calabrese2011

Review
THEMED ARTICLE y Demyelinating diseases
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Cortical pathology and
cognitive impairment in
multiple sclerosis
Expert Rev. Neurother. 11(3), 425–432 (2011)
Massimiliano
Calabrese†1,
Francesca Rinaldi1,
Paola Grossi1 and
Paolo Gallo1
Multiple Sclerosis Centre of Veneto
Region, First Neurology Clinic,
Department of Neurosciences,
University Hospital of Padova,
Via Giustiniani 5, Padova, 35128, Italy
†
Author for correspondence:
Tel.: +39 049 821 3615
Fax: +39 049 821 2574
calabresem@hotmail.it
1
Cognitive impairment constitutes a relevant clinical aspect of multiple sclerosis (MS). Depending
on the disease phase and type, 40–65% of MS patients develop various degrees of cognitive
dysfunction. Pathological and MRI studies have failed to demonstrate the existence of a strict
relationship between cognitive impairment and subcortical white matter pathology. The
correlation is also poor when MRI metrics of whole brain (white plus gray matter) atrophy are
considered. Over the last decade, increasing observations have provided evidence of a primary
role of cortical pathology – that is, inflammatory focal lesions (cortical lesions) and atrophy
(cortical thickness) – in determining global and/or selective cognitive disability in MS. By applying
a new semi-automated software (Freesurfer) to analyze the global and regional cortical thickness
and the double inversion recovery sequence to identify cortical lesions, it has been observed
that specific cognitive deficits, such as memory impairment, attention deficits and reduced
mental processing speed, could be better explained by cortical structural abnormalities rather
than subcortical white matter lesions. Therefore, MRI evaluation of cortical pathology should
be included in the routine examination of MS patients, especially those with initial signs/symptoms
of cognitive dysfunctions.
Keywords : cognitive impairment • cortical thickness • gray matter atrophy • magnetic resonance imaging
• multiple sclerosis
“In most of the patients affected by multilocular
sclerosis … there is a marked enfeeblement of
the memory; conceptions are formed slowly; the
intellectual and emotional faculties are blunted
in their totality.”
– Charcot, 1877 [1] .
Since this remarkable description of the cognitive impairment (CI) developed by multiple sclerosis (MS) patients was made by Charcot, several
studies, especially during the last three decades,
have pointed out that cognitive dysfunctions are
frequent and often severe in MS, and constitute
a major clinical aspect of the disease. Indeed, CI
disrupts the lives, lifestyles, employment status
and yearly earnings of MS patients, and has detrimental effects on personal, occupational and
social functioning, thereby affecting overall
quality of life [2–4] .
Depending on disease stage and type, various
degrees of CI can be demonstrated in 40–65%
of MS patients [5–8] . Early studies suggested that
cognitive dysfunctions were more common and
disabling in patients with progressive rather than
relapsing–remitting (RR) forms of MS [5,9] ,
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10.1586/ERN.10.155
being more severe in patients with secondary
progressive MS (SPMS) than in patients with
primary progressive MS (PPMS) [10,11] . However,
the available literature data on the identification of distinct patterns of CI in different MS
subtypes appear quite conflicting [12,13] , and
various degrees of CI can be observed from the
early stages of the disease [5] . Indeed, Callanan
et al. [14] and Feinstein and colleagues [15] demonstrated the presence of CI at MS clinical presentation, and, more recently, several authors have
confirmed significant cognitive deficits in more
than 50% of patients with a diagnosis of possible
MS [6,13,16,17] .
Although MS typically affects young adults,
5% of the cases occur in children or adolescents [18] . Based on the assumption that axonal damage and neuronal loss in childhood
may interfere with the primary process of CNS
myelinogenesis, several studies have investigated the negative impact of pediatric MS on
the development of intellectual faculties and,
consequently, on general intelligence [19,20] .
Recently, Amato and colleagues, studying a
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Calabrese, Rinaldi, Grossi & Gallo
cohort of 63 childhood and juvenile patients, have found that
MS was frequently associated with CI and sometimes with significantly low intelligence quotient (IQ) scores, compared with
healthy children [21] .
The symptoms and the severity of CI in MS can be extremely
variable. This may depend on several factors, such as the patient’s
age, disease duration (usually more prolonged in patients with
progressive forms of MS) and clinical phenotype (being SPMS and
PPMS, as abovementioned, is usually associated with more severe
cognitive dysfunctions) [5,9] . The pattern of CI developed by MS
patients may also result from other elements, such as a patient’s
level of education and cognitive reserve. Indeed, Sumowski and
colleagues, based on a functional neuroimaging approach, suggested that in MS patients, intellectual enrichment was more
associated with cerebral efficiency, protecting against the negative effects of the disease on cognition [22] . Finally, CI may be
influenced by emotional factors, such as depression and fatigue,
that are thought to affect cognition, but are hardly approachable
by neuroimaging [23] .
In adult-onset MS, attention and concentration, information
processing speed, executive functions and long-term memory
seem to be the most affected functions [2,8,24,25] , whereas overt
dementia is rare [26] . In children and adolescents affected by MS,
the cognitive dysfunction, which also involves verbal comprehension and fluency and global intelligence, is mainly characterized
by a slow and delayed acquisition of intellectual faculties rather
than a loss of previously acquired capacities. For all of these reasons, the assessment of CI is actually considered to be a valid
instrument for monitoring disease progression [27] and, in some
cases, it may help in predicting an earlier conversion to MS in
patients with clinically isolated syndrome [28] . Thus, increasing
evidence suggests the opportunity of including the assessment
of cognitive functions in the routine clinical evaluation of MS
patients. Indeed, the early recognition of CI may lead to a specific therapeutic intervention in order to prevent further decline
of cognitive functions and reduce its impact on patient quality
of life [29] . Although preliminary observations indicate that the
currently used immunomodulatory drugs are effective in slowing
down the CI in MS patients [4] , further studies are required to
better clarify the pathogenetic substrates of MS-related CI and,
thus, to define its optimal treatment.
White matter pathology & MS-related
cognitive impairment
Multiple sclerosis has been traditionally considered an inflammatory T-cell mediated disorder of the CNS, affecting myelin
and oligodendrocytes in the cerebral white matter (WM). As a
consequence, several studies based on conventional MRI have
tried to demonstrate an association between subcortical WM
pathology and CI [30] . The leading hypothesis was that the
accumulation of widespread damage of the subcortical WM
would have necessarily led to anatomical and/or functional
disconnections between different cortical areas and deep
gray matter (GM) structures, thus determining the progressive development of a sort of ‘subcortical’ cognitive decline.
426
Nevertheless, all of the efforts aimed at correlating CI with
conventional T2-hyperintense WM lesions load (T2WMLV)
only gave modest results [31,32] .
Several studies have tried to identify a relationship between
specific locations of WM lesions and selective cognitive defects
by measuring the regional T2WMLV. Swirsky-Sacchetti et al.
found that lesions in the left frontal subcortical WM predicted
perseverative responses on the Wisconsin Card Sorting Test
(WCST) [33] . When MS patients were divided into two groups
matched for T2WMLV, one group with and one group without
high frontal lesion load, the former had a worse performance on
the WCST [34] . However, quite different findings were obtained
in a more recent study aimed at correlating executive ability
and WM lesion volume (WMLV) [35] . In this study, T2WMLV
was quantified using an automated method with a line drawn
through the central sulcus to demarcate the frontal regions. The
authors found a high correlation between frontal lesion area
and T2WMLV, and both measures correlated with failures on
executive tasks. However, when the sample was divided based
on a median split of the frontal/total lesion volume ratio, there
was no difference in any of the executive measures. Thus, no
consistent evidence supports a relationship between localized
T2WM lesions and specific cognitive deficits.
In a longitudinal study, frontal lesion volume represented the
greatest proportion of total lesion volume at all time points, and
the highest percentage of WM classified as ‘lesion’ was observed
in frontal and parietal regions [36] . When compared with ageand educational level-matched control subjects, the cognitive
performance of MS patients negatively correlated with WMLV in
frontal and parietal regions at baseline, 1-year and 4-year followup (r = -0.55 to -0.73; p < 0.001). The authors concluded that
MS lesions show a propensity for frontal and parietal WM and
that lesion burden in these areas was strongly associated with
performance on tasks requiring sustained complex attention and
working verbal memory. This relationship was consistent over a
4-year period, suggesting that disruption of fronto-parietal subcortical networks may underlie the pattern of neuropsychological
impairment seen in many patients with MS [36] .
Other studies that do not use conventional MRI techniques,
such as magnetization transfer ratio (MTR) [37] and MR spectroscopy [38] , have analyzed the normal-appearing white matter (NAWM). A lower average MTR and peak location of the
NAWM histogram was observed in patients with CI, and logistic regression ana­lysis demonstrated that 68% of the total variance was explained by average NAWM-MTR alone [37] . A good,
albeit still partial, correlation between CI and NAWM was also
obtained in an exploratory study with diffusion-tensor MRI [39] .
This study revealed a moderate������������������������������
correlation between mean diffusivity and fractional anisotropy in NAWM and the symbol
digit modalities test, verbal fluency test and 10/36 spatial recall
test scores [39] .
Together, these conflicting observations suggest that the severity of CI in MS cannot be totally explained by WM pathology.
In as much as cerebral WM contains a network of tracts connecting various regions of the cerebral cortex, some difficulties
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Cortical pathology & cognitive impairment in multiple sclerosis
in demonstrating specific correlations between WM lesions and
cognitive decline are expected. Indeed, when the contribution of
tract-specific WM injury to dysfunction in different cognitive
domains was analyzed by applying tract-based spatial statistics
to diffusion tensor imaging in 37 MS patients, cognitively relevant tract localizations only partially overlapped with areas of
high fluid attenuated inversion recovery (FLAIR) lesion probability, suggesting a contribution of NAWM abnormality to
CI [40] . However, the finding that tract localizations associated
with CI were found to interconnect cortical regions involved in
several cognitive tasks, or in possible compensatory processing
pathways, suggested that tract injury may play a role in determining cognitive dysfunction in MS. Whether tract pathology
may be a consequence of neuronal degeneration in the cortical
areas where tracts arise from needs to be investigated. Thus, the
use of nonconventional MRI techniques (i.e., MTR and diffusion tensor imaging) that disclose tissue abnormalities in the
NAWM have significantly increased the correlation between CI
and WM pathology, confirming that WM damage is, at least
partly, responsible for CI in MS.
Gray matter pathology & MS-related
cognitive impairment
A relevant body of histopathological and neuroimaging evidence
strongly suggests that MS cannot be considered a pure inflammatory disease of myelin for any longer. The dramatic loss of
axons within acute active inflammatory lesions [41] and relevance
of GM pathology, especially in the cortex, in the form of both
focal (cortical lesions, Figure 1) [42,43] and diffuse cortical damage
(Figure 2) [44–47] , has recently led to a new and more appropriate vision of MS, a disease in which neurodegenerative processes
appear early and significantly influence the clinical expression of
the disease.
Focal cortical pathology & cognitive impairment
Extensive inflammation, with a relevant number of focal lesions
(cortical lesions [CLs]; Figure 1), characterizes the cortex of MS
patients [48,49] . CLs have been histologically characterized [42,48]
and reproduced in an experimental model of autoimmune demyelination in primates [50] . Unfortunately, CLs can hardly be
visualized with conventional MRI techniques, since their signal
intensity is very close to that of the cortical GM, making them
almost indistinguishable. A significant improvement in their
in vivo detection was obtained by the development and application of double inversion recovery (DIR) sequence. The use of
DIR imaging demonstrated an average increase of 152% in CLs
detection per patient when compared with FLAIR, and 500%
when compared with T2-weighted sequences [43] . However, only
10–20% of the CLs observed on immunohistological specimens
are detected in vivo by DIR [51] , and thus it has to be considered
that the major portion of CLs remain currently undetectable.
By applying DIR, a number of recent studies have demonstrated
that CLs are a frequent phenomenon in MS [52] , and, as previously
depicted by histopathological studies [49] , can be observed in all
disease types [53] . Moreover, they may be observed from the early
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Figure 1. Cortical lesions (white spots) identified using 3D
double inversion recovery imaging in a relapsing–remitting
multiple sclerosis patients with cognitive impairment. A 3D
reconstruction of the cortex was obtained by means of Medical
Image Processing, Analysis and Visualization [101] .
disease stages [52] and even at clinical onset in patients who have
no WM lesions [54] . Furthermore, CLs were found to play an
important role in determining the clinical course of MS [55] , to be
associated with critical symptoms, such as epilepsy [56] , and to correlate significantly with cognitive decline in RRMS patients [57,58] .
All of these findings are even more relevant if we consider, as
stated above, the limits of DIR in detecting CLs.
A possible impact of CLs on CI was suggested by Roosendaal
et al. in a relatively low number of MS patients in which two cognitive domains (i.e., processing speed of visual information and
visuospatial memory) were tested [57] . We have recently quantified [58] the extent of CLs detectable on DIR images in 70 RRMS
patients that were tested by means of the Rao’s Brief Repeatable
Battery of Neuropsychological Tests [59] , which maps a large number of cognitive functions (i.e., verbal immediate and delayed
Figure 2. Lateral view of the pial surface 3D representation
with cortical thickness map overlaid in a blue/light yellow
color scale of a 31-year-old cognitive impaired
relapsing–remitting multiple sclerosis man having 5 years
of disease duration, mean CTh = 2.05 ± 0.47. Cortical areas
thinner that 2.0 mm are represented in light yellow, while cortical
areas thicker than 2.0 mm are in blue.
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Calabrese, Rinaldi, Grossi & Gallo
recall memory, spatial immediate and delayed recall memory,
sustained attention, speed of information processing and verbal
fluency on semantic stimulus). We found that CL number and
volume were significantly higher in cognitively impaired patients
compared with those having normal cognitive performances. The
multivariate ana­lysis revealed that only CL volume and, even if at
a lesser extent, the normalized cortical volume were independent
predictors of the composite cognitive score [58] . These findings
indicate that focal CLs are one of the major substrates of cognitive
deficits in MS, and that the potential benefit of the new and more
effective anti-inflammatory therapies for MS may include the prevention of the accumulation of new CLs. Indeed, in a preliminary
study in a cohort of patients treated with natalizumab for 1 year,
we observed that this drug was able to prevent not only WM
pathology, but also the development of new CLs [60] . Moreover,
a recent work on a small group of RRMS patients followed-up
for 2 years demonstrated the efficacy of natalizumab in all the
clinical domains, including cognitive deterioration [61] .
verbal memory impairment, thus suggesting the contribution of
both WM and GM pathology in determining cognitive decline
in MS [77] .
Furthermore, MRI studies that assessed the extent of brain tissue loss on a regional basis indicated that cortical volume loss is
more closely associated with cognition decline than whole-brain
atrophy [78–80] .
Following previous preliminary studies on regional WM lesion
load [80,81] and regional brain atrophy [82,83] , more recent studies have focused on the identification of a relationship between
regional cortical atrophy and different patterns of cognitive dysfunction [84–86] . Specific patterns of CI were found to correlate
significantly with a decreased GM volume in cortical regions
pertinent to the tasks required [84–86] . Compared with healthy
controls, MS patients with a cognitive deficit were found to have
a more extensive loss of cortical volume in frontal, temporal and
parietal regions [85] – that is, cortical regions previously recognized
to be areas of cortical thinning in MS [45] .
Diffuse cortical pathology & cognitive impairment
Cortical thinning & cognitive impairment
Besides focal areas of demyelination, which may determine
axonal and neuronal dysfunction, the cortex of MS patients
also displays diffuse neuronal loss and atrophy, and extensive
microglia activation and proliferation [42,49,62–64] . The neurodegenerative features observed in the MS cortex have traditionally
been interpreted as secondary to subcortical WM damage leading to axonal injury and, ultimately, neuron degeneration [65] .
Neurodegeneration was, indeed, considered a characteristic
feature of the progressive forms of MS. However, over the last
decade quantitative MRI studies have disclosed that cortical
GM dysfunction and neuronal loss not only occur from the
earliest clinical manifestations of the disease [44,46,47,66,67] , but
also evolve faster than, and largely independently from, WM
atrophy [64,67] , thus suggesting a dissociation between inflammatory pathology occurring in the WM and the neurodegenerative
process occurring in the cortex [68] .
Although not completely explaining the pathogenesis of
MS-related CI, measures of brain atrophy were particularly sensitive in elucidating the relationship between brain integrity and
cognitive status [69–72] . For instance, the width of the third ventricle has a strong association with cognitive status [73] , while atrophy
in the thalamus is a strong predictor of cognitive dysfunction [74] .
More recently, the development of computerized techniques,
which allow a more accurate measurement of cortical volume,
has revealed a central role of cortical-GM pathology in the
development of MS-related CI. Indeed, cortical GM damage
was found to correlate not only with the degree of physical disability, but especially with CI, and this correlation was significantly higher compared with that obtained when WM T2 or T1
(black holes) lesion loads were evaluated [75–77] . Nevertheless, it
has to be considered that CI in MS comprises various cognitive
domains, which are likely affected by both WM and GM dysfunction. Indeed, Sanfilipo and colleagues have observed that,
while WM volume was the best predictor of mental processing
speed and working memory impairment, GM volume predicted
Voxel-based morphometry (VBM) is one of the most commonly
applied techniques to calculate cortical atrophy. It is relatively
simple to use, has moderate demands on computational resources
and is available in common software packages, such as FMRIB
Software Library (FSL; FMRIB Analysis Group, Oxford, UK)
and Statistical Parametric Mapping (SPM; Wellcome Department
of Imaging Neuroscience, London, UK). This technique relies on
the segmentation of MR images into different tissue types (e.g.,
GM, WM and cerebrospinal fluid) using information derived
from image intensity. However, to provide new insights into the
GM pathology in MS patients and to improve our knowledge
of its role in determining the disease-related physical and cognitive disability, a significant contribution came from the study of
cerebral cortical thickness (CTh).
Since the cortex has a complex 3D structure, the measurement
of CTh is tricky and labor intensive. Anatomical images of the
cortex can be acquired by means of routinely available 1-mm3 resolution T1 sequences, with an optimal contrast between GM and
WM [87,88] , which are processed automatically to auto­matically
obtain the CTh [89–93] . Thanks to the semi-automatic techniques
that are currently available (i.e., Freesurfer), it has become more
accurate and easier to analyze large populations of subjects and
make comparisons between patients and controls. Moreover, measuring the thickness of the cortex provides a closer approximation to
the underlying anatomical reality than voxel density as measured by
VBM. In other words, the tissue matter maps used by VBM are only
useful within a statistical context, whereas an individual thickness
map can already tell the investigator something about the subject.
A novel methodology based on cortical surface reconstruction
and transformation, followed by inter-subject high-resolution
alignment [94,95] , was applied by Sailer and colleagues [45] to analyze the cortical thickness in MS patients. They found a significant overall thinning of the cerebral cortex (more pronounced in
temporal, frontal and motor areas) in MS patients compared with
healthy controls. In a longitudinal study, aimed at investigating
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Cortical pathology & cognitive impairment in multiple sclerosis
possible differences in global and regional measures of CTh
between patients with a stable disease course and patients with
a progressive disease course, Chen and colleagues measured the
global and regional CTh and the integrity of the interface cortical
GM/subcortical WM on T1-weighted MRI, and found that disability progression was associated with increasing CTh [96] . These
data on CTh have been further confirmed and extended in a large
sample of MS patients [47] , in which CTh was found to be a diffuse
and early phenomenon in MS, being already detectable at clinical
onset and having a significant impact on clinical disability [48] .
As a consequence of this relationship with clinical disability,
we decided to apply Freesurfer software [94,95] to the global and
regional CTh ana­lysis in a large sample of RRMS patients and in
a control group of 42 age- and gender-matched healthy volunteers.
The aim of the study was the identification of a specific pattern
of CTh associated with MS-related CI [97] .
In line with previous studies [45,47] , we found a significant frontotemporal bilateral cortical thinning in cognitive un­impaired MS
patients, compared with normal controls. However, the ana­lysis
of cognitive-impaired RRMS patients revealed a different pattern
of cortical atrophy, characterized by a widespread cortical thinning involving almost all the cortical regions, even those that are
generally spared in cognitive normal patients.
These results, combined with literature data, suggest that cortical atrophy in MS starts in frontal and temporal areas, whose
thickness is found to be reduced even in cognitive unimpaired
patients. The progressive widespread diffusion of cortical thinning
may lead to the failure of the mechanisms of cortical functional
reorganization, which seems to have a significant role in limiting
the clinical consequences of the local structural damage [98,99] ,
thus bringing to light physical and cognitive deficits.
Conclusion
The neuropsychological profile of MS patients that arises from the
literature data cannot be defined as either ‘pure cortical’ or ‘pure
subcortical’ [100] . Beyond the subcortical WM damage (i.e., tract
disconnection and NAWM pathology), a central role is probably
played by cortical pathology, which has been demonstrated to
be particularly severe and diffuse in patients with cognitive dysfunction, and which leads to an early failure in the compensatory
cortical mechanisms. We observed that both focal inflammatory
pathology and widespread GM loss in the cortex significantly
Review
contribute to the cognitive decline observed in MS patients. Our
findings, together with the observations made by others, suggest
that differences in the severity of the cortical pathology and in
the degree of cortical reorganization may contribute to the clinical
heterogeneity of cognitive deficits in MS. We believe that studies
on cortical pathology have contributed to interpret several clinical
aspects of MS more appropriately. Therefore, in order to analyze
the complexity of the clinical domains of MS-related CI in a more
comprehensive way, longitudinal studies that investigate, in the
same MS population, the respective contribution of WM and GM
damage to the pathogenesis of CI are advisable.
Expert commentary
Several recent studies indicate that focal CLs are one of the major
substrates of cognitive deficits in MS. New and more effective
anti-inflammatory therapies for MS may prevent the accumulation of new CLs, thus slowing down the CI. Indeed, in a preliminary study, natalizumab was able to prevent not only WM
pathology, but also the development of new CLs. Moreover, a
recent study on a small group of RRMS patients followed-up for
2 years demonstrated the efficacy of natalizumab in all of the
clinical domains, including cognitive deterioration.
Further studies are needed to better clarify the pathogenetic substrates of MS-related CI and, thus, to define its optimal treatment.
Five-year view
The assessment of CI is actually considered to be a valid instrument
for monitoring disease progression and, in some cases, it may help
in predicting an earlier conversion to MS in patients with clinically
isolated syndrome. In the coming years, the assessment of cognitive
functions will be included in the routine clinical evaluation of MS
patients. The early recognition of CI will lead to a specific therapeutic intervention in order to prevent further decline of cognitive
functions and reduce its impact on patient quality of life.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with
the subject matter or materials discussed in the manuscript. This includes
employment, consultancies, honoraria, stock ownership or options, expert
testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
• Cognitive impairment (CI) constitutes a relevant clinical aspect of multiple sclerosis (MS).
• The correlation between CI and conventional T2-hyperintense white matter (WM) lesion load is only modest.
• A better, albeit still partial, correlation with CI has been observed analyzing the pathology of normal-appearing WM with
nonconventional MRI techniques, such as magnetization transfer ratio, magnetic resonance spectroscopy and diffusion tensor imaging.
• Beyond the subcortical WM damage (i.e., tract disconnection and normal-appearing WM pathology), a central role in determining the
cognitive dysfunction is probably played by cortical pathology.
• Cortical lesions (CLs) and cortical atrophy have, indeed, been demonstrated to be common in MS from disease onset and to be
particularly severe and diffuse in patients with cognitive dysfunction, thus leading to an early failure in the compensatory
cortical mechanisms.
• These findings indicate that focal CLs are one of the major substrates of cognitive deficits in MS and that the potential benefit of the
new and more effective anti-inflammatory therapies for MS may include the prevention of the accumulation of new CLs.
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Calabrese, Rinaldi, Grossi & Gallo
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