Plasma levels of soluble NCAM in multiple sclerosis

https://doi.org/10.1016/j.jns.2018.10.023Get rights and content

Highlights

  • Plasma levels of sNCAM and sVCAM-1 were increased in P-MS compared to healthy individuals.

  • Significant correlations among plasma levels of sNCAM and sVCAM-1 were detected in MS patients and in healthy individuals.

  • Correlations of sNCAM, sVCAM-1 and sICAM-1 plasma levels with global and regional brain atrophy were not detected.

  • Differences in sVCAM plasma levels were found among patients receiving different disease-modifying treatments.

Abstract

In multiple sclerosis (MS), several adhesion molecules are involved within the central nervous system in inflammatory and neurodegenerative processes that are associated to progressive disability and increasing brain atrophy. The neural cell adhesion molecule (NCAM) has been suggested to participate in the reparative mechanisms and in the remyelination processes, key issues in MS pathology. We aimed at investigating plasma levels of the seldom investigated soluble (s)NCAM, and as comparison those of intercellular adhesion molecule-1 (sICAM-1) and vascular adhesion molecule-1 (sVCAM-1), and their association with clinical and MRI measures of lesion volumes and of global and regional atrophy. The cross-sectional study was conducted in 85 relapsing-remitting (RR)-MS, 53 progressive (P)-MS patients, and 42 healthy individuals (HI).

Correlation of MRI measures with plasma levels of these adhesion molecules were not observed.

In the MS and HI groups, sNCAM levels were significantly and positively associated with sVCAM-1 levels. Differently, the correlation between sICAM-1 and sVCAM-1 was observed only in MS patients. sNCAM and sVCAM-1 levels were higher in P-MS compared to HI (P = 0.05 and P = 0.028 respectively). The sVCAM-1 levels differed (P < 0.001) among DMTs groups and HI.

The association of sNCAM plasma levels with MS disease, as well as differences in sVCAM-1 levels in patients receiving different DMTs, deserve further investigation.

Introduction

In multiple sclerosis (MS), several adhesion molecules are suggested to be involved in inflammatory processes promoting neurodegeneration within the central nervous system (CNS), that are associated with progressive disability and increasing brain atrophy [1,2].

The members of the immunoglobulin superfamily, intercellular adhesion molecule-1 (ICAM-1) and vascular adhesion molecule-1 (VCAM-1), through binding to integrins LFA-1 and VLA-4 respectively, are critical in leucocyte-endothelia interaction, promoting the immuno-inflammatory response in MS [3,4]. The soluble forms sICAM-1 and sVCAM-1 are considered to be markers of blood-brain barrier (BBB) disruption [5] and might regulate functions of the corresponding cell-bound forms [[6], [7], [8]]. A large number of studies investigated plasma or serum levels of sICAM-1 and sVCAM-1 in MS providing often conflicting data and highlighting heterogeneity in “immunological/adhesion pattern” among MS clinical phenotypes [[9], [10], [11], [12], [13]].

The neural cell adhesion molecule (NCAM, also known as CD56), another member of the immunoglobulin superfamily, is involved in cell migration, axonal growth and fasciculation, organization and modulation of synapses (reviewed in [14]). Its possible involvement in the reparative mechanisms and in the remyelination processes, key issues in MS [15], has been suggested [16]. Shedding of sNCAM molecules from cell membrane of neural and glial cells might have a role in brain plasticity, as it differentially alters neurite branching in a cell-type dependent manner [17,18].

The large majority of the studies have investigated sNCAM levels in the cerebrospinal fluid (CSF), which appeared to be lower in MS patients CSF compared to controls and to decrease in a step-wise manner through the progression of MS disease (reviewed in [14]). Differently, only one study investigated sNCAM in serum of MS patients [19].

Neuroimaging investigation of MS–adhesion molecule associations received considerable attention over the years, mainly evaluating the presence/absence of brain lesions, or T2 lesion volumes [13,[20], [21], [22]] by magnetic resonance imaging (MRI). Brain atrophy assessment has become important for the evaluation of neurodegeneration and MS disease progression. The whole brain volume (BV), the cortical volume (CV) or lateral ventricular volume (LVV), reflect regional axonal loss as well as demyelination in white and gray matter tissue structures [23,24]. Moreover, atrophy of the deep gray matter (DGM) and particularly of the thalamus, which has a prominent role in integrating signals of complex cognitive and motor functions, is associated to physical and cognitive disability in MS [25].

Up to now, the relationship between brain atrophy parameters and levels in plasma of soluble forms of adhesion molecules has not been explored in MS.

In this study, we aimed at investigating associations of soluble plasma levels of key adhesion molecules, the seldom studied sNCAM and as comparison sICAM-1 and sVCAM-1, with clinical and MRI measures of disease severity, in a cohort of MS patients and in healthy individuals (HI).

Section snippets

Study population

The population of this cross-sectional study included subjects recruited in a case-control study of cardiovascular, environmental and genetic risk factors for disease progression in patients with MS (CEG-MS study; IRB ID: MODCR00000352) [26].

Subjects with the following characteristics were included: having MS according to the revised McDonald criteria [27] or being a healthy individual (HI), having an MRI scan at the 3 T scanner using the standardized MRI protocol, age between 18 and 75 years

Results

The demographic and clinical characteristics of the study populations are summarized in Table 1 and have been previously reported [32]. The patient population (n = 138) included 85 relapsing remitting (RR-MS) and 46 secondary-progressive and 7 primary-progressive MS, categorized as progressive (P-MS) group for the purpose of the analyses.

Discussion

Adhesion molecules are suggested to take part in the different processes that lead to the development of lesions and neurodegeneration in MS. Based on the functional importance in MS pathogenesis, we investigated the levels of sNCAM, and in comparison, those of sICAM-1 and sVCAM-1, in a large cohort of subjects, in which multiple clinical and MRI measures of disease severity were assessed. Levels were evaluated in plasma by a multiplex assay, which favors detection of associations by decreasing

Conclusions

In a large cohort of patients characterized for multiple MRI measures of disease severity, sNCAM levels in plasma were evaluated for the first time, and compared with those of sICAM-1 and sVCAM-1. Plasma levels of sNCAM, sICAM-1 and sVCAM-1 did not correlate with clinical and MRI measures of disease severity.

Whereas correlation between plasma levels of sNCAM and sVCAM-1 were detectable both in patients and HI, that between sICAM-1 and sVCAM-1 was observed only in MS patients. In progressive MS,

Conflicting interests

Nicole Ziliotto, Dejan Jakimovski, Marcello Baroni, Veronica Tisato, Paola Secchiero, Niels Bergsland, Deepa P. Ramasamy, Francesco Bernardi and Giovanna Marchetti have nothing to disclose.

Dr. Robert Zivadinov has received speaker honoraria and consultant fees from Genzyme-Sanofi, Novartis, Claret Medical, Celgene and EMD Serono. He has received research support from EMD Serono, Genzyme-Sanofi, Claret Medical, Protembis, QuintilesIMS and Novartis.

Dr. Bianca Weinstock-Guttman received honoraria

Ethics approval and consent to participate

The study protocol was approved by the local Institutional Review Boards of University of Buffalo, USA (CEG-MS study; IRB ID: MODCR00000352) and of University/Hospital of Ferrara, Italy (IRB ID: 170585). All participants gave their written informed consent.

Acknowledgements

This study was funded in part by the Annette Funicello Research Fund for Neurological Diseases and internal resources of the Buffalo Neuroimaging Analysis Center. In addition, we received support from the Jacquemin Family Foundation.

Research reported in this publication was also funded in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under award Number UL1TR001412. The content is solely the responsibility of the authors and does not

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