J Neurol DOI 10.1007/s00415-014-7409-5

ORIGINAL COMMUNICATION

Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis Laura Parisi • Maria A. Rocca • Flavia Mattioli • Gianna C. Riccitelli • Ruggero Capra • Chiara Stampatori Fabio Bellomi • Massimo Filippi



Received: 28 April 2014 / Revised: 6 June 2014 / Accepted: 6 June 2014 Ó Springer-Verlag Berlin Heidelberg 2014

Abstract We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort) MS in comparison to classical (c) MS patients. Nine cort-MS, nine c-MS and nine age-matched healthy controls (HC) underwent a brain MRI exam, including FLAIR and highresolution T1-weighted scans. MS patients underwent neurological and neuropsychological assessment. Betweengroup differences of GM and WM volumes and their correlations with neuropsychological performances were assessed with voxel-based morphometry. FLAIR and T1 lesion probability maps (LPMs) were also obtained. Performance at neuropsychological tests was worse in cort-MS than in c-MS patients. Compared to HC, MS patients had a distributed pattern of GM and WM atrophy. No GM/WM area was more atrophic in c-MS vs cort-MS patients. Compared to c-MS, cort-MS patients experienced GM atrophy of frontal–temporal–parietal areas and cingulate cortex and WM atrophy of the cingulum bundle, bilateral

L. Parisi  M. A. Rocca  G. C. Riccitelli  M. Filippi (&) Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy e-mail: [email protected] M. A. Rocca  M. Filippi Department of Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy F. Mattioli  C. Stampatori  F. Bellomi Clinical Neuropsychology, Spedali Civili of Brescia, Brescia, Italy R. Capra Multiple Sclerosis Center, Spedali Civili of Brescia, Brescia, Italy

cerebral peduncles, right inferior longitudinal fasciculus and left superior longitudinal fasciculus. FLAIR and T1 LPMs did not differ between c-MS vs cort-MS patients. A higher susceptibility to neurodegenerative processes in key brain regions known to be related to cognitive functions is likely to underlie the clinical manifestations of cort-MS. Keywords Cortical multiple sclerosis  MRI  Regional damage  White matter  Gray matter

Introduction Cognitive and neuropsychiatric deficits can be the first manifestation of multiple sclerosis (MS) in a minority of patients, followed by the development of more typical disease symptoms, leading to a definitive diagnosis, often several years later [1–3]. Based on this, Zarei and colleagues have proposed a variant of the disease called ‘‘cortical’’ or ‘‘cerebral-type’’ (cort) MS, which is characterized by a severe progressive cognitive impairment, focal cortical syndromes (e.g., aphasia and apraxia), and cortical signs (e.g., seizures and psychiatric disorders), with a relative sparing of motor, sensory and cerebellar functions at disease onset. Similarly to ‘‘classical’’ MS (c-MS), cort-MS has a female prevalence, occurs between 18 and 60 years of age and can manifest with different disease clinical phenotypes (primary progressive, relapsing–remitting and secondary progressive) [4]. Distinctive imaging features of cort-MS have not been identified yet. T2 white matter (WM) lesions and cortical atrophy have been reported in about half of these patients [5]. Likely associated to its prominent cognitive and neuropsychiatric symptomatology, cort-MS is believed to lead to a more severe involvement of the cortical gray matter

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(GM) and a relatively modest involvement of periventricular regions or corpus callosum than c-MS [5]. Regretfully, available MRI studies in this rare condition have been performed mainly for diagnostic purposes, and more advanced analysis methods have not been applied [5]. In the past few years, several MR approaches have been extensively used to define the extent and regional distribution of damage to the WM and GM in MS patients, with the ultimate goal of improving the understanding of the wide and heterogeneous spectrum of clinical manifestations of the disease. Studies which have applied voxelbased morphometry (VBM) have consistently demonstrated that cognitive impairment in MS (which is usually characterized by slow processing speed and deficits of executive functions, learning, memory and visual–spatial abilities) [6] is associated with atrophy of several cortical and subcortical structures, which are mainly located in the frontal and temporal lobes, with a more distributed involvement in patients with secondary progressive (SP) compared to those with relapsing–remitting (RR) MS [7, 8]. Against this background, we applied VBM to investigate the patterns of regional distribution of focal lesions as well as WM and GM atrophy in patients with cort-MS in comparison to c-MS patients. Our working hypothesis was that a more distributed involvement of GM structures is likely to characterize patients with this rare variant of MS.

consisted of treatment with steroids or acute relapse within the past 3 months, history of traumatic brain injury, past or current history of alcohol or drug abuse. All the subjects underwent ApoEe4 screening test, which was negative. Neuropsychological assessment Within 3 days of MRI acquisition, neuropsychological assessment was performed by an experienced neuropsychologist blinded to MRI findings and included: (a) Mini Mental State Examination (MMSE) (global cognitive conditions); (b) Raven’s colored progressive matrices (logical-deductive intelligence and visual-perceptive abilities); [9], (c) Token test (verbal comprehension); [10], (d) Semantic fluency test (word-searching ability with semantic access, and executive functions); [11], (e) Phonemic fluency test (control functions and executive functions); (f) Digit span [12] and Corsi test [13] (short-term verbal and visuo-spatial memory); (g) Selective Reminding Test—SRT (for verbal learning) and 10/36 Spatial Recall Test—SPART (for visuo-spatial learning) from the Italian version of the Brief Repeatable Battery of Neuropsychological Tests (BRBNT); [14] and (h) Montgomery–Asberg Depression Rating Scale (MADRS) [15] (mood state). For each patient, the results from all neuropsychological tests were scored using a standardized method based upon a comparison with normative Italian studies [14]. MRI acquisition

Materials and methods Subjects Nine patients with cort-MS [5] were enrolled consecutively from the outpatient MS clinic population of Spedali Civili, Brescia. According to Zarei et al. [5], this variant was defined whenever cognitive deterioration was the main symptom at clinical presentation and during the course of the disease, with a relatively mild motor disability. The main demographic, clinical and paraclinical tests of these patients at disease onset and during the follow-up are summarized in Table 1. The main presenting symptoms were cognitive impairment (77 %), psychiatric manifestations (55 %), and seizures (22 %). Two control groups were selected from the population of patients and controls attending the outpatient MS clinic population of Spedali Civili, Brescia. The first group included 9 sex- and age-matched healthy controls (HC) with no previous history of neurological, psychiatric, or cardiovascular disorders, and a normal neurological exam. The second included nine patients with c-MS, matched to cort-MS patients for sex, age, disease duration and disability (Table 2). Patient exclusion criteria

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Using a 1.5-T scanner (Intera, Philips Medical Systems, Best, The Netherlands), the following brain scans were acquired from all subjects: (a) fast fluid-attenuated inversion recovery (FLAIR) (TR = 8,200 ms, TE = 122 ms, TI = 2,398 ms, ETL = 14, flip angle = 150°, 42 contiguous axial slices with a thickness = 3.0 mm, matrix size = 320 9 168, FOV = 172 9 230 mm); and (b) 3D T1-weighted magnetization prepared rapid acquisition gradient echo (MPRAGE) (TR = 1,930 ms, TE = 3.4 ms, TI = 1,100 ms, flip angle = 15°, matrix size = 256 9 192, FOV = 192 mm 9 256 mm, 176 contiguous axial slices, voxel size = 0.5 9 0.5 9 1 mm). For all scans, slices were positioned to run parallel to a line that joined the most inferoanterior and inferoposterior margins of the corpus callosum. Image analysis FLAIR-hyperintense lesions were identified by an experienced observer blinded to neuropsychological evaluation; and FLAIR lesion volume (LV) was quantified using a local thresholding segmentation technique (Jim 5, Xinapse Systems Ltd., Northants, UK). T1-hypointense lesions

J Neurol Table 1 Main demographic, clinical characteristics and paraclinical findings of the enrolled cortical multiple sclerosis patients Case

Age/sex

Initial symptoms

Paraclinical findings

Follow-up

1

56/F

Progressive worsening of cognitive abilities

VEP: delayed

24 years

CSF: not done

Last evaluation: cognitive impairment, mild left hemiparesis and mild ataxia

MRI: multiple brain T2-hyperintense WM lesions Neuropsychology: frontal behavior, slowness in ideation, reduced memory and impaired naming (familiar items and faces) 2

60/F

Progressive worsening of cognitive abilities, apathy and social retirement

VEP: normal

8 years

CSF: OB?

Last evaluation: cognitive impairment, apathy, mild gait ataxia, mild left upper limb paresis, reduced ocular convergence and vibration sense in both legs

MRI: multiple brain T2-hyperintense WM lesions Neuropsychology: deficits at verbal fluency, attention and memory domains; apraxia

3

37/M

Behavioral symptoms

VEP: not done

6 years

CSF: OB?

Last evaluation: behavioral and cognitive symptoms, mild motor signs

MRI: multiple brain T2-hyperintense WM lesions Neuropsychology: deficits at attentive, executive and memory domains 4

43/F

Depression and chronic headache

VEP: normal

2 years

CSF: OB?

History of an acute psychotic episode

MRI: multiple brain T2-hyperintense WM lesions

Last evaluation: motor signs, cognitive impairment

Neuropsychology: impaired memory, reasoning and executive functions; slowness in information processing; depression 5

49/F

Depression and progressive worsening of cognitive abilities

VEP: not done

29 years

CSF: OB ?

History of an acute psychotic episode

MRI: multiple brain and cervical cord T2hyperintense lesions

Last evaluation: mild right hemiparesis, mild gait ataxia, severe cognitive impairment

Neuropsychology: impaired memory, attention and executive functions; depression 6

36/F

Progressive worsening of cognitive abilities

VEP: delayed

17 years

CSF: OB? MRI: multiple brain and cervical cord T2hyperintense lesions

Last evaluation: right arm sensory–motor symptoms, diplopia, cognitive impairment

Neuropsychology: severely impaired verbal and spatial memory, deficits at attention and information processing speed, slowness in ideation, poor judgement 7

63/F

Progressive worsening of cognitive abilities

VEP: delayed

31 years

CSF: not done

Last evaluation: gait ataxia, dysarthria and right mild cerebellar signs, cognitive impairment

MRI: multiple brain and cervical cord T2hyperintense lesions Neuropsychology: fatuity, slowness in ideation, deficits at memory and language domains

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J Neurol Table 1 continued Case

Age/sex

Initial symptoms

Paraclinical findings

Follow-up

8

42/M

Generalized seizures and slightly cognitive symptoms

VEP: delayed

3 years

CSF: OB?

Last evaluation: ataxic hyperreflexic paraparesis, intranuclear ophthalmoplegia, cognitive impairment

MRI: multiple brain and cervical cord T2hyperintense lesions Neuropsychology: memory and attention deficits, anosognosia 9

54/F

Depression, partial motor seizures and progressive worsening of cognitive abilities

VEP: delayed

4 years

CSF: OB ?

Last evaluation: mild ataxic gait, motor signs, severe cognitive impairment

MRI: multiple brain and cervical cord T2hyperintense lesions Neuropsychology: severe impairment of visuo-spatial abilities, language and memory functions; depression

CSF cerebrospinal fluid, F female, M male, MRI magnetic resonance imaging, WM white matter, OB oligoclonal bands, VEP visual-evoked potentials Table 2 Main demographic, clinical and conventional MRI data from healthy controls (HC) and patients with multiple sclerosis according to the diagnosis of ‘‘cortical’’ MS (cort-MS) or classical MS (c-MS) HC (n = 9)

c-MS (n = 9)

cort-MS (n = 9)

p

p (c-MS vs cort-MS)

Gender (women/men)

6/3

7/2

7/2

1**



Mean age (SD) (years)

54.4 (12.1)

50.2 (11.0)

48.9 (9.9)

0.5***

0.75*

Median disease duration (range) (years)



14 (4–20)

8 (2–31)



0.82*

Median EDSS (range)



3.0 (1.5–6.0)

4.0 (1.0–6.0)



0.26*

Therapy (none/IFNs/GA/Nat)



(3/1/2/3)

(6/2/1/0)



0.19**

Mean education (years)



10.6 (2.9)

8.4 (3.2)



0.16*

Mean FLAIR LV (SD) (ml) Mean T1 LV (SD) (ml)

– –

10.8 (4.7) 3.6 (1.7)

34.3 (23.1) 18.1 (13.6)

– –

0.005* 0.002*

Mean NBV(SD) (ml)

1,578 (60)

1,504 (65)

1,317 (146)

0.003***

0.02*

Mean GMV (SD) (ml)

806 (30)

765 (31)

655 (110)

0.005***

0.04*

Mean WMV (SD) (ml)

772 (47)

739 (46)

663 (65)

0.006***

0.03*

FLAIR fast fluid-attenuated inversion recovery, SD standard deviation, EDSS Expanded Disability Status Scale, NBV normalized brain volume, GMV gray matter volume, WMV white matter volume, LV lesion volume, IFNs interferons beta, GA glatiramer acetate, Nat Natalizumab * Mann–Whitney test, **Pearson Chi-square test, ***Kruskal–Wallis test

were identified and quantified on the 3D MPRAGE images, which were previously coregistered to the FLAIR scans to facilitate their identification. To avoid a possible bias in image segmentation due to the presence of T1-hypointense lesions, such lesions (transformed back to the original space) were refilled with values randomly extracted from a Gaussian distribution with means and SDs estimated from the normal-appearing (NA) WM [16]. Using 3D MPRAGE images, normalized brain volumes (NBV), WM volume (WMV) and GM volume (GMV) were measured using the SIENAx software [17]. VBM analysis was performed using SPM8. First, MPRAGE images were segmented into GM, WM and cerebrospinal fluid. Then, WM and GM segmented images of all subjects, in the closest possible rigid-body alignment

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with each other, were used to produce GM and WM templates and to drive the deformation to the templates. At each iteration, the deformations, calculated using the Diffeomorphic Anatomical Registration using Exponentiated Lie algebra (DARTEL) registration method, were applied to GM and WM, with an increasingly good alignment of subject morphology, and averaged to produce a new template. The final template is obtained after six iterations. Raw probability maps of GM and WM, after spatial normalization, were then modulated to ensure that the overall amount of each tissue class was not altered by the spatial normalization procedure. To better align the final template with the Montreal Neurologic Institute (MNI) space, an affine registration between the customized GM template and the SPM GM template (in the MNI space) was also

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calculated and added to the header of each image as a new orientation, to have all images in a standard space. The same transformation was applied to the WM customized template. The images were then smoothed with an 8-mm FWHM Gaussian kernel. In MS patients, probability maps of FLAIR-hyperintense and T1-hypointense lesions were created. To this aim, binarized lesion masks from FLAIR and T1 lesions were obtained, normalized to the GM template (using the DARTEL non-linear transformation), and averaged to obtain FLAIR/T1 lesion probability maps (LPMs).

Table 3 Performance at individual neuropsychological tests in the two groups of MS patients

Statistical analysis Between-group comparisons of demographic, clinical, neuropsychological and conventional MRI data were performed using the SPSS software (version 13.0) and nonparametric test because of the relatively small sample size. The regional distribution of FLAIR lesions, T1 lesions, GM and WM atrophy in MS patients was investigated using SPM8 and a full factorial analysis of covariance, including age, gender and the normalization factor derived from SIENAx (when appropriate) (which can be considered as a measure of head size) as nuisance covariates. Given that this is an exploratory study, for all analyses ran with SPM, results were assessed at a threshold of p \ 0.001, uncorrected for multiple comparisons. The localization of areas of WM and GM atrophy was defined using available atlases [18, 19]. In MS patients, a linear regression analysis was used to assess the correlations between regional tissue loss and clinical and neuropsychological variables (p \ 0.001, uncorrected), using age, gender and the normalization factor derived from SIENAx as covariates.

Results Clinical, neuropsychological and conventional MRI data. Table 2 summarizes the main demographic, clinical, and conventional MRI characteristics of the three study groups. All c-MS and six cort-MS patients had RRMS. One of the remaining cort-MS patients had primary progressive MS and two SPMS. Performance at neuropsychological tests was significantly worse in cort-MS vs c-MS patients (p ranging from \0.0001 to 0.01), except for digit span (Table 3). Compared to c-MS, cort-MS patients had higher FLAIR LV (p = 0.005) and T1 LV (p = 0.002), as well as lower NBV (p = 0.02), GMV (p = 0.04) and WMV (p = 0.03). Voxel-wise analysis

Neuropsychological test (Mean, SD)

cort-MS (n = 9)

*p

MMSE

28.7 (0.8)

23.1 (4.3)

0.004

Token test

34.5 (1.4)

25.6 (5.6)

\0.0001

Raven progressive matrices Digit span

32.7 (2.3) 5.2 (0.9)

15.2 (8.9) 4.8 (0.7)

\0.0001 0.48

Corsi test

4.7 (0.6)

3.8 (0.6)

0.01

Phonemic fluency test

36.7 (9.0)

15 (4.6)

\0.0001

Semantic fluency test

43.7 (14.5)

19.7 (4.9)

0.001

10/36 SPART I recall

20.8 (4.5)

12.1 (5.8)

0.005

10/36 SPART D recall

7.2 (2.4)

3.5 (1.9)

0.008

SRT LTS

37.7 (13.6)

8.1 (7.9)

0.001

SRT CLTR

30.7 (12.6)

2.3 (3.1)

\0.0001

SRT DR

7.5 (2.6)

1.8 (1.6)

0.001

MADRS

7.3 (7.3)

18.1 (2.9)

0.007

MMSE mini mental status examination, 10/36 SPART I recall 10/36 spatial recall test immediate recall, 10/36 SPART D recall 10/36 spatial recall test delayed recall, SRT selective reminding test, LTS long-term storage, CLTR consistent long-term retrieval, DR delayed recall, MADRS Montgomery–Asberg Depression Scale * Mann–Whitney test

VBM analysis disclosed atrophy of cortical and subcortical GM structures as well as WM tracts in both groups of MS patients vs HC (Table 4). Compared to c-MS, cort-MS patients showed GM atrophy of the left (L) cingulate cortex, right (R) anterior cingulate cortex (ACC), R middle temporal gyrus (MTG), L supplementary motor area, L supramarginal gyrus and L inferior parietal lobe (IPL) (Table 4; Fig. 2). They also showed more significant WM atrophy of the bilateral (B) cingulum bundle, R inferior longitudinal fasciculus (ILF), B brainstem (at the level of the cerebral peduncles), and L superior longitudinal fasciculus (SLF) (Table 4; Fig. 2). No GM/WM area was more atrophic in c-MS vs cort-MS patients. Since the cort-MS group also included three patients with progressive disease phenotypes, the previous between-group comparisons were re-ran excluding these patients. As shown in Table 4, many of the areas identified during the original analysis were still present when including only six cort-RRMS patients. Analysis of correlations In the whole group of patients, significant correlations (p \ 0.001) were found between: 1.

FLAIR-hyperintense and T1-hypointense lesion distribution did not differ between c-MS and cort-MS patients (Fig. 1).

c-MS (n = 9)

MMSE scores and GM atrophy of the L cingulate cortex (r = 0.79) (Fig. 3) and R superior frontal gyrus (r = 0.77) as well as WM atrophy of the L cingulum

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Fig. 1 Representative sections showing T1 lesion probability maps (LPMs) superimposed on the customized white matter template in cortical (cort) and classical (C) multiple sclerosis (MS) patients. The

LPMs are thresholded to show voxels in which lesion frequency is C10 %, up to a maximum lesion frequency of 50 %. Images are shown in neurologic convention. See text for further details

bundle (r = 0.82) (Fig. 3), R ILF (r = 0.81), L SLF (r = 0.83), and B cerebral peduncle (r = 0.79 for the L and r = 0.75 for the R); Semantic fluency test scores and GM atrophy of the R MTG (r = 0.86); Token test scores and GM atrophy of the L supramarginal gyrus (r = 0.86); Raven test scores and the GM atrophy of L supplementary motor area (r = 0.93) and L ACC (r = 0.86) (Fig. 3) as well as WM atrophy of the L cingulum bundle (r = 0.92) (Fig. 3), R ILF (r = 0.92) and L SLF (r = 0.79); Phonemic fluency test scores and the GM atrophy of R MTG (r = 0.83); SRT/DR scores and the GM atrophy of the L supramarginal gyrus (r = 0.93) as well as WM atrophy of the L cingulum bundle (r = 0.83), R ILF (r = 0.80) and L SLF (r = 0.84).

distribution of damage to the WM and GM in such patients and that investigated the magnitude of the association of the brain abnormalities observed with the clinical manifestations of this rare variant. Similarly to the series reported by Zarei et al. [5], our cort-MS patients showed a severe cognitive impairment, and a past history of seizures or psychiatric disorders. Furthermore, the cognitive domains most frequently involved in cort-MS patients compared to those with c-MS were general reasoning, memory, and language production. These cognitive deficits have been considered among the distinctive features of this subtype of MS [5]. To define whether the structural abnormalities we detected could contribute to characterize this form of the disease, we also selected, in addition to healthy controls, a group of c-MS patients, with similar disease duration and disability, to avoid possible confounding effects of these variables on our findings. In addition, a standardized protocol of acquisition and a common neuropsychological evaluation have been applied to evaluate all patients enrolled in the study. Despite previous reports have suggested that a more severe involvement of the GM might characterize cort-MS patients [4, 5], an objective estimate of such a damage using automated segmentation techniques has never been performed. The first intriguing finding of our analysis is that all measures of structural brain damage, including not only

2. 3. 4.

5. 6.

Discussion Albeit performed in a relatively small sample of patients (a limitation which is due to the low prevalence of cort-MS), this is the first study that applied conventional and advanced MRI techniques to quantify the extent and

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J Neurol Table 4 Results from voxel-based morphometry showing regions of significant gray matter (GM) and white matter (WM) atrophy in the three study groups (p \ 0.001, uncorrected) Side

Anatomical regions

MNI coordinates (x, y, z)

T values

L

Vermis (BA27)

-2, -47, -4

6.27

L

Cerebellum (BA30)

-8, -40, -9

4.74

L

Middle temporal gyrus (BA22)

-54, -16, -6

3.59

L

*Middle temporal gyrus (BA22)

-54, -16, -8

3.88

R

*Middle occipital gyrus (BA19)

35, -74, 30

3.91

R R

*Thalamus *Superior temporal gyrus (BA48)

10, -26, 10 48, -26, 2

4.26 3.93

L

*Angular gyrus (BA46)

-35, -49, 35

3.83

L

*Cingulate cortex

-14, -39, 44

9.78

R

*Anterior cingulate cortex (BA 32)

11, 28, 46

6.67

R

Middle temporal gyrus (BA21)

56, -27, 0

6.59

L

Supplementary motor area (BA6)

-6, 6, 57

5.95

L

*Supramarginal gyrus (BA48)

-49, -29, 32

5.71

L

Inferior parietal lobe (BA7)

-27, -50, 43

4.84

c-MS vs HC

L

Superior longitudinal fasciculus

-49, 16, 17

3.74

cort-MS vs HC



*Corpus callosum, splenium

5, -42, 14

3.92

cort-MS vs c-MS

L

*Cingulum bundle

-16, -52, 44

6.21

R

*Inferior longitudinal fasciculus

46, -34, 18

5.82

R

*Cingulum bundle

11, 39, 25

5.51

R L

*Cerebral peduncle *Cerebral peduncle

14, -27, -18 -14, -21, -11

4.85 4.68

L

*Superior longitudinal fasciculus

-29, 8, 25

4.21

GM atrophy c-MS vs HC

cort-MS vs HC

cort-MS vs c-MS

WM atrophy

MS multiple sclerosis, HC healthy controls, c-MS classical MS, cort-MS cortical MS, GM gray matter, WM white matter, BA Brodmann Areas, R right, L left, MNI Montreal Neurologic Institute * Areas significantly different between groups when considering cort-MS patients with relapsing–remitting disease course only (n = 6)

FLAIR and T1 LV, but also NBV, NGV and NWM, were significantly more altered in cort-MS vs c-MS patients, despite the two groups had similar age, disability and disease duration. This suggests that both inflammatory and neurodegenerative phenomena involving the GM and WM of the brain are accumulated at a faster rate in the former group of patients. Regretfully, since our subjects were not studied at the onset of the disease and this is a cross-sectional study, we cannot define whether the GM was affected prior to WM. The more severe involvement of both brain WM and GM in cort-MS than in c-MS patients was also confirmed by the results of the VBM analysis, which showed different patterns of regional tissue loss in these two patient groups. Two of the areas which were more affected in cort-MS patients were the cingulum bundle and the cingulate cortex. The cingulum connects sites involved in cognitive control, such as the ACC, as well as medial and dorsal prefrontal areas to the medial parietal and temporal lobes. While the anterior portion of this network (particularly the ACC) is

associated to top-down attentional control processes and goal-directed behavior and emotional aspects, the posterior one contributes to learning and episodic memory [20]. Several studies in patients with Alzheimer’s disease (AD) have suggested that structural integrity of the cingulum is central for the preservation of cognitive functions. Indeed, a posterior–anterior gradient of AD pathology in the cingulum parallels the progression of cognitive decline (from episodic memory deficits to progressive cognitive impairment to dementia). Gross atrophy of the cingulum also distinguishes AD from mild cognitive impairment patients [21, 22]. In line with the functional role of the cingulum bundle and cingulate cortex, the analysis of correlation showed that tissue loss in these structures is associated to global cognitive function (as measured with the MMSE), logical-deductive intelligence (as measured with Raven test), and tests for long-term memory (as measured with SRT/DR). GM atrophy in cort-MS patients also involved the left IPL, another key region for cognitive functions. The human

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Fig. 2 Statistical parametric mapping (SPM) regions of: a gray matter (GM) atrophy (yellow-coded for t values) superimposed on the customized GM template and b white matter (WM) atrophy superimposed on the customized WM template contrasting cortical

and classical multiple sclerosis patients. Images are shown in neurological convention. See text for further details. L left, R right, A anterior, P posterior

IPL comprises the lateral bank of the intraparietal sulcus, angular gyrus and supramarginal gyrus, defined on the basis of anatomical landmarks and cytoarchitectural organization of neurons [23]. All these three regions have been demonstrated to be involved in memory encoding and retrieval [24] with a hemispheric specialization, being the left side involved in semantic and language processing [23] and word reading [25]. Another region involved in language functions that was found to be more atrophic in cortMS than c-MS patients was the R MTG, which contributes to syllable processing [26] and perception of figurative language [27]. The correlations found between performances at tests for language (verbal memory, language comprehension and verbal fluency) and atrophy of L IPL and R MTG further support the role of these structures in the genesis of patients’ clinical manifestations. We also

detected atrophy of the left supplementary motor area in cort-MS vs c-MS patients, which could contribute to explain deficits of cognitive control of motor plans, motor learning, planning motor sequences and in starting voluntary actions, which are all known to occur in cort-MS patients [28, 29]. Another intriguing finding of this study was that compared to c-MS, cort-MS patients showed also a distributed pattern of WM atrophy involving several associative tracts, which included, in addition to the cingulum bundle, the ILF and SLF. The ILF is involved in face recognition [30], visual perception, reading, visual memory and other functions related to language [31]. The SLF is known to contribute to verbal working memory [32] in the left hemisphere, and nonverbal–auditory information, attention, and visual–spatial functions in the right hemisphere

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Fig. 3 Plots of gray matter (a and c) and white matter (b and d) values adjusted for covariates vs neuropsychological tests [Mini Mental State Examination (MMSE) and Raven test]. The gray solid

line represents the fitted regressor of interest from statistical parametric mapping (SPM) analysis. Circle, cortical multiple sclerosis patients; cross, classical multiple sclerosis patients

[33]. Consistently with their functions, atrophy of these WM tracts correlated with performance at neuropsychological tests for long-term memory, global functioning and abstract reasoning. Atrophy of the cerebral peduncles was another feature of cort-MS patients, which might be secondary to damage of long noradrenergic/colinergic projections [34], which in turn can contribute to cognitive impairment. As mentioned, the cross-sectional and retrospective design of our study did not allow us to define whether the observed abnormalities of the brain GM and WM simply reflect secondary degenerative phenomena, due to the accumulation of lesions, or rather a primary neurodegeneration, which might be at work in these peculiar group of patients. However, the observation that, despite

higher FLAIR and T1 LV, the regional distribution of these lesions did not differ significantly between cort-MS and c-MS patients supports the notion that in this disease phenotype neurodegenerative processes might accumulate at least partially independently of the presence of focal WM lesions. According to the retrogenesis hypothesis, the later-myelinating associative fibers, such as the cingulum, ILF and SLF, are more susceptible to myelin breakdown than earlier myelinating fibers [35]. As a consequence, it is tempting to speculate that pathological processes in cort-MS patients could more severely involve the most vulnerable WM tracts; this might then cause neuronal death and atrophy, which in turn might contribute to the development of cognitive impairment.

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Our study is not without limitations. First, we could not investigate the relative contribution of cortical lesions and microscopic tissue damage to the clinical manifestation of cortMS, since we did not acquire MR sequences to study these aspects to reduce acquisition time and hence improve patient compliance and image quality. Second, considering the low number of subjects, we ran an exploratory analysis applying an uncorrected statistical threshold during VBM analysis. Therefore, our results need to be replicated in a different, possibly larger, group of cort-MS patients. Finally, as reported in the original descriptions [4, 5], cort-MS group also included three patients with progressive MS, which may experience a more distributed structural damage than RRMS patients. However, most of the areas identified at the between-group comparison were still detected when excluding these three subjects, a finding which confirms the validity of our conclusions. Conflicts of interests Laura Parisi, Flavia Mattioli, Ruggero Capra, Chiara Stampatori, and Fabio Bellomi report no disclosures. Maria A. Rocca received speakers honoraria from Biogen Idec, Novartis and Serono Symposia International Foundation and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. Massimo Filippi serves on scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Bayer Schering Pharma, Biogen Idec, Merck Serono, and Teva Pharmaceutical Industries; and receives research support from Bayer Schering Pharma, Biogen Idec, Merck Serono, Teva Pharmaceutical Industries, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla, Cure PSP, and the Jacques and Gloria Gossweiler Foundation (Switzerland). Ethical standard This study was approved by the Local Ethical Committes on human studies and written informed consent from each subject was obtained prior to their enrolment. Statement of Human and Animal Rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors. Informed consent Informed consent was obtained from all individual participants included in the study.

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Patterns of regional gray matter and white matter atrophy in cortical multiple sclerosis.

We investigated the patterns of regional distribution of focal lesions, white matter (WM) and gray matter (GM) atrophy in patients with cortical (cort...
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