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1. Dimethyl Fumarate in the Treatment of Relapsing-Remitting Multiple Sclerosis: Patient Reported Outcomes and Perspectives

Author

Ozel O, Vaughn CB, Eckert SP, Jakimovski D, Lizarraga AA, and Weinstock-Guttman B

Subjects
multiple sclerosis, patient-reported outcomes, outcome measures, quality of life, dimethyl fumarate, Medicine (General), R5-920
Abstract

Osman Ozel,1 Caila B Vaughn,1 Svetlana P Eckert,1 Dejan Jakimovski,2 Alexis A Lizarraga,1 Bianca Weinstock-Guttman1 1Jacobs MS Center for Treatment and Research, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, Buffalo, NY, USA; 2Buffalo Neuroimaging Analysis Center, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, State University of New York, Buffalo, NY, USACorrespondence: Bianca Weinstock-GuttmanJacobs MS Center for Treatment and Research, Department of Neurology, Jacobs School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 1010 Main Street, 2 nd Floor, Buffalo, NY 14202, USATel +1 716 829 5063Fax +1 716 829 4001Email bw8@buffalo.eduAbstract: Dimethyl fumarate (DMF) is a commonly prescribed oral medication for the treatment of relapsing forms of multiple sclerosis (MS) with a wide range of hypothesized downstream mechanisms of action. Randomized clinical trials have established its clinical efficacy by using standard objective clinical measures. However, MS is a chronic disease that, apart from physical ailments, can affect an individual’s mood, psychosocial status, and quality of life which cannot be captured by using only objective assessment tools. Given the challenge of determining the efficacy of the treatment in a real-world clinical setting, the use of patient-reported outcomes (PROs) may help us to better address these aspects of patient care and establish a more patient-centered approach to MS care. To date, a review of PubMed identified six studies which reported on PROs in patients who are taking DMF. In total, twelve different kinds of PRO measures were utilized and 6359 patients provided at least one form of PRO in these studies. Upon review of these studies, we were able to conclude that people with MS had decreased quality of life compared to the healthy population in the US. MS patients on DMF, however, had better health-related quality of life assessment scores compared to those using a placebo. Previous studies also suggested that DMF decreased work productivity impairment scores after one year of use compared to baseline. DMF was associated with less impairment in fatigue and depression scales along with improved treatment quality assessment and adherence scores. This review will present a brief synopsis of the published literature and will provide indications for future directions with respect to PROs and DMF in people with MS.Keywords: multiple sclerosis, patient-reported outcomes, outcome measures, quality of life, dimethyl fumarate

Published
2019

3. Relationships among circulating levels of hemostasis inhibitors, chemokines, adhesion molecules, and mri characteristics in multiple sclerosis

Author

Ziliotto, N, Zivadinov, R, Jakimovski, D, Baroni, M, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F, Ziliotto N., Zivadinov R., Jakimovski D., Baroni M., Bergsland N., Ramasamy D. P., Weinstock-Guttman B., Ramanathan M., Marchetti G., Bernardi F., Ziliotto, N, Zivadinov, R, Jakimovski, D, Baroni, M, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F, Ziliotto N., Zivadinov R., Jakimovski D., Baroni M., Bergsland N., Ramasamy D. P., Weinstock-Guttman B., Ramanathan M., Marchetti G., and Bernardi F.

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 adhesionmolecules (sNCAM, sICAM1, sVCAM1, and sVAP1) were evaluated by multiplex in 138MS 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

Published
2020

4. High-density lipoprotein cholesterol is associated with multiple sclerosis fatigue: A fatigue-metabolism nexus?

Author

Browne, R, Jakimovski, D, Ziliotto, N, Kuhle, J, Bernardi, F, Weinstock-Guttman, B, Zivadinov, R, Ramanathan, M, Browne R. W., Jakimovski D., Ziliotto N., Kuhle J., Bernardi F., Weinstock-Guttman B., Zivadinov R., Ramanathan M., Browne, R, Jakimovski, D, Ziliotto, N, Kuhle, J, Bernardi, F, Weinstock-Guttman, B, Zivadinov, R, Ramanathan, M, Browne R. W., Jakimovski D., Ziliotto N., Kuhle J., Bernardi F., Weinstock-Guttman B., Zivadinov R., and Ramanathan M.

Abstract

Background: Fatigue is a frequent symptom in multiple sclerosis (MS). The role of cholesterol and lipids in MS fatigue has not been investigated. Objective: To investigate the associations of cholesterol biomarkers and serum neurofilament light chain (sNfL) with fatigue in relapsing-remitting MS. Methods: This cross-sectional study included 75 relapsing-remitting MS patients (69% female, mean age ± SD: 49.6 ± 11 years and median Expanded Disability Status Scale score: 2.0). Fatigue, disability, and depression were assessed with Fatigue Severity Scale (FSS), Expanded Disability Status Scale, and the Beck Depression Index–Fast Screen, respectively. sNfL was measured using single-molecule array technology. Plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and an apolipoprotein panel data were obtained. Soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), chemokine (C-C motif) ligand 5 (CCL5 or RANTES), and CCL18 levels were measured to assess inflammation. Results: The mean FSS was 4.27 ± 1.73, and 57% had severe fatigue status (SFS, FSS ≥ 4.0). In regression analyses adjusted for age, sex, disability, and depression, lower FSS and SFS were associated with greater HDL-C (P =.006 for FSS, and P =.016 for SFS) and lower TC to HDL-C ratio (P =.011 for FSS, and P =.009 for SFS). Apolipoprotein A-II was also associated with FSS (P =.022). sNfL, CCL5, CCL18, sICAM-1, and sVCAM-1 levels were not associated with fatigue after adjusting for disability and depression. Conclusions: TC to HDL-C ratio is associated with MS fatigue. Our results implicate a potential role for the HDL-C pathway in MS fatigue and could provide possible targets for the treatment of MS fatigue.

Published
2019

5. Correlation between Protein C and CCL18 levels in Multiple Sclerosis

Author

Ziliotto, N, Zivadinov, R, Baroni, M, Jakimovski, D, Bergsland, N, Ramasamy, DP, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F., Ziliotto, N, Zivadinov, R, Baroni, M, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, and Bernardi, F

Subjects
multiple sclerosi, neurodegeneration, CCL18, protein C
Published
2020

6. Association of plasma Protein C and CCL18 levels with neurodegenerative measures in Multiple Sclerosis patients

Author

Ziliotto, N, Zivadinov, R, Baroni, M, Jakimovski, D, Bergsland, N, Ramasamy, DP, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F., FALANGA, ANNA, Ziliotto, N, Zivadinov, R, Baroni, M, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F, and Falanga, A

Subjects
multiple sclerosi, neurodegeneration, hemostasis inhibitor, CCL18, Protein C
Published
2020

7. Correlation between ADAMTS13 and VAP1 levels in Multiple Sclerosis with cerebral microbleeds

Author

Ziliotto, N, Zivadinov, R, Baroni, M, Jakimovski, D, Bergsland, N, Ramasamy, Dp, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F, Ziliotto, N, Zivadinov, R, Baroni, M, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, and Bernardi, F

Subjects
multiple sclerosi, ADAMSTS13, cerebral microbleed, VAP-1
Abstract

Background: The progressive failure of blood–brain barrier (BBB) integrity, which may have the pathological feature of cerebral microbleeds (CMBs), leads to focal extravascular leakage of blood components and subsequently induces several inflammatory responses. CMBs have been associated with worsening of physical and cognitive disability in multiple sclerosis (MS). Adhesion molecules, which participate in BBB disruption and in inflammatory responses, could be involved in the formation of CMBs. The anti-inflammatory properties of hemostasis inhibitors offer a rational link for their study in the presence of CMBs. Aims: To explore plasma levels, and correlations of hemostasis inhibitors and adhesion molecules in relation to CMBs in MS. Methods: Plasma levels of coagulation inhibitors (PC, TM, EPCR, PS, TFPI, HCII, ADAMTS13, PAI1) and soluble adhesion molecules (sNCAM, sICAM1, sVCAM1, sVAP1), were evaluated by Multiplex and ELISA in 125 MS patients and 42 healthy individuals (HI) who underwent 3T MRI exams. CMBs were assessed on susceptibility-weighted minimum intensity projection images and susceptibility maps. Spearman’s correlation and Mann–Whitney test were used, as appropriate. Results: Patients with CMBs (n=12) showed, in addition to significantly lower ADAMTS13 levels (p=0.025), significantly higher sNCAM levels (p=0.017) and a trend for higher levels of VAP1 compared to MS patients without CMBs (n=113). Only in MS with CMBs, ADAMSTS13-VAP1 levels were correlated (r=0.67, p=0.020). In MS with CMBs and in HI, levels of PAI1-sVCAM1 were correlated (r=0.73, p=0.009 and r=0.33, p=0.031). Conclusions: With the limitation of the low number of patients with CMBs, our findings suggest an intriguing molecular relationship between adhesion molecules and hemostasis inhibitors in development of CMBs in MS. The reactive oxygen species produced by VAP-1, an inflammatory adhesion molecule endowed with enzymatic properties, could interfere with ADAMTS13/von Willebrand factor function, a hypothesis that deserves further investigation.

Published
2020

8. Brain atrophy and lesion burden are associated with disability progression in a multiple sclerosis real-world dataset using only T2-FLAIR: the NeuroSTREAM MSBase study

Author

Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), Barnett, M.; Bergsland, N.; Weinstock Guttman, B.; Butzkueven, H.; Kalıncık, T.; Desmond, P.; Gaillard, F.; van Pesch, V.; Özakbaş, S.; Rojas, JI.; Boz, C.; Wang, C.; Dwyer, MG.; Yang, S.; Jakimovski, D.; Kyle, K.; Ramasamy, DP.; Zivadinov, R., Altıntaş, Ayşe (ORCID 0000-0002-8524-5087 & YÖK ID 11611), and Barnett, M.; Bergsland, N.; Weinstock Guttman, B.; Butzkueven, H.; Kalıncık, T.; Desmond, P.; Gaillard, F.; van Pesch, V.; Özakbaş, S.; Rojas, JI.; Boz, C.; Wang, C.; Dwyer, MG.; Yang, S.; Jakimovski, D.; Kyle, K.; Ramasamy, DP.; Zivadinov, R.

Abstract

Background: methodological challenges limit the use of brain atrophy and lesion burden measures in the followup of multiple sclerosis (MS) patients on clinical routine datasets. Objective: to determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. Methods: a total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. Results: longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). Conclusions: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.

Published
2021

9. Brain atrophy and lesion burden are associated with disability progression in a multiple sclerosis real-world dataset using only T2-FLAIR: The NeuroSTREAM MSBase study

Author

Barnett, M, Bergsland, N, Weinstock-Guttman, B, Butzkueven, H, Kalincik, T, Desmond, P, Gaillard, F, van Pesch, V, Ozakbas, S, Ignacio Rojas, J, Boz, C, Altintas, A, Wang, C, Dwyer, MG, Yang, S, Jakimovski, D, Kyle, K, Ramasamy, DP, Zivadinov, R, Barnett, M, Bergsland, N, Weinstock-Guttman, B, Butzkueven, H, Kalincik, T, Desmond, P, Gaillard, F, van Pesch, V, Ozakbas, S, Ignacio Rojas, J, Boz, C, Altintas, A, Wang, C, Dwyer, MG, Yang, S, Jakimovski, D, Kyle, K, Ramasamy, DP, and Zivadinov, R

Abstract

BACKGROUND: Methodological challenges limit the use of brain atrophy and lesion burden measures in the follow-up of multiple sclerosis (MS) patients on clinical routine datasets. OBJECTIVE: To determine the feasibility of T2-FLAIR-only measures of lateral ventricular volume (LVV) and salient central lesion volume (SCLV), as markers of disability progression (DP) in MS. METHODS: A total of 3,228 MS patients from 9 MSBase centers in 5 countries were enrolled. Of those, 2,875 (218 with clinically isolated syndrome, 2,231 with relapsing-remitting and 426 with progressive disease subtype) fulfilled inclusion and exclusion criteria. Patients were scanned on either 1.5 T or 3 T MRI scanners, and 5,750 brain scans were collected at index and on average after 42.3 months at post-index. Demographic and clinical data were collected from the MSBase registry. LVV and SCLV were measured on clinical routine T2-FLAIR images. RESULTS: Longitudinal LVV and SCLV analyses were successful in 96% of the scans. 57% of patients had scanner-related changes over the follow-up. After correcting for age, sex, disease duration, disability, disease-modifying therapy and LVV at index, and follow-up time, MS patients with DP (n = 671) had significantly greater absolute LVV change compared to stable (n = 1,501) or disability improved (DI, n = 248) MS patients (2.0 mL vs. 1.4 mL vs. 1.1 mL, respectively, ANCOVA p < 0.001, post-hoc pair-wise DP vs. Stable p = 0.003; and DP vs. DI, p = 0.002). Similar ANCOVA model was also significant for SCLV (p = 0.03). CONCLUSIONS: LVV-based atrophy and SCLV-based lesion outcomes are feasible on clinically acquired T2-FLAIR scans in a multicenter fashion and are associated with DP over mid-term.

Published
2021

10. Hemostasis biomarkers in multiple sclerosis

Author

Ziliotto, N, Bernardi, F, Jakimovski, D, Baroni, M, Marchetti, G, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Schweser, F, Zamboni, P, Ramanathan, M, Zivadinov, R, Ziliotto, N., Bernardi, F., Jakimovski, D., Baroni, M., Marchetti, G., Bergsland, N., Ramasamy, D. P., Weinstock-Guttman, B., Schweser, F., Zamboni, P., Ramanathan, M., Zivadinov, R., Ziliotto, N, Bernardi, F, Jakimovski, D, Baroni, M, Marchetti, G, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Schweser, F, Zamboni, P, Ramanathan, M, Zivadinov, R, Ziliotto, N., Bernardi, F., Jakimovski, D., Baroni, M., Marchetti, G., Bergsland, N., Ramasamy, D. P., Weinstock-Guttman, B., Schweser, F., Zamboni, P., Ramanathan, M., and Zivadinov, R.

Abstract

Background and purpose: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. Methods: In all, 138 MS patients [85 with relapsing–remitting MS (RR-MS) and 53 with progressive MS (P-MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age- and sex-matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI-1)] were evaluated by magnetic Luminex assays and enzyme-linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. Results: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI-1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P-MS subgroup compared to RR-MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. Conclusions: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI-1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected.

Published
2018

11. Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis

Author

Ziliotto, N, Zivadinov, R, Baroni, M, Marchetti, G, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Straudi, S, Manfredini, F, Ramanathan, M, Bernardi, F, Ziliotto, Nicole, Zivadinov, Robert, Baroni, Marcello, Marchetti, Giovanna, Jakimovski, Dejan, Bergsland, Niels, Ramasamy, Deepa P, Weinstock-Guttman, Bianca, Straudi, Sofia, Manfredini, Fabio, Ramanathan, Murali, Bernardi, Francesco, Ziliotto, N, Zivadinov, R, Baroni, M, Marchetti, G, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Straudi, S, Manfredini, F, Ramanathan, M, Bernardi, F, Ziliotto, Nicole, Zivadinov, Robert, Baroni, Marcello, Marchetti, Giovanna, Jakimovski, Dejan, Bergsland, Niels, Ramasamy, Deepa P, Weinstock-Guttman, Bianca, Straudi, Sofia, Manfredini, Fabio, Ramanathan, Murali, and Bernardi, Francesco

Abstract

Background and purpose The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. Methods In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme-linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI-1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. Results There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC-HCII, PC-FXII and sEPCR-sTM values were detectable in MS patients, whilst PC-PS and PS-PAI-1 correlations were present in healthy individuals only. Conclusions Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS.

Published
2020

13. Coagulation pathways in neurological diseases: Multiple sclerosis

Author

Ziliotto, N, Bernardi, F, Jakimovski, D, Zivadinov, R, Ziliotto, Nicole, Bernardi, Francesco, Jakimovski, Dejan, Zivadinov, Robert, Ziliotto, N, Bernardi, F, Jakimovski, D, Zivadinov, R, Ziliotto, Nicole, Bernardi, Francesco, Jakimovski, Dejan, and Zivadinov, Robert

Abstract

Significant progress has been made in understanding the complex interactions between the coagulation system and inflammation and autoimmunity. Increased blood-brain-barrier (BBB) permeability, a key event in the pathophysiology of multiple sclerosis (MS), leads to the irruption into the central nervous system of blood components that include virtually all coagulation/hemostasis factors. Besides their cytotoxic deposition and role as a possible trigger of the coagulation cascade, hemostasis components cause inflammatory response and immune activation, sustaining neurodegenerative events in MS. Early studies showing the contribution of altered hemostasis in the complex pathophysiology of MS have been strengthened by recent studies using methodologies that permitted deeper investigation. Fibrin(ogen), an abundant protein in plasma, has been identified as a key contributor to neuroinflammation. Perturbed fibrinolysis was found to be a hallmark of progressive MS with abundant cortical fibrin(ogen) deposition. The immune-modulatory function of the intrinsic coagulation pathway still remains to be elucidated in MS. New molecular details in key hemostasis components participating in MS pathophysiology, and particularly involved in inflammatory and immune responses, could favor the development of novel therapeutic targets to ameliorate the evolution of MS. This review article introduces essential information on coagulation factors, inhibitors, and the fibrinolytic pathway, and highlights key aspects of their involvement in the immune system and inflammatory response. It discusses how hemostasis components are (dys)regulated in MS, and summarizes histopathological post-mortem human brain evidence, as well as cerebrospinal fluid, plasma, and serum studies of hemostasis and fibrinolytic pathways in MS. Studies of disease-modifying treatments as potential modifiers of coagulation factor levels, and case reports of autoimmunity affecting hemostasis in MS are also discussed.

Published
2019

14. Plasma levels of soluble NCAM in multiple sclerosis

Author

Ziliotto, N, Zivadinov, R, Jakimovski, D, Baroni, M, Tisato, V, Secchiero, P, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Bernardi, F, Ramanathan, M, Marchetti, G, Ziliotto, Nicole, Zivadinov, Robert, Jakimovski, Dejan, Baroni, Marcello, Tisato, Veronica, Secchiero, Paola, Bergsland, Niels, Ramasamy, Deepa P., Weinstock-Guttman, Bianca, Bernardi, Francesco, Ramanathan, Murali, Marchetti, Giovanna, Ziliotto, N, Zivadinov, R, Jakimovski, D, Baroni, M, Tisato, V, Secchiero, P, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Bernardi, F, Ramanathan, M, Marchetti, G, Ziliotto, Nicole, Zivadinov, Robert, Jakimovski, Dejan, Baroni, Marcello, Tisato, Veronica, Secchiero, Paola, Bergsland, Niels, Ramasamy, Deepa P., Weinstock-Guttman, Bianca, Bernardi, Francesco, Ramanathan, Murali, and Marchetti, Giovanna

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.

Published
2019

15. Are Plasma Levels of Vascular Adhesion Protein-1 Associated Both with Cerebral Microbleeds in Multiple Sclerosis and Intracerebral Haemorrhages in Stroke?

Author

Ziliotto, N, Zivadinov, R, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F, Ziliotto, Nicole, Zivadinov, Robert, Jakimovski, Dejan, Bergsland, Niels, Ramasamy, Deepa P, Weinstock-Guttman, Bianca, Ramanathan, Murali, Marchetti, Giovanna, Bernardi, Francesco, Ziliotto, N, Zivadinov, R, Jakimovski, D, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Ramanathan, M, Marchetti, G, Bernardi, F, Ziliotto, Nicole, Zivadinov, Robert, Jakimovski, Dejan, Bergsland, Niels, Ramasamy, Deepa P, Weinstock-Guttman, Bianca, Ramanathan, Murali, Marchetti, Giovanna, and Bernardi, Francesco

Published
2019

19. Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow‐up

Author

Murali, N., primary, Browne, R. W., additional, Fellows Maxwell, K., additional, Bodziak, M. L., additional, Jakimovski, D., additional, Hagemeier, J., additional, Bergsland, N., additional, Weinstock‐Guttman, B., additional, Zivadinov, R., additional, and Ramanathan, M., additional

Published
2019
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20. Brain Atrophy Is Associated with Disability Progression in Patients with MS followed in a Clinical Routine

Author

Ghione, E., primary, Bergsland, N., additional, Dwyer, M.G., additional, Hagemeier, J., additional, Jakimovski, D., additional, Paunkoski, I., additional, Ramasamy, D.P., additional, Silva, D., additional, Carl, E., additional, Hojnacki, D., additional, Kolb, C., additional, Weinstock-Guttman, B., additional, and Zivadinov, R., additional

Published
2018
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21. Increased CCL18 plasma levels are associated with neurodegenerative MRI outcomes in multiple sclerosis patients

Author

Ziliotto, N, Bernardi, F, Jakimovski, D, Baroni, M, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Zamboni, P, Marchetti, G, Zivadinov, R, Ramanathan, M, Ziliotto, Nicole, Bernardi, Francesco, Jakimovski, Dejan, Baroni, Marcello, Bergsland, Niels, Ramasamy, Deepa P., Weinstock-Guttman, Bianca, Zamboni, Paolo, Marchetti, Giovanna, Zivadinov, Robert, Ramanathan, Murali, Ziliotto, N, Bernardi, F, Jakimovski, D, Baroni, M, Bergsland, N, Ramasamy, D, Weinstock-Guttman, B, Zamboni, P, Marchetti, G, Zivadinov, R, Ramanathan, M, Ziliotto, Nicole, Bernardi, Francesco, Jakimovski, Dejan, Baroni, Marcello, Bergsland, Niels, Ramasamy, Deepa P., Weinstock-Guttman, Bianca, Zamboni, Paolo, Marchetti, Giovanna, Zivadinov, Robert, and Ramanathan, Murali

Abstract

Background: Chemokine ligands and co-stimulatory factors are involved in macrophage activation and differentiation processes that could contribute to multiple sclerosis (MS) pathogenesis. Objective: To investigate associations of C-C motif Ligand 18 (CCL18), C-C motif ligand 5 (CCL5) and soluble Cluster of Differentiation 86 (sCD86) with clinical and MRI measures in MS patients. Methods: Plasma levels of CCL18, CCL5 and sCD86 were evaluated in 138 MS patients (85 relapsing-remitting, RR-MS; 53 progressive, P-MS), and in 42 age- and sex-matched healthy individuals (HI). All subjects underwent standardized 3T MRI and clinical examinations. Multiple regression analysis of MRI outcomes as dependent variables was performed with age, gender, having P-MS, and plasma proteins as predictor variables. Results: Higher CCL18 plasma levels were found in P-MS (median = 51.5, IQR = 41.0–63.6 ng/mL) compared to RR-MS (median = 43.0, IQR = 29.1–55.0 ng/mL, p = 0.014) and to HI (median = 41.3, IQR = 30.9–54.1 ng/mL, p = 0.009). Disease-modifying treatments altered CCL5 (p = 0.036) and sCD86 (p < 0.001) levels. Higher CCL18 levels were associated with increased lateral ventricular volume (p = 0.006) and T2 lesion volume (LV) (p = 0.034), and decreased grey matter (p = 0.006), thalamic (p = 0.007) and cortical (p = 0.01) volumes. Conclusions: Our results provide evidence that higher CCL18 plasma levels are associated with more severe inflammatory and neurodegenerative brain MRI outcomes in MS.

Published
2018

22. Plasma levels of hemostasis inhibitors and MRI outcomes in multiple sclerosis (P3.368)

Author

Ziliotto, N, Bernardi, F, Jakimovski, D, Baroni, M, Marchetti, G, Bergsland, N, Weinstock-Guttman, B, Zamboni, P, Ramanathan, M, Zivadinov, R, Ziliotto Nicole, Bernardi Francesco, Jakimovski Dejan, Baroni Marcello, Marchetti Giovanna, Bergsland Niels, Weinstock-Guttman Bianca, Zamboni Paolo, Ramanathan Murali, Zivadinov Robert, Ziliotto, N, Bernardi, F, Jakimovski, D, Baroni, M, Marchetti, G, Bergsland, N, Weinstock-Guttman, B, Zamboni, P, Ramanathan, M, Zivadinov, R, Ziliotto Nicole, Bernardi Francesco, Jakimovski Dejan, Baroni Marcello, Marchetti Giovanna, Bergsland Niels, Weinstock-Guttman Bianca, Zamboni Paolo, Ramanathan Murali, and Zivadinov Robert

Abstract

Objective: To investigate the association between plasma levels of hemostasis inhibitors and MRI outcomes in multiple sclerosis (MS).Background: The role of hemostasis inhibitors in MS is not well understood. Several studies suggest the crosstalk between inflammation, immunity and coagulation in the MS pathogenesis. Improved knowledge of the role of hemostasis inhibitors could lead to better understanding of the anticoagulation/anti-inflammatory pathways in MS.Design/Methods: 3T MRI exams and plasma levels of hemostasis inhibitors levels were evaluated in 138 MS patients (mean age, 54 years; 72.5% female; median EDSS 3.5; average mean disease duration 21 years) and 42 age- and sex-matched healthy individuals (HI), collected in the Cardiovascular, Genetic and Environmental (CEG) study in MS. In particular, disintegrin-like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13), heparin cofactor II (HCII), tissue factor pathway inhibitor (TFPI) and thrombomodulin (TM) plasma profiles were evaluated by magnetic Luminex assays and ELISA. Associations between hemostasis inhibitors and MRI outcomes were assessed. Results: Lower ADAMTS13 levels were found in MS patients compared to HI (1548±481 ng/mL vs 1733±562 ng/mL, p=0.038), and in MS with cerebral microbleeds compared to those without (1257±459 ng/mL vs 1566±479 ng/mL, p=0.028). In HI, decreased HCII levels were associated with larger cortical (p=0.003), brain parenchyma (p=0.005) and thalamus (p=0.013) volumes, and lower lateral ventricular volume (p=0.043) and T2 (p=0.045) lesion volumes (p=0.048).Conclusions: Normal levels of HCII, TM and TFPI, and decreased ADAMTS13 levels, particularly in patients with cerebral microbleeds are observed in MS patients. Data suggest a protective role of HCII on MRI outcomes in HI, not evident in MS patients. Further studies are needed to clarify the association of hemostasis inhibitors with the tissue injury in the CNS.

Published
2018

23. CCL18 plasma levels are increased in progressive MS patients and associated with MRI outcomes of tissue injury (P1.396)

Author

Ziliotto, N, Marchetti, G, Jakimovski, D, Baroni, M, Bergsland, N, Weinstock-Guttman, B, Zamboni, P, Bernardi, F, Ramanathan, M, Zivadinov, R, Ziliotto Nicole, Marchetti Giovanna, Jakimovski Dejan, Baroni Marcello, Bergsland Niels, Weinstock-Guttman Bianca, Zamboni Paolo, Bernardi Francesco, Ramanathan Murali, Zivadinov Robert, Ziliotto, N, Marchetti, G, Jakimovski, D, Baroni, M, Bergsland, N, Weinstock-Guttman, B, Zamboni, P, Bernardi, F, Ramanathan, M, Zivadinov, R, Ziliotto Nicole, Marchetti Giovanna, Jakimovski Dejan, Baroni Marcello, Bergsland Niels, Weinstock-Guttman Bianca, Zamboni Paolo, Bernardi Francesco, Ramanathan Murali, and Zivadinov Robert

Abstract

Objective: To investigate correlations of C-C motif ligand 18 (CCL18) levels with clinical and MRI measures in multiple sclerosis (MS) patients.Background: CCL18 is a cytokine that may play a role in both humoral and cell-mediated immunity responses. Very limited information are available in relation to MS. CCL18 has been found highly expressed by foamy macrophages inside MS lesions together with other markers involved in anti-inflammatory processes.Design/Methods: CCL18 plasma levels were evaluated in 138 MS patients (85 relapsing-remitting-RRMS, 53 progressive-PMS) and in 42 age- and sex-matched healthy controls (HC) enrolled in the Cardiovascular, Genetic and Environmental (CEG) study in MS. Association of CCL18 levels with MRI outcomes of disease severity was performed. Partial correlation corrected for age and Mann–Whitney test were used, as appropriate.Results: Higher CCL18 plasma levels were found in PMS compared to RRMS (54.0±20.2 vs 48.1±29.8 ng/mL, p=0.014) and to HC (54.0±20.2 vs 43.5±19.3 ng/mL, p=0.01). Higher CCL18 levels in PMS, were associated with increased T2 lesion volume (LV) (p=0.006), T1-LV (p=0.001), lateral ventricular volume (p=0.032), and decreased grey matter (p=0.012) and cortical (p=0.03) volumes. No associations between CCL18 and lesion and brain volume outcomes were detected in RRMS patients.Conclusions: The study provides in-vivo evidence that CCL18 plasma levels are associated with more severe inflammatory and neurodegenerative MRI outcomes in progressive MS patients.

Published
2018

24. Plasma levels of protein C pathway proteins and brain magnetic resonance imaging volumes in multiple sclerosis.

Author

Ziliotto, N., Zivadinov, R., Baroni, M., Marchetti, G., Jakimovski, D., Bergsland, N., Ramasamy, D. P., Weinstock‐Guttman, B., Straudi, S., Manfredini, F., Ramanathan, M., and Bernardi, F.

Subjects
PROTEIN C, BLOOD proteins, MAGNETIC resonance imaging, MULTIPLE sclerosis, BRAIN proteins
Abstract

Background and purpose: The involvement of protein C (PC) pathway components in multiple sclerosis (MS) has scarcely been explored. The aim was to investigate their levels in relation to clinical and neurodegenerative magnetic resonance imaging (MRI) outcomes in patients. Methods: In all, 138 MS patients and 42 healthy individuals were studied. PC, protein S (PS) and soluble endothelial protein C receptor (sEPCR) were evaluated by multiplex assays and enzyme‐linked immunosorbent assay. Regression analyses between 3 T MRI outcomes and PC pathway components were performed. ancova was used to compare MRI volumes based on protein level quartiles. Partial correlation was assessed amongst levels of PC pathway components and hemostasis protein levels, including soluble thrombomodulin (sTM), heparin cofactor II (HCII), plasminogen activator inhibitor 1 (PAI‐1) and factor XII (FXII). The variation of PC concentration across four time points was evaluated in 32 additional MS patients. Results: There was an association between PC concentration, mainly reflecting the zymogen PC, and MRI measures for volumes of total gray matter (GM) (P = 0.003), thalamus (P = 0.007), cortex (P = 0.008), deep GM (P = 0.009) and whole brain (P = 0.026). Patients in the highest PC level quartile were characterized by the lowest GM volumes. Correlations of PC–HCII, PC–FXII and sEPCR–sTM values were detectable in MS patients, whilst PC–PS and PS–PAI‐1 correlations were present in healthy individuals only. Conclusions: Protein C plasma concentrations might be associated with neurodegenerative MRI outcomes in MS. Several differences in correlation amongst protein plasma levels suggest dysregulation of PC pathway components in MS patients. The stability of PC concentration over time supports a PC investigation in relation to GM atrophy in MS. [ABSTRACT FROM AUTHOR]

Published
2020
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28. Hemostasis biomarkers in multiple sclerosis

Author

Ziliotto, N., primary, Bernardi, F., additional, Jakimovski, D., additional, Baroni, M., additional, Marchetti, G., additional, Bergsland, N., additional, Ramasamy, D. P., additional, Weinstock‐Guttman, B., additional, Schweser, F., additional, Zamboni, P., additional, Ramanathan, M., additional, and Zivadinov, R., additional

Published
2018
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30. Impact of endothelial tight junction alterations on cavernous malformation bleeding propensity

Author

Jakimovski, D, Schneider, H, Frei, K, Kennes, LN, and Bertalanffy, H

Subjects
bleeding propensity, ddc: 610, tight junction, 610 Medical sciences, Medicine, cavernous malformation
Abstract

Objective: Endothelial tight junction (TJ) expression in cerebral cavernous malformations (CCM) is mostly absent, which causes increased perilesional erythrocyte and fluid oozing. However, in a subset of CCM lesions, foci of preserved TJ staining are observed along endothelial cell contacts. We evaluated[for full text, please go to the a.m. URL], 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Published
2014
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31. Long-term follow-up of Gamma knife treatment in acromegaly: endocrinological results and adverse effects

Author

Jakimovski, D, Clusmann, HR, and Huffmann, BC

Subjects
ddc: 610, gamma knife, follow-up, acromegaly, 610 Medical sciences, Medicine
Abstract

Objective: Primary treatment to achieve the important cure of acromegaly is surgery and medical therapy. An adjunct option for unresponsive cases is Gamma knife radiosurgery. Our aim was to evaluate its results and adverse effects during a long-term follow-up. Method: All patients treated for acromegaly[for full text, please go to the a.m. URL], 65. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC)

Published
2014
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33. Hemostasis biomarkers in multiple sclerosis.

Author

Bernardi, F., Baroni, M., Ziliotto, N., Jakimovski, D., Bergsland, N., Ramasamy, D. P., Schweser, F., Zivadinov, R., Marchetti, G., Weinstock‐Guttman, B., Zamboni, P., and Ramanathan, M.

Subjects
HEMOSTASIS, BIOLOGICAL tags, MULTIPLE sclerosis, MAGNETIC resonance imaging, BLOOD coagulation factors, THROMBOSPONDIN-1, PLASMINOGEN activator inhibitors
Abstract

Background and purpose: The aim was to investigate the plasma levels of hemostasis components in multiple sclerosis (MS) and their association with clinical and magnetic resonance imaging (MRI) outcomes. Methods: In all, 138 MS patients [85 with relapsing–remitting MS (RR‐MS) and 53 with progressive MS (P‐MS) with a mean age of 54 years; 72.5% female; median Expanded Disability Status Scale 3.5; mean disease duration 21 years] and 42 age‐ and sex‐matched healthy individuals (HI) were studied. All subjects were examined with 3 T MRI and clinical examinations. Plasma levels of hemostasis factors [procoagulant, factor XII (FXII)] and inhibitors [tissue factor pathway inhibitor (TFPI), thrombomodulin, heparin cofactor II, a disintegrin‐like and metalloprotease with thrombospondin type 1 motif 13 (ADAMTS13) and plasminogen activator inhibitor 1 (PAI‐1)] were evaluated by magnetic Luminex assays and enzyme‐linked immunosorbent assay. Associations between hemostasis plasma levels and clinical and MRI outcomes were assessed. Results: Lower ADAMTS13 levels were found in MS patients compared to HI (P = 0.008) and in MS patients presenting with cerebral microbleeds compared to those without (P = 0.034). Higher PAI‐1 levels were found in MS patients compared to HI (P = 0.02). TFPI levels were higher in the P‐MS subgroup compared to RR‐MS patients (P = 0.011) and compared to HI (P = 0.002). No significant associations between hemostasis plasma levels and clinical or MRI outcomes were found. Conclusions: Decreased ADAMTS13, particularly in MS patients with cerebral microbleeds, which deserves further investigation, and increased PAI‐1 and TFPI levels were observed in MS patients, which deserves further investigation. No relationship between hemostasis plasma levels and measures of disease severity was detected. [ABSTRACT FROM AUTHOR]

Published
2018
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41. Polarization of Balmer alpha radiation resulting from H++H collisions in Debye plasmas.

Author

Jakimovski, D. and Janev, R. K.

Subjects
*POLARIZATION (Electricity), *BALMER series, *COLLISIONS (Nuclear physics), *PLASMA gases, *DEBYE-Huckel theory
Abstract

The linear polarization degree of Balmer alpha radiation resulting from H+ + H(1s) collisions in a hot, dense weakly coupled plasma is studied in the energy range 1-140 keV=u by adopting the Debye-H€uckel potential to represent the screened interaction between charged plasma particles. Due to the energy splitting of nl hydrogen states in the short range Debye-Huckel potential, the Balmer alpha radiation contains three components corresponding to 3s-2p, 3p-2s, and 3d-2p transitions, of which only the last two can be linearly polarized. For calculation of 3lm excitation and electron capture cross sections, the two-center expansion atomic orbital close coupling method is used for a number of Debye screening lengths. The effects of plasma screening on the 3lm cross sections are manifested in significant changes of their magnitudes and energy behavior with respect to the ones in the unscreened case, producing significant changes in the polarization degree of Balmer 3p-2s and 3d-2p lines. [ABSTRACT FROM AUTHOR]

Published
2015
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43. The capture of slow antiprotons by noble gas atoms.

Author

Briggs, J. S., Jakimovski, D., and Solov'ev, E. A.

Subjects
*ANTIPROTONS, *GASES, *ATOMS, *KRYPTON, *XENON, *COLLISIONS (Nuclear physics)
Abstract

The capture of slow antiprotons (impact energies less than 1.0 au) by the noble gases krypton and xenon is studied following the paper of Briggs at al, where the transient collision complex is treated as a diatomic molecule with the positively-charged atomic ion and antiproton as ‘nuclei’. Estimates of the population of long-lived ‘circular’ states suggest that the probability of capture of antiprotons into such states is negligible. The capture cross sections for Kr and Xe are two orders of magnitude smaller than for He in agreement with experimental data. © 2005 American Institute of Physics [ABSTRACT FROM AUTHOR]

Published
2005
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47. Electron capture and excitation in H⁺-He (1s2s; ¹,³S) collisions.

Author

Liu, L., Jakimovski, D., Wang, J. G., and Janev, R. K.

Subjects
*ELECTRON capture, *NUCLEAR excitation, *HYDROGEN, *HELIUM, *ATOMS, *ATOMIC orbitals, *NUCLEAR cross sections
Abstract

The electron capture and excitation processes in collisions of H⁺ with excited He.(1s2s; ¹,³S) atoms are investigated theoretically by using the two-centre atomic orbital close-coupling method in the energy range 2.200 keV u-1. The interaction of active electrons with the target ion is represented by a model potential different for the singlet and triplet systems of He states. In the electron capture studies, the basis included all the He (1s, n ≤ 6) discrete states and all the H (n ≤ 7) states plus 202 pseudostates, while for the excitation studies all the He (1s, n ≤ 8) states plus 244 pseudostates and all the H (n ≤ 5) discrete states were included in the basis. The excitation cross section results of the present calculations are compared with other theoretical results and good agreement is obtained at high collision energies. For energies below 6 keV u-1, the present excitation and electron capture results are compared with those from the recent quantal molecular orbital close-coupling calculations showing good agreement for the dominant channels. It is found that the cross sections for excitation and state-selective electron capture are significantly different for the singlet and triplet states, particularly in the low-energy region. [ABSTRACT FROM AUTHOR]

Published
2012
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49. Cholesterol and neurodegeneration: longitudinal changes in serum cholesterol biomarkers are associated with new lesions and gray matter atrophy in multiple sclerosis over 5 years of follow‐up.

Author

Murali, N., Browne, R. W., Fellows Maxwell, K., Bodziak, M. L., Jakimovski, D., Hagemeier, J., Bergsland, N., Weinstock‐Guttman, B., Zivadinov, R., and Ramanathan, M.

Subjects
BLOOD cholesterol, CHOLESTEROL, MULTIPLE sclerosis, LIPOPROTEIN lipase, SINGLE nucleotide polymorphisms, APOLIPOPROTEIN E4
Abstract

Background and purpose: Cholesterol is an important structural component of myelin and essential for brain homeostasis. Our objective was to investigate whether longitudinal changes in cholesterol biomarkers are associated with neurodegeneration in multiple sclerosis (MS). Methods: This prospective, longitudinal study (n = 154) included 41 healthy controls, 76 relapsing–remitting MS subjects and 37 progressive MS subjects. Neurological examination, brain magnetic resonance imaging and blood samples were obtained at baseline and at 5‐year follow‐up visits. Cholesterol biomarkers measured included plasma total cholesterol, high‐density lipoprotein cholesterol (HDL‐C), low‐density lipoprotein cholesterol and the apolipoproteins ApoA‐I, Apo‐II, ApoB, ApoC‐II and ApoE. Key cholesterol pathway single nucleotide polymorphisms were genotyped. Results: Greater percentage increases in HDL‐C and ApoA‐I levels were associated with a lower rate of gray matter and cortical volume loss. Greater percentage increases in low‐density lipoprotein cholesterol were associated with increases in new T2 lesions. The percentage increases in HDL‐C (P = 0.032) and ApoA‐I (P = 0.007) were smaller in patients with relapsing–remitting MS at baseline who converted to secondary progressive MS during the 5‐year follow‐up period. Changes in HDL‐C and ApoA‐I were associated with lipoprotein lipase rs328 genotype status. Conclusions: Increases in HDL‐C and ApoA‐I have protective associations with magnetic resonance imaging measures of neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Published
2020
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50. Hypertension and heart disease are associated with development of brain atrophy in multiple sclerosis: a 5‐year longitudinal study.

Author

Jakimovski, D., Gandhi, S., Paunkoski, I., Bergsland, N., Hagemeier, J., Ramasamy, D. P., Hojnacki, D., Kolb, C., Benedict, R. H. B., Weinstock‐Guttman, B., and Zivadinov, R.

Subjects
*CARDIOVASCULAR diseases, *HYPERTENSION, *MULTIPLE sclerosis, *CEREBRAL atrophy, *ELECTRONIC health records
Abstract

Background: Cardiovascular diseases (CVDs) are more frequent in multiple sclerosis (MS) patients when compared to controls. In particular, CVDs are linked with higher accumulation of lesions and advanced brain atrophy. Objective: To investigate whether CVDs contribute to accelerated lesion accumulation and brain atrophy over 5 years in patients with MS. Methods: 194 MS patients and 43 controls without neurologic disease were followed for 5 years. Full physical, neurological evaluation, and structured questionnaire investigating CVD and risk factors (hypertension, hyperlipidemia, heart disease, smoking, diabetes, obesity/overweight) were collected using interview‐based questionnaire and further cross‐reference with electronic medical records. Lesion and brain atrophy outcomes were assessed with 3T MRI. ANCOVA adjusted for age, gender, and disease duration were used accordingly. False discovery rate correction was performed using Benjamini‐Hochberg correction. Results: Patients with diagnosis of heart disease showed higher white matter and whole brain volume loss compared to those without (−4.2% vs. −0.7%, P = 0.01 and −3.4% vs. −1.6%, P = 0.01, respectively). The percentage lateral ventricle volume change in MS patients with hypertension was higher compared to non‐hypertensive patients (24.5% vs. 14.1%, P = 0.05). Hyperlipidemia, smoking, and obesity/overweight were not associated with progression of MRI‐derived outcomes. CVDs did not contribute to larger lesion volume accrual over the 5‐year period. The presence of CVDs was not associated with MRI‐derived changes in the controls. Conclusions: Hypertension and heart disease contribute to advanced brain atrophy in MS patients. CVDs did not contribute to additional lesion accrual. CVD comorbidities in MS patients may contribute to neurodegenerative tissue injury that can be detected with brain MRI. [ABSTRACT FROM AUTHOR]

Published
2019
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