Elevated plasma homocysteine levels are associated

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crosis factor-alpha (TNF-α) regulate adherence and diape- ..... TNFR2, tumor necrosis fator receptor 2; PECAM-1: platelet endothelial cell adhesion molecule 1; ...
Metabolic Brain Disease https://doi.org/10.1007/s11011-018-0224-4

ORIGINAL ARTICLE

Elevated plasma homocysteine levels are associated with disability progression in patients with multiple sclerosis Sayonara Rangel Oliveira 1 & Tamires Flauzino 2 & Beatriz Sardinha Sabino 3 & Ana Paula Kallaur 2 & Daniela Frizon Alfieri 2 & Damacio Ramon Kaimen-Maciel 4 & Helena Kaminami Morimoto 1 & Elaine Regina Delicato de Almeida 1 & Marcell Alysson Batisti Lozovoy 1 & Edna Maria Vissoci Reiche 1 & Isaias Dichi 5 & Andréa Name Colado Simão 1 Received: 6 November 2017 / Accepted: 26 March 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract The aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in Multiple Sclerosis (MS) patients and whether TNF pathways and cellular adhesion molecules (CAM) are involved in this process. This study included 180 MS patients, who were divided according to their levels of homocysteine (Hyperhomocysteinemia ≥11.35 μmol/L) and 204 healthy individuals (control group). MS patients showed higher levels of homocysteine (p < 0.001), tumor necrosis factor alpha (TNF-α, p < 0.001), TNF receptor 1 (TNFR1, p = 0.038), TNF receptor 2 (TNFR2, p < 0.001), and lower levels of PECAM (p = 0.001), ICAM (p < 0.001) and VCAM (p = 0.005) than controls. The multivariate binary logistic regression analysis showed that plasma levels of homocysteine, TNFR1, TNFR2 and PECAM were associated with the presence of disease. MS patients with hyperhomocysteinemia showed higher disease progression evaluated by the Multiple Sclerosis Severity Score (MSSS, p < 0.001), disability evaluated by Expanded Disability Status Score EDSS (p < 0.001), TNFR1 (p = 0.039) and ICAM (p = 0.034) than MS patients with lower levels of homocysteine. Hyperhomocysteinemia was independently associated with MSSS in MS patients, but were not associated with TNF-α, TNFR, and CAM. Homocysteine levels was higher in progressive forms than relapsing-remitting MS (p < 0.001), independently of sex and age. In conclusion, this is the first study in which homocysteinemia was associated with progression of the disease (MSSS), although this finding was not directly related to TNF-α and TNFR pathways or to CAM. Keywords Homocysteine . Multiple sclerosis . Disability . Progression of disease . TNF-alpha . Adhesion molecule

Introduction Multiple sclerosis (MS) is a neurological disease characterized by inflammation and demyelination in the central nervous

* Andréa Name Colado Simão [email protected] 1

Department of Pathology, Clinical Analysis and Toxicology, Health Sciences Center, University Hospital, State University of Londrina, Av. Robert Koch 60, Vila Operária, Londrina, Paraná CEP 86038-350, Brazil

2

Postgraduate Program, Health Sciences Center, University of Londrina, Londrina, Paraná, Brazil

3

Applied Immunology Laboratory, University of Londrina, Londrina, Paraná, Brazil

4

Department of Clinical Medicine, University of Londrina, Londrina, Paraná, Brazil

5

Department of Internal Medicine, University of Londrina, Londrina, Paraná, Brazil

system (CNS) (Kocer et al. 2009). High concentrations of homocysteine have been associated with neurodegenerative disorders, such as MS and Alzheimer disease and may be a risk factor for these conditions (Seshadri 2006). Homocysteine is a non-essential sulfur-containing amino acid that is derived from methionine metabolism and depends on folate, vitamin B12, and vitamin B6. Several studies have shown increased plasma levels of homocysteine in MS patients when compared to healthy subjects (Ramsaransing et al. 2006; Moghaddasi et al. 2013). Some articles have already shown that hyperhomocysteinemia was significantly associated and/or correlated with cognitive impairment, visual abnormalities, and clinical progression in patients with MS (Russo et al. 2008; Teunissen et al. 2008). Homocysteine is considered an inflammatory marker and there is strong evidence that homocysteine itself is able to induce blood-brain barrier (BBB) disruption (Kamath et al. 2006). MS is characterized by an inflammatory process in the CNS and BBB breakdown and recruitment of

Metab Brain Dis

activated immune cells from the peripheral blood into CNS are early events in the development of inflammatory MS lesions (Kuenz et al. 2005). In addition, cellular adhesion molecules (CAM), such as intercellular adhesion molecule1 (ICAM-1), vascular cell-adhesion-molecule-1 (VCAM1), platelet-endothelial-cell-adhesion-molecule-1 (PECAM-1) and inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) regulate adherence and diapedesis of immune cells across the BBB into the CNS and seems to be associated with physiopathology of MS (Kalinowska-Lyszczars et al. 2016). It was previously observed that serum PECAM-1 and VCAM-1 levels were elevated in MS patients during relapses, but remained low in the progressive phase of the disease (Kuenz et al. 2005). The hypothesis of a possible association between elevated plasma homocysteine levels and progression of the disease in MS patients is supported by some studies (Obeid and Herrmann 2006; Skovierová et al. 2016), which have showed that homocysteine might cause neuronal damage by some mechanisms: first, increasing the production of reactive oxygen species (Faraci and Lentz 2004); second, promoting excitotoxicity via stimulation of N-methyl-D-asparate receptors (NMDA), damaging neuronal DNA, and thereby triggering apoptosis (Ho et al. 2002). Few studies have evaluated the relationship of the clinical forms in MS and homocysteine levels. Besler and Comoglu (2003) found elevated plasma homocysteine levels in patients with secondary progressive MS (SPMS) compared with healthy controls, whereas other studies showed that homocysteine levels did not differ between the progressive forms and relapsing-remitting multiple sclerosis (RR-MS) (Ramsaransing et al. 2006; Teunissen et al. 2008). Although the age in which it begins as well as the different forms of the disease can aid in the prediction of the prognosis, the search for other sensitive biomarkers is an important issue (Renoux 2011; Koch et al. 2015). To our knowledge, the relationship between hyperhomocysteinemia, TNF-α and CAM, and disability progression, evaluated by Multiple Sclerosis Severity Score (MSSS), has not been investigated yet. In addition, there are controversy about association between hyperhomocysteinemia and clinical forms of MS. Thus, the aims of this study were to verify whether hyperhomocysteinemia is associated with disability progression in MS patients and whether TNF pathways and CAM is involved in this process.

Subjects and methods

Clinical Hospital, State University of Londrina. All patients were diagnosed with definite MS according to McDonald’s criteria (Polman et al. 2011). Initially, demographic and inflammatory biomarkers were analyzed in the control group and in MS patients. After that, MS patients were divided into two groups, according to the median, in patients with levels of homocysteine