Clinical correlates of grey matter pathology in multiple sclerosis

Charles University in Prague, Praha, Praha, 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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    • "GM loss was more pronounced in the first 3 months than the second 3 months, and only loss in the first 3 months was statistically significant. While pseudoatrophy owing to WM volume has been noted during treatment with natalizumab [9], the longer term brain tissue changes in RRMS and clinical measures (such as physical and cognitive disability) have been associated more with GM volume changes rather than loss of WM volume [36, 37]. This conflicting finding of a GM rather than a WM effect may be due to a number of factors. "
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    ABSTRACT: Background Brain volume atrophy is observed in relapsing–remitting multiple sclerosis (RRMS). Methods Brain volume changes were evaluated in 23 patients with RRMS treated with interferon β-1a 44 μg given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed. Results Interferon β-1a 44 μg SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; –0.95 %; P = 0.030, –1.52 %; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume. Conclusions These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon β-1a 44 μg SC tiw, rather than disease-related tissue loss. Trial registration; NCT01085318
    Full-text · Article · Nov 2015 · BMC Neurology
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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.
    Full-text · Article · Sep 2014 · Multiple Sclerosis and Related Disorders
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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.
    Full-text · Article · Dec 2013 · PLoS ONE
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