Extent of cerebellum, subcortical and cortical atrophy in patients with MS: A case-control study

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Abstract

Cortical and subcortical atrophy occurs in multiple sclerosis (MS) and relates to clinical outcomes. FreeSurfer, a voxel-based automated software for brain reconstruction was used to investigate the extent of subcortical and cortical atrophy in 71 MS and 17 clinically isolated syndrome (CIS) patients, and 38 normal controls (NC), and to relate group differences to disease type and severity. Segmentation was performed on 3D SPGR T1-weighted MRI 1.5T images. Region-specific subcortical tissue volumes were calculated in mm3 and cortical thickness in mm. Logistic regression and general linear model analyses, adjusted for age and intracranial volume, examined differences between NC, MS and CIS patients and disease subtypes. The MS group was characterized by significantly lower volumes of thalamus (left and right p < 0.0001), left inferior lateral ventricle, third ventricle (p < 0.0001), ventral diencephalon, pallidum and putamen bilaterally, as well as of right accumbens and brainstem with corresponding bilateral increase in volumes of lateral ventricles (p < 0.01). Focal cortical atrophy areas in the thalamus, inferior parietal lobule of left hemisphere and in right precuneus were also significant in the MS sample. Versus CIS patients, RR or progressive MS patients showed significantly lower volumes of subcortical regions and cortical thinning. Hippocampal atrophy appeared only in advanced disease stages. Cerebellum WM volumes were significantly lower in MS and CIS patients vs. NC. Subcortical and cortical atrophy correlated with higher disability as measured by EDSS. This study confirmed selective deep gray matter atrophy (mostly thalamic), revealed cerebellum WM atrophy from the earliest clinical stages, and showed that cortical thinning advances with disease progression.

Introduction

Multiple sclerosis (MS) is an immune mediated demyelinating disease of the central nervous system characterized by lesion formation and atrophy. Although traditional thinking has considered MS to be more closely associated with white matter (WM) [1], [2] than gray matter (GM) atrophy, recent studies have confirmed greater tissue loss in the GM compartment [3], [4], [5], [6], [7]. Moreover, patients who convert into clinically definite MS over a period of 3 years develop significant GM atrophy but not WM atrophy, thus confirming that GM atrophy can present very early in some patients [8]. Other longitudinal studies have shown increasing GM but not WM atrophy over the short- to mid-term in different stages of relapsing–remitting (RR) MS [5], [9], [10]. It has also been established that GM lesions are more common in the hippocampus (parahippocampal and intrahippocampal areas) [11], cingulate [12], [13], temporal lobe and insula [14], [15] than in other GM regions. Bilateral focal thinning of the cortex in frontal and temporal lobes occurs even in MS patients with short disease duration or mild impairment [16], [17].

Regional parenchyma brain atrophy is an important topic of discussion in the literature and many different segmentation methods have been used for tissue parcellation in MS studies [18]. Manual tracing of lobes or structures is a labor intensive process and prone to poor reproducibility. To increase reliability of manual parcellation of different brain structures, our group previously used a digital 3D version of the Harvard Medical School brain atlas as a reference [19]. We also demonstrated that normalized regional brain parenchyma measures correlated better with different MRI and clinical outcomes than the absolute ones [19], [20], [21]. Further, we recently used the semi-automated brain region extraction (SABRE) technique to parcellate the brain into 26 regions (divided into GM/WM) and showed that GM atrophy was prominent in the superior frontal/parietal lobes and deep brain structures [17]. Using the same technique, we showed an independent relationship between cortical atrophy and cognitive impairment after accounting for the effects of central atrophy [22]. Other studies that assessed brain atrophy in specific regions confirmed diminished corpus callosum area [23] and lower volume of the thalamus [24], [25] and caudate [26]; [4].

Until now, a comprehensive effort to calculate the individual volumes of subcortical and cortical structures and to quantify their extent of regional atrophy simultaneously in patients with MS has not been conducted. Only a few studies have investigated the relationship between regional cortical atrophy and disease severity in MS [13], [16], [27]. Therefore, the association between cortical thinning and atrophy of deep GM (DGM) in MS patients is yet to be investigated in more detail.

FreeSurfer software, a set of voxel-based automated tools for brain reconstruction, offers an opportunity to investigate the characteristics of subcortical and cortical atrophy in MS [28]. FreeSurfer was previously used to assess region-specific cortical atrophy in MS [16]. This study reported significant thinning in the frontal, temporal and motor areas in MS patients, and revealed that thinning of the motor cortex was significantly related to higher physical disability.

The aim of this study was to investigate the extent of subcortical and cortical atrophy in MS patients compared to normal controls (NC) and between different disease types. We also examined the relationship between subcortical and cortical atrophy and disease severity as measured by EDSS.

Section snippets

Participants

We enrolled prospectively 71 patients with a diagnosis of MS according to the Polman criteria [29], 17 patients with clinically isolated syndrome (CIS) and 38 NCs. Patients were consecutively enrolled either at the time of their routine clinical follow-up visit (MS patients) or their first visit (CIS patients). The inclusion criteria were: age 18–70 years, Expanded Disability Status Scale (EDSS) < 8 and MRI examination performed at the time of their clinical visit. Patients with any pre-existing

Demographic characteristics of NC, CIS and MS patients

Demographic characteristics of NC, CIS and MS patients are shown in Table 1. MS patients, but not CIS patients, were somewhat older than NC (Table 1).

Cerebral and cerebellum hemispheric GM and WM atrophy

Table 2 shows mean normalized GM and WM volumes for each cerebral hemisphere. MS patients had lower left (p = 0.01) and right (p = 0.007) cerebral GM compared to NC, when adjusted for age and intracranial volume. The mean percent change was − 7.1% and − 5.5% for left and right cerebral GM, and − 2.9% and − 4.2% for left and right cerebral WM,

Discussion

This case-control regional brain parcellation study, using FreeSurfer software, uncovers selective subcortical (mostly thalamic) and cerebellum WM atrophy in MS patients that is present in patients with early and late or progressive disease. Focal cortical atrophy was significant in the regions of thalamus and inferior parietal lobe of the left hemisphere and right precuneus of MS patients when compared to NC and the severity of subcortical and cortical atrophy was related to higher disability.

Conclusions

This study confirms selective DGM (mostly thalamic) atrophy, and reveals cerebellum WM atrophy in MS patients from the earliest clinical stages. Cortical thinning is found in the more advanced stages of MS. Severity of subcortical and cortical atrophy is related to higher neurological disability.

Acknowledgement

The authors wish to thank Eve Salczynski for technical assistance in the preparation of this manuscript.

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