In Vivo Imaging of Fibrin Deposition and Its Correlates in Multiple Sclerosis
Abstract
FY21 MSRP Focus Area: Factors Contributing to MS Etiology, Prodrome, Onset, and Disease Course Several experimental studies provide strong evidence that fibrin(ogen) and its products of degradation, which are main components of the coagulation cascade, represent main triggers of the initiation and maintenance of the pathological processes that are responsible for damage to regions of the brain in multiple sclerosis (MS). Despite this compelling evidence, the role of these coagulation proteins in determining brain inflammation, demyelination and neurodegeneration in MS is understudied because routine clinical imaging techniques are not able to visualize and quantify them. The role of fibrin(ogen) brain deposition in vivo, thus, is yet unknown. Advanced imaging techniques, including integrated magnetic resonance-positron emission tomography molecular imaging (MR-PET) have the potential to overcome some of the technical limitations of clinical imaging tools. In this study, we propose to translate a novel molecular imaging approach for detecting in vivo fibrin deposition in the brain of people with MS. Specifically, we propose to use a 64Cu-FBP8, an MR-PET probe developed by investigators at Massachusetts General Hospital, which has demonstrated excellent safety and stability in animal and human studies, to image and quantify the deposition of fibrin in different regions of the brain in people with MS. We have obtained initial data in a small cohort of people with MS that demonstrate abnormal brain uptake of the 64Cu-FBP8 radiotracer, which suggests fibrin deposition, relative to age-matched controls. For this study, we will recruit 20 people with relapsing-remitting and 10 matched healthy individuals that will serve as controls and study them using MR-PET imaging with 64Cu-FBP8, to assess brain fibrin deposition. Specifically, we will assess whether tracer uptake will be measurable at the site of the acute white matter MS lesions, as suggested by experimental models of MS and by our initial acquisitions in patients. We will also investigate whether fibrin deposition can be detected in the cortex, a brain region extensively involved by the MS pathological process from the earliest disease stages, and which postmortem examinations have identified as a common site of abnormal fibrin(ogen) deposition. By combining 64Cu-FBP8 MR-PET with morphometric protocols that can be acquired during the same molecular imaging session or in another session performed at ultra-high field (7 Tesla), we further propose to assess whether the amount of fibrin deposition in the brain of people with MS is associated with either short- or long-term (1-year follow up) detrimental structural pathology both in typical white matter lesions and in the cortex. We have shown that all the proposed methods are robust, reproducible, and highly sensitive to MS pathology. If successful, this novel PET probe could prove as a powerful tool for assessing in vivo fibrin deposition in MS, which in turn could be used for studying the earliest events that lead to brain damage in the disease. Quantification of fibrin deposition using our novel molecular imaging tool will be used to track the evolution of brain tissue damage in MS by assessing whether, and to which extent, the amount of fibrin deposition relates or can even predict changes in MS lesions and brain tissue with subsequent degeneration. This will, in turn, allow establishing in vivo whether there is a link between fibrin deposition and detrimental brain structural pathology. In the long term, this will be crucial for investigating the relevance and contribution of fibrin to MS disease pathogenesis. It will be also relevant for developing novel radiological markers of disease activity and progression. Indeed, if limiting fibrin deposition is developed as a novel therapeutic target in MS, 64Cu-FBP8 MR-PET imaging would represent an ideal imaging outcome to measure this potential therapeu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2211053
Entities
People
- Caterina Mainero
Organizations
- Massachusetts General Hospital
- United States Army