The development of biomarkers as a tool for improving the diagnosis and treatment of multiple sclerosis

  • Simona Palusci

Student thesis: Doctoral Thesis


Multiple Sclerosis (MS) is an immuno-mediated, demyelinating disease of the central nervous system. Due to the complex nature of MS, in conjunction with the lack of specificity of the diagnostic tests currently available, efforts have been directed towards the identification of MS biomarkers, but very few are currently used for clinical purposes. This thesis aimed to identify a subset of molecules that can be measured in blood and provide a simple and cost-effective tool for MS diagnosis.

A gene expression analysis was performed on blood-derived RNA from 10 relapsing-remitting MS (RRMS) patients and 10 controls (n=20). Five upregulated (IFI44L, DEFA4, RSAD2, IFI44, FTH1) and three downregulated genes (NOTCH1, ANPEP, SYTL2) were able to discriminate between RRMS and controls with high diagnostic accuracy (AUC = 0.976 and AUC = 0.967, respectively). Ingenuity pathway analysis (IPA) identified three pathways potentially linked to MS disease, namely the sphingosine1-phosphate (S1P), NOTCH1 and Amyloid β pathways. Among the genes involved in the S1P pathway, SPTSSA and DEGS1 were significantly upregulated while SMPD1, SMPD4, SGPL1, S1PR1, S1PR3, S1PR5 and AKT1 were significantly downregulated in RRMS (p < 0.005). NOTCH1, NOTCH2 and their downstream effectors MAML2 and DTX2 were also downregulated in RRMS (p < 0.005). Interestingly, the blood-specific APP770 was down-regulated in RRMS, while the brain-specific APP695 was upregulated, suggesting an efflux of CNS transcripts into the peripheral blood.

Immunohistochemistry analysis showed increased S1PR1, S1PR3 and NOTCH1 protein expression within the CNS in MS individuals compared to controls. Increased expression
of S1PR3 was also found in white matter (WM) lesions compared to normal appearing WM (NAWM) in PPMS patients, while higher expression of S1PR1 and NOTCH1 in WM lesions was found in SPMS but not in PPMS patients. The application of an in vitro model allowed to evaluate the expression of the sphingosine receptors and NOTCH proteins in inflammatory conditions and their involvement in the context of MS disease. The dysregulation of specific biomarkers in both blood and brain tissue suggests that blood biomarkers could represent a useful tool to detect changes happening within the CNS, reducing the need of cerebrospinal fluid (CSF) collection. The identification of MS biomarkers in blood could improve the patient’s experience during diagnosis other than facilitate an early detection of the disease. Besides, it could allow clinicians to apply treatment strategies more effectively. Following further analysis and investigation, in fact, the MS-related molecules identified in this study could be used to discriminate between MS and other inflammatory diseases and could potentially function as novel targets for drug development.
Date of Award2023
Original languageEnglish
SupervisorBarira Islam (Co-Supervisor) & Patrick McHugh (Co-Supervisor)

Cite this