Role of Microglial Activation and Norepinephrine Transporter Abnormalities in Pathogenesis of MS-Related Fatigue
Abstract
This project addresses the FY18 MSRP Exploration - Hypothesis Development Award Focus Area biology and measurement of MS symptoms. Fatigue is the most disabling symptom in a majority of MS patients and may be present in up to 80% of patients over their lifetime. The biological mechanism of fatigue in MS patients is not clear. This proposal aims to utilize novel imaging techniques to assess the role of the brains intrinsic inflammation and neurochemical alterations as a potential cause of fatigue in MS patients. Our project involves the use of an imaging technique called Positron Emission Tomography (PET). This technique uses a small amount of a radioactive dye that binds to its targets and yields information about location and severity of abnormalities in the brain with the help of a PET scanner. Rationale/Objective: There are abnormally active immune cells in the brain in patients with multiple sclerosis. Microglia are a type of immune cell that live in the brain and become abnormally activated in MS. These cells are resident immune cells of the brain. This means that these cells live in the brain, do not have to come from outside during a relapse (unlike other cells, like T cells), and may be persistently active in MS patients. These abnormally active microglia may be harmful for MS patients, but their role in the development of fatigue in MS is not known. [F-18]PBR06 PET is a novel imaging technique that studies these activated cells. Moreover, inflammation may be related to a chemical imbalance in the brains of MS patients. One of these chemicals is called norepinephrine. Norepinephrine may have a role in the expression of certain MS symptoms such as fatigue and modulate the intrinsic immune system in the brain. [C-11]MRB PET is a novel imaging technique that studies the technique. The overarching aim of this proposal is to study the brains resident immune cells and norepinephrine system and assess its relation with severity of fatigue in MS patients. We also aim to combine this information with additional data about lesions in the thinking parts of the brain (referred to as cortical grey matter) and with information about overall shrinkage of brain, using a high-strength 7-Tesla MRI scanner, which provides much greater anatomical information than the commonly used 3-Tesla or 1.5-Tesla MRI scanners. Potential Impact: We anticipate that this research can help MS patients who are suffering from fatigue. It can help establish the underlying mechanism for fatigue in MS patients, which may include both inflammatory and neurochemical mechanisms. This understanding could eventually impact individualizing treatment of fatigue in MS patients with anti-inflammatory and neurochemistry-oriented agents. A patient-related outcome may be achieved in 2-4 years. Diagnostically, this could include development of novel approaches to perform better imaging to track progression of biological changes related to MS symptoms and disease progression. Therapeutically, this could lead to a paradigm shift in patient selection for treatment of fatigue in MS symptoms as larger studies are conducted.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910836
Entities
People
- Tarun Singhal
Organizations
- Brigham and Women's Hospital
- United States Army