Investigating Lesion-Specific Mechanisms Driving Retrograde Transsynaptic Degeneration of the Visual Axis in Multiple Sclerosis
Abstract
Background: Multiple sclerosis (MS) results in the accelerated death of nerve cells in the brain, retina, and spinal cord. The exact mechanisms and types of lesions that promote this significant cell death are poorly understood. This accelerated nerve cell death in turn contributes to the long-term disability experienced by MS patients, even those who do not have evidence of active inflammation in the brain, spinal cord, or visual pathway. Most treatments available to treat MS target the inflammatory components of the disease, but there are no current interventions available to help slow down the nerve cell death that occurs with this condition. Trans-synaptic degeneration refers to the spread of nerve cell death, from one nerve cell to adjacent cells, across the connections between these cells, which are called synapses. In MS, trans-synaptic degeneration of the retina occurs in response to some but, importantly, not all lesions that affect the visual pathways in the brain. We know very little about which types of lesions promote this process and how someone s predisposition to develop trans-synaptic degeneration is associated with visual loss, clinical disability, or accelerated nerve cell death in the other areas of the brain or spinal cord. Recently, several types of lesions have been shown to be more specific for MS pathology, such as those that form around small veins in the brain (called central vein sign lesions), while other lesion types have been shown to reflect chronic active inflammation and higher risk of disability accumulation (called paramagnetic rim lesions). The relationship between different lesion types and the occurrence of trans-synaptic degeneration has not been investigated previously in MS and can help shed light on the specific lesion types that are related to higher cumulative nerve cell loss. Objectives and rationale: This project will address the FY22 MSRP Focus Areas (1) Correlates of Disease Activity and Progression in MS, and (2) Biology and Measurement of MS Symptoms. We aim to use the visual pathway as a model to investigate innovative ways to quantify trans-synaptic degeneration in the retina, using a retinal imaging technique called optical coherence tomography. For our first aim, we will track the effect of two different MS lesion types (central vein sign positive and paramagnetic rim lesions) in the visual pathway in the brain and study how these lesions contribute to the spread of nerve cell degeneration to the retina. For our second aim, we will study how the process of trans-synaptic degeneration affects the visual symptoms experienced by MS patients, and how it relates to visual loss in specific parts of the visual field over time using a test called standard automated perimetry. For our third aim, we will use brain magnetic resonance imaging (MRI) scans and obtain regular disability assessments on study participants to examine whether the presence of trans-synaptic degeneration in the visual pathway can be used as a biomarker for widespread nerve cell loss in the brain and/or spinal cord, as well as the risk of patients experiencing progressively worsening disability over a 2-year follow-up period. These results will help validate the role of trans-synaptic degeneration in predicting long-term disability risks in MS. What types of patients could it potentially help and how? This project is expected to help all patients with MS, including both relapsing-remitting and progressive forms, by studying factors contributing to the chain death of nerve cells in the visual pathway. Additionally, this work will also help MS patients who experience visual symptoms by measuring visual symptom severity and the visual field findings that are specifically caused by trans-synaptic degeneration in the visual pathway of MS patients. What are the potential clinical applications, benefits, and risks? We anticipate that in the short term (within approximately 5 years of com
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310571
Entities
People
- Omar Al-louzi
Organizations
- Cedars-Sinai Medical Center
- United States Army