An NINDS R01 longitudinal imaging study examining pathological fibrin deposition in the living human brain. It investigates how this vascular and inflammatory process relates to progressive neurodegeneration, using repeated noninvasive measurements to track changes over time.
Project 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 neurodegenerat…Read the full abstractCollapse 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.
Research connections
Publications
2024
eLife
Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartm…Read the full abstractCollapse abstract
Axonal degeneration is a central pathological feature of multiple sclerosis and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity and clinical applicability, and by the lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls. AxCaliber is sensitive to acute axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the targeted tract, which correlated with neurofilament staining. Electron microscopy confirmed that increased mean axonal diameter is associated with acute axonal pathology. In humans with multiple sclerosis, we uncovered a diffuse increase in mean axonal caliber in most areas of the normal-appearing white matter, preferentially affecting patients with short disease duration. Our results demonstrate that MRI-based axonal diameter mapping is a sensitive and specific imaging biomarker that links noninvasive imaging contrasts with the underlying biological substrate, uncovering generalized axonal damage in multiple sclerosis as an early event.