Non invasive in vivo imaging of pathological fibrin deposition in the human brain

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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 traumatic brain injury, Alzheimer disease, and multiple sclerosis (MS), a neuroinflammatory and neurodegenerative disorder of the CNS and the second most common cause of neurological disability (after trauma) in young adults in Western countries. Fibrinogen is a 340 kDa glycoprotein generally considered a good surrogate marker of blood brain barrier (BBB) disruption because of its abundance, restriction to the intravascular compartment and lack of expression in the healthy CNS. Upon activation of the coagulation cascade, fibrinogen is converted into insoluble fibrin by thrombin. Previous studies have demonstrated that fibrin deposition is a prominent pathological feature of MS and is present throughout the course of the disease. Neuropathological examinations of ex vivo progressive MS brains have provided evidence that fibrin deposition in the disease is not only confined to the white matter (WM), but it can be also extensive and frequent in the MS cortex, where it correlates with neuronal loss. In MS, cortical demyelination and neurodegeneration represent main components of disease pathology, particularly in progressive stages, and key substrates of irreversible neurological disability. Here, we propose to combine 7-Tesla ultra-high resolution magnetic resonance imaging (MRI), which shows increased sensitivity relative to lower field MRI to cortical lesion pathology, with molecular positron emission tomography using 64Cu-FBP8, a novel molecular imaging probe developed at Massachusetts General Hospital, which selectively binds to fibrin, to image and quantify in vivo pathological deposition of fibrin in the brain of people with progressive MS, with a specific focus on the cortex and its association to local lesions and tissue loss. Safety data demonstrate that 64Cu-FBP8 shows nanomolar affinity for fibrin, high selectivity for fibrin over plasma proteins, is metabolically stable, and is rapidly renally excreted.The ability to track in vivo fibrin deposition in MS will be crucial for better understanding the pathological events that lead to neuroinflammation and cortical damage in MS, and for developing novel biomarkers for monitoring early events that lead to neuroinflammation in MS.