A Study of Potential Plasma Biomarkers of Disease Conversion and Progression in Multiple Sclerosis

• Author / Creator

  Cheng, Catherine F

• Multiple sclerosis (MS) is a complex and heterogeneous disease of the central nervous system (CNS) characterized by leukocyte infiltration, myelin damage, local gliosis, and axonal injury. Relapsing-remitting MS (RRMS) is the most common disease course. Although the pathogenesis remains unclear, it is believed that MS is initiated by a breakdown of immune tolerance to CNS antigens due to genetic and/or environmental factors. Clinically Isolated Syndrome (CIS) is a demyelinating event isolated in time that is compatible with the possible future development of MS. In patients with MS, comorbid psychiatric disorders, such as depressive disorders and anxiety disorders, are common. There has been increasing evidence of the role of neuroinflammation in both MS and neuropsychiatric conditions, suggesting that inflammatory changes may contribute to disease occurrence, interaction and progression. Currently no established plasma markers for MS exist. Limited diagnostic cerebrospinal fluid (CSF) markers have been identified, however they do not correlate with disease severity or prognosis.In this study, plasma levels of amino acids [glutamate, glutamine, aspartate, asparagine, glycine, arginine D-serine, L-serine, L-serine-O-phosphate (LSOP), alanine, and taurine] and neuroactive steroids (allopregnanolone, pregnanolone, pregnenolone, epiallopregnanolone, DHEA, and THDOC) were measured in controls (n=17), CIS (n=31) and RRMS (n=33) patient cohorts to identify trends with progression and severity of symptoms, and potential neuroinflammatory biomarkers of MS. Demographic and clinical variables including treatment with disease modifying therapies (DMTs) and corticosteroids, comorbidities, and changes in Expanded Disability Status Scale (EDSS), original Multiple Sclerosis Severity Scale (MSSS), updated MSSS, and Age-Related MSS (ARMSS) scores were determined via retrospective chart review to assess for correlates of change in disability scores. A three-step hierarchical regression was then conducted with change in disability score as the dependent variable.Plasma concentrations of the amino acids alanine, arginine and glutamine were significantly lower in the RRMS group compared to controls, while concentrations of LSOP and taurine were found to be significantly higher in the RRMS group compared to controls. Aspartate and taurine were also significantly higher in the RRMS group compared to the CIS group. Alanine and arginine concentrations were significantly lower in the CIS group compared to controls. Median plasma concentration of the neuroactive steroid allopregnanolone was significantly higher and the concentration of epiallopregnanolone was significantly lower in the RRMS group compared to the CIS group. Among clinical variables, the likelihood of depression was significantly greater in the RRMS group compared to controls. Initial EDSS scores were significantly higher in the RRMS group compared to the CIS group and both initial and final ARMSS scores were higher in the RRMS group compared to the CIS group. During the median study period of 1.85 years, 51.6% of CIS patients converted to RRMS.In terms of correlates of change in disability scores, an increase in EDSS scores across both groups was significantly and inversely correlated with plasma pregnanolone concentrations (r = -0.267; p = 0.041) and positively correlated with disease duration at final EDSS assessment (r = 0.310; p = 0.013). A three-step hierarchical regression to assess predictors of EDSS change scores found that step 1 (age, sex and disease duration) accounted for 14.3% of the variance, with disease duration at final EDSS assessment significantly associated with an increase in change score. Adding pregnanolone and THDOC to the model (step 2) further explained 11.0% of the variance. Plasma concentrations of THDOC were significantly positively associated with increases in EDSS, whereas pregnanolone concentrations were inversely associated but not significant.Based on these findings, some plasma amino acids and neuroactive steroids are promising as biomarkers of MS disease progression in the context of neuroinflammation and immunomodulation, and warrant further investigation. The identification of neuroinflammatory biomarkers in MS is fundamental to the diagnosis, prognostication and treatment of this debilitating condition.

• Subjects / Keywords

  • biomarkers
  • neuroactive steroids
  • amino acids
  • multiple sclerosis
  • glutamate
  • neuroinflammation

• Graduation date

  Fall 2020

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/r3-r0z0-wm41

• License

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