Abstract
Background: Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS).Objectives: This study aimed to evaluate the combined contribution of the hemostasis inhibitor protein C (PC) and chemokine C-C motif ligand 18 (CCL18) levels to brain atrophy in MS and to identify disease-relevant correlations among circulating levels of hemostasis inhibitors, chemokines, and adhesion molecules, particularly in CMB occurrence in MS.Methods: Plasma levels of hemostasis inhibitors (ADAMTS13, PC, and PAI1), CCL18, and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138 MS patients [85 relapsing-remitting (RR-MS) and 53 progressive (P-MS)] and 42 healthy individuals (HI) who underwent 3-T MRI exams. Association of protein levels with MRI outcomes was performed by regression analysis. Correlations among protein levels were assessed by partial correlation and Pearson's correlation.Results: In all patients, regression analysis showed that higher PC levels were associated with lower brain volumes, including the brain parenchyma (p = 0.002), gray matter (p < 0.001), cortex (p = 0.001), deep gray matter (p = 0.001), and thalamus (p = 0.001). These associations were detectable in RR-MS but not in P-MS patients. Higher CCL18 levels were associated with higher T2-lesion volumes in all MS patients (p = 0.03) and in the P-MS (p = 0.003). In the P-MS, higher CCL18 levels were also associated with lower volumes of the gray matter (p = 0.024), cortex (p = 0.043), deep gray matter (p = 0.029), and thalamus (p = 0.022). PC-CCL18 and CCL18-PAI1 levels were positively correlated in both MS and HI, PC–sVAP1 and PAI1–sVCAM1 only in MS, and PC–sICAM1 and PC–sNCAM only in HI. In MS patients with CMBs (n = 12), CCL18–PAI1 and PAI1–sVCAM1 levels were better correlated than those in MS patients without CMBs, and a novel ADAMTS13–sVAP1 level correlation (r = 0.78, p = 0.003) was observed.Conclusions: Differences between clinical phenotype groups in association of PC and CCL18 circulating levels with MRI outcomes might be related to different aspects of neurodegeneration. Disease-related pathway dysregulation is supported by several protein level correlation differences between MS patients and HI. The integrated analysis of plasma proteins and MRI measures provide evidence for new relationships among hemostasis, inflammation, and immunity pathways, relevant for MS and for the occurrence of CMBs.
Highlights
In multiple sclerosis (MS) pathogenesis, blood–brain barrier (BBB) disruption and vascular changes interact in a vicious cycle with altered immune trafficking and the inflammatory processes, supported by adhesion molecules and chemokines [1,2,3]
In the current study, (i) we evaluated the combined contribution of the main coagulation inhibitor protein C (PC) and the CCL18 chemokine levels to MS brain atrophy, (ii) we compared PC and CCL18 plasma concentrations for their ability to explain the observed neurodegeneration, and (iii) we investigated the correlations among circulating levels of hemostasis inhibitors (PC, ADAMTS13, and PAI1), CCL18, and adhesion molecules [sICAM, soluble neural cell adhesion molecules (CAMs), soluble vascular adhesion protein 1 (sVAP1), and sVCAM1], in relation to cerebral microbleeds (CMBs)
Protein Level Correlations in Patients With Cerebral Microbleeds In MS patients with CMBs, the correlation between CCL18 and PAI1 (r = 0.85, p = 0.001, confidence intervals (CIs) 95% = 0.74, 0.97) was even stronger than in MS patients without CMBs (r = 0.26, p = 0.003, CI 95% = 0.10, 0.42)
Summary
In multiple sclerosis (MS) pathogenesis, blood–brain barrier (BBB) disruption and vascular changes interact in a vicious cycle with altered immune trafficking and the inflammatory processes, supported by adhesion molecules and chemokines [1,2,3]. Several studies suggested the cross talk of immunity and inflammation with hemostasis, potentially reflected in MS pathogenesis and progression of neurodegeneration [4]. PC has coagulation inhibitor activity and anti-inflammatory and cell protective properties [6]. In MS-related vascular changes, circulating soluble (s) forms of cell adhesion molecules (CAMs) can result from activated membranes shedding in response to endothelial damage [9]. Several studies suggested cross talk among components of hemostasis, inflammation, and immunity pathways in the pathogenesis, neurodegeneration, and occurrence of cerebral microbleeds (CMBs) in multiple sclerosis (MS)
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