Measurement and clinical effect of grey matter pathology in multiple sclerosis

Department of Anatomy and Neurosciences, Section of Clinical Neuroscience, VU University Medical Center, Amsterdam, Netherlands. Electronic address: .
The Lancet Neurology (Impact Factor: 21.9). 12/2012; 11(12):1082-92. DOI: 10.1016/S1474-4422(12)70230-2
Source: PubMed


During the past 10 years, the intense involvement of the grey matter of the CNS in the pathology of multiple sclerosis has become evident. On gross inspection, demyelination in the grey matter is rather inconspicuous, and lesions in the grey matter are mostly undetectable with traditional MRI sequences. However, the results of immunohistochemical studies have shown extensive involvement of grey matter, and researchers have developed and applied new MRI acquisition methods as a result. Imaging techniques specifically developed to visualise grey matter lesions indicate early involvement, and image analysis techniques designed to measure the volume of grey matter show progressive loss. Together, these techniques have shown that grey matter pathology is associated with neurological and neuropsychological disability, and the strength of this association exceeds that related to white matter lesions or whole brain atrophy. By focusing on the latest insights into the in-vivo measurement of grey matter lesions and atrophy, we can assess their clinical effects.

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    • "This is particularly relevant since there is a significant relationship between cortical pathology and some clinical aspects of MS, especially cognitive impairment [8] [9]. Increasing evidence suggests that cortical gray matter pathology, especially cortical atrophy, is strictly related to disability progression in MS [17]. We have previously observed that a low degree of cortical pathology was associated with the so-called " benign " course of MS [18], while the results of several independent studies converge in the suggestion that patients with a more severe physical and cognitive impairment are characterized by a more diffuse and marked gray matter atrophy, especially cortical thinning [19] [20] [21] [22]. "
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    ABSTRACT: Cortical lesions (CLs) and atrophy are pivotal in multiple sclerosis (MS) pathology. This study determined the effect of disease modifying drugs (DMDs) on CL development and cortical atrophy progression in patients with relapsing-remitting MS (RRMS) over 48 months. Patients (n = 165) were randomized to sc IFN β-1a 44 μg, im IFN β-1a 30 μg, or glatiramer acetate 20 mg. The reference population comprised 50 DMD-untreated patients with RRMS. After 24 months, 43 of the untreated patients switched to DMDs. The four groups of patients were followed up for an additional 24 months. At 48 months the mean standard deviation number of new CLs was significantly lower in patients treated with sc IFN β-1a (1.4 ± 1.0, range 0-5) compared with im IFN β-1a (2.3 ± 1.3, range 0-6, P = 0.004) and glatiramer acetate (2.2 ± 1.5, range 0-7, P = 0.03). Significant reductions in CL accumulation and new white matter and gadolinium-enhancing lesions were also observed in the 43 patients who switched to DMDs after 24 months, compared with the 24 months of no treatment. Concluding, this study confirms that DMDs significantly reduce CL development and cortical atrophy progression compared with no treatment.
    02/2015; 2015:369348. DOI:10.1155/2015/369348
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    • "Cortical quantitative T 2 * and cortical thickness We investigated the relationship between laminar quantitative T 2 * and cortical thickness in multiple sclerosis. Although the clinical relevance of cortical tissue loss assessment in multiple sclerosis has been consistently reported in cross-sectional and longitudinal studies, the underlying mechanisms are still unknown (Geurts et al., 2012). Cortical thinning may be the consequence of axonal transection by white matter lesions leading to neuronal loss or may underlie a degenerative process that primarily targets the cortical grey matter. "
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    ABSTRACT: We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients' normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10(-10) and P < 10(-7)), and mean cortical T2* in controls (P < 10(-5) and P < 10(-6)). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email:
    Brain 02/2015; 138(4). DOI:10.1093/brain/awv011 · 9.20 Impact Factor
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    • "The use of new MRI sequences has shown that cortical lesions in MS are more common than previously thought [8, 17, 26] and are supposed to contribute to cognitive impairment [7, 44] and epilepsy [9] in MS. Therefore, cortical involvement may represent an important pathophysiological substrate for disease manifestation, progression and therapy in MS [12, 18, 30]. "
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    ABSTRACT: Cerebral cortex shows a high endogenous propensity for remyelination. Yet, widespread subpial cortical demyelination (SCD) is a common feature in progressive multiple sclerosis (MS) and can already be found in early MS. In the present study, we compared oligodendroglial loss in SCD in early and chronic MS. Furthermore, we addressed in an experimental model whether repeated episodes of inflammatory SCD could alter oligodendroglial repopulation and subsequently lead to persistently demyelinated cortical lesions. NogoA+ mature oligodendrocytes and Olig2+ oligodendrocyte precursor cells were examined in SCD in patients with early and chronic MS, normal-appearing MS cortex, and control cortex as well as in the rat model of repeated targeted cortical experimental autoimmune encephalomyelitis (EAE). NogoA+ and Olig2+ cells were significantly reduced in SCD in patients with chronic, but not early MS. Repeated induction of SCD in rats resulted only in a transient loss of NogoA+, but not Olig2+ cells during the demyelination phase. This phase was followed by complete oligodendroglial repopulation and remyelination, even after four episodes of demyelination. Our data indicate efficient oligodendroglial repopulation in subpial cortical lesions in rats after repeated SCD that was similar to early, but not chronic MS cases. Accordingly, four cycles of experimental de- and remyelination were not sufficient to induce sustained remyelination failure as found in chronic cortical MS lesions. This suggests that alternative mechanisms contribute to oligodendrocyte depletion in chronic cortical demyelination in MS. Electronic supplementary material The online version of this article (doi:10.1007/s00401-014-1260-8) contains supplementary material, which is available to authorized users.
    Acta Neuropathologica 02/2014; 128(2). DOI:10.1007/s00401-014-1260-8 · 10.76 Impact Factor
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