Traumatic brain injury (TBI) is a heterogeneous condition that challenges prognosis and therapeutic development due to variability in injury characteristics, co-morbidities, and limited sensitivity of conventional imaging biomarkers. This proposal seeks to address this gap by evaluating white matter integrity in TBI using a multimodal imaging approach that integrates both in vivo and ex vivo data. Our central hypothesis is that positron emission tomography (PET) coupled with a radiotracer sensitive to myelin and axonal integrity ([¹⁸F]3F4AP), in combination with ultra-high-field magnetic resonance imaging (MRI), will provide improved sensitivity and specificity for detecting axonal injury and white matter pathology.
In the in vivo phase of the study, we will acquire ultra-high field 7 Tesla (7T) MRI and [¹⁸F]3F4AP PET scans from 30 participants (25 TBI and 5 healthy controls). [¹⁸F]3F4AP is a novel PET tracer which binds to exposed voltage-gated potassium channels (Kv1.1 and Kv1.2) that redistribute and upregulate in response to demyelination and axonal injury. Preclinical studies have shown that [¹⁸F]3F4AP PET signal increases by approximately 40% on the injured side in mouse models of TBI and is elevated even three years post-injury in non-human primates. Human studies in multiple sclerosis (MS) further demonstrate the tracer's ability to differentiate lesions beyond what is observable with MRI FLAIR or myelin water fraction (MWF) imaging. Results from this novel PET tracer will be compared to and combined with submillimeter diffusion metrics from 7T MRI.
In the ex vivo phase, utilizing a state-of-the-art TBI brain bank at the University of Washington, we will assess correlations of high-resolution ex vivo MRI with advanced histopathology. White matter lesions identified on ex vivo MRI will be sampled and undergo quantitative assessment for myelin and axonal integrity. These lesions on ex vivo MRI will be compared to those on in vivo MRI to draw inferences regarding the ability of the in vivo neuroimaging measures to capture axonal and white matter pathology. This approach builds upon foundational MRI work at UCSF by Dr. Pratik Mukherjee, and radiological-histopathological correlation analysis at UW pioneered by Drs. Christine Mac Donald, C. Dirk Keene, and Amber Nolan.
UCSF