Author ORCID Identifier

https://orcid.org/0000-0001-9313-4347

Date of Award

Spring 2-13-2024

Document Type

Thesis (Ph.D.)

Department or Program

Integrative Neuroscience

First Advisor

Francesca Gilli

Abstract

Multiple sclerosis (MS) is a heterogeneous disease, differing on many variables, including disease course, sex, and overall activity. Key characteristics of the disease encompass demyelination, axonal damage, neuronal loss, glial cell activation, and the infiltration of peripheral immune cells. Molecular proxies of these functions are secreted proteins, including cytokines and immunoglobulins, which, in the central nervous system (CNS), can be secreted into the cerebrospinal fluid (CSF). A detailed analysis of these secreted proteins can offer insights into the evolving immunological and neurodegenerative features as the disease progresses. To understand the dynamic biological processes involved in MS, I used network analysis to untangle intricacies of protein-to-protein relationships.

To determine these complex relationships, I measured 60 proteins, in both CSF and serum, from 87 patients with MS. Forty-six (n=46) of these proteins were inflammatory mediators, while the remaining 14 were markers of neuroaxonal injury or glial activation. Markers were measured for their intrathecal synthesis in each individual patient. For each analysis patients were then categorized based on their 1) disease course, 2) sex, and 3) disease activity. Network analysis was ultimately performed to distinguish patterns of inflammation and neurodegeneration between each group.

I first found that network analysis of intrathecal proteins effectively distinguishes disease courses, revealing 1) a unique B-cell signaling pathway in patients with relapsing-remitting MS (RRMS), 2) a CNS immune cell-driven inflammatory pattern in progressive MS (PMS), and 3) a lack of inflammatory regulation in patients presenting with clinically isolated syndrome (CIS), potentially leading to conversion to RRMS. Next, I found distinct differences between sexes in RRMS. Networks in female patients were almost exclusively associated with inflammatory proteins, whereas networks in male patients showed robust connections to neuroaxonal injury and glial activation proteins. Finally, I found unique proteins relationships in those RRMS patients with higher likelihood to manifest disease activity within the following 12 months. Particularly, the correlation between CXCL10 and IgG1 successfully predicted disease activity as well as conversion from CIS to RRMS.

In conclusion, my findings here suggest that network analysis of intrathecally synthesized proteins was able to distinguish novel molecular pathways between disease course, sex, and disease activity in MS.

Original Citation

Chapter 3, https://doi.org/10.1212/NXI.0000000000200200

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