Biomarker Signatures of Disease Progression in Multiple Sclerosis
Abstract
Multiple sclerosis (MS) is a chronic disease of the nervous system that affects approximately 2.8 million people worldwide. While most people with MS initially experience symptoms that wax and wane (i.e., relapsing-remitting MS), the majority enter the progressive phase after about 15 years. The progressive phase typically lasts decades and is associated with accumulation of irreversible disability, such as loss of mobility or memory impairment, that leads to a significant reduction in quality of life. The costs to the healthcare system and economy are staggering, totaling several billion dollars per year. It is known that long-standing inflammation in MS causes permanent damage to the brain and spinal cord. Nerve fibers in the spinal cord that control voluntary movements commonly die in progressive MS, which leads to irreversible loss of mobility and reduced quality of life. The fluid that bathes our brain and spinal cord, cerebrospinal fluid (CSF), has neurotoxic mediators that have been linked to nerve fiber loss. Given this, many researchers have interrogated the CSF of people with MS (pwMS) to determine the proteins that associate with worsening disability. However, the substantial biological variation between pwMS who might have similar levels of disability and the use of insensitive analysis methods have frustrated the ability to detect proteins that lead to nerve fiber demise in a reliable and reproducible way. As a result, we are unable to identify pwMS at greatest risk of this nerve fiber loss (and hence accumulation of permanent disability). Further, we do not have effective therapies that prevent nerve fiber loss. Our laboratory recently developed a novel approach that has started to fill these important knowledge gaps. To overcome the limitations of previous research, we profiled the proteins in the CSF derived from a post-mortem MS cohort for which we had detailed quantitative information about many pathological variables relevant to MS, including nerve fiber loss. In doing so, we were able to control for the biological variation that is often seen in studies of people living with MS to evaluate the specific proteins that associate with nerve fiber loss in the spinal cord. In addition, we had access to a novel and sensitive biocomputational analysis method to evaluate the link between CSF proteins and nerve fiber loss. Through these strategies, we identified nine proteins in the CSF that associate with nerve fiber loss, which we now aim to validate in the proposed research study. Our goals perfectly align with the Correlates of Disease Activity and Progression in Multiple Sclerosis Focus Area and will take advantage of both post-mortem and living cohorts of pwMS on whom a vast amount of robust and objective quantitative data have already been collected over many years. We will use these well-characterized cohorts for our work. First, we will evaluate how the CSF proteins that associate with nerve fiber loss are expressed in spinal cord tissue and confirm whether they relate to the amount of nerve fiber loss. For the protein markers that associate with nerve fiber loss, we will determine whether the levels of these proteins in the CSF obtained from spinal taps of people living with MS relate to measures of disability we can detect clinically and on magnetic resonance imaging (MRI) scans. Similarly, we plan to use our well-defined clinical and MRI measures of disability to see whether certain proteins in the CSF associate with worse outcomes. Given our access to post-mortem CSF and spinal cord tissue, we are uniquely positioned to determine whether the CSF proteins identified in our clinical cohort also associate with nerve fiber loss in our post-mortem cohort. This iterative approach will allow us to control for the biological factors that have limited previous research. In doing so, we believe this will increase the likelihood of identifying proteins in the CSF that associate with n
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110970
Entities
People
- Gabriele De Luca
Organizations
- United States Army
- University of Oxford