Gray matter atrophy correlates with MS disability progression measured with MSFC but not EDSS

Mellen Center for MS Treatment and Research U10, Neurologic Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Journal of the neurological sciences (Impact Factor: 2.47). 12/2008; 282(1-2):106-11. DOI: 10.1016/j.jns.2008.11.018
Source: PubMed


Gray matter (GM) pathology is an important component of the multiple sclerosis (MS) disease process. Accelerated gray matter atrophy has been observed in MS patients, but its relationship to neurological disability is not defined. This study was done to determine the relationship between whole brain, GM, and white matter (WM) atrophy and MS disability progression.
Patients with MS and Clinically Isolated Syndromes (CIS), and age- and gender-matched healthy controls were entered into an observational protocol. Baseline brain parenchymal fraction (BPF), GM fraction, and WM fraction, and change over 4 years were correlated with sustained disability progression over the entire study duration. Disability progression was measured using the Multiple Sclerosis Functional Composite (MSFC) and the Expanded Disability Status Scale (EDSS).
Seventy MS and CIS patients and 17 HCs were studied for an average of 6.6 years (range, 3.6-7.8 years). At the final visit, 7 patients were classified as CIS, 36 as relapsing-remitting MS (RRMS), and 27 as secondary progressive MS (SPMS). Baseline whole brain, GM, and WM atrophy predicted EDSS >6.0 at the last study visit. Twenty-one (33%) patients worsened using the EDSS to define disability progression; 29 (46%) worsened using MSFC to define disability progression. Patients with MSFC progression had significantly higher GM atrophy rates compared with patients who were stable on MSFC. White matter atrophy was similar in patients with and without disability progression. Atrophy rates were not different in patients with or without disability progression defined using EDSS.
Whole brain, GM, and WM atrophy predicted MS disability progression observed over the next 6.6 years. Gray matter atrophy rates over 4 years correlated with disability progression measured with the MSFC, but not EDSS. This indicates that MSFC defined disability progression is more closely linked to brain atrophy than EDSS defined disability progression, and provides important new insight into the poor correlation between MRI and clinical disability in MS. The findings confirm the clinical relevance of gray matter atrophy in MS.

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Available from: Elizabeth Fisher, Jun 16, 2014
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    • "hippocampal lesions [8,9], are present which may explain functional deficits seen in MS patients [51,52]. Moreover, GML correlate better with various clinical parameters than WML [53–55]. It is therefore of utmost interest to understand the pathological features of GML versus WML, because that may give direction to the identification of novel therapeutic targets. "
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    ABSTRACT: A remarkable pathological difference between grey matter lesions (GML) and white matter lesions (WML) in Multiple Sclerosis (MS) patients is the paucity of infiltrating leukocytes in GML. To better understand these pathological differences, we hypothesize that the chemokine monocyte chemotactic protein-1 (MCP-1 or CCL2), of importance for leukocyte migration, and its receptor CCR2 are more abundantly expressed in WML than in GML of MS patients. To this end, we analyzed CCL2 and CCR2 expression in the hippocampus, comprising WML and GML, of post-mortem MS patients, and of control subjects. CCL2 and CCR2 mRNA were significantly increased in demyelinated MS hippocampus. Semi-quantification of CCL2 and CCR2 immunoreactivity showed that CCL2 is present in astrocytes only in active WML. CCR2 is upregulated in monocytes/macrophages or amoeboid microglia in active WML, and in ramified microglia in active GML, although to a lesser extent. As a follow-up, we observed a significantly increased CCL2 production by WM-, but not GM-derived astrocytes upon stimulation with bz-ATP in vitro. Finally, upon CCL2 stimulation, GM-derived microglia significantly increased their proliferation rate. We conclude that within hippocampal lesions, CCL2 expression is mainly restricted to WML, whereas the receptor CCR2 is upregulated in both WML and GML. The relative absence of CCL2 in GML may explain the lack of infiltrating immune cells in this type of lesions. We propose that the divergent expression of CCL2 and CCR2 in WML and GML explains or contributes to the differences in WML and GML formation in MS.
    Full-text · Article · Aug 2014
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    • "Brain volume and atrophy measurements correlate with measures of disability [48, 50, 51] and cognitive function [52, 53]. Considering the previously discussed limitations to using EDSS as a primary outcome measure, the validity of brain atrophy as a surrogate marker for disability progression is of interest in studies on clinical trial design for relapsing-remitting MS. "
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    ABSTRACT: Multiple sclerosis (MS) is a chronic inflammatory and neurodegenerative disease that manifests as acute relapses and progressive disability. As a primary endpoint for clinical trials in MS, disability is difficult to both characterize and measure. Furthermore, the recovery from relapses and the rate of disability vary considerably among patients. Given these challenges, investigators have developed and studied the performance of various outcome measures and surrogate endpoints in MS clinical trials. This review defines the outcome measures and surrogate endpoints used to date in MS clinical trials and presents challenges in the design of both adult and pediatric trials.
    Full-text · Article · May 2014
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    • "Nonclinical early predictors of long-term disability have also been identified: brain atrophy rate [28-31], baseline lesion volume [31,32] and long-term increase in lesion volume [30-33]. More recently, long-term disability has also been correlated to measures of gray matter atrophy [34-36] and altered evoked potentials [37-39]. Further research is needed to clarify the source of proinflammatory cytokines during apparent clinical and radiological remission to better define the role of smoldering inflammation in long-term accumulation of neuronal damage and disability. "
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    ABSTRACT: Absence of clinical and radiological activity in relapsing-remitting multiple sclerosis (RRMS) is perceived as disease remission. We explored the role of persisting inflammation during remission in disease evolution. Cerebrospinal fluid (CSF) levels of interleukin 1beta (IL-1beta), a major proinflammatory cytokine, were measured in 170 RRMS patients at the time of clinical and radiological remission. These patients were then followed up for at least 4 years, and clinical, magnetic resonance imaging (MRI) and optical coherence tomography (OCT) measures of disease progression were recorded. Median follow-up of RRMS patients was 5 years. Detection of CSF IL-1beta levels at the time of remission did not predict earlier relapse or new MRI lesion formation. Detection of IL-1beta in the CSF was instead associated with higher progression index (PI) and Multiple Sclerosis Severity Scale (MSSS) scores at follow-up, and the number of patients with sustained Expanded Disability Status Scale (EDSS) or Multiple Sclerosis Functional Composite worsening at follow-up was higher in individuals with detectable levels of IL-1beta. Patients with undetectable IL-1beta in the CSF had significantly lower PI and MSSS scores and a higher probability of having a benign MS phenotype. Furthermore, patients with undetectable CSF levels of IL-1beta had less retinal nerve fiber layer thickness and macular volume alterations visualized by OCT compared to patients with detectable IL-1beta. Our results suggest that persistence of a proinflammatory environment in RRMS patients during clinical and radiological remission influences midterm disease progression. Detection of IL-1beta in the CSF at the time of remission appears to be a potential negative prognostic factor in RRMS patients.
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