Clinical correlates of grey matter pathology in multiple sclerosis

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.
BMC Neurology (Impact Factor: 2.04). 03/2012; 12(1):10. DOI: 10.1186/1471-2377-12-10
Source: PubMed


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.

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    • "Natalizumab also improved the overall rate of confirmed complete relapse recovery (assessed by the cumulative probability of 12-week and 24-week confirmed complete EDSS recovery from relapse). The sudden onset or worsening of MS symptoms that occurs during a relapse is thought to be the clinical manifestation of acute inflammatory demyelinating events in the CNS (Frohman et al., 2008; Stadelmann et al., 2011); residual disability may result from incomplete remyelination, reduced CNS plasticity, axonal damage, or neuronal loss that follows (Fisniku et al., 2008; Giorgio et al., 2010; Horakova et al., 2012; Tallantyre et al., 2010). Natalizumab is known to attenuate the infiltration of effector immune cells into the CNS during inflammatory events that compromise the blood brain barrier. "
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    ABSTRACT: Objectives Compare relapse clinical severity, post-relapse residual disability, and the probability of confirmed complete recovery from relapse between patients who relapsed during natalizumab (n=183/627 [29%]) and placebo (n=176/315 [56%]) treatments in the AFFIRM trial. Methods In this post hoc analysis, relapse clinical severity and residual disability were defined by change in Expanded Disability Status Scale (EDSS) score occurring between pre-relapse and at-relapse assessment and between pre-relapse and post-relapse assessment, respectively. Patients were considered completely recovered from relapse when their post-relapse EDSS score was less than or equal to their pre-relapse EDSS score, and this was maintained for 12 or 24 weeks. Results At relapse, an increase in EDSS score of ≥0.5 points occurred in 71% of natalizumab and 84% of placebo patients (P=0.0088); an increase of ≥1.0 point occurred in 49% of natalizumab and 61% of placebo patients (P=0.0349) (mean increase in EDSS at relapse: natalizumab=0.77; placebo=1.09; P=0.0044). After relapse, residual disability of ≥0.5 EDSS points remained in 31% of natalizumab and 45% of placebo patients (P=0.0136) (mean post-relapse residual EDSS increase: natalizumab=0.06; placebo=0.28; P=0.0170). In patients with an increase in EDSS of ≥0.5 or ≥1.0 during relapse, natalizumab increased the probability of 12-week confirmed complete recovery from relapse by 55% (hazard ratio [HR]=1.554; P=0.0161) and 67% (HR=1.673; P=0.0319) compared to placebo, respectively. Conclusions In AFFIRM, natalizumab treatment decreased the clinical severity of relapses and improved recovery from disability induced by relapses. These beneficial effects would limit the step-wise accumulation of disability.
    Multiple Sclerosis and Related Disorders 09/2014; 3(6). DOI:10.1016/j.msard.2014.08.005 · 0.88 Impact Factor
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    • "MS-related cognitive impairment has been consistently associated with brain atrophy also in the earliest disease stages [27], [50], [51], and damage to several GM structures can be associated with impairment of specific cognitive functions [52]. Here we have demonstrated that variants of CNR1 gene have a direct effect on executive functioning measured by WLG test, ST (inhibition of automatic response), D-KEFS Sorting test (verbal/nonverbal modality-specific problem-solving skills, ability to transfer sorting concepts into action and ability to inhibit previous description responses to engage in flexibility of thinking). "
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    ABSTRACT: Genetic ablation of type-1 cannabinoid receptors (CB1Rs) exacerbates the neurodegenerative damage of experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS). To address the role on CB1Rs in the pathophysiology of human MS, we first investigated the impact of AAT trinucleotide short tandem repeat polymorphism of CNR1 gene on CB1R cell expression, and secondly on the inflammatory neurodegeneration process responsible for irreversible disability in MS patients. We found that MS patients with long AAT repeats within the CNR1 gene (≥12 in both alleles) had more pronounced neuronal degeneration in response to inflammatory white matter damage both in the optic nerve and in the cortex. Optical Coherence Tomography (OCT), in fact, showed more severe alterations of the retinal nerve fiber layer (RNFL) thickness and of the macular volume (MV) after an episode of optic neuritis in MS patients carrying the long AAT genotype of CNR1. MS patients with long AAT repeats also had magnetic resonance imaging (MRI) evidence of increased gray matter damage in response to inflammatory lesions of the white matter, especially in areas with a major role in cognition. In parallel, visual abilities evaluated at the low contrast acuity test, and cognitive performances were negatively influenced by the long AAT CNR1 genotype in our sample of MS patients. Our results demonstrate the biological relevance of the (AAT)n CNR1 repeats in the inflammatory neurodegenerative damage of MS.
    PLoS ONE 12/2013; 8(12):e82848. DOI:10.1371/journal.pone.0082848 · 3.23 Impact Factor
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    • "Moreover, the conventional MRI studies have shown the presence of atrophy of the caudate nucleus and thalamus even in the earliest stages of the disease [13, 50]. Such thalamic damage in MS patients has been associated with physical disability and cognitive impairment [51, 52]. Thus, based on these data, the DTI indices of NADGM may be useful indicators of disability accumulation in early MS. "
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    ABSTRACT: The aim of this study was to evaluate diffusion tensor imaging (DTI) indices in the corpus callosum and pyramidal tract in normal-appearing white matter (NAWM) and the caudate nucleus and thalamus in deep grey matter (NADGM) in all MS subtypes and clinically isolated syndrome (CIS). Furthermore, it was determined whether these metrics are associated with clinical measures and the serum levels of candidate immune biomarkers. Apparent diffusion coefficients (ADC) values were significantly higher than in controls in all six studied NAWM regions in SPMS, 4/6 regions in RRMS and PPMS and 2/6 regions in CIS. In contrast, decreased fractional anisotropy (FA) values in comparison to controls were detected in 2/6 NAWM regions in SPMS and 1/6 in RRMS and PPMS. In RRMS, the level of neurological disability correlated with thalamic FA values (r = 0.479, P = 0.004). In chronic progressive subtypes and CIS, ADC values of NAWM and NADGM were associated with the levels of MIF, sFas, and sTNF- α . Our data indicate that DTI may be useful in detecting pathological changes in NAWM and NADGM in MS patients and that these changes are related to neurological disability.
    12/2013; 2013(9):265259. DOI:10.1155/2013/265259
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