosis and fatigue. AJNR Am J Neuroradiol 2011,
Morgen K, Sammer G, Courtney SM, Wolters T, Melchior H, Blecker CR,
Oschmann P, Kaps M, Vaitl D: Evidence for a direct association between
cortical atrophy and cognitive impairment in relapsing-remitting MS.
Neuroimage 2006, 30(3):891-898.
Bermel RA, Innus MD, Tjoa CW, Bakshi R: Selective caudate atrophy in
multiple sclerosis: a 3D MRI parcellation study. Neuroreport 2003,
Horakova et al. BMC Neurology 2012, 12:10
Page 7 of 10
72.Cifelli A, Arridge M, Jezzard P, Esiri MM, Palace J, Matthews PM: Thalamic
neurodegeneration in multiple sclerosis. Ann Neurol 2002, 52(5):650-653.
Ciccarelli O, Werring DJ, Wheeler-Kingshott CA, Barker GJ, Parker GJ,
Thompson AJ, Miller DH: Investigation of MS normal-appearing brain
using diffusion tensor MRI with clinical correlations. Neurology 2001,
Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, Barachino L,
Morra A, Rinaldi L, Romualdi C, Perini P, et al: Detection of cortical
inflammatory lesions by double inversion recovery magnetic resonance
imaging in patients with multiple sclerosis. Arch Neurol 2007,
Calabrese M, Battaglini M, Giorgio A, Atzori M, Bernardi V, Mattisi I, Gallo P,
De Stefano N: Imaging distribution and frequency of cortical lesions in
patients with multiple sclerosis. Neurology 2010, 75(14):1234-1240.
Geurts JJ, Bo L, Roosendaal SD, Hazes T, Daniels R, Barkhof F, Witter MP,
Huitinga I, van der Valk P: Extensive hippocampal demyelination in
multiple sclerosis. J Neuropathol Exp Neurol 2007, 66(9):819-827.
Gilmore CP, Bo L, Owens T, Lowe J, Esiri MM, Evangelou N: Spinal cord
gray matter demyelination in multiple sclerosis-a novel pattern of
residual plaque morphology. Brain Pathol 2006, 16(3):202-208.
Huitinga I, De Groot CJ, Van der Valk P, Kamphorst W, Tilders FJ, Swaab DF:
Hypothalamic lesions in multiple sclerosis. J Neuropathol Exp Neurol 2001,
Vercellino M, Plano F, Votta B, Mutani R, Giordana MT, Cavalla P: Grey
matter pathology in multiple sclerosis. J Neuropathol Exp Neurol 2005,
Calabrese M, Mattisi I, Rinaldi F, Favaretto A, Atzori M, Bernardi V,
Barachino L, Romualdi C, Rinaldi L, Perini P, et al: Magnetic resonance
evidence of cerebellar cortical pathology in multiple sclerosis. J Neurol
Neurosurg Psychiatry 2010, 81(4):401-404.
van Horssen J, Brink BP, de Vries HE, van der Valk P, Bo L: The blood-brain
barrier in cortical multiple sclerosis lesions. J Neuropathol Exp Neurol 2007,
Dolezal O, Dwyer MG, Horakova D, Havrdova E, Minagar A, Balachandran S,
Bergsland N, Seidl Z, Vaneckova M, Fritz D, et al: Detection of cortical
lesions is dependent on choice of slice thickness in patients with
multiple sclerosis. International review of neurobiology 2007, 79:475-489.
Rinaldi F, Calabrese M, Grossi P, Puthenparampil M, Perini P, Gallo P:
Cortical lesions and cognitive impairment in multiple sclerosis. Neurol Sci
2010, 31(Suppl 2):S235-237.
Davies GR, Altmann DR, Hadjiprocopis A, Rashid W, Chard DT, Griffin CM,
Tofts PS, Barker GJ, Kapoor R, Thompson AJ, et al: Increasing normal-
appearing grey and white matter magnetisation transfer ratio
abnormality in early relapsing-remitting multiple sclerosis. J Neurol 2005,
Oreja-Guevara C, Rovaris M, Iannucci G, Valsasina P, Caputo D, Cavarretta R,
Sormani MP, Ferrante P, Comi G, Filippi M: Progressive gray matter
damage in patients with relapsing-remitting multiple sclerosis: a
longitudinal diffusion tensor magnetic resonance imaging study. Arch
Neurol 2005, 62(4):578-584.
Versijpt J, Debruyne JC, Van Laere KJ, De Vos F, Keppens J, Strijckmans K,
Achten E, Slegers G, Dierckx RA, Korf J, et al: Microglial imaging with
positron emission tomography and atrophy measurements with
magnetic resonance imaging in multiple sclerosis: a correlative study.
Mult Scler 2005, 11(2):127-134.
Rashid W, Parkes LM, Ingle GT, Chard DT, Toosy AT, Altmann DR,
Symms MR, Tofts PS, Thompson AJ, Miller DH: Abnormalities of cerebral
perfusion in multiple sclerosis. J Neurol Neurosurg Psychiatry 2004,
Rocca MA, Pagani E, Ghezzi A, Falini A, Zaffaroni M, Colombo B, Scotti G,
Comi G, Filippi M: Functional cortical changes in patients with multiple
sclerosis and nonspecific findings on conventional magnetic resonance
imaging scans of the brain. Neuroimage 2003, 19(3):826-836.
Geurts JJ, Roosendaal SD, Calabrese M, Ciccarelli O, Agosta F, Chard DT,
Gass A, Huerga E, Moraal B, Pareto D, et al: Consensus recommendations
for MS cortical lesion scoring using double inversion recovery MRI.
Neurology 2011, 76(5):418-424.
Audoin B, Zaaraoui W, Reuter F, Rico A, Malikova I, Confort-Gouny S,
Cozzone PJ, Pelletier J, Ranjeva JP: Atrophy mainly affects the limbic
system and the deep grey matter at the first stage of multiple sclerosis.
J Neurol Neurosurg Psychiatry 2010, 81(6):690-695.
91.Calabrese M, Atzori M, Bernardi V, Morra A, Romualdi C, Rinaldi L,
McAuliffe MJ, Barachino L, Perini P, Fischl B, et al: Cortical atrophy is
relevant in multiple sclerosis at clinical onset. J Neurol 2007,
Fisniku LK, Altmann DR, Cercignani M, Tozer DJ, Chard DT, Jackson JS,
Miszkiel KA, Schmierer K, Thompson AJ, Miller DH: Magnetization transfer
ratio abnormalities reflect clinically relevant grey matter damage in
multiple sclerosis. Mult Scler 2009, 15(6):668-677.
Henry RG, Shieh M, Amirbekian B, Chung S, Okuda DT, Pelletier D:
Connecting white matter injury and thalamic atrophy in clinically
isolated syndromes. J Neurol Sci 2009, 282(1-2):61-66.
Henry RG, Shieh M, Okuda DT, Evangelista A, Gorno-Tempini ML, Pelletier D:
Regional grey matter atrophy in clinically isolated syndromes at
presentation. J Neurol Neurosurg Psychiatry 2008, 79(11):1236-1244.
Roosendaal SD, Bendfeldt K, Vrenken H, Polman CH, Borgwardt S,
Radue EW, Kappos L, Pelletier D, Hauser SL, Matthews PM, et al: Grey
matter volume in a large cohort of MS patients: relation to MRI
parameters and disability. Mult Scler 2011.
Calabrese M, Rinaldi F, Mattisi I, Bernardi V, Favaretto A, Perini P, Gallo P:
The predictive value of gray matter atrophy in clinically isolated
syndromes. Neurology 2011, 77(3):257-263.
Raz E, Cercignani M, Sbardella E, Totaro P, Pozzilli C, Bozzali M, Pantano P:
Gray- and white-matter changes 1 year after first clinical episode of
multiple sclerosis: MR imaging. Radiology 2010, 257(2):448-454.
Rocca MA, Agosta F, Sormani MP, Fernando K, Tintore M, Korteweg T,
Tortorella P, Miller DH, Thompson A, Rovira A, et al: A three-year, multi-
parametric MRI study in patients at presentation with CIS. J Neurol 2008,
Bakshi R, Benedict RH, Bermel RA, Jacobs L: Regional brain atrophy is
associated with physical disability in multiple sclerosis: semiquantitative
magnetic resonance imaging and relationship to clinical findings. J
Neuroimaging 2001, 11(2):129-136.
100. Sanfilipo MP, Benedict RH, Sharma J, Weinstock-Guttman B, Bakshi R: The
relationship between whole brain volume and disability in multiple
sclerosis: a comparison of normalized gray vs. white matter with
misclassification correction. Neuroimage 2005, 26(4):1068-1077.
101. Amato MP, Portaccio E, Goretti B, Zipoli V, Battaglini M, Bartolozzi ML,
Stromillo ML, Guidi L, Siracusa G, Sorbi S, et al: Association of neocortical
volume changes with cognitive deterioration in relapsing-remitting
multiple sclerosis. Arch Neurol 2007, 64(8):1157-1161.
102. Horakova D, Dwyer MG, Havrdova E, Cox JL, Dolezal O, Bergsland N,
Rimes B, Seidl Z, Vaneckova M, Zivadinov R: Gray matter atrophy and
disability progression in patients with early relapsing-remitting multiple
sclerosis: a 5-year longitudinal study. J Neurol Sci 2009, 282(1-2):112-119.
103. Bonati U, Fisniku LK, Altmann DR, Yiannakas MC, Furby J, Thompson AJ,
Miller DH, Chard DT: Cervical cord and brain grey matter atrophy
independently associate with long-term MS disability. J Neurol Neurosurg
Psychiatry 2011, 82(4):471-472.
104. Hayton T, Furby J, Smith KJ, Altmann DR, Brenner R, Chataway J,
Hughes RA, Hunter K, Tozer DJ, Miller DH, et al: Grey matter magnetization
transfer ratio independently correlates with neurological deficit in
secondary progressive multiple sclerosis. J Neurol 2009, 256(3):427-435.
105. Rovaris M, Judica E, Sastre-Garriga J, Rovira A, Sormani MP, Benedetti B,
Korteweg T, De Stefano N, Khaleeli Z, Montalban X, et al: Large-scale,
multicentre, quantitative MRI study of brain and cord damage in
primary progressive multiple sclerosis. Mult Scler 2008, 14(4):455-464.
106. Calabrese M, Filippi M, Rovaris M, Bernardi V, Atzori M, Mattisi I, Favaretto A,
Grossi P, Barachino L, Rinaldi L, et al: Evidence for relative cortical sparing
in benign multiple sclerosis: a longitudinal magnetic resonance imaging
study. Mult Scler 2009, 15(1):36-41.
107. Drayer B, Burger P, Hurwitz B, Dawson D, Cain J: Reduced signal intensity
on MR images of thalamus and putamen in multiple sclerosis: increased
iron content? AJR American journal of roentgenology 1987, 149(2):357-363.
108. Bakshi R, Dmochowski J, Shaikh ZA, Jacobs L: Gray matter T2
hypointensity is related to plaques and atrophy in the brains of multiple
sclerosis patients. J Neurol Sci 2001, 185(1):19-26.
109. Bakshi R, Shaikh ZA, Janardhan V: MRI T2 shortening (’black T2’) in
multiple sclerosis: frequency, location, and clinical correlation.
Neuroreport 2000, 11(1):15-21.
110. Neema M, Stankiewicz J, Arora A, Dandamudi VS, Batt CE, Guss ZD, Al-
Sabbagh A, Bakshi R: T1- and T2-based MRI measures of diffuse gray
Horakova et al. BMC Neurology 2012, 12:10
Page 8 of 10
matter and white matter damage in patients with multiple sclerosis. J
Neuroimaging 2007, 17(Suppl 1):16S-21S.
111. Neema M, Arora A, Healy BC, Guss ZD, Brass SD, Duan Y, Buckle GJ,
Glanz BI, Stazzone L, Khoury SJ, et al: Deep gray matter involvement on
brain MRI scans is associated with clinical progression in multiple
sclerosis. J Neuroimaging 2009, 19(1):3-8.
112. Brass SD, Benedict RH, Weinstock-Guttman B, Munschauer F, Bakshi R:
Cognitive impairment is associated with subcortical magnetic resonance
imaging grey matter T2 hypointensity in multiple sclerosis. Mult Scler
113. Bermel RA, Puli SR, Rudick RA, Weinstock-Guttman B, Fisher E,
Munschauer FE, Bakshi R: Prediction of longitudinal brain atrophy in
multiple sclerosis by gray matter magnetic resonance imaging T2
hypointensity. Arch Neurol 2005, 62(9):1371-1376.
114. Tovar-Moll F, Evangelou IE, Chiu AW, Richert ND, Ostuni JL, Ohayon JM,
Auh S, Ehrmantraut M, Talagala SL, McFarland HF, et al: Thalamic
involvement and its impact on clinical disability in patients with
multiple sclerosis: a diffusion tensor imaging study at 3T. AJNR Am J
Neuroradiol 2009, 30(7):1380-1386.
115. Niepel G, Tench Ch R, Morgan PS, Evangelou N, Auer DP,
Constantinescu CS: Deep gray matter and fatigue in MS: a T1 relaxation
time study. J Neurol 2006, 253(7):896-902.
116. Filippi M, Rocca MA, Colombo B, Falini A, Codella M, Scotti G, Comi G:
Functional magnetic resonance imaging correlates of fatigue in multiple
sclerosis. Neuroimage 2002, 15(3):559-567.
117. Calabrese M, Rinaldi F, Grossi P, Mattisi I, Bernardi V, Favaretto A, Perini P,
Gallo P: Basal ganglia and frontal/parietal cortical atrophy is associated
with fatigue in relapsing-remitting multiple sclerosis. Mult Scler 2010,
118. Poonawalla AH, Datta S, Juneja V, Nelson F, Wolinsky JS, Cutter G,
Narayana PA: Composite MRI scores improve correlation with EDSS in
multiple sclerosis. Mult Scler 2010, 16(9):1117-1125.
119. Sepulcre J, Masdeu JC, Goni J, Arrondo G, Velez de Mendizabal N,
Bejarano B, Villoslada P: Fatigue in multiple sclerosis is associated with
the disruption of frontal and parietal pathways. Mult Scler 2009,
120. Manconi M, Rocca MA, Ferini-Strambi L, Tortorella P, Agosta F, Comi G,
Filippi M: Restless legs syndrome is a common finding in multiple
sclerosis and correlates with cervical cord damage. Mult Scler 2008,
121. Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, Barachino L,
Rinaldi L, Morra A, McAuliffe MM, Perini P, et al: Extensive cortical
inflammation is associated with epilepsy in multiple sclerosis. J Neurol
122. Poser CM, Brinar VV: Epilepsy and multiple sclerosis. Epilepsy Behav 2003,
123. Moreau T, Sochurkova D, Lemesle M, Madinier G, Billiar T, Giroud M,
Dumas R: Epilepsy in patients with multiple sclerosis: radiological-clinical
correlations. Epilepsia 1998, 39(8):893-896.
124. Sokic DV, Stojsavljevic N, Drulovic J, Dujmovic I, Mesaros S, Ercegovac M,
Peric V, Dragutinovic G, Levic Z: Seizures in multiple sclerosis. Epilepsia
125. Meier DS, Weiner HL, Guttmann CR: Time-series modeling of multiple
sclerosis disease activity: a promising window on disease progression
and repair potential? Neurotherapeutics: the journal of the American Society
for Experimental NeuroTherapeutics 2007, 4(3):485-498.
126. Filippi M, Rocca MA, Falini A, Caputo D, Ghezzi A, Colombo B, Scotti G,
Comi G: Correlations between structural CNS damage and functional
MRI changes in primary progressive MS. Neuroimage 2002, 15(3):537-546.
127. Lee M, Reddy H, Johansen-Berg H, Pendlebury S, Jenkinson M, Smith S,
Palace J, Matthews PM: The motor cortex shows adaptive functional
changes to brain injury from multiple sclerosis. Ann Neurol 2000,
128. Reddy H, Narayanan S, Arnoutelis R, Jenkinson M, Antel J, Matthews PM,
Arnold DL: Evidence for adaptive functional changes in the cerebral
cortex with axonal injury from multiple sclerosis. Brain 2000, 123(Pt
129. Valsasina P, Rocca MA, Absinta M, Sormani MP, Mancini L, De Stefano N,
Rovira A, Gass A, Enzinger C, Barkhof F, et al: A multicentre study of motor
functional connectivity changes in patients with multiple sclerosis. Eur J
Neurosci 2011, 33(7):1256-1263.
130. Rico A, Zaaraoui W, Franques J, Attarian S, Reuter F, Malikova I, Confort-
Gouny S, Soulier E, Pouget J, Cozzone PJ, et al: Motor cortical
reorganization is present after a single attack of multiple sclerosis
devoid of cortico-spinal dysfunction. MAGMA 2011, 24(2):77-84.
131. Cader S, Cifelli A, Abu-Omar Y, Palace J, Matthews PM: Reduced brain
functional reserve and altered functional connectivity in patients with
multiple sclerosis. Brain 2006, 129(Pt 2):527-537.
132. Parry AM, Scott RB, Palace J, Smith S, Matthews PM: Potentially adaptive
functional changes in cognitive processing for patients with multiple
sclerosis and their acute modulation by rivastigmine. Brain 2003, 126(Pt
133. Audoin B, Ibarrola D, Ranjeva JP, Confort-Gouny S, Malikova I, Ali-Cherif A,
Pelletier J, Cozzone P: Compensatory cortical activation observed by fMRI
during a cognitive task at the earliest stage of MS. Hum Brain Mapp
134. Giorgio A, Portaccio E, Stromillo ML, Marino S, Zipoli V, Battaglini M,
Blandino A, Bartolozzi ML, Siracusa G, Amato MP, et al: Cortical functional
reorganization and its relationship with brain structural damage in
patients with benign multiple sclerosis. Mult Scler 2010, 16(11):1326-1334.
135. Agosta F, Valsasina P, Rocca MA, Caputo D, Sala S, Judica E, Stroman PW,
Filippi M: Evidence for enhanced functional activity of cervical cord in
relapsing multiple sclerosis. Magn Reson Med 2008, 59(5):1035-1042.
136. Goldman MD, Motl RW, Rudick RA: Possible clinical outcome measures for
clinical trials in patients with multiple sclerosis. Ther Adv Neurol Disord
137. Hobart J, Freeman J, Thompson A: Kurtzke scales revisited: the
application of psychometric methods to clinical intuition. Brain 2000,
138. Polman CH, Rudick RA: The multiple sclerosis functional composite: a
clinically meaningful measure of disability. Neurology 2010, 74(Suppl 3):
139. Rudick RA, Lee JC, Nakamura K, Fisher E: Gray matter atrophy correlates
with MS disability progression measured with MSFC but not EDSS. J
Neurol Sci 2009, 282(1-2):106-111.
140. Patti F: Cognitive impairment in multiple sclerosis. Mult Scler 2009,
141. Rao SM: Neuropsychology of multiple sclerosis. Curr Opin Neurol 1995,
142. Tur C, Penny S, Khaleeli Z, Altmann D, Cipolotti L, Ron M, Thompson A,
Ciccarelli O: Grey matter damage and overall cognitive impairment in
primary progressive multiple sclerosis. Mult Scler 2011.
143. Chiaravalloti ND, DeLuca J: Cognitive impairment in multiple sclerosis.
Lancet Neurol 2008, 7(12):1139-1151.
144. Till C, Ghassemi R, Aubert-Broche B, Kerbrat A, Collins DL, Narayanan S,
Arnold DL, Desrocher M, Sled JG, Banwell BL: MRI correlates of cognitive
impairment in childhood-onset multiple sclerosis. Neuropsychology 2011,
145. Amato MP, Goretti B, Ghezzi A, Lori S, Zipoli V, Moiola L, Falautano M, De
Caro MF, Viterbo R, Patti F, et al: Cognitive and psychosocial features in
childhood and juvenile MS: two-year follow-up. Neurology 2010,
146. Benedict RH, Zivadinov R: Risk factors for and management of cognitive
dysfunction in multiple sclerosis. Nat Rev Neurol 2011, 7(6):332-342.
147. Amato MP, Zipoli V, Portaccio E: Multiple sclerosis-related cognitive
changes: a review of cross-sectional and longitudinal studies. J Neurol Sci
148. Calabrese M, Rinaldi F, Grossi P, Gallo P: Cortical pathology and cognitive
impairment in multiple sclerosis. Expert Rev Neurother 2011, 11(3):425-432.
149. Calabrese M, Rinaldi F, Mattisi I, Grossi P, Favaretto A, Atzori M, Bernardi V,
Barachino L, Romualdi C, Rinaldi L, et al: Widespread cortical thinning
characterizes patients with MS with mild cognitive impairment.
Neurology 2010, 74(4):321-328.
150. Blinkenberg M, Rune K, Jensen CV, Ravnborg M, Kyllingsbaek S, Holm S,
Paulson OB, Sorensen PS: Cortical cerebral metabolism correlates with
MRI lesion load and cognitive dysfunction in MS. Neurology 2000,
151. Filippi M, Alberoni M, Martinelli V, Sirabian G, Bressi S, Canal N, Comi G:
Influence of clinical variables on neuropsychological performance in
multiple sclerosis. Eur Neurol 1994, 34(6):324-328.
Horakova et al. BMC Neurology 2012, 12:10
Page 9 of 10
152. Benedict RH, Carone DA, Bakshi R: Correlating brain atrophy with Download full-text
cognitive dysfunction, mood disturbances, and personality disorder in
multiple sclerosis. J Neuroimaging 2004, 14(3 Suppl):36S-45S.
153. Sanfilipo MP, Benedict RH, Weinstock-Guttman B, Bakshi R: Gray and white
matter brain atrophy and neuropsychological impairment in multiple
sclerosis. Neurology 2006, 66(5):685-692.
154. Benedict RH, Bruce JM, Dwyer MG, Abdelrahman N, Hussein S, Weinstock-
Guttman B, Garg N, Munschauer F, Zivadinov R: Neocortical atrophy, third
ventricular width, and cognitive dysfunction in multiple sclerosis. Arch
Neurol 2006, 63(9):1301-1306.
155. Zarei M: Clinical characteristics of cortical multiple sclerosis. J Neurol Sci
156. Zarei M, Chandran S, Compston A, Hodges J: Cognitive presentation of
multiple sclerosis: evidence for a cortical variant. J Neurol Neurosurg
Psychiatry 2003, 74(7):872-877.
157. Batista S, Zivadinov R, Hoogs M, Bergsland N, Heininen-Brown M,
Dwyer MG, Weinstock-Guttman B, Benedict RH: Basal ganglia, thalamus
and neocortical atrophy predicting slowed cognitive processing in
multiple sclerosis. J Neurol 2011.
158. Benedict RH, Hussein S, Englert J, Dwyer MG, Abdelrahman N, Cox JL,
Munschauer FE, Weinstock-Guttman B, Zivadinov R: Cortical atrophy and
personality in multiple sclerosis. Neuropsychology 2008, 22(4):432-441.
159. Benedict RH, Ramasamy D, Munschauer F, Weinstock-Guttman B,
Zivadinov R: Memory impairment in multiple sclerosis: correlation with
deep grey matter and mesial temporal atrophy. J Neurol Neurosurg
Psychiatry 2009, 80(2):201-206.
160. Anderson VM, Fisniku LK, Khaleeli Z, Summers MM, Penny SA, Altmann DR,
Thompson AJ, Ron MA, Miller DH: Hippocampal atrophy in relapsing-
remitting and primary progressive MS: a comparative study. Mult Scler
161. Houtchens MK, Benedict RH, Killiany R, Sharma J, Jaisani Z, Singh B,
Weinstock-Guttman B, Guttmann CR, Bakshi R: Thalamic atrophy and
cognition in multiple sclerosis. Neurology 2007, 69(12):1213-1223.
162. Hildebrandt H, Hahn HK, Kraus JA, Schulte-Herbruggen A, Schwarze B,
Schwendemann G: Memory performance in multiple sclerosis patients
correlates with central brain atrophy. Mult Scler 2006, 12(4):428-436.
163. Roosendaal SD, Moraal B, Pouwels PJ, Vrenken H, Castelijns JA, Barkhof F,
Geurts JJ: Accumulation of cortical lesions in MS: relation with cognitive
impairment. Mult Scler 2009, 15(6):708-714.
164. Bagnato F, Salman Z, Kane R, Auh S, Cantor FK, Ehrmantraut M, Gallo A,
Ikonomidou VN, Ohayon J, Pellicano C, et al: T1 cortical hypointensities
and their association with cognitive disability in multiple sclerosis. Mult
Scler 2010, 16(10):1203-1212.
165. Calabrese P, Penner IK: Cognitive dysfunctions in multiple sclerosis–a
“multiple disconnection syndrome"? J Neurol 2007, 254(Suppl 2):II18-21.
166. Barkhof F, Calabresi PA, Miller DH, Reingold SC: Imaging outcomes for
neuroprotection and repair in multiple sclerosis trials. Nat Rev Neurol
167. Tintore M, Rovira A, Rio J, Nos C, Grive E, Tellez N, Pelayo R, Comabella M,
Sastre-Garriga J, Montalban X: Baseline MRI predicts future attacks and
disability in clinically isolated syndromes. Neurology 2006, 67(6):968-972.
168. Daumer M, Neuhaus A, Herbert J, Ebers G: Prognosis of the individual
course of disease: the elements of time, heterogeneity and precision. J
Neurol Sci 2009, 287(Suppl 1):S50-55.
169. Rio J, Castillo J, Rovira A, Tintore M, Sastre-Garriga J, Horga A, Nos C,
Comabella M, Aymerich X, Montalban X: Measures in the first year of
therapy predict the response to interferon beta in MS. Mult Scler 2009,
170. Li DK, Held U, Petkau J, Daumer M, Barkhof F, Fazekas F, Frank JA, Kappos L,
Miller DH, Simon JH, et al: MRI T2 lesion burden in multiple sclerosis: a
plateauing relationship with clinical disability. Neurology 2006,
171. Zivadinov R, Leist TP: Clinical-magnetic resonance imaging correlations in
multiple sclerosis. J Neuroimaging 2005, 15(4 Suppl):10S-21S.
172. Zivadinov R, Reder AT, Filippi M, Minagar A, Stuve O, Lassmann H,
Racke MK, Dwyer MG, Frohman EM, Khan O: Mechanisms of action of
disease-modifying agents and brain volume changes in multiple
sclerosis. Neurology 2008, 71(2):136-144.
173. Kelemen A, Dwyer MG, Horakova D, Vaneckova M, Havrdova E, Zivadinov R:
Measurement of gray matter volume is less susceptible to
pseudoatrophy effect than that of white matter or whole brain volume
in patients with multiple sclerosis. Results from Avonex-Steroids-
Azathioprine combination study. Mult Scler 2008, 14(280):S11.
174. Rovaris M, Gallo A, Valsasina P, Benedetti B, Caputo D, Ghezzi A,
Montanari E, Sormani MP, Bertolotto A, Mancardi G, et al: Short-term
accrual of gray matter pathology in patients with progressive multiple
sclerosis: an in vivo study using diffusion tensor MRI. Neuroimage 2005,
175. Filippi M, Rocca MA, Calabrese M, Sormani MP, Rinaldi F, Perini P, Comi G,
Gallo P: Intracortical lesions: relevance for new MRI diagnostic criteria for
multiple sclerosis. Neurology 2010, 75(22):1988-1994.
176. Brex PA, Jenkins R, Fox NC, Crum WR, O’Riordan JI, Plant GT, Miller DH:
Detection of ventricular enlargement in patients at the earliest clinical
stage of MS. Neurology 2000, 54(8):1689-1691.
177. Agosta F, Rovaris M, Pagani E, Sormani MP, Comi G, Filippi M:
Magnetization transfer MRI metrics predict the accumulation of
disability 8 years later in patients with multiple sclerosis. Brain 2006,
178. Bo L, Vedeler CA, Nyland H, Trapp BD, Mork SJ: Intracortical multiple
sclerosis lesions are not associated with increased lymphocyte
infiltration. Mult Scler 2003, 9(4):323-331.
179. Brink BP, Veerhuis R, Breij EC, van der Valk P, Dijkstra CD, Bo L: The
pathology of multiple sclerosis is location-dependent: no significant
complement activation is detected in purely cortical lesions. J
Neuropathol Exp Neurol 2005, 64(2):147-155.
180. Geurts JJ, Barkhof F: Grey matter pathology in multiple sclerosis. Lancet
Neurol 2008, 7(9):841-851.
181. Calabrese M, Bernardi V, Atzori M, Mattisi I, Favaretto A, Rinaldi F, Perini P,
Gallo P: Effect of disease-modifying drugs on cortical lesions and
atrophy in relapsing-remitting multiple sclerosis. Mult Scler 2011.
182. Zivadinov R, Locatelli L, Cookfair D, Srinivasaraghavan B, Bertolotto A,
Ukmar M, Bratina A, Maggiore C, Bosco A, Grop A, et al: Interferon beta-1a
slows progression of brain atrophy in relapsing-remitting multiple
sclerosis predominantly by reducing gray matter atrophy. Mult Scler
183. Tur C, Khaleeli Z, Ciccarelli O, Altmann DR, Cercignani M, Miller DH,
Thompson AJ: Complementary roles of grey matter MTR and T2 lesions
in predicting progression in early PPMS. J Neurol Neurosurg Psychiatry
The pre-publication history for this paper can be accessed here:
Cite this article as: Horakova et al.: Clinical correlates of grey matter
pathology in multiple sclerosis. BMC Neurology 2012 12:10.
Submit your next manuscript to BioMed Central
and take full advantage of:
• Convenient online submission
• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution
Submit your manuscript at
Horakova et al. BMC Neurology 2012, 12:10
Page 10 of 10