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: firstname.lastname@example.org
† 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
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Cite this article as: Horakova et al.: Clinical correlates of grey matter
pathology in multiple sclerosis. BMC Neurology 2012 12:10.
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