Circulating CNS Cell-Derived Extracellular Vesicle-Based Biomarkers to Identify Neurodegeneration and Glial Activation in Multiple Sclerosis
Abstract
Multiple sclerosis (MS) has both inflammatory and degenerative components. Besides the loss of nerve fibers (axons) and nerve insulation (myelin), the loss of connections between nerve cells (synapses) is extremely common in MS. Synaptic loss occurs in both the brain and spinal cord and is even noted in areas that do not demonstrate loss of myelin. The loss of connections between nerve cells could contribute to MS disease progression. Deposition of inflammatory proteins, called complement, on synapses can lead to their destruction by inflammatory cells. Complement may be produced by activated cells in the brain and spinal cord called astrocytes, or from other sources). Indeed, complement-producing astrocytes are toxic to nerve cells and are increased in several other degenerative conditions such as Alzheimer s disease. This proposal targets the MSRP IIRA focus area Correlates of Disease Activity and Progression in MS and proposes novel methods to monitor these processes. Particles called extracellular vesicles, derived from cells in the brain and spinal cord, can be detected and isolated from blood. We recently showed that levels of proteins related to synapses were markedly reduced in nerve cell-derived particles from people with MS compared to healthy people (controls). We also showed that levels of complement proteins in astrocyte-derived particles were higher in MS compared to controls. These findings mirror the pathological findings in MS brain tissue. Identifying markers of neurodegeneration would help track disease progression and aid in identifying treatments that may either halt or reverse this process. What are the goals of the study? The first goal of this study is to determine whether levels of synaptic proteins in circulating particles derived from nerve cells are good markers of nerve cell destruction in the brain and spinal cord. The second goal is to determine whether levels of inflammatory proteins in circulating particles derived from astrocytes are good markers of future disease progression. Finally, we also hope to determine whether there are differences in these markers over time between participants who were treated with ibudilast versus those on placebo in the SPRINT MS trial. How will the study be conducted? The SPRINT MS trial enrolled 255 participants with progressive MS and demonstrated that over 2 years ibudilast treatment reduced brain shrinkage by 48% compared to treatment with placebo. We will utilize blood samples (collected yearly) from this trial to isolate nerve cell-derived and astrocyte-derived particles. We will then measure levels of proteins related to synapses in the nerve cell-derived particles and inflammatory proteins (complement) in the astrocyte-derived particles. Using the clinical data (regarding the extent of neurological disability) and imaging (brain and eye scans) from SPRINT MS, we will determine whether the levels of synapse-related proteins in nerve cell-derived particles are related to both the clinical or imaging measures of MS disease severity and whether changes over time in these markers predict disease progression. This will allow us to determine whether synapse-related protein levels are good markers of neurodegeneration. We will also study whether the levels of complement protein levels in astrocyte-derived particles predict worsening of disease over time. Finally, we will evaluate whether ibudilast treatment led to a reduction in inflammatory protein levels compared to placebo. This will allow us to determine whether complement levels predict future neurodegeneration and could serve as outcomes for studies of other medications that might protect the brain and spinal cord or promote repair. What patient groups could this study potentially help? Though the SPRINT MS trial included only progressive MS participants, the phenomena being studied occur throughout the MS disease process. Hence, the results of this study will potentiall
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210846
Entities
People
- Pavan Bhargava
Organizations
- Johns Hopkins University
- United States Army