Examining the Link Between Hippocampal Pathology and Meningeal Inflammation in Progressive MS
Abstract
Focus Area: This fiscal year 2022 Multiple Sclerosis Research Program Investigator-Initiated Research Award project addresses the Focus Area Correlates of Disease Activity and Progression in Multiple Sclerosis. In this project we will use brain specimens acquired from the Netherlands Brain Bank to look for molecules and cells that are specifically associated with progressive MS (PMS) compared to relapsing-remitting MS (RRMS) and other non-MS conditions. We will focus our efforts on the compartment that ensheaths the brain -- the leptomeninges -- and assess how molecules and clusters of cells in the leptomeninges impacts the hippocampus. These tissues, along with a unique animal model that recapitulates aspects of PMS disease, will support our research activities. Proposal Rationale: Patients living with MS experience major cognitive disabilities including memory impairment. There is substantial evidence that the hippocampus, a specialized area of the temporal cortex, is critical for the consolidation and recollection of episodic memories, social memory, and the temporal organization of events. Studies on MS brain tissue collected at autopsy have shown that the PMS hippocampus can be profoundly damaged. Thus, hippocampal injury may explain some of the clinical deficits experienced by PMS patients including impaired memory and learning as well as depressive symptoms. The hippocampus is lined with meninges -- the envelope that ensheaths the brain. Hypothesis: The leptomeninges of progressive MS patients harbours an assortment of immune cells that contribute to hippocampal pathology in the progressive stage of MS. Proposal Objectives: To test this hypothesis, we will (1) provide a complete inventory of the amount and types of immune cells as well as their by-products in the area of the leptomeninges that is adjacent to the hippocampus; (2) use all of the pathology and clinical metadata that we have for each subject to determine if what we detect in the hippocampus is relevant to the overall disease state of the PMS patient; (3) use a new animal model that mimics the same kind of hippocampus pathology and shows evidence of a PMS disease course (See Zuo et al, JCI Insight 2022) to test the relevance of what we find in human patients to the overall disease process, i.e., ascertain causality. With these tissues (both human and mouse) we will apply an innovative technique that we have already validated in the MS brain (see Ramaglia et al, ELife, 2019) and has been recently used in the COVID-19 brain (see Schwabenland et al, Immunity 2021). This technique allows us to measure ~50 separate markers (proteins) on a single slice of brain tissue. Combined with other molecular approaches, our proposed project represents an unprecedented opportunity to gain a deeper understanding of how the hippocampus is injured in PMS and to use our animal model to test these findings and develop therapies. Applicability to MS Patient Care: The mechanisms that explain how the MS hippocampus is damaged are not fully understood. Because the hippocampus is involved in memory, understanding what goes wrong in this tissue could improve the lives of people living with MS. Risk versus Benefits: The drugs we have available to treat MS have largely failed to impact cognitive decline in PMS. Thus, a better understanding of PMS is urgently needed, and identifying drug targets that reduce the burden of PMS disease is an obvious benefit. The risk in this project is that we may fail to identify druggable targets that are specific to MS hippocampal injury in Aim 1. However, we have already identified some leading candidates based on both our recently published data (See Zuo et al, JCI Insight 2022) and additional preliminary data, that will be prioritized for further inquiry in the proposed project. Moreover, our animal model has the advantage of allowing us to monitor and measure the signs of disease progression over time, and also p
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310933
Entities
People
- Jennifer Gommerman
Organizations
- United States Army
- University of Toronto