Non-invasive Imaging of Pathological Fibrin Deposition and its Effect on Progressive Neurodegeneration in the Human Brain: an in vivo longitudinal study

Massachusetts General Hospital, Boston MA

Investigators

Abstract

A growing body of evidence indicates that fibrinogen and the pathways that control the formation and degradation of fibrin could represent early triggers that contribute to the initiation of neuroinflammation and the promotion of neurodegeneration in a variety of neurological disorders including multiple sclerosis (MS), a neuroinflammatory and neurodegenerative disorder of the CNS and the most common cause of neurological disability (after trauma) in young adults in Western countries. In MS, accumulating evidence indicates that fibrin deposition is prominent and diffuse throughout the course of the disease, both in the white matter (WM) and in the cortex, where it is thought to trigger demyelination, axonal and neuronal loss. Using a novel fibrin-specific molecular imaging approach based on 64Cu-FBP8 brain positron emission tomography (PET), developed at Massachusetts General Hospital for detecting fibrin deposition in the human brain, we have obtained preliminary in vivo data that demonstrate abnormal fibrin deposition in the brain and cortex of progressive MS cases. The significance of such findings is still unknown. Our overall hypothesis is that in vivo quantification of fibrin deposition by 64Cu-FBP8 uptake could be used to track the evolution of areas of cortical and WM pathology related to MS disease progression by investigating whether, and to which extent, the amount of fibrin deposition relates or can even predict different components of tissue damage including demyelination and/or neurodegeneration, as suggested by postmortem examinations. To test our hypothesis, we propose an innovative, longitudinal, imaging approach that will combine 64Cu-FBP8 imaging on an integrated 3 Tesla (T) magnetic resonance-PET system with the Rapid Estimation of Myelin for Diagnostic Imaging (REMyDI) a novel MRI-based myelin quantification technique and with 7T MRI to assess cortical lesion load and chronic active WM lesions, harboring a peripheral rim of iron-laden microglia, visible as a paramagnetic rim on susceptibility-sensitive MRI, which are associated with, remyelination failure. 7T imaging has been crucial for in vivo visualization of cortical demyelinating lesions in MS and following its evolution. Our study will help establishing the existence of an in vivo link between fibrin deposition and detrimental brain structural pathology in progressive MS and for assessing 64Cu-FBP8 molecular imaging as a non- invasive imaging biomarker for fibrin related pathology in the CNS.